ctDNA guided adjuvant chemotherapy versus standard of care adjuvant chemotherapy after curative surgery in patients with high risk stage II or stage III colorectal cancer: a multi-centre, prospective, randomised control trial (TRACC Part C).

BACKGROUND: Circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) is emerging as a biomarker to predict recurrence in patients with curatively treated early stage colorectal cancer (CRC). ctDNA risk stratifies patients to guide adjuvant treatment decisions. We are conducting the UK's first multi-centre, prospective, randomised study to determine whether a de-escalation strategy using ctDNA to guide adjuvant chemotherapy (ACT) decisions is non-inferior to standard of care (SOC) chemotherapy, as measured by 3-year disease free survival (DFS) in patients with resected CRC with no evidence of MRD (ctDNA negative post-operatively). In doing so we may be able to spare patients unnecessary chemotherapy and associated toxicity and achieve significant cost savings for the National Health Service (NHS). METHODS: We are recruiting patients with fully resected high risk stage II and stage III CRC who are being considered for ACT into the study which uses results from a plasma-only ctDNA assay to guide treatment decisions. Eligible patients are randomised 1:1 to receive ctDNA-guided chemotherapy versus SOC chemotherapy. The primary endpoint is the difference in DFS at 3 years between the trial arms. Secondary endpoints include the proportion of patients in the ctDNA-guided arm who are ctDNA negative post-operatively and receive de-escalated ACT compared to the standard arm, the difference in overall survival (OS), neurotoxicity and quality of life between the arms, and the cost-effectiveness of ctDNA-guided therapy compared to SOC treatment. We hypothesise that using a ctDNA-guided approach to ACT decisions is non-inferior to SOC. Target accrual is 1621 patients over 4 years, which will provide a power of 80% with an alpha of 0.1 to demonstrate non-inferiority with a margin of 1.25 in survival of the ctDNA-guided approach compared to SOC. We anticipate approximately 50 UK centres will participate. The study opened with the Guardant Reveal plasma-only ctDNA assay in August 2022. DISCUSSION: The trial will determine whether ctDNA guided ACT is non-inferior to SOC ACT in patients with fully resected high risk stage II and stage III resected CRC, with the potential to significantly reduce unnecessary ACT and the toxicity associated with it. TRIAL REGISTRATION: NCT04050345.

Blood Substitutes and Oxygen Therapeutics: A Review.

Despite the exhaustive search for an acceptable substitute to erythrocyte transfusion, neither chemical-based products such as perfluorocarbons nor hemoglobin-based oxygen carriers have succeeded in providing a reasonable alternative to allogeneic blood transfusion. However, there remain scenarios in which blood transfusion is not an option, due to patient's religious beliefs, inability to find adequately cross-matched erythrocytes, or in remote locations. In these situations, artificial oxygen carriers may provide a mortality benefit for patients with severe, life-threatening anemia. This article provides an up-to-date review of the history and development, clinical trials, new technology, and current standing of artificial oxygen carriers as an alternative to transfusion when blood is not an option.

Cost-effectiveness of exercise as a therapy for behavioural and psychological symptoms of dementia within the EVIDEM-E randomised controlled trial.

OBJECTIVE: Although available evidence is modest, exercise could be beneficial in reducing behavioural and psychological symptoms of dementia. We aim to evaluate the cost-effectiveness of a dyadic exercise regimen for individuals with dementia and their main carer as therapy for behavioural and psychological symptoms of dementia. METHODS: Cost-effectiveness analysis within a two-arm, pragmatic, randomised, controlled, single-blind, parallel-group trial of a dyadic exercise regimen (individually tailored, for 20-30 min at least five times per week). The study randomised 131 community-dwelling individuals with dementia and clinically significant behavioural and psychological symptoms with a carer willing and able to participate in the exercise regimen; 52 dyads provided sufficient cost data for analyses. RESULTS: Mean intervention cost was £284 per dyad. For the subsample of 52 dyads, the intervention group had significantly higher mean cost from a societal perspective (mean difference £2728.60, p = 0.05), but costs were not significantly different from a health and social care perspective. The exercise intervention was more cost-effective than treatment as usual from both societal and health and social care perspectives for the measure of behavioural and psychological symptoms (Neuropsychiatric Inventory). It does not appear cost-effective in terms of cost per quality-adjusted life year gain. CONCLUSIONS: The exercise intervention has the potential to be seen as cost-effective when considering behavioural and psychological symptoms but did not appear cost-effective when considering quality-adjusted life year gains.

