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This paper aims to explore the intersubjective relationship between the whipper (paki) and the parrier (ta’ang) in caci, a traditional dance from Manggarai, East Nusa Tenggara Province. For that purpose, this study applied the phenomenological method. In this method, caci is described based on what actually transpires during the performance when the researchers made direct observations. As a native Manggarai, the researcher has watched the dance for many years. Data from the phenomenological study were analyzed using Armada Riyanto’s philosophical concept of intersubjective relationality. This study found that the relationship between the whipper and the parrier in caci is not a subject-object but intersubjective one. The intersubjectivity of the whipper-parrier relationship is demonstrated by several facts. First, there is subjective identity of the whipper and parrier in the form of their names. Second, there is affirmation of identity and its confirmation during the dance. Third, the act of whipping and parrying does not involve a large group of people, but only the whipper and parrier as individual actors. Fourth, the whipper and parrier are aware of the other party’s presence and role. Fifth, the whipper is aware of the presence and role of the parrier and vice versa. Sixth, the whipper and parrier are encountering each other with mutual respect. The intersubjective element of the whipper-parrier relationship is highly relevant to the promotion of elegant intercultural dialogues in Indonesia.

Objective To determine the balance of costs, risks, and benefits for different thromboprophylaxis strategies for medical patients during hospital admission.Design Decision analysis modelling study.Setting NHS hospitals in England.Population Eligible adult medical inpatients, excluding patients in critical care and pregnant women.Interventions Pharmacological thromboprophylaxis (low molecular weight heparin) for all medical inpatients, thromboprophylaxis for none, and thromboprophylaxis given to higher risk inpatients according to risk assessment models (Padua, Caprini, IMPROVE, Intermountain, Kucher, Geneva, and Rothberg) previously validated in medical cohorts.Main outcome measures Lifetime costs and quality adjusted life years (QALYs). Costs were assessed from the perspective of the NHS and Personal Social Services in England. Other outcomes assessed were incidence and treatment of venous thromboembolism, major bleeds including intracranial haemorrhage, chronic thromboembolic complications, and overall survival.Results Offering thromboprophylaxis to all medical inpatients had a high probability (>99%) of being the most cost effective strategy (at a threshold of £20 000 (€23 440; $25 270) per QALY) in the probabilistic sensitivity analysis, when applying performance data from the Padua risk assessment model, which was typical of that observed across several risk assessment models in a medical inpatient cohort. Thromboprophylaxis for all medical inpatients was estimated to result in 0.0552 additional QALYs (95% credible interval 0.0209 to 0.1111) while generating cost savings of £28.44 (−£47 to £105) compared with thromboprophylaxis for none. No other risk assessment model was more cost effective than thromboprophylaxis for all medical inpatients when assessed in deterministic analysis. Risk based thromboprophylaxis was found to have a high (76.6%) probability of being the most cost effective strategy only when assuming a risk assessment model with very high sensitivity is available (sensitivity 99.9% and specificity 23.7% v base case sensitivity 49.3% and specificity 73.0%).Conclusions Offering pharmacological thromboprophylaxis to all eligible medical inpatients appears to be the most cost effective strategy. To be cost effective, any risk assessment model would need to have a very high sensitivity resulting in widespread thromboprophylaxis in all patients except those at the very lowest risk, who could potentially avoid prophylactic anticoagulation during their hospital stay.

Background Pharmacological prophylaxis during hospital admission can reduce the risk of acquired blood clots (venous thromboembolism) but may cause complications, such as bleeding. Using a risk assessment model to predict the risk of blood clots could facilitate selection of patients for prophylaxis and optimise the balance of benefits, risks and costs. Objectives We aimed to identify validated risk assessment models and estimate their prognostic accuracy, evaluate the cost-effectiveness of different strategies for selecting hospitalised patients for prophylaxis, assess the feasibility of using efficient research methods and estimate key parameters for future research. Design We undertook a systematic review, decision-analytic modelling and observational cohort study conducted in accordance with Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines. Setting NHS hospitals, with primary data collection at four sites. Participants Medical and surgical hospital inpatients, excluding paediatric, critical care and pregnancy-related admissions. Interventions Prophylaxis for all patients, none and according to selected risk assessment models. Main outcome measures Model accuracy for predicting blood clots, lifetime costs and quality-adjusted life-years associated with alternative strategies, accuracy of efficient methods for identifying key outcomes and proportion of inpatients recommended prophylaxis using different models. Results We identified 24 validated risk assessment models, but low-quality heterogeneous data suggested weak accuracy for prediction of blood clots and generally high risk of bias in all studies. Decision-analytic modelling showed that pharmacological prophylaxis for all eligible is generally more cost-effective than model-based strategies for both medical and surgical inpatients, when valuing a quality-adjusted life-year at £20,000. The findings were more sensitive to uncertainties in the surgical population; strategies using risk assessment models were more cost-effective if the model was assumed to have a very high sensitivity, or the long-term risks of post-thrombotic complications were lower. Efficient methods using routine data did not accurately identify blood clots or bleeding events and several pre-specified feasibility criteria were not met. Theoretical prophylaxis rates across an inpatient cohort based on existing risk assessment models ranged from 13% to 91%. Limitations Existing studies may underestimate the accuracy of risk assessment models, leading to underestimation of their cost-effectiveness. The cost-effectiveness findings do not apply to patients with an increased risk of bleeding. Mechanical thromboprophylaxis options were excluded from the modelling. Primary data collection was predominately retrospective, risking case ascertainment bias. Conclusions Thromboprophylaxis for all patients appears to be generally more cost-effective than using a risk assessment model, in hospitalised patients at low risk of bleeding. To be cost-effective, any risk assessment model would need to be highly sensitive. Current evidence on risk assessment models is at high risk of bias and our findings should be interpreted in this context. We were unable to demonstrate the feasibility of using efficient methods to accurately detect relevant outcomes for future research. Future work Further research should evaluate routine prophylaxis strategies for all eligible hospitalised patients. Models that could accurately identify individuals at very low risk of blood clots (who could discontinue prophylaxis) warrant further evaluation. Study registration This study is registered as PROSPERO CRD42020165778 and Researchregistry5216. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and will be published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information. Plain language summary People who are admitted to hospital are at risk of blood clots that can cause serious illness or death. Patients are often given low doses of blood-thinning drugs to reduce this risk. However, these drugs can cause side effects, such as bleeding. Hospitals currently use complex risk assessment models (risk scores, which usually include patient, disease, mobility and intervention factors) to determine the individual risk of blood clots and identify people most likely to benefit from blood-thinning drugs. There are a lot of different risk scores and we do not know which one is best. We also do not know how these scores compare to each other or whether using scores to decide who should get blood-thinning drugs provides good value for money to the NHS. We reviewed all previous studies of risk scores. We found that they did not predict blood clots very well and we could not recommend one score over another. We then created a mathematical model to simulate the use of blood-thinning drugs in people admitted to hospital. The model suggested that giving blood-thinning drugs to everyone who could have them would probably provide the best value for money, in medical patients. Our findings were the same, but less certain, for surgical patients. We also collected information from four NHS hospitals to explore possibilities for future research. Our work showed that routinely collected electronic data on blood clots and bleeding events is not very accurate and that using different scores could result in variable use of blood-thinning medications. Our findings suggest that it may be better value to the NHS and better for patients if we were to offer blood-thinning medications to everyone on admission to hospital, without using any risk score. However, this approach needs further research to ensure it is safe and effective. Such research would not be able to rely on routine