OBJECTIVES:Complex critical syndromes like sepsis and coronavirus disease 2019 may be composed of underling “endotypes,” which may respond differently to treatment. The aim of this study was to test ...whether a previously defined bacterial sepsis endotypes classifier recapitulates the same clinical and immunological endotypes in coronavirus disease 2019.
DESIGN:Prospective single-center observational cohort study.
SETTING:Patients were enrolled in Athens, Greece, and blood was shipped to Inflammatix (Burlingame, CA) for analysis.
PATIENTS:Adult patients within 24 hours of hospital admission with coronavirus disease 2019 confirmed by polymerase chain reaction and chest radiography.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:We studied 97 patients with coronavirus disease 2019, of which 50 went on to severe respiratory failure (SRF) and 16 died. We applied a previously defined 33-messenger RNA classifier to assign endotype (Inflammopathic, Adaptive, or Coagulopathic) to each patient. We tested endotype status against other clinical parameters including laboratory values, severity scores, and outcomes. Patients were assigned as Inflammopathic (29%), Adaptive (44%), or Coagulopathic (27%), similar to our prior study in bacterial sepsis. Adaptive patients had lower rates of SRF and no deaths. Coagulopathic and Inflammopathic endotypes had 42% and 18% mortality rates, respectively. The Coagulopathic group showed highest D-dimers, and the Inflammopathic group showed highest C-reactive protein and interleukin-6 levels.
CONCLUSIONS:Our predefined 33-messenger RNA endotypes classifier recapitulated immune phenotypes in viral sepsis (coronavirus disease 2019) despite its prior training and validation only in bacterial sepsis. Further work should focus on continued validation of the endotypes and their interaction with immunomodulatory therapy.
Arbeitsbezogener Stress und Geschlechtsidentität Wacker, E.; Fischer, A.; Schorlemmer, J.
Zentralblatt für Arbeitsmedizin, Arbeitsschutz und Ergonomie,
09/2021, Volume:
71, Issue:
5
Journal Article
Peer reviewed
Open access
Zusammenfassung
Hintergrund
Die steigende Prävalenz psychischer Erkrankungen in den letzten Jahrzehnten wird u. a. in Verbindung mit erhöhtem beruflichem Stress gesehen. Dabei zeigen Untersuchungen ...stets höhere Werte für Stress und Burnout bei Frauen als bei Männern, das biologische Geschlecht trägt jedoch nur wenig zur Varianzaufklärung der Werte bei. Die geplante Studie soll einen Beitrag zur Ursachenforschung leisten.
Fragestellung
Es werden die Effekte der Person-Umwelt-Passung in Feminität und Maskulinität auf subjektive Burnout-Werte, psychosomatische Beschwerden, Steroidwerte in Haarproben als biologische Langzeitstress-Marker sowie auf Arbeitsengagement unter Berücksichtigung von Arbeitsplatzbedingungen untersucht. Im Beitrag wird die geplante Untersuchung vorgestellt.
Material und Methoden
Für die Studie werden 411 Beschäftigte eines medizinischen Dienstleistungsunternehmens zur Befragung eingeladen und können Haarproben für eine Steroid-Analyse abgeben. Durch Selbstauskunftsskalen werden individuelle und arbeitsplatzbezogene Feminitäts- und Maskulinitätswerte, Arbeitsplatzbedingungen, Burnout-Symptome, psychosomatische Beschwerden und Arbeitsengagement erfasst. Die Operationalisierung der Person-Umwelt-Passung erfolgt durch die Subtraktion der Feminitäts- und Maskulinitätswerte des Arbeitsumfeldes von den entsprechenden individuellen Werten. In den Haarproben werden mittels Flüssigkeitschromatographie-Massenspektrometrie (LC-MS/MS) die Werte für Cortisol, Cortison, Dehydroepiandrosteron (DHEA), Testosteron und Progesteron ermittelt.
Ziele
Die Effekte der Feminität und Maskulinität als arbeitsplatzbezogene Person-Umwelt-Passung sollen als Prädiktoren für arbeitsbezogenen Stress untersucht werden, um zu überprüfen, ob diese sinnvollere Erklärungen als Geschlechtsgruppen-Erfassung bieten.