The effect of exercise on behavioural and psychological symptoms of dementia: the EVIDEM-E randomised controlled clinical trial.

OBJECTIVE: The objective of this study is to evaluate the effectiveness of a simple dyadic (person with dementia and their main carer) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia. METHOD: A two arm, pragmatic, randomised, controlled, single-blind, parallel-group trial of a dyadic exercise regimen (individually tailored walking regimen designed to become progressively intensive and last between 20-30 min, at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following: clinically significant behavioural and psychological symptoms, a carer willing and able to co-participate in the exercise regimen, and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study. RESULTS: One hundred and thirty-one dyads were recruited to this study. There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not (adjusted difference in means (intervention minus control) = -1.53, p = 0.6, 95% CI [-7.37, 4.32]). There was a significant between-group difference in caregiver's burden as measured by the Zarit Caregiver Burden Inventory at week 12 (OR = 0.18, p = 0.01, CI [0.05, 0.69]) favouring the exercise group. CONCLUSIONS: This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia, but did seem to attenuate caregiver burden. Further study to improve exercise uptake are needed.

Analysis of neuron-specific enolase and S100B as biomarkers of cognitive decline following surgery in older people.

BACKGROUND/AIMS: Post-operative cognitive decline is frequent in older individuals following major surgery; however, biomarkers of this decline are less clearly defined. METHODS: Sixty-eight participants over the age of 60 provided blood samples at baseline and 24 h post-surgery. Cognitive decline was measured at baseline and 52 weeks post-surgery using the Cambridge Assessment for Mental Disorder in the Elderly, section B (CAMCOG) score. Plasma levels of neuron-specific enolase (NSE) and S100B were measured by ELISA. RESULTS: Baseline NSE and the change in NSE levels between baseline and 24 h were correlated with the change in CAMCOG score between baseline and 52 weeks. CONCLUSION: NSE concentrations may be a useful predictor of individuals at risk of more severe long-term cognitive decline.

High-Velocity Penetrating Abdominal Injury Secondary to a Motorized Wire Brush in the Workplace.

Penetrating injuries are one of the most common types of workplace accidents. The majority of these injury patterns are due to non-missile type, low-velocity sharp objects. We present an uncommon presentation of subacute abdominal pain secondary to non-missile type, high-velocity workplace injury. It is important to keep a wide differential in mind when evaluating patients with lingering abdominal pain without an obvious cause. Additionally, collecting the patient's employment history, occupational exposures, and job tasks are important when a workplace injury is suspected. We present the case of a 59-year-old male with abdominal pain for five weeks. Outpatient CT scan of the abdomen/pelvis demonstrated a metallic foreign body within the abdominal cavity. The patient underwent laparoscopic removal of the intra-abdominal foreign body while utilizing fluoroscopy. He recovered without sequelae and he was free of abdominal pain at six months postoperatively. Overall, it is important to maintain a wide differential when evaluating atypical abdominal pain.

Developing a Dementia Research Registry: a descriptive case study from North Thames DeNDRoN and the EVIDEM programme.

