Optimal redesign study of the harm wing

The purpose of this project was to investigate the use of optimization techniques to improve the flutter margins of the HARM AGM-88A wing. The missile has four cruciform wings, located near mid-fuselage, that are actuated in pairs symmetrically and antisymmetrically to provide pitch, yaw, and roll control. The wings have a solid stainless steel forward section and a stainless steel crushed-honeycomb aft section. The wing restraint stiffness is dependent upon wing pitch amplitude and varies from a low value near neutral pitch attitude to a much higher value at off-neutral pitch attitudes, where aerodynamic loads lock out any free play in the control system. The most critical condition for flutter is the low-stiffness condition in which the wings are moved symmetrically. Although a tendency toward limit-cycle flutter is controlled in the current design by controller logic, wing redesign to improve this situation is attractive because it can be accomplished as a retrofit. In view of the exploratory nature of the study, it was decided to apply the optimization to a wing-only model, validated by comparison with results obtained by Texas Instruments (TI). Any wing designs that looked promising were to be evaluated at TI with more complicated models, including body modes. The optimization work was performed by McIntosh Structural Dynamics, Inc. (MSD) under a contract from TI

ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide–specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity

Allogeneic Hematopoietic Stem Cell Transplantation After Prior Lung Transplantation for Hereditary Pulmonary Alveolar Proteinosis: A Case Report

Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, post-lung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus-disease (PAP) effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP

Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19

In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform

Lobular capillary haemangioma of the nasal cavity: observation of three specific cases.

Lobular Capillary Haemangioma of the nasal cavity: Observation of three specific cases. Lobular Capillary Haemangioma, unproperly called "Pyogenic granuloma", is a benign vascular tumour pedunculated on the skin and on mucous membranes of the oral and nasal cavities. Microtrauma and pregnancy are the most often evocated aetiologic factors. Epistaxis and nasal obstruction are the most marked symptoms of this irregular and friable mass. We report three cases (two adult and one paediatric) of this pathology. Two have as trigger factor a nasal microtrauma, the third an oestro-progestative impregnation. A clinical, radiological and histological description allows us to expose the characteristics of this lesion that remains obscure to many rhinologists. Lobular Capillary Haemangioma has to be evocated in the differential diagnosis of each haemorrhagic endonasal mass

Role of F-18-FDG PET/CT in Restrictive Allograft Syndrome After Lung Transplantation

BACKGROUND: Differential diagnosis of phenotypes of chronic lung allograft dysfunction (CLAD) remains troublesome. We hypothesized that F-fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) may help in differential diagnosis of CLAD phenotypes, as it showed promising results regarding diagnosis and prognosis in interstitial lung diseases. METHODS: A monocentric, retrospective study was performed including all lung transplant recipients suffering from bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) who underwent F-FDG PET/CT scan, in comparison with stable lung transplant recipients. Maximum standardized uptake value (SUVmax) was associated with pulmonary function and survival. Proof-of-concept microCT and glucose transporter-1 staining served as morphologic validation for regions with different SUVmax. RESULTS: Maximum standardized uptake value was higher in RAS (median, 2.6; n = 29) compared with BOS (median, 1.0; n = 15) and stable patients (median, 0.59; n = 8) (P < 0.0001). In RAS, high SUVmax was associated with worse survival after F-FDG PET/CT (P = 0.0004; hazard ratio, 1.82). Forced vital capacity at F-FDG PET/CT inversely correlated with SUVmax (R = -0.40, P = 0.03). MicroCT analysis revealed extensive fibrosis in regions of high SUVmax, with an increased number of glucose transporter-1-positive cells. CONCLUSIONS: F-fluorodeoxyglucose positron emission tomography with CT may noninvasively differentiate RAS from BOS. RAS patients with areas of increased lung metabolism have worse outcome, demonstrating the potential use of F-FDG PET/CT during follow-up after lung transplantation.status: publishe