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Lapses in concentration while driving can be fatal, so if a person experiences a seizure – whether behind the wheel or not – UK authorities require that person to take time off driving until the risk of another seizure falls below a set threshold. But how much time off is required? Laura Bonnett explains how statistics helped find an answer

Background Catheter ablation of ventricular tachycardia (VT) is associated with potential major complications, including mortality. The risk of acute complications in patients with ischaemic cardiomyopathy (ICM) and non-ischaemic cardiomyopathy (NICM) has not been systematically evaluated. Methods PubMed was searched for studies of catheter ablation of VT published between September 2009 and September 2019. Pre-specified primary outcomes were (1) rate of major acute complications, including death, and (2) mortality rate. Results A total of 7395 references were evaluated for relevance. From this, 50 studies with a total of 3833 patients undergoing 4319 VT ablation procedures fulfilled the inclusion criteria (mean age 59 years; male 82%; 2363 [62%] ICM; 1470 [38%] NICM). The overall major complication rate in ICM cohorts was 9.4% (95% CI, 8.1–10.7) and NICM cohorts was 7.1% (95% CI, 6.0–8.3). Reported complication rates were highly variable between studies (ICM I2 = 90%; NICM I2 = 89%). Vascular complications (ICM 2.5% [95% CI, 1.9–3.1]; NICM 1.2% [95% CI, 0.7–1.7]) and cerebrovascular events (ICM 0.5% [95% CI, 0.2–0.7]; NICM, 0.1% [95% CI, 0–0.2]) were significantly higher in ICM cohorts. Acute mortality rates in the ICM and NICM cohorts were low (ICM 0.9% [95% CI, 0.5–1.3]; NICM 0.6% [95% CI, 0.3–1.0]) with the majority of overall deaths (ICM 75%; NICM 80%) due to either recurrent VT or cardiogenic shock. Conclusion Overall acute complication rates of VT ablation are comparable between ICM and NICM patients. However, the pattern and predictors of complications vary depending on the underlying cardiomyopathy.

Highlights • Model predicts risk of seizure recurrence after single fit or epilepsy diagnosis. • Model performs well in independent data. • Future work required to ensure the model is adopted in clinical practice. • Model can improve the lives of people with single seizures and early epilepsy., Purpose Following a single seizure, or recent epilepsy diagnosis, it is difficult to balance risk of medication side effects with the potential to prevent seizure recurrence. A prediction model was developed and validated enabling risk stratification which in turn informs treatment decisions and individualises counselling. Methods Data from a randomised controlled trial was used to develop a prediction model for risk of seizure recurrence following a first seizure or diagnosis of epilepsy. Time-to-event data was modelled via Cox's proportional hazards regression. Model validity was assessed via discrimination and calibration using the original dataset and also using three external datasets – National General Practice Survey of Epilepsy (NGPSE), Western Australian first seizure database (WA) and FIRST (Italian dataset of people with first tonic-clonic seizures). Results People with neurological deficit, focal seizures, abnormal EEG, not indicated for CT/MRI scan, or not immediately treated have a significantly higher risk of seizure recurrence. Discrimination was fair and consistent across the datasets (c-statistics: 0.555 (NGPSE); 0.558 (WA); 0.597 (FIRST)). Calibration plots showed good agreement between observed and predicted probabilities in NGPSE at one and three years. Plots for WA and FIRST showed poorer agreement with the model underpredicting risk in WA, and over-predicting in FIRST. This was resolved following model recalibration. Conclusion The model performs well in independent data especially when recalibrated. It should now be used in clinical practice as it can improve the lives of people with single seizures and early epilepsy by enabling targeted treatment choices and more informed patient counselling.

Objectives To examine the association between subjective health complaints, sleep quantity and new injury within an endurance sport population. Design Prospective cohort study. Methods Ninety-five endurance sporting participants were recruited from running, triathlon, swimming, cycling and rowing disciplines. Over 52-week period participants submitted weekly data regarding subjective health complaints (SHCs) (cardiorespiratory, gastrointestinal and psychological/lifestyle), sleep quantity, training load and new injury episodes. Applying a 7- and 14-day lag period, a shared frailty model was used to explore new injury risk associations with total SHCs and sleep quantity. Results 92.6% of 95 participants completed all 52 weeks of data submission and the remainder of the participants completed ≥30 weeks. Seven-day lag psychological/lifestyle SHCs were significantly associated with new injury risk (Hazard ratio (HR) = 1.32; CI 95% = 1.01–1.72, p 7 h/day sleep quantity (HR = 0.63, CI 95% = 0.45–0.87, p

IntroductionEndoscopic mucosal resection (EMR) is an invaluable technique, however it is associated with significant risks. In the elderly in particular, the long-term survival benefits of polyp resection with EMR are unknown. The aim of this study was to determine the long-term outcomes in elderly patients who had undergone EMR and to identify any adverse factors.MethodA retrospective observational study on patients of 75 years of age or greater, who underwent EMR of colorectal polyps, in a single tertiary centre, from 2005 to 2014. Demographics of the patients, including Charlson Comorbidity Index (CCI), endoscopic and histological data, were reviewed to identify potential factors predicting outcomes.ResultsThe patients’ median age was 80 years. In total 239 procedures were performed in 206 unique patients. The complication rate was 1.6%. Mean overall survival was 6.7 years with only one patient dying from metastatic colorectal cancer (0.5%) and 49 dying from non-colorectal cancer conditions (24%). Age more than 79 years and CCI more than 2 were independent predictors of significantly shorter survival (p=ConclusionEMR of colonic polyps is safe even for elderly patients. However, the decision to proceed to complex endoscopic therapy should be individualised considering the patients’ age and comorbidities. CCI can help to objectively assess the comorbid state of a patient prior to such decisions.

Background Clinical prediction models are widely used to guide medical advice and therapeutic interventions. Asthma is one of the most common chronic diseases globally and is characterised by acute deteriorations. These exacerbations are largely preventable, so there is interest in using clinical prediction models in this area. The objective of this review was to identify studies which have developed such models, determine whether consistent and appropriate methodology was used and whether statistically reliable prognostic models exist. Methods We searched online databases MEDLINE (1948 onwards), CINAHL Plus (1937 onwards), The Cochrane Library, Web of Science (1898 onwards) and ClinicalTrials.gov, using index terms relating to asthma and prognosis. Data was extracted and assessment of quality was based on GRADE and an early version of PROBAST (Prediction study Risk of Bias Assessment Tool). A meta-analysis of the discrimination and calibration measures was carried out to determine overall performance across models. Results Ten unique prognostic models were identified. GRADE identified moderate risk of bias in two of the studies, but more detailed quality assessment via PROBAST highlighted that most models were developed using highly selected and small datasets, incompletely recorded predictors and outcomes, and incomplete methodology. None of the identified models modelled recurrent exacerbations, instead favouring either presence/absence of an event, or time to first or specified event. Preferred methodologies were logistic regression and Cox proportional hazards regression. The overall pooled c-statistic was 0.77 (95% confidence interval 0.73 to 0.80), though individually some models performed no better than chance. The meta-analysis had an I2 value of 99.75% indicating a high amount of heterogeneity between studies. The majority of studies were small and did not include internal or external validation, therefore the individual performance measures are likely to be optimistic. Conclusions Current prognostic models for asthma exacerbations are heterogeneous in methodology, but reported c-statistics suggest a clinically useful model could be created. Studies were consistent in lacking robust validation and in not modelling serial events. Further research is required with respect to incorporating recurrent events, and to externally validate tools in large representative populations to demonstrate the generalizability of published results.

Background: The ‘Prediction Of Survival in Advanced Sorafenib-treated HCC’ (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. Methods: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. Results: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9-4.6months). A total of 920 patients (n=615 in training set, n=305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59). Conclusions: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies.