AIM: To describe the development of a dementia research registry, outlining the conceptual, practical and ethical challenges, and to report initial experiences of recruiting people with dementia to it from primary and secondary care. BACKGROUND: Women, the oldest old and ethnic minorities have been under-represented in clinical trials in dementia. Such under-representation biases estimates of absolute effect, absolute harm and cost-effectiveness. Research on dementia should include patient populations that more exactly reflect the population at risk. One of the impediments to this is the lack of a suitable tool for identification of patients suitable for studies. CONSTRUCTION & CONTENTS: A technology development methodology was used to develop a registry of people with dementia and their carers. This involved phases of modelling and prototype creation, 'bench testing' the prototype with experts and then 'field testing' the refined prototype in exemplar sites. The evaluation of the field testing described here is based on a case study methodology. UTILITY: This case study suggests that construction and population of a dementia research registry is feasible, but initial development is complex because of the ethical and organisational difficulties. Recruitment from primary care is particularly costly in terms of staff time and only identifies a very small number of people with dementia who were not already known to specialist services. Recruiting people with dementia through secondary care is a resource intensive process that takes up to six months to complete. Identifying the components of a minimum dataset was easy but its usefulness for pre-screening potential research populations has yet to be established. Acceptance rates are very high in the first clinic to recruit to the registry, but this may reflect the efforts of registry 'champions'. DISCUSSION AND CONCLUSIONS: Easier recruitment may perpetuate potential selection biases and we are not yet able to assess the representativeness of the research-ready population recruited to the registry. The need to recruit from wider populations, through primary and social care, remains. The success of this registry will be measured by the proportion of people from it who are recruited to research projects, and its impact on overall accrual to studies.

The Deleterious Effects of COVID-19 in the Peripartum Period: A Case Report.

While the Coronavirus Disease 2019 (COVID-19) pandemic continues to wreak havoc across the nation and the globe as one of the most significant global health crises of our time, recent attention has been turned to the effects of COVID-19 on pregnancy and the puerperium. Although most cases have been asymptomatic, for some patients, the disease may be accompanied by serious complications such as pneumonia, acute respiratory distress, multi organ failure, and death. Several case studies have noted that patients with co-morbidities are at a significant risk of these complications. In a recent systematic review and meta-analysis, authors conclude that cardiovascular disease was associated with increased composite poor outcome in patients with COVID-19. The following case report highlights the multi-system complications and severity of symptoms that can take place after childbirth in a patient with co-morbid obstetric and prenatal conditions and an initially asymptomatic COVID-19 infection.

Subtle deficits of attention after surgery: quantifying indicators of sub syndrome delirium.

OBJECTIVE: To determine whether attentional impairments are reliable neuropsychological markers of sub syndrome delirium. METHOD: A prospective cohort study with repeated assessment beginning pre-operatively and continuing through the first post-operative week. Computerized assessments of attention and the Mini-Mental State Examination were administered with one hundred patients admitted for elective orthopedic surgery, 70 years and over and free of dementia. Acute change of cognitive status was used to identify cases of sub syndrome delirium. RESULTS: There were significant differences of post-surgical performance between the 'no delirium' and 'sub-syndrome delirium' groups of reaction time, global cognition, accuracy and greater variability of reaction time (p < 0.041). There were significant within subject main effects on reaction time (p = 0.001), variability of reaction time (p = 0.022) and MMSE (p = 0.000) across the cohort; but no significant interaction effect of 'diagnosis' * 'time' on the computerized measures of attention (p > 0.195). CONCLUSION: The distinction between people with sub syndrome delirium and no delirium is difficult to quantify but computerized measures of attention might provide a sensitive indicator. Sub syndrome delirium is an observable marker of a clinical abnormality that should be exploited to improve care management for vulnerable patients.

Continuous Erector Spinae Plane Blocks for Adult Pectus Excavatum Repair.

