Circulating Autoantibodies Recognizing Immunodominant Epitopes From Human Apolipoprotein B Associate With Cardiometabolic Risk Factors, but Not With Atherosclerotic Disease

Rationale: Atherosclerosis is a chronic inflammatory disease of large arteries that involves an autoimmune response with autoreactive T cells and auto-antibodies recognizing Apolipoprotein B (ApoB), the core protein of low-density lipoprotein (LDL). Here, we aimed to establish a clinical association between circulating human ApoB auto-antibodies with atherosclerosis and its clinical risk factors using a novel assay to detect auto-antibodies against a pool of highly immunogenic ApoB-peptides. Methods and Results: To detect polyclonal IgM- and IgG-antibodies recognizing ApoB, we developed a chemiluminescent sandwich ELISA with 30 ApoB peptides selected by an in silico assay for a high binding affinity to MHC-II, which cover more than 80% of known MHC-II variants in a Caucasian population. This pre-selection of immunogenic self-peptides accounted for the high variability of human MHC-II, which is fundamental to allow T cell dependent generation of IgG antibodies. We quantified levels of ApoB-autoantibodies in a clinical cohort of 307 patients that underwent coronary angiography. Plasma anti-ApoB IgG and IgM concentrations showed no differences across healthy individuals (n = 67), patients with coronary artery disease (n = 179), and patients with an acute coronary syndrome (n = 61). However, plasma levels of anti-ApoB IgG, which are considered pro-inflammatory, were significantly increased in patients with obesity (p = 0.044) and arterial hypertension (p < 0.0001). In addition, patients diagnosed with the metabolic syndrome showed significantly elevated Anti-ApoB IgG (p = 0.002). Even when normalized for total plasma IgG, anti-ApoB IgG remained highly upregulated in hypertensive patients (p < 0.0001). We observed no association with triglycerides, total cholesterol, VLDL, or LDL plasma levels. However, total and normalized anti-ApoB IgG levels negatively correlated with HDL. In contrast, total and normalized anti-ApoB IgM, that have been suggested as anti-inflammatory, were significantly lower in diabetic patients (p = 0.012) and in patients with the metabolic syndrome (p = 0.005). Conclusion: Using a novel ELISA method to detect auto-antibodies against ApoB in humans, we show that anti-ApoB IgG associate with cardiovascular risk factors but not with the clinical appearance of atherosclerosis, suggesting that humoral immune responses against ApoB are shaped by cardiovascular risk factors but not disease status itself. This novel tool will be helpful to develop immune-based risk stratification for clinical atherosclerosis in the future.Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Albert Ludwigs University of Freiburg; AlemaniaFil: Malchow, Sara. Albert Ludwigs University of Freiburg; AlemaniaFil: Caceres, Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Albert Ludwigs University of Freiburg; AlemaniaFil: El Rabih, Abed Al Hadi. Albert Ludwigs University of Freiburg; AlemaniaFil: Hansen, Sophie. Albert Ludwigs University of Freiburg; AlemaniaFil: Mwinyella, Timothy. Albert Ludwigs University of Freiburg; AlemaniaFil: Spiga, Lisa. Albert Ludwigs University of Freiburg; AlemaniaFil: Piepenburg, Sven. Albert Ludwigs University of Freiburg; AlemaniaFil: Horstmann, Hauke. Albert Ludwigs University of Freiburg; AlemaniaFil: Olawale, Tijani. Albert Ludwigs University of Freiburg; AlemaniaFil: Li, Xiaowei. Albert Ludwigs University of Freiburg; AlemaniaFil: Mitre, Lucia Sol. Albert Ludwigs University of Freiburg; AlemaniaFil: Gissler, Mark Colin. Albert Ludwigs University of Freiburg; AlemaniaFil: Bugger, Heiko. University of Graz; AustriaFil: Zirlik, Andreas. University of Graz; AustriaFil: Heidt, Timo. Albert Ludwigs University of Freiburg; AlemaniaFil: Hilgendorf, Ingo. Albert Ludwigs University of Freiburg; AlemaniaFil: Stachon, Peter. Albert Ludwigs University of Freiburg; AlemaniaFil: von zur Muehlen, Constantin. Albert Ludwigs University of Freiburg; AlemaniaFil: Bode, Christoph. Albert Ludwigs University of Freiburg; AlemaniaFil: Wolf, Dennis. Albert Ludwigs University of Freiburg; Alemani

