Incidental findings in MRI of the brain.

This review investigates that there has been an increase in incidental brain MRI findings due to better technology and more scans. These unexpected, asymptomatic anomalies range from harmless to serious, requiring careful clinical and ethical handling. The prevalence of incidental findings with brain MRI is 4.2% and even higher when including white matter hyperintensities. There is a significant variation in this number dependent on the age of the person being scanned and the MRI quality.

Intracranial pressure following surgery of an unruptured intracranial aneurysm-a model for normal intracranial pressure in humans.

OBJECTIVE: Optimizing the treatment of several neurosurgical and neurological disorders relies on knowledge of the intracranial pressure (ICP). However, exploration of normal ICP and intracranial pressure pulse wave amplitude (PWA) values in healthy individuals poses ethical challenges, and thus the current documentation remains scarce. This study explores ICP and PWA values for healthy adults without intracranial pathology expected to influence ICP. METHODS: Adult patients (age > 18 years) undergoing surgery for an unruptured intracranial aneurysm without any other neurological co-morbidities were included. Patients had a telemetric ICP sensor inserted, and ICP was measured in four different positions: supine, lateral recumbent, standing upright, and 45-degree sitting, at day 1, 14, 30, and 90 following the surgery. RESULTS: ICP in each position did not change with time after surgery. Median ICP was 6.7 mmHg and median PWA 2.1 mmHg in the supine position, while in the upright standing position median ICP was - 3.4 mmHg and median PWA was 1.9 mmHg. After standardization of the measurements from the transducer site to the external acoustic meatus, the median ICPmidbrain was 8.3 mmHg in the supine position and 1.2 mmHg in the upright standing position. CONCLUSION: Our study provides insights into normal ICP dynamics in healthy adults following a uncomplicated surgery for an unruptured aneurysm. These results suggest a slightly wider normal reference range for invasive intracranial pressure than previously suggested, and present the first normal values for PWA in different positions. Further studies are, however, essential to enhance our understanding of normal ICP. Trial registration The study was preregistered at www. CLINICALTRIALS: gov (NCT03594136) (11 July 2018).

Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg-1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg-1 AP30663, 5 mg kg-1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg-1 and 5 mg kg-1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg-1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .

Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI): a multicentre observational cohort study.

BACKGROUND: Patients with traumatic brain injury are a heterogeneous population, and the most severely injured individuals are often treated in an intensive care unit (ICU). The primary injury at impact, and the harmful secondary events that can occur during the first week of the ICU stay, will affect outcome in this vulnerable group of patients. We aimed to identify clinical variables that might distinguish disease trajectories among patients with traumatic brain injury admitted to the ICU. METHODS: We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. We included patients aged 18 years or older with traumatic brain injury who were admitted to the ICU at one of the 65 CENTER-TBI participating centres, which range from large academic hospitals to small rural hospitals. For every patient, we obtained pre-injury data and injury features, clinical characteristics on admission, demographics, physiological parameters, laboratory features, brain biomarkers (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], S100 calcium-binding protein B [S100B], tau, neurofilament light [NFL], glial fibrillary acidic protein [GFAP], and neuron-specific enolase [NSE]), and information about intracranial pressure lowering treatments during the first 7 days of ICU stay. To identify clinical variables that might distinguish disease trajectories, we applied a novel clustering method to these data, which was based on a mixture of probabilistic graph models with a Markov chain extension. The relation of clusters to the extended Glasgow Outcome Scale (GOS-E) was investigated. FINDINGS: Between Dec 19, 2014, and Dec 17, 2017, 4509 patients with traumatic brain injury were recruited into the CENTER-TBI core dataset, of whom 1728 were eligible for this analysis. Glucose variation (defined as the difference between daily maximum and minimum glucose concentrations) and brain biomarkers (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were consistently found to be the main clinical descriptors of disease trajectories (ie, the leading variables contributing to the distinguishing clusters) in patients with traumatic brain injury in the ICU. The disease trajectory cluster to which a patient was assigned in a model was analysed as a predictor together with variables from the IMPACT model, and prediction of both mortality and unfavourable outcome (dichotomised GOS-E ≤4) was improved. INTERPRETATION: First-day ICU admission data are not the only clinical descriptors of disease trajectories in patients with traumatic brain injury. By analysing temporal variables in our study, variation of glucose was identified as the most important clinical descriptor that might distinguish disease trajectories in the ICU, which should direct further research. Biomarkers of brain injury (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were also top clinical descriptors over time, suggesting they might be important in future clinical practice. FUNDING: European Union 7th Framework program, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences Corporation, and NeuroTrauma Sciences.

