The vast majority of studies on cracked rotors assume that the breathing response of a fatigue crack is weight-dominant i.e. the effect of dynamic forces on the breathing response is negligible. In ...this study, the assumption of weight-dominance is removed and the coupling effect of unbalance angle and magnitude on the breathing behaviour of a crack is examined. The proposed breathing model is shown to be greatly influenced by unbalance eccentricity and rotor speed, whereas weight-dominant breathing models are unaffected by these factors. A significant difference in the vibration behaviour of a weight-dominant model and the proposed model was particularly seen around the critical speed of deeply cracked rotors. High unbalance eccentricity and a 180° placement of the unbalanced mass resulted in the disappearance of 2X and/or 3X harmonic components at one-half and one-third of the rotor critical speed when the vibration was predicted using the proposed model. This result suggests careful placement and size of the unbalance mass may allow for the isolation of rotor cracks from other rotor faults in the frequency domain by negating the effects of the crack breathing.
We assessed the feasibility and desirability of public health entrepreneurship (PHE) in governmental public health.
Using a qualitative case study approach with semistructured interview protocols, we ...conducted interviews between April 2010 and January 2011 at 32 local health departments (LHDs) in 18 states. Respondents included chief health officers and senior LHD staff, representatives from national public health organizations, health authorities, and public health institutes.
Respondents identified PHE through 3 overlapping practices: strategic planning, operational efficiency, and revenue generation. Clinical services offer the strongest revenue-generating potential, and traditional public health services offer only limited entrepreneurial opportunities. Barriers include civil service rules, a risk-averse culture, and concerns that PHE would compromise core public health values.
Ongoing PHE activity has the potential to reduce LHDs' reliance on unstable general public revenues. Yet under the best of circumstances, it is difficult to generate revenue from public health services. Although governmental public health contains pockets of entrepreneurial activity, its culture does not sustain significant entrepreneurial activity. The question remains as to whether LHDs' current public revenue sources are sustainable and, if not, whether PHE is a feasible or desirable alternative.
Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to ...escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C–C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0–7 and patient D (p=0.027) from day 0–14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.
•Leronlimab is a monoclonal antibody in clinical trials to treat the cytokine storm.•Critically ill patients received leronlimab through compassionate use and had remarkable recoveries measured objectively.•The CCR5 receptor is important in recruiting inflammatory cells mainly T cells and macrophages.•Leronlimab disrupted this signal and may have been responsible for restoration of the immune system, improved survival and decrease in IL-6.
Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated ...rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine.
MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds ...pathogen-derived peptide Ags for presentation to CD8
T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8
T cells. Indeed, SIV-specific, Mamu-E-restricted CD8
T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4
T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology.
Highlights ► Picture naming elicited gamma-augmentation in occipital, temporal, premotor and Rolandic areas. ► Word reading elicited gamma-augmentation in occipital, temporal, parietal and Rolandic ...areas. ► Longer words elicited greater gamma-augmentation in medial occipital areas.
Hepatitis B virus (HBV) is a major global health concern, and the development of curative therapeutics is urgently needed. Such efforts are impeded by the lack of a physiologically relevant, ...pre-clinical animal model of HBV infection. Here, we report that expression of the HBV entry receptor, human sodium-taurocholate cotransporting polypeptide (hNTCP), on macaque primary hepatocytes facilitates HBV infection in vitro, where all replicative intermediates including covalently closed circular DNA (cccDNA) are present. Furthermore, viral vector-mediated expression of hNTCP on hepatocytes in vivo renders rhesus macaques permissive to HBV infection. These in vivo macaque HBV infections are characterized by longitudinal HBV DNA in serum, and detection of HBV DNA, RNA, and HBV core antigen (HBcAg) in hepatocytes. Together, these results show that expressing hNTCP on macaque hepatocytes renders them susceptible to HBV infection, thereby establishing a physiologically relevant model of HBV infection to study immune clearance and test therapeutic and curative approaches.
Describe the utility of anterior segment optical coherence tomography angiography (AS-OCTA) to assess ocular surface lesions.
Retrospective, case-control study of 10 eyes of 9 patients with malignant ...lesions and 23 eyes of 22 patients with benign lesions. Lesions included 13 epithelial, 10 pigmented and 10 lymphoid lesions. Graders performed an average of 3 depth and diameter measurements of peri-lesional vessels entering each lesion on AS-OCTA. Statistical models to assess differences between groups accounted for bilateral eye inclusion and lesion thickness (on AS-OCT). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were performed for each parameter.
