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Rev 21.3b is a conundrum for translation. The text-critical data point to the UBS5 reading as original but copyists and translators have struggled with the awkwardness of the text. This article reviews translations of Rev 21.3b and the text-critical data and suggests that the translation “and ‘God-with-them’ himself will be their God” resolves the problem and is consistent with the UBS5 reading. This translation finds corroboration in other characteristics of the Apocalypse.

Background: Wixela Inhub (trademarks of Viatris, Inc.) is a dry powder inhaler (DPI) that delivers a fixed-dose combination of fluticasone propionate and salmeterol and is approved as a generic equivalent to Advair Diskus (trademarks of GlaxoSmithKline plc) for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The dosing performance of DPIs is dependent on the patient's inspiratory capability, which may be impacted in disease populations such as those with severe COPD. The objective of this study was to evaluate the in vitro dose delivery of fluticasone propionate and salmeterol from the Inhub inhaler with in vivo inhalation profiles of severe COPD patients, using two types of breathing simulator with different modes of operation. Materials and Methods: Two breathing simulators (Si-Plan and Copley BRS3100) were used with United States Pharmacopoeia (USP) apparatus 5 (Next Generation Impactor and accessories) to measure the total emitted dose and fine particle mass of fluticasone propionate and salmeterol for Wixela Inhub (250/50 mcg) using 13 severe COPD patient inhalation profiles. Results: Wixela Inhub demonstrated low flow dependency across the range of COPD patient profiles tested (peak inspiratory flow rate 60.8-84.9 L minute-1), when assessed by total emitted dose and fine particle mass. The results were similar to literature results reported for fluticasone propionate from the Diskus inhaler, tested using a proprietary breathing simulator and Andersen Cascade Impactor. Comparison between the breathing simulators showed no significant difference in fluticasone propionate results, but a small difference was observed between the breathing simulators for salmeterol total emitted dose and fine particle mass. Conclusions: This study demonstrates that severe COPD patients are likely to achieve a consistent inhaled dose from Wixela Inhub, with low flow dependency observed within this patient population. In addition, both breathing simulators, which differ significantly in design, produced similar results for fluticasone propionate, but yielded slightly (but statistically significant) different results for salmeterol.

A man in his 70s was admitted to hospital due to a fall, urinary tract infection and delirium. The patient had a ‘do not attempt cardiopulmonary resuscitation’ order in place and a ward-based ceiling of care was agreed. He tested positive for COVID-19 while on a geriatric ward and subsequently developed bilateral pulmonary emboli with haemodynamic instability. The patient had a significant bleeding risk; however, the expected morbidity and mortality risk from the pulmonary emboli was high. A decision was made to give the patient low-dose thrombolysis on the geriatric ward, following which he made a full recovery. Acute thrombolysis is normally performed in emergency department, high dependency unit (HDU) or intensive care unit (ICU) settings; however, this was not possible in this case due to the burden the COVID-19 pandemic had placed on HDU/ICU services and bed capacity. Adaptation of treatment guidelines allowed for emergency life-saving treatment to be delivered to this patient.

Discharge summaries are important medical documents that summarise a patient’s hospital admission. The Royal College of Physicians provides standardised guidance on the content of discharge summaries, given their important role as a handover document to general practitioners (GPs). Our project started in June 2020 on an acute medical ward, where significant variation had been noted in the quality and content of discharge summaries. A multidisciplinary team (MDT) was formed including doctors, nurses and hospital/community pharmacists, as well as a patient representative, to ensure active patient co-design. The problem was scoped by asking GPs to provide feedback via surveys and process mapping. Our aim was to increase the compliance of discharge summaries with 10 core criteria from a baseline of 55% to 95% by June 2021. Change ideas were developed by the MDT and were tested using plan–do–study–act (PDSA) cycles that included additional pharmacy support, a discharge summary template and individualised feedback. The project reached its goal of 95% compliance in January 2021, 5 months ahead of the target date, and this improvement has been sustained since. The project expanded to a second acute medical unit ward in May 2021. The expanded project reached its goal of 90% compliance within 6 weeks and maintained sustained improvement with further PDSA cycles. A standard operating procedure has been created to help embed the changes on these wards. Our future aims are to redesign and improve the current electronic system and to help spread positive changes throughout the Trust.

Summary The COVID-19 pandemic signalled a radical shift in health and social care services globally. In UK, many of the people with existing social care needs were identified as ‘clinically vulnerable’ to COVID-19. Those at greatest risk were encouraged to adhere to additional public health measures that inadvertently exacerbated social disadvantages. Social workers were challenged to ‘dig deep’ to continue to provide services as usual. However, problems implementing new ways of working were reported but not examined in-depth through research. Our study explored experiences and perceptions of social workers responding to the first wave (April–July 2020) of COVID-19, in England, UK. Interviews with thirteen social workers, all working in the West Midlands region, were conducted via telephone or online video. Transcripts were analysed using reflexive thematic analysis. We use ‘managing uncertainty’ as a central concept underpinning the four themes identified after analysis: (1) providing social care at a physical distance, (2) negotiating home/work boundaries, (3) managing emerging risks and (4) long-term implications for social work. We discuss our findings in the context of resilience and organisational adaptation. Social workers in our study demonstrated resilience in action and rapid adaptation to new practices, but equally expressed concern about short-term efficiencies being prioritised over individual service user needs., The COVID-19 pandemic signalled a dramatic shift in how health and social care services were delivered to members of the public. Social workers reported challenges implementing new ways of working during the first wave of COVID-19. However, such challenges received little coverage in the media or in research. This article explores the views and experiences of social workers responding to the first COVID-19 wave in England, UK (April–July 2020). Telephone and online interviews were carried out with thirteen social workers active in the West Midlands region. Social workers shared experiences of how they managed uncertainty—a core theme in the study. Interviewees described managing the uncertainty of: (1) providing social care at a physical distance, (2) negotiating home/work boundaries, (3) managing emerging risks and (4) contemplating the future of social work practice. Our study demonstrates how social work professionals adapted rapidly to new practices during the first wave. However, social workers raised concerns about the impact of short-term solutions on long-term needs of service users. Implications for research and practice are discussed with reference to key literature.

