Glutarate regulates T cell metabolism and anti-tumour immunity.

T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.

Single tertiary cancer center experience on the management of pT3b prostate cancer after robotic-assisted laparoscopic prostatectomy.

Background: Pathological involvement of the seminal vesicle poses a treatment dilemma following robotic prostatectomy. Margin status plays an important role in deciding further management. A wide range of treatment options are available, including active monitoring, adjuvant radiotherapy, salvage radiotherapy, and occasionally androgen deprivation therapy. Patients undergoing postoperative radiotherapy tend to have higher risk of urinary and bowel morbidities. The recent RADICALS-RT concluded that adjuvant radiotherapy did not have any benefit compared with salvage radiotherapy. We aim to audit the incidence, margin status, and management of T3b cancer cases at our center. Materials and methods: A retrospective analysis was conducted of all patients diagnosed with pathological T3b (pT3b) prostate cancer following robotic-assisted laparoscopic prostatectomy from January 2012 to July 2020. Preoperative parameters analyzed included prostate-specific antigen (PSA), T stage, and age. A chi-square test and 2-tailed t test were used to determine the relationship between categorical and continuous variables, respectively. Kaplan-Meier survival curves were generated to assess overall survival in patients with pT3b prostate cancer and used to compare unadjusted progression-free survival among those who underwent adjuvant and salvage radiotherapy. Results: A total of 83 (5%) of 1665 patients who underwent robotic prostatectomy were diagnosed with pT3b prostate cancer between January 2012 and July 2020. Among these, 36 patients (44%) did not receive any radiotherapy during follow-up, compared with 26 patients (31%) who received adjuvant radiotherapy and 21 (25%) who received salvage radiotherapy. The median age of our cohort was 64 (SD, 6.4) years. Mean PSA at presentation was 12.7 µg/L. Positive margins were seen in 36 patients (43%); however, there was no statistically significant difference between treatment groups (p = 0.49). The median overall survival was 96%. There was no significant difference between the adjuvant and salvage groups in terms of biochemical progression-free survival (p = 0.66). Five-year biochemical progression-free survival was 94% for those in the adjuvant radiotherapy group and 97% for those in the salvage radiotherapy group. Conclusions: Our audit corroborates with the recently concluded RADICALS-RT study, although we had fewer patients with positive margins. Radiotherapy can be avoided in patients with T3b prostate cancer, even if margin is positive, until there is definitive evidence of PSA recurrence. In keeping with the conclusion of RADICALS-RT, salvage radiotherapy may be preferable to adjuvant radiotherapy.

Secondary neoplasms of the urinary bladder-clinical management and oncological outcomes.

BACKGROUND: Secondary neoplasms of the bladder account for 4.5% of all bladder neoplasms however there is limited literature reporting management and survival. This is the largest single centre series presented in current literature with long term oncological follow up. METHODS: This is a single institutional, retrospective cohort study of patients with a histological diagnosis of a secondary bladder neoplasm from January 2007 to December 2017 (n=40). Prognostic variables examined included age at diagnosis, histology, disease free survival and treatment. Kaplan-Meier analysis was used to calculate survival. We used multiple regression analysis to identify the most significant treatments for each population group in terms of their survival. RESULTS: Twenty-one patients were male (53%) with a median age of 68 and 19 were female (47%) with a median age of 64. The most common secondary neoplasms and their median survival were prostate [12 patients (30%), 446 days], colorectal [9 patients (23%), 403 days], ovarian [5 patients (13%), 369 days], cervical [4 patients (10%), 148 days], breast [3 patients (8%), 241 days], lymphoma [3 patients (8%), 145 days], gastric [2 patients (5%), 66 days], and renal [2 patients (5%), 854 days]. Those receiving treatment following a secondary diagnosis demonstrated statistical significance in survival for colorectal (surgery P=0.013), prostate (radiotherapy P=0.0012 and hormonal therapy P=0.004) and ovarian cancer (chemotherapy P=0.00002). CONCLUSIONS: Prognosis and treatment depends upon the primary neoplasm. There is some survival benefit in well selected patients receiving treatment following a diagnosis of a bladder secondary.

Emerging Opportunities Provided by Technology to Advance Research in Child Health Globally.