A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation.

AIMS: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial. METHODS: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. RESULTS: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h. CONCLUSION: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the IKr channel.

Prediction of shunt response in idiopathic normal pressure hydrocephalus by combined lumbar infusion test and preoperative imaging scoring.

BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable disorder, but prognostic tests or biomarkers are lacking. The aim was to study the predictive power of clinical, neuroimaging and lumbar infusion test parameters (resistance to outflow Rout , cardiac-related pulse amplitude PA and the PA to intracranial pressure ICP ratio). METHODS: In all, 127 patients diagnosed with iNPH who had a lumbar infusion test, a subsequent ventriculo-peritoneal shunt operation and at least 2 months of postoperative follow-up were retrospectively included. Preoperative magnetic resonance images were visually scored for NPH features using the iNPH Radscale. Preoperative and postoperative assessment was performed using cognitive testing, as well as gait and incontinence scales. RESULTS: At follow-up (7.4 months, range 2-20 months), an overall positive response was seen in 82% of the patients. Gait was more severely impaired at baseline in responders compared to non-responders. The iNPH Radscale score was borderline significantly higher in responders compared with non-responders, whereas no significant differences in infusion test parameters were seen between responders and non-responders. Infusion test parameters performed modestly with high positive (75%-92%) but low negative (17%-23%) predictive values. Although not significant, PA and PA/ICP seemed to perform better than Rout , and the odds ratio for shunt response seemed to increase in patients with higher PA/ICP, especially in patients with lower iNPH Radscale scores. CONCLUSION: Although only indicative, lumbar infusion test results increased the likelihood of a positive shunt outcome. Pulse amplitude measures showed promising results that should be further explored in prospective studies.

Association between primary care electrocardiogram markers and Alzheimer's disease.

OBJECTIVE: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population. METHODS: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more. RESULTS: We followed 172,236 subjects for a median of 7.5 years. Increased PR interval (hazard ratio for PR > 188 ms: 0.76 [95% confidence interval: 0.69-0.83, p < 0.001) and increased QTc interval (hazard ratio for QTc = [426;439]: 0.90 [0.83-0.98], p = 0.02) were associated with a decreased rate of Alzheimer's disease. A positive Sokolow-Lyon index >35 mm (1.22 [1.13-1.33], p < 0.001) and increased T-wave amplitude >4.1 mm (1.15 [1.04-1.27]) were associated with an increased rate of Alzheimer's disease. Upon addition of ECG markers to a reference model, 10-year prediction area under the receiver-operator characteristics curve (AUC) improved by 0.39 [0.06-0.67] %-points. The 10-year absolute risk of Alzheimer's disease was 6.5% and 5.2% for an 82-year old female and a male, respectively, with a favorable ECG, and 12% and 9.2%, respectively, with an unfavorable ECG, almost twice as high. CONCLUSIONS: We identified several common ECG markers which were associated with Alzheimer's disease, and which improved risk prediction for Alzheimer's disease.

Mortality among patients treated for aneurysmal subarachnoid hemorrhage in Eastern Denmark 2017-2019.

OBJECTIVE: The aim of the study was to investigate (1) the 30-day, 3-month, and 12-month cumulative mortalities for patients who underwent aneurysm occlusion, and (2) the causes of death, and (3) the potential risk factors for death. METHODS: All patients who underwent surgical clipping or endovascular treatment of a ruptured aneurysm at Copenhagen University Hospital, during the period of January 1, 2017-December 31, 2019, were included and followed up for 12 months. Data regarding vital status, causes of death, comorbidities, treatment, and clinical presentations on admission was collected. The absolute mortality risk was estimated as a function of time with a 95% confidence interval. The associations between potential risk factors and death were estimated as odds ratios with 95% confidence intervals using logistic regression models. RESULTS: A total of 317 patients were included. The overall cumulative mortalities after 30 days, 3 months, and 12 months were 10.7%, 12.9%, and 16.1%, respectively. The most common cause of death was severe primary hemorrhage (52.9%), followed by infections (15.7%) and rebleeding (11.8%). WFNS score > 3 and Fisher score > 3 on admission, preprocedural hydrocephalus, and preprocedural rebleeding were found significantly associated with higher risk of death. CONCLUSIONS: Considerable mortality was seen. Possible preventable causes accounted for approximately 22% of the deaths. The occurrence of both pre- and postprocedural rebleeding's indicates an opportunity of further improvement of the mortality by (1) further reduction of time from aSAH to aneurysm occlusion and (2) continuous efforts in improving methods of aneurysm occlusion.