electronic data to identify blood clots or bleeding events, in isolation. Scientific summary Background Venous thromboembolism (VTE) is a composite diagnosis including deep-vein thrombosis (DVT) and pulmonary embolism (PE). The condition is a global health burden, affecting over 1:1000 adults worldwide, every year. Previous epidemiological studies have shown more than half of all VTE events to be hospital-associated (or acquired) thrombosis (HAT), occurring during admission or within 90 days of discharge. Current evidence suggests that many HAT events are potentially preventable. Pharmacological prophylaxis in medical and surgical inpatients has been shown to be clinically effective in several large studies and meta-analyses. However, although prophylaxis reduces the risk of VTE for hospital inpatients, it also incurs costs and potentially increases the risk of bleeding. As such, international guidelines recommend a process of individualised VTE risk assessment at the point of hospital admission. Several risk assessment models (RAMs) have been developed to aid this process. The accuracy and cost-effectiveness of these models are uncertain. Further prospective studies in this area are challenging due to national guidance, contract standards and high rates of routine prescribing (> 70%). We sought to assess the clinical and cost-effectiveness of VTE RAMs through secondary research methods, by conducting a systematic review of RAM accuracy and subsequent decision-analytic modelling. In addition, we sought to evaluate the accuracy of routine data sources to identify core VTE and bleeding outcomes and estimate key clinical parameters for any future implementation study. Objectives The prespecified and combined project objectives were as follows: Update existing systematic reviews to identify VTE RAMs for hospital inpatients and determine their comparative accuracy for predicting the risk of VTE. Undertake decision-analytic modelling to determine the cost-effectiveness of pharmacological prophylaxis guided by a RAM, compared to prophylaxis for all and prophylaxis for none. Use the decision-analytic model to identify key areas of uncertainty and determine the value of gathering additional information to reduce uncertainty. Pilot the use and evaluate the accuracy of efficient methods to measure core clinical VTE and bleeding outcomes. Estimate key parameters for planning a future implementation study. Methods Workstream 1 used a systematic review and economic analysis to address objectives 1, 2 and 3. We extended and updated overlapping systematic reviews of available RAMs, performed quality assessment of relevant studies and synthesised performance measures (e.g. sensitivity, specificity and concordance (C) statistics) to evaluate the prognostic accuracy of individual RAMs. We subsequently used this information to inform decision-analytic modelling. The target population for the conceptual model was hospital inpatients, including medical, surgical and trauma patients but excluding critical care patients, children and women admitted to hospital for pregnancy-related reasons. Patients at increased risk of bleeding were assumed not to receive pharmacological prophylaxis under any strategy and were excluded from the model. We compared strategies of using no pharmacological prophylaxis, pharmacological prophylaxis for all and pharmacological prophylaxis given in accordance with validated RAMs. The use of mechanical prophylaxis was considered out of scope for the modelling. We used a lifetime horizon and reported primary outcomes of costs and quality-adjusted life-years (QALYs). Multiple scenario and sensitivity analyses were conducted by subgroup. Workstream two used primary research to address objectives four and five. We conducted a multicentre observational cohort study across four hospitals to compare prespecified methods of efficient data collection to formal case note review. We identified a target population hospitalised during 2019 and extracted data from prospectively completed VTE risk assessments, when available. Research assistants undertook further retrospective case note review for each patient episode. We used electronic health records to evaluate additional risk characteristics and record all relevant clinical outcomes, including the subsequent diagnosis of HAT, major bleeding and clinically relevant non-major bleeding events. We then collated multiple routine data sources for each patient episode to determine the accuracy of these methods in identifying relevant clinical outcomes, compared to a gold standard of case note review. The primary outcome measures for workstream two were contingency tables with sensitivity, specificity and predictive values. Feasibility criteria for any future study using efficient data methods were set a priori. We also estimated the potential variation in prescribing recommendations using multiple validated RAMs and estimated key parameters for any future implementation study. The Venous ThromboEmbolism Assessment Methods study received a favourable opinion from the Proportionate Review Sub-committee of the London – West London & Gene Therapy Advisory Committee (GTAC) Research Ethics Committee and approval from the Health Research Authority (HRA) and Care Research Wales (HCRW) on 18 September 2019 (reference 19/LO/1303, IRAS project ID 262220). Results Workstream 1 Our updated systematic review included 51 studies, comprising 24 unique validated RAMs. The vast majority of studies evaluated VTE RAMs in medical (n = 21), surgical (n = 15) or mixed (n = 4) cohorts of hospital inpatients. The most widely evaluated models were the Caprini RAM (22 studies), the Padua prediction score (16 studies), the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) models (8 studies), the Geneva Risk Score (4 studies) and the Kucher Score (4 studies). All studies had a high or unclear risk of bias, with the main issues related to patient selection, outcome and analysis factors. C-statistics varied markedly between these studies and between models, with no RAM performing obviously better than other models. Similarly, estimates for sensitivity and specificity were highly variable. In the decision analytic modelling, we estimate that in medical inpatients, prophylaxis reduces serious adverse outcomes [fatal PEs, fatal bleeding and non-fatal intracranial haemorrhage (ICH)] from 53 per 10,000 to 42 per 10,000, with a reduction in symptomatic DVTs and non-fatal PEs that is higher than the increase in other bleeds. In the long-term outcomes at 5 years, there is a large reduction in the number of patients experiencing post-thrombotic syndrome (PTS) following prophylaxis from 787 per 10,000 to 385 per 10,000, but minimal difference in overall survival. Modelling showed that thromboprophylaxis for all has a high probability (> 99%) of being the most cost-effective strategy (£20,000 per QALY threshold) based on the performance of existing RAMs in cohorts of medical inpatients. This finding was generally robust under the scenario and sensitivity analyses with one exception; targeting thromboprophylaxis using a Padua score ≥ 3 (84% of cohort) had a 76.6% probability of being the most cost-effective strategy when assuming higher RAM performance (sensitivity 99.9%; specificity 23.7%). The overall expected value of perfect information (EVPI) associated with all parameters included in the probabilistic sensitivity analysis (PSA) when valuing a QALY at £20,000 was £0.06 per patient per year due to the high probability that prophylaxis for all is the optimal strategy. However, the EVPI would be £2.42 per person per year if a more accurate RAM could be developed for medical inpatients. In surgical inpatients, the risk of a serious adverse outcome (as above) is low at 7 per 10,000 but it is increased slightly by prophylaxis to 11 per 10,000 due to the additional risk of fatal bleeding or non-fatal ICH. Although the risk of any symptomatic VTE is reduced form 140 per 10,000 to 41 per 10,000, the risk of any major bleeding is increased from 125 per 10,000 to 370 per 10,000. Prophylaxis still reduces the risk of PTS in surgical inpatients, from 367 per 10,000 to 107 per 10,000, but PTS is less common in the surgical cohort than in the medical cohort. Modelling showed that giving prophylaxis to all surgical inpatients has the highest probability of being cost-effective at £20,000 per QALY, with a 70% likelihood of being optimal, but there is also a 17% likelihood that using a Pannucci score of ≥ 3 would be optimal and a 9% likelihood that using a Pannucci score of ≥ 1 would be optimal. These findings were sensitive to some uncertainties explored in the scenario and sensitivity analyses. In particular, prophylaxis for all may no longer be the optimal strategy for surgical inpatients when the risk of PTS is lower, when using an extended duration of prophylaxis or where a RAM is assumed to have a very high sensitivity. The overall EVPI associated with all parameters included in the PSA when valuing a QALY at £20,000 was £16.35 per person. This does not include the uncertainty of considering which RAM to use as the EVPI and does not include any uncertainty not captured in the PSA, such as uncertainty around the model assumptions or the choice of data sources, or uncertainty around the estimates of sensitivity and specificity. In the analysis of parameter EVPI [expected value of partial perfect information (EVPPI)], the relative risk of VTE for patients having thromboprophylaxis compared to patients not having thromboprophylaxis was the parameter with the largest EVPPI. In specific surgical populations requiring longer durations of prophylaxis, we found that pharmacological prophylaxis for all eligible patients remained optimal in those having elective knee replacement. Offering