We present a case of cytokine release syndrome (CRS) that occurred five days after vaccination with BTN162b2 (tozinameran), an mRNA COVID-19 vaccine, in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-y/IL-2R/IL-18/IL-16/IL-10), and steroid responsiveness.

SummaryAntigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naïve patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+T-cells to enhance cytotoxicity.

Intra-tumour genetic heterogeneity (ITH) fuels cancer evolution. The role of clonal diversity and genetic complexity in the progression of clear-cell renal cell carcinomas (ccRCCs) has been characterised, but the ability to predict clinically relevant evolutionary trajectories remains limited. Here, towards enhancing this ability, we investigated spatial features of clonal diversification through a combined computational modelling and experimental analysis in the TRACERx Renal study. We observe through modelling that spatial patterns of tumour growth impact the extent and trajectory of subclonal diversification. Moreover, subpopulations with high clonal diversity, and parallel evolution events, are frequently observed near the tumour margin. In-silico time-course studies further showed that budding structures on the tumour surface could indicate future steps of subclonal evolution. Such structures were evident radiologically in 15 early-stage ccRCCs, raising the possibility that spatially resolved sampling of these regions, when combined with sequencing, may enable identification of evolutionary potential in early-stage tumours.

Background Global Public Health Days (GPHD) are public health interventions which serve to improve public awareness of specific health conditions. Google Trends is a publicly available tool that allows the user to view the popularity of a searched keyword during a specified time period and across a predetermined region. Our objective was to use Google Trends to assess the impact of four GPHD (World Heart Day, World Mental Health Day, World Diabetes Day and World Hypertension Day) on online health information-seeking behaviour (OHISB), 4 weeks before and a week after the GPHD, across six countries of the Arabian Peninsula (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates). Methods Relative Search Volume (RSV) was extracted for the aforementioned countries from 28 days before the GPHD and 7 days afterwards. Statistical analysis, undertaken using joinpoint regression software, showed that GPHD have significant changes for Saudi Arabia (Diabetes, Mental Health and Heart day) and UAE (Mental Health day) but were short-lived with a fall in RSV of up to 80% after peak interest. Conclusion GPHD appears to be effective in some countries while further research is needed to investigate the reason of its limitations.

Background The prevention of self-harm is an international public health priority. It is vital to identify at-risk populations, particularly as self-harm is a risk factor for suicide. This study aims to examine the risk of self-harm in people with vertebral fractures. Methods Retrospective cohort study. Patients with vertebral fracture were identified within the Clinical Practice Research Datalink and matched to patients without fracture by sex and age. Incident self-harm was defined by primary care record codes following vertebral fracture. Overall incidence rates (per 10,000 person-years (PY)) were reported. Cox regression analysis determined risk (hazard ratios (HR), 95 % confidence interval (CI)) of self-harm compared to the matched unexposed cohort. Initial crude analysis was subsequently adjusted and stratified by median age and sex. Results The number of cases of vertebral fracture was 16,293, with a matched unexposed cohort of the same size. Patients were predominantly female (70.1 %), median age was 76.3 years. Overall incidence of self-harm in the cohort with vertebral fracture was 12.2 (10.1, 14.8) /10,000 PY. There was an initial crude association between vertebral fracture and self-harm, which remained after adjustment (HR 2.4 (95 %CI 1.5, 3.6). Greatest risk of self-harm was found in those with vertebral fractures who were aged below 76.3 years (3.2(1.8, 5.7)) and male (3.9(1.8, 8.5)). Conclusions Primary care patients with vertebral fracture are at increased risk of self-harm compared to people without these fractures. Male patients aged below 76 years of age appear to be at greatest risk of self-harm. Clinicians need to be aware of the potential for self-harm in this patient group.

Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, and timely health care seeking is imperative for its prevention, early detection, and management. While online health information–seeking behavior (OHISB) is increasingly popular due to widespread internet connectivity, little is known about how OHISB for COPD has changed in comparison with the COPD disease burden, particularly at a country-specific level. Objective This study aimed to examine the trends in OHISB for COPD and how that compared with the estimates of COPD disease burden in Singapore, a highly wired country with a steadily increasing COPD disease burden. Methods To examine the trends in OHISB for COPD, we performed Prais-Winsten regression analyses on monthly search volume data for COPD from January 2004 to June 2020 downloaded from Google Trends. We then conducted cross-correlational analyses to examine the relationship between annualized search volume on COPD topics and estimates of COPD morbidity and mortality reported in the Global Burden of Disease study from 2004 to 2017. Results From 2004 to 2020, the trend in COPD search volume was curvilinear (β=1.69, t194=6.64, P Conclusions Google search volume on COPD increased from 2007 to 2020; this trend correlated with the upward trajectory of several COPD morbidity estimates, suggesting increasing engagement in OHISB for COPD in Singapore. These findings underscore the importance of making high-quality, web-based information accessible to the public, particularly COPD patients and their carers.