Current approaches to longitudinal assessment of children's developmental and psychological well-being, as mandated in the United Nations Sustainable Development Goals, are expensive and time consuming. Substantive understanding of global progress toward these goals will require a suite of new robust, cost-effective research tools designed to assess key developmental processes in diverse settings. While first steps have been taken toward this end through efforts such as the National Institutes of Health's Toolbox, experience-near approaches including naturalistic observation have remained too costly and time consuming to scale to the population level. This perspective presents 4 emerging technologies with high potential for advancing the field of child health and development research, namely (1) affective computing, (2) ubiquitous computing, (3) eye tracking, and (4) machine learning. By drawing attention of scientists, policy makers, investors/funders, and the media to the applications and potential risks of these emerging opportunities, we hope to inspire a fresh wave of innovation and new solutions to the global challenges faced by children and their families.

Human resources and curricula content for early child development implementation: multicountry mixed methods evaluation.

OBJECTIVE: The WHO recommends responsive caregiving and early learning (RCEL) interventions to improve early child development (ECD), and to achieve the Sustainable Development Goals' vision of a world where all children thrive. Implementation of RCEL programmes in low and middle-income countries (LMIC) requires evidence to inform decisions about human resources and curricula content. We aimed to describe human resources and curricula content for implementation of RCEL projects across diverse LMICs, using data from the Grand Challenges Canada Saving Brains ECD portfolio. SETTING: We evaluated 32 RCEL projects across 17 LMICs on four continents. PARTICIPANTS: Overall, 2165 workers delivered ECD interventions to 25 909 families. INTERVENTION: Projects were either stand-alone RCEL or RCEL combined with health and nutrition, and/or safety and security. PRIMARY AND SECONDARY OUTCOMES: We undertook a mixed methods evaluation of RCEL projects within the Saving Brains portfolio. Quantitative data were collected through standardised reporting tools. Qualitative data were collected from ECD experts and stakeholders and analysed using thematic content analysis, informed by literature review. RESULTS: Major themes regarding human resources included: worker characteristics, incentivisation, retention, training and supervision, and regarding curricula content: flexible adaptation of content and delivery, fidelity, and intervention duration and dosage. Lack of an agreed standard ECD package contributed to project heterogeneity. Incorporation of ECD into existing services may facilitate scale-up but overburdened workers plus potential reductions in service quality remain challenging. Supportive training and supervision, inducement, worker retention, dosage and delivery modality emerged as key implementation decisions. CONCLUSIONS: This mixed methods evaluation of a multicountry ECD portfolio identified themes for consideration by policymakers and programme leaders relevant to RCEL implementation in diverse LMICs. Larger studies, which also examine impact, including high-quality process and costing evaluations with comparable data, are required to further inform decisions for implementation of RCEL projects at national and regional scales.

Contextual design choices and partnerships for scaling early child development programmes.

Translating the Nurturing Care Framework and unprecedented global policy support for early child development (ECD) into action requires evidence-informed guidance about how to implement ECD programmes at national and regional scale. We completed a literature review and participatory mixed-method evaluation of projects in Saving Brains®, Grand Challenges Canada® funded ECD portfolio across 23 low- and middle-income countries (LMIC). Using an adapted programme cycle, findings from evaluation related to partnerships and leadership, situational analyses, and design for scaling ECD were considered. 39 projects (5 'Transition to Scale' and 34 'Seed') were evaluated. 63% were delivered through health and 84% focused on Responsive Caregiving and Early Learning (RCEL). Multilevel partnerships, leadership and targeted situational analysis were crucial to design and adaptation. A theory of change approach to consider pathways to impact was useful for design, but practical situational analysis tools and local data to guide these processes were lacking. Several RCEL programmes, implemented within government services, had positive impacts on ECD outcomes and created more enabling caregiving environments. Engagement of informal and private sectors provided an alternative approach for reaching children where government services were sparse. Cost-effectiveness was infrequently measured. At small-scale RCEL interventions can be successfully adapted and implemented across diverse settings through processes which are responsive to situational analysis within a partnership model. Accelerating progress will require longitudinal evaluation of ECD interventions at much larger scale, including programmes targeting children with disabilities and humanitarian settings with further exploration of cost-effectiveness, critical content and human resources.

Counting outcomes, coverage and quality for early child development programmes.