The biophysical characterization of purified membrane proteins typically requires detergent mediated extraction from native lipid membrane environments. In the case of human G protein-coupled ...receptors (GPCRs), this process has been complicated by their conformational heterogeneity and the general lack of understanding the composition and interactions within the diverse human cellular membrane environment. Several successful GPCR structure determination efforts have shown that the addition of cholesterol analogs is often critical for maintaining protein stability. We have identified sterols that substantially increase the stability of the NOP receptor (ORL-1), a member of the opioid GPCR family, in a mixed micelle environment. Using dynamic light scattering and small-angle X-ray scattering, we have determined that the most thermal stabilizing sterol, cholesteryl hemisuccinate, induces the formation of a bicelle-like micelle architecture when mixed with dodecyl maltoside detergent. Together with mutagenesis studies and recent GPCR structures, our results provide indications that stabilization is attained through a combination of specific sterol binding to GPCRs and modulation of micelle morphology.
The in vivo generator 134Ce/134La has the potential to serve as a PET imaging surrogate for both alpha-emitting 225Ac and 227Th radionuclides due to the unique CeIII/CeIV redox couple and the ...relatively long half-life of 134Ce. The purpose of this study was to demonstrate the compatibility of 134Ce with DOTA-based antibody drug conjugates, which would act as therapeutic agents when incorporating 225Ac.
The in vivo biodistributions of 134CeCe-DOTA and 134CeCe-citrate were assayed by microPET imaging over 25 h in Swiss Webster mice to determine the in vivo stability of the 134CeCe-DOTA complex. L3-edge X-ray absorption spectroscopy measurements were used to confirm the Ce oxidation state and the formation of a fully coordinated Ce-DOTA complex. The in vivo biodistribution of 134CeCe-DOTA-Trastuzumab was assayed over 147 h by microPET imaging in SK-OV-3 tumor-bearing NOD SCID mice to evaluate tumor uptake and in vivo stability. Mice were euthanized at 214 h after administration of the radiolabeled antibody conjugate, and imaged 1 h later. An ex vivo biodistribution experiment was then performed in order to corroborate the PET images.
134CeCe-DOTA displayed rapid renal elimination and high in vivo stability over 25 h, with negligible bone and liver uptake, in comparison to 134CeCe-citrate. L3-edge X-ray absorption spectroscopy experiments confirmed the 3+ oxidation state within the stable Ce-DOTA complex. MicroPET images of 134CeCe-DOTA-Trastuzumab displayed elevated tumor uptake over 214 h, with minimal bone and liver uptake analogous to previously reported 225AcAc-DOTA-Trastuzumab biodistribution results, and the ex vivo biodistribution of 134CeCe-DOTA-Trastuzumab corroborated the final PET images.
These results demonstrate that 134Ce allows for long-term tumor targeting with DOTA-based antibody drug conjugates and may therefore be used to trace antibody drug conjugates incorporating 225Ac.
Display omitted
•Ce-134 can be an imaging surrogate for the Ac-225 due to its chemical similarity.•Ce-134 has high in vivo stability with DOTA-based antibody drug conjugates.•Ce-134's long half-life allows for long term monitoring of tumor uptake of antibodies.
Most laboratories prepare carbonates samples for radiocarbon analysis by acid decomposition in evacuated glass tubes and subsequent reduction of the evolved CO2 to graphite in self-made reduction ...manifolds. This process is time consuming and labor intensive. In this work, we have tested a new approach for the preparation of carbonate samples, where any high-vacuum system is avoided and helium is used as a carrier gas. The liberation of CO2 from carbonates with phosphoric acid is performed in a similar way as it is often done in stable isotope ratio mass spectrometry where CO2 is released with acid in septum sealed tube under helium atmosphere. The formed CO2 is later flushed in a helium flow by means of a double-walled needle mounted from the tubes to the zeolite trap of the automated graphitization equipment (AGE). It essentially replaces the elemental analyzer normally used for the combustion of organic samples. The process can be fully automated from sampling the released CO2 in the septum-sealed tubes with a commercially available auto-sampler to the graphitization with the automated graphitization. The new method yields in low sample blanks of about 50000years. Results of processed reference materials (IAEA-C2, FIRI-C) are in agreement with their consensus values.