SUMMARYThere is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.

To examine the risk of self-harm in rheumatic conditions.We conducted a retrospective cohort study using data from the Clinical Practice Research Datalink. Patients with ankylosing spondylitis, fibromyalgia, osteoarthritis, or rheumatoid arthritis were identified from 1990 to 2016 and matched to patients without these conditions. Incident self-harm was defined by medical record codes following a rheumatic diagnosis. Incidence rates (per 10,000 person-years) were reported for each condition, both overall and year-on-year (2000-2016). Cox regression analysis determined risk (hazard ratio [HR] and 95% confidence interval [95% CI]) of self-harm for each rheumatic cohort compared to the matched unexposed cohort. Initial crude analysis was subsequently adjusted and stratified by age and sex. Due to nonproportionality over time, osteoarthritis was also stratified by disease duration (1 year, ≥1 to5 years, ≥5 to10 years, and ≥10 years).The incidence of self-harm was highest in patients with fibromyalgia (HR 25.12 [95% CI 22.45-28.11] per 10,000 person-years) and lowest for osteoarthritis (HR 6.48 [95% CI 6.20-6.76]). There was a crude association with each rheumatic condition and self-harm, except for ankylosing spondylitis. Although attenuated, these associations remained after adjustment for fibromyalgia (HR 2.06 [95% CI 1.60-2.65]), rheumatoid arthritis (HR 1.59 [95% CI 1.20-2.11]), and osteoarthritis (1 to5 years HR 1.12 [95% CI 1.01-1.24]; ≥5 to10 years HR 1.35 [95% CI 1.18-1.54]). Age and sex were weak effect modifiers for these associations.Primary care patients with fibromyalgia, osteoarthritis, or rheumatoid arthritis (but not ankylosing spondylitis) are at increased risk of self-harm compared to people without these rheumatic conditions. Clinicians need to be aware of the potential for self-harm in patients with rheumatic conditions (particularly fibromyalgia), explore mood and risk with them, and offer appropriate support and management.

International audience; Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias isinherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mmbiopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB butlow clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, and timely health care seeking is imperative for its prevention, early detection, and management. While online health information–seeking behavior (OHISB) is increasingly popular due to widespread internet connectivity, little is known about how OHISB for COPD has changed in comparison with the COPD disease burden, particularly at a country-specific level. OBJECTIVE This study aimed to examine the trends in OHISB for COPD and how that compared with the estimates of COPD disease burden in Singapore, a highly wired country with a steadily increasing COPD disease burden. METHODS To examine the trends in OHISB for COPD, we performed Prais-Winsten regression analyses on monthly search volume data for COPD from January 2004 to June 2020 downloaded from Google Trends. We then conducted cross-correlational analyses to examine the relationship between annualized search volume on COPD topics and estimates of COPD morbidity and mortality reported in the Global Burden of Disease study from 2004 to 2017. RESULTS From 2004 to 2020, the trend in COPD search volume was curvilinear (β=1.69, t194=6.64, P<.001), with a slope change around the end of 2006. There was a negative linear trend (β=–0.53, t33=–3.57, P=.001) from 2004 to 2006 and a positive linear trend (β=0.51, t159=7.43, P CONCLUSIONS Google search volume on COPD increased from 2007 to 2020; this trend correlated with the upward trajectory of several COPD morbidity estimates, suggesting increasing engagement in OHISB for COPD in Singapore. These findings underscore the importance of making high-quality, web-based information accessible to the public, particularly COPD patients and their carers.

Background\ud Public health awareness can help prevent illness and result in earlier intervention when it does occur. For this reason, health promotion and disease awareness campaigns have great potential to alleviate the global burden of disease. Global Public Health Days (GPHD) are frequently implemented with this intent, but research evaluating their effectiveness, especially in the developing world setting, is scant.\ud \ud Objectives\ud We aimed to evaluate the impact of four GPHDs (World Cancer Day, World Diabetes Day, World Mental Health Day, World AIDS Day) on online health information seeking behaviour (OHISB) in five Central and South American (CSA) countries which differ in their stage of economic development and epidemiological transition (Uruguay, Chile, Brazil, Colombia, Nicaragua).\ud \ud Methods\ud Google Trends data was used as a ‘surrogate’ of OHISB. This was measured on the 28 days leading up to the GPHD, on the date of the GPHD, and on the seven days following it. The Joinpoint regression programme was used to perform a time trend analysis on the Google Trends data. This allowed us to identify statistically significant time points of a change in trend, which reflect significant ‘changes’ to OHISB.\ud \ud Results\ud GPHDs were inconsistently effective at influencing internet search query activity in the studied countries. In situations where an effect was significant, this impact was consistently short-term, with Relative Search Volume level returning to precampaign levels within 7 days of the GPHD.\ud \ud Conclusions\ud Our findings imply the need to revise GPHDs or create alternative health awareness campaigns, perhaps with a more long-term approach and tailored to the specific health needs of the CSA population. Developing effective preventive strategies is vital in helping combat the rising threat of NCDs in this region.