Associations between primary care electrocardiography and non-Alzheimer dementia.

OBJECTIVES: To determine whether electrocardiogram (ECG) markers are associated with incident non-Alzheimer's dementia (non-AD) and whether these markers also improve risk prediction for non-AD. MATERIALS AND METHODS: We retrospectively included 170,605 primary care patients aged 60 years or older referred for an ECG by their general practitioner and followed them for a median of 7.6 years. Using Cox regression, we reported hazard ratios (HRs) for electrocardiogram markers. Subsequently, we evaluated if addition of these electrocardiogram markers to a clinical model improved risk prediction for non-AD using change in area under the receiver-operator characteristics curve (AUC). RESULTS: The 5-year cumulative incidence of non-AD was 3.4 %. Increased heart rate (HR=1.06 pr. 10 bpm [95% confidence interval: 1.04-1.08], p<0.001), shorter QRS duration (HR=1.07 pr. 10 ms [1.05-1.09], p<0.001), elevated J-amplitude (HR=1.16 pr. mm [1.08-1.24], p<0.001), decreased T-peak amplitude (HR=1.02 pr. mm [1.01-1.04], p=0.002), and increased QTc (HR=1.08 pr. 20 ms [1.05-1.10], p<0.001) were associated with an increased rate of non-AD. Atrial fibrillation on the ECG (HR=1.18 [1.08-1.28], p<0.001) Sokolow-Lyon index > 35 mm (HR=1.31 [1.18-1.46], p<0.001) and borderline (HR=1.18 [1.11-1.26], p<0.001) or abnormal (HR=1.40 [1.27-1.55], p<0.001) QRS-T angle were also associated with an increased rate of non-AD. Upon addition of ECG markers to the Cox model, 5-year and 10-year C-statistic (AUC) improved significantly (delta-AUC, 0.36 [0.18-0.50] and 0.20 [0.03-0.35] %-points, respectively). CONCLUSIONS: ECG markers typical of an elevated cardiovascular risk profile were associated with non-AD and improved both 5-year and 10-year risk predictions for non-AD.

Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study.

BACKGROUND: While the Glasgow coma scale (GCS) is one of the strongest outcome predictors, the current classification of traumatic brain injury (TBI) as 'mild', 'moderate' or 'severe' based on this fails to capture enormous heterogeneity in pathophysiology and treatment response. We hypothesized that data-driven characterization of TBI could identify distinct endotypes and give mechanistic insights. METHODS: We developed an unsupervised statistical clustering model based on a mixture of probabilistic graphs for presentation (< 24 h) demographic, clinical, physiological, laboratory and imaging data to identify subgroups of TBI patients admitted to the intensive care unit in the CENTER-TBI dataset (N = 1,728). A cluster similarity index was used for robust determination of optimal cluster number. Mutual information was used to quantify feature importance and for cluster interpretation. RESULTS: Six stable endotypes were identified with distinct GCS and composite systemic metabolic stress profiles, distinguished by GCS, blood lactate, oxygen saturation, serum creatinine, glucose, base excess, pH, arterial partial pressure of carbon dioxide, and body temperature. Notably, a cluster with 'moderate' TBI (by traditional classification) and deranged metabolic profile, had a worse outcome than a cluster with 'severe' GCS and a normal metabolic profile. Addition of cluster labels significantly improved the prognostic precision of the IMPACT (International Mission for Prognosis and Analysis of Clinical trials in TBI) extended model, for prediction of both unfavourable outcome and mortality (both p < 0.001). CONCLUSIONS: Six stable and clinically distinct TBI endotypes were identified by probabilistic unsupervised clustering. In addition to presenting neurology, a profile of biochemical derangement was found to be an important distinguishing feature that was both biologically plausible and associated with outcome. Our work motivates refining current TBI classifications with factors describing metabolic stress. Such data-driven clusters suggest TBI endotypes that merit investigation to identify bespoke treatment strategies to improve care. Trial registration The core study was registered with ClinicalTrials.gov, number NCT02210221 , registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582).