Background Pyrazinamide (PZA) is a key component of current and future regimens for tuberculosis (TB). Inclusion of PZA at higher doses and for longer durations may improve efficacy outcomes but must be balanced against the potential for worse safety outcomes. Methods We will search for randomised and quasi-randomised clinical trials in adult participants with and without the inclusion of PZA in TB treatment regimens in the Cochrane infectious diseases group’s trials register, Cochrane central register of controlled trials (CENTRAL), MEDLINE, EMBASE, LILACS, the metaRegister of Controlled Trials (mRCT) and the World Health Organization (WHO) international clinical trials registry platform. One author will screen abstracts and remove ineligible studies (10% of which will be double-screened by a second author). Two authors will review full texts for inclusion. Safety and efficacy data will be extracted to pre-piloted forms by one author (10% of which will be double-extracted by a second author). The Cochrane risk of bias tool will be used to assess study quality. The study has three objectives: the association of (1) inclusion, (2) dose and (3) duration of PZA with efficacy and safety outcomes. Risk ratios as relative measures of effect for direct comparisons within trials (all objectives) and proportions as absolute measures of effect for indirect comparisons across trials (for objectives 2 and 3) will be calculated. If there is insufficient data for direct comparisons within trials for objective 1, indirect comparisons between trials will be performed. Measures of effect will be pooled, with corresponding 95% confidence intervals and p values. Meta-analysis will be performed using the generalised inverse variance method for fixed effects models (FEM) or the DerSimonian-Laird method for random effects models (REM). For indirect comparisons, meta-regression for absolute measures against dose and duration data will be performed. Heterogeneity will be quantified through the I2-statistic for direct comparisons and the τ2 statistic for indirect comparisons using meta-regression. Discussion The current use of PZA for TB is based on over 60 years of clinical trial data, but this has never been synthesised to guide rationale use in future regimens and clinical trials. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO) CRD42019138735

Background Routinely recorded data held in electronic health records can be used to inform the conduct of randomised controlled trials (RCTs). However, limitations with access and accuracy have been identified. Objective: Using epilepsy as an exemplar condition, we assessed the attributes and agreement of routinely recorded data compared to data collected using case report forms in a UK RCT assessing antiepileptic drug treatments for individuals newly diagnosed with epilepsy. Methods The case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK multicentre RCT assessing the clinical and cost-effectiveness of antiepileptic drugs as treatments for epilepsy. Ninety-eight of 470 eligible participants provided consent for access to routinely recorded secondary care data that were retrieved from NHS Digital Hospital Episode Statistics (N=71) and primary and secondary care data from The Secure Anonymised Information Linkage Databank (N=27). We assessed data items relevant to the identification of individuals eligible for inclusion in SANAD II, baseline and follow-up visits. The attributes of routinely recorded data were assessed including the degree of missing data. The agreement between routinely recorded data and data collected on case report forms in SANAD II was assessed using calculation of Cohen’s kappa for categorical data and construction of Bland-Altman plots for continuous data. Results There was a significant degree of missing data in the routine record for 15 of the 20 variables assessed, including all clinical variables. Agreement was poor for the majority of comparisons, including the assessments of seizure occurrence and adverse events. For example, only 23/62 (37%) participants had a date of first-ever seizure identified in routine datasets. Agreement was satisfactory for the date of prescription of antiepileptic drugs and episodes of healthcare resource use. Conclusions There are currently significant limitations preventing the use of routinely recorded data for participant identification and assessment of clinical outcomes in epilepsy, and potentially other chronic conditions. Further research is urgently required to assess the attributes, agreement, additional benefits, cost-effectiveness and ‘optimal mix’ of routinely recorded data compared to data collected using standard methods such as case report forms at clinic visits for people with epilepsy. Trial registration Standard and New Antiepileptic Drugs II (SANAD II (EudraCT No: 2012-001884-64, registered 05/09/2012; ISRCTN Number: ISRCTN30294119, registered 03/07/2012))

Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%, p = 0.0002), in both imatinib (45% vs. 11%, p = 0.02) and dasatinib recipients (36% vs. 4%, p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.

Aim Making an accurate diagnosis of asthma can be challenging. Approaches used to assess the probability of asthma vary between clinicians; a prediction model could help to standardise clinical assessment. We aimed to derive and internally validate a clinical prediction model to support health professionals in primary care to assess the probability of an asthma diagnosis in children and young people presenting with symptoms suggestive of asthma. Methods We created a dataset from the Avon Longitudinal Study of Parents and Children (ALSPAC) enhanced with data from linked primary care electronic health records. Individuals with at least three inhaled corticosteroid prescriptions in one year and a ‘specific’ asthma Read code were designated as having asthma. Potential candidate predictors were included if data were available in at least 60% of participants. Remaining missing data were handled using multiple imputation. The prediction model was derived using logistic regression. Bootstrap re-sampling was used to internally validate the model. Results 11972 individuals aged Conclusion Information readily available from a patient’s electronic health records can support primary care clinicians weigh up the likelihood of a child/young person having asthma. We plan to externally validate the prediction model in a dataset created from primary care electronic health records. We will then develop the prediction model into a clinical decision support system (CDSS), co-produced with clinicians and patients, and test the feasibility of using the CDSS in clinical practice prior to prospective evaluation.

ObjectivesTo devise an assessment tool to aid discharge and admission decision-making in relation to children and young people in hospital urgent and emergency care facilities, and thereby improve the quality of care that patients receive, using a clinical prediction modelling approach.DesignObservational cohort study with internal and external validation of a predictive tool.SettingTwo general emergency departments (EDs) and an urgent care centre in the North of England.ParticipantsThe eligibility criteria were children and young people 0–16 years of age who attended one of the three hospital sites within one National Health Service (NHS) organisation. Children were excluded if they opted out of the study, were brought to the ED following their death in the community or arrived in cardiac arrest when the heart rate and respiratory rate would be unmeasurable.Main outcome measuresAdmission or discharge. A participant was defined as being admitted to hospital if they left the ED to enter the hospital for further assessment, (including being admitted to an observation and assessment unit or hospital ward), either on first presentation or with the same complaint within 7 days. Those who were not admitted were defined as having been discharged.ResultsThe study collected data on 36 365 participants. 15 328 participants were included in the final analysis cohort (21 045 observations) and 17 710 participants were included in the validation cohort (23 262 observations). There were 14 variables entered into the regression analysis. Of the 13 that remained in the final model, 10 were present in all 500 bootstraps. The resulting Paediatric Admission Guidance in the Emergency Department (PAGE) score demonstrated good internal validity. The C-index (area under the ROC) was 0.779 (95% CI 0.772 to 0.786).ConclusionsFor units without the immediate availability of paediatricians the PAGE score can assist staff to determine risk of admission. Cut-off values will need to be adjusted to local circumstance.Study protocolThe study protocol has been published in an open access journal: Riazet alRefining and testing the diagnostic accuracy of an assessment tool (Pennine Acute Hospitals NHS Trust-Paediatric Observation Priority Score) to predict admission and discharge of children and young people who attend an ED: protocol for an observational study. BMC Pediatr 18, 303 (2018).https://doi.org/10.1186/s12887-018-1268-7.Trial registration numberThe protocol has been published and the study registered (NIHR RfPB Grant: PB-PG-0815–20034; ClinicalTrials.gov:213469).