Our goal in this study was to test the relationship between speaking up--i.e., questioning, correcting, or clarifying a current procedure--and technical team performance in anesthesia. Hypothesis 1: ...team members' higher levels of speaking up are related to higher levels of technical team performance. Hypothesis 2: team members will react to speaking up by either clarifying their procedure or initiating a procedural change. Hypothesis 3: higher levels of speaking up during an earlier phase of teamwork will be related to higher levels of speaking up during a later phase.
This prospective observational study involved 2-person ad hoc anesthesia teams performing simulated inductions of general anesthesia with minor nonroutine events (e.g., bradycardia) in a large teaching hospital. Subjects were registered anesthesia nurses and residents. Each team consisted of 1 nurse and 1 resident. Synchronized video and vital parameter recordings were obtained. Two trained observers blinded to the hypotheses coded speaking up and further team communication and coordination behavior on the basis of 12 distinct categories. All teamwork measures were quantified as percentage of total time spent on the respective teamwork category. Two experienced staff anesthesiologists blinded to the hypotheses evaluated technical team performance using a Delphi-validated rating checklist. Hypotheses 1 and 3 were tested using linear regression with residents' and nurses' levels of speaking up as 2 separate predictor variables. Hypothesis 2 was analyzed using lag sequential analysis, resulting in Z values representing the extent to which the observed value for a conditional transition significantly differs from its unconditional value.
Thirty-one nurses and 31 residents participated. Technical team performance could be predicted by the level of speaking up from nurses (R(2) = 0.18, P = 0.017) but not from residents (R(2) = 0.19, P = 0.053); this result supports Hypothesis 1 for nurses. Supporting Hypothesis 2, residents reacted to speaking up with clarifying the procedure by providing information (Z = 18.08, P < 0.001), initiating procedural change by giving instructions (Z = 4.74, P < 0.001) and team member monitoring (Z = 3, P = 0.0013). Likewise, nurses reacted with clarifying the procedure by providing or evaluating information (Z = 16.09, P < 0.001; Z = 3.72, P < 0.001) and initiating procedural change by providing assistance (Z = 0.57, P < 0.001). Indicating a trend for Hypothesis 3, nurses' level of speaking up before intubation predicted their level of speaking up during intubation (R(2) = 0.15, P = 0.034), although this did not reach the Bonferroni-corrected significance level of P = 0.025. No respective relationship was found for residents (R(2) = 0.15, P = 0.096).
This study provides empirical evidence and shows mechanisms for the positive relationship between speaking-up behavior and technical team performance.
The kynurenine pathway of tryptophan degradation is hypothesized to play an important role in Huntington disease, a neurodegenerative disorder caused by a polyglutamine expansion in the protein ...huntingtin. Neurotoxic metabolites of the kynurenine pathway, generated in microglia and macrophages, are present at increased levels in the brains of patients and mouse models during early stages of disease, but the mechanism by which kynurenine pathway up-regulation occurs in Huntington disease is unknown. Here we report that expression of a mutant huntingtin fragment was sufficient to induce transcription of the kynurenine pathway in yeast and that this induction was abrogated by impairing the activity of the histone deacetylase Rpd3. Moreover, numerous genetic suppressors of mutant huntingtin toxicity that are functionally unrelated converged unexpectedly on the kynurenine pathway, supporting a critical role for the kynurenine pathway in mediating mutant huntingtin toxicity in yeast. Histone deacetylase-dependent regulation of the kynurenine pathway was also observed in a mouse model of Huntington disease, in which treatment with a neuroprotective histone deacetylase inhibitor blocked activation of the kynurenine pathway in microglia expressing a mutant huntingtin fragment in vitro and in vivo. These findings suggest that a mutant huntingtin fragment can perturb transcriptional programs in microglia, and thus implicate these cells as potential modulators of neurodegeneration in Huntington disease that are worthy of further investigation.
