SARS-CoV-2 pneumonia and bacterial pneumonia patients differ in a second hit immune response model

Secondary infections have been shown to complicate the clinical course and worsen the outcome of critically ill patients. Severe Coronavirus Disease 2019 (COVID-19) may be accompanied by a pronounced cytokine release, and immune competence of these patients towards most pathogenic antigens remains uncompromised early in the disease. Patients with bacterial sepsis also exhibit excessive cytokine release with systemic hyper-inflammation, however, typically followed by an anti-inflammatory phase, causing immune paralysis. In a second hit immune response model, leukocyte activation capacity of severely ill patients with pneumonia caused by SARS-CoV-2 or by bacteria were compared upon ICU admission and at days 4 and 7 of the ICU stay. Blood cell count and release of the pro-inflammatory cytokines IL-2, IFNγ and TNF were assessed after whole-blood incubation with the potent immune stimulus pokeweed mitogen (PWM). For comparison, patients with bacterial sepsis not originating from pneumonia, and healthy volunteers were included. Lymphopenia and granulocytosis were less pronounced in COVID-19 patients compared to bacterial sepsis patients. After PWM stimulation, COVID-19 patients showed a reduced release of IFNγ, while IL-2 levels were found similar and TNF levels were increased compared to healthy controls. Interestingly, concentrations of all three cytokines were significantly higher in samples from COVID-19 patients compared to samples from patients with bacterial infection. This fundamental difference in immune competence during a second hit between COVID-19 and sepsis patients may have implications for the selection of immune suppressive or enhancing therapies in personalized medicine

Differential effects of hypergravity on immune dysfunctions induced by simulated microgravity

Microgravity (μg) is among the major stressors in space causing immune cell dysregulations. These are frequently expressed as increased pro-inflammatory states of monocytes and reduced activation capacities in T cells. Hypergravity (as artificial gravity) has shown to have beneficial effects on the musculoskeletal and cardiovascular system both as a countermeasure option for μg-related deconditioning and as gravitational therapy on Earth. Since the impact of hypergravity on immune cells is sparsely explored, we investigated if an application of mild mechanical loading of 2.8 g is able to avoid or treat μg-mediated immune dysregulations. For this, T cell and monocyte activation states and cytokine pattern were first analyzed after whole blood antigen incubation in simulated μg (s-μg) by using the principle of fast clinorotation or in hypergravity. Subsequent hypergravity countermeasure approaches were run at three different sequences: one preconditioning setting, where 2.8 g was applied before s-μg exposure and two therapeutic approaches in which 2.8 g was set either intermediately or at the end of s-μg. In single g-grade exposure experiments, monocyte pro-inflammatory state was enhanced in s-μg and reduced in hypergravity, whereas T cells displayed reduced activation when antigen incubation was performed in s-μg. Hypergravity application in all three sequences did not alleviate the increased pro-inflammatory potential of monocytes. However, in T cells the preconditioning approach restored antigen-induced CD69 expression and IFNy secretion to 1 g control values and beyond. This in vitro study demonstrates a proof of concept that mild hypergravity is a gravitational preconditioning option to avoid adaptive immune cell dysfunctions induced by (s-)μg and that it may act as a booster of immune cell function

Miniature probe for the delivery and monitoring of a photopolymerizable material

Photopolymerization is a common method to cure materials initially in a liquid state, such as dental implants or bone or tissue fillers. Recent advances in the development of biocompatible gel- and cement-systems open up an avenue for in situ photopolymerization. For minimally invasive surgery, such procedures require miniaturized surgical endoscopic probes to activate and control photopolymerization in situ. We present a miniaturized light probe in which a photoactive material can be (1) mixed, pressurized, and injected, (2) photopolymerized/photoactivated, and (3) monitored during the chemical reaction. The device is used to implant and cure poly(ethylene glycol) dimethacrylate-hydrogel-precursor in situ with ultraviolet A (UVA) light (365 nm) while the polymerization reaction is monitored in real time by collecting the fluorescence and Raman signals generated by the 532 nm excitation light source. Hydrogels could be delivered, photopolymerized, and monitored by the probe up to a curing depth of 4 cm. The size of the photopolymerized samples could be correlated to the fluorescent signal collected by the probe, and the reproducibility of the procedure could be demonstrated. The position of the probe tip inside a bovine caudal intervertebral disc could be estimated in vitro based on the collected fluores- cence and Raman signal

Photo-polymerization, swelling and mechanical properties of cellulose fibre reinforced poly(ethylene glycol) hydrogels

The application of hydrogels as load-bearing biomedical components is often limited by their mechanical properties. Often an attempt to improve a hydrogel's stiffness is accompanied by a loss of toughness and swelling properties. In this work, we show that the addition of nanofibrillated cellulose (NFC) provides a mean to tailor both the swelling and the mechanical properties of the hydrogel. Various volume fractions of NFC were added to poly(ethylene glycol) dimethacrylate (PEGDM) precursors with two different molecular weights (6 and 20 kDa). The viscosity measurements of the precursor solutions indicated that the dispersed NFCs form a network-like structure in the hydrogel precursor. Such a structure, as observed in the photo-rheology experiments, serves as a light-scattering source when the solution is illuminated by UV light, which provides a uniform polymerization of the hydrogel in three-dimension and reduces the curing time. Mechanical properties of the neat and composite hydrogels were characterized using monotonic and cyclic compression tests. NFC reinforcement increases the hydrogel's stiffness by a factor 2 and 3.5 for the PEGDM matrixes with molecular weights of 6 and 20 kDa respectively without compromising their toughness. Moreover, the desired stiffness and swelling properties can be simultaneously achieved by adapting the reinforcement concentration and the hydrogel cross-link density. The obtained composite hydrogels offer enhanced and tuneable properties and are proposed for injectable and photo-curable load-bearing implants