Purpose: This article presents data challenging the widely held but untested view that concurrently playing mid-week Union of European Football Associations (UEFA) Europa League matches adversely affects domestic league performance. Method: Over 16 seasons we compared next-season domestic league performance of the two highest finishing UEFA Europa League qualifying clubs with the two highest finishing non-qualifiers in England and Spain. Results: Clubs concurrently playing UEFA Europa League football showed significantly superior domestic league performance including wins, losses, goals, goal difference and points tally. The number of European matches played was not related to domestic league performance. Conclusions: The absence of prior rigorous analysis including appropriate comparison data has led to the proliferation of a widespread confirmatory bias, defined as the tendency to seek out evidence that backs one&rsquo, s hunches and to ignore evidence that contradicts them. Based on our evidence, football professionals, journalists, pundits, and fans should consider the UEFA Europa League competition more favorably.

Background Depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. The number of prescriptions for antidepressants has risen dramatically in recent years yet up to 50% of patients who are treated for depression with antidepressants do not report feeling better as a result of treatment, and do not show the desired improvement on depression measures. We report a qualitative study embedded in a trial of second antidepressant for people who had not responded to one antidepressant, exploring the acceptability of a combination of antidepressants from the perspectives of both patients and practitioners, together with experiences of participating in a clinical trial. Methods A qualitative study embedded in a randomized controlled trial investigating the effectiveness and cost-effectiveness of combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants versus SNRI or SSRI therapy alone (the MIR trial). 59 interviews were conducted with people who declined to participate in the trial, people who completed the study and people who withdrew from the intervention, and 16 general practitioners. Results Across the data-sets, four main themes were identified: the hard work of managing depression, uncertainties over the value of a second antidepressant, help-seeking at a point of crisis, and attainment and maintenance of a hard-won equilibrium. Conclusions Exploring reasons for declining to participate in a trial of a second antidepressant in people who had not responded to one antidepressant suggests that people who are already taking one antidepressant may be reluctant to take a second, being wary of possible side-effects, but also being unconvinced of the logic behind such a combination. In addition, people describe being in a state of equilibrium and reluctant to make a change, reflecting that this equilibrium is ‘hard-won’ and they are unwilling to risk disturbing this. This makes some people reluctant to enrol in a clinical trial. Understanding a patient’s view on medication is important for GPs when discussing antidepressants. Trial registration MIR Trial Registration: ISRCTN 06653773.

IntroductionThere is a significant treatment gap, with only a few community-based services for people with schizophrenia in low-income and middle-income countries. Poor treatment adherence in schizophrenia is associated with poorer health outcomes, suicide attempts and death. We previously reported the effectiveness of supervised treatment in outpatients for schizophrenia (STOPS) for improving treatment adherence in patients with schizophrenia. However, STOPS was evaluated in a tertiary care setting with no primary care involvement, limiting its generalisability to the wider at-risk population. We aim to evaluate the effectiveness of STOPS+ in scaling up the primary care treatment of schizophrenia to a real-world setting.Methods and analysisThe effectiveness of the STOPS+ intervention in improving the level of functioning and medication adherence in patients with schizophrenia in Pakistan will be evaluated using a cluster randomised controlled trial design. We aim to recruit 526 participants from 24 primary healthcare centres randomly allocated in 1:1 ratio to STOPS+ intervention and enhanced treatment as usual arms. Participants will be followed-up for 12 months postrecruitment. The sample size is estimated for two outcomes (1) the primary clinical outcome is level of functioning, measured using the Global Assessment of Functioning scale and (2) the primary process outcome is adherence to treatment regimen measured using a validated measure. An intention-to-treat approach will be used for the primary analysis.Ethics and disseminationEthical approval has been obtained from Keele University Ethical Review Panel (ref: MH-190017) and Khyber Medical University Ethical Review Board (ref: DIR-KMU-EB/ST/000648). The results of the STOPS+ trial will be reported in peer-reviewed journals and academic conferences and disseminated to local stakeholders and policymakers.Trial registration numberISRCTN93243890.

ObjectiveTo investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care.DesignTwo parallel group multicentre phase III randomised placebo controlled trial.Setting106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015.Participants480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up.Main outcome measuresDepressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks.ResultsBeck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.ConclusionThis study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited.Trial registrationCurrent Controlled TrialsISRCTN06653773.

Background Anxiety and depression are common among older people, with up to 20% reporting such symptoms, and the prevalence increases with co-morbid chronic physical health problems. Access to treatment for anxiety and depression in this population is poor due to a combination of factors at the level of patient, practitioner and healthcare system. There is evidence to suggest that older people with anxiety and/or depression may benefit both from one-to-one interventions and group social or educational activities, which reduce loneliness, are participatory and offer some activity. Non-traditional providers (support workers) working within third-sector (voluntary) organisations are a valuable source of expertise within the community but are under-utilised by primary care practitioners. Such a resource could increase access to care, and be less stigmatising and more acceptable for older people. Methods The study is in three phases and this paper describes the protocol for phase III, which will evaluate the feasibility of recruiting general practices and patients into the study, and determine whether support workers can deliver the intervention to older people with sufficient fidelity and whether this approach is acceptable to patients, general practitioners and the third-sector providers. Phase III of the NOTEPAD study is a randomised controlled trial (RCT) that is individually randomised. It recruited participants from approximately six general practices in the UK. In total, 100 participants aged 65 years and over who score 10 or more on PHQ9 or GAD7 for anxiety or depression will be recruited and randomised to the intervention or usual general practice care. A mixed methods approach will be used and follow-up will be conducted 12 weeks post-randomisation. Discussion This study will inform the design and methods of a future full-scale RCT. Trial registration ISRCTN, ID: ISRCTN16318986. Registered 10 November 2016. The ISRCTN registration is in line with the World Health Organization Trial Registration Data Set. The present paper represents the original version of the protocol. Any changes to the protocol will be communicated to ISRCTN. Electronic supplementary material The online version of this article (10.1186/s13063-018-2550-6) contains supplementary material, which is available to authorized users.