Improved measurement in early child development (ECD) is a strategic focus of the WHO, UNICEF and World Bank Nurturing Care Framework. However, evidence-based approaches to monitoring and evaluation (M&E) of ECD projects in low-income and middle-income countries (LMIC) are lacking. The Grand Challenges Canada®-funded Saving Brains® ECD portfolio provides a unique opportunity to explore approaches to M&E of ECD programmes across diverse settings. Focused literature review and participatory mixed-method evaluation of the Saving Brains portfolio was undertaken using an adapted impact framework. Findings related to measurement of quality, coverage and outcomes for scaling ECD were considered. Thirty-nine ECD projects implemented in 23 LMIC were evaluated. Projects used a 'theory of change' based M&E approach to measure a range of inputs, outputs and outcomes. Over 29 projects measured cognitive, language, motor and socioemotional outcomes. 18 projects used developmental screening tools to measure outcomes, with a trade-off between feasibility and preferred practice. Environmental inputs such as the home environment were measured in 15 projects. Qualitative data reflected the importance of measurement of project quality and coverage, despite challenges measuring these constructs across contexts. Improved measurement of intervention quality and measurement of coverage, which requires definition of the numerator (ie, intervention) and denominator (ie, population in need/at risk), are needed for scaling ECD programmes. Innovation in outcome measurement, including intermediary outcome measures that are feasible and practical to measure in routine services, is also required, with disaggregation to better target interventions to those most in need and ensure that no child is left behind.

Accountability for funds for Nurturing Care: what can we measure?

BACKGROUND: Understanding donor, government and out-of-pocket funding for early child development (ECD) is important for tracking progress. We aimed to estimate a baseline for the WHO, UNICEF and World Bank Nurturing Care Framework (NCF) with a special focus on childhood disability. METHODS: To estimate development assistance spending, the Organisation for Economic Cooperation and Development's Creditor Reporting System (OECD-CRS) database was searched for 2007-2016, using key words derived from domains of the NCF (good health, nutrition and growth, responsive caregiving, security and safety, and early learning), plus disability. Associated funds were analysed by domain, donor, recipient and region. Trends of ECD/NCF were compared with reproductive, maternal, newborn and child health (RMNCH) disbursements. To assess domestic or out-of-pocket expenditure for ECD, we searched electronic databases of indexed and grey literature. RESULTS: US$79.1 billion of development assistance were disbursed, mostly for health and nutrition (US$61.9 billion, 78% of total) and least for disability (US$0.7 billion, 2% of total). US$2.3 per child per year were disbursed for non-health ECD activities. Total development assistance for ECD increased by 121% between 2007 and 2016, an average increase of 8.3% annually. Per child disbursements increased more in Africa and Asia, while minimally in Latin America and the Caribbean and Oceania. We could not find comparable sources for domestic funding and out-of-pocket expenditure. CONCLUSIONS: Estimated international donor disbursements for ECD remain small compared with RMNCH. Limitations include inconsistent donor terminology in OECD data. Increased investment will be required in the poorest countries and for childhood disability to ensure that progress is equitable.

Rating early child development outcome measurement tools for routine health programme use.

BACKGROUND: Identification of children at risk of developmental delay and/or impairment requires valid measurement of early child development (ECD). We systematically assess ECD measurement tools for accuracy and feasibility for use in routine services in low-income and middle-income countries (LMIC). METHODS: Building on World Bank and peer-reviewed literature reviews, we identified available ECD measurement tools for children aged 0-3 years used in ≥1 LMIC and matrixed these according to when (child age) and what (ECD domains) they measure at population or individual level. Tools measuring <2 years and covering ≥3 developmental domains, including cognition, were rated for accuracy and feasibility criteria using a rating approach derived from Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: 61 tools were initially identified, 8% (n=5) population-level and 92% (n=56) individual-level screening or ability tests. Of these, 27 tools covering ≥3 domains beginning <2 years of age were selected for rating accuracy and feasibility. Recently developed population-level tools (n=2) rated highly overall, particularly in reliability, cultural adaptability, administration time and geographical uptake. Individual-level tool (n=25) ratings were variable, generally highest for reliability and lowest for accessibility, training, clinical relevance and geographical uptake. CONCLUSIONS AND IMPLICATIONS: Although multiple measurement tools exist, few are designed for multidomain ECD measurement in young children, especially in LMIC. No available tools rated strongly across all accuracy and feasibility criteria with accessibility, training requirements, clinical relevance and geographical uptake being poor for most tools. Further research is recommended to explore this gap in fit-for-purpose tools to monitor ECD in routine LMIC health services.

