Evaluation of at-sea flight testing of the MV-22 Osprey for operational employment

The MV-22 Osprey tiltrotor aircraft is a radically new air vehicle designed to replace aging helicopters and support the US Marine Corp\u27s future concept of operational maneuver from the sea. Unfortunately the aircraft has been plagued with political and programmatic delays throughout its 19-year history that prevented early and comprehensive at-sea testing. With an operational evaluation in October 1999, shortened at-sea test period was required late in the aircraft development in January 1999.This thesis analyzes the compressed developmental test process used to prepare this novelair vehicle for sea service in a short time period.The dynamic interface testing of Naval aircraft and ships is not new, although the advent of tiltrotors incorporating digital fly-by-wire technology has challenged traditional developmental procedures. The MV-22 required extensive test planning, flying qualities evaluations and engineering tests to define safe operational limits in the shipboard environment. An analysis of a lateral control instability problem encountered during the testing and the subsequent test process innovations for this unique aircraft substantiate the need to conduct comprehensive and extensive developmental testing.It is the author\u27s opinion that at-sea testing is risky and the final exam for a Naval Aircraft. The risks of a shortened test process were that deficiencies would be uncovered and that uncharted capabilities would not be exploited for operational employment. The Documented successes and failures of the MV-22 at-sea test process yield lessons that should be put into practice by future amphibious Vertical Take Off and Landing (VTOL)aircraft such as the Joint Strike Fighter (JSF) and other follow-on VSTOL aircraft

Arguing for Adaptive Clinical Trials in Sepsis

Sepsis is life-threatening organ dysfunction due to dysregulated response to infection. Patients with sepsis exhibit wide heterogeneity stemming from genetic, molecular, and clinical factors as well as differences in pathogens, creating challenges for the development of effective treatments. Several gaps in knowledge also contribute: (i) biomarkers that identify patients likely to benefit from specific treatments are unknown; (ii) therapeutic dose and duration is often poorly understood; and (iii) short-term mortality, a common outcome measure, is frequently criticized for being insensitive. To date, the majority of sepsis trials use traditional design features, and have largely failed to identify new treatments with incremental benefit over standard of care. Traditional trials are also frequently conducted as part of a drug evaluation process that is segmented into several phases, each requiring separate trials, with a long time delay from inception through design and execution to incorporation of results into clinical practice. By contrast, adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of the trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs. Adoption of new treatments in clinical practice can be accelerated if these trials are incorporated in electronic health records as part of a learning health system. In this review, we discuss challenges in the evaluation of treatments for sepsis, and explore potential benefits and weaknesses of recent advances in adaptive trial methodologies to address these challenges

Reducing cognitive arousal and sleep effort alleviates insomnia and depression in pregnant women with DSM-5 insomnia disorder treated with a mindfulness sleep program

OBJECTIVES: Combining mindfulness with behavioral sleep strategies has been found to alleviate symptoms of insomnia and depression during pregnancy, but mechanisms for this treatment approach remain unclear. The present study examined nocturnal cognitive arousal and sleep effort as potential treatment mechanisms for alleviating insomnia and depression via a mindfulness sleep program for pregnant women. METHODS: Secondary analysis from a proof-of-concept trial of 12 pregnant women with DSM-5 insomnia disorder who were treated with Perinatal Understanding of Mindful Awareness for Sleep (PUMAS), which places behavioral sleep strategies within a mindfulness framework. Data were collected across eight weekly assessments: pretreatment, six sessions, and posttreatment. Measures included the insomnia severity index (ISI), Edinburgh postnatal depression scale (EPDS), pre-sleep arousal scale\u27s cognitive factor (PSASC), and the Glasgow sleep effort scale (GSES). We used linear mixed modeling to test cognitive arousal and sleep effort as concurrent and prospective predictors of insomnia and depression. RESULTS: Most patients reported high cognitive arousal before PUMAS (75.0%), which decreased to 8.3% after treatment. All insomnia remitters reported low cognitive arousal after treatment, whereas half of nonremitters continued reporting high cognitive arousal. Both nocturnal cognitive arousal and sleep effort were associated with same-week changes in insomnia throughout treatment, and sleep effort yielded a prospective effect on insomnia. Lower levels of nocturnal cognitive arousal and sleep effort prospectively predicted reductions in depression. CONCLUSIONS: The present study offers preliminary evidence that reducing sleep effort and nocturnal cognitive arousal may serve as key mechanisms for alleviating insomnia and depression via mindfulness-based insomnia therapy. ClinicalTrials.gov ID: NCT04443959

Red blood cell transfusion and outcomes in patients with acute lung injury, sepsis and shock

