The STAMPEDE2 Trial: a Site Survey of Current Patterns of Care, Access to Imaging and Treatment of Metastatic Prostate Cancer.

AIMS: The forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2. MATERIALS AND METHODS: The survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 (177Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging. RESULTS: From 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment. CONCLUSION: There is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial.

A demonstration of using formal consensus methods within guideline development; a case study.

BACKGROUND: Recommendations within guidelines are developed by synthesising the best available evidence; when limited evidence is identified recommendations are generally based on informal consensus. However, there are potential biases in group decision making, and formal consensus methods may help reduce these. METHODS: We conducted a case study using formal consensus, to develop one set of recommendations within the Neonatal Parenteral Nutrition guideline being produced for the National Institute for Health and Care Excellence. Statements were generated through identification of published guidelines on several topics relating to neonatal parenteral nutrition. Ten high quality guidelines were included, and 28 statements were generated; these statements were rated by the committee via two rounds of voting. The statements which resulted in agreement were then used to develop the recommendations. RESULTS: The approach was systematic and provided transparency. Additionally, a number of lessons were learnt; including the value of selecting the appropriate topic, giving adequate time to the process, and ensuring methodologies are understood by the committee for their value and relevance. CONCLUSION: Formal consensus is a valuable option for use within guideline development when specific criteria are met. The approach provides transparent methodology, ensuring clarity on how recommendations are developed.

An experimental evaluation of the benefits and costs of providing fertility information to adolescents and emerging adults.

STUDY QUESTION: Does the provision of fertility (compared to control) information affect fertility-related knowledge, perceived threat of infertility, anxiety, physical stress and fertility plans in adolescents and emerging adults? SUMMARY ANSWER: The provision of fertility information was associated with increased fertility knowledge (emerging adults) and greater infertility threat (adolescents and emerging adults). WHAT IS KNOWN ALREADY: According to fertility education research, adolescents and emerging adults know less than they should know about fertility topics. Fertility knowledge can be improved through the provision of information in older adults. STUDY DESIGN, SIZE, DURATION: Experimental design. Secondary and university students completed pre-information questionnaires, were randomly assigned via computer to an experimental group, read either fertility (FertiEduc group) or healthy pregnancy information (Control group), and completed post-information questionnaires. Data were collected in group sessions via an online portal. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible participants were aged 16-18 (adolescents) or 21-24 years (emerging adults), childless, not currently pregnant (for men, partner not pregnant) or trying to conceive, presumed fertile and intending to have a child in the future. Of the 255 invited, 208 (n = 93 adolescents, n = 115 emerging adults) participated. The FertiEduc group received 'A Guide to Fertility', four online pages of information about fertility topics (e.g. 'When are men and women most fertile?') and the Control group received four online pages from the National Health Service (NHS) pregnancy booklet 'Baby Bump and Beyond'. Participants completed a questionnaire (fertility knowledge, perceived threat of infertility, anxiety, physical stress and fertility plans, moderators) prior to and after the provision of information. Mixed factorial analysis of variance was used to examine the effects of information provision and hierarchical multiple regression to assess potential moderators of knowledge. MAIN RESULTS AND THE ROLE OF CHANCE: The FertiEduc and Control groups were equivalent on age, gender, disability, relationship status and orientation at baseline. Results showed that fertility information significantly increased fertility knowledge for emerging adults only (P < 0.001) and threat of infertility for emerging adults and adolescents (P = 0.05). The moderators were not significant. Participation in the study was associated with an increase in feelings of anxiety but a decrease in physical stress reactions. Adolescents had more optimal fertility plans compared to emerging adults due to being younger. LIMITATIONS, REASONS FOR CAUTION: This was an experimental study on a self-selected sample of men and women from selected educational institutions and only short term effects of information were studied. WIDER IMPLICATIONS OF THE FINDINGS: Provision of fertility information can have benefits (increased fertility knowledge) but also costs (increase potential threat of infertility). Adolescents find fertility information positive but do not learn from it. Fertility education should be tailored according to age groups and created to minimise negative effects. Longitudinal examination of the effects of fertility information in multi-centre studies is warranted and should include measures of perceived threat of infertility. STUDY FUNDING/COMPETING INTEREST(S): Cardiff University funded this research. All authors have no conflicts of interest to declare.

Imprinted and DNA methyltransferase gene expression in the endometrium during the pre- and peri-implantation period in cattle.