Scaling early child development: what are the barriers and enablers?

The Sustainable Development Goals, Global Strategy for Women's, Children's and Adolescents' Health (2016-2030) and Nurturing Care Framework all include targets to ensure children thrive However, many projects to support early childhood development (ECD) do not 'scale well' and leave large numbers of children unreached. This paper is the fifth in a series examining effective scaling of ECD programmes. This qualitative study explored experiences of scaling-up among purposively recruited implementers of ECD projects in low- and middle-income countries. Participants were sampled, by means of snowball sampling, from existing networks notably through Saving Brains®, Grand Challenges Canada®. Findings of a recent literature review on scaling-up frameworks, by the WHO, informed the development of a semistructured interview schedule. All interviews were conducted in English, via Skype, audio recorded and transcribed verbatim. Interviews were analysed using framework analysis. Framework analysis identified six major themes based on a standard programme cycle: planning and strategic choices, project design, human resources, financing and resource mobilisation, monitoring and evaluation, and leadership and partnerships. Key informants also identified an overarching theme regarding what scaling-up means. Stakeholders have not found existing literature and available frameworks helpful in guiding them to successful scale-up. Our research suggests that rather than proposing yet more theoretical guidelines or frameworks, it would be better to support stakeholders in developing organisational leadership capacity and partnership strategies to enable them to effectively apply a practical programme cycle or systematic process in their own contexts.

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer.

BACKGROUND: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer. METHODS: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken. RESULTS: The 3 M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant). CONCLUSIONS: Overall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care.

Single-centre Experience of Use of Radium 223 with Clinical Outcomes Based on Number of Cycles and Bone Marrow Toxicity.

BACKGROUND: Bone is the most common site of metastatic disease in advanced prostate cancer. Radium-223 (223Ra) is a calcium-mimetic alpha-particle emitter, which has been shown to have activity in prostate cancer with clinical benefit in patients with symptomatic bone metastasis. The recommended schedule is six cycles of 223Ra, 5 kBq/kg, at 4-weekly intervals. Although previous studies have assessed clinical outcomes in patients who received six cycles of Ra223, there is very little information about outcomes of patients receiving fewer courses of treatment. PATIENTS AND METHODS: Patients with hormone-refractory metastatic prostate cancer treated from May 2014 to August 2016 were included in this retrospective study. A total of 113 patients were identified with a median age of 76 (range=52-92) years. The median number of cycles administered was 5 (range=1-6) with 54 (48%) completing six cycles of treatment. Eighty-five patients (75%) received 223Ra prior to docetaxel chemotherapy and 28 (25%) received it after receiving docetaxel. RESULTS: Eleven patients developed grade 2/3 thrombocytopenia, and none of these received further 223Ra. Only 25% of patients who had a haemoglobin level of 10 g/dl or below at the start of the treatment were able to complete six courses of 223Ra. Of the patients who completed fewer than six cycles of 223Ra (1-5 cycles), the survival was 121 days, compared to 398 days in men who received six cycles (odds ratio(OR)=4.767, 95% confidence internal(CI)=1.07-21.25; p=0.0005). CONCLUSION: Careful selection of patients is essential to obtain good clinical outcomes from 223Ra therapy. When fewer than six cycles were delivered then a beneficial survival effect was not seen.

Multi-disciplinary simulation training for anaesthetic practitioners.

A multi-disciplinary simulation training course devised and implemented at Morriston Hospital is described. The participants in the simulation exercise included both medical and non-medical professionals in a pilot study intended to analyse the effectiveness of a multi-disciplinary approach to this training technique. Questionnaires completed by the participants both immediately after the training session and again some months later highlight the desirability of this multi-disciplinary training. The success of the training course and the lessons learned from its implementation are being used to plan a similar second session in the near future.

Squamous cell carcinoma antigen: a potentially useful prognostic marker in squamous cell carcinoma of the anal canal and margin.