Introduction: In this study, we sought to determine the association between red blood cell (RBC) transfusion and outcomes in patients with acute lung injury (ALI), sepsis and shock.Methods: We performed a secondary analysis of new-onset ALI patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment Trial (2000 to 2005) who had a documented ALI risk factor of sepsis or pneumonia and met shock criteria (mean arterial pressure (MAP) < 60 mmHg or vasopressor use) within 24 hours of randomization. Using multivariable logistic regression, we examined the association between RBC transfusion and 28-day mortality after adjustment for age, sex, race, randomization arm and Acute Physiology and Chronic Health Evaluation III score. Secondary end points included 90-day mortality and ventilator-free days (VFDs). Finally, we examined these end points among the subset of subjects meeting prespecified transfusion criteria defined by five simultaneous indicators: hemoglobin < 10.2 g/dL, central or mixed venous oxygen saturation < 70%, central venous pressure ≥ 8 mmHg, MAP ≥ 65 mmHg, and vasopressor use.Results: We identified 285 subjects with ALI, sepsis, shock and transfusion data. Of these, 85 also met the above prespecified transfusion criteria. Fifty-three (19%) of the two hundred eighty-five subjects with shock and twenty (24%) of the subset meeting the transfusion criteria received RBC transfusion within twenty-four hours of randomization. We found no independent association between RBC transfusion and 28-day mortality (odds ratio = 1.49, 95% CI (95% confidence interval) = 0.77 to 2.90; P = 0.23) or VFDs (mean difference = -0.35, 95% CI = -4.03 to 3.32; P = 0.85). Likewise, 90-day mortality and VFDs did not differ by transfusion status. Among the subset of patients meeting the transfusion criteria, we found no independent association between transfusion and mortality or VFDs.Conclusions: In patients with new-onset ALI, sepsis and shock, we found no independent association between RBC transfusion and mortality or VFDs. The physiological criteria did not identify patients more likely to be transfused or to benefit from transfusion. © 2011 Parsons et al. licensee BioMed Central Ltd

Jet Shapes and Jet Algorithms in SCET

Jet shapes are weighted sums over the four-momenta of the constituents of a jet and reveal details of its internal structure, potentially allowing discrimination of its partonic origin. In this work we make predictions for quark and gluon jet shape distributions in N-jet final states in e+e- collisions, defined with a cone or recombination algorithm, where we measure some jet shape observable on a subset of these jets. Using the framework of Soft-Collinear Effective Theory, we prove a factorization theorem for jet shape distributions and demonstrate the consistent renormalization-group running of the functions in the factorization theorem for any number of measured and unmeasured jets, any number of quark and gluon jets, and any angular size R of the jets, as long as R is much smaller than the angular separation between jets. We calculate the jet and soft functions for angularity jet shapes \tau_a to one-loop order (O(alpha_s)) and resum a subset of the large logarithms of \tau_a needed for next-to-leading logarithmic (NLL) accuracy for both cone and kT-type jets. We compare our predictions for the resummed \tau_a distribution of a quark or a gluon jet produced in a 3-jet final state in e+e- annihilation to the output of a Monte Carlo event generator and find that the dependence on a and R is very similar.Comment: 62 pages plus 21 pages of Appendices, 13 figures, uses JHEP3.cls. v2: corrections to finite parts of NLO jet functions, minor changes to plots, clarified discussion of power corrections. v3: Journal version. Introductory sections significantly reorganized for clarity, classification of logarithmic accuracy clarified, results for non-Mercedes-Benz configurations adde

Reframing Sepsis Immunobiology for Translation

Sepsis is a common and deadly condition. The current framing of dysregulated host immune responses within the sepsis immunobiology model into pro-inflammatory and immunosuppressive responses for testing novel treatments, have not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalized immunomodulation. In this perspective we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should broaden beyond subtyping, onto identifying deterministic molecularnetworks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as pathologic disruption and/or alteration in homeostasis of the immune-driven resistance, tolerance and resolution mechanisms occurring concurrently. Our reframing highlights novel treatment opportunities and could enable successful immunomodulation in the future.Keywords: Sepsis, immunobiology, precision medicine, molecular mechanisms, subtyping, immunomodulation<br/

Bioprinting Cell- and Spheroid-Laden Protein-Engineered Hydrogels as Tissue-on-Chip Platforms

Human tissues, both in health and disease, are exquisitely organized into complex three-dimensional architectures that inform tissue function. In biomedical research, specifically in drug discovery and personalized medicine, novel human-based three-dimensional (3D) models are needed to provide information with higher predictive value compared to state-of-the-art two-dimensional (2D) preclinical models. However, current in vitro models remain inadequate to recapitulate the complex and heterogenous architectures that underlie biology. Therefore, it would be beneficial to develop novel models that could capture both the 3D heterogeneity of tissue (e.g., through 3D bioprinting) and integrate vascularization that is necessary for tissue viability (e.g., through culture in tissue-on-chips). In this proof-of-concept study, we use elastin-like protein (ELP) engineered hydrogels as bioinks for constructing such tissue models, which can be directly dispensed onto endothelialized on-chip platforms. We show that this bioprinting process is compatible with both single cell suspensions of neural progenitor cells (NPCs) and spheroid aggregates of breast cancer cells. After bioprinting, both cell types remain viable in incubation for up to 14 days. These results demonstrate a first step toward combining ELP engineered hydrogels with 3D bioprinting technologies and on-chip platforms comprising vascular-like channels for establishing functional tissue models