Direct oral anticoagulants or vitamin K antagonists in emergencies: comparison of management in an observational study.

Background: Restoring hemostasis in patients on oral anticoagulants presenting with major hemorrhage (MH) or before surgical intervention has changed, with the replacement of vitamin K antagonist (VKA) with direct oral anticoagulants (DOACs). Objectives: To observe the difference in urgent hemostatic management between patients on VKA and those on DOACs. Methods: A multicenter observational study evaluated the variation in laboratory testing, hemostatic management, mortality, and hospital length of stay (LOS) in patients on VKA or DOACs presenting with MH or urgent hemostatic restoration. Results: Of the 1194 patients analyzed, 783 had MH (61% VKA) and 411 required urgent hemostatic restoration before surgery (56% VKA). Compared to the international normalized ratio (97.6%), plasma DOAC levels were measured less frequently (<45%), and the time taken from admission for the coagulation sample to reach the laboratory varied widely (median, 52.3 minutes; IQR, 24.8-206.7). No significant plasma DOAC level (<50 ng/mL) was found in up to 19% of patients. There was a poor relationship between plasma DOAC level and the usage of a hemostatic agent. When compared with patients receiving VKA (96.5%) or dabigatran (93.7%), fewer patients prescribed a factor Xa inhibitor (75.5%) received a prohemostatic reversal agent. The overall 30-day mortality for MH (mean: 17.8%) and length of stay (LOS) (median: 8.7 days) was similar between VKA and DOAC patients. Conclusion: In DOAC patients, when compared to those receiving VKA, plasma DOAC levels were measured less frequently than the international normalized ratio and had a poor relationship with administering a hemostatic reversal agent. In addition, following MH, mortality and LOS were similar between VKA and DOAC patients.

Modelling lung cancer diagnostic pathways using discrete event simulation.

The United Kingdom has one of the poorest lung cancer survival rates in Europe. In this study, to help design and evaluate a single lung cancer pathway (SCP) for Wales, existing diagnostic pathways and processes have been mapped and then modelled with a discrete event simulation. The validated models have been used to provide key performance indicators and to examine different diagnostic testing strategies. Under the current diagnostic pathways, the mean time to treatment was 72 days for surgery patients, 56 days for chemotherapy patients, and 61 days for radiotherapy patients. Our research demonstrated that by ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 11 days from the current lung cancer pathway resulting in a 21% increase in patients receiving treatment within the Welsh Government set target of 62 days.

Routine CTA screening identifies blunt cerebrovascular injuries missed by clinical risk factors.

Objectives: Current guidelines for screening for blunt cerebrovascular injury (BCVI) are commonly based on the expanded Denver criteria, a set of risk factors that identifies patients who require CT-angiographic (CTA) screening for these injuries. Based on previously published data from our center, we have adopted a more liberal screening guideline than those outlined in the expanded Denver criteria. This entails routine CTA of the neck for all blunt trauma patients already undergoing CT of the cervical spine and/or CTA of the chest. The aim of this study was to analyze the incidence of patients with BCVI who did not meet any of the risk factors included in the expanded Denver criteria. Methods: A retrospective review of all patients diagnosed with BCVI between June 2014 and December 2019 at a Level I Trauma Center were identified from the trauma registry. Medical records were reviewed for the presence or absence of risk factors as outlined in the expanded Denver criteria. Demographic data, time to CTA and treatment, BCVI grade, Glasgow Coma Scale and Injury Severity Score were collected. Results: During the study period, 17 054 blunt trauma patients were evaluated, and 29% (4923) underwent CTA of the neck to screen for BCVI. 191 BCVIs were identified in 160 patients (0.94% of all blunt trauma patients, 3.25% of patients screened with CTA). 16% (25 of 160) of patients with BCVI had none of the risk factors outlined in the Denver criteria. Conclusion: Our findings indicate that reliance on the expanded Denver criteria alone for BCVI screening will result in missed injuries. We recommend CTA screening in all patients with blunt trauma undergoing CT of the cervical spine and/or CTA of the chest to minimize this risk. Level of evidence: Level III, therapeutic/care management.

The changing use of anticoagulants in New Zealand.