BACKGROUND: The objective of this retrospective study was to investigate the predictive value of pretreatment serum squamous cell carcinoma antigen (SCCAg) levels in 174 patients with squamous cell carcinoma of the anus who received concurrent chemoradiation between 1997 and 2010. METHODS: Pretreatment serum SCCAg measurements in patients with histologically diagnosed squamous cell carcinoma of the anal canal and margin who received chemoradiation were compared with clinical tumor classification and lymph node status for prognostic/predictive ability, including 1) tumor response after the completion of chemoradiation treatment, 2) disease recurrence, and 3) overall survival. Clinical measurements and scores were compared using Spearman rank tests, and survival was assessed in both univariate and multivariate survival analyses. RESULTS: The median pretreatment levels of SCCAg according to clinical tumor classification and clinical lymph node status were 0.8 µg/L in T1 tumors, 1.90 µg/L in T2 tumors, 2.5 µg/L in T3 tumors, 3.8 µg/L in T4 tumors, 1.35 µg/L in patients with N0 status, and 3.05 µg/L in patients with N0+ status (correlation coefficient: T-classification, 0.43; lymph node status, 0.38; both P < .00001). Of the patients who had normal SCCAg levels, 95% achieved a complete response after initial treatment; and, of those who had elevated SCCAg levels, 86% achieved a complete response (P = .05). Overall survival (hazard ratio, 2.5; P = .007) and disease-free survival (hazard ratio, 2.2; P = .058) were worse for those who had elevated pretreatment serum SCCAg concentrations. CONCLUSIONS: Pretreatment SCCAg levels in patients with squamous cell carcinoma of the anal canal and margin were correlated with clinical tumor classification and clinical lymph node status. Elevated levels of SCCAg were associated with a reduced chance of achieving a complete response and an increased chance of recurrence and death. The authors recommend further studies to determine the prognostic value of SCCAg in anal squamous cell carcinoma and suggest the potential use of SCCAg as a stratification factor in future trials.

The evolution of global health teaching in undergraduate medical curricula.

BACKGROUND: Since the early 1990s there has been a burgeoning interest in global health teaching in undergraduate medical curricula. In this article we trace the evolution of this teaching and present recommendations for how the discipline might develop in future years. DISCUSSION: Undergraduate global health teaching has seen a marked growth over the past ten years, partly as a response to student demand and partly due to increasing globalization, cross-border movement of pathogens and international migration of health care workers. This teaching has many different strands and types in terms of topic focus, disciplinary background, the point in medical studies in which it is taught and whether it is compulsory or optional. We carried out a survey of medical schools across the world in an effort to analyse their teaching of global health. Results indicate that this teaching is rising in prominence, particularly through global health elective/exchange programmes and increasing teaching of subjects such as globalization and health and international comparison of health systems. Our findings indicate that global health teaching is moving away from its previous focus on tropical medicine towards issues of more global relevance. We suggest that there are three types of doctor who may wish to work in global health - the 'globalised doctor', 'humanitarian doctor' and 'policy doctor' - and that each of these three types will require different teaching in order to meet the required competencies. This teaching needs to be inserted into medical curricula in different ways, notably into core curricula, a special overseas doctor track, optional student selected components, elective programmes, optional intercalated degrees and postgraduate study. SUMMARY: We argue that teaching of global health in undergraduate medical curricula must respond to changing understandings of the term global health. In particular it must be taught from the perspective of more disciplines than just biomedicine, in order to reflect the social, political and economic causes of ill health. In this way global health can provide valuable training for all doctors, whether they choose to remain in their countries of origin or work abroad.

Conceptualising global health: theoretical issues and their relevance for teaching.

BACKGROUND: There has long been debate around the definition of the field of education, research and practice known as global health. In this article we step back from attempts at definition and instead ask what current definitions tell us about the evolution of the field, identifying gaps and points of debate and using these to inform discussions of how global health might be taught. DISCUSSION: What we now know as global health has its roots in the late 19(th) century, in the largely colonial, biomedical pursuit of 'international health'. The twentieth century saw a change in emphasis of the field towards a much broader conceptualisation of global health, encompassing broader social determinants of health and a truly global focus. The disciplinary focus has broadened greatly to include economics, anthropology and political science, among others. There have been a number of attempts to define the new field of global health. We suggest there are three central areas of contention: what the object of knowledge of global health is, the types of knowledge to be used and around the purpose of knowledge in the field of global health. We draw a number of conclusions from this discussion. First, that definitions should pay attention to differences as well as commonalities in different parts of the world, and that the definitions of global health themselves depend to some extent on the position of the definer. Second, global health's core strength lies in its interdisciplinary character, in particular the incorporation of approaches from outside biomedicine. This approach recognises that political, social and economic factors are central causes of ill health. Last, we argue that definition should avoid inclusion of values. In particular we argue that equity, a key element of many definitions of global health, is a value-laden concept and carries with it significant ideological baggage. As such, its widespread inclusion in the definitions of global health is inappropriate as it suggests that only people sharing these values may be seen as 'doing' global health. Nevertheless, discussion of values should be a key part of global health education. SUMMARY: Our discussions lead us to emphasise the importance of an approach to teaching global health that is flexible, interdisciplinary and acknowledges the different interpretations and values of those practising and teaching the field.