Background Bariatric surgery promotes weight loss and improves co-morbid conditions, with patients who are more physically active having better outcomes. However, levels of physical activity and sedentary behaviour often remain unchanged following surgery. Objectives To identify interventions and components thereof that are able to facilitate changes in physical activity and sedentary behaviour. Eligibility Physical activity and/or sedentary behaviour must have been measured, pre and post intervention, in patients who have undergone bariatric surgery. Study appraisal and synthesis methods : Four databases were searched with key-words. Two researchers conducted paper screening, data extraction and risk-of-bias assessment. Results Twelve studies were included; eleven were randomised. Two were delivered pre-surgery and ten post-surgery; five found positive effect. Moderate to vigorous physical activity increased in three studies, two of which also found a significant increase in step count. The fourth found a significant increase in strenuous activity and the fifth a significant increase in metabolic equivalent of task/day and reduced time spent watching television. Funding Jennifer James is funded by a NIHR ICA Clinical Doctoral Research Fellowship. Limitations Meta-analysis could not be conducted due to heterogeneity of outcomes and the tools used. Conclusion and implications of key findings This review has identified interventions and components thereof that were able to provoke positive effect. However, intervention and control conditions were not always well described particularly in terms of behaviour change techniques and the rationale for their use. Systematic review registration number PROSPERO (CRD42019121372)

Background Non-traumatic coma is a common acute childhood presentation to healthcare facilities in Africa and is associated with high morbidity and mortality. Historically, the majority of cases were attributed to cerebral malaria (CM). With the recent drastic reduction in malaria incidence, non-malarial coma is becoming a larger proportion of cases and determining the aetiology is diagnostically challenging, particularly in resource-limited settings. The purpose of this study will be to evaluate the aetiology and prognosis of non-traumatic coma in African children. Methods With no date restrictions, systematic searches of MEDLINE, Embase, and Scopus will identify prospective and retrospective studies (including randomised controlled trials, cluster randomised trials, cohort studies, cross-sectional, and case-control studies) recruiting children (1 month–16 years) with non-traumatic coma (defined by Blantyre Coma Score ≤ 2 or comparable alternative) from any African country. Disease-specific studies will be included if coma is associated and reported. The primary outcome is to determine the aetiology (infectious and non-infectious) of non-traumatic coma in African children, with pooled prevalence estimates of causes (e.g., malaria). Secondary outcomes are to determine overall estimates of morbidity and mortality of all-cause non-traumatic coma and disease-specific states of non-traumatic coma, where available. Random effects meta-analysis will summarise aetiology data and in-hospital and post-discharge mortality. Heterogeneity will be quantified with τ2, I2, and Cochran’s Q test. Discussion This systematic review will provide a summary of the best available evidence on the aetiology and outcome of non-traumatic coma in African children. Systematic review registration PROSPERO CRD42020141937

Background Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. Methods A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. Results Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was −0.19 (95 per cent c.i. −0.39 to −0.12) and − 0.01 (− 0.17 to −0.03) respectively. Conclusion Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

BackgroundPredictive models within epilepsy are frequently developed via Cox’s proportional hazards models. These models estimate risk of a specified event such as 12-month remission. They are relatively simple to produce, have familiar output, and are useful to answer questions about short-term prognosis. However, the Cox model only considers time to first event rather than all seizures after starting treatment for example. This makes assessing change in seizure rates over time difficult. Variants to the Cox model exist enabling recurrent events to be modelled. One such variant is the Prentice, Williams and Peterson – Total Time (PWP-TT) model. An alternative is the negative binomial model for event counts. This study aims to demonstrate the differences between the three approaches, and to consider the benefits of the PWP-TT approach for assessing change in seizure rates over time.MethodsTime to 12-month remission and time to first seizure after randomisation were modelled using the Cox model. Risk of seizure recurrence was modelled using the PWP-TT model, including all seizures across the whole follow-up period. Seizure counts were modelled using negative binomial regression. Differences between the approaches were demonstrated using participants recruited to the UK-based multi-centre Standard versus New Antiepileptic Drug (SANAD) study.ResultsResults from the PWP-TT model were similar to those from the conventional Cox and negative binomial models. In general, the direction of effect was consistent although the variables included in the models and the significance of the predictors varied. The confidence intervals obtained via the PWP-TT model tended to be narrower due to the increase in statistical power of the model.ConclusionsThe Cox model is useful for determining the initial response to treatment and potentially informing when the next intervention may be required. The negative binomial model is useful for modelling event counts. The PWP-TT model extends the Cox model to all included events. This is useful in determining the longer-term effects of treatment policy. Such a model should be considered when designing future clinical trials in medical conditions typified by recurrent events to improve efficiency and statistical power as well as providing evidence regarding changes in event rates over time.

Objectives The goal of this study was to determine whether a strategy of early re-isolation of pulmonary vein (PV) reconnection in all patients, regardless of symptoms, would reduce the recurrence of atrial fibrillation (AF) and improve quality of life. Background Lasting pulmonary vein isolation (PVI) remains elusive. PV reconnection is strongly linked to the recurrence of arrhythmia. Methods A total of 80 patients with paroxysmal AF were randomized 1:1 after contact force-guided PVI to receive either standard care or undergo a repeat electrophysiology study after 2 months regardless of symptoms (repeat study). At the initial procedure, PVI was demonstrated by entrance/exit block and adenosine administration after a minimum 20-min wait. At the repeat study, all sites of PV reconnection were re-ablated. Patients recorded electrocardiograms daily and whenever symptomatic for 12 months using a handheld monitor. Recurrence was defined as ≥30 s of atrial tachyarrhythmia (AT) after a 3-month blanking period. The Atrial Fibrillation Effect on Quality-of-Life Questionnaire was completed at baseline and at 6 and 12 months. Results All 40 patients randomized to repeat study attended for this after 62 ± 6 days, of whom 25 (62.5%) had reconnection of 41 (26%) PVs. There were no complications related to these procedures. Subjects recorded a total of 32,203 electrocardiograms (380 [335 to 447] per patient) during 12.6 (12.2 to 13.2) months of follow-up. AT recurrence was significantly lower for the repeat study group (17.5% vs. 42.5%; p = 0.03), as was AT burden (p = 0.03). Scores on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire were higher in the repeat study group at 6 months (p Conclusions A strategy of routine repeat assessment with re-isolation of PV reconnection improved freedom from AT recurrence, AT burden, and quality of life compared with current standard care. (The Effect of Early Repeat Atrial Fibrillation [AF] on AF Recurrence [PRESSURE]; NCT01942408)

SummaryBackgroundCOVID-19 pandemic has developed rapidly and the ability to stratify the most vulnerable patients is vital. However, routinely used severity scoring systems are often low on diagnosis, even in non-survivors. Therefore, clinical prediction models for mortality are urgently required.MethodsWe developed and internally validated a multivariable logistic regression model to predict inpatient mortality in COVID-19 positive patients using data collected retrospectively from Tongji Hospital, Wuhan (299 patients). External validation was conducted using a retrospective cohort from Jinyintan Hospital, Wuhan (145 patients). Nine variables commonly measured in these acute settings were considered for model development, including age, biomarkers and comorbidities. Backwards stepwise selection and bootstrap resampling were used for model development and internal validation. We assessed discrimination via the C statistic, and calibration using calibration-in-the-large, calibration slopes and plots.FindingsThe final model included age, lymphocyte count, lactate dehydrogenase and SpO2as independent predictors of mortality. Discrimination of the model was excellent in both internal (c=0·89) and external (c=0·98) validation. Internal calibration was excellent (calibration slope=1). External validation showed some over-prediction of risk in low-risk individuals and under-prediction of risk in high-risk individuals prior to recalibration. Recalibration of the intercept and slope led to excellent performance of the model in independent data.InterpretationCOVID-19 is a new disease and behaves differently from common critical illnesses. This study provides a new prediction model to identify patients with lethal COVID-19. Its practical reliance on commonly available parameters should improve usage of limited healthcare resources and patient survival rate.FundingThis study was supported by following funding: Key Research and Development Plan of Jiangsu Province (BE2018743 and BE2019749), National Institute for Health Research (NIHR) (PDF-2018-11-ST2-006), British Heart Foundation (BHF) (PG/16/65/32313) and Liverpool University Hospitals NHS Foundation Trust in UK.Research in contextEvidence before this studySince the outbreak of COVID-19, there has been a pressing need for development of a prognostic tool that is easy for clinicians to use. Recently, a Lancet publication showed that in a cohort of 191 patients with COVID-19, age, SOFA score and D-dimer measurements were associated with mortality. No other publication involving prognostic factors or models has been identified to date.Added value of this studyIn our cohorts of 444 patients from two hospitals, SOFA scores were low in the majority of patients on admission. The relevance of D-dimer could not be verified, as it is not included in routine laboratory tests. In this study, we have established a multivariable clinical prediction model using a development cohort of 299 patients from one hospital. After backwards selection, four variables, including age, lymphocyte count, lactate dehydrogenase and SpO2remained in the model to predict mortality. This has been validated internally and externally with a cohort of 145 patients from a different hospital. Discrimination of the model was excellent in both internal (c=0·89) and external (c=0·98) validation. Calibration plots showed excellent agreement between predicted and observed probabilities of mortality after recalibration of the model to account for underlying differences in the risk profile of the datasets. This demonstrated that the model is able to make reliable predictions in patients from different hospitals. In addition, these variables agree with pathological mechanisms and the model is easy to use in all types of clinical settings.Implication of all the available evidenceAfter further external validation in different countries the model will enable better risk stratification and more targeted management of patients with COVID-19. With the nomogram, this model that is based on readily available parameters can help clinicians to stratify COVID-19 patients on diagnosis to use limited healthcare resources effectively and improve patient outcome.

