Pharmacokinetics and pharmacodynamics of mibavademab (a leptin receptor agonist): Results from a first-in-human phase I study.

Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single-ascending-dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5-8 ng/mL in men and 5-24 ng/mL in women). Fifty-six and 55 participants completed the single-ascending-dose and multiple-dose parts, respectively. In the single-ascending-dose cohorts, mibavademab PKs were nonlinear with target-mediated elimination, greater than dose-proportional increases in exposure, and there were no dose-dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple-dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment-emergent anti-mibavademab antibodies were observed in any mibavademab-treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency.

Energy-Efficient Neuromorphic Architectures for Nuclear Radiation Detection Applications.

A comprehensive analysis and simulation of two memristor-based neuromorphic architectures for nuclear radiation detection is presented. Both scalable architectures retrofit a locally competitive algorithm to solve overcomplete sparse approximation problems by harnessing memristor crossbar execution of vector-matrix multiplications. The proposed systems demonstrate excellent accuracy and throughput while consuming minimal energy for radionuclide detection. To ensure that the simulation results of our proposed hardware are realistic, the memristor parameters are chosen from our own fabricated memristor devices. Based on these results, we conclude that memristor-based computing is the preeminent technology for a radiation detection platform.

American Association for the Surgery of Trauma/American College of Surgeons Committee on Trauma: Clinical protocol for damage-control resuscitation for the adult trauma patient.

ABSTRACT: Damage-control resuscitation in the care of critically injured trauma patients aims to limit blood loss and prevent and treat coagulopathy by combining early definitive hemorrhage control, hypotensive resuscitation, and early and balanced use of blood products (hemostatic resuscitation) and the use of other hemostatic agents. This clinical protocol has been developed to provide evidence-based recommendations for optimal damage-control resuscitation in the care of trauma patients with hemorrhage.

Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage.

Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.

Prehospital Simple Thoracostomy Does Not Improve Patient Outcomes Compared to Needle Thoracostomy in Severely Injured Trauma Patients.

BACKGROUND: ATLS suggests simple thoracostomy (ST) after failure of needle thoracostomy (NT) in thoracic trauma. Some EMS agencies have adopted ST into their practice. We sought to describe our experience implementing ST in the prehospital setting, hypothesizing that prehospital ST would reduce failure rates and improve outcomes compared to NT. METHODS: This was a retrospective review of adult trauma patients who received prehospital ST or NT from 2017 to 2020. RESULTS: There were 48 patients with 64 procedures included. 83.7% were male and 65.8% injured by penetrating mechanism and of median (IQR) age of 31 (25-46) years. 28 (43.8%) procedures were NT and 36 (56.3%) were ST. Rates of improved patient response (P = .15), noted return of blood/air (P = .19), and return of spontaneous circulation (P = .62) did not differ. On-scene times were higher for ST (16.8 vs 11.5 minutes; P < .02). Overall mortality did not differ between ST and NT (68.2% vs 46.4%, respectively; P = .125). For patients that survived beyond the ED, procedure-related complication rates were 2 of 21 patients (9.5%) in ST and 1 of 12 (8.3%) in NT. In penetrating trauma, simple thoracostomy had longer on-scene time and total prehospital time. DISCUSSION: ST did not improve success rates of ROSC and was associated with prolonged prehospital times, especially in penetrating trauma patients. Given the benefit of "scoop and run" in urban penetrating trauma, consideration should be given to direct transport in lieu of ST. Use of ST in blunt trauma should be evaluated prospectively.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Qualitative interviews in patients with lipodystrophy to assess the patient experience: evaluation of hunger and other symptoms.