Monozygotic (MZ) and dizygotic (DZ) twins participate in research that partitions variance in health, disease, and behavior into genetic and environmental components. However, there are other innovative roles for twins in medical research. One such way is involving MZ and/or DZ twins in co-twin control-designed randomized controlled trials (RCTs). To our knowledge, no reviews have been conducted that summarizes the involvement of twins in RCTs. Therefore, we conducted a systematic literature search using the U.S. Clinical Trials Database, NHS electronic databases, MEDLINE, EMBASE, and PsychINFO for RCTs on publications involving MZ and/or DZ twins as RCT participants. Out of the 186,027 clinical trials registered in the U.S. clinical trial register ClinicaTrails.gov, only six RCTs used twins as participants. From 1,598 articles identified in our search, 50 peer-reviewed English language publications met our pre-defined inclusion criteria. Sample sizes for RCTs have ranged from a total number of participants from 2 to 1,162; however, 32 (64%) studies had a sample size of 100 or less, and of those, 12 (24%) had fewer than 10. Both MZ and DZ twins have been recruited to the RCTs. In most instances (33/50) each twin from a pair were assigned to different study arms. Most of those studies included MZ twins only. Despite the methodological advantages, the use of MZ and DZ twins as participants in interventional RCTs appeared limited. The continuous development of innovative twin designs, especially RCTs, indicates that twin research can extend beyond the more widely recognized heritability estimates.

Medicated, non-dementing mild-to-moderate Parkinson's disease (PD) patients usually show recall/recollection impairments but have only occasionally shown familiarity impairments. We aimed to assess two explanations of this pattern of impairment. Recollection typically improves when effortful planning of encoding and retrieval processing is engaged. This depends on prefrontally-dependent executive processes, which are often disrupted in PD. Relative to an unguided encoding and retrieval of words condition (C1), giving suitable guidance at encoding alone (C2) or at encoding and retrieval (C3) should, if executive processes are disrupted, improve PD recollection more than control recollection and perhaps raise it to normal levels. Familiarity, being a relatively automatic kind of memory, whether impaired or intact, should be unaffected by guidance. According to the second explanation, PD deficits are amnesia-like and caused by medial temporal lobe dysfunction and although poorer recollection, which is caused by hippocampal disruption, may be improved by guidance, it should not improve more than control recollection. Familiarity impairment will also occur if the perirhinal cortex is disrupted, but will be unimproved by guidance. Without guidance, recollection/recall was impaired in thirty PD patients relative to twenty-two healthy controls and remained relatively equally impaired when full guidance was provided (C1 vs C3), both groups improving to broadly the same extent. Although impaired, and markedly less so than recollection, familiarity was not improved by guidance in both groups. The patients showed elevated rates of subclinical depressive symptoms, which weakly correlated with recall/recollection in all three conditions. PD executive function was also deficient and correlated with unguided/C1 recollection only. Our results are consistent with a major cause of the patients' recall/recollection impairments being hippocampal disruption, probably exacerbated by subclinical depressive symptoms. However, the results do not exclude a lesser prefrontal cortex contribution because patient executive functions were impaired and correlated solely with unguided overall recollection.

Background One-in-five people in the UK experience anxiety and/or depression in later life. However, anxiety and depression remain poorly detected in older people, particularly in those with chronic physical ill health. In the UK, a stepped care approach, to manage common mental health problems, is advocated which includes service provision from non-statutory organisations (including third/voluntary sector). However, evidence to support such provision, including the most effective interventions, is limited. The qualitative study reported here constitutes the first phase of a feasibility study which aims to assess whether third sector workers can deliver a psychosocial intervention to older people with anxiety and/or depression. The aim of this qualitative study is to explore the views of older people and third sector workers about anxiety and depression among older people in order to refine an intervention to be delivered by third sector workers. Methods Semi-structured interviews with participants recruited through purposive sampling from third sector groups in North Staffordshire. Interviews were digitally recorded with consent, transcribed and analysed using principles of constant comparison. Results Nineteen older people and 9 third sector workers were interviewed. Key themes included: multiple forms of loss, mental health as a personal burden to bear, having courage and providing/receiving encouragement, self-worth and the value of group activities, and tensions in existing service provision, including barriers and gaps. Conclusions The experience of loss was seen as central to feelings of anxiety and depression among community-dwelling older people. This study contributes to the evidence pointing to the scale and severity of mental health needs for some older people which can arise from multiple forms of loss, and which present a significant challenge to health, social care and third sector services. The findings informed development of a psychosocial intervention and training for third sector workers to deliver the intervention.