CT based PSI blocks for osteotomies around the knee provide accurate results when intraoperative imaging is used

Purpose!#!Correction osteotomies around the knee are common methods for the treatment of varus or valgus malalignment of the lower extremity. In recent years, patient specific instrumentation (PSI) guides were introduced in order to enhance the accuracy of these procedures. The purpose of this study was to determine the accuracy of CT based PSI guides for correction osteotomies around the knee of low volume osteotomy surgeons and to evaluate if CT based PSI blocks deliver a high degree of accuracy without using intraoperative fluoroscopy.!##!Methods!#!Two study arms with CT based PSI cutting blocks for osteotomies around the knee were conducted. Part one: A retrospective analysis of 19 osteotomies was made in order to evaluate the accuracy in the hands of a low volume surgeon on long-leg radiographs. Part two: A cadaveric study with 8 knees was performed for the purpose of analyzing the accuracy without using intraoperative fluoroscopy on pre- and postoperative CT scans. Hip-Knee-Ankle angle (HKA), lateral distal femoral angle (LDFA) and medial proximal tibial angle (MPTA) were analyzed. The mean absolute delta (∂) between the planned and postoperative parameters were calculated. The accuracy of both study arms were compared.!##!Results!#!Part one: The mean MPTA ∂, LDFA ∂ and HKA ∂ was 0.9°, 1.9° and 1.5°, respectively. Part two: The mean MPTA ∂ and LDFA ∂ was 3.5° and 2.2°, respectively. The mean ∂ of MPTA is significantly different between clinical patients with fluoroscopic control and cadaveric specimens without fluoroscopic control (P &amp;lt; 0.001). All surgeries were performed without complications such as a hinge fracture.!##!Conclusion!#!The clinical use of PSI guides for osteotomies around the knee in the hands of low volume surgeons is a safe procedure. The PSI guides deliver a reliable accuracy under fluoroscopic control whereas their non-use of intraoperative fluoroscopy leads to a lack of accuracy. The use of fluoroscopic control during PSI guided correction osteotomies is highly recommended.!##!Level of evidence!#!IV - Retrospective and experimental Study

Effects of a Short Physical Exercise Intervention on Patients with Multiple Sclerosis (MS)

Background: The aim of this prospective randomized controlled trial was to investigate if a short-term endurance or combined endurance/resistance exercise program was sufficient to improve aerobic capacity and maximum force in adult patients (18–65 years) with multiple sclerosis (MS). Methods: All patients performed a three-month exercise program consisting of two training sessions per week, lasting 40 min each, with moderate intensity. All patients had a maximum value of 6 (low to moderate disability) on the Expanded Disability Status Scale (EDSS). One group (combined workout group (CWG); 15 females, 4 males) completed a combined endurance/resistance workout (20 min on a bicycle ergometer, followed by 20 min of resistance training), while the other group (endurance workout group (EWG); 13 females, 5 males) completed a 40 min endurance training program. Aerobic capacity was assessed as peak oxygen uptake, ventilatory anaerobic threshold, and workload expressed as Watts. Maximum force of knee and shoulder extensors and flexors was measured using isokinetic testing. Quality of life was assessed with the SF-36 questionnaire, and fatigue was measured using the Modified Fatigue Impact Scale. Results: Both training groups increased in aerobic capacity and maximum force. EWG, as well as CWG, showed improvement in several subscales of the SF-36 questionnaire and decrease of their fatigue. Conclusion: A short exercise intervention increased both aerobic capacity and maximum force independent of whether endurance or combined endurance/resistance workouts were performed