The endometrium plays a key role in providing an optimal environment for attachment of the preimplantation embryo during the early stages of pregnancy. Investigations over the past 2 decades have demonstrated that vital epigenetic processes occur in the embryo during the preimplantation stages of development. However, few studies have investigated the potential role of imprinted genes and their associated modulators, the DNA methyltransferases (DNMTs), in the bovine endometrium during the pre- and peri-implantation period. Therefore, in the present study we examined the expression profiles of the DNMT genes (3A, 3A2 and 3B) and a panel of the most comprehensively studied imprinted genes in the endometrium of cyclic and pregnant animals. Intercaruncular (Days 5, 7, 13, 16 and 20) and caruncular (Days 16 and 20) regions were analysed for gene expression changes, with protein analysis also performed for DNMT3A, DNMT3A2 and DNMT3B on Days 16 and 20. An overall effect of day was observed for expression of several of the imprinted genes. Tissue-dependent gene expression was detected for all genes at Day 20. Differences in DNMT protein abundance were mostly observed in the intercaruncular regions of pregnant heifers at Day 16 when DNMT3A, DNMT3A2 and DNMT3B were all lower when compared with cyclic controls. At Day 20, DNMT3A2 expression was lower in the pregnant caruncular samples compared with cyclic animals. This study provides evidence that epigenetic mechanisms in the endometrium may be involved with implantation of the embryo during the early stages of pregnancy in cattle.

How short should short-term risk assessment be? Determining the optimum interval for START reassessment in a secure mental health service.

ACCESSIBLE SUMMARY: The Short-Term Assessment of Risk and Treatability (START) is a tool used in some mental health services to assess patients to see if they are at risk of violence, self-harm, self-neglect or victimization. The recommended time between assessments is 3 months but there is currently no evidence to show that this is best practice. We have investigated whether assessing at 1- or 2-month intervals would be more accurate and therefore facilitate more individualized risk management interventions. We found that many patients who were rated as low risk had been involved in risk behaviours before 3 months had passed; some patients who were rated at increased risk did not get involved in risk behaviours at all. Results are mixed for different outcomes but on balance, we think that the recommendation to conduct START assessment every 3 months is supported by the evidence. However, reassessment should be considered if risk behaviours are not prevented and teams should always consider whether risk management practices are too restrictive. ABSTRACT: The Short-Term Assessment of Risk and Treatability (START) guides assessment of potential adverse outcomes. Assessment is recommended every 3 months but there is no evidence for this interval. We aimed to inform whether earlier reassessment was warranted. We collated START assessments for N = 217 adults in a secure mental health hospital, and subsequent aggressive, self-harm, self-neglect and victimization incidents. We used receiver operating characteristic analysis to assess predictive validity; survival function analysis to examine differences between low-, medium-, and high-risk groups; and hazard function analysis to determine the optimum interval for reassessment. The START predicted aggression and self-harm at 1, 2 and 3 months. At-risk individuals engaged in adverse outcomes earlier than low-risk patients. About half warranted reassessment before 3 months due to engagement in risk behaviour before that point despite a low-risk rating, or because of non-engagement by that point despite an elevated risk rating. Risk assessment should occur at appropriate intervals so that management strategies can be individually tailored. Assessment at 3-month intervals is supported by the evidence. START assessments should be revisited earlier if risk behaviours are not prevented; teams should constantly re-evaluate the need for restrictive practices.

Predictive validity of the HCR-20 for inpatient aggression: the effect of intellectual disability on accuracy.

BACKGROUND: People with intellectual disability (ID) account for a large proportion of aggressive incidents in secure and forensic psychiatric services. Although the Historical, Clinical, Risk Management 20 (HCR-20) has good predictive validity in inpatient settings, it does not perform equally in all groups and there is little evidence for its efficacy in those with ID. METHOD: A pseudo-prospective cohort study of the predictive efficacy of the HCR-20 for those with ID (n = 109) was conducted in a UK secure mental health setting using routinely collected risk data. Performance of the HCR-20 in the ID group was compared with a comparison group of adult inpatients without an ID (n = 504). Analysis controlled for potential covariates including security level, length of stay, gender and diagnosis. RESULTS: The HCR-20 total score was a significant predictor of any aggression and of physical aggression for both groups, although the area under the curve values did not reach the threshold for a large effect size. The clinical subscale performed significantly better in those without an ID compared with those with. The ID group had a greater number of relevant historical and risk management items. The clinicians' summary judgment significantly predicted both types of aggressive outcomes in the ID group, but did not predict either in those without an ID. CONCLUSIONS: This study demonstrates that, after controlling for a range of potential covariates, the HCR-20 is a significant predictor of inpatient aggression in people with an ID and performs as well as for a comparison group of mentally disordered individuals without ID. The potency of HCR-20 subscales and items varied between the ID and comparison groups suggesting important target areas for improved prediction and risk management interventions in those with ID.

Aven is dynamically regulated during Xenopus oocyte maturation and is required for oocyte survival.

