Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

Association of Blood Biomarkers of Inflammation With Acute Concussion in Collegiate Athletes and Military Service Academy Cadets.

BACKGROUND AND OBJECTIVES: The objective was to characterize the acute effects of concussion (a subset of mild traumatic brain injury) on serum interleukin (IL)-6 and IL-1 receptor antagonist (RA) and 5 additional inflammatory markers in athletes and military service academy members from the Concussion Assessment, Research, and Education Consortium and to determine whether these markers aid in discrimination of concussed participants from controls. METHODS: Athletes and cadets with concussion and matched controls provided blood at baseline and postinjury visits between January 2015 and March 2020. Linear models investigated changes in inflammatory markers measured using Meso Scale Discovery assays across time points (baseline and 0-12, 12-36, 36-60 hours). Subanalyses were conducted in participants split by sex and injury population. Logistic regression analyses tested whether acute levels of IL-6 and IL-1RA improved discrimination of concussed participants relative to brain injury markers (glial fibrillary acidic protein, tau, neurofilament light, ubiquitin c-terminal hydrolase-L1) or clinical data (Sport Concussion Assessment Tool-Third Edition, Standardized Assessment of Concussion, Balance Error Scoring System). RESULTS: Participants with concussion (total, N = 422) had elevated IL-6 and IL-1RA at 0-12 hours vs controls (n = 345; IL-6: mean difference [MD] (standard error) = 0.701 (0.091), p < 0.0001; IL-1RA: MD = 0.283 (0.042), p < 0.0001) and relative to baseline (IL-6: MD = 0.656 (0.078), p < 0.0001; IL-1RA: MD = 0.242 (0.038), p < 0.0001), 12-36 hours (IL-6: MD = 0.609 (0.086), p < 0.0001; IL-1RA: MD = 0.322 (0.041), p < 0.0001), and 36-60 hours (IL-6: MD = 0.818 (0.084), p < 0.0001; IL-1RA: MD = 0.317 (0.040), p < 0.0001). IL-6 and IL-1RA were elevated in participants with sport (IL-6: MD = 0.748 (0.115), p < 0.0001; IL-1RA: MD = 0.304 (0.055), p < 0.0001) and combative-related concussions (IL-6: MD = 0.583 (0.178), p = 0.001; IL-1RA: MD = 0.312 (0.081), p = 0.0001). IL-6 was elevated in male (MD = 0.734 (0.105), p < 0.0001) and female participants (MD = 0.600 (0.177), p = 0.0008); IL-1RA was only elevated in male participants (MD = 0.356 (0.047), p < 0.0001). Logistic regression showed the inclusion of IL-6 and IL-1RA at 0-12 hours improved the discrimination of participants with concussion from controls relative to brain injury markers (χ2(2) = 17.855, p = 0.0001; area under the receiver operating characteristic curve [AUC] 0.73 [0.66-0.80] to 0.78 [0.71-0.84]), objective clinical measures (balance and cognition; χ2(2) = 40.661, p < 0.0001; AUC 0.81 [0.76-0.86] to 0.87 [0.83-0.91]), and objective and subjective measures combined (χ2(2) = 13.456, p = 0.001; AUC 0.97 [0.95-0.99] to 0.98 [0.96-0.99]), although improvement in AUC was only significantly relative to objective clinical measures. DISCUSSION: IL-6 and IL-1RA (male participants only) are elevated in the early-acute window postconcussion and may aid in diagnostic decisions beyond traditional blood markers and common clinical measures. IL-1RA results highlight sex differences in the immune response to concussion which should be considered in future biomarker work.

Refinements to rodent head fixation and fluid/food control for neuroscience.

The use of head fixation in mice is increasingly common in research, its use having initially been restricted to the field of sensory neuroscience. Head restraint has often been combined with fluid control, rather than food restriction, to motivate behaviour, but this too is now in use for both restrained and non-restrained animals. Despite this, there is little guidance on how best to employ these techniques to optimise both scientific outcomes and animal welfare. This article summarises current practices and provides recommendations to improve animal wellbeing and data quality, based on a survey of the community, literature reviews, and the expert opinion and practical experience of an international working group convened by the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). Topics covered include head fixation surgery and post-operative care, habituation to restraint, and the use of fluid/food control to motivate performance. We also discuss some recent developments that may offer alternative ways to collect data from large numbers of behavioural trials without the need for restraint. The aim is to provide support for researchers at all levels, animal care staff, and ethics committees to refine procedures and practices in line with the refinement principle of the 3Rs.

Left Atrial Appendage Ligation Using the AtriClip Device: Single-Center Study of Device Safety and Efficacy.

Objective: Left atrial appendage (LAA) occlusion at the time of cardiac surgery in patients with atrial fibrillation has been shown to reduce the incidence of postoperative embolic stroke. However, the optimal method for LAA occlusion is not universally accepted. We sought to examine the safety and effectiveness of LAA occlusion with the AtriClip epicardial occlusion device. Methods: Cardiac surgical patients with atrial fibrillation who underwent LAA AtriClip placement were evaluated prospectively. Clip placement and clinical outcomes were examined after 1 year of follow-up with transesophageal echocardiography (TEE). The presence of a 10 mm or greater residual pouch, presence of flow into the LAA, or device-related thrombus (DRT) were considered failures. Results: Ninety-seven patients were analyzed. The mean CHA2DS2-VASc score was 2.4 ± 1.4. The postoperative follow-up period ranged from 366 to 1,693 days (mean 685 days or 1.87 years). Seventy-four AtriClips were placed with video-assisted thoracic surgery, whereas 23 were placed via sternotomy or thoracotomy. Successful closure was found in 96% (93 of 97) of patients at follow-up. Failure occurred in 4 patients. No clip migration or DRT was seen on 3-dimensional imaging. Of all 97 patients, 76 (78%) were on presurgical oral anticoagulation, whereas 5 (5.1%) were on postprocedure oral anticoagulation. There were no postoperative thromboembolic events at the time of the study TEE. Conclusions: The AtriClip epicardial surgical occlusion device can provide an excellent rate of successful closure of the LAA during surgical ablation procedures without DRT.