Improving Maximal Strength in the Initial Postoperative Phase After Anterior Cruciate Ligament Reconstruction Surgery: Randomized Controlled Trial of an App-Based Serious Gaming Approach

Background: Anterior cruciate ligament reconstruction surgery is one of the most common orthopedic procedures. One of the main factors that influence the outcome is regaining strength in the postoperative phase. Because anterior cmciate ligament reconstruction surgeries are often performed in young patients, we combined the concept of prehabilitation with an app-based serious gaming approach to improve maximal strength postoperatively. Objective: Our objective was to conduct a prospective randomized trial to evaluate whether an app based active muscle training program (GenuSport Knee Trainer) can improve postoperative strength by starting rehabilitation immediately after primary anterior cruciate ligament reconstruction surgery. Methods: We designed a pilot study in which we randomly assigned patients receiving primary anterior cruciate ligament reconstruction to either the serious gaming training (intervention) group or a conventional rehabilitation (control) group. Except for the serious gaming-based training, both groups followed the same postoperative treatment protocol. Outcome parameters were absolute and relative change in maximal strength, as well as the International Knee Documentation Committee Subjective Knee evaluation form, Knee Injury and Osteoarthritis Outcome Score, and Lysholm Knee Score. Results: In total 26 patients agreed to participate (14 patients in the intervention group and 12 patients in the control group, 1 of whom was lost to follow-up). We noted a difference in absolute maximum strength between the exergaming intervention and the control groups. Mean maximum strength preoperatively was 155.1 (SD 79.2) N in the intervention group (n=14) and 157.0 (SD 40.8) N in the control group (n=11). Postoperative mean maximum strength was 212.8 (SD 78.5) N in the intervention group and 154.5 (SD 27.1) N in the control group. Mean absolute change in maximum strength was 57.7 (SD 95.2) N in the intervention group and -4.8 (22.2) N in the control group. The analysis of covariance model with absolute change as the dependent variable and treatment group and baseline maximum strength as covariates showed a relevant difference in relative change between treatment groups (intervention - control) of 59.7 N (95% CI 10.1-109.3; P=.02). Similarly to the absolute increase, the relative change in maximum strength was relevantly higher in the exergaming group. The mean relative change in maximum strength was 1.7 (SD 1.17) in the intervention group and 1 (SD 0.13) in the control group. No adverse events or problems were reported during the study period. Conclusions: Implementation of an app-based active muscle training program in the early postoperative therapy scheme was associated with an improvement in maximal strength. Therefore, we considered the use of GenuSport training after anterior cruciate ligament reconstruction to be a helpful complement to rehabilitation after anterior cruciate ligament reconstruction surgery to improve strength in the early postoperative phase. To our knowledge this was the first study to analyze immediate postoperative serious gaming-based training with the GenuSport device based on strength improvement

Measuring Impact Craters on the ISS Columbus Module

A photographic survey of the outer surface of the Columbus module with emphasis on the forward facing areas is proposed. This is to perform a status check of the Columbus meteoroid and debris protection system (MDPS) and to obtain information on the space debris and meteoroid environment of the ISS. The majority of impacts is expected on the front/forward side of the cylindrical area. Two possibilities to perform the survey are investigated: by a camera on the robotic arm SSRMS with the possible utilization of Dextre/SPDM, as well as by an astronaut during an EVA with the standard Nikon D4 camera. Both methods are discussed in detail, including planning effort, execution requirements and constraints, the results and effort expected, and advantages and disadvantages of both methods are summarized. The predicted crater size distribution is calculated using ESA's MASTER model, and the proposed survey is compared with historical mission data that were used to validate the MASTER population in the past. The different directionality of man-made space debris and natural meteoroids particle populations leads to a relative difference in expected impact crater distributions between the front facing and the zenith facing areas, which can be analyzed. 1 Paper ID: 43898 oral The main aim of the survey is to generate measurement data for particle environment models (MASTER and ORDEM). This data would allow for a quantitative assessment of the particle impact risk for the entire ISS with an unprecedented accuracy. Also, it would allow to re-assess the assumptions that were made during the Columbus module shield design process and thus would allow re-evaluating the actual impact risk. Since the Columbus module surface will be covered partially by the commercial platform \Bartolomeo" soon, there is a limited time slot for the actual performance of this study. Having this in mind, the data generated by this survey can also help secure the economic investment that is planned for Bartolomeo in two ways: The improved particle models will help to understand what Bartolomeo is going to expect out there, and the new pictures of the Columbus surface may help to plan the installation process.