Background The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson’s disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. Methods Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. Results A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON–OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. Conclusions This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. Trial registration EudraCT 2012-000801-64

Bodily symptoms are common in community samples, but not all people consult for medical advice about such symptoms. Medically unexplained symptoms (MUS) refer to persistent bodily complaints for which adequate examination (including investigation) does not reveal sufficiently explanatory structural or other specified pathology.1 MUS are common, with a spectrum of severity, and patients are found everywhere within the healthcare system.2 It has been estimated that MUS account for up to 45% of all general practice consultations,3 while a study based in secondary care indicated that about 50% of patients had no clear diagnosis at 3 months.2 The annual NHS cost for MUS in adults of working age in England was estimated to be £2.89 billion in 2008/2009 (approximately 10% of total NHS expenditure on these services for the working age population), while sickness absence and decreased quality of life for people with MUS was estimated as costing over £14 billion per annum to the UK economy.4 Although the costs to the NHS and the economy are important considerations, the personal cost to the patient can also be significant. Patients often experience stress, distress, and anxiety because of their unexplained symptoms. They report feeling that their concerns are not taken seriously by their doctor, which can exacerbate the presentation of somatic symptoms. The suggestion that ‘negative test results means that nothing is wrong’ is cited as the most common explanation given by doctors,5 but patients can feel that their symptoms are not believed, and may disengage from health care (including for other …

A selective deficit in the recollection of episodic details is frequently reported in Parkinson's disease (PD). Previous explanations implicate dopamine dysregulation in prefrontal structures on which strategic memory processes rely. However, neuroimaging advancements suggest dopaminergic dysregulation of hippocampally dependent memory processes. Accordingly, dopamine agonists, which target D3 receptors in the hippocampus, may impair hippocampal functioning, causing a more pronounced recollection decline. Recognition memory (RM), familiarity, and recollection were examined in 21 patients with mild-to-moderate PD (Hoehn and Yahr mean: 2.67). Patients were subdivided into two subgroups according to dopamine agonist (pramipexole [PPX] or ropinirole [RPR]), and completed matched versions of an RM test in a medicated and unmedicated condition (termed ON and OFF, respectively). Ten demographically matched healthy volunteers (HVs) also completed both RM tasks in two separate sessions. The PD group (PPX and RPR subgroups combined) showed impairments in RM and recollection, but spared familiarity. When subdivided by dopamine agonist, the PPX subgroup's ON-medication recollection performance was significantly lower than that of both the HVs and RPR subgroup. There was no evidence of decline in OFF-medication recollection or familiarity in either the PPX or RPR subgroups. Recollection in both PD subgroups correlated positively with a composite measure of recall, but not prefrontally dependent measures of cognitive control. These findings suggest that mild-to-moderate PD patients may show relatively preserved recollection and familiarity, but that recollection is selectively disrupted by PPX, but not RPR and that this effect may depend on disrupted hippocampal function rather than impaired pre-frontally dependent executive functions.

The catechin, epigallocatechin gallate (eGCG), found in green tea, has inhibitory activity against a number of protein toxins and was investigated in relation to its impact upon ricin toxin (RT) in vitro. The IC50 for RT was 0.08 ± 0.004 ng/mL whereas the IC50 for RT + 100 μM eGCG was 3.02 ± 0.572 ng/mL, indicating that eGCG mediated a significant (p

Idiopathic nondementing Parkinson’s disease (PD) is marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area. Recent brain imaging work implicates these structures in dopamine modulated networks subserving episodic memory. These findings are of relevance to PD because they suggest that dopamine depletion contributes to the disease-dependent decline in episodic memory, and therefore, this decline should, at least partially, be remediated by dopaminergic medication. Recognition memory (RM), recollection and familiarity during recognition was examined in 17 PD patients, 12 of whom were medicated with a D2 dopamine agonist (pramipexole or ropinirole) and l-dopa, with a further 5 PD control patients on l-dopa but no D2 agonist. Memory was tested “ON” and, following a period of medication withdrawal, “OFF” and compared to a group of 14 matched healthy volunteers (HV). The HVs were also tested twice in the absence of medication. The patients on the agonists PD showed significant impairments in recollection ON- and OFF-medication, whereas the l-dopa control patients exhibited a decline in OFF-recollection only. RM and familiarity were spared in both groups ON- and OFF-medication. These findings suggest that D2 dopamine agonists (combined with l-dopa) contribute to disease-dependent episodic memory impairment.

2565Background: Estimation of glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing. However, the most accurate method to estimate GFR in patients with cancer is unknown...