BACKGROUND: New treatments are being evaluated for lipodystrophy; however, limited information is available on the patient experience. Results of a prior patient panel showed that hunger and temperature-related symptoms were an issue for participants. Therefore, evaluation of any changes in these symptoms is recommended for inclusion in new treatment options. The objective of this study was to further understand the patient experience and to evaluate newly developed items of hunger and temperature regulation. METHODS: Individual, in-depth telephone interviews were conducted via semi-structured discussion guide. Telephone interviews were conducted with 21 US patients with generalized lipodystrophy (GLD) or partial lipodystrophy (PLD). Eligibility requirements included self-reported PLD or GLD. Interviews included open-ended concept elicitation followed by a review of newly developed items assessing hunger, temperature sensations, and patient globals. Interviews were conducted in two rounds, with the newly developed items assessing hunger revised after each round of interviews based on participant feedback. RESULTS: Results indicated that hunger-related symptoms were considered a current issue for greater than half (N = 11) of participants, and all but one reported this as an issue at some point in their lives. Specifically, participants most often reported symptoms of increased appetite and not feeling full. The cognitive debriefing process indicated that the hunger-related symptoms, temperature, and global impression of change and severity items were correctly interpreted and easily completed by the participants. While not a focus of the interviews, the concept elicitation results demonstrated that pain was a frequently reported and bothersome symptom in this patient population. CONCLUSIONS: This qualitative research provided evidence to support the use of clinical outcomes assessments such as hunger and temperature-related items in clinical trials.

Leptin mediates the regulation of muscle mass and strength by adipose tissue.

Adipose tissue secretes numerous cytokines (termed 'adipokines') that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic 'fat-free' mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat-free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast-twitch muscles, a slowing of contractile dynamics and decreased cross-sectional area of fast twitch fibres compared to wild-type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin-knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild-type mice is dependent on adipose-secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. KEY POINTS: Adipose-derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under-appreciated roles in muscle physiology. Here we use a fat-free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength. Through add-back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation. This expands our understanding of leptin's role in adipose-muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.

Array of Graphene Variable Capacitors on 100 mm Silicon Wafers for Vibration-Based Applications.

Highly flexible, electrically conductive freestanding graphene membranes hold great promise for vibration-based applications. This study focuses on their integration into mainstream semiconductor manufacturing methods. We designed a two-mask lithography process that creates an array of freestanding graphene-based variable capacitors on 100 mm silicon wafers. The first mask forms long trenches terminated by square wells featuring cone-shaped tips at their centers. The second mask fabricates metal traces from each tip to its contact pad along the trench and a second contact pad opposite the square well. A graphene membrane is then suspended over the square well to form a variable capacitor. The same capacitor structures were also built on 5 mm by 5 mm bare dies containing an integrated circuit underneath. We used atomic force microscopy, optical microscopy, and capacitance measurements in time to characterize the samples.

Does Gender Matter: A Multi-Institutional Analysis of Viscoelastic Profiles for 1565 Trauma Patients With Severe Hemorrhage.

BACKGROUND: Viscoelastic tests including thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are being used in patients with severe hemorrhage at trauma centers to guide resuscitation. Several recent studies demonstrated hypercoagulability in female trauma patients that was associated with a survival advantage. The objective of our study was to elucidate the effects of gender differences in TEG/ROTEM values on survival in trauma patients with severe hemorrhage. METHODS: A retrospective review of consecutive adult patients receiving massive transfusion protocol (MTP) at 7 Level I trauma centers was performed from 2013 to 2018. Data were stratified by gender and then further examined by TEG or ROTEM parameters. Results were analyzed using univariate and multi-variate analyses. RESULTS: A total of 1565 patients were included with 70.9% male gender (n = 1110/1565). Female trauma patients were older than male patients (43.5 ± .9 vs 41.1 ± .6 years, P = .01). On TEG, females had longer reaction times (6.1 ± .9 min vs 4.8 ± .2 min, P = .03), increased alpha angle (68.6 ± .8 vs 65.7 ± .4, P < .001), and higher maximum amplitude (59.8 ± .8 vs 56.3 ± .4, P < .001). On ROTEM, females had significantly longer clot time (99.2 ± 13.7 vs 75.1 ± 2.6 sec, P = .09) and clot formation time (153.6 ± 10.6 sec vs 106.9 ± 3.8 sec, P < .001). When comparing by gender, no difference for in-hospital mortality was found for patients in the TEG or ROTEM group (P > .05). Multivariate analysis showed no survival difference for female patients (OR 1.11, 95% CI .83-1.50, P = .48). CONCLUSIONS: Although a difference between male and females was found on TEG/ROTEM for certain clotting parameters, no difference in mortality was observed. Prospective multi-institutional studies are needed.

