Clinician preference instrumental variable analysis of the effectiveness of magnesium supplementation for atrial fibrillation prophylaxis in critical care.

Atrial fibrillation is a frequently encountered condition in critical illness and causes adverse effects including haemodynamic decompensation, stroke and prolonged hospital stay. It is a common practice in critical care to supplement serum magnesium for the purpose of preventing episodes of atrial fibrillation. However, no randomised studies support this practice in the non-cardiac surgery critical care population, and the effectiveness of magnesium supplementation is unclear. We sought to investigate the effectiveness of magnesium supplementation in preventing the onset of atrial fibrillation in a mixed critical care population. We conducted a single centre retrospective observational study of adult critical care patients. We utilised a natural experiment design, using the supplementation preference of the bedside critical care nurse as an instrumental variable. Using routinely collected electronic patient data, magnesium supplementation opportunities were defined and linked to the bedside nurse. Nurse preference for administering magnesium was obtained using multilevel modelling. The results were used to define "liberal" and "restrictive" supplementation groups, which were inputted into an instrumental variable regression to obtain an estimate of the effect of magnesium supplementation. 9114 magnesium supplementation opportunities were analysed, representing 2137 critical care admissions for 1914 patients. There was significant variation in magnesium supplementation practices attributable to the individual nurse, after accounting for covariates. The instrumental variable analysis showed magnesium supplementation was associated with a 3% decreased relative risk of experiencing an atrial fibrillation event (95% CI - 0.06 to - 0.004, p = 0.03). This study supports the strategy of routine supplementation, but further work is required to identify optimal serum magnesium targets for atrial fibrillation prophylaxis.

Embedded point of care randomisation for evaluating comparative effectiveness questions: PROSPECTOR-critical care feasibility study protocol.

INTRODUCTION: Many routinely administered treatments lack evidence as to their effectiveness. When treatments lack evidence, patients receive varying care based on the preferences of clinicians. Standard randomised controlled trials are unsuited to comparisons of different routine treatment strategies, and there remains little economic incentive for change.Integrating clinical trial infrastructure into electronic health record systems offers the potential for routine treatment comparisons at scale, through reduced trial costs. To date, embedded trials have automated data collection, participant identification and eligibility screening, but randomisation and consent remain manual and therefore costly tasks.This study will investigate the feasibility of using computer prompts to allow flexible randomisation at the point of clinical decision making. It will compare the effectiveness of two prompt designs through the lens of a candidate research question-comparing liberal or restrictive magnesium supplementation practices for critical care patients. It will also explore the acceptability of two consent models for conducting comparative effectiveness research. METHODS AND ANALYSIS: We will conduct a single centre, mixed-methods feasibility study, aiming to recruit 50 patients undergoing elective surgery requiring postoperative critical care admission. Participants will be randomised to either 'Nudge' or 'Preference' designs of electronic point-of-care randomisation prompt, and liberal or restrictive magnesium supplementation.We will judge feasibility through a combination of study outcomes. The primary outcome will be the proportion of prompts displayed resulting in successful randomisation events (compliance with the allocated magnesium strategy). Secondary outcomes will evaluate the acceptability of both prompt designs to clinicians and ascertain the acceptability of pre-emptive and opt-out consent models to patients. ETHICS AND DISSEMINATION: This study was approved by Riverside Research Ethics Committee (Ref: 21/LO/0785) and will be published on completion. TRIAL REGISTRATION NUMBER: NCT05149820.

Establishing a colorectal cancer research database from routinely collected health data: the process and potential from a pilot study.

OBJECTIVE: Colorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source. METHODS: Clinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically. RESULTS: Three pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed. DISCUSSION: Algorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer. CONCLUSION: The data set has great potential to facilitate research into colorectal cancer.

Combining faecal immunochemical testing with blood test results for colorectal cancer risk stratification: a consecutive cohort of 16,604 patients presenting to primary care.

