Prognostic models for identifying risk of poor outcome in people with acute ankle sprains: the SPRAINED development and external validation study

BACKGROUND: Ankle sprains are very common injuries. Although recovery can occur within weeks, around one-third of patients have longer-term problems. OBJECTIVES: To develop and externally validate a prognostic model for identifying people at increased risk of poor outcome after an acute ankle sprain. DESIGN: Development of a prognostic model in a clinical trial cohort data set and external validation in a prospective cohort study. SETTING: Emergency departments (EDs) in the UK. PARTICIPANTS: Adults with an acute ankle sprain (within 7 days of injury). SAMPLE SIZE: There were 584 clinical trial participants in the development data set and 682 recruited for the external validation study. PREDICTORS: Candidate predictor variables were chosen based on availability in the clinical data set, clinical consensus, face validity, a systematic review of the literature, data quality and plausibility of predictiveness of the outcomes. MAIN OUTCOME MEASURES: Models were developed to predict two composite outcomes representing poor outcome. Outcome 1 was the presence of at least one of the following symptoms at 9 months after injury: persistent pain, functional difficulty or lack of confidence. Outcome 2 included the same symptoms as outcome 1, with the addition of recurrence of injury. Rates of poor outcome in the external data set were lower than in the development data set, 7% versus 20% for outcome 1 and 16% versus 24% for outcome 2. ANALYSIS: Multiple imputation was used to handle missing data. Logistic regression models, together with multivariable fractional polynomials, were used to select variables and identify transformations of continuous predictors that best predicted the outcome based on a nominal alpha of 0.157, chosen to minimise overfitting. Predictive accuracy was evaluated by assessing model discrimination (c-statistic) and calibration (flexible calibration plot). RESULTS: (1) Performance of the prognostic models in development data set - the combined c-statistic for the outcome 1 model across the 50 imputed data sets was 0.74 [95% confidence interval (CI) 0.70 to 0.79], with good model calibration across the imputed data sets. The combined c-statistic for the outcome 2 model across the 50 imputed data sets was 0.70 (95% CI 0.65 to 0.74), with good model calibration across the imputed data sets. Updating these models, which used baseline data collected at the ED, with an additional variable at 4 weeks post injury (pain when bearing weight on the ankle) improved the discriminatory ability (c-statistic 0.77, 95% CI 0.73 to 0.82, for outcome 1 and 0.75, 95% CI 0.71 to 0.80, for outcome 2) and calibration of both models. (2) Performance of the models in the external data set - the combined c-statistic for the outcome 1 model across the 50 imputed data sets was 0.73 (95% CI 0.66 to 0.79), with a calibration plot intercept of -0.91 (95% CI -0.98 to 0.44) and slope of 1.13 (95% CI 0.76 to 1.50). The combined c-statistic for the outcome 2 model across the 50 imputed data sets was 0.63 (95% CI 0.58 to 0.69), with a calibration plot intercept of -0.25 (95% CI -0.27 to 0.11) and slope of 1.03 (95% CI 0.65 to 1.42). The updated models with the additional pain variable at 4 weeks had improved discriminatory ability over the baseline models but not better calibration. CONCLUSIONS: The SPRAINED (Synthesising a clinical Prognostic Rule for Ankle Injuries in the Emergency Department) prognostic models performed reasonably well, and showed benefit compared with not using any model; therefore, the models may assist clinical decision-making when managing and advising ankle sprain patients in the ED setting. The models use predictors that are simple to obtain. LIMITATIONS: The data used were from a randomised controlled trial and so were not originally intended to fulfil the aim of developing prognostic models. However, the data set was the best available, including data on the symptoms and clinical events of interest. FUTURE WORK: Further model refinement, including recalibration or identifying additional predictors, may be required. The effect of implementing and using either model in clinical practice, in terms of acceptability and uptake by clinicians and on patient outcomes, should be investigated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12726986. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 64. See the NIHR Journals Library website for further project information. Funding was also recieved from the NIHR Collaboration for Leadership in Applied Health Research, Care Oxford at Oxford Health NHS Foundation Trust, NIHR Biomedical Research Centre, Oxford, and the NIHR Fellowship programme

Molecular Mechanism of the Constitutive Activation of the L250Q Human Melanocortin-4 Receptor Polymorphism †

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65471/1/j.1747-0285.2006.00362.x.pd

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Role of miR-2392 in driving SARS-CoV-2 infection

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans

Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980�2015: the Global Burden of Disease Study 2015

Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. Findings Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95 uncertainty interval UI 3·1�3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5�2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6�40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7�1·9 million) in 2005, to 1·2 million deaths (1·1�1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. Interpretation Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. Funding Bill & Melinda Gates Foundation, and National Institute of Mental Health and National Institute on Aging, National Institutes of Health. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Electron and photon energy calibration with the ATLAS detector using LHC Run 2 data