Elevated K/iCa ratio is an ancillary predictor for mortality in patients with severe hemorrhage: A decision tree analysis.

INTRODUCTION: Trauma patients receiving massive transfusion protocol (MTP) are at risk of citrate-induced hypocalcemia and hyperkalemia. Here we evaluate potassium (K), ionized calcium (iCa), and K/iCa ratio as predictors of mortality. METHODS: This retrospective study includes all adult trauma patients who received MTP within 1 h at our level I trauma center between 2014 and 2019. Receiver operating characteristic curve analysis assessed predictive accuracy of K/iCa ratio at admission on 120-day mortality. RESULTS: Of 614 patients, 146 received MTP within 1 h and 38 expired. Patients who expired had higher K/iCa ratio than survivors (median [IQR] = 5.7 [3.8-7.2] vs 3.7 [3.1-4.9], p < 0.001). Area under the curve of K/iCa was 0.72 (95%CI = 0.62-0.82, p < 0.001) with sensitivity = 63.2% and specificity = 77.6%. At the optimum K/iCa cutoff (5.07), patients with high ratios had 4 times higher mortality risk (HR = 3.97, 95%CI = 1.89-8.32, p < 0.001). CONCLUSION: Elevated K/iCa ratio was an independent predictor of mortality in trauma patients managed with MTP.

A bone-specific adipogenesis pathway in fat-free mice defines key origins and adaptations of bone marrow adipocytes with age and disease.

Bone marrow adipocytes accumulate with age and in diverse disease states. However, their origins and adaptations in these conditions remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In this study, by analyzing bone and adipose tissues in the lipodystrophic 'fat-free' mouse, we define a novel, secondary adipogenesis pathway that relies on the recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress in the fat-free mouse model, resulting in the expansion of bone marrow adipocytes specialized for lipid storage with compromised lipid mobilization and cytokine expression within regions traditionally devoted to hematopoiesis. This finding further distinguishes bone marrow from peripheral adipocytes and contributes to our understanding of bone marrow adipocyte origins, adaptations, and relationships with surrounding tissues with age and disease.

Taxonomic changes in the gut microbiota are associated with cartilage damage independent of adiposity, high fat diet, and joint injury.

Lipodystrophic mice are protected from cartilage damage following joint injury. This protection can be reversed by the implantation of a small adipose tissue graft. The purpose of this study was to evaluate the relationship between the gut microbiota and knee cartilage damage while controlling for adiposity, high fat diet, and joint injury using lipodystrophic (LD) mice. LD and littermate control (WT) mice were fed a high fat diet, chow diet, or were rescued with fat implantation, then challenged with destabilization of the medial meniscus surgery to induce osteoarthritis (OA). 16S rRNA sequencing was conducted on feces. MaAslin2 was used to determine associations between taxonomic relative abundance and OA severity. While serum LPS levels between groups were similar, synovial fluid LPS levels were increased in both limbs of HFD WT mice compared to all groups, except for fat transplanted animals. The Bacteroidetes:Firmicutes ratio of the gut microbiota was significantly reduced in HFD and OA-rescued animals when compared to chow. Nine novel significant associations were found between gut microbiota taxa and OA severity. These findings suggest the presence of causal relationships the gut microbiome and cartilage health, independent of diet or adiposity, providing potential therapeutic targets through manipulation of the microbiome.

Surgical stabilization of traumatic rib fractures is associated with reduced readmissions and increased survival.

BACKGROUND: Surgical stabilization for rib fractures (SSRF) in trauma patients remains controversial, with guidelines currently suggesting the procedure for only select patient groups. How surgical stabilization for rib fractures affect hospital readmission in patients with traumatic rib fractures is unknown. We hypothesized that surgical stabilization for rib fractures would not decrease the risk of readmission. METHODS: The National Readmission Database was examined for adults with any rib fractures from 2010 to 2017. Readmission up to 90 days was examined. Patients receiving surgical stabilization for rib fractures were compared with those receiving nonoperative treatment. RESULTS: In total, 864,485 patients met criteria, with 13,701 (1.6%) receiving SSRF. For patients receiving SSRF, 338 (1.5%) were readmitted. Readmitted patients had higher Charlson Comorbidity Index and were more likely to have flail chest. On multivariate propensity score-matched analysis, SSRF (Hazard Ratio [HR]: 0.55, 95% confidence interval [CI] 0.33-0.92, P = .022) was associated with reduced readmission. Addition of surgical stabilization for rib fractures to video-assisted thoracoscopic surgery (VATS) (Odds Ratio [OR]: 0.95, 95% CI 0.52-1.73, P = .86) or thoracotomy (OR: 1.97, 95% CI 0.83-4.70, P = .13) was not associated with increased readmission. On further propensity matched analysis, VATS + SSRF when compared with SSRF alone (HR: 0.75, 95% CI 0.18-3.20, P = .696), and VATS + SSRF when compared with VATS alone (HR: 0.49, 95% CI 0.11-2.22, P = .355) was also not associated with increased readmission. SSRF on primary admission was associated with increased in-hospital survival (HR: 0.27, 95% CI 0.22-0.32, P < .001). For patients with retained hemothorax who underwent VATS, addition of SSRF did not improve survival (HR = 0.92, 95% CI 0.58-1.46, P = .72). However, for patients requiring thoracotomy for retained hemothorax, concomitant SSRF was associated with improved survival (HR = 0.14, 95% CI 0.06-0.32, P < .001). CONCLUSION: Surgical stabilization for rib fractures is associated with reduced readmission risk while also being associated with improved survival. Patients who had a thoracotomy for retained hemothorax appear to especially benefit from concomitant surgical stabilization for rib fractures.

After 800 Mtp Events, Mortality Due to Hemorrhagic Shock Remains High and Unchanged Despite Several In-Hospital Hemorrhage Control Advancements.

BACKGROUND: Numerous advancements in hemorrhage control and volume replacement that comprise damage control resuscitation (DCR) have been implemented in the last decade to reduce deaths from bleeding. We sought to determine the impact of DCR interventions on mortality over 12 years in a massive transfusion protocol (MTP) population. We hypothesized that mortality would be decreased in later years, which would have used more DCR interventions. STUDY DESIGN: This was a retrospective review of all MTP patients treated at a large regional Level I trauma center from 2008 to 2019. Interventions by year of implementation examined included MTP 1:1 ratio (2009), liquid plasma (2010), tranexamic acid (2012), prehospital tourniquets (2013), REBOA/TEG (2017), satellite blood station (2018), and whole blood transfusion (2019). Relative risk and odds of mortality for DCR interventions were examined. RESULTS: There were 824 MTP patients included. The cohort was primarily male (80.6%) injured by penetrating mechanism (68.1%) with median (interquartile range) age 31 years (23-44) and New Injury Severity Score 25 (16-34). Overall mortality was unchanged [(38.3%-56.6%); P = 0.26]. Tourniquets (P = 0.02) and whole blood (WB) (P = 0.03) were associated with lower unadjusted mortality; only tourniquets remained significant after adjustment (OR: 0.39; 95% CI: 0.17-0.89; P = 0.03). CONCLUSIONS: Despite lower mortality with use of tourniquets and WB, mortality rates due to hemorrhage have not improved at our high MTP volume institution, suggesting implementation of new in-hospital strategies is insufficient to reduce mortality. Future efforts should be directed toward moving hemorrhage control and effective resuscitation interventions to the injury scene.

Adipose tissue is a critical regulator of osteoarthritis.

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects individuals with obesity. The mechanisms by which obesity leads to the onset and progression of OA are unclear due to the complex interactions among the metabolic, biomechanical, and inflammatory factors that accompany increased adiposity. We used a murine preclinical model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or posttraumatic OA, on either a chow or high-fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to posttraumatic OA was reintroduced into LD mice using implantation of a small adipose tissue depot derived from wild-type animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a mediator of joint degeneration.

Surgical stabilization of rib fractures is associated with improved survival but increased acute respiratory distress syndrome.

BACKGROUND: How the surgical stabilization of rib fractures after trauma affects the development of acute respiratory distress syndrome and impacts survival has yet to be determined in a large database. We hypothesized that surgical stabilization of rib fractures would not decrease the incidence of acute respiratory distress syndrome. METHODS: The National Trauma Data Bank was queried for all traumatic rib fractures in 2016. Patients were divided into groups with single rib fractures, multiple rib fractures, and flail chest. Nonoperative therapy was compared with stabilization of rib fractures of 1 to 2 ribs or 3+ ribs. RESULTS: There were 114,972 total patients with rib fractures meeting inclusion criteria, with 5,106 (4.4%) having flail chest, 24,726 (21.5%) having single rib fractures, and 85,140 (74.1%) having multiple rib fractures. Those with flail chest (15.9%) were most likely to get rib plating in comparison to multiple rib fractures (0.9%) and single rib fractures (0.2%); P < .001. On logistic regression, surgical stabilization of rib fractures 1 to 2 ribs (odds ratio: 0.17, 95% confidence interval: 0.10-0.28) or 3+ ribs (odds ratio: 0.17, 95% confidence interval: 0.11-0.28), with nonoperative therapy as the reference was associated with survival. Variables associated with mortality included increasing age, male sex, increasing injury severity score, decreased Glasgow coma scale, requirement of transfusions, and hypotension on admission. Surgical stabilization of rib fractures 3+ ribs (odds ratio: 2.30, 95% confidence interval: 1.58-3.37) was associated with acute respiratory distress syndrome but not 1 to 2 ribs (odd ratio: 1.55, 95% confidence interval: 0.97-2.48). On logistic regression of only patients with flail chest, stabilization of rib fractures was associated with decreased mortality but not increased risk of acute respiratory distress syndrome. CONCLUSION: The increased risk of acute respiratory distress syndrome should be considered in the preoperative assessment for stabilization of rib fractures.

Sex Differences in the Massively Transfused Trauma Patient.

INTRODUCTION: Recent studies have suggested the female hypercoaguable state may have a protective effect in trauma. However, whether this hypercoagulable profile confers a survival benefit in massively transfused trauma patients has yet to be determined. We hypothesized that females would have better outcomes than males after traumatic injury that required massive transfusion protocol (MTP). PATIENTS AND METHODS: All trauma patients who underwent MTP at an urban, level 1, academic trauma center were reviewed from November 2007 to October 2018. Female MTP patients were compared to their male counterparts. RESULTS: There were a total of 643 trauma patients undergoing MTP. Of these, 90 (13.8%) were female and 563 (86.2%) were male. Presenting blood pressure, heart rate, shock index, and injury severity score (ISS) were not significantly different. Overall mortality and incidence of venous thromboembolism were similar. Complication profile and hospital stay were similar. On logistic regression, female sex was not associated with survival (HR: 1.04, 95% CI: 0.56-1.92, P = 0.91). Variables associated with mortality included age (HR: 1.02, 95% CI: 1.05-1.09, P = 0.03) and ISS (HR: 1.07, 95% CI: 1.05-1.09, P < 0.001). Increasing Glascow Coma Scale was associated with survival (HR: 0.85, 95% CI: 0.82-0.89, P < 0.001). On subset analysis, premenopausal women (age < 50) did not have a survival advantage in comparison with similar aged males (HR: 0.68, 95% CI: 0.36-1.28, P = 0.24). DISCUSSION: Sex differences in coagulation profile do not result in a survival advantage for females when MTP is required.