Use of continuous erector spinae plane (ESP) blocks for pectus excavatum repair may be a valuable alternative to thoracic epidural placement. This report describes the successful use of bilateral ESP blocks in 2 patients with complex medical histories in which thoracic epidural placement was either contraindicated or unsuccessful. The benefits of continuous ESP blocks in this subset of patients include pain control with a focus on opioid sparing, early extubation, decreased atelectasis, improved mobilization and physical therapy, and decreased length of hospital stay.

Protocol for a feasibility randomised controlled trial of a musculoskeletal exercise intervention versus usual care for children with haemophilia.

INTRODUCTION: Haemophilia is a rare, inherited disorder in which blood does not clot normally, resulting in bleeding into joints and muscles. Long-term consequence is disabling joint pain, stiffness, muscle weakness, atrophy and reduced mobility. The purpose of this proposed feasibility of a randomised controlled trial (RCT) is to test the feasibility of an age-appropriate physiotherapy intervention designed to improve muscle strength, posture and the way boys use their joints during walking and everyday activities. METHODS AND ANALYSIS: A small-scale two-centre RCT of a 12-week muscle strengthening exercise intervention versus usual care for young children with haemophilia will be conducted. Primary outcomes will be safety and adherence to the exercise intervention. Secondary outcomes will include recruitment, retention and adverse event rates, clinical data, muscle strength, joint biomechanics and foot loading patterns during walking, 6 min timed walk, timed-up-and-down-stairs, EQ-5D-Y, participants' perceptions of the study, training requirements and relevant costs. Recruitment, follow-up, safety and adherence rates will be described as percentages. Participant diary and interview data will be analysed using a framework analysis. Demographic and disease variable distributions will be analysed for descriptive purposes and covariant analysis. Estimates of differences between treatment arms (adjusted for baseline) and 75% and 95% CIs will be calculated. ETHICS AND DISSEMINATION: The study has ethical approval from the London-Fulham Research Ethics Committee (17/LO/2043) as well as Health Research Authority approval. As well as informing the design of the definitive trial, results of this study will be presented at local, national and international physiotherapy and haemophilia meetings as well as manuscripts submitted to peer-reviewed journals. We will also share the main findings of the study to all participants and the Haemophilia Society.

Quantifying the association between computerised measures of attention and confusion assessment method defined delirium: a prospective study of older orthopaedic surgical patients, free of dementia.

OBJECTIVE: To determine whether attentional impairments are reliable neuropsychological markers of delirium. METHOD: A prospective cohort of one hundred patients admitted for elective orthopaedic surgery, 70 years and over, and free of dementia were recruited from an Orthopaedic unit in a university teaching hospital. Computerized assessments of attention and the Mini Mental State Examination were administered pre and post operatively. The Confusion Assessment Method was used to evaluate signs and symptoms of delirium. RESULTS: Over the first post operative week after surgery people with delirium scored lower on the MMSE (F = 23.53 (1, 53); p = 0.000); and performed less accurately (F = 20.02 (1, 55); p = 0.000), slower (F = 14.58 (1, 54); p = 0.000) and with greater variability of reaction time (F = 31.52 (1, 53); p = 0.000) than people without delirium. The group with delirium's neuropsychological performance was marked by a quadratic trend of accuracy (F = 10.5 (1, 8); p = 0.018) across the first post operative week. Conversely the group without delirium demonstrate quadratic trends for reaction time (F = 6.91 (1, 49); p = 0.011); and linear trends for the variability of reaction time (F = 7.06 (1, 49); p = 0.011) over this period. CONCLUSIONS: To date the absence of any well validated neuropsychological markers of delirium has hindered progress of research of delirium. The data within this study suggest key indices of attention and in particular fluctuating cognition may offer excellent discriminative utility for this clinically important condition.

Making Inference across Mobilisation and Influence Research: Comparing Top-Down and Bottom-Up Mapping of Interest Systems.