prophylaxis at a Pannucci score of ≥ 3 (sensitivity of 84% and specificity of 49%) was optimal when prescribing 28 days of low-molecular-weight heparin (LMWH) to patients having elective hip replacement. These conclusions were sensitive to prophylaxis strategy; using direct oral anticoagulants (DOACs) rather than LMWH resulted in prophylaxis for all as the optimal strategy for both hip and knee patients. Workstream 2 The observational cohort study was conducted across all four sites, enrolling 2115 patient hospitalisation episodes, with 2008 eligible for analysis. Medical and surgical cases were evenly balanced, but with more emergency (73.7%) than elective (25.8%) admissions. The sensitivity of routine coding data for detection of HAT and major bleeding events was 62% [95% confidence interval (CI) 54 to 69] and 38% (95% CI 27 to 50), respectively. Local VTE data sets performed better, with sensitivity of 81% (95% CI 75 to 87). The specificity of routine coding data for VTE and bleeding was 98% (95% CI 97 to 99) and 95% (95% CI 94 to 96), respectively, and the specificity of local VTE data sets was 100% (95% CI 99 to 100). We were unable to demonstrate overall feasibility of using efficient outcome measures and did not meet several prespecified criteria. In a smaller subgroup of patients with prospectively collected data, we evaluated potential variation in pharmacological prophylaxis using different RAMs. We identified 543 hospital episodes with VTE risk assessment performed during 2019, with 254 episodes suitable for inclusion, data extraction and comparative analysis. Overall recommendations for pharmacological prophylaxis varied substantially between seven RAMs, ranging from 13% of admitted patients for the IMPROVE associative score (95% CI 9.4 to 17.7) to 91% (95% CI 86.3 to 93.6) for the Department of Health (now Department of Health and Social Care) VTE risk assessment tool. The latter tool resulted in an absolute increase of 28% for prophylaxis recommendation, compared to other RAMs. Within this multicentre cohort of hospitalised inpatients, the HAT event rate was 1.6% (95% CI 1.0 to 2.2) and the major bleeding event rate was 2.5% (95% CI 1.8 to 3.2). Conclusions We updated prior systematic reviews to conclude that that the available evidence has significant methodological limitations and demonstrates current RAMs to have weak predictive accuracy. Decision-analytic modelling showed that the balance of VTE or major bleeding risks, combined with the RAM performance in medical cohorts, means that thromboprophylaxis for all is the optimal strategy within our model for medical inpatients. These findings were robust to multiple scenarios and sensitivity analyses. The optimal strategy for surgical inpatients is to offer thromboprophylaxis to all. However, the scenario analyses for surgical inpatients found that the optimal strategy was sensitive to many of the individual model inputs and assumptions tested. In addition, the optimal strategy for surgical patients receiving extended duration thromboprophylaxis appeared dependent on duration of therapy and prophylaxis strategy. The findings from our cohort study suggest that efficient methods for identifying VTE or major bleeding events during hospital admission or within 90 days of discharge, are not sufficiently sensitive for use in a large data-enabled study. We did not reach several predefined feasibility metrics. We also found limitations in the ability of efficient methods to identify individual risk variables and facilitate RAM comparison in future work. The majority of our sites did not collect contemporaneous data on risk assessment in a digital, or easily accessible format. Implications for policy-makers If, despite drug costs and potential harms, pharmacological prophylaxis for all is the most cost-effective strategy, use of unvalidated RAMs may be suboptimal. Based on our findings, it may be preferable for policy-makers to consider evaluating a new paradigm of ‘opt-out’ VTE prevention, in which all eligible patients are routinely offered pharmacological prophylaxis on hospital admission without complex risk assessment. In this circumstance, patients who are ineligible for pharmacological prophylaxis due to high bleeding risk, specific contraindications or personal choice could opt out, but still utilise evidence-based mechanical thromboprophylaxis strategies. The findings from our cohort study have implications for funders looking to support further work in this area. These data suggest large studies entirely reliant on routine data collection methods for complex time-dependent outcome measures (such as HAT or major bleeding) are likely to be inaccurate. Recommendations for future research Further research should evaluate the following themes in this area of clinical care: Evaluation of routine pharmacological prophylaxis for all eligible medical and surgical patients on hospital admission, compared to current practice of risk assessment using a RAM. Such work would need to be conducted at scale and could not rely on efficient methods for outcome measurement in isolation. Development and validation of RAMs to identify individuals receiving prophylaxis at very low risk of blood clots, who could therefore potentially discontinue pharmacological prophylaxis early during hospital stay. Our analysis was inevitably limited in scope and did not examine the use of RAMs to identify accurate prediction of bleeding risk, the use of mechanical prophylaxis in medical patients with increased bleeding risk (or contraindications to pharmacological prophylaxis) or patients at risk of thromboprophylaxis failure. These issues could be priorities for future research. Study registration This study is registered as Research Registry 5216, PROSPERO CRD42020165778. Funding This award was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and is published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information.

Background Pharmacological prophylaxis to prevent venous thromboembolism is currently recommended for women assessed as being at high risk of venous thromboembolism during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide thromboprophylaxis involves weighing the benefits, harms and costs, which vary according to the individual’s venous thromboembolism risk. It is unclear whether the United Kingdom’s current risk stratification approach could be improved by further research. Objectives To quantify the current decision uncertainty associated with selecting women who are pregnant or in the puerperium for thromboprophylaxis and to estimate the value of one or more potential future studies that would reduce that uncertainty, while being feasible and acceptable to patients and clinicians. Methods A decision-analytic model was developed which was informed by a systematic review of risk assessment models to predict venous thromboembolism in women who are pregnant or in the puerperium. Expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty and should be the target of future research. To find out whether future studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood-thinning drugs and surveyed healthcare professionals. Expected value of sample information analysis was used to estimate the value of potential future research studies. Results The systematic review included 17 studies, comprising 19 unique externally validated risk assessment models and 1 internally validated model. Estimates of sensitivity and specificity were highly variable ranging from 0% to 100% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns. The decision analysis found that there is substantial decision uncertainty regarding the use of risk assessment models to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was uncertainty around the effectiveness of thromboprophylaxis for preventing venous thromboembolism in women who are pregnant or in the puerperium. We found that a randomised controlled trial of thromboprophylaxis in obese postpartum women is likely to have substantial value and is more likely to be acceptable and feasible than a trial recruiting women who have had a previous venous thromboembolism. In unselected postpartum women and women following caesarean section, the poor performance of risk assessment models meant that offering prophylaxis based on these models had less favourable cost effectiveness with lower decision uncertainty. Limitations The performance of the risk assessment model for obese postpartum women has not been externally validated. Conclusions Future research should focus on estimating the efficacy of pharmacological thromboprophylaxis in pregnancy and the puerperium, and clinical trials would be more acceptable in women who have not had a previous venous thromboembolism. Study registration This study is registered as PROSPERO CRD42020221094. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary Women who are pregnant or who have given birth in the previous 6 weeks are at increased risk of developing blood clots that can cause serious illness or death. Small doses of blood thinners given by injection are safe in pregnancy and can reduce the risk of blood clots, but they can slightly increase the risk of bleeding. Healthcare professionals use risk assessment tools to decide if a woman is at high risk of blood clots and should be offered blood thinners. We wanted to find out what research would be useful to help them make better decisions. We reviewed previous research to establish which risk assessment tools are best at predicting who will have a blood clot. We then created a mathematical model to predict what would happen when using different risk assessment tools to decide who should be offered blood thinners, both during pregnancy and after giving birth. We found that there was a lot of uncertainty about which women should be offered blood thinners. This was mainly because there have only been a few small studies comparing blood thinners to no treatment in pregnant women or women who have recently given birth. We estimated the value of future studies comparing blood thinners to no treatment, in groups of women with different risk factors, by predicting what information we would gain and how this would be used to improve decisions about using blood thinners. To find out whether these studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood thinners and surveyed healthcare professionals. We found that a study in obese women who have recently given birth would have substantial value and may be more acceptable than a study in pregnant women with a previous blood clot. Scientific summary Background Pharmacological prophylaxis to prevent venous thromboembolism (VTE) is currently recommended for women who are deemed to be at high risk of VTE during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide prophylaxis involves weighing the benefits, harms and costs, which will vary according to the individual’s VTE risk. It is unclear whether the current risk stratification approach could be improved by further research. Aims and objectives The aim of this research was to determine whether further primary research is worthwhile to inform NHS practice on the use of risk assessment models (RAMs) for the prediction of VTE and appropriate provision of thromboprophylaxis for women in pregnancy and in the puerperium. The specific objectives were: to estimate the expected costs and health benefits of providing thromboprophylaxis using current and alternative RAMs and quantify decision uncertainty to determine which factors are the most important drivers of uncertainty when trying to determine the optimal risk-based thromboprophylaxis strategy to identify one or more potential future studies that would reduce the current decision uncertainty, while being feasible and acceptable to patients and clinicians to evaluate the value of future research studies in terms of the net health benefits to patients and the cost of the research. Methods To identify all relevant RAMs and their predictive performance, we undertook a systematic review in accordance with the preferred reporting items for systematic review and meta-analysis (PRISMA) statement. Systematic searches were performed across five electronic databases, including MEDLINE, EMBASE and the Cochrane Library, from inception to February 2021. We included all primary validation studies that examined the comparative accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium. Two or more reviewers independently undertook study selection, data extraction and risk of bias assessments using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). We used narrative synthesis to summarise the findings. A decision-analytic model was used to estimate lifetime expected costs and quality-adjusted life-years (QALYs) under alternative thromboprophylaxis strategies. The decision-analytic modelling focused on the following subgroups for which data were available on the performance of RAMs: high-risk antepartum women (e.g. prior VTE or known thrombophilia) unselected postpartum women obese postpartum women postpartum women following caesarean section. In the analysis for high-risk antepartum women, the strategies compared were: antepartum and postpartum prophylaxis for all (from booking to 6 weeks postpartum) antepartum prophylaxis according to a RAM followed by 6 weeks postpartum prophylaxis for all six weeks postpartum prophylaxis for all no prophylaxis. In the analyses for postpartum women, the strategies compared were: postpartum prophylaxis for all (10 days) postpartum prophylaxis according to a RAM (10 days) no prophylaxis. In all cases, the thromboprophylaxis agent was assumed to be low-molecular-weight heparin (LMWH). In high-risk antepartum women, the RAMs compared were the Lyon RAM and the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIG) RAM. For the unselected postpartum population, the RAMs compared were Royal College of Obstetricians and Gynaecologists (RCOG), Swedish Society of Obstetrics and Gynecology (SFOG), Caprini and the novel Sultan RAM. In the subgroup of obese postpartum women, the only RAM included was the novel Ellis-Kahana RAM. In the subgroup of postpartum women following caesarean section, the RAMs compared were RCOG and the novel Binstock RAM. We also conducted an analysis assuming that a RAM was available for the post-caesarean section population with performance similar to the Sultan RAM in the unselected postpartum population. The model takes a United Kingdom (UK) NHS and Personal Social Services perspective with future costs and QALYs discounted at 3.5% per annum. Costs are reported in Great British pounds based on 2020 prices. Short-term outcomes are captured in a decision-tree phase and long-term outcomes in a lifetime state-transition model. The decision tree is used to estimate for each strategy: the number of women receiving thromboprophylaxis; the impact of thromboprophylaxis on VTE outcomes (fatal and non-fatal pulmonary embolisms and deep-vein thromboses); and the incidence of major bleeds during either thromboprophylaxis or VTE treatment with anticoagulants and wound haematoma. Major bleeds are separated into fatal bleeds, non-fatal intracerebral haemorrhages (ICH) and other major bleeds. Symptomatic VTEs are assumed to result in 3 months of anticoagulant treatment which should be continued until at least 6 weeks post delivery. Outcomes captured in the long-term model include post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension. These are in addition to the long-term model capturing the QALY losses from fatalities and ongoing morbidity from ICH. For women being assessed for postpartum prophylaxis, a single decision tree captures the short-term outcomes. For women being assessed for antepartum prophylaxis, the decision-tree phase of the model is repeated to capture the antepartum and postpartum periods separately. Those patients who have experienced a symptomatic VTE or a non-fatal ICH in the antepartum model are assumed to remain in the same health state in the postpartum phase; all other patients remain at risk of VTE and progress to the postpartum decision tree. All model parameters were based on published literature or clinical opinion where published evidence was lacking. Sources specific to the target population were identified for the following parameters: data related to population characteristics [age, body mass index (BMI) and life expectancy]; absolute risks of VTE, bleeding and PTS; costs of prophylaxis and VTE treatment. There is a paucity of data on the efficacy of thromboprophylaxis during pregnancy and in the puerperium. Based on the clinical expert’s understanding of the mechanism of action of prophylaxis, their personal experience and the prothrombotic physiologic changes during pregnancy, it was decided that the relative risk (RR) for VTE should be based on a single small pilot trial in antepartum women with prior VTE, while the RR for bleeding should be extrapolated from studies in medical inpatients. Other data were generally based on sources used in a published cost-effectiveness analysis of thromboprophylaxis in hospitalised patients (who are not pregnant or in the puerperium), with costs updated to reflect changes in prices. Parameter uncertainty was incorporated using probabilistic sensitivity analysis and structural uncertainty was explored using deterministic scenario analysis. Expected value of perfect information (EVPI) analysis was used to identify the key drivers of decision uncertainty that could be reduced by future studies. We held workshops with women with a prior VTE or who had been offered thromboprophylaxis during pregnancy, and undertook a survey of healthcare professionals, to understand whether potential future trials would be acceptable to the individuals who would be invited to take part. Expected value of sample information (EVSI) analysis was then used to estimate the value of these potential future research studies. Results Our systematic review of RAMs included 17 studies, comprising 19 unique externally validated RAMs and 1 internally validated model (Ellis-Kahana). Estimates of sensitivity were highly variable ranging from 0% to 100% for RAMs that were applied to antepartum women and 0% to 100% for RAMs applied to postpartum women. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns, mainly due to limitations in participant selection and statistical analysis. In the decision analysis for high-risk antepartum women, using the EThIG RAM to select patients for antepartum prophylaxis had a 42% probability of having an incremental cost-effectiveness ratio (ICER) under £30,000 per QALY compared to a strategy of offering only postpartum prophylaxis. This led to considerable decision uncertainty, with an overall EVPI of £1454 per patient for high-risk antepartum women, equivalent to £21.8 million over 5 years of births. A high proportion of this (94%) was related to uncertainty in the effectiveness of LWMH to reduce VTE risk compared to no prophylaxis. The EVSI analysis found that a randomised controlled trial (RCT) of 30 patients per arm comparing LMWH with no prophylaxis would have a value of £13.1 million over 5 years of births, rising to £19.7 million for a RCT of 500 patients per arm. Small trials such as these would have substantial value compared to the typical cost of trials in these populations (£1.1–2.0 million), assuming decision-makers are willing to use the estimates of efficacy obtained, to make better informed decisions about prophylaxis in this population, without requiring them to meet a formal hypothesis test. In the decision analysis for unselected postpartum women, the poor performance of the available RAMs (including RCOG, SFOG and Sultan), combined with the relatively low absolute risk of VTE, meant that a strategy of offering no prophylaxis had an 89% probability of being optimal, when valuing a QALY at £30,000. This was reflected in an EVPI of £0.68 per person; £2.0 million over 5 years of births. No EVSI was conducted for this population due to the low EVPI estimates. In the decision analysis for obese postpartum women, there was substantial decision uncertainty, with the Ellis-Kahana RAM having a 64% probability of being the optimal strategy when valuing a QALY at £30,000, despite the fact that on average it had lower QALYs and higher costs than a strategy of offering no prophylaxis. The overall EVPI was £22.35 per patient, or £13.4 million across 5 years of births, with a high proportion (99%) being related to the RR of VTE. The EVSI analysis found that a RCT of LMWH versus no prophylaxis in obese postpartum women would have a value of £2.8 million, over 5 years of births, if it enrolled 300 patients per arm, rising to £11.6 million if enrolling 10,000 patients per arm. In the decision analysis for postpartum women following caesarean section, neither of the RAMs that had been specifically validated in women following caesarean section (RCOG and Binstock) performed sufficiently well to have an ICER under £30,000 per QALY compared to a strategy of offering no prophylaxis. Offering no prophylaxis had the highest probability of being the optimal strategy (when valuing a QALY at £30,000) even when assuming that a RAM could be identified for the post-caesarean section group which performed similarly to the Sultan RAM in the unselected cohort. In this scenario, the EVPI was £7.74 per patient, equivalent to £5.6 million over 5 years of births and 68% of the overall EVPI was related to the RR of VTE. In the post-caesarean section group, a RCT of 5000 patients per arm would be needed to generate an EVSI of £2.2 million over 5 years of births, when assuming that a RAM is available which performs similarly to the Sultan RAM. The only RAM validated in an unselected antepartum population had poor performance; therefore, analysis in this group was limited to an exploratory analysis which suggested that for a RAM to be cost-effective for use in an unselected antepartum population, it would need to have high specificity (90–95% for a sensitivity of 100–53%). Exploratory analyses were also conducted for women with three antepartum risk factors. This found that offering antepartum prophylaxis from 28 weeks to women with three antepartum risk factors (excluding prior VTE) as per current RCOG guidance is unlikely to have an ICER under £30,000 per QALY. However, a formal analysis of EVPI could not be conducted as the absolute risk in this group is not well quantified. The workshops indicated that a study randomising women to LMWH or placebo would be less acceptable to women who have had a prior VTE or thrombophilia than for other groups of women. Surveyed healthcare professionals reported lower clinical equipoise for women with prior VTE, thrombophilia or BMI > 40 kg/m2. The survey also suggests that healthcare professionals have greater clinical equipoise for a study determining the effectiveness of thromboprophylaxis in antepartum women with three clinical risk factors (other than prior VTE or thrombophilia) who are currently eligible for prophylaxis from 28 weeks. The survey results also suggest that in postpartum women there is greater clinical equipoise in women whose risk factors are an elective caesarean section combined with either age over 35 years or obesity, and women whose only clinical risk factors are age and a BMI between 30 and 40 kg/m2. Workshop participants reported receiving limited information about VTE or risks and benefits of thromboprophylaxis during pregnancy and the puerperium and those without prior VTE often did not understand why they had received treatment. However, women with experience of a prior VTE felt that it would not be ethical to randomise women to placebo given the perceived risk of VTE and the perceived effectiveness of LMWH in this group. Although the workshop participants generally favoured cluster randomisation over individual randomisation, clinicians felt individual randomisation was more acceptable. Conclusions The benefits of thromboprophylaxis clearly outweigh the risks in those with the highest risk of VTE, such as women with a prior VTE, but the balance of benefits and harms is less clear in lower-risk groups. There is substantial decision uncertainty regarding the use of RAMs to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was related to the RR reduction of thromboprophylaxis for preventing VTE due to a lack of RCTs in pregnancy and the puerperium. This uncertainty is reflected in the widely variant strategies and guidelines for use of thromboprophylaxis in obstetric populations in different countries, notably the USA and UK. The expected benefits of conducting further trials to reduce this uncertainty are highly relative to typical research costs, but in the UK, clinical trials are more likely to be acceptable and feasible in the group of women who have not had a previous VTE. In unselected postpartum women and women following caesarean section, the poor performance of available RAMs (including RCOG) meant that RAM-based prophylaxis strategies had less favourable cost-effectiveness with lower decision uncertainty. Recommendations for future research Future research should focus on estimating the efficacy of thromboprophylaxis in preventing VTE in pregnancy and the puerperium. Clinical trials comparing LMWH with no prophylaxis would be more acceptable to both healthcare professionals and the public, in women who have not had a previous VTE, but who have other risk factors, such as obesity. Study registration This study is registered as PROSPERO CRD42020221094. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information.

ObjectivesTo assess whether different cervical spine immobilisation strategies (full immobilisation, movement minimisation or no immobilisation), impact neurological and/or other outcomes for patients with suspected cervical spinal injury in the pre-hospital and emergency department setting.DesignSystematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Data sourcesMEDLINE, EMBASE, CINAHL, Cochrane Library and two research registers were searched until September 2023.Eligibility criteriaAll comparative studies (prospective or retrospective) that examined the potential benefits and/or harms of immobilisation practices during pre-hospital and emergency care of patients with a potential cervical spine injury (pre-imaging) following blunt trauma.Data extraction and synthesisTwo authors independently selected and extracted data. Risk of bias was appraised using the Cochrane ROBINS-I tool for non-randomised studies. Data were synthesised without meta-analysis.ResultsSix observational studies met the inclusion criteria. The methodological quality was variable, with most studies having serious or critical risk of bias. The effect of cervical spine immobilisation practices such as full immobilisation or movement minimisation during pre-hospital and emergency care did not show clear evidence of benefit for the prevention of neurological deterioration, spinal injuries and death compared with no immobilisation. However, increased pain, discomfort and anatomical complications were associated with collar application during immobilisation.ConclusionsDespite the limited evidence, weak designs and limited generalisability, the available data suggest that pre-hospital cervical spine immobilisation (full immobilisation or movement minimisation) was of uncertain value due to the lack of demonstrable benefit and may lead to potential complications and adverse outcomes. High-quality randomised comparative studies are required to address this important question.Trial registrationPROSPERO REGISTRATION Fiona Lecky, Abdullah Pandor, Munira Essat, Anthea Sutton, Carl Marincowitz, Gordon Fuller, Stuart Reid, Jason Smith. A systematic review of cervical spine immobilisation following blunt trauma in pre-hospital and emergency care. PROSPERO 2022 CRD42022349600 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022349600.

ObjectivesTo evaluate the diagnostic accuracy of the aortic dissection detection risk score (ADD-RS) used alone or in combination with D-dimer for detecting acute aortic syndrome (AAS) in patients presenting with symptoms suggestive of AAS.MethodsWe searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic accuracy studies that assessed the use of ADD-RS alone or with D-Dimer for diagnosing AAS compared with a reference standard test (e.g. computer tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two reviewers independently selected and extracted data. Risk of bias was appraised using QUADAS-2 tool. Data were synthesised using hierarchical meta-analysis models.ResultsWe selected 13 studies from the 2017 citations identified, including six studies evaluating combinations of ADD-RS alongside D-dimer>500ng/L. Summary sensitivities and specificities (95% credible interval) were: ADD-RS>0 94.6% (90%, 97.5%) and 34.7% (20.7%, 51.2%), ADD-RS>1 43.4% (31.2%, 57.1%) and 89.3% (80.4%, 94.8%); ADD RS>0 or D-Dimer>500ng/L 99.8% (98.7%, 100%) and 21.8% (12.1%, 32.6%); ADD RS>1 or D-Dimer>500ng/L 98.3% (94.9%, 99.5%) and 51.4% (38.7%, 64.1%); ADD RS>1 or ADD RS = 1 with D-dimer>500ng/L 93.1% (87.1%, 96.3%) and 67.1% (54.4%, 77.7%).ConclusionsCombinations of ADD-RS and D-dimer can be used to select patients with suspected AAS for imaging with a range of trade-offs between sensitivity (93.1% to 99.8%) and specificity (21.8% to 67.1%).