Identifying causal relationships of cancer treatment and long-term health effects among 5-year survivors of childhood cancer in Southern Sweden.

Background: Survivors of childhood cancer can develop adverse health events later in life. Infrequent occurrences and scarcity of structured information result in analytical and statistical challenges. Alternative statistical approaches are required to investigate the basis of late effects in smaller data sets. Methods: Here we describe sex-specific health care use, mortality and causal associations between primary diagnosis, treatment and outcomes in a small cohort (n = 2315) of 5-year survivors of childhood cancer (n = 2129) in southern Sweden and a control group (n = 11,882; age-, sex- and region-matched from the general population). We developed a constraint-based method for causal inference based on Bayesian estimation of distributions, and used it to investigate health care use and causal associations between diagnoses, treatments and outcomes. Mortality was analyzed by the Kaplan-Meier method. Results: Our results confirm a significantly higher health care usage and premature mortality among childhood cancer survivors as compared to controls. The developed method for causal inference identifies 98 significant associations (p < 0.0001) where most are well known (n = 73; 74.5%). Hitherto undescribed associations are identified (n = 5; 5.1%). These were between use of alkylating agents and eye conditions, topoisomerase inhibitors and viral infections; pituitary surgery and intestinal infections; and cervical cancer and endometritis. We discuss study-related biases (n = 20; 20.4%) and limitations. Conclusions: The findings contribute to a broader understanding of the consequences of cancer treatment. The study shows relevance for small data sets and causal inference, and presents the method as a complement to traditional statistical approaches.

[Arachnoid cysts can be associated with cognitive and affective symptoms].

Arachnoid cysts are frequent incidental findings on brain scans. Traditionally, they are regarded as harmless, congenital structures which do not require surgical treatment. In the rare cases where surgery is indicated it can be due to haemorrhage, hydrocephalus or cranial nerve affection caused by the cyst. However, recent literature suggests a correlation between arachnoid cysts and cognitive and affective symptoms. The hypothesised pathomechanisms include pressure, affected neuronal or glial metabolism and inflammation. If this is correct a more active approach might benefit the patients as suggested in this review.

Fascicular heart blocks and risk of adverse cardiovascular outcomes: Results from a large primary care population.

BACKGROUND: Fascicular heart blocks can progress to complete heart blocks, but this risk has not been evaluated in a large general population. OBJECTIVE: The purpose of this study was to investigate the association between various types of fascicular blocks diagnosed by electrocardiographic (ECG) readings and the risk of incident higher degree atrioventricular block (AVB), syncope, pacemaker implantation, and death. METHODS: We studied primary care patients referred for ECG recording between 2001 and 2015. Cox regression models were used to estimate hazard ratios (HRs) as well as absolute risks of cardiovascular outcomes. RESULTS: Of 358,958 primary care patients (median age 54 years; 55% women), 13,636 (3.8%) had any type of fascicular block. Patients were followed up to 15.9 years. We found increasing HRs of incident syncope, pacemaker implantation, and third-degree AVB with increasing complexity of fascicular block. Compared with no block, isolated left anterior fascicular block (LAFB) was associated with 0%-2% increased 10-year risk of developing third-degree AVB (HR 1.6; 95% confidence interval [CI] 1.25-2.05), whereas right bundle branch block combined with LAFB and first-degree AVB was associated with up to 23% increased 10-year risk (HR 11.0; 95% CI 7.7-15.7), depending on age and sex group. Except for left posterior fascicular block (HR 2.09; 95% CI 1.87-2.32), we did not find any relevant associations between fascicular block and death. CONCLUSION: We found that higher degrees of fascicular blocks were associated with increasing risk of syncope, pacemaker implantation, and complete heart block, but the association with death was negligible.

Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial.

