A meta-analysis of immune-cell fractions at high resolution reveals novel associations with common phenotypes and health outcomes

Background: Changes in cell-type composition of tissues are associated with a wide range of diseases and environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect shifts in tissue composition. Methods: Here we derive a DNA methylation reference matrix for 12 immune-cell types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix, we perform a directional Stouffer and fixed effects meta-analysis comprising 23,053 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes. In a separate cohort of 4386 blood samples, we assess associations between immune-cell fractions and health outcomes. Results: Our meta-analysis reveals many associations of cell-type fractions with age, sex, smoking and obesity, many of which we validate with single-cell RNA sequencing. We discover that naïve and regulatory T-cell subsets are higher in women compared to men, while the reverse is true for monocyte, natural killer, basophil, and eosinophil fractions. Decreased natural killer counts associated with smoking, obesity, and stress levels, while an increased count correlates with exercise and sleep. Analysis of health outcomes revealed that increased naïve CD4 + T-cell and N-cell fractions associated with a reduced risk of all-cause mortality independently of all major epidemiological risk factors and baseline co-morbidity. A machine learning predictor built only with immune-cell fractions achieved a C-index value for all-cause mortality of 0.69 (95%CI 0.67–0.72), which increased to 0.83 (0.80–0.86) upon inclusion of epidemiological risk factors and baseline co-morbidity. Conclusions: This work contributes an extensively validated high-resolution DNAm reference matrix for blood, which is made freely available, and uses it to generate a comprehensive map of associations between immune-cell fractions and common phenotypes, including health outcomes

Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension.

BACKGROUND: The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. METHODS: From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. RESULTS: The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03). CONCLUSIONS: At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).Supported by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (grant no. 09/800/16), and by the NIHR Cambridge Biomedical Research Centre, the Academy of Medical Sciences and Health Foundation (Senior Fellowship, to Dr. Hutchinson), and the Evelyn Trust. Dr. Hutchinson is supported by a Research Professorship from the NIHR, the NIHR Cambridge Biomedical Research Centre, a European Union Seventh Framework Program grant (CENTER-TBI; grant no. 602150), and the Royal College of Surgeons of England; Dr. Kolias, by a Royal College of Surgeons of England Research Fellowship and a Sackler Studentship; Dr. Pickard, by the NIHR Brain Injury Healthcare Technology Co-operative and a Senior Investigator award from the NIHR; and Dr. Menon, by a Senior Investigator award from the NIHR and a European Union Seventh Framework Program grant (CENTER-TBI; grant no. 602150). The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust were the trial sponsors.This is the author accepted manuscript. The final version is available from the Massachusetts Medical Society via http://dx.doi.org/10.1056/NEJMoa160521

Biomechanical Factors Influencing the Performance of Elite Alpine Ski Racers

BackgroundAlpine ski racing is a popular international winter sport that is complex and challenging from physical, technical, and tactical perspectives. Despite the vast amount of scientific literature focusing on this sport, including topical reviews on physiology, ski-snow friction, and injuries, no review has yet addressed the biomechanics of elite alpine ski racers and which factors influence performance. In World Cup events, winning margins are often mere fractions of a second and biomechanics may well be a determining factor in podium place finishes. Objective The aim of this paper was to systematically review the scientific literature to identify the biomechanical factors that influence the performance of elite alpine ski racers, with an emphasis on slalom, giant slalom, super-G, and downhill events. Methods Four electronic databases were searched using relevant medical subject headings and key words, with an additional manual search of reference lists, relevant journals, and key authors in the field. Articles were included if they addressed human biomechanics, elite alpine skiing, and performance. Only original research articles published in peer-reviewed journals and in the English language were reviewed. Articles that focused on skiing disciplines other than the four of primary interest were excluded (e.g., mogul, ski-cross and freestyle skiing). The articles subsequently included for review were quality assessed using a modified version of a validated quality assessment checklist. Data on the study population, design, location, and findings relating biomechanics to performance in alpine ski racers were extracted from each article using a standard data extraction form. Results A total of 12 articles met the inclusion criteria, were reviewed, and scored an average of 69 ± 13 % (range 40–89 %) upon quality assessment. Five of the studies focused on giant slalom, four on slalom, and three on downhill disciplines, although these latter three articles were also relevant to super-G events. Investigations on speed skiing (i.e., downhill and super-G) primarily examined the effect of aerodynamic drag on performance, whereas the others examined turn characteristics, energetic principles, technical and tactical skills, and individual traits of high-performing skiers. The range of biomechanical factors reported to influence performance included energy dissipation and conservation, aerodynamic drag and frictional forces, ground reaction force, turn radius, and trajectory of the skis and/or centre of mass. The biomechanical differences between turn techniques, inter-dependency of turns, and abilities of individuals were also identified as influential factors in skiing performance. In the case of slalom and giant slalom events, performance could be enhanced by steering the skis in such a manner to reduce the ski-snow friction and thereby energy dissipated. This was accomplished by earlier initiation of turns, longer path length and trajectory, earlier and smoother application of ground reaction forces, and carving (rather than skidding). During speed skiing, minimizing the exposed frontal area and positioning the arms close to the body were shown to reduce the energy loss due to aerodynamic drag and thereby decrease run times. In actual races, a consistently good performance (i.e., fast time) on different sections of the course, terrains, and snow conditions was a characteristic feature of winners during technical events because these skiers could maximize gains from their individual strengths and minimize losses from their respective weaknesses. Limitations Most of the articles reviewed were limited to investigating a relatively small sample size, which is a usual limitation in research on elite athletes. Of further concern was the low number of females studied, representing less than 4 % of all the subjects examined in the articles reviewed. In addition, although overall run time is the ultimate measure of performance in alpine ski racing, several other measures of instantaneous performance were also employed to compare skiers, including the aerodynamic drag coefficient, velocity, section time, time lost per change in elevation, and mechanical energy behaviours, which makes cross-study inferences problematic. Moreover, most studies examined performance through a limited number of gates (i.e., 2–4 gates), presumably because the most commonly used measurement systems can only capture small volumes on a ski field with a reasonable accuracy for positional data. Whether the biomechanical measures defining high instantaneous performance can be maintained throughout an entire race course remains to be determined for both male and female skiers. Conclusions Effective alpine skiing performance involves the efficient use of potential energy, the ability to minimize ski-snow friction and aerodynamic drag, maintain high velocities, and choose the optimal trajectory. Individual tactics and techniques should also be considered in both training and competition. To achieve better run times, consistency in performance across numerous sections and varied terrains should be emphasized over excellence in individual sections and specific conditions.Publ online 28 Dec 2013Swedish Winter Sports Research Centr