Background: Accurately diagnosing asthma can be challenging. Uncertainty about the best combination of clinical features and investigations for asthma diagnosis is reflected in conflicting recommendations from international guidelines. One solution could be a clinical prediction model to support health professionals estimate the probability of an asthma diagnosis. However, systematic review evidence identifies that existing models for asthma diagnosis are at high risk of bias and unsuitable for clinical use. Being mindful of previous limitations, this protocol describes plans to derive and validate a prediction model for use by healthcare professionals to aid diagnostic decision making during assessment of a child or young person with symptoms suggestive of asthma in primary care. Methods: A prediction model will be derived using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and linked primary care electronic health records (EHR). Data will be included from study participants up to 25 years of age where permissions exist to use their linked EHR. Participants will be identified as having asthma if they received at least three prescriptions for an inhaled corticosteroid within a one-year period and have an asthma code in their EHR. To deal with missing data we will consider conducting a complete case analysis. However, if the exclusion of cases with missing data substantially reduces the total sample size, multiple imputation will be used. A multivariable logistic regression model will be fitted with backward stepwise selection of candidate predictors. Apparent model performance will be assessed before internal validation using bootstrapping techniques. The model will be adjusted for optimism before external validation in a dataset created from the Optimum Patient Care Research Database. Discussion: This protocol describes a robust strategy for the derivation and validation of a prediction model to support the diagnosis of asthma in children and young people in primary care.

Background Empirical evidence is uncertain regarding the value of nonblanchable erythema in predicting the incidence of stage 2 (or more severe) pressure ulcers. Objectives To investigate whether nonblanchable erythema is an independent prognostic factor for pressure ulcer incidence using individual patient data. Methods We performed an electronic database search in February 2017 to identify longitudinal studies that considered nonblanchable erythema for predicting pressure ulcer risk in any population. We collected individual participant data for the included studies, and assessed the risk of bias of these studies using the Quality In Prognosis Studies tool. We analysed individual participant data in Stata using mixed-effects logistic regression to investigate the association of interest. The certainty of evidence from individual participant data analysis was assessed using the Grades of Recommendation Assessment, Development and Evaluation. The study was registered with PROSPERO (CRD42017081151). Results From the 13 included studies (total 68 077 participants) we had access to individual participant data from four (n = 3223), and 11·9% of participants (383 of 3223) developed new pressure ulcers of stage 2 or above within 28 days. Mixed-effects logistic regression showed that participants with nonblanchable erythema had higher odds of developing new pressure ulcers of stage 2 or above within 28 days of follow-up than those without nonblanchable erythema (multivariable association: n = 2684; odds ratio 2·72, 95% confidence interval 2·02-3·69; τ2 = 0; moderate-certainty evidence). Conclusions This first prognostic factor review with individual-level data analysis in patients with pressure ulcers suggests that people with nonblanchable erythema are more likely to develop new pressure ulcers of stage 2 or above within 28 days than people without nonblanchable erythema. It is important to identify nonblanchable erythema in practice and to intervene appropriately to prevent pressure ulceration. What's already known about this topic? Pressure ulcer reduction is a high priority for healthcare systems. Regularly inspecting skin to identify skin abnormalities is one key practice for preventing ulceration. Nonblanchable erythema - discoloration of the skin that does not turn white when pressed - is one clinically important skin abnormality. Empirical evidence synthesized using conventional meta-analysis is uncertain regarding the value of nonblanchable erythema for predicting open pressure ulcer incidence; this is partly because the conventional technique has weakness in terms of pooling prognostic effects of different multivariable analyses across studies. What does this study add? This prognostic factor review used individual-level data analysis to overcome the limitations of the conventional meta-analysis technique. For the first time there is confirmatory and moderate-certainty evidence on the association of nonblanchable erythema with pressure ulcer incidence. People with nonblanchable erythema are more likely to develop new pressure ulcers of stage 2 or more severe within 28 days than people without nonblanchable erythema, regardless of their age, baseline pressure ulcer risk or received support surfaces.

Background\ud In sub-Saharan Africa, there is a dearth of epidemiologic data on the burden of cerebral ath-erosclerosis. This is explained by the limited availability and the high cost of standard vascu-\ud lar imaging techniques. Neurovascular ultrasound is portable, cheaper and non-invasive and could, therefore, represent a reasonable alternative to fill this knowledge gap. We explored the feasibility of neurovascular ultrasound in Malawian adults with acute stroke-like syndrome to inform the design of future large stroke studies comparing its diagnostic perfor-\ud mance to that of gold standard vascular imaging techniques in sub-Saharan Africa.\ud Methods\ud We enrolled consecutive patients diagnosed with acute stroke-like syndrome based on the World Health Organization definition. Clinical and demographic data were recorded, and a comprehensive neurovascular ultrasound was performed. Fisher’s exact and Kruskal-Wallis\ud tests were used to study the relationship between atherosclerosis and potential risk factors.\ud Results\ud Sixty-six patients were enrolled (mean age: 58.7 years). The frequency of extracranial ath-erosclerosis was 39.4% (n = 26, 95% CI: 28.6–52.2). There were 12 patients with abnormal carotid intima media thickness (18.2%, 95% CI: 9.8–29.6) and 14 patients with a carotid pla-que (21.2%, 95% CI: 12.1–33.0). The frequency of intracranial atherosclerosis was 19.2%(95%CI: 6.6–39.4) in 26 patients with successful transcranial insonation. Hypertension(80.8 versus 52.5%, p = 0.03) and hypercholesterolemia (11.5 versus 0.0%, p = 0.05) were more prevalent in patients with extracranial atherosclerosis.\ud Conclusions\ud This study demonstrates the feasibility of neurovascular ultrasound to assess cervical arter-ies in adults with stroke-like syndrome in sub-Saharan Africa. There is a high rate of tran-scranial insonation failure in this setting, highlighting the need for echocontrast agents.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3&rsquo, s performance using discrimination and calibration methods. LUMPO3&rsquo, s ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.

Background Prognostic models for repeated events of the same type are highly useful in predicting when a patient may have a recurrence of a chronic disease or illness. Whilst methods are currently available for analysing recurrent event data in prognostic models, to our knowledge, most are not widely known or applied in a medical setting. As a result, often only the first recurrence is analysed meaning valuable information for multiple recurrences is discarded. Therefore, the aim of this review is to systemically review models for repeated medical events of the same type, to determine what modelling techniques are available and how they are applied. Methods MEDLINE will be used as the primary method to search sources. Various databases from the Cochrane Library and EMBASE will also be searched. Trial registries such as Clinicaltrials.gov.uk will be searched, as will registered trials that are ongoing and not yet published. Abstracts submitted to conferences will also be searched, and non-English sources will also be considered. Studies to be included in the review will be decided based on PICO guidelines, where the study population and outcomes correspond to this study’s aims and target population. The prognostic models used in each study chosen for inclusion in the review will be summarised qualitatively. Discussion As recurrent event data is not widely analysed in prognostic models, the results from this systematic review will identify which methods are available and which are commonly used. It is also unknown if certain methods which will be identified in the review perform better given certain conditions. Therefore, if included studies assess predictive performance, the results of this review could also provide evidence to determine if certain models are better fitting dependant on the event rate of the chronic condition. The results will be used to determine if model selection varies across disease area. The review will also provide an insight into the development of any new methods used for analysing recurrent events. Trial registration The review has been registered on PROSPERO (CRD42019116031).