Background Severe acute respiratory syndrome coronavirus 2 is the virus that causes coronavirus disease 2019. Over six million deaths worldwide have been associated with coronavirus disease 2019. Objective To assess the cost-effectiveness of treatments used for the treatment of coronavirus disease 2019 in hospital or used in the community in patients with coronavirus disease 2019 at high risk of hospitalisation. Setting Treatments provided in United Kingdom hospital and community settings. Methods Clinical effectiveness estimates were taken from the coronavirus disease-network meta-analyses initiative and the metaEvidence initiative. A mathematical model was constructed to explore how the interventions impacted on patient health, measured in quality-adjusted life-years gained. The costs associated with treatment, including those of hospital care, were also estimated and used to form a cost per quality-adjusted life-year gained value which was compared with thresholds published by the National Institute for Health and Care Excellence. Estimates of cost-effectiveness compared against current standard of care were produced in both the hospital and community settings at three different levels of efficacy: mean, low and high. Public list prices were used for interventions with neither confidential patient access schemes nor confidential list prices considered. Results incorporating confidential pricing data were provided to the National Institute for Health and Care Excellence appraisal committee. Results The treatments were estimated to be clinically effective although not all reached statistical significance. All treatments in the hospital setting, or community, were estimated to plausibly have a cost per quality-adjusted life-year gained value below National Institute for Health and Care Excellence’s thresholds when compared with standard of care. However, almost all drugs could plausibly have cost per quality-adjusted life-years above National Institute for Health and Care Excellence’s thresholds. However, there is considerable uncertainty in the results as the prevalent severe acute respiratory syndrome coronavirus 2 variant, vaccination status, history of being infected with severe acute respiratory syndrome coronavirus 2 and standard of care have all evolved since the pivotal studies were conducted which could have significant impact on the efficacy of each drug. For drugs used in high-risk patients in the community setting, the proportion of people at high risk who need hospital admission was a large driver of the cost per quality-adjusted life-year. Limitations No studies were identified that were conducted in current conditions. This may be a large limitation as the severe acute respiratory syndrome coronavirus 2 variant changes. No head-to-head studies of interventions were identified. Conclusions The results produced could be informative to decision-makers, although conclusions regarding the most clinical – and cost-effectiveness of each intervention should be tentative due to the evolving nature of the decision problem and, in this report, the use of list prices only. Comparisons between interventions should also be treated with caution due to potentially large heterogeneity between studies. Future work Research assessing the relative clinical effectiveness of interventions within head-to-head studies in current conditions would be beneficial. Contemporary information related to the probability of hospital admission and death for patients at high risk in the community would improve the precision of the estimates generated. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information. Plain language summary Coronavirus disease 2019 is an infectious disease that can cause death and long-term ill-health. Treatments exist that can be provided in hospital to reduce the number of deaths from coronavirus disease 2019. Treatments also exist which can be provided in the community for people at high risk of needing to be admitted to hospital to reduce the number of admissions and to reduce the number of deaths from coronavirus disease 2019. However, the value for money of these treatments has not been estimated. We took the clinical effectiveness of nine treatments from published literature sources and built a model that estimated the value for money of six treatments compared with care without these treatments. Three treatments were excluded due to confidential prices. The results of the model showed that many treatments in a hospital setting had estimates of cost-effectiveness that would normally be seen to be good value for money using the thresholds published by the National Institute of Health and Care Excellence. The same was true for some treatments in a community setting. However, it is also possible that these treatments are not good value for money. The benefit of the drugs and value for money is highly uncertain as studies trying to estimate the gain have been done with (1) previous variants of the virus causing coronavirus disease 2019 being widespread, (2) where the proportion of people who have had vaccinations or who had previously had coronavirus disease 2019 is low and (3) where standard treatment was that when coronavirus disease 2019 was first identified, and not the drugs used now. Because of these differences, and the unknown price of some interventions, we cannot confidently say which (if any) treatments help patients the most, or which treatment represents the best value for money. Further research, in current conditions, would improve the accuracy of our answers. Scientific summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). At the time of writing (January 2023) there had been over 620 million confirmed cases and over six-and-a-half million deaths worldwide associated with COVID-19. For the UK, these values are more than 24 million cases and nearly 200,000 deaths. In addition to the widespread vaccination programme, treatments exist that can help people who have been hospitalised due to COVID-19 (casirivimab and imdevimab (henceforth casirivimab/imdevimab), tocilizumab, remdesivir, baricitinib, and baricitinib with remdesivir) or be used in patients who have COVID-19 and are at high risk of needing hospitalisation [casirivimab/imdevimab, molnupiravir, nirmatrelvir and ritonavir (henceforth nirmatrelvir/ritonavir), remdesivir, sotrovimab, and tixagevimab and cilgavimab (henceforth tixagevimab/cilgavimab)]. For reasons related to urgency, these treatments, unlike interventions in other disease areas, have not received positive guidance from the National Institute of Health and Care Excellence (NICE) before being routinely used. As the pandemic subsides there is more need for a formal evaluation of the clinical and cost-effectiveness of these treatments. Objectives The objective of this study is to summarise the current knowledge related to the clinical efficacy of the interventions and to conduct an economic evaluation that estimates the cost-effectiveness of each intervention against standard of care (SoC), as of January 2023. A full incremental analysis is performed while noting the caveats in the comparison of all interventions simultaneously. Methods Given the timescale of the project, where there were ˂ 3 months between the publication of the final scope and the deadline of a report for NICE and the consultation process, a literature review following best practice was not possible. Instead, a pragmatic, alternative approach was undertaken where evidence was taken from two living systematic reviews (supported by the COVID-network meta-analyses (NMA) initiative and the metaEvidence initiative) in line with current best practice guidelines. For interventions related to use in hospitals, data were extracted on time to death, clinical improvement and time to discharge. For interventions that are used in the community for patients at high risk of hospitalisation, data were extracted on the risks of hospitalisation or death, and the risks of death. These measures of efficacy were assumed generalisable to January 2023 despite changes in background conditions which include the SoC, the percentage of people who have been vaccinated and a change in the dominant SARS-CoV-2 variant. This is noted as a very large limitation as drugs that have looked effective in previous variants have not worked as well in later variants and sensitivity analysis on the efficacy of the interventions has been conducted. A mathematical model was constructed that used the data from the living systematic reviews to simulate the experiences of patients in hospital, and requirement for supplemental oxygen, until discharge or death in hospital. Due to the (conditional) marketing authorisations of the interventions, the model was developed such that results could be produced for the supplemental oxygen group and the non-supplemental oxygen group separately. The model structure used an eight-point ordinal scale that was used in clinical trials to categorise patients during their admissions. Outputs from this model included the costs associated with interventions and care, and the quality-adjusted life-years (QALYs) gained by the patient both within the hospital episode and after discharge, incorporating decrements in health-related quality of life associated with the lasting impact of COVID-19. For interventions used in the hospital, these values allowed a cost per QALY gained to be calculated for each treatment compared with SoC, and for completeness, a full incremental analysis to be conducted although the External Assessment Group (EAG) cautions against comparisons between treatments due to the heterogenous conditions when pivotal studies were undertaken. The costs of each intervention were taken from public sources where available. However, baricitinib, sotrovimab and tocilizumab have confidential patient access schemes agreed, which discount the price of the intervention, and are not considered in this document, but were provided to the NICE Appraisal Committee in a separate confidential appendix. The price of three treatments (casirivimab/imdevimab, molnupiravir and tixagevimab/cilgavimab) were not publicly available at the time of writing and the cost-effectiveness results for these three drugs are contained in a confidential appendix. For patients at high risk of hospitalisation treated in the community, a decision tree was put before the hospital model, which simulated the reduced need for hospitalisation associated with early treatment. The total costs and QALYs associated with treatment options were estimated to allow an evaluation of the cost per QALY of each treatment against SoC and for completeness, a full incremental analysis to be undertaken, noting the same caveat as for interventions used in hospital when comparing treatments. The modelling did not assess the logistical aspects of treatment in the community, but the EAG notes that this could be a large factor in deciding which treatments could be preferred, as oral treatments could be more acceptable to patients and healthcare systems than treatments that are given intravenously or subcutaneously. The costs of providing treatment within the community were provided by National Health Service (NHS) England. Three scenarios were run changing the efficacy of interventions. The ‘mean efficacy’ estimate used the mean of each distribution extracted from the living systematic reviews, the ‘high efficacy’ estimate used the most favourable limits of the 95% confidence intervals (CIs) and the ‘low efficacy’ estimate used the least favourable limits of the 95% CIs. The EAG has acknowledged a limitation that the CI is influenced by the number of observed events and the sample size, such that two