Measuring impact craters on the ISS Columbus Module: Paper presented at 69th International Astronautical Congress, Bremen, Germany, October 1-5, 2018

This paper presents the plan and first results of a photographic survey of the outer surface of the Columbus module with emphasis on the forward facing areas. This is to perform a status check of the Columbus meteoroid and debris protection system (MDPS) and to obtain information on the space debris and meteoroid environment of the ISS (International Space Station). The expected different impact crater count between zenith and forward facing panels will allow a distinction between man-made space debris and natural meteoroids. The majority of impacts is expected on the forward side of the cylindrical area. The survey is performed using image acquisition hardware available onboard the ISS. Different acquisition options are discussed, with the SSRMS (Canadarm2) tip LEE (Latching End Effector, i.e. the tip of the arm) camera being the most realistic option, but also the one with the lowest expected resolution. The predicted crater size distribution is calculated using ESA's MASTER model, and the proposed survey is compared with historical mission data that were used to validate the MASTER population in the past. The first part of the survey was performed on 5 September 2018, the second part between 21 and 23 September 2018, and some initial results are presented. The data acquired will be analyzed to yield size and position information of all craters identifiable from the video stream. The main aim of the survey is to generate measurement data for particle environment models (MASTER and ORDEM). This data will allow for a quantitative assessment of the particle impact risk for the entire ISS with an unprecedented accuracy. Also, it will allow to re-assess the validity of the impact risk assessments done for the Columbus module in the past. Since the Columbus module surface will be covered partially by the commercial platform “Bartolomeo” and the ColKa communication terminal soon, there is a limited time slot for the actual performance of this study

Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH

BACKGROUND & AIMS: Previous single-cell RNA-sequencing analyses have shown that Trem2-expressing macrophages are present in the liver during obesity, non-alcoholic steatohepatitis (NASH) and cirrhosis. Herein, we aimed to functionally characterize the role of bone marrow-derived TREM2-expressing macrophage populations in NASH. METHODS: We used bulk RNA sequencing to assess the hepatic molecular response to lipid-dependent dietary intervention in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single-cell sequencing were applied to functionally characterize the role of TREM2+ macrophage populations in NASH. RESULTS: We found that the hepatic transcriptomic profile during steatohepatitis mirrors the dynamics of recruited bone marrow-derived monocytes that already acquire increased expression of Trem2 in the circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels were superior to traditionally used laboratory parameters for distinguishing between different fatty liver disease stages in two separate clinical cohorts. Spatial transcriptomics revealed that TREM2+ macrophages localize to sites of hepatocellular damage, inflammation and fibrosis in the steatotic liver. Finally, using multiple murine models and in vitro experiments, we demonstrate that hematopoietic Trem2 deficiency causes defective lipid handling and extracellular matrix remodeling, resulting in exacerbated steatohepatitis, cell death and fibrosis. CONCLUSIONS: Our study highlights the functional properties of bone marrow-derived TREM2+ macrophages and implies the clinical relevance of systemic soluble TREM2 levels in the context of NASH. LAY SUMMARY: Our study defines the origin and function of macrophages (a type of immune cell) that are present in the liver and express a specific protein called TREM2. We find that these cells have an important role in protecting against non-alcoholic steatohepatitis (a progressive form of fatty liver disease). We also show that the levels of soluble TREM2 in the blood could serve as a circulating marker of non-alcoholic fatty liver disease