This paper presents the electron and photon energy calibration obtained with the ATLAS detector using 140 fb-1 of LHC proton-proton collision data recorded at √(s) = 13 TeV between 2015 and 2018. Methods for the measurement of electron and photon energies are outlined, along with the current knowledge of the passive material in front of the ATLAS electromagnetic calorimeter. The energy calibration steps are discussed in detail, with emphasis on the improvements introduced in this paper. The absolute energy scale is set using a large sample of Z-boson decays into electron-positron pairs, and its residual dependence on the electron energy is used for the first time to further constrain systematic uncertainties. The achieved calibration uncertainties are typically 0.05% for electrons from resonant Z-boson decays, 0.4% at ET ∼ 10 GeV, and 0.3% at ET ∼ 1 TeV; for photons at ET ∼ 60 GeV, they are 0.2% on average. This is more than twice as precise as the previous calibration. The new energy calibration is validated using J/ψ → ee and radiative Z-boson decays

Measurement of the tt¯ cross section and its ratio to the Z production cross section using pp collisions at √s = 13.6 TeV with the ATLAS detector

The inclusive top-quark-pair production cross section σtt¯ and its ratio to the Z-boson production cross section have been measured in proton–proton collisions at √s = 13.6 TeV, using 29 fb−1 of data collected in 2022 with the ATLAS experiment at the Large Hadron Collider. Using events with an opposite-charge electron-muon pair and b-tagged jets, and assuming Standard Model decays, the top-quark-pair production cross section is measured to be σtt¯=850±3(stat.)±18(syst.)±20(lumi.) pb. The ratio of the tt¯ and the Z-boson production cross sections is also measured, where the Z-boson contribution is determined for inclusive e+e− and μ+μ− events in a fiducial phase space. The relative uncertainty on the ratio is reduced compared to the tt¯ cross section, thanks to the cancellation of several systematic uncertainties. The result for the ratio, Rtt¯/Z=1.145±0.003(stat.)±0.021(syst.)±0.002(lumi.) is consistent with the Standard Model prediction using the PDF4LHC21 PDF set

Search for flavour-changing neutral tqH interactions with H → γγ in pp collisions at √s = 13 TeV using the ATLAS detector

A search for flavour-changing neutral interactions involving the top quark, the Higgs boson and an up-type quark q (q = c, u) is presented. The proton-proton collision data set used, with an integrated luminosity of 139 fb−1, was collected at √s = 13 TeV by the ATLAS experiment at the Large Hadron Collider. Both the decay process t → qH in tt¯ production and the production process pp → tH, with the Higgs boson decaying into two photons, are investigated. No significant excess is observed and upper limits are set on the t → cH and the t → uH branching ratios of 4.3 × 10−4 and 3.8 × 10−4, respectively, at the 95% confidence level, while the expected limits in the absence of signal are 4.7 × 10−4 and 3.9 × 10−4. Combining this search with ATLAS searches in the H → τ+τ− and H → b¯b final states yields observed (expected) upper limits on the t → cH branching ratio of 5.8 × 10−4 (3.0 × 10−4) at the 95% confidence level. The corresponding observed (expected) upper limit on the t → uH branching ratio is 4.0 × 10−4 (2.4 × 10−4)

Evidence of pair production of longitudinally polarised vector bosons and study of CP properties in ZZ → 4ℓ events with the ATLAS detector at √s = 13 TeV

A study of the polarisation and CP properties in ZZ production is presented. The used data set corresponds to an integrated luminosity of 140 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the Large Hadron Collider. The ZZ candidate events are reconstructed using two same-flavour opposite-charge electron or muon pairs. The production of two longitudinally polarised Z bosons is measured with a significance of 4.3 standard deviations, and its cross-section is measured in a fiducial phase space to be 2.45 ± 0.60 fb, consistent with the next-to-leading-order Standard Model prediction. The inclusive differential cross-section as a function of a CP-sensitive angular observable is also measured. The results are used to constrain anomalous CP-odd neutral triple gauge couplings

Measurement of the Bs0→ μμ effective lifetime with the ATLAS detector

This paper reports the first ATLAS measurement of the B0s → μμ effective lifetime. The measurement is based on the data collected in 2015–2016, amounting to 26.3 fb−1 of 13 TeV LHC proton-proton collisions. The proper decay-time distribution of 58 ± 13 background-subtracted signal candidates is fit with simulated signal templates parameterised as a function of the B0s effective lifetime, with statistical uncertainties extracted through a Neyman construction. The resulting effective measurement of the B0s → μμ lifetime is 0.99+0.42−0.07 (stat.) ± 0.17 (syst.) ps and it is found to be consistent with the Standard Model