Purpose
With a limited overall survival (OS) of 20 months in patients diagnosed with intermediate stage hepatocellular carcinoma (HCC), the preservation of quality of life (QoL) during transarterial ...chemoembolization (TACE) procedures remains a primary goal. The aim of our study was to evaluate the change in QoL amongst patients undergoing repetitive TACE and to identify specific risk factors that may predict change in QoL.
Methods
QoL was assessed in 82 patients undergoing at least two TACE, before and 14 days after TACE, using validated EORTC QLQ-C30 and EORTC HCC18 questionnaires. Tumour response was assessed using established response criteria. Laboratory and clinical parameters were analysed.
Results
Functional scores decreased due to first TACE treatment (
p
< 0.01), conversely symptom scores increased significantly (
p
< 0.01). During repetitive TACE no statistically significant changes were observed. Higher Global Health- and Physical Functioning scores at baseline were identified as independent prognostic factors for greater decrease in QoL. Tumour response did not alter QoL at all. Furthermore higher symptom scales including pain (
p
= 0.00), nausea and vomiting (
p
= 0.00) and fever (
p
< 0.01 for repetitive TACE) at baseline were predictive of a significantly lesser increase of symptom severity, and a greater reduction in pain during a course of TACE. Higher C-reactive protein (CRP) at baseline and female gender were associated with a greater decrease of functional scales and increase of symptom scales.
Conclusion
QoL amongst patients receiving repetitive TACE showed neither significant nor clinically relevant changes over time. Pre-treatment assessment of QoL-scores, clinical and laboratory parameters can improve patient selection for TACE whilst optimizing QoL.
Background
Whether or not to administer antibiotics is a common and challenging clinical decision in patients with suspected infections presenting to the emergency department (ED). We prospectively ...validate InSep, a 29-mRNA blood-based host response test for the prediction of bacterial and viral infections.
Methods
The PROMPT trial is a prospective, non-interventional, multi-center clinical study that enrolled 397 adult patients presenting to the ED with signs of acute infection and at least one vital sign change. The infection status was adjudicated using chart review (including a syndromic molecular respiratory panel, procalcitonin and C-reactive protein) by three infectious disease physicians blinded to InSep results. InSep (version BVN-2) was performed using PAXgene Blood RNA processed and quantified on NanoString nCounter SPRINT. InSep results (likelihood of bacterial and viral infection) were compared to the adjudicated infection status.
Results
Subject mean age was 64 years, comorbidities were significant for diabetes (17.1%), chronic obstructive pulmonary disease (13.6%), and severe neurological disease (6.8%); 16.9% of subjects were immunocompromised. Infections were adjudicated as bacterial (14.1%), viral (11.3%) and noninfected (0.25%): 74.1% of subjects were adjudicated as indeterminate. InSep distinguished bacterial vs. viral/noninfected patients and viral vs. bacterial/noninfected patients using consensus adjudication with AUROCs of 0.94 (95% CI 0.90–0.99) and 0.90 (95% CI 0.83–0.96), respectively. AUROCs for bacterial vs. viral/noninfected patients were 0.88 (95% CI 0.79–0.96) for PCT, 0.80 (95% CI 0.72–89) for CRP and 0.78 (95% CI 0.69–0.87) for white blood cell counts (of note, the latter biomarkers were provided as part of clinical adjudication). To enable clinical actionability, InSep incorporates score cutoffs to allocate patients into interpretation bands. The Very Likely (rule in) InSep bacterial band showed a specificity of 98% compared to 94% for the corresponding PCT band (> 0.5 µg/L); the Very Unlikely (rule-out) band showed a sensitivity of 95% for InSep compared to 86% for PCT. For the detection of viral infections, InSep demonstrated a specificity of 93% for the Very Likely band (rule in) and a sensitivity of 96% for the Very Unlikely band (rule out).
Conclusions
InSep demonstrated high accuracy for predicting the presence of both bacterial and viral infections in ED patients with suspected acute infections or suspected sepsis. When translated into a rapid, point-of-care test, InSep will provide ED physicians with actionable results supporting early informed treatment decisions to improve patient outcomes while upholding antimicrobial stewardship.
Registration number at Clinicaltrials.gov NCT 03295825.
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