AIMS: To assess the change in the use of oral anticoagulants in New Zealand over 10 years since the introduction of dabigatran and rivaroxaban. METHODS: Data were collected from the National Pharmaceutical database from January 2011 to March 2021. Seven and a half million prescriptions for oral anticoagulants were analysed. RESULTS: The total number of people taking oral anticoagulants increased from 46,000 in July 2011 to 105,000 by March 2021. The growth was predominantly from the increased use of direct oral anticoagulants (DOACs). Initially, dabigatran was the only funded DOAC in New Zealand; approximately 50,000 people were taking this medication by August 2018, when rivaroxaban was introduced. Subsequent growth has predominantly been from rivaroxaban, with 23,000 users by March 2021. Warfarin use has dropped by 50% over the last 10 years. CONCLUSIONS: The introduction of the DOACs was expected to reduce the use of warfarin. However, the rapid rise in DOAC use was not predicted. The increase is most likely in patients with atrial fibrillation with the positive benefit of reducing the incidence of embolic stroke. However, having a high proportion of the elderly population (15% of people over 75-years) on anticoagulants has implications for the health sector, making hospital admissions and surgery more complex.

Constructing operating theatre schedules using partitioned graph colouring techniques.

In hospitals, scheduled operations can often be cancelled in large numbers due to the unavailability of beds for post-operation recovery. Operating theatre scheduling is known to be an N P -hard optimisation problem. Previous studies have shown that the correct scheduling of surgical procedures can have a positive impact on the availability of beds in hospital wards, thereby allowing a reduction in number of elective operation cancellations. This study proposes an exact technique based on the partitioned graph colouring problem for constructing optimal master surgery schedules, with the goal of minimising the number of cancellations. The resultant schedules are then simulated in order to measure how well they cope with the stochastic nature of patient arrivals. Our results show that the utilisation of post-operative beds can be increased, whilst the number of cancellations can be decreased, which may ultimately lead to greater patient throughput and reduced waiting times. A scenario-based model has also been employed to integrate the stochastic-nature associated with the bed requirements into the optimisation process. The results indicate that the proposed model can lead to more robust solutions.

Factors influencing the delivery of cancer pathways: a summary of the literature.

PURPOSE: The study aims to summarise the literature on cancer care pathways at the diagnostic and treatment phases. The objectives are to find factors influencing the delivery of cancer care pathways; to highlight any interrelating factors; to find gaps in the literature concerning areas of research; to summarise the strategies and recommendations implemented in the studies. DESIGN/METHODOLOGY/APPROACH: The study used a qualitative approach and developed a causal loop diagram to summarise the current literature on cancer care pathways, from screening and diagnosis to treatment. A total of 46 papers was finally included in the analysis, which highlights the recurring themes in the literature. FINDINGS: The study highlights the myriad areas of research applied to cancer care pathways. Factors influencing the delivery of cancer care pathways were classified into different albeit interrelated themes. These include access barriers to care, hospital emergency admissions, fast track diagnostics, delay in diagnosis, waiting time to treatment and strategies to increase system efficiency. ORIGINALITY/VALUE: As far as the authors know, this is the first study to present a visual representation of the complex relationship between factors influencing the delivery of cancer care pathways.

Examining the diagnostic pathway for lung cancer patients in Wales using discrete event simulation.

BACKGROUND: UK's National Health Service (NHS) has one of the poorest lung cancer survival rates in Europe. To improve patient outcomes, a single cancer pathway was introduced in the NHS. In this study, a Discrete Event Simulation was developed to understand bottlenecks during lung cancer treatment. METHODS: This study focused on the lung cancer diagnostic pathways at two Welsh hospitals. Discrete Event Simulation is a computer-based method that has been effectively used in demand and capacity planning. In this study, simulation models were developed for the current and proposed single cancer pathways. The validated models were used to provide Key Performance Indicators. Several "what-if" scenarios were considered for the current and proposed pathways. RESULTS: Under the current diagnostic pathway, the mean time to treatment for a surgery patient was 68 days at the Royal Glamorgan Hospital and 79 days at Prince Charles Hospital. For chemotherapy patients, the mean time to treatment was 52 days at the Royal Glamorgan Hospital and 57 days at Prince Charles Hospital. For radiotherapy patients, the mean time to treatment was 44 days at Royal Glamorgan Hospital and 54 days at Prince Charles Hospital. Ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 20 days from the current lung cancer pathway resulting in a 20-25% increase of patients receiving treatment within 62 days. Ensuring that patients begin their treatment within 21 days of diagnosis sees almost all patients comply with the 62-day target. CONCLUSIONS: Discrete Event Simulation coupled with a detailed statistical analysis provides a useful decision support tool which can be used to examine the current and proposed lung cancer pathways in terms of time spent on the pathway.

