Management of severe acute respiratory distress syndrome: A primer

This narrative review explores the physiology and evidence-based management of patients with severe acute respiratory distress syndrome (ARDS) and refractory hypoxemia, with a focus on mechanical ventilation, adjunctive therapies, and veno-venous extracorporeal membrane oxygenation (V-V ECMO). Severe ARDS cases increased dramatically worldwide during the Covid-19 pandemic and carry a high mortality. The mainstay of treatment to improve survival and ventilator-free days is proning, conservative fluid management, and lung protective ventilation. Ventilator settings should be individualized when possible to improve patient-ventilator synchrony and reduce ventilator-induced lung injury (VILI). Positive end-expiratory pressure can be individualized by titrating to best respiratory system compliance, or by using advanced methods, such as electrical impedance tomography or esophageal manometry. Adjustments to mitigate high driving pressure and mechanical power, two possible drivers of VILI, may be further beneficial. In patients with refractory hypoxemia, salvage modes of ventilation such as high frequency oscillatory ventilation and airway pressure release ventilation are additional options that may be appropriate in select patients. Adjunctive therapies also may be applied judiciously, such as recruitment maneuvers, inhaled pulmonary vasodilators, neuromuscular blockers, or glucocorticoids, and may improve oxygenation, but do not clearly reduce mortality. In select, refractory cases, the addition of V-V ECMO improves gas exchange and modestly improves survival by allowing for lung rest. In addition to VILI, patients with severe ARDS are at risk for complications including acute cor pulmonale, physical debility, and neurocognitive deficits. Even among the most severe cases, ARDS is a heterogeneous disease, and future studies are needed to identify ARDS subgroups to individualize therapies and advance care

Flight Measurements of Flying Qualities of a P-47D-30 Airplane (AAF No. 43-3441) to Determine Longitudinal Stability and Control and Stalling Characteristics

Flight tests have been made to determine the longitudinal stability and control and stalling characteristics of the P-47.E-30 airplane. The teat results show the airplane to be unstable stick free in any power-on condition even at the most forward center-of-gravity position tested. At the rearward center-of-gravity position tested the airplane also had neutral to negative stick-fixed stability with power on. The characteristics in accelerated flight were acceptable at the forward center-of-gravity position at low and high altitudes except at high speed where the control-force variations with acceleration were high. At the rearward center-of-gravity position, elevator-force reversals were experienced in turns at low speeds, and the force per g was low at all the other speeds. Ample stall warning was afforded in all the conditions tested and the stalling characteristics were very satisfactory except in the approach and wave-off conditions

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

Empirically Derived Integrated Stellar Yields of Fe-Peak Elements

We present here the initial results of a new study of massive star yields of Fe-peak elements. We have compiled from the literature a database of carefully determined solar neighborhood stellar abundances of seven iron-peak elements, Ti, V, Cr, Mn, Fe, Co, and Ni and then plotted [X/Fe] versus [Fe/H] to study the trends as functions of metallicity. Chemical evolution models were then employed to force a fit to the observed trends by adjusting the input massive star metallicity-sensitive yields of Kobayashi et al. Our results suggest that yields of Ti, V, and Co are generally larger as well as anticorrelated with metallicity, in contrast to the Kobayashi et al. predictions. We also find the yields of Cr and Mn to be generally smaller and directly correlated with metallicity compared to the theoretical results. Our results for Ni are consistent with theory, although our model suggests that all Ni yields should be scaled up slightly. The outcome of this exercise is the computation of a set of integrated yields, i.e., stellar yields weighted by a slightly flattened time-independent Salpeter initial mass function and integrated over stellar mass, for each of the above elements at several metallicity points spanned by the broad range of observations. These results are designed to be used as empirical constraints on future iron-peak yield predictions by stellar evolution modelers. Special attention is paid to the interesting behavior of [Cr/Co] with metallicity -- these two elements have opposite slopes -- as well as the indirect correlation of [Ti/Fe] with [Fe/H]. These particular trends, as well as those exhibited by the inferred integrated yields of all iron-peak elements with metallicity, are discussed in terms of both supernova nucleosynthesis and atomic physics.Comment: 27 pages, 6 figures; Accepted for Publication in the Astrophysical Journa

An Experimental Paradigm for the Prediction of Post-Operative Pain (PPOP)

Many women undergo cesarean delivery without problems, however some experience significant pain after cesarean section. Pain is associated with negative short-term and long-term effects on the mother. Prior to women undergoing surgery, can we predict who is at risk for developing significant postoperative pain and potentially prevent or minimize its negative consequences? These are the fundamental questions that a team from the University of Washington, Stanford University, the Catholic University in Brussels, Belgium, Santa Joana Women's Hospital in São Paulo, Brazil, and Rambam Medical Center in Israel is currently evaluating in an international research collaboration. The ultimate goal of this project is to provide optimal pain relief during and after cesarean section by offering individualized anesthetic care to women who appear to be more 'susceptible' to pain after surgery

Centerscope

Centerscope, formerly Scope, was published by the Boston University Medical Center "to communicate the concern of the Medical Center for the development and maintenance of improved health care in contemporary society.

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember&#8482;, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

AGB Stars: Summary and Warning

The Asymptotic Giant Branch (AGB) phase is very short but its importance is seen in its nucleosynthesis. A revolution in stellar modelling has taken place in the last 20 years, inspired jointly by this rich nucleosynthesis and partly by new data. For example, the isotopic data coming from pre-solar grains (see this volume) forces theorists to include species that were previously ignored, species which are energetically of no importance (i.e. they play no role in determining the stellar structure) but which can be used to constrain the models. Nucleosynthesis is now important as a tracer of temperature and mixing, and not simply a by-product of energy generation. But along with these advances come more quantitative demands. It is now increasingly important to know what is known well and what is less sure. This is the goal of this paper.Comment: 9 pages, review presented at Ringberg Workshop on "Astronomy with Radioactivites", to appear in New Astronomy Review