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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Identification of a candidate therapeutic antibody for treatment of canine B-cell lymphoma.

B-cell lymphoma is one of the most frequently observed non-cutaneous neoplasms in dogs. For both human and canine BCL, the standard of care treatment typically involves a combination chemotherapy, e.g. "CHOP" therapy. Treatment for human lymphoma greatly benefited from the addition of anti-CD20 targeted biological therapeutics to these chemotherapy protocols; this type of therapeutic has not been available to the veterinary oncologist. Here, we describe the generation and characterization of a rituximab-like anti-CD20 antibody intended as a candidate treatment for canine B-cell lymphoma. A panel of anti-canine CD20 monoclonal antibodies was generated using a mouse hybridoma approach. Mouse monoclonal antibody 1E4 was selected for construction of a canine chimeric molecule based on its rank ordering in a flow cytometry-based affinity assay. 1E4 binds to approximately the same location in the extracellular domain of CD20 as rituximab, and 1E4-based chimeric antibodies co-stain canine B cells in flow cytometric analysis of canine leukocytes using an anti-canine CD21 antibody. We show that two of the four reported canine IgG subclasses (cIgGB and cIgGC) can bind to canine CD16a, a receptor involved in antibody-dependent cellular cytotoxicity (ADCC). Chimeric monoclonal antibodies were assembled using canine heavy chain constant regions that incorporated the appropriate effector function along with the mouse monoclonal 1E4 anti-canine CD20 variable regions, and expressed in CHO cells. We observed that 1E4-cIgGB and 1E4-cIgGC significantly deplete B-cell levels in healthy beagle dogs. The in vivo half-life of 1E4-cIgGB in a healthy dog was ∼14 days. The antibody 1E4-cIgGB has been selected for further testing and development as an agent for the treatment of canine B-cell lymphoma.

Characterization of an avirulent FCV strain with a broad serum cross-neutralization profile and protection against challenge of a highly virulent vs feline calicivirus.

Highly virulent, systemic strains of Feline calicivirus (vs FCV) have been described in recent years. These vs FCV isolates cause severe edema, cutaneous ulcers, lameness and other upper respiratory and oral clinical signs typically associated with FCV infection in cats. Vs FCV isolates can cause high mortality even in cats vaccinated with currently available commercial vaccines. This study reports identification and characterization of an avirulent FCV strain (FCV 21). This strain offers a broader serum cross-neutralization profile in comparison with the commonly used vaccine strain (FCV F9), as tested with two separate viral panels of FCV isolates. The first viral panel consists of 45 FCV strains isolated around 1993. The second viral panel consists of 26 FCV strains with most isolated around 2003. The potential of using this strain as a vaccine, in a 3-way (FCV+FHV+FPV) or 4-way (FCV+FHV+FPV+FCp) format, was tested by using a highly virulent vs FCV strain (FCV-33585) as a challenge virus. The mortality induced by this vs FCV in unvaccinated control cats was 78% (7 out of 9 cats). The mortality decreased to 44% (4 out of 9 cats) in cats vaccinated with a 4-way vaccine containing FCV F9. However, when this novel FCV vaccine strain (FCV 21) was used, either in combination with FCV F9 or by itself, the mortality decreased to 0% (0 out of 10 cats). The 3-way vaccine (FCV+FHV+FPV) that contained both FCV 21 and FCV F9 also had mortality of 0% (0 out of 10 cats). The clinical scores, as calculated taking into consideration the frequency and severity of various clinical signs, correlated with mortality data. The results suggested this FCV vaccine has the potential to be broadly protective against newly emergent FCV isolates, including complete protection against challenge with a highly virulent vs FCV 33585.

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.

Semantic annotation of mutable data.

Electronic annotation of scientific data is very similar to annotation of documents. Both types of annotation amplify the original object, add related knowledge to it, and dispute or support assertions in it. In each case, annotation is a framework for discourse about the original object, and, in each case, an annotation needs to clearly identify its scope and its own terminology. However, electronic annotation of data differs from annotation of documents: the content of the annotations, including expectations and supporting evidence, is more often shared among members of networks. Any consequent actions taken by the holders of the annotated data could be shared as well. But even those current annotation systems that admit data as their subject often make it difficult or impossible to annotate at fine-enough granularity to use the results in this way for data quality control. We address these kinds of issues by offering simple extensions to an existing annotation ontology and describe how the results support an interest-based distribution of annotations. We are using the result to design and deploy a platform that supports annotation services overlaid on networks of distributed data, with particular application to data quality control. Our initial instance supports a set of natural science collection metadata services. An important application is the support for data quality control and provision of missing data. A previous proof of concept demonstrated such use based on data annotations modeled with XML-Schema.

Functional expression and characterization of the C. elegans G-protein-coupled FLP-2 Receptor (T19F4.1) in mammalian cells and yeast.

Profound neuropeptide diversity characterizes the nematode nervous system, but it has proven challenging to match neuropeptide G protein-coupled receptors (GPCR) with their cognate ligands in heterologous systems. We have expressed the Caenorhabditis elegans GPCR encoded in the locus T19F4.1, previously matched with FMRFamide-like peptides encoded on the flp-2 precursor gene, in mammalian cells and in the yeast Saccharomyces cerevisiae. Pharmacological characterization revealed that the receptor is potently activated by flp-2 peptides in CHO cells (∼10 nM EC50) and in yeast (∼100 nM EC50), signaling through a Gqα pathway in each system. The yeast GPCR expression system provides a robust assay for screening for agonists of the flp-2 receptor and is the target of an ongoing high-throughput screening exercise.

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.