Scholars of mobilisation and policy influence employ two quite different approaches to mapping interest group systems. Those interested in research questions on mobilisation typically rely on a bottom-up mapping strategy in order to characterise the total size and composition of interest group communities. Researchers with an interest in policy influence usually rely on a top-down strategy in which the mapping of politically active organisations depends on samples of specific policies. But some scholars also use top-down data gathered for other research questions on mobilisation (and vice versa). However, it is currently unclear how valid such large-N data for different types of research questions are. We illustrate our argument by addressing these questions using unique data sets drawn from the INTEREURO project on lobbying in the European Union and the European Union's Transparency Register. Our findings suggest that top-down and bottom-up mapping strategies lead to profoundly different maps of interest group communities.

Regional Anesthesia in the Setting of Arm Replantation: A Case Report.

The perioperative implementation of continuous peripheral nerve blocks is poorly described within the literature for replantation surgeries beyond digital replantation. The management of replantation patients presents a challenging balance between pain control and limb perfusion. We report the successful use of a continuous interscalene catheter in a therapeutically anticoagulated patient after midshaft humerus arm replantation. The benefits of the continuous peripheral nerve block for the patient included improved pain control and potentially improved limb perfusion making it a valuable component of this patient's treatment.

Effects of preoperative and postoperative resistance exercise interventions on recovery of physical function in patients undergoing abdominal surgery for cancer: a systematic review of randomised controlled trials.

OBJECTIVE: To systematically review the effects of preoperative and postoperative resistance exercise training on the recovery of physical function in patients undergoing abdominal surgery for cancer. DATA SOURCES: A systematic review of English articles using Medline, Physiotherapy Evidence Database, CINAHL and the Cochrane Library electronic databases was undertaken. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they used a randomised, quasi-randomised or controlled trial study design and compared the effects of a muscle-strengthening exercise intervention (±other therapy) with a comparative non-exercise group; involved adult participants (≥18 years) who had elected to undergo abdominal surgery for cancer; and used muscle strength, physical function, self-reported functional ability, range of motion and/or a performance-based test as an outcome measure. RESULTS: Following screening of titles and abstracts of the 588 publications retrieved from the initial search, 24 studies met the inclusion criteria and were accessed for review of the full-text version of the article, and 2 eligible studies met the inclusion criteria and were included in the review. One exercise programme was undertaken preoperatively and the other postoperatively, until discharge from hospital. The exercise interventions of the included studies were performed for five and eight sessions, respectively. There were no differences between groups in either study. CONCLUSION: The only two studies designed to determine whether preoperative or postoperative resistance muscle-strengthening exercise programmes improved or negatively affected physical function outcomes in patients undergoing abdominal surgery for cancer provide inconclusive results.

A novel signature-tagged mutagenesis system for Streptococcus suis serotype 2.

Streptococcus suis is an economically important, zoonotic pathogen causing death and disease in swine. The objectives of this study were to develop a signature-tagged mutagenesis (STM) system for S. suis serotype 2 and to identify genes required for in vivo virulence. Identification of such candidate genes may lead to a better understanding of the pathogenesis of S. suis and may provide substrate for the discovery of new vaccines. A novel STM approach was designed to allow for a higher throughput assay of mutants using the Luminex xMAP system. Additionally, to speed the identification process, a direct genomic DNA sequencing method was developed that overcomes the problems associated with the presence of repetitive insertion sequences. Approximately 2600 mutants were screened through both mouse and caesarian-derived, colostrum-deprived (CDCD) pig models. The disrupted ORF was identified for each potential attenuated mutant, and mutants with distinct and unique mutated ORFs were analyzed individually for attenuation in mouse and CDCD pig models. A variety of genes were identified, including previously known genes essential to the virulence of other organisms, genes involved in capsule biosynthesis, a regulator of suilysin expression, and several conserved or predicted genes. Of the 22 mutants identified as attenuated in either animal model, eight insertion mutants caused no mortality in both mouse and pig models.

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20.

Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. As robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47 blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting. Cancer Immunol Res; 4(12); 1072-87. ©2016 AACR.