Resource optimization for cancer pathways with aggregate diagnostic demand: a perishable inventory approach.

This work proposes a novel framework for planning the capacity of diagnostic tests in cancer pathways that considers the aggregate demand of referrals from multiple cancer specialties (sites). The framework includes an analytic tool that recursively assesses the overall daily demand for each diagnostic test and considers general distributions for both the incoming cancer referrals and the number of required specific tests for any given patient. By disaggregating the problem with respect to each diagnostic test, we are able to model the system as a perishable inventory problem that can be solved by means of generalized G/D/C queuing models, where the capacity [Formula: see text] is allowed to vary and can be seen as a random variable that is adjusted according to prescribed performance measures. The approach aims to provide public health and cancer services with recommendations to align capacity and demand for cancer diagnostic tests effectively and efficiently. Our case study illustrates the applicability of our methods on lung cancer referrals from UK's National Health Service.

Modified Needleman-Wunsch algorithm for clinical pathway clustering.

Clinical pathways are used to guide clinicians to provide a standardised delivery of care. Because of their standardisation, the aim of clinical pathways is to reduce variation in both care process and patient outcomes. When learning clinical pathways from data through data mining, it is common practice to represent each patient pathway as a string corresponding to their movements through activities. Clustering techniques are popular methods for pathway mining, and therefore this paper focuses on distance metrics applied to string data for k-medoids clustering. The two main aims are to firstly, develop a technique that seamlessly integrates expert information with data and secondly, to develop a string distance metric for the purpose of process data. The overall goal was to allow for more meaningful clustering results to be found by adding context into the string similarity calculation. Eight common distance metrics and their applicability are discussed. These distance metrics prove to give an arbitrary distance, without consideration for context, and each produce different results. As a result, this paper describes the development of a new distance metric, the modified Needleman-Wunsch algorithm, that allows for expert interaction with the calculation by assigning groupings and rankings to activities, which provide context to the strings. This algorithm has been developed in partnership with UK's National Health Service (NHS) with the focus on a lung cancer pathway, however the handling of the data and algorithm allows for application to any disease type. This method is contained within Sim.Pro.Flow, a publicly available decision support tool.

Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

Exposure Reconstruction and Risk Analysis for Six Semiconductor Workers With Lymphohematopoietic Cancers.

OBJECTIVE: To investigate whether workplace exposures to recognized lymphohematopoietic carcinogens were possibly related to cancers in six semiconductor-manufacturing workers. METHODS: A job-exposure matrix was developed for chemical and physical process agents and anticipated by-products. Potential cumulative occupational exposures of the six cases were reconstructed. The role of workplace exposures in cancer was evaluated through quantitative risk assessment and by comparison with epidemiological literature. RESULTS: Two workers were potentially exposed to agents capable of causing their diagnosed cancers. Reconstructed exposures were similar to levels in outdoor environments and lower than exposures associated with increased risks in epidemiological studies. Cancer risks were estimated to be less than 1 in 10,000 persons. CONCLUSIONS: The development of cancer among the six workers was unlikely to be explained by occupational exposures to recognized lymphohematopoietic carcinogens.

An update of consensus guidelines for warfarin reversal.