BACKGROUND: Faecal immunochemical tests (FITs) are used to triage primary care patients with symptoms that could be caused by colorectal cancer for referral to colonoscopy. The aim of this study was to determine whether combining FIT with routine blood test results could improve the performance of FIT in the primary care setting. METHODS: Results of all consecutive FITs requested by primary care providers between March 2017 and December 2020 were retrieved from the Oxford University Hospitals NHS Foundation Trust. Demographic factors (age, sex), reason for referral, and results of blood tests within 90 days were also retrieved. Patients were followed up for incident colorectal cancer in linked hospital records. The sensitivity, specificity, positive and negative predictive values of FIT alone, FIT paired with blood test results, and several multivariable FIT models, were compared. RESULTS: One hundred thirty-nine colorectal cancers were diagnosed (0.8%). Sensitivity and specificity of FIT alone at a threshold of 10 µg Hb/g were 92.1 and 91.5% respectively. Compared to FIT alone, blood test results did not improve the performance of FIT. Pairing blood test results with FIT increased specificity but decreased sensitivity. Multivariable models including blood tests performed similarly to FIT alone. CONCLUSIONS: FIT is a highly sensitive tool for identifying higher risk individuals presenting to primary care with lower risk symptoms. Combining blood test results with FIT does not appear to lead to better discrimination for colorectal cancer than using FIT alone.

Developing and validating subjective and objective risk-assessment measures for predicting mortality after major surgery: An international prospective cohort study.

BACKGROUND: Preoperative risk prediction is important for guiding clinical decision-making and resource allocation. Clinicians frequently rely solely on their own clinical judgement for risk prediction rather than objective measures. We aimed to compare the accuracy of freely available objective surgical risk tools with subjective clinical assessment in predicting 30-day mortality. METHODS AND FINDINGS: We conducted a prospective observational study in 274 hospitals in the United Kingdom (UK), Australia, and New Zealand. For 1 week in 2017, prospective risk, surgical, and outcome data were collected on all adults aged 18 years and over undergoing surgery requiring at least a 1-night stay in hospital. Recruitment bias was avoided through an ethical waiver to patient consent; a mixture of rural, urban, district, and university hospitals participated. We compared subjective assessment with 3 previously published, open-access objective risk tools for predicting 30-day mortality: the Portsmouth-Physiology and Operative Severity Score for the enUmeration of Mortality (P-POSSUM), Surgical Risk Scale (SRS), and Surgical Outcome Risk Tool (SORT). We then developed a logistic regression model combining subjective assessment and the best objective tool and compared its performance to each constituent method alone. We included 22,631 patients in the study: 52.8% were female, median age was 62 years (interquartile range [IQR] 46 to 73 years), median postoperative length of stay was 3 days (IQR 1 to 6), and inpatient 30-day mortality was 1.4%. Clinicians used subjective assessment alone in 88.7% of cases. All methods overpredicted risk, but visual inspection of plots showed the SORT to have the best calibration. The SORT demonstrated the best discrimination of the objective tools (SORT Area Under Receiver Operating Characteristic curve [AUROC] = 0.90, 95% confidence interval [CI]: 0.88-0.92; P-POSSUM = 0.89, 95% CI 0.88-0.91; SRS = 0.85, 95% CI 0.82-0.87). Subjective assessment demonstrated good discrimination (AUROC = 0.89, 95% CI: 0.86-0.91) that was not different from the SORT (p = 0.309). Combining subjective assessment and the SORT improved discrimination (bootstrap optimism-corrected AUROC = 0.92, 95% CI: 0.90-0.94) and demonstrated continuous Net Reclassification Improvement (NRI = 0.13, 95% CI: 0.06-0.20, p < 0.001) compared with subjective assessment alone. Decision-curve analysis (DCA) confirmed the superiority of the SORT over other previously published models, and the SORT-clinical judgement model again performed best overall. Our study is limited by the low mortality rate, by the lack of blinding in the 'subjective' risk assessments, and because we only compared the performance of clinical risk scores as opposed to other prediction tools such as exercise testing or frailty assessment. CONCLUSIONS: In this study, we observed that the combination of subjective assessment with a parsimonious risk model improved perioperative risk estimation. This may be of value in helping clinicians allocate finite resources such as critical care and to support patient involvement in clinical decision-making.

The complete costs of genome sequencing: a microcosting study in cancer and rare diseases from a single center in the United Kingdom.