We have analyzed the expression and function of the cell death and cell cycle regulator Aven in Xenopus. Analysis of Xenopus Aven expression in oocytes and embryos revealed a band close to the predicted molecular weight of the protein (36 kDa) in addition to two bands of higher molecular weight (46 and 49 kDa), one of which was determined to be due to phosphorylation of the protein. The protein is primarily detected in the cytoplasm of oocytes and is tightly regulated during meiotic and mitotic cell cycles. Progesterone stimulation of oocytes resulted in a rapid loss of Aven expression with the protein levels recovering before germinal vesicle breakdown (GVBD). This loss of Aven is required for the G2-M1 cell cycle transition. Aven morpholino knockdown experiments revealed that early depletion of the protein increases progesterone sensitivity and facilitates GVBD, but prolonged depletion of Aven results in caspase-3 activation and oocyte death by apoptosis. Phosphorylated Aven (46 kDa) was found to bind Bcl-xL in oocytes, but this interaction was lost in apoptotic oocytes. Thus, Aven alters progesterone sensitivity in oocytes and is critical for oocyte survival.

Expression, regulation, and function of progesterone receptors in bovine cumulus oocyte complexes during in vitro maturation.

Progesterone (P4) exerts its effects by binding to specific genomic (nPR-A/B) and non-genomic (mPRalpha/beta, PGRMC1/2) receptors. P4 has a role in the regulation of the ovulatory cycle, but its participation in oocyte maturation in mammals has not yet been clarified. Therefore, the aim of the present study was to characterize the protein expression of P4 receptors (PRs) in bovine oocytes and cumulus cells during in vitro maturation (IVM) and to study the effect of P4 and its receptors on oocyte developmental competence. Cumulus-oocyte complexes (COCs) were subjected to IVM, in vitro fertilization, and in vitro culture. IVM was performed for 24 h in the presence or absence of P4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), trilostane, promegestone (R5020), mifepristone (RU 486), or antibodies against mPRalpha or mPRbeta. Protein expression of PRs was studied by Western blotting and immunofluorescence. The results demonstrate the presence of both genomic and nongenomic PRs in bovine COCs. The dynamic changes observed in the protein expression of PRs following IVM or in response to supplementation with LH, FSH, or P4 suggest an important role during bovine oocyte maturation. Inhibition of P4 synthesis by cumulus cells or blocking of nPR and mPR alpha activity produced a decrease in bovine embryo development, indicating that P4 intracellular signaling is mediated by its interaction with nuclear and membrane PRs and is important for oocyte developmental competence.

Home assessment of activities of daily living in patients with severe chronic obstructive pulmonary disease on long-term oxygen therapy.

In patients with severe chronic obstructive pulmonary disease (COPD) using long-term oxygen therapy (LTOT), few studies have investigated activities of daily living (ADL). We examined the relationships between ADL, quality of life, mood state and airways obstruction in patients using long-term oxygen therapy (LTOT) and in patients not requiring LTOT. We studied 23 patients (14 males, 9 females; median age 71, range 60-84 yrs) with COPD who received LTOT using oxygen concentrators (LTOT group). We also studied a control group of 19 patients (14 males, 5 females; median age 72, range 62-75 yrs) with COPD but without severe hypoxaemia (non-LTOT group). We found no significant difference between groups in health status using the St George's Respiratory Questionnaire (SGRQ). Median Nottingham Extended Activities of Daily Living (EADL) total scores were: LTOT group 10, non-LTOT 17; (p=0.01). Significant correlations (p<0.001) with Nottingham EADL score were found for Hospital Anxiety and Depression (HAD) score (rho=0.59), SGRQ Total score (rho=0.65) and percentage predicted forced expiratory volume in one second (FEV1) (rho=0.66). In conclusion, in patients with severe chronic obstructive pulmonary disease and broadly similar health status, those using long-term oxygen therapy were less independent in activities of daily living than those not requiring long-term oxygen therapy. Reduced independence in activities of daily living is, however, associated with the extent of airflow limitation, depression and poor health status, and does not, therefore, appear to be simply a result of restriction in movements imposed by the stationary device.

Collaboration and school reform: a twenty-first-century perspective.

Collaboration and school reform are current social-political issues that affect many individuals and school districts. In this series summary, the authors examine national goals, federal legislation, and local reform practices. A twenty-first-century perspective predicting the integration of collaboration and school reform may help to guide future teaching, research, and/or service efforts. How families and professionals work together today will affect how we educate students during the next century.

Neonatal 6-hydroxydopamine attenuates the neural and behavioral effects of enriched rearing in the rat.

Newborn male rats were administered subcutaneous 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine and after weaning were reared in normal or enriched environments. Subsequently the 6-OHDA treated rats and their vehicle controls were trained in a Lashley type III maze and then sacrificed for assay of regional brain weights and brain catecholamines. Whereas for the control rats, enriched rearing was found to: (1) increase hypothalamic and posterior cortical dopamine; (2) increase forebrain and decrease hypothalamic weight; and (3) to enhance maze acquisition, none of these consequences of enriched rearing was found in the 6-OHDA treated rats. We conclude that forebrain norepinephrine plays a permissive role in the neuroanatomical, neurochemical and behavioral alterations induced by the enriched rearing of weanling rats and that it is essential to at least some aspects of the shaping of the brain by experiential factors.