• Despite the associated bleeding risk, warfarin is the most commonly prescribed anticoagulant in Australia and New Zealand. Warfarin use will likely continue for anticoagulation indications for which novel agents have not been evaluated and among patients who are already stabilised on it or have severe renal impairment. • Strategies to manage over-warfarinisation and warfarin during invasive procedures can reduce the risk of haemorrhage. • For most warfarin indications, the target international normalised ratio (INR) is 2.0-3.0 (venous thromboembolism and single mechanical heart valve excluding mitral). For mechanical mitral valve or combined mitral and aortic valves, the target INR is 2.5-3.5. • Risk factors for bleeding with warfarin use include increasing age, history of bleeding and specific comorbidities. • For patients with elevated INR (4.5-10.0), no bleeding and no high risk of bleeding, withholding warfarin with careful subsequent monitoring seems safe. • Vitamin K1 can be given to reverse the anticoagulant effect of warfarin. When oral vitamin K1 is used for this purpose, the injectable formulation, which can be given orally or intravenously, is preferred. • For immediate reversal, prothrombin complex concentrates (PCC) are preferred over fresh frozen plasma (FFP). Prothrombinex-VF is the only PCC routinely used for warfarin reversal in Australia and New Zealand. It contains factors II, IX, X and low levels of factor VII. FFP is not routinely needed in combination with Prothrombinex-VF. FFP can be used when Prothrombinex-VF is unavailable. Vitamin K1 is essential for sustaining the reversal achieved by PCC or FFP. • Surgery can be conducted with minimal increased risk of bleeding if INR ≤ 1.5. For minor procedures where bleeding risk is low, warfarin may not need to be interrupted. If necessary, warfarin can be withheld for 5 days before surgery, or intravenous vitamin K1 can be given the night before surgery. Prothrombinex-VF use for warfarin reversal should be restricted to emergency settings. Perioperative management of anticoagulant therapy requires an evaluation of the risk of thrombosis if warfarin is temporarily stopped, relative to the risk of bleeding if it is continued or modified.

Tumour doubling times and the length bias in breast cancer screening programmes.

Screening for early detection of breast cancer is considered to be an important element of preventive medicine. In this paper, we use numerical simulations to examine the length bias in regular interval screening programmes, by computing the doubling times of breast cancer tumours detected through regular mammographies compared to self-detection. Our analysis shows that doubling times of tumours detected by a regular screening programme are longer than doubling times in the original whole population and considerably longer than those self-detected. Hence regular interval mammographies may be missing a high proportion of fast growing tumours and therefore the benefits of current screening programmes may need to be re-evaluated. We examine the likely size of the length bias for the present UK breast cancer screening programme and perform a sensitivity analysis by varying the screen detection probabilities to reflect future advances in mammographic detection.

Trends in NHS primary dental care for older people in England: implications for the future.

OBJECTIVE: To examine trends over time in the National Health Service (NHS) dental service provision for older people in England and consider the implications for future care. BACKGROUND: The number and proportion of older people in the population nationally are increasing and their oral health needs are changing as more people retain teeth into older age. MATERIALS AND METHODS: Descriptive analysis of routinely collected activity data for primary dental care in England was undertaken over the 6-year period, 1999/2000-2004/05. Data were cleaned, grouped into age bands for analysis. Activity rates per head of population were calculated for key aspects of care. Population forecasts and national survey data were used to inform future predictions of care required. RESULTS: There was an increase in absolute terms of total items (14.4%) and items per capita (10.7%) between 1999/2000 and 2004/05, with a peak of 15.7 million items claimed in 2003/04. Over the 6-year period, increases per capita were seen for dental examinations (11.3%), periodontal treatments (8.9%), fillings (1.9%), crowns (14.3%) and extractions (4.9%) amongst older people as a group. In contrast, there was a marked decrease in the episodes of care involving domiciliary care (-46.4%) and upper complete dentures (-32.9%) per capita over this period, items that were most commonly provided for the oldest age-band (85 years and over). Apart from complete dentures, the demand for care is predicted to increase. CONCLUSION: The volume of primary dental care provided for older people has been increasing at a rate which exceeds population growth, but remains low. Planners and commissioners should urgently review the provision of dental care of older people to ensure that their oral health needs are being met particularly in relation to dentures and domiciliary care.

Posttreatment ultrasound-detected residual venous thrombosis: a risk factor for recurrent venous thromboembolism and mortality.