PURPOSE: The translation of genome sequencing into routine health care has been slow, partly because of concerns about affordability. The aspirational cost of sequencing a genome is $1000, but there is little evidence to support this estimate. We estimate the cost of using genome sequencing in routine clinical care in patients with cancer or rare diseases. METHODS: We performed a microcosting study of Illumina-based genome sequencing in a UK National Health Service laboratory processing 399 samples/year. Cost data were collected for all steps in the sequencing pathway, including bioinformatics analysis and reporting of results. Sensitivity analysis identified key cost drivers. RESULTS: Genome sequencing costs £6841 per cancer case (comprising matched tumor and germline samples) and £7050 per rare disease case (three samples). The consumables used during sequencing are the most expensive component of testing (68-72% of the total cost). Equipment costs are higher for rare disease cases, whereas consumable and staff costs are slightly higher for cancer cases. CONCLUSION: The cost of genome sequencing is underestimated if only sequencing costs are considered, and likely surpasses $1000/genome in a single laboratory. This aspirational sequencing cost will likely only be achieved if consumable costs are considerably reduced and sequencing is performed at scale.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

SNAP-2 EPICCS: the second Sprint National Anaesthesia Project-EPIdemiology of Critical Care after Surgery: protocol for an international observational cohort study.

INTRODUCTION: The admission of high-risk patients to critical care after surgery is a recommended standard of care. Nevertheless, poor compliance against this recommendation has been repeatedly demonstrated in large epidemiological studies. It is unclear whether this is due to reasons of capacity, equipoise, poor quality clinical care or because hospitals are working creatively to create capacity for augmented care on normal surgical wards. The EPIdemiology of Critical Care after Surgery study aims to address these uncertainties. METHODS AND ANALYSIS: One-week observational cohort study in the UK and Australasia. All patients undergoing inpatient (overnight stay) surgery will be included. All will have prospective data collection on risk factors, surgical procedure and postoperative outcomes including the primary outcome of morbidity (measured using the Postoperative Morbidity Survey on day 7 after surgery) and secondary outcomes including length of stay and mortality. Data will also be collected on critical care referral and admission, surgical cancellations and critical care occupancy. The epidemiology of patient characteristics, processes and outcomes will be described. Inferential techniques (multilevel multivariable regression, propensity score matching and instrumental variable analysis) will be used to evaluate the relationship between critical care admission and postoperative outcome. ETHICS AND DISSEMINATION: The study has received ethical approval from the National Research Ethics Service in the UK and equivalent in Australasia. The collection of patient identifiable data without prior consent has been approved by the Confidentiality Advisory Group (England and Wales) and the Public Privacy and Patient Benefit Panel (Scotland). In these countries, patient identifiable data will be used to link prospectively collected data with national registers of death and inpatient administrative data. The study findings will be disseminated using a multimedia approach with the support of our lay collaborators, to patients, public, policy-makers, clinical and academic audiences.

A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.

This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

Position statement on ethics, equipoise and research on charged particle radiation therapy.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

EADB: an estrogenic activity database for assessing potential endocrine activity.

Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body's endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/BioinformaticsTools/EstrogenicActivityDatabaseEADB/default.htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of chemicals. As a case study, a classification model was developed using EADB for predicting ER binding of chemicals.

A metadata-aware application for remote scoring and exchange of tissue microarray images.

BACKGROUND: The use of tissue microarrays (TMA) and advances in digital scanning microscopy has enabled the collection of thousands of tissue images. There is a need for software tools to annotate, query and share this data amongst researchers in different physical locations. RESULTS: We have developed an open source web-based application for remote scoring of TMA images, which exploits the value of Microsoft Silverlight Deep Zoom to provide a intuitive interface for zooming and panning around digital images. We use and extend existing XML-based standards to ensure that the data collected can be archived and that our system is interoperable with other standards-compliant systems. CONCLUSION: The application has been used for multi-centre scoring of TMA slides composed of tissues from several Phase III breast cancer trials and ten different studies participating in the International Breast Cancer Association Consortium (BCAC). The system has enabled researchers to simultaneously score large collections of TMA and export the standardised data to integrate with pathological and clinical outcome data, thereby facilitating biomarker discovery.

The EDKB: an established knowledge base for endocrine disrupting chemicals.