Evaluation of outcomes among patients with traumatic intracranial hypertension treated with decompressive craniectomy vs standard medical care at 24 month

Importance Trials often assess primary outcomes of traumatic brain injury at 6 months. Longer-term data are needed to assess outcomes for patients receiving surgical vs medical treatment for traumatic intracranial hypertension. Objective To evaluate 24-month outcomes for patients with traumatic intracranial hypertension treated with decompressive craniectomy or standard medical care. Design, Setting, and Participants Prespecified secondary analysis of the Randomized Evaluation of Surgery With Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) randomized clinical trial data was performed for patients with traumatic intracranial hypertension (&gt;25 mm Hg) from 52 centers in 20 countries. Enrollment occurred between January 2004 and March 2014. Data were analyzed between 2018 and 2021. Eligibility criteria were age 10 to 65 years, traumatic brain injury (confirmed via computed tomography), intracranial pressure monitoring, and sustained and refractory elevated intracranial pressure for 1 to 12 hours despite pressure-controlling measures. Exclusion criteria were bilateral fixed and dilated pupils, bleeding diathesis, or unsurvivable injury. Interventions Patients were randomly assigned 1:1 to receive a decompressive craniectomy with standard care (surgical group) or to ongoing medical treatment with the option to add barbiturate infusion (medical group). Main Outcomes and Measures The primary outcome was measured with the 8-point Extended Glasgow Outcome Scale (1 indicates death and 8 denotes upper good recovery), and the 6- to 24-month outcome trajectory was examined. Results This study enrolled 408 patients: 206 in the surgical group and 202 in the medical group. The mean (SD) age was 32.3 (13.2) and 34.8 (13.7) years, respectively, and the study population was predominantly male (165 [81.7%] and 156 [80.0%], respectively). At 24 months, patients in the surgical group had reduced mortality (61 [33.5%] vs 94 [54.0%]; absolute difference, −20.5 [95% CI, −30.8 to −10.2]) and higher rates of vegetative state (absolute difference, 4.3 [95% CI, 0.0 to 8.6]), lower or upper moderate disability (4.7 [−0.9 to 10.3] vs 2.8 [−4.2 to 9.8]), and lower or upper severe disability (2.2 [−5.4 to 9.8] vs 6.5 [1.8 to 11.2]; χ27 = 24.20, P = .001). For every 100 individuals treated surgically, 21 additional patients survived at 24 months; 4 were in a vegetative state, 2 had lower and 7 had upper severe disability, and 5 had lower and 3 had upper moderate disability, respectively. Rates of lower and upper good recovery were similar for the surgical and medical groups (20 [11.0%] vs 19 [10.9%]), and significant differences in net improvement (≥1 grade) were observed between 6 and 24 months (55 [30.0%] vs 25 [14.0%]; χ22 = 13.27, P = .001). Conclusions and Relevance At 24 months, patients with surgically treated posttraumatic refractory intracranial hypertension had a sustained reduction in mortality and higher rates of vegetative state, severe disability, and moderate disability. Patients in the surgical group were more likely to improve over time vs patients in the medical group