PURPOSE OF REVIEW: The cumulative risk of recurrent venous thrombosis may rise to 30% over 8 years. Extended oral anticoagulation is effective but major bleeding is increased. To balance these risks attention has focused on identifying patients with the highest likelihood of recurrence for whom continued therapy is most beneficial. Another issue of interest has been the increased probability of death after venous thrombosis, due primarily to malignancy but also to vascular disease. RECENT FINDINGS: Unprovoked events and cancer are known to be associated with recurrent thrombosis. Residual posttreatment thrombosis confirmed by compression ultrasound is regarded as another risk for recurrence. Confounders in the published studies are the patient mix and the ultrasound technique employed. Other variables such as gender and D-dimer may also predict risk. Although arterial disease is increased in patients with venous thromboses, the association between idiopathic venous thromboembolism and atherosclerosis remains circumstantial. SUMMARY: There are no validated approaches for predicting recurrent venous events. Ultrasound interrogation for residual thrombosis after primary therapy may improve treatment stratification by defining patients suitable for extended anticoagulation.

Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis.

For most warfarin indications, the target maintenance international normalised ratio (INR) is 2-3. Risk factors for bleeding complications with warfarin use include age, history of past bleeding and specific comorbid conditions. To reverse the effects of warfarin, vitamin K(1) can be given. Immediate reversal is achieved with a prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP). Vitamin K(1) is essential for sustaining the reversal achieved by PCC and FFP. When oral vitamin K(1) is used for warfarin reversal, the injectable formulation of vitamin K(1) is preferable to tablets because of its flexible dosing; this formulation can be given orally or injected. To temporarily reverse the effect of warfarin when there is a need to continue warfarin therapy, vitamin K(1) should be given in a dose that will quickly lower the INR to a safe, but not subtherapeutic, range and will not cause resistance once warfarin is reinstated. Prothrombinex-HT is the only PCC approved in Australia and New Zealand for warfarin reversal. It contains factors II, IX and X, and low levels of factor VII. FFP should be added to Prothrombinex-HT as a source of factor VII when used for warfarin reversal. Simple dental or dermatological procedures may not require interruption to warfarin therapy. If necessary, warfarin therapy can be withheld 5 days before elective surgery, when the INR usually falls to below 1.5 and surgery can be conducted safely. Bridging anticoagulation therapy for patients at high risk for thromboembolism should be undertaken in consultation with the relevant experts.

Long-term planning to meet UK government coronary heart disease revascularization targets.

The National Service Framework (NSF) for Coronary Heart Disease, published in the UK in 2000, gave target intervention rates of 750 procedures per million population (pmp) for both percutaneous transluminal angioplasty (PTCA) and coronary artery bypass graft (CABG). This paper describes how one Regional Office of the Department of Health, with CABG and PTCA rates of around half the NSF target levels, designed a strategy to plan rationally to meet the derived population need for these procedures. A bottom-up needs assessment model was used to predict the population need for these procedures for the Eastern Region of the UK. The Excel-based model took account of the effects of demographic change, anticipated reduction in incidence of heart disease due to primary prevention programmes and the expected improvement in cardiology and cardiac surgery technologies. The model predicted that excess procedures would be required across the region over the next 20 years. Further access study modelling was used to determine the best location for additional tertiary cardiac centres. Further, a commissioning tool was produced that could compare the predicted need, including additional procedures needed to meet waiting list targets, with capacity available from a range of providers. These tools have been used successfully in the Eastern Region to increase the regional revascularization rates from 371 pmp CABG and 322 pmp PTCA in 2000 to planned rates of 453 pmp CABG and 447 pmp PTCA in 2002/2003, to recommend the building of a new tertiary cardiac centre in Essex in the next decade and to inform the commissioning of revascularization rates in three coronary heart disease networks.

'Slide whistle' breath sounds: acoustical correlates of variable tracheal obstruction.

We report a case of a man who developed severe shortness of breath and the finding of breath sounds that rose in frequency during inspiration and fell during expiration. These unusual sounds were caused by a spherical tumour arising from the main carina that nearly completely obstructed the distal trachea. The frequency variation disappeared after the removal of the mass. We evaluated this phenomenon using a modelling technique that we had previously developed to analyse the human airways as acoustical tubes. This analysis revealed that the acoustical conditions in the trachea were substantially modified by the presence of the solid mass as the trachea slightly dilated during inspiration, partially relieving the obstruction. Most of the anomalous characteristics of the breath sounds could be explained using this model. We conclude that a detailed understanding of the acoustic conditions of the airways allows correlation with anatomical and physiological conditions and may be of use in diagnosis or evaluation of the airways in health and disease.