Surgical therapy of thymic tumours with pleural involvement: an ESTS Thymic Working Group Project

OBJECTIVES Surgery for thymic epithelial tumours (TETs) with pleural involvement is infrequently performed. Thus, the value of surgical therapy for primary or recurrent TETs with pleural involvement is not sufficiently defined yet. METHODS Twelve institutions contributed retrospective data on 152 patients undergoing surgery (1977-2014) on behalf of the ESTS Thymic Working group. Outcome measures included overall (OS), cause-specific (CSS) and disease-free (DFS) survival as well as freedom from recurrence (FFR). RESULTS In 70.4% of cases, pleural involvement was present at the time of primary intervention, whereas 29.6% had surgery for recurrent disease involving the pleura. Pleural involvement resulted from thymomas (88.8%) and thymic carcinomas (11.2%). Forty extrapleural pneumonectomies (EPPs), 23 total pleurectomies (TPs), and 88 local pleurectomies (LPs) were performed (completeness of resection in 76.8%). OS for the entire patient population at 1, 3, 5 and 10 years was 96.4%, 91.0%, 87.2% and 62.7%, respectively. There was no statistically significant difference regarding FFR and OS for patients with local or advanced disease undergoing EPP, TP or LP. Thymic carcinomas in comparison with thymomas had a negative impact on OS [hazard ratio 6.506, P  = 0.002], CSS and FFR. Incomplete resections predicted worse OS [hazard ratio 6.696, P  = 0.003]. CONCLUSIONS Complete resection remains the mainstay of treatment for TETs with pleural involvement. Study populations treated with EPP, TP and LP had similar survival that may be factual as observed, but in the presence of selection bias, we can further conclude from the results that EPP, TP and LP are equally effective procedures. Procedural choice depends upon the extent of tumour distribution. EPPs, TPs and LPs performed within a multimodality setting seem to be efficient procedures for local control of disease, as they yield excellent results regarding OS, DFS, CSS and FFR

Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight

Space flight exerts a specific conglomerate of stressors on humans that can modulate the immune system. The mechanism remains to be elucidated and the consequences for cosmonauts in the long term are unclear. Most of the current research stems from short-term spaceflights as well as pre- and post-flight analyses due to operational limitations. Immune function of 12 cosmonauts participating in a long-duration (>140 days) spaceflight mission was monitored pre-, post-, and on two time-points in-flight. While the classical markers for stress such as cortisol in saliva where not significantly altered, blood concentrations of the endocannabinoid system (ECS) were found to be highly increased in-flight indicating a biological stress response. Moreover, subjects showed a significant rise in white blood cell counts. Neutrophils, monocytes and B cells increased by 50% whereas NK cells dropped by nearly 60% shortly after landing. Analysis of blood smears showed that lymphocyte percentages, though unchanged pre- and post-flight were elevated in-flight. Functional tests on the ground revealed stable cellular glutathione levels, unaltered baseline and stimulated ROS release in neutrophils but an increased shedding of L-selectin post-flight. In vitro stimulation of whole blood samples with fungal antigen showed a highly amplified TNF and IL-1β response. Furthermore, a significant reduction in CD4+CD25+CD27low regulatory T cells was observed post-flight but returned to normal levels after one month. Concomitantly, high in-flight levels of regulatory cytokines TGF-β, IL-10 and IL-1ra dropped rapidly after return to Earth. Finally, we observed a shift in the CD8+ T cell repertoire toward CD8+ memory cells that lasted even one month after return to Earth.Conclusion: Long-duration spaceflight triggered a sustained stress dependent release of endocannabinoids combined with an aberrant immune activation mimicking features of people at risk for inflammation related diseases. These effects persisted in part 30 days after return to Earth. The currently available repertoire of in-flight testing as well as the post-flight observation periods need to be expanded to tackle the underlying mechanism for and consequences of these immune changes in order to develop corresponding mitigation strategies based on a personalized approach for future interplanetary space explorations

Dynamic configuration of the CMS Data Acquisition cluster

The CMS Data Acquisition cluster, which runs around 10000 applications, is configured dynamically at run time. XML configuration documents determine what applications are executed on each node and over what networks these applications communicate. Through this mechanism the DAQ System may be adapted to the required performance, partitioned in order to perform (test-) runs in parallel, or re-structured in case of hardware faults. This paper presents the CMS DAQ Configurator tool, which is used to generate comprehensive configurations of the CMS DAQ system based on a high-level description given by the user. Using a database of configuration templates and a database containing a detailed model of hardware modules, data and control links, nodes and the network topology, the tool automatically determines which applications are needed, on which nodes they should run, and over which networks the event traffic will flow. The tool computes application parameters and generates the XML configuration documents as well as the configuration of the run-control system. The performance of the tool and operational experience during CMS commissioning and the first LHC runs are discussed

The Run Control and Monitoring System of the CMS Experiment

The CMS experiment at the LHC at CERN will start taking data in 2008. To configure, control and monitor the experiment during data-taking the Run Control and Monitoring System (RCMS) was developed. This paper describes the architecture and the technology used to implement the RCMS, as well as the deployment and commissioning strategy of this important component of the online software for the CMS experiment