BACKGROUND: It is unknown whether screening for atrial fibrillation and subsequent treatment with anticoagulants if atrial fibrillation is detected can prevent stroke. Continuous electrocardiographic monitoring using an implantable loop recorder (ILR) can facilitate detection of asymptomatic atrial fibrillation episodes. We aimed to investigate whether atrial fibrillation screening and use of anticoagulants can prevent stroke in individuals at high risk. METHODS: We did a randomised controlled trial in four centres in Denmark. We included individuals without atrial fibrillation, aged 70-90 years, with at least one additional stroke risk factor (ie, hypertension, diabetes, previous stroke, or heart failure). Participants were randomly assigned in a 1:3 ratio to ILR monitoring or usual care (control) via an online system in permuted blocks with block sizes of four or eight participants stratified according to centre. In the ILR group, anticoagulation was recommended if atrial fibrillation episodes lasted 6 min or longer. The primary outcome was time to first stroke or systemic arterial embolism. This study is registered with ClinicalTrials.gov, NCT02036450. FINDINGS: From Jan 31, 2014, to May 17, 2016, 6205 individuals were screened for inclusion, of whom 6004 were included and randomly assigned: 1501 (25·0%) to ILR monitoring and 4503 (75·0%) to usual care. Mean age was 74·7 years (SD 4·1), 2837 (47·3%) were women, and 5444 (90·7%) had hypertension. No participants were lost to follow-up. During a median follow-up of 64·5 months (IQR 59·3-69·8), atrial fibrillation was diagnosed in 1027 participants: 477 (31·8%) of 1501 in the ILR group versus 550 (12·2%) of 4503 in the control group (hazard ratio [HR] 3·17 [95% CI 2·81-3·59]; p<0·0001). Oral anticoagulation was initiated in 1036 participants: 445 (29·7%) in the ILR group versus 591 (13·1%) in the control group (HR 2·72 [95% CI 2·41-3·08]; p<0·0001), and the primary outcome occurred in 318 participants (315 stroke, three systemic arterial embolism): 67 (4·5%) in the ILR group versus 251 (5·6%) in the control group (HR 0·80 [95% CI 0·61-1·05]; p=0·11). Major bleeding occurred in 221 participants: 65 (4·3%) in the ILR group versus 156 (3·5%) in the control group (HR 1·26 [95% CI 0·95-1·69]; p=0·11). INTERPRETATION: In individuals with stroke risk factors, ILR screening resulted in a three-times increase in atrial fibrillation detection and anticoagulation initiation but no significant reduction in the risk of stroke or systemic arterial embolism. These findings might imply that not all atrial fibrillation is worth screening for, and not all screen-detected atrial fibrillation merits anticoagulation. FUNDING: Innovation Fund Denmark, The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation, Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, The AFFECT-EU Consortium (EU Horizon 2020), Læge Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat, and Medtronic.

[Endoscopic treatment of hydrocephalus].

Endoscopic treatment of hydrocephalus provides an opportunity to reach deeply located intraventricular obstacles and, as such, it is currently the primary treatment for obstructive hydrocephalus in Denmark. This review provides an overview of conditions treatable with endoscopic neurosurgery including the surgical principles, success rate and challenges with this neurosurgical procedure.

Temporal patterns of organ dysfunction after severe trauma.

BACKGROUND: Understanding temporal patterns of organ dysfunction (OD) may aid early recognition of complications after trauma and assist timing and modality of treatment strategies. Our aim was to analyse and characterise temporal patterns of OD in intensive care unit-admitted trauma patients. METHODS: We used group-based trajectory modelling to identify temporal trajectories of OD after trauma. Modelling was based on the joint development of all six subdomains comprising the sequential organ failure assessment score measured daily during the first two weeks post trauma. Further, the time for trajectories to stabilise and transition to final group assignments were evaluated. RESULTS: Six-hundred and sixty patients were included in the final model. Median age was 40 years, and median ISS was 26 (IQR 17-38). We identified five distinct trajectories of OD. Group 1, mild OD (n = 300), median ISS of 20 (IQR 14-27), had an early resolution of OD and a low mortality. Group 2, moderate OD (n = 135), and group 3, severe OD (n = 87), were fairly similar in admission characteristics and initial OD but differed in subsequent OD trajectories, the latter experiencing an extended course and higher mortality. In group 3, 56% of the patients developed sepsis as compared with 19% in group 2. Group 4, extreme OD (n = 40), received most blood transfusions, had the highest proportion of shock at admission and a median ISS of 41 (IQR 29-50). They experienced significant and sustained OD affecting all organ systems and a 28-day mortality of 30%. Group 5, traumatic brain injury with OD (n = 98), had the highest mortality of 35% and the shortest time to death for non-survivors, median 3.5 (IQR 2.4-4.8) days. Groups 1 and 5 reached their final group assignment early, > 80% of the patients within 48 h. In contrast, groups 2 and 3 had a prolonged time to final group assignment. CONCLUSIONS: We identified five distinct trajectories of OD after severe trauma during the first two weeks post-trauma. Our findings underline the heterogeneous course after trauma and describe some potentially important clinical insights that are suggested by the groupings and temporal trajectories.