Background: COVID-19 pandemic has developed rapidly and the ability to stratify the most vulnerable patients is vital. However, routinely used severity scoring systems are often low on diagnosis, even in non-survivors. Therefore, clinical prediction models for mortality are urgently required. Methods: We developed and internally validated a multivariable logistic regression model to predict inpatient mortality in COVID-19 positive patients using data collected retrospectively from Tongji Hospital, Wuhan (299 patients). External validation was conducted using a retrospective cohort from Jinyintan Hospital, Wuhan (145 patients). Nine variables commonly measured in these acute settings were considered for model development, including age, biomarkers and comorbidities. Backwards stepwise selection and bootstrap resampling were used for model development and internal validation. We assessed discrimination via the C statistic, and calibration using calibration-in-the-large, calibration slopes and plots. Findings: The final model included age, lymphocyte count, lactate dehydrogenase and SpO2 as independent predictors of mortality. Discrimination of the model was excellent in both internal (c=0·89) and external (c=0·98) validation. Internal calibration was excellent (calibration slope=1). External validation showed some over-prediction of risk in low-risk individuals and under-prediction of risk in high-risk individuals prior to recalibration. Recalibration of the intercept and slope led to excellent performance of the model in independent data. Interpretation: COVID-19 is a new disease and behaves differently from common critical illnesses. This study provides a new prediction model to identify patients with lethal COVID-19. Its practical reliance on commonly available parameters should improve usage of limited healthcare resources and patient survival rate. Funding Statement: This work wassupported, in part, by the research grants 2020YFC0841300 and 2020YFC0843700 from Ministry of Science and Technology of China, and by NIHR(PDF-2018-11-ST2-006), BHF (PG/16/65/32313) and Liverpool University Hospitals NHS Foundation Trust in UK. Declaration of Interests: All the authors declare no conflict of interest. Ethics Approval Statement: The protocol was approved by the local Institutional Ethics Committee (Approval Number: KY-2020-10.02).

Background: Antibiotics are routinely given to COPD patients presenting with lower respiratory tract infection (LRTI) symptoms in primary care. Yet the optimal drug and duration for effective first line treatment is unclear. Aim: To characterise antibiotic prescriptions for LRTI in COPD patients and investigate factors associated with repeat prescriptions. Methods: A retrospective analysis of antibiotic prescriptions for non-pneumonic LRTI in COPD patients from 2010 to 2015 using the UK primary care Optimum Patient Care Research Database. Second antibiotic prescriptions for LRTI or all indications within 14 days were the primary and secondary outcomes respectively, a proxy of initial treatment failure. We derived a model for repeat courses using uni- and multivariable logistic regression analysis. Results: 8.4% of the 9,042 incident events received further antibiotics for LRTI, 15.5% further courses for any indication. Amoxicillin and doxycycline were the commonest index and second line drugs respectively (58.7% and 28.7%), mostly given for 7 days. Index drugs other than amoxicillin, cardiovascular disease, pneumococcal vaccination and more primary care consultations were significantly associated with repeat prescriptions for LRTI (p Conclusion: Almost one in twelve patients received two antibiotic courses for LRTI within two weeks. There was no consensus antibiotic strategy. The data supported the preference for amoxicillin as index drug but confirmation by interventional methods is needed.

IntroductionAntibiotics are routinely given to people with chronic obstructive pulmonary disease (COPD) presenting with lower respiratory tract infection (LRTI) symptoms in primary care. Population prescribing habits and their consequences have not been well-described.MethodsWe conducted a retrospective analysis of antibiotic prescriptions for non-pneumonic exacerbations of COPD from 2010 to 2015 using the UK primary care Optimum Patient Care Research Database. As a proxy of initial treatment failure, second antibiotic prescriptions for LRTI or all indications within 14 days were the primary and secondary outcomes, respectively. We derived a model for repeat courses using univariable and multivariable logistic regression analysis.ResultsA total of 8.4% of the 9042 incident events received further antibiotics for LRTI, 15.5% further courses for any indication. Amoxicillin and doxycycline were the most common index and second-line drugs, respectively (58.7% and 28.7%), mostly given for 7 days. Index drugs other than amoxicillin, cardiovascular disease, pneumococcal vaccination and more primary care consultations were statistically significantly associated with repeat prescriptions for LRTI (pDiscussionThe prescription of multiple antibiotic courses for COPD exacerbations was relatively common—one in twelve patients receiving antibiotics for LRTI had a further course within 2 weeks. The findings support the current preference for amoxicillin as index drug within the limitations of this observational study. Further clinical trials to determine best practice in this common clinical situation appear required.

BackgroundOutcomes of reverse total shoulder arthroplasty (RTSA) have typically been assessed using the same instruments as anatomical shoulder arthroplasties. However, to date, there has been a lack of investigation with respect to the correlation of such scores and patient satisfaction in the RTSA population.MethodsThe Oxford Shoulder Score (OSS) and Quick Disabilities of the Arm, Shoulder and Hand (QD) score were prospectively collected in 38 RTSA patients (41 shoulders) postoperatively. Scores were then evaluated to establish whether or not they correlated with patient satisfaction at a minimum of 1 year postoperatively.ResultsThe correlation coefficient for the OSS and patient satisfaction was found to be 0.313 (p = 0.011) and the correlation coefficient for the QD score and patient satisfaction was -0.292 (p = 0.017), showing a statistically significant but moderately weak relationship between the OSS and QD scores with patient satisfaction (p ConclusionsThe present study showed no strongly significant relationship between patient-reported outcome measure (PROM) scores and patient satisfaction following elective RTSA. These findings emphasise the need to question the appropriateness of standard PROM scores for the assessment of outcome and success following elective RTSA.

Purpose: To determine the association between training-load (TL) factors, baseline characteristics, and new injury and/or pain (IP) risk in an endurance sporting population (ESP). Methods: Ninety-five ESP participants from running, triathlon, swimming, cycling, and rowing disciplines initially completed a questionnaire capturing baseline characteristics. TL and IP data were submitted weekly over a 52-wk study period. Cumulative TL factors, acute:chronic workload ratios, and exponentially weighted moving averages were calculated. A shared frailty model was used to explore time to new IP and association to TL factors and baseline characteristics. Results: 92.6% of the ESP completed all 52 wk of TL and IP data. The following factors were associated with the lowest risk of a new IP episode: (a) a low to moderate 7-d lag exponentially weighted moving averages (0.8–1.3: hazard ratio [HR] = 1.21; 95% confidence interval [CI], 1.01–1.44; P = .04); (b) a low to moderate 7-d lag weekly TL (1200–1700 AU: HR = 1.38; 95% CI, 1.15–1.65; P P P = .04). Conclusions: To minimize new IP risk, an ESP should avoid high spikes in acute TL while maintaining moderate to high chronic TLs. A history of previous IP should be considered when prescribing TLs. The demonstration of a lag between a TL factor and its impact on new IP risk may have important implications for future ESP TL analysis.

Background In sub-Saharan Africa, detecting resistance-associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. Objectives The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. Methods RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load >400 copies/mL) were explored by logistic regression analysis. Trial name = MANET (NCT02155101). Results After NNRTI-based therapy, participants (n = 81) had received PI/r-based therapy for a median of 3.2 years and had a confirmed viral load Conclusions Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTI-sparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.