In the benign and malignant groups, age was 49.5 ± 22.4 and 64.3 ± 10.6 years (p = 0.145) with 45% males and 55% males (p = 0.458), in their respective groups. AS-OCTA showed greater peri-lesional vessel depth and diameter in malignant lesions (315.2 ± 73.0 μm, p < 0.001 and 76.4 ± 18.2 μm, p < 0.001; respectively) compared to benign lesions (199.4 ± 34.1 μm and 44.0 ± 9.4 μm, respectively). Malignant lesions showed deep and dilated peri-lesional vessels, which may represent feeder vessels. Vessel depth showed AUC = 0.980, 90.9% sensitivity and 100.0% specificity with a 236.5 μm cutoff. Vessel diameter showed AUC = 0.960, 100.0% sensitivity and 88.9% specificity with a 53.9 μm cutoff.
AS-OCTA shows greater peri-lesional vessel depth and diameter of malignant lesions compared to benign lesions. This imaging modality provides novel and non-invasive functional vascular parameters that can potentially aid the assessment of ocular surface lesions.
•Malignant lesions showed greater peri-lesional vessel depth and vessel diameter.•AS-OCTA can identify feeder vessels in malignant conjunctival lesions.•AS-OCTA provided novel vascular parameters for ocular surface lesion assessment.•AS-OCTA is a promising non-invasive objective tool to assess ocular surface lesions.
Methicillin-resistant
Staphylococcus aureus
(MRSA) is a
S. aureus
strain with resistance to beta-lactam antibiotics, making it a global human and veterinary health concern. Specifically, ...immunosuppressed patients have a remarkably higher risk of clinical MRSA infections with significantly increased rates of prolonged clinical recovery, morbidity, and mortality. The current treatment of choice for MRSA is vancomycin. Importantly, we report the first known vancomycin-resistant
S. aureus
(VRSA) carriers in a cohort of Mauritian cynomolgus macaques (CM) imported to the Oregon National Primate Research Center (ONPRC), with a MRSA carrier rate of 76.9% (10/13 animals). All MRSA isolates also demonstrated resistance to vancomycin with prevalence of vancomycin-intermediate
Staphylococcus aureus
(VISA) at 30% (3/10 MRSA-positive CMs) and VRSA at 70% (7/10 MRSA-positive CMs). Additionally, we identified VRSA in a rhesus macaque (RM) housed within the same room as the VRSA-positive CMs and identified a MRSA/VISA carrier rate of 18.8% in RMs (3/16 positive for both MRSA and VISA) in unexposed recently assigned animals directly from the ONPRC RM breeding colony. Considering that the MRSA and VRSA/VISA-positive CMs future study aims included significant immunosuppression, MRSA/VRSA/VISA decolonization treatment and expanded “MRSA-free” practices were employed to maintain this status. We report the first controlled study using in-depth analyses with appropriate diagnostic serial testing to definitively show an MRSA decolonization therapy (90% success rate) and expanded barrier practice techniques to successfully prevent recolonization (100%) of a cohort of CMs MRSA-free (up to 529 days with a total of 4,806 MRSA-free NHP days).
For the large-scale offshore wind turbine blades, the governing equations in fluid domain and the motion equations in structural domain with geometric nonlinearity were developed based on ALE ...description, and the corresponding discrete equations were obtained. Blade entity model was built up using Pro/E, and the blade vibration characteristics under fluid–structure interaction (FSI) were simulated using ANSYS. Numerical results show that wind shear effect greatly increases the peak values of response curves for displacement and stress, makes the effect of bi-directional fluid–structure interaction (BFSI) more obvious, and also accelerates the attenuation of vibration curves. The displacement of blade airfoil increases nonlinearly along the span direction, and reaches the maximum at the blade tip. The maximum Mises stress appears in the middle of the blade, and reduces gradually towards each end of the blade. Furthermore, the contribution of wind shear effect (WSE) to displacement and Mises stress is much greater than that of FSI.
•The maximum peaks of displacement and Mises stress occur under WSE and BFSI.•WSE greatly increases the peaks of response curves for displacement and stress.•WSE also accelerates the attenuation of vibration curves.•The contribution of WSE to displacement and stress is much greater than that of FSI.•The influences of WSE and FSI on displacement and stress are revealed.
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