identical treatments could have markedly different confident intervals purely due to the size of the pivotal study. Seven scenario analyses were performed, explored the impact of changing: (1) the duration of long COVID (ranging from half to double that of the base case); (2) changing the rate of hospital admission in the community with people being at ‘high risk’ of hospitalisation from a value of 2.79% to 1.00%, 5.00% and 10.00%; (3) changing the average age of patients at high risk of hospitalisation in the community from 55 years to 50 and 60 years; (4) using a hazard ratio (HR) of unity for all interventions in relation to time to hospital discharge and time to clinical improvement; (5) changing the baseline distribution of supplemental oxygen requirements from that associated with SoC (19% no supplemental oxygen, 55% high-flow oxygen, 16% non-invasive ventilation and 10% invasive ventilation) to an arbitrarily less severe baseline distribution (25% no supplemental oxygen, 60% high-flow oxygen, 10% non-invasive ventilation and 5% invasive ventilation) for patients who have received an intervention in the community; (6) assuming a utility decrement of 0.02 per day for patients receiving intravenous (i.v.) treatment in the community; and (7) changing the standardised mortality ratio for people during the period of long COVID from 7.7 to 5.0 and 10.0. Two scenario analyses were conducted that explored the use of different efficacy measures based on the Solidarity study for remdesivir and the ‘Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19’ (TACKLE) study for tixagevimab/cilgavimab. Results were presented in terms of incremental cost-effectiveness ratios (ICERs) measured in cost per QALYs gained and also using incremental net monetary benefit (NMB). An advantage of NMB is that interventions can be compared using different assumptions on efficacy for different interventions, and interventions can be omitted without the need to recalculate efficiency frontiers. Results Due to changes between the conditions when the pivotal studies were undertaken and the current conditions in terms of the SoC, the percentage of people who have been vaccinated and a change in the dominant SARS-CoV-2 variant all results should be treated with caution. Caution should also be applied when comparing between interventions. The results also do not incorporate confidential price discounts for baricitinib, sotrovimab and tocilizumab, nor were any cost-effectiveness results presented for casirivimab/imdevimab, molnupiravir and tixagevimab/cilgavimab which had confidential list prices. These analyses were seen by the NICE appraisal committee in a confidential appendix. All treatments used for hospitalised patients, had a median HR for death below one, indicating a benefit, although all CIs crossed unity apart from those for baricitinib, casirivimab/imdevimab and tocilizumab. The overlapping CIs and heterogeneous studies meant that no firm conclusions could be made regarding the relative efficacy of these treatments. There was less data relating to the relative risks (RRs) of clinical improvement at 28 days and the HRs for the time to discharge, although these were generally close to unity and had CIs that crossed unity. No clear conclusions could be made on the relative efficacy of treatments for these two measures compared with SoC. All treatments used in the community had favourable median RRs for hospitalisation and death at 28 days with the upper limit of the CI being below 1 for all drugs except molnupiravir. The median RRs associated with death at 28 days were favourable for all interventions, except for remdesivir where the median estimate was unity as no deaths were observed in the study within COVID-NMA. The CIs were wide and spanned one for all treatments except for molnupiravir and nirmatrelvir/ritonavir. For hospitalised patients requiring supplemental oxygen, all treatments had estimated ICERs compared with SoC below £12,000 in both the mean efficacy and high efficacy scenarios. However, in the low efficacy scenario only baricitinib and tocilizumab generated more QALYs than SoC. Baricitinib had an estimated ICER under £9000, while tocilizumab had an estimated ICER under £29,000. For hospitalised patients not requiring supplemental oxygen, all treatments had estimated ICERs compared with SoC below £12,000 in both the mean efficacy and high efficacy scenarios. However, in the low efficacy scenario, only baricitinib generated more QALYs than SoC with an estimated ICER below £6000. For interventions used in the community, the estimated ICERs compared with SoC were more varied. In the mean efficacy scenario, the estimated ICERs were below £7000 for nirmatrelvir/ritonavir, below £35,000 for sotrovimab and below £91,000 for remdesivir. In the high efficacy scenario, the estimated ICERs were below £5000 for nirmatrelvir/ritonavir, below £19,000 for sotrovimab and below £25,000 for remdesivir. In the low efficacy scenario, the estimated ICER was below £12,000 for nirmatrelvir/ritonavir, with remdesivir and sotrovimab having ICERs in excess of £10,000. Only one of the scenario analyses noticeably changed the ICERs for all interventions, which was changing the proportion of people with COVID-19 in the community at high risk of hospitalisation who are hospitalised when treated with SoC. Treatments became more cost-effective as the admission proportion increased at the mean and high efficacy scenarios. The ranges in the ICERs assuming mean efficacy for the drugs, when using 1%, 10% and 20%, rather than 2.82% as assumed in the base case, were: nirmatrelvir/ritonavir (£25,544, dominant and dominant), remdesivir (£280,819, £16,170 and £1512) and sotrovimab (£111,318, £4870 and dominant). If data from Solidarity are included, the low efficacy scenarios for remdesivir had a positive NMB regardless of the willingness-to-pay threshold and oxygen status assumed. For patients requiring supplemental oxygen the ICER was £25,903; the corresponding ICER was £34,550 for those not requiring supplementary oxygen. Conclusions There is considerable uncertainty in the efficacy of treatments compared to SoC observed in the studies due to the small number of events, which results in wide CIs for HRs and RRs. Some treatments (baricitinib and tocilizumab in the hospitalised setting and casirivimab/imdevimab, molnupiravir and nirmatrelvir/ritonavir in the community setting) were estimated to have a statistically significant benefit related to death due to COVID-19, however, this may also have been shown for other treatments if the pivotal studies had had larger sample sizes. However, the dominant SARS-CoV-2 variant, the SoC and the percentage of people who have had a vaccination, have all changed since the pivotal studies were undertaken meaning that the efficacies for treatments are highly uncertain. This is demonstrated by sotrovimab having favourable median and mean efficacies in prevention hospitalisation, but this drug is not authorised in the USA, as it is unlikely to be effective against the Omicron BA.2 subvariant. Further the World Health Organization has made strong recommendations against the use of sotrovimab. Given potential further changes in the variant, the results presented in this report, and within the confidential appendix, should be treated with caution. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information.

The Church believed that her faith had social relevance. God, who is believed in, is responded to in concrete cultural and political situations. Therefore, the Church is no longer an isolated religious institution but integral to people's life experiences. Currently, the Indonesian nation is not only in a political crisis but also a crisis of political behavior. This crisis is exacerbated because the political elite has no shame in politics. Empirically, it is effortless to find examples of how there is no sense of shame because they have been guilty in society, and most prominently in the attitudes of political elites. It is no secret that many leaders and political elites are guilty of causing various crises, but when appearing in public, they do not show that they are guilty. Thus, this study aims to find the ethical values of the passion story of Jesus based on the Gospel of John. John presents the story of Jesus' passion for showing Jesus' empire as King through His "exaltation" on the Cross. Through this reading, leaders and public officials know and behave as leaders in front of the people. This research is a critical reading of the story of the passion of Jesus so that ethical points are found on how the political elite should act in the public sphere.

The research aimed to analyze the metaphor constructions and pedagogic values in the tiba meka dance. Students’ character building through metaphor construction in traditional dance had not been widely investigated; meanwhile, the metaphors used in this dance contain great values for encouraging students’ positive attitudes. Metaphor construction had a fundamental role for the students to have creative thought and deepen their understanding of its nature and role as a real communication language. The proper metaphor’s construction encouraged a student to be a catalyst in cross-cultural communication and appreciated the values contained in the metaphor delivered. The research was carried out between February and December 2019 and involved 30 respondents. The instruments used in collecting data were a set of stationery, questionnaire, interview, documentation, field notes, and recordings. These data were analyzed qualitatively through the phenomenological method. The findings show that the tiba meka dance is inseparable from the use of metaphors, namely bird, vegetation, body, sun, and water metaphors that have great pedagogic values, such as honesty, responsibility, and disciplin that contribute to the character building for students. The ideologies that underline tiba meka dance are morals, identity, and economy.

Objectives To assess the comparative accuracy of risk assessment models (RAMs) to identify women during pregnancy and the early postnatal period who are at increased risk of venous thromboembolism (VTE).Design Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Data sources MEDLINE, Embase, Cochrane Library and two research registers were searched until February 2021.Eligibility criteria All validation studies that examined the accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium (within 6 weeks post-delivery).Data extraction and synthesis Two authors independently selected and extracted data. Risk of bias was appraised using PROBAST (Prediction model Risk Of Bias ASsessment Tool). Data were synthesised without meta-analysis.Results Seventeen studies, comprising 19 externally validated RAMs and 1 internally validated model, met the inclusion criteria. The most widely evaluated RAMs were the Royal College of Obstetricians and Gynaecologists guidelines (six studies), American College of Obstetricians and Gynecologists guidelines (two studies), Swedish Society of Obstetrics and Gynecology guidelines (two studies) and the Lyon score (two studies). In general, estimates of sensitivity and specificity were highly variable with sensitivity estimates ranging from 0% to 100% for RAMs that were applied to antepartum women to predict antepartum or postpartum VTE and 0% to 100% for RAMs applied postpartum to predict postpartum VTE. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively.Conclusions Available data suggest that external validation studies have weak designs and limited generalisability, so estimates of prognostic accuracy are very uncertain.PROSPERO registration number CRD42020221094.