Background Psychotic disorders affect about 3% of the population worldwide and are associated with high personal, social and economic costs. They tend to have their first onset in adolescence. Increasing emphasis has been placed on early intervention to detect illness and minimise disability. In the late 1990s, criteria were developed to identify individuals at high risk for psychotic disorder. These are known as the at-risk mental state (ARMS) criteria. While ARMS individuals have a risk of psychosis much greater than the general population, most individuals meeting the ARMS criteria will not develop psychosis. Despite this, the National Institute for Health and Care Excellence recommends cognitive behavioural therapy (CBT) for all ARMS people. Clinical prediction models that combine multiple patient characteristics to predict individual outcome risk may facilitate identification of patients who would benefit from CBT and conversely those that would benefit from less costly and less intensive regular mental state monitoring. The study will systematically review the evidence on clinical prediction models aimed at making individualised predictions for the transition to psychosis. Methods Database searches will be conducted on PsycINFO, Medline, EMBASE and CINAHL. Reference lists and subject experts will be utilised. No language restrictions will be placed on publications, but searches will be restricted to 1994 onwards, the initial year of the first prospective study using ARMS criteria. Studies of any design will be included if they examined, in ARMS patients, whether more than one factor in combination is associated with the risk of transition to psychosis. Study quality will be assessed using the prediction model risk of bias assessment tool (PROBAST). Clinical prediction models will be summarised qualitatively, and if tested in multiple validation studies, their predictive performance will be summarised using a random-effects meta-analysis model. Discussion The results of the review will identify prediction models for the risk of transition to psychosis. These will be informative for clinicians currently treating ARMS patients and considering potential preventive interventions. The conclusions of the review will also inform the possible update and external validation of prediction models and clinical prediction rules to identify those at high or low risk of transition to psychosis. Trial registration The review has been registered with PROSPERO (CRD42018108488).

Aim To determine whether acoustic radiation force imaging (ARFI) of the liver/spleen could be used in patients with cirrhosis to predict the presence of gastroesophageal varices (GOVs). Materials and methods Fifty-eight patients with cirrhosis who were undergoing 6-monthly ultrasound examinations for hepatoma surveillance and who were due to have oesophagogastroduodenoscopy (OGD) within 6 months of their ultrasound were recruited. During routine ultrasound, the patient's liver and spleen were also assessed using ARFI. Other clinical parameters (platelet count, spleen size, and transient elastography measurements) were also collected. Logistic regression was used to determine which variables were significantly associated with presence or absence of varices univariably and multivariably Results Fourteen patients (24%) had GOVs. Patients with GOVs had higher ARFI measurements in the liver and spleen than patients without GOVs (liver: 2.39 versus 2.13, spleen: 2.89 versus 2.82), but these results were not statistically significant (odds ratio=1.75, 95% confidence interval [CI]=0.82, 3.91 and odds ratio=1.12, 95% CI=0.33, 3.97, respectively). The platelet/splenic ratio, in comparison, was associated with the presence or absence of GOVs in multivariate analysis (odds ratio=0.32, 95% CI=0.008, 0.91). Conclusion Although patients with GOVs had overall higher ARFI liver and spleen results, this was not statistically significant. As such, ARFI cannot yet replace OGD in predicting GOVs in this patient group.

Antiretroviral treatment (ART) programs in sub-Saharan Africa have for many years included lamivudine as the sole hepatitis B virus (HBV) inhibitor. Long-term outcomes and the effects of introducing tenofovir as part of ART in these populations have not been characterized.The study comprised a cross-sectional analysis of 106 human immunodeficiency virus (HIV)/HBV-coinfected subjects maintained on lamivudine, as well as a prospective analysis of 76 lamivudine-experienced subjects who introduced tenofovir. Patients underwent assessment of liver fibrosis by transient elastography (TE) and testing to characterize HIV type 1 (HIV-1) and HBV replication.After a median of 45 months of lamivudine treatment, HIV-1 RNA and HBV DNA were detectable in 35 of 106 (33.0%) and 54 of 106 (50.9%) subjects, respectively, with corresponding drug resistance rates of 17 of 106 (16.0%) and 31 of 106 (29.2%), respectively. Median TE values were 5.7 kPa (interquartile range, 4.7-7.2 kPa) and independently associated with HBV DNA load, aspartate aminotransferase levels, and platelet counts; 13 of 106 (12.3%) subjects had TE measurements9.4 kPa. Twelve months after the first assessment, and a median of 7.8 months after introducing tenofovir, HBV DNA levels declined by a mean of 1.5 log10 IU/mL (P.001). TE values changed by a mean of -0.2 kPa (P = .097), and declined significantly in subjects who had pretenofovir HBV DNA levels2000 IU/mL (mean, -0.8 kPa; P = .048) or TE values7.6 kPa (mean, -1.2 kPa; P = .021). HIV-1 RNA detection rates remained unchanged.A proportion of HIV/HBV-coinfected patients on long-term lamivudine-containing ART had poor HIV and HBV suppression, drug resistance, and TE values indicative of advanced liver fibrosis. Tenofovir improved HBV control and reduced liver stiffness in subjects with high HBV DNA load and TE values.

IntroductionThe literature suggests that there is variation in various features of the written radiology report for a range of body areas and imaging modalities. The retrospective study presented here aims to determine if similar variation is demonstrated in a group of 5 reporting radiographers in a UK NHS Trust.MethodsFull reports for 1530 knee radiographic examinations performed from accident and emergency referrals were extracted for a 12-month period from a Radiology Information System (RIS) into Excel. Copied into Word, the word count function was used for each report and the number of words and characters (without spaces) was returned into Excel. Average word count and word length per report, by radiographer, were calculated for the following sections of the report: report title, main body and signature. SPSS was used to perform inferential statistical analysis.ResultsA wide range in the maximum and minimum average report lengths (60.88 v 17.83 words) was demonstrated. Statistically significant differences (p ConclusionVariation in report structure and length, as well as word length, was seen, comparable to studies of radiologist reports. Further research is required to investigate the drivers of this variation, and determine if there is any clinical significance.

© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Viral meningitis is increasingly recognised, but little is known about the frequency with which it occurs, or the causes and outcomes in the UK. We aimed to determine the incidence, causes, and sequelae in UK adults to improve the management of patients and assist in health service planning. Methods: We did a multicentre prospective observational cohort study of adults with suspected meningitis at 42 hospitals across England. Nested within this study, in the National Health Service (NHS) northwest region (now part of NHS England North), was an epidemiological study. Patients were eligible if they were aged 16 years or older, had clinically suspected meningitis, and either underwent a lumbar puncture or, if lumbar puncture was contraindicated, had clinically suspected meningitis and an appropriate pathogen identified either in blood culture or on blood PCR. Individuals with ventricular devices were excluded. We calculated the incidence of viral meningitis using data from patients from the northwest region only and used these data to estimate the population-standardised number of cases in the UK. Patients self-reported quality-of-life and neuropsychological outcomes, using the EuroQol EQ-5D-3L, the 36-Item Short Form Health Survey (SF-36), and the Aldenkamp and Baker neuropsychological assessment schedule, for 1 year after admission. Findings: 1126 patients were enrolled between Sept 30, 2011, and Sept 30, 2014. 638 (57%) patients had meningitis: 231 (36%) cases were viral, 99 (16%) were bacterial, and 267 (42%) had an unknown cause. 41 (6%) cases had other causes. The estimated annual incidence of viral meningitis was 2·73 per 100 000 and that of bacterial meningitis was 1·24 per 100 000. The median length of hospital stay for patients with viral meningitis was 4 days (IQR 3–7), increasing to 9 days (6–12) in those treated with antivirals. Earlier lumbar puncture resulted in more patients having a specific cause identified than did those who had a delayed lumbar puncture. Compared with the age-matched UK population, patients with viral meningitis had a mean loss of 0·2 quality-adjusted life-years (SD 0·04) in that first year. Interpretation: Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services. Funding: Meningitis Research Foundation and UK National Institute for Health Research.

Ablation Effectiveness Quotient Introduction Inability to predict clinical outcome despite acutely successful pulmonary vein isolation (PVI) remains the Achilles’ heel of atrial fibrillation ablation (AFA). Arrhythmia recurrence is frequently due to recovery of radiofrequency (RF) ablation lesions believed to be complete at the original procedure. Objectives We hypothesized that a high ratio between post-AFA levels of serum high sensitivity cardiac troponin T (HScTnT), a highly specific marker of acute myocardial injury, and duration of RF application (the ablation effectiveness quotient, AEQ) would indicate effective ablation and correlate with early clinical success. Methods We prospectively measured HScTnT levels in 60 patients (42 [70%] male, 22 [37%] with paroxysmal AF [PAF], mean age 62.5 ± 10.6 years) 12–18 hours after AFA and calculated the AEQ for each. Patients were followed-up with ECGs and Holter monitors for recurrence of atrial tachyarrhythmia (AT). Results Early recurrence of AT within 6 months occurred in 22 (37%). AT recurrence was not significantly related to left atrial size or comorbidities, nor to RF time or HScTnT level. Mean AEQ was significantly lower in those with recurrence than those without (0.35 ± 0.14 ng/L/s vs. 0.45 ± 0.18 ng/L/s), P = 0.02. Subgroup analysis showed this finding was due to patients with PAF in whom early significance was maintained to one year, with an AEQ >0.4 ng/L/s having 75% sensitivity and 90% specificity in predicting freedom from AT. Conclusion A high AEQ correlates well with freedom from AT in patients with PAF in both the short and medium term. If confirmed in further studies, AEQ may become a useful marker of risk of AT post-AFA.

BackgroundMaintaining sinus rhythm in patients with non-paroxysmal atrial fibrillation (AF) is an elusive goal. Some suggest that hybrid ablation, combining minimally-invasive epicardial surgical ablation with endocardial catheter ablation, may be more effective than either modality alone. However, randomised trials are lacking. ObjectivesWe investigated whether hybrid ablation is more effective than epicardial ablation alone at preventing recurrent AF by performing a systematic review and meta-analysis.MethodsThe review was prospectively registered with PROSPERO (CRD42016043389). MEDLINE and EMBASE were searched for studies of standalone minimally invasive epicardial ablation of AF and/or hybrid ablation, identifying 41 non-overlapping studies comprising 2737 patients. A random-effects meta-analysis, meta-regression, and sensitivity analysis were performed.ResultsSingle-procedure survival free from atrial arrhythmias without antiarrhythmic drugs (AADs) was similar between epicardial-alone and hybrid approaches at 12 (epicardial-alone 71.5%, 95% confidence intervals (CI) 66.1-76.9%; hybrid 63.2%, CI 51.5-75.0%) and 24 months (epicardial-alone 68.5%, CI 57.7-79.3%; hybrid 57.0%, CI 33.6-80.4%). Freedom from atrial arrhythmias with AADs and rates of unplanned additional catheter ablations were also similar between groups. Major complications occurred more often with hybrid ablation (epicardial-alone 2.9%, CI 1.9-3.9%; hybrid 7.3%, CI 4.2-10.5%). Meta-regression suggested that bipolar radiofrequency energy and thoracoscopic access were associated with greater efficacy, but adjusting for these factors did not unmask any difference between epicardial-alone and hybrid ablation.ConclusionsHybrid and epicardial ablation alone appear to be equally effective treatments for AF, although hybrid ablation may be associated with higher complication rates. This data derived from observational studies should be verified with randomised data.

Objectives A breakthrough seizure is one occurring after at least 12 months seizure freedom while on treatment. The Driver and Vehicle Licensing Agency (DVLA) allows an individual to return to driving once they have been seizure free for 12 months following a breakthrough seizure. This is based on the assumption that the risk of a further seizure in the next 12 months has dropped

Background Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required. Methods A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Results Of 248 included studies, 229 considered “on-treatment” outcomes whilst 148 reported “off-treatment” outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of “intensive” and “continuation” phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome. Conclusions Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials. Electronic supplementary material The online version of this article (10.1186/s13063-018-2522-x) contains supplementary material, which is available to authorized users.

Background— Catheter ablation (CA) is commonly performed for persistent atrial fibrillation, but few high-quality randomized controlled trials (RCTs) exist, leading to funding restrictions being proposed in several countries. We performed a random-effects meta-analysis of RCTs and non-RCTs to assess the efficacy of CA for persistent atrial fibrillation. Methods and Results— We systematically searched PubMed, EMBASE, CENTRAL, OpenGrey, and clinicaltrials.gov for RCTs and non-RCTs reporting clinical outcomes after CA for persistent atrial fibrillation. Forty-six eligible studies were identified containing 3819 patients. After a single procedure, CA significantly reduced the risk of recurrent atrial fibrillation compared with medical therapy (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.20–0.53; P P =0.01), and electrical isolation reduced AF recurrence compared with purely anatomic encirclement (OR, 0.33; 95% CI, 0.13–0.86; P =0.02). Linear ablation within the left atrium (OR, 0.22; 95% CI, 0.10–0.49; P P =0.15), significantly reduced AF recurrence. Results were not improved by performing more extensive linear lesion sets (OR, 0.77; 95% CI, 0.41–1.43; P =0.40) or from biatrial ablation (OR, 0.62; 95% CI, 0.31–1.24; P =0.17). Where data were available, the relative benefits seen held true both after a single or multiple procedure(s). Sensitivity analyses showed that inclusion of non-RCTs increased statistical power without biasing the calculated effect sizes. Conclusions— For patients with persistent atrial fibrillation, CA achieves significantly greater freedom from recurrent atrial fibrillation compared with medical therapy. The most efficacious strategy is likely to combine isolation of the pulmonary veins with limited linear ablation within the left atrium.

Aims The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD). Methods Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (

Objectives: We assessed the likelihood of 12-month seizure remission and treatment failure after failure of a first antiepileptic drug, and identified factors influencing these outcomes. Methods: SANAD (Standard and New Antiepileptic Drug) was a randomized controlled trial comparing monotherapy with standard and new antiepileptic drugs. Patients were followed up to study completion, even if they were switched from their randomized treatment. After a first treatment failure, we assessed the probability of 12-month seizure remission and treatment failure. Prognostic modeling identified predictors of these outcomes. Results: Forty-four percent of patients in the SANAD trial had a first treatment failure. Seventy-five percent of these subsequently achieved 12-month remission by 6 years of follow-up. Significant prognostic factors included sex, age at treatment failure, time on randomized treatment at treatment failure, neurologic insult, total number of tonic-clonic seizures at treatment failure, reason for treatment failure, seizure type, and CT/MRI scan result. After a first treatment failure, young patients without tonic-clonic seizures, with a normal CT/MRI scan and failing their treatment because of unacceptable adverse events, had the highest likelihood of 12-month remission. Approximately 50% of patients who failed a first treatment also failed their second. Significant prognostic factors included total number of tonic-clonic seizures at first treatment failure, reason for first treatment failure, and CT/MRI scan result. Patients with tonic-clonic seizures and failing because of inadequate seizure control had the highest risk of a second treatment failure. Conclusions: A high proportion of patients will achieve 12-month remission after a first treatment failure. Clinical factors can stratify patients according to likely outcome.

Vascular Ultrasound for AFA Introduction The most frequent complications of AF ablation (AFA) are related to vascular access, but there is little evidence as to how these can be minimized. Methods Consecutive patients undergoing AFA at a high-volume center received either standard care (Group S) or routine ultrasound-guided vascular access (Group U). Vascular complications were assessed before hospital discharge and by means of postal questionnaire 1 month later. Outcome measures were BARC 2+ bleeding complications, postprocedural pain, and prolonged bruising. Results Patients in Group S (n = 146) and U (n = 163) were well matched at baseline. Follow-up questionnaires were received from 92.6%. Patients in Group U were significantly less likely to have a BARC 2+ bleed, 10.4% versus 19.9% P = 0.02, were less likely to suffer groin pain after discharge (27.1% vs. 42.8%; P = 0.006) and were less likely to experience prolonged local bruising (21.5% vs. 40.4%; P = 0.001). Multivariable logistic regression analysis revealed a significant association of vascular complications with nonultrasound guided access (OR 3.12 95%CI 1.54–5.34; P = 0.003) and increasing age (OR 1.05 95%CI 1.01–1.09; P = 0.02). Conclusion Routine use of ultrasound-guided vascular access for AFA is associated with a significant reduction in bleeding complications, postprocedural pain, and prolonged bruising when compared to standard care.

Aims To validate the European Heart Rhythm Association (EHRA) symptom classification in atrial fibrillation (AF) and test whether its discriminative ability could be improved by a simple modification. Methods and results We compared the EHRA classification with three quality of life (QoL) measures: the AF-specific Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire; two components of the EQ-5D instrument, a health-related utility which can be used to calculate cost-effectiveness, and the visual analogue scale (VAS) which demonstrates patients' own assessment of health status. We then proposed a simple modification [modified EHRA (mEHRA)] to improve discrimination at the point where major treatment decisions are made. quality of life data and clinician-allocated EHRA class were prospectively collected on 362 patients with AF. A step-wise, negative association was seen between the EHRA class and both the AFEQT and the VAS scores. Health-related utility was only significantly different between Classes 2 and 3 ( P < 0.001). We developed and validated the mEHRA score separating Class 2 (symptomatic AF not limiting daily activities), based on whether the patients were ‘troubled by their AF’ (Class 2b) or not (Class 2a). This produced two distinct groups with lower AFEQT and VAS scores and, importantly, both clinically and statistically significant lower health utility (Δutility 0.9, P = 0.01) in Class 2b than Class 2a. Conclusion Based on patients' own assessment of their health status and the disease-specific AFEQT, the EHRA score can be considered a useful semi-quantitative classification. The mEHRA score has a clearer separation in health utility to assess the cost efficacy of interventions such as ablation, where Class 2b symptoms appear to be the appropriate treatment threshold.

ObjectivesTo develop prognostic models for risk of a breakthrough seizure, risk of seizure recurrence after a breakthrough seizure, and likelihood of achieving 12-month remission following a breakthrough seizure. A breakthrough seizure is one that occurs following at least 12 months remission whilst on treatment.MethodsWe analysed data from the SANAD study. This long-term randomised trial compared treatments for participants with newly diagnosed epilepsy. Multivariable Cox models investigated how clinical factors affect the probability of each outcome. Best fitting multivariable models were produced with variable reduction by Akaike's Information Criterion. Risks associated with combinations of risk factors were calculated from each multivariable model.ResultsSignificant factors in the multivariable model for risk of a breakthrough seizure following 12-month remission were number of tonic-clonic seizures by achievement of 12-month remission, time taken to achieve 12-month remission, and neurological insult. Significant factors in the model for risk of seizure recurrence following a breakthrough seizure were total number of drugs attempted to achieve 12-month remission, time to achieve 12-month remission prior to breakthrough seizure, and breakthrough seizure treatment decision. Significant factors in the model for likelihood of achieving 12-month remission after a breakthrough seizure were gender, age at breakthrough seizure, time to achieve 12-month remission prior to breakthrough, and breakthrough seizure treatment decision.ConclusionsThis is the first analysis to consider risk of a breakthrough seizure and subsequent outcomes. The described models can be used to identify people most likely to have a breakthrough seizure, a seizure recurrence following a breakthrough seizure, and to achieve 12-month remission following a breakthrough seizure. The results suggest that focussing on achieving 12-month remission swiftly represents the best therapeutic aim to reduce the risk of a breakthrough seizure and subsequent negative outcomes. This will aid individual patient risk stratification and the design of future epilepsy trials.

Summary Background Epilepsy is a heterogeneous disorder, with outcomes ranging from immediate remission after taking a first antiepileptic drug to frequent unremitting seizures with multiple treatment failures. Few prognostic models enable prediction of outcome; we therefore aimed to use data from the SANAD study to predict outcome overall and for patients receiving specific treatments. Methods The SANAD study was a randomised controlled trial in which standard antiepileptic drugs were compared with new treatments. Arm A included patients for whom carbamazepine was considered the first-line treatment, most of whom were newly diagnosed with focal epilepsy. Patients were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Outcomes were time to treatment failure overall, because of inadequate seizure control, and because of adverse events, and time to 12 months of remission from seizures. In this post-hoc study we used regression multivariable modelling to investigate how clinical factors affect the probability of treatment failure and the probability of achieving 12 months of remission. Findings For time to treatment failure, we identified several significant risk factors: sex (male vs female, hazard ratio [HR] 0·86, 95% CI 0·75–0·99), treatment history (taking non-SANAD antiepileptic drugs [other than those listed above] vs treatment naive, 1·27, 1·05–1·53), age (eg, older than 71 years vs 10 years or younger, 0·68, 0·51–0·91), total number of seizures (eg, four to 11 seizures vs two or fewer, 1·08, 1·05–1·11), electroencephalogram results (epileptiform abnormality vs normal, 1·26, 1·07–1·50), seizure type (eg, secondary generalised vs simple or complex partial only, 0·78, 0·66–0·91), site of onset (not localised vs temporal lobe, 1·25, 1·06–1·47), and treatment (lamotrigine vs carbamazepine, 0·76, 0·61–0·95). Significant factors for time to 12 months of remission were sex (male vs female, 1·19, 1·05–1·35), treatment history (taking a non-SANAD antiepileptic drug vs treatment naive, 0·64, 0·52–0·78), age (eg, older than 71 years vs 10 years or younger, 1·60, 1·26–2·03), time from first seizure (60–239 months vs ≥2 months, 1·14, 1·01–1·29; >240 months vs ≤2 months, 1·39, 1·04–1·86), neurological insult (present vs absent, 0·75, 0·61–0·93), total number of seizures before randomisation (eg, four to 11 vs two or fewer, 0·87, 0·85–0·90), and treatment (gabapentin vs carbamazepine, 0·71, 0·59–0·86; topiramate vs carbamazepine, 0·81, 0·68–0·98). Interpretation We present a thorough investigation of prognostic factors from a large randomised controlled trial in patients starting antiepileptic monotherapy. If validated, our models could aid in individual patient risk stratification and the design and analysis of epilepsy trials. Funding National Institute for Health Research (UK).

Background Patients with asthma who present with lower respiratory tract infections (LRTIs) often receive antibiotics. There is uncertainty about the need for and consequences of antibiotic administration. Objective To describe the demographic characteristics of and antibiotic prescriptions for adult patients with asthma with LRTI and investigate factors associated with repeat antibiotic courses. Methods We analyzed prescriptions of antibiotics for LRTIs in UK primary care from 2010 to 2015 using the Optimum Care Database. The primary outcome was a second antibiotic prescription for an LRTI code within 14 days of index prescription, as a proxy of initial treatment failure. A model for repeat prescriptions was derived using univariable and multivariable logistic regression analyses. Results We assessed 28,289 cases with complete data sets, 6.5% of which received a second antibiotic course. Amoxicillin and clarithromycin respectively were used most commonly as index and second agents. The most frequent course length was 7 days for both index and repeat prescriptions. Multivariable analysis demonstrated that age, index antibiotic and duration, smoking status, location, and number of consultations and oral steroid courses in the previous year were significantly associated with repeat prescriptions. The derived model predicted the binary outcome adequately (Cox-Snell R2, 0.012; area under curve, 0.62; 95% CI, 0.61-0.63). Comorbidities, vaccinations, asthma treatment, and number of exacerbations were significant only in the univariable analysis. Conclusions The current index prescribing preference of 7 days of amoxicillin correlated to fewer repeat courses. Baseline asthma treatment was not associated with risk of further prescriptions. Antibiotic administration in older patients with a smoking history could be a target for future studies.