Inefficient cytosolic delivery and vector toxicity contribute to the limited use of antisense oligonucleotides (ASOs) and siRNA as therapeutics. As anthrax toxin (Atx) accesses the cytosol, the purpose of this study was to evaluate the potential of disarmed Atx to deliver either ASOs or siRNA. We hypothesized that this delivery strategy would facilitate improved transfection efficiency while eliminating the toxicity seen for many vectors due to membrane destabilization. Atx complex formation with ASOs or siRNA was achieved via the in-frame fusion of either Saccharomyces cerevisiae GAL4 or Homo sapien sapien PKR (respectively) to a truncation of Atx lethal factor (LFn), which were used with Atx protective antigen (PA). Western immunoblotting confirmed the production of: LFN-GAL4, LFn-PKR and PA which were detected at ~45.9 kDa, ~37 kDa, and ~83 kDa respectively and small angle neutron scattering confirmed the ability of PA to form an annular structure with a radius of gyration of 7.0 ± 1.0 nm when placed in serum. In order to form a complex with LFn-GAL4, ASOs were engineered to contain a double-stranded region, and a cell free in vitro translation assay demonstrated that no loss of antisense activity above 30 pmol ASO was evident. The in vitro toxicity of both PA:LFn-GAL4:ASO and PA:LFn-PKR:siRNA complexes was low (IC50100 μg/mL in HeLa and Vero cells) and subcellular fractionation in conjunction with microscopy confirmed the detection of LFn-GAL4 or LFn-PKR in the cytosol. Syntaxin5 (Synt5) was used as a model target gene to determine pharmacological activity. The PA:LFn-GAL4:ASO complexes had transfection efficiency approximately equivalent to Nucleofection® over a variety of ASO concentrations (24h post-transfection) and during a 72 h time course. In HeLa cells, at 200 pmol ASO (with PA:LFN-GAL4), 5.4 ± 2.0% Synt5 expression was evident relative to an untreated control after 24h. Using 200 pmol ASOs, Nucleofection® reduced Synt5 expression to 8.1 ± 2.1% after 24h. PA:LFn-GAL4:ASO transfection of non- or terminally-differentiated THP-1 cells and Vero cells resulted in 35.2 ± 19.1%, 36.4 ± 1.8% and 22.9 ± 6.9% (respectively) Synt5 expression after treatment with 200 pmol of ASO and demonstrated versatility. Nucleofection® with Stealth RNAi™ siRNA reduced HeLa Synt5 levels to 4.6 ± 6.1% whereas treatment with the PA:LFn-PKR:siRNA resulted in 8.5 ± 3.4% Synt5 expression after 24h (HeLa cells). These studies report for the first time an ASO and RNAi delivery system based upon protein toxin architecture that is devoid of polycations. This system may utilize regulated membrane back-fusion for the cytosolic delivery of ASOs and siRNA, which would account for the lack of toxicity observed. High delivery efficiency suggests further in vivo evaluation is warranted.

e14074 Background: The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing, however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods: Data on age, sex, height, weight, serum creatinine, and results for GFR from 51Cr-EDTA excretion measurements (51Cr-EDTA GFR) were obtained from Caucasian patients aged 18 years or older with histologically confirmed cancer diagnoses at the University of Cambridge Hospital NHS Trust, UK. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared to the estimated GFR (eGFR) from seven published and our new model using an internal validation data set and root-mean-squared-error (RMSE) and median residuals. A comparison of carboplatin dosing accuracy based on an absolute percentage error more than 20% (APE > 20%) was undertaken. Results: Between August 2006 and January 2013 data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE 15.00ml/min (95% CI 14.12-16.00)) compared to all published models. Body surface area (BSA) adjusted CKD-EPI was the most accurate published models for eGFR (RMSE 16.30ml/min (95% CI 15.34-17.38)) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose APE > 20% to 14.17% in contrast to 18.62% for BSA adjusted CKD-EPI and 25.51% for the Cockcroft-Gault model. The results were externally validated. Conclusions: In a large data set, from patients with cancer, a new model improves eGFR and carboplatin dose calculations, when compared to BSA adjusted CKD-EPI, the model we identified as the best published model for determination of eGFR in patients with cancer.

e16061 Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( < 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( < 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p < 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p < 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P < 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.

Background: Single cycle carboplatin, dosed by glomerular filtration rate (GFR), is standard adjuvant therapy for stage 1 seminoma. Accurate measurement of GFR is essential for correct dosing. Isotopic methods remain the gold standard for the determination of GFR. Formulae to estimate GFR have improved the assessment of renal function in non-oncological settings. We assessed the utility of these formulae for carboplatin dosing.\ud \ud Methods: We studied consecutive subjects receiving adjuvant carboplatin for stage 1 seminoma at our institution between 2007 and 2012. Subjects underwent 51Cr-ethylene diamine tetra-acetic acid (EDTA) measurement of GFR with carboplatin dose calculated using the Calvert formula. Theoretical carboplatin doses were calculated from estimated GFR using Chronic Kidney Disease-Epidemiology (CKD-EPI), Management of Diet in Renal Disease (MDRD) and Cockcroft–Gault (CG) formulae with additional correction for actual body surface area (BSA). Carboplatin doses calculated by formulae were compared with dose calculated by isotopic GFR; a difference \ud \ud Results: 115 patients were identified. Mean isotopic GFR was 96.9 ml/min/1.73 m2. CG and CKD-EPI tended to overestimate GFR whereas MDRD tended to underestimate GFR. The CKD-EPI formula had greatest accuracy. The CKD-EPI formula, corrected for actual BSA, performed best; 45.9% of patients received within 10% of correct carboplatin dose. Patients predicted as underdosed (13.5%) by CKD-EPI were more likely to be obese (p = 0.013); there were no predictors of the 40.5% receiving an excess dose.\ud \ud Conclusions: Our data support further evaluation of the CKD-EPI formula in this patient population but clinically significant variances in carboplatin dosing occur using non-isotopic methods of GFR estimation. Isotopic determination of GFR should remain the recommended standard for carboplatin dosing when accuracy is essential.