Comparison of the three-level and the five-level versions of the EQ-5D.

EQ-5D is a generic instrument to measure health-related quality of life. In 2009, a new version, EQ-5D-5L, was introduced as an attempt to reduce ceiling effects and improve sensitivity to small changes over time. The objective of this study was to assess the measurement properties of the EQ-5D-5L instrument compared to the EQ-5D-3L instrument in an elderly general population with a moderate to a high degree of comorbidity. A subgroup of participants in a large clinical trial completed the EQ-5D-3L and the EQ-5D-5L questionnaires. Based on the collected data, we tested for feasibility and ceiling and floor effects. Furthermore, we assessed the redistribution properties of the responses and examined the level of inconsistency, informativity, and convergent validity. A total of 1002 persons diagnosed with hypertension, diabetes, heart failure, and/or previous stroke completed both the EQ-5D-3L and the EQ-5D-5L questionnaires. The overall ceiling effect decreased from 46% with the EQ-5D-3L to 30% with the EQ-5D-5L and absolute and relative informativity were higher for EQ-5D-5L, and there was a stronger correlation between EQ-5D-5L and EQ VAS. The EQ-5D-5L seemed to perform better than the EQ-5D-3L in terms of feasibility, ceiling effect, discriminatory power, and convergent validity. The overall ceiling effect was higher than that found in patient samples in previous studies but lower than the one found in population studies.

Electrocardiographic T-wave morphology and risk of mortality.

BACKGROUND: Electrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QTc interval, but few measurements of T-wave morphology can be interpreted in clinical practice. Morphology combination score (MCS) is a combination of T-wave flatness/peakedness, asymmetry, and notching, enabling easy visual assessment of T-wave morphology. We aimed to test the association between T-wave morphology, quantified by MCS, and mortality. METHODS: We included electrocardiograms recorded in 2001-2011 from 342,294 primary care patients. Using Cox regression, we evaluated the association between MCS, cardiovascular death, and all-cause mortality, adjusting for heart rate, QTc, QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure. RESULTS: 270,039 individuals (44% men, median age 55 [inter-quartile range: 42-67 years]) were included and followed for a median of 9.3 years, during which time 13,489 (5.0%) died from cardiovascular causes and 50,481 (18.7%) from any cause. High values of MCS (i.e. asymmetric, flattened, and/or notched T waves) were associated with an adjusted mortality Hazard Ratio of 1.75 (95% CI 1.62-1.89) and 1.61 (1.43-1.92) for women and men, respectively. Low values of MCS (i.e. peaked and symmetric T waves) were associated with a Hazard Ratio of 1.18 (1.08-1.28) and 1.71 (1.48-1.98) for women and men, respectively. CONCLUSIONS: In a large primary care population, we found that T-wave asymmetry, flatness, and notching provided prognostic information on mortality independent of heart rate, QTc, and baseline comorbidities.

Early glycaemic changes after initiation of oral antidiabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes.

AIMS: To determine the risk of major adverse cardiovascular events (MACE) and death, associated with an early large and rapid decline in glycated haemoglobin (HbA1C) following first time initiation of an oral antidiabetic drug (OAD). METHODS AND RESULTS: We included 10 518 primary care patients with type 2 diabetes, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5-4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep [≥9 mmol/mol (≥0.8%)] and flat decline [<9 mmol/mol per 3 months (<0.8%)]. Pre-treatment HbA1C was categorized by the median, into levels of low (48-62 mmol/mol) and high (>62 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C. Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7 years, 1625 developed MACE and 2323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.69-0.94; P = 0.005] and low pre-treatment HbA1C (HR 0.79; 95% CI 0.66-0.96; P = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C. We found no significant association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA1C and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00-2.29; P = 0.048) and hypoglycaemia (HR 1.82; 95% CI 1.11-2.98; P = 0.017). CONCLUSION: A combination of a high pre-treatment HbA1C and a steep decline in HbA1C was associated with a decreased short-term risk of MACE. A low pre-treatment HbA1C and a steep decline was associated with a long-term reduced risk of MACE, but a short-term increased risk of death and hypoglycaemia.

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study.

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels.