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PURPOSE: Approximately 5.7 million people in the US are affected by congestive heart failure. This study aimed to quantitatively evaluate cardiothoracic morphology and variability within a cohort of heart failure patients for the purpose of optimally engineering cardiac devices for a variety of heart failure patients. METHODS: Co-registered cardiac-gated and non-gated chest computed tomography (CT) scans were analyzed from 20 heart failure patients (12 males; 8 females) who were primarily older adults (79.5±8.8 years). Twelve cardiothoracic measurements were collected and compared to study sex and left ventricular (LV) ejection fraction (EF) type differences in cardiothoracic morphology. RESULTS: Four measures were significantly greater in males compared to females: LV long-axis length, LV end diastolic diameter (LVEDD) at 50% length of the LV long-axis, the minimal distance between the sternum and heart, and the angle between the LV long-axis and coronal plane. Four measures were significantly greater in patients with reduced EF compared to preserved LV: LV long-axis length, LVEDD at 50% length of the LV long-axis, left ventricular volume normalized by body surface area, and the angle between the mitral valve plane and LV long-axis. CONCLUSIONS: These cardiothoracic morphology measurements are important to consider in the design of cardiac devices for heart failure management (e.g. cardiac pacemakers, ventricular assist devices, and implantable defibrillators), since morphology differs by sex and ejection fraction.

Deficiencies in many coagulation factors and protease-activated receptors (PARs) affect embryonic development. We describe a defect in definitive erythropoiesis in PAR2-deficient mice. Embryonic PAR2 deficiency increases embryonic death associated with variably severe anemia in comparison with PAR2-expressing embryos. PAR2-deficient fetal livers display reduced macrophage densities, erythroblastic island areas, and messenger RNA expression levels of markers for erythropoiesis and macrophages. Coagulation factor synthesis in the liver coincides with expanding fetal liver hematopoiesis during midgestation, and embryonic factor VII (FVII) deficiency impairs liver macrophage development. Cleavage-insensitive PAR2-mutant mice recapitulate the hematopoiesis defect of PAR2-deficient embryos, and macrophage-expressed PAR2 directly supports erythroblastic island function and the differentiation of red blood cells in the fetal liver. Conditional deletion of PAR2 in macrophages impairs erythropoiesis, as well as increases inflammatory stress, as evidenced by upregulation of interferon-regulated hepcidin antimicrobial peptide. In contrast, postnatal macrophage PAR2 deficiency does not have any effect on steady-state Kupffer cells, bone marrow macrophage numbers, or erythropoiesis, but erythropoiesis in macrophages from PAR2-deficient mice is impaired following hemolysis. These data identify a novel function for macrophage PAR2 signaling in adapting to rapid increases in blood demand during gestational development and postnatal erythropoiesis under stress conditions.

Objective: Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization with Escherichia coli augmented the adhesion of leukocytes, which was dependent on the TLR4 (Toll-like receptor-4)/TRIF (TIR-domain–containing adapter-inducing interferon-β) pathway. Although neutrophil accumulation was decreased in I/R-injured venules of GF mice, NETosis following I/R injury was significantly enhanced compared with conventionally raised mice or mice colonized with the minimal microbial consortium altered Schaedler flora. Also ex vivo, neutrophils from GF and antibiotic-treated mice showed increased LPS (lipopolysaccharide)-induced NETosis. Enhanced TLR4 signaling in GF neutrophils was due to elevated TLR4 expression and augmented IRF3 (interferon regulatory factor-3) phosphorylation. Likewise, neutrophils from antibiotic-treated conventionally raised mice had increased NET formation before and after ischemia. Increased NETosis in I/R injury was abolished in conventionally raised mice deficient in the TLR adaptor TRIF. In support of the desensitizing influence of enteric LPS, treatment of GF mice with LPS via drinking water diminished LPS-induced NETosis in vitro and in the mesenteric I/R injury model. Conclusions: Collectively, our results identified that the gut microbiota suppresses NETing neutrophil hyperreactivity in mesenteric I/R injury, while ensuring immunovigilance by enhancing neutrophil recruitment.

Expanding evidence indicates multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Here we show in a tissue factor (TF)-dependent model of flow restriction-induced venous thrombosis that complement factors make distinct contributions to platelet activation and fibrin deposition. Complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition in the ligated inferior vena cava, and diminished platelet activation in vitro. Initial fibrin deposition at the vessel wall over 6 hours in this model was dependent on protein disulfide isomerase (PDI) and TF expression by myeloid cells, but did not require neutrophil extracellular trap formation involving peptidyl arginine deiminase 4. In contrast to C3-/- mice, C5-deficient mice had no apparent defect in platelet activation in vitro, and vessel wall platelet deposition and initial hemostasis in vivo. However, fibrin formation, the exposure of negatively charged phosphatidylserine (PS) on adherent leukocytes, and clot burden after 48 hours were significantly reduced in C5-/- mice compared with wild-type controls. These results delineate that C3 plays specific roles in platelet activation independent of formation of the terminal complement complex and provide in vivo evidence for contributions of complement-dependent membrane perturbations to prothrombotic TF activation on myeloid cells.

Objective. Colorectal surgeons report difficulty in positioning surgical devices in males, particularly those with a narrower pelvis. The objectives of this study were to (1) characterize the anatomy of the pelvis and surrounding soft tissue from magnetic resonance and computed tomography scans from 10 average males (175 cm, 78 kg) and (2) develop a model representing the mean configuration to assess variability. Methods. The anatomy was characterized from existing scans using segmentation and registration techniques. Size and shape variation in the pelvis and soft tissue morphology was characterized using the Generalized Procrustes Analysis to compute the mean configuration. Results. There was considerable variability in volume of the psoas, connective tissue, and pelvis and in surface area of the mesorectum, pelvis, and connective tissue. Subject height was positively correlated with mesorectum surface area (P = .028, R2 = 0.47) and pelvis volume ( P = .041, R2 = 0.43). The anterior-posterior distance between the inferior pelvic floor muscle and pubic symphysis was positively correlated with subject height ( P = .043, r = 0.65). The angle between the superior mesorectum and sacral promontory was negatively correlated with subject height ( P = .042, r = −0.65). The pelvic inlet was positively correlated with subject weight ( P = .001, r = 0.89). Conclusions. There was considerable variability in organ volume and surface area among average males with some correlations to subject height and weight. A physical trainer model created from these data helped surgeons trial and assess device prototypes in a controllable environment.

This study aimed to quantify lumbar volumetric bone mineral density (vBMD) for 873 seriously injured Crash Injury Research and Engineering Network (CIREN) motor vehicle crash occupants (372 male, 501 female) from 8 centers using phantomless computed tomography scans and to associate vBMD with age, fracture incidence, and osteopenia/osteoporosis diagnoses. The novelty of this work is that it associates vBMD with region of injury by applying an established method for vBMD measurement using phantomless computed tomography (CT).A validated phantomless CT calibration method that uses patient-specific fat and muscle measurements to calibrate vBMD measured from the L1-L5 trabeculae was applied on 873 occupants from various CIREN centers. CT-measured lumbar vBMD145 mg/cc is indicative of osteopenia using a published threshold. CIREN occupant lumbar vBMD in milligrams per cubic centimeter was regressed against age, osteopenia/osteoporosis comorbidities, height, weight, body mass index (BMI), and the incidence of fracture in vertebral (cervical, thoracic, lumbar) and rib/sternum regions.Among the 873 occupants analyzed, 11% (92 occupants) were diagnosed as osteopenic in CIREN. Of these 92 occupants, 42% (39 occupants) had normal vBMD measures (≥145 mg/cc), suggesting possible misclassification in CIREN. Of the 134 occupants classified as osteopenic in vBMD analysis, 60% were not classified as osteopenic in CIREN, suggesting undiagnosed osteopenia, and 40% were correctly classified in CIREN. Age was negatively correlated with vBMD (P.0001) and occupants with145 mg/cc vBMD sustained a median number of 2 rib/sternum fractures compared to a median value of 0 rib/sternum fractures for the ≥145 mg/cc vBMD group (P.0001). Vertebral fracture analysis revealed that the thoracolumbar region was the most common region of injury in the spine. Though the incidence of fracture was not significantly different in the thoracic (10% versus 6%, P =.122) and lumbar (16% versus 13%, P =.227) regions between the 2 bone quality groups, the proportion of thoracolumbar fractures was significantly higher in occupants with145 mg/cc vBMD versus occupants with ≥145 mg/cc vBMD (24% versus 17%, P =.043).Low lumbar vertebral bone quality is associated with an increased number of rib/sternum fractures and a greater incidence of thoracolumbar vertebral body fractures within the CIREN population analyzed.

Neutrophils, the most abundant human immune cells, are rapidly recruited to sites of infection, where they fulfill their life-saving antimicrobial functions. While traditionally regarded as short-lived phagocytes, recent findings on long-term survival, neutrophil extracellular trap (NET) formation, heterogeneity and plasticity, suppressive functions, and tissue injury have expanded our understanding of their diverse role in infection and inflammation. This review summarises our current understanding of neutrophils in host-pathogen interactions and disease involvement, illustrating the versatility and plasticity of the neutrophil, moving between host defence, immune modulation, and tissue damage.

A B S T R A C T Objective: To study if neutrophil extracellular traps (NETs) are present in the peritoneal fluid of endometriosis patients. NETs play a crucial role in fighting against microorganisms. However, exaggerated NET production may lead to tissue damage in their vicinity in pathological conditions. Our study evaluates the presence of NETs in endometriosis peritoneal fluid. Study design: Peritoneal fluid (PF) was collected in a case-control study from 52 women, who underwent either diagnostic or operative laparoscopy. The control group consisted of 17 women with infertility, chronic pelvic pain, simple or functional cysts or irregular bleeding. The endometriosis group, altogether 35 patients, comprised 19 patients with stage I and II and 16 patients with stage III and IV endometriosis. First we tested whether the PF is able to stimulate NET production. Neutrophils from healthy volunteers were treated with the PF of endometriosis patients and controls and NETs were detected with Sytox orange extracellular DNA dye and immunofluorescence microscopy. Then we evaluated if NETs were already present in the collected PF using the specific myeloperoxidase (MPO)-DNA capture ELISA method, based on the MPO associated with the NET scaffold. Results: The PF of endometriosis patients did not stimulate NET release from healthy granulocytes. However, pre-existent NETs could be detected in 17 endometriosis patients out of 35 (49%). In contrary, in the control group NETs were present in only 3 patients out of 17 (18%), (p = 0.03, OR: 4.4). Moreover, the quantification of NETs showed a significantly higher amount of NETs in endometriosis compared to the controls (0.097 vs. 0.02, p = 0.04). Conclusion: This is the first study, which evaluated and described the presence of NETs in the PF of endometriosis patients. Our study shows, that NETs may be involved in the complex pathophysiology of endometriosis.