High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence.

PURPOSE: To evaluate genitourinary (GU) and gastrointestinal (GI) morbidity and biochemical control of disease in patients with localized prostate adenocarcinoma treated with escalating doses per fraction of high-dose rate brachytherapy alone. METHODS AND MATERIALS: A total of 197 patients were treated with 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, or 26 Gy in two fractions. Median follow-up times were 60, 54, 36, and 6 months, respectively. RESULTS: Incidence of early Grade ≥ 3 GU morbidity was 3% to 7%, and Grade 4 was 0% to 4%. During the first 12 weeks, the highest mean International Prostate Symptom Score (IPSS) value was 14, and between 6 months and 5 years it was 8. Grade 3 or 4 early GI morbidity was not observed. The 3-year actuarial rate of Grade 3 GU was 3% to 16%, and was 3% to 7% for strictures requiring surgery (4-year rate). An incidence of 1% Grade 3 GI events was seen at 3 years. Late Grade 4 GU or GI events were not observed. At 3 years, 99% of patients with intermediate-risk and 91% with high-risk disease were free of biochemical relapse (log-rank p = 0.02). CONCLUSIONS: There was no significant difference in urinary and rectal morbidity between schedules. Biochemical control of disease in patients with intermediate and high risk of relapse was good.

Establishing quality assurance criteria for serial dilution operations on liquid-handling equipment.

Since the advent of high-throughput screening (HTS) in the early 1990s, parallel multichannel liquid handlers have become a mainstay in every drug discovery setting. Although several peer-reviewed publications have discussed methods and criteria for stamping multiwell copies, there is very little information about establishing a standard operating procedure (SOP) for standard (microliter-level) serial dilutions of compounds used in dose-response experiments. The authors discuss the 4 main criteria any serial dilution process must pass (accuracy, precision, fold dilution, and outliers) and the process for establishing thresholds for all of these values in a compound management or biological screening laboratory. The thresholds need to be both low enough to be acceptable from a biological potency variability perspective and high enough to allow the instruments to pass the quality assurance (QA) analysis on a regular basis. In this article, the authors suggest suitable thresholds arrived at by a variety of methods, including trend analysis of QA data, survey questionnaire from the main stakeholders (screening scientists, chemists), and published criteria for single-shot stamping. A mathematical analysis of the effect of threshold values on estimated XC(50)s was performed to ensure that the variability introduced by the serial dilution step is within acceptable overall variability limits.

A survey of patient and keyworker satisfaction with the Gloucester mental health rehabilitation service.

Despite well described methodological problems, previous studies have consistently found patients to report reasonable satisfaction with their mental health treatment. Few studies have compared patient and mental health professionals' levels of satisfaction. rehabilitation case register were surveyed. Satisfaction with six aspects of care was assessed by a 5- point Likert rating scale, generating raw scores in each domain and a cumulative Total Satisfaction Score. Satisfaction among patients and their keyworkers were assessed on the same scale. Patients and keyworkers were more likely to be satisfied than dissatisfied with most aspects of their care. Patients had lowest satisfaction with knowledge of treatment, keyworkers with the patient's finances. Except for satisfaction with their treatment by the local satisfaction scores than keyworkers in all domains. Patient and keyworker satisfaction scores were at best weakly correlated. Other than for in-patient and compulsory treatment status, there was no significant association between satisfaction and demographic/illness-related factors, including psychopathology, insight, knowledge of treatment and cognitive function. The weak relationship between patient and keyworker satisfaction suggests a need for caution in interpreting our view of our patients' care. The findings imply problems in communicating about treatment with people suffering from severe mental illness. Assessment of patient satisfaction may be a useful component of individual care planning. 174/199 (87%) patients on the Gloucester community, patients had significantly lower.