Risk factors for pulmonary arterial hypertension in children and young adults.

OBJECTIVES: Pulmonary hypertension (PH) has been linked to preterm birth explained by congenital heart defects and pulmonary diseases. WORKING HYPOTHESIS: Other factors may influence the risk of PH among adolescences and children born premature. STUDY DESIGN: This national registry-based study assess risk of PH following premature birth adjusted for known risk factors. PATIENT-SUBJECT SELECTION AND METHODOLOGY: All cases born 1993-2010, identified by diagnostic codes applicable to PH and retrieved from the Swedish Registry of Congenital Heart Disease (N = 67). Six controls were randomly selected and matched to each case by year of birth and hospital by the Swedish Medical Birth Register (N = 402). Maternal and infant data related to preterm birth, pulmonary diseases, and congenital defects were retrieved. The association between preterm birth and pulmonary hypertension was calculated by conditional logistic regression taking into account potential confounding factors. RESULTS: One third of the cases and seven percent of the controls were born preterm in our study. Preterm birth was associated with PH, OR = 8.46 (95%CI 2.97-24.10) (P < 0.0001) even after adjusting for confounding factors. Other factors, such as acute pulmonary diseases, congenital heart defects, congenital diaphragm herniation, and chromosomal disorders were also associated with PH in the multivariate analysis. CONCLUSIONS: Children and young adults born preterm are known to have an increased risk of PH, previously explained by congenital heart defects and pulmonary diseases. By adjusting for such factors, our study indicates that new factors may play a role in the risk of developing PH among children born preterm. Pediatr Pulmonol. 2017;52:636-641. © 2016 Wiley Periodicals, Inc.

Some neonatal risk factors for adult pulmonary arterial hypertension remain unknown.

AIM: Pulmonary hypertension has been linked to premature birth, chronic lung disease, bronchopulmonary dysplasia and congenital heart disease. This national population-based registry study assessed the risk of adult pulmonary hypertension following premature birth, adjusted for known risk factors. METHODS: We focused on adults in the Swedish Pulmonary Arterial Hypertension Registry, who were born prematurely, and controls randomly selected from the Swedish medical birth register and matched to each case by birth year and delivery hospital. Information on perinatal factors was also retrieved from the medical birth register. Conditional multiple logistic regression was used to evaluate the association between premature birth and adult pulmonary hypertension, taking into account the potential confounding factors. RESULTS: The study population comprised 427 adults born between 1973 and 1996, with 61 cases and 366 controls. Adult pulmonary hypertension was associated with premature birth, with an odds ratio of 3.08 and 95% confidence interval of 1.21-7.87. The association did not alter after adjusting for potential confounders. CONCLUSION: By adjusting for factors linked to adult pulmonary hypertension, namely congenital heart defects, pulmonary diseases and premature birth, we were able to show that other unknown factors may influence the risk for pulmonary hypertension among adults who were born premature.

The Nurse-Based Age Independent Intervention to Limit Evolution of Disease After Acute Coronary Syndrome (NAILED ACS) Risk Factor Trial: Protocol for a Randomized Controlled Trial.

BACKGROUND: Secondary prevention after acute coronary syndrome (ACS) is essential to reduce morbidity and mortality, but related studies have been fairly small or performed as clinical trials with non-representative patient selection. Long-term follow-up data are also minimal. A nurse-led follow-up for risk factor improvement may be effective, but the evidence is limited. OBJECTIVE: The aims of this study are to perform an adequately sized, nurse-led, long-term secondary preventive follow-up with inclusion of an unselected population of ACS patients. The focus will be on lipid and blood pressure control as well as tobacco use and physical activity. METHODS: The study will consist of a randomized, controlled, long-term, population-based trial with two parallel groups. Patients will be included during the initial hospital stay. Important outcome variables are total cholesterol, low-density lipoprotein (LDL) cholesterol, and sitting systolic and diastolic blood pressure. Outcomes will be measured after 12, 24, and 36 months of follow-up. Trained nurses will manage the intervention group with the aim of achieving set treatment goals as soon as possible. The control group will receive usual care. At least 250 patients will be included in each group to reliably detect a difference in mean LDL of 0.5 mmol/L and in mean systolic blood pressure of 5 mmHg. RESULTS: The study is ongoing and recruitment of participants will continue until December 31, 2014. CONCLUSIONS: This study will test the hypothesis that a nurse-led, long-term follow-up after an ACS with a focus on achieving treatment goals as soon as possible is an effective secondary preventive method. If proven effective, this method could be implemented in general practice at a low cost. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 96595458; http://www.controlled-trials.com/ISRCTN96595458 (Archived by WebCite at http://www.webcitation.org/6RlyhYTYK).