BACKGROUND: Endocrine disruptors (EDs) and their broad range of potential adverse effects in humans and other animals have been a concern for nearly two decades. Many putative EDs are widely used in commercial products regulated by the Food and Drug Administration (FDA) such as food packaging materials, ingredients of cosmetics, medical and dental devices, and drugs. The Endocrine Disruptor Knowledge Base (EDKB) project was initiated in the mid 1990's by the FDA as a resource for the study of EDs. The EDKB database, a component of the project, contains data across multiple assay types for chemicals across a broad structural diversity. This paper demonstrates the utility of EDKB database, an integral part of the EDKB project, for understanding and prioritizing EDs for testing. RESULTS: The EDKB database currently contains 3,257 records of over 1,800 EDs from different assays including estrogen receptor binding, androgen receptor binding, uterotropic activity, cell proliferation, and reporter gene assays. Information for each compound such as chemical structure, assay type, potency, etc. is organized to enable efficient searching. A user-friendly interface provides rapid navigation, Boolean searches on EDs, and both spreadsheet and graphical displays for viewing results. The search engine implemented in the EDKB database enables searching by one or more of the following fields: chemical structure (including exact search and similarity search), name, molecular formula, CAS registration number, experiment source, molecular weight, etc. The data can be cross-linked to other publicly available and related databases including TOXNET, Cactus, ChemIDplus, ChemACX, Chem Finder, and NCI DTP. CONCLUSION: The EDKB database enables scientists and regulatory reviewers to quickly access ED data from multiple assays for specific or similar compounds. The data have been used to categorize chemicals according to potential risks for endocrine activity, thus providing a basis for prioritizing chemicals for more definitive but expensive testing. The EDKB database is publicly available and can be found online at http://edkb.fda.gov/webstart/edkb/index.html.

In vitro assessment of image-guided otologic surgery: submillimeter accuracy within the region of the temporal bone.

OBJECTIVES: Application of image-guided surgery to otology has been limited by the need for submillimeter accuracy via a fiducial system that is easily usable (noninvasive and nonobstructive). METHODS: A dental bite-block was fitted with a rigid frame with 7 fiducial markers surrounding each external ear. The temporal bones of 3 cadaveric skulls were removed and replaced with surgical targets arranged in a bull's-eye pattern about the centroid of each temporal bone. The surgical targets were identified both within CT scans and in physical space using an infrared optical tracking system. The difference between positions in CT space versus physical space was calculated as target registration error. RESULTS: A total of 234 independent target registration errors were calculated. Mean +/- standard deviation = 0.73 mm +/- 0.25 mm. CONCLUSIONS: These findings show that image-guided otologic surgery with submillimeter accuracy is achievable with a minimally invasive fiducial frame. Significance In vivo validation of the system is ongoing. With such validation, this system may facilitate clinically applicable image-guided otologic surgery. EBM RATING: A.

The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd.

The mechanism by which the high-bone-mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates canonical Wnt signaling was investigated. The mutation was previously shown to reduce DKK1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for DKK-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperone protein for LRP5/6 that is required for transport of the coreceptors to cell surfaces, resulting in fewer LRP5 molecules on the cell surface. Although the reduction in the number of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine DKK1, we think that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine DKK1 to antagonize without affecting the activity of autocrine Wnt.

Submillimetric target-registration error using a novel, non-invasive fiducial system for image-guided otologic surgery.

OBJECTIVE: Otologic surgery is undertaken to treat ailments of the ear, including persistent infections, hearing loss, vertigo, and cancer. Typically performed on otherwise-healthy patients in outpatient facilities, the application of image-guided surgery (IGS) has been limited because accurate (<1 mm), non-invasive fiducial systems for otologic surgery have not been available. We now present such a fiducial system. METHODS: A dental bite-block was fitted with a custom-designed rigid frame with 7 fiducial markers surrounding each external ear. The bones containing the ear (i.e., the temporal bones) of 3 cadaveric skulls were removed and replaced with discs containing 13 surgical targets arranged in a cross-hair pattern about the centroid of each ear. The surgical targets (26/skull) and fiducial markers (14/skull) were identified both within CT scans using a published algorithm and in physical space using an infrared optical tracking system. Fiducial registration error (FRE), fiducial localization error (FLE), and target registration error (TRE) were calculated. RESULTS: For all trials, root mean square FRE = 0.66, FLE = 0.72, and TRE = 0.77 mm. The mean TRE for n = 234 independent targets was 0.73 with a standard deviation of 0.25 mm. CONCLUSIONS: Using a novel, non-invasive fiducial system (the EarMark), submillimetric accuracy was repeatably achieved. This system will facilitate image-guided otologic surgery.