The effect of disease severity and dopaminergic medication on the assessment of familiarity and the recollection of episodic details during recognition in nondementing idiopathic Parkinson's is uncertain. Some studies have reported familiarity as deficient in mild Parkinson's yet others have found it intact even in moderate Parkinson's. Recollection has been found to be both preserved and deficient in mild and moderate Parkinson's. The extent to which these conflicting findings are explained by disease severity or dopaminergic medication or a combination of the two is uncertain, as all studies assessed patients in a medicated state, and disease severity has not always been consistently reported. Twelve patients with mild Parkinson's and 11 with moderate Parkinson's (medicated Hoehn and Yahr mean: 2.1 and 3.2, respectively), completed matched versions of a yes/no recognition memory test in a medicated and unmedicated condition (termed ON and OFF, respectively). Twenty-one matched healthy volunteers also completed both memory tasks in 2 separate sessions (termed Blue and Green, respectively). In the ON/Green condition, the moderate Parkinson's recollection performance was significantly poorer than the healthy volunteers and mild Parkinson's. By contrast, recognition memory and familiarity measures in both Parkinson's group were relatively spared. In the OFF/Blue condition, the moderate Parkinson's recollection was impaired, but only in relation to the healthy volunteer set. There were no significant differences in recollection performance between the mild and moderate Parkinson's groups. Again, recognition memory and familiarity measures in both Parkinson's group were relatively spared. Further analyses showed the moderate patients' recollection rates to be significantly poorer ON-medication compared to OFF. These findings are discussed in relation to the staging of disease progression on medial temporal areas which separately support recollection and familiarity, and the putative effects the different classes of dopaminergic drugs may have on these areas.

Introduction The internet offers a wealth of information for patients with chronic disease, facilitating education and shared decision making; however, this can often be unregulated and inaccurate. 1 Inflammatory bowel disease (IBD) patients use of the internet has been investigated 2 but no studies have examined whether internet use alters with disease activity or influences patients decisions regarding health. We evaluated patients internet use for health-related information (HRI), including factors influencing website choice and whether this information influences decisions regarding healthcare or changes with disease severity. Methods A prospective, pilot survey of 170 consecutive patients attending the IBD clinic over a one month period in November 2013. The anonymous questionnaire included demographic information on age, gender, education level, diagnosis and disease activity. There were also questions regarding use of the internet for HRI, determinants of website quality and influences of information found on the internet on decisions affecting their health. Results A total of 136 IBD patients completed the questionnaire (80% response rate), 60 [44%] male, age 18–85 years [median age 37 years] 67 [49%] had CD; 84 [62%] reported a flare of symptoms in the preceding 6 months. 126 (93%) use the internet, 110 (81%) of which access HRI information via the internet. 94% of patients were educated to completion of high school or above and level of education did not affect internet use. Using NHS direct (46%), Crohn’s and colitis UK (40%) and IBD forums (29%), patients searched for general health (77; 57%); IBD specific (63; 46%) and medication (47; 35%) information. 45 (33%) stated that information found on the internet would influence their choice of medication, irrespective of a flare within the last 6 months. 71% (96) felt confident that they could obtain factual information on the internet, although when determining website quality, overall appearance and position in search engines and whether the site was non-commercial were ranked least important and IBD-specific sites from a reputable source most important. Conclusion In our study, internet use is shown to be a major source of disease –specific information and can affect patients’ decision making. Internet usage and type of information sought do not alter with disease activity, suggesting that information is equally useful to all patients with IBD. References 1 Fortinsky et al . Innflam Bow. Dis 2012; 18(6):1156–63 2 Cima et al . Inflamm Bowel Dis 2012; 13 (10)1266–1270 Disclosure of Interest None Declared.

This paper describes an SOC design of a complex, low power and high performance open multimedia application platform (OMAP/sup TM/) for 3G wireless. The design integrates a high performance DSP subsystem based on a low power TMS320C55x DSP and an MPU subsystem based on the ARM9 microprocessor for the optimal combination of high performance with low power consumption. This paper explains the system design and the SoC implementations of the platform.

2589 Background: Accurate determination of GFR is essential for correct dosing of carboplatin, the standard adjuvant therapy for stage 1 seminoma. Isotopic methods (e.g. 51Cr-EDTA) remain the gold standard for determination of GFR. However, the use of eGFR could reduce the need for such isotope studies. As novel formulae to estimate GFR such as CKD-EPI and MDRD4 have improved the assessment of renal function in non-oncological settings, we investigated their utility for carboplatin dosing. Methods: 115 patients (pts) (mean age 40.3, std dev. 10.1) who received adjuvant carboplatin for stage 1 seminoma at our institution between 2007-2012 were identified. All pts underwent 51Cr-EDTA measurement of GFR with carboplatin dose calculated using the Calvert formula, based on GFR uncorrected for body surface area (BSA). Theoretical carboplatin doses were then calculated using eGFR values obtained using the CKD-EPI and MDRD4 formulae with additional calculation to uncorrect for BSA. Creatinine clearance was calculated by Cockcroft-Gault (CG) formula. For each pt the carboplatin doses calculated by eGFR were compared with the actual dose calculated by the gold-standard method; a difference of less than 10% was considered acceptable. Results: The Table shows the percentage of pts who would have received an equivalent carboplatin dose using each eGFR formula compared to the dose calculated using 51Cr-EDTA. The CKD-EPI formula performed best with 58.9% of pts receiving within 10% of the correct dose. Pts predicted to be underdosed by CKD-EPI eGFR were more likely to be obese (BMI >30) (p=0.01); there were no predictors of the 18.8% who would have received an excess dose. Conclusions: Our data support further evaluation of the CKD-EPI formula but highlight the clinically significant variances in carboplatin dosing when using non-isotopic methods of GFR estimation. [Table: see text]