Objectives: To evaluate the diagnostic accuracy of the aortic dissection detection risk score (ADD-RS) used alone or in combination with D-dimer for detecting acute aortic syndrome (AAS) in patients presenting with symptoms suggestive of AAS. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic accuracy studies that assessed the use of ADD-RS alone or with D-Dimer for diagnosing AAS compared with a reference standard test (e.g. computer tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two reviewers independently selected and extracted data. Risk of bias was appraised using QUADAS-2 tool. Data were synthesised using hierarchical meta-analysis models. Results: We selected 13 studies from the 2017 citations identified, including six studies evaluating combinations of ADD-RS alongside D-dimer>500ng/L. Summary sensitivities and specificities (95% credible interval) were: ADD-RS>0 94.6% (90%, 97.5%) and 34.7% (20.7%, 51.2%), ADD-RS>1 43.4% (31.2%, 57.1%) and 89.3% (80.4%, 94.8%); ADD RS>0 or D-Dimer>500ng/L 99.8% (98.7%, 100%) and 21.8% (12.1%, 32.6%); ADD RS>1 or D-Dimer>500ng/L 98.3% (94.9%, 99.5%) and 51.4% (38.7%, 64.1%); ADD RS>1 or ADD RS = 1 with D-dimer>500ng/L 93.1% (87.1%, 96.3%) and 67.1% (54.4%, 77.7%). Conclusions: Combinations of ADD-RS and D-dimer can be used to select patients with suspected AAS for imaging with a range of trade-offs between sensitivity (93.1% to 99.8%) and specificity (21.8% to 67.1%). [ABSTRACT FROM AUTHOR]

Introduction Hospital-acquired thrombosis accounts for a large proportion of all venous thromboembolism (VTE), with significant morbidity and mortality. This subset of VTE can be reduced through accurate risk assessment and tailored pharmacological thromboprophylaxis. This systematic review aimed to determine the comparative accuracy of risk assessment models (RAMs) for predicting VTE in patients admitted to hospital.Methods A systematic search was performed across five electronic databases (including MEDLINE, EMBASE and the Cochrane Library) from inception to February 2021. All primary validation studies were eligible if they examined the accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in hospitalised inpatients. Two or more reviewers independently undertook study selection, data extraction and risk of bias assessments using the PROBAST (Prediction model Risk Of Bias ASsessment Tool) tool. We used narrative synthesis to summarise the findings.Results Among 6355 records, we included 51 studies, comprising 24 unique validated RAMs. The majority of studies included hospital inpatients who required medical care (21 studies), were undergoing surgery (15 studies) or receiving care for trauma (4 studies). The most widely evaluated RAMs were the Caprini RAM (22 studies), Padua prediction score (16 studies), IMPROVE models (8 studies), the Geneva risk score (4 studies) and the Kucher score (4 studies). C-statistics varied markedly between studies and between models, with no one RAM performing obviously better than other models. Across all models, C-statistics were often weak (0.8). Similarly, estimates for sensitivity and specificity were highly variable. Sensitivity estimates ranged from 12.0% to 100% and specificity estimates ranged from 7.2% to 100%.Conclusion Available data suggest that RAMs have generally weak predictive accuracy for VTE. There is insufficient evidence and too much heterogeneity to recommend the use of any particular RAM.PROSPERO registration number Steve Goodacre, Abdullah Pandor, Katie Sworn, Daniel Horner, Mark Clowes. A systematic review of venous thromboembolism RAMs for hospital inpatients. PROSPERO 2020 CRD42020165778. Available from https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=165778https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=165778

It is believed that Inquiry-Based Learning (IBL) affords relevant and meaningful L2 instruction given its contextualised and experiential approach. IBL, which only recently gained popularity in the L2 classroom, strongly differs from that of traditionally didactic methodologies and can present challenges for L2 educators. Research shows that many struggle to adopt a well-rounded inquiry approach and instead tend to over-rely on strategies aiming to make meaning comprehensible to learners, thus neglecting a focus on language form, language use and inquiry skills. This literature review examines current trends in L2 teaching and learning when implementing a structured inquiry approach in the primary school setting and attempts to uncover and evaluate various scaffolding strategies that can be employed to support a more holistic approach to IBL. The language scaffolding practices described in this paper are categorised into four areas of focus: focus on meaning, focus on form, focus on language use, and inquiry skills.

Background: Thromboprophylaxis can reduce the risk of venous thromboembolism (VTE) during lower-limb immobilisation, but it is unclear whether or not this translates into meaningful health benefit, justifies the risk of bleeding or is cost-effective. Risk assessment models (RAMs) could select higher-risk individuals for thromboprophylaxis. Objectives: To determine the clinical effectiveness and cost-effectiveness of different strategies for providing thromboprophylaxis to people with lower-limb immobilisation caused by injury and to identify priorities for future research. Data sources: Ten electronic databases and research registers (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects, the Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluation Database, Science Citation Index Expanded, ClinicalTrials.gov and the International Clinical Trials Registry Platform) were searched from inception to May 2017, and this was supplemented by hand-searching reference lists and contacting experts in the field. Review methods: Systematic reviews were undertaken to determine the effectiveness of pharmacological thromboprophylaxis in lower-limb immobilisation and to identify any study of risk factors or RAMs for VTE in lower-limb immobilisation. Study quality was assessed using appropriate tools. A network meta-analysis was undertaken for each outcome in the effectiveness review and the results of risk-prediction studies were presented descriptively. A modified Delphi survey was undertaken to identify risk predictors supported by expert consensus. Decision-analytic modelling was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained of different thromboprophylaxis strategies from the perspectives of the NHS and Personal Social Services. Results: Data from 6857 participants across 13 trials were included in the meta-analysis. Thromboprophylaxis with low-molecular-weight heparin reduced the risk of any VTE [odds ratio (OR) 0.52, 95% credible interval (CrI) 0.37 to 0.71], clinically detected deep-vein thrombosis (DVT) (OR 0.40, 95% CrI 0.12 to 0.99) and pulmonary embolism (PE) (OR 0.17, 95% CrI 0.01 to 0.88). Thromboprophylaxis with fondaparinux (Arixtra®, Aspen Pharma Trading Ltd, Dublin, Ireland) reduced the risk of any VTE (OR 0.13, 95% CrI 0.05 to 0.30) and clinically detected DVT (OR 0.10, 95% CrI 0.01 to 0.94), but the effect on PE was inconclusive (OR 0.47, 95% CrI 0.01 to 9.54). Estimates of the risk of major bleeding with thromboprophylaxis were inconclusive owing to the small numbers of events. Fifteen studies of risk factors were identified, but only age (ORs 1.05 to 3.48), and injury type were consistently associated with VTE. Six studies of RAMs were identified, but only two reported prognostic accuracy data for VTE, based on small numbers of patients. Expert consensus was achieved for 13 risk predictors in lower-limb immobilisation due to injury. Modelling showed that thromboprophylaxis for all is effective (0.015 QALY gain, 95% CrI 0.004 to 0.029 QALYs) with a cost-effectiveness of £13,524 per QALY, compared with thromboprophylaxis for none. If risk-based strategies are included, it is potentially more cost-effective to limit thromboprophylaxis to patients with a Leiden thrombosis risk in plaster (cast) [L-TRiP(cast)] score of ≥ 9 (£20,000 per QALY threshold) or ≥ 8 (£30,000 per QALY threshold). An optimal threshold on the L-TRiP(cast) receiver operating characteristic curve would have sensitivity of 84–89% and specificity of 46–55%. Limitations: Estimates of RAM prognostic accuracy are based on weak evidence. People at risk of bleeding were excluded from trials and, by implication, from modelling. Conclusions: Thromboprophylaxis for lower-limb immobilisation due to injury is clinically effective and cost-effective compared with no thromboprophylaxis. Risk-based thromboprophylaxis is potentially optimal but the prognostic accuracy of existing RAMs is uncertain. Future work: Research is required to determine whether or not an appropriate RAM can accurately select higher-risk patients for thromboprophylaxis. Study registration: This study is registered as PROSPERO CRD42017058688. Funding: The National Institute for Health Research Health Technology Assessment programme.