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Introduction: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. Methods: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. Results: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups). By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14–6.33, p ≤ 0.01)). Conclusion: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.
In der vorliegenden Dissertation wurde untersucht, ob die endotracheale Intubation (ETI) der alternativen Atemwegssicherung mittels Larynxtubus (LT) bezüglich der Überlebenswahrscheinlichkeit bei außerklinisch reanimierten Patienten überlegen ist.
Das retrospektiv erfasste Kollektiv dieser monozentrischen Studie umfasst 222 Patienten, die in den Jahren 2006 bis 2014 nach nicht-traumatischem Herz-Kreislauf-Stillstand außerhalb der Klinik (engl.: Out-of-hospital cardiac arrest, OHCA) präklinisch primär mit Endotrachealtubus (ET) oder LT versorgt und anschließend auf die internistische Intensivstation des Universitätsklinikums Frankfurt am Main aufgenommen wurden. Endpunkte der Studie waren die innerklinische Gesamtmortalität während des Krankenhausaufenthaltes sowie die Überlebensrate nach 24 Stunden.
In die Analyse wurden 208 Patienten einbezogen, von denen präklinisch 48 Patienten mit LT (23 %) und 160 Patienten mit ET (77 %) intubiert wurden. Die innerklinische Sterblichkeitsrate lag insgesamt bei 85 % (n=176); darunter 23 % LT- und 77 % ET-versorgte Patienten. Zwischen den beiden Methoden zur Atemwegssicherung zeigten sich sowohl in einer univariaten Analyse (Hazard ratio [HR]=0,98; 95 % Konfidenzintervall [K.I.] 0,69-1,39; p=0,92) als auch in einer multivariaten Cox-Regressionsmodell (adjustierte HR=1,01; 95 % K.I. 0,76-1,56; p=0,62) keine Unterschiede. Die ersten 24 Stunden nach OHCA überlebten 38 % aller Patienten; auch hier unterschieden sich die beiden Patientenkollektive nicht signifikant voneinander (univariate HR=1,04; 95 % K.I. 0,71-1,52; p=0,83).
Ferner veranschaulichte eine Propensity-Score-Matching-Analyse (PSM) mit einer Subgruppe von 120 Patienten, zusammengestellt in einem 3:1 Verhältnis (ET:LT), sowohl mit Blick auf die Überlebensrate bis zur Krankenhausentlassung (Propensity-adjustierte HR=0,99; 95 % K.I. 0,65-1,51; p=0,97) als auch auf die Mortalität in den ersten 24 Stunden (Propensity-adjustierte HR=1,04; 95 % K.I. 0,44-2,36; p=0,96) vergleichbare Ergebnisse beim Atemwegsmanagement mit LT bzw. ET.
Die frühe Durchführung einer Herzkatheteruntersuchung (HR=0,47; 95 % K.I. 0,28-0,77; p=0,003) sowie der frühe Beginn einer systemischen empirischen antibiotischen Therapie (HR=0,28; 95% K.I. 0,17-0,45; p<0,001) konnten überdies als signifikant positive Prädiktoren für das Überleben in einer angepassten Cox-Regressionsanalyse herausgearbeitet werden.
Im Gesamten konnte somit demonstriert werden, dass die initiale präklinische Anwendung des LT nach OHCA der ETI hinsichtlich der Überlebenswahrscheinlichkeit nicht untergeordnet ist. Neuester Literatur zufolge ist sie womöglich sogar überlegen. Dies gilt es in weiteren Studien zu bestätigen.
Purpose: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy.
Methods: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected.
Results: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI.
Conclusion: A broad range of actionable alterations was targeted with available molecular therapeutics.
However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.
Background: Hypoxia is a key driver for infiltrative growth in experimental gliomas. It has remained elusive whether tumor hypoxia in glioblastoma patients contributes to distant or diffuse recurrences. We therefore investigated the influence of perioperative cerebral ischemia on patterns of progression in glioblastoma patients.
Methods: We retrospectively screened MRI scans of 245 patients with newly diagnosed glioblastoma undergoing resection for perioperative ischemia near the resection cavity. 46 showed relevant ischemia nearby the resection cavity. A control cohort without perioperative ischemia was generated by a 1:1 matching using an algorithm based on gender, age and adjuvant treatment. Both cohorts were analyzed for patterns of progression by a blinded neuroradiologist.
Results: The percentage of diffuse or distant recurrences at first relapse was significantly higher in the cohort with perioperative ischemia (61.1%) compared to the control cohort (19.4%). The results of the control cohort matched well with historical data. The change in patterns of progression was not associated with a difference in survival.
Conclusions: This study reveals an unrecognized association of perioperative cerebral ischemia with distant or diffuse recurrence in glioblastoma. It is the first clinical study supporting the concept that hypoxia is a key driver of infiltrative tumor growth in glioblastoma patients.
Introduction: Current classifications of complete knee dislocations do not capture the extent of the complex concomitant ligamentous and bony injuries, which may have an impact on future outcomes. The purpose of this retrospective study was to evaluate the epidemiology of complete knee dislocations as well as to present an updated classification system based on the author’s experience at a Level-I trauma center.
Materials and methods: Only patients with complete loss of contact of the articulating bones and ≥ 18 years of age who admitted in our level-I trauma center between 2002 and 2019 were included. Patients were identified using a retrospective systematical query in the Hospital Information System (HIS) using the International Statistical Classification of Diseases and Related Health Problems Version10 (ICD-10) codes of the German Diagnosis Related Groups (G-DRG).
Results: Final data included 80 patients, with the majority of patients being male (n = 64; 80.0%). Mean age was 34.9 years (range: 18–70 years). External protective fixation was applied in 32 patients (40.0%). Reconstruction of the posterior cruciate ligament and the anterior cruciate ligament were performed in 56.3% (n = 45) and 55.0% (n = 44) of cases, respectively. The lateral collateral ligament complex was surgically addressed in 47.5% (n = 38), while the medial collateral ligament complex was reconstructed in 40% (n = 32). Surgery of the lateral meniscus and the medial meniscus was needed in 31.1% (n = 25) and 30.0% (n = 24). Neurovascular surgery occurred in 13.8% (n = 11). From the characteristic injury-patterns the authors of this study present a new classification system that ranks the injuries from Grade-A to Grade-D according to their severity.
Conclusion: This retrospective study demonstrates that the historically used classification systems for dislocations of the knee are insufficient for these severe injuries. Concomitant ligamentous, neurovascular, bony, and meniscal injuries were frequent, and required several staged procedures. Consequently, an updated classification system is proposed.
We present data on charged kaons (K±) and ϕ mesons in Au(1.23A GeV)+Au collisions. It is the first simultaneous measurement of K− and ϕ mesons in central heavy-ion collisions below a kinetic beam energy of 10A GeV. The ϕ/K− multiplicity ratio is found to be surprisingly high with a value of 0.52±0.16 and shows no dependence on the centrality of the collision. Consequently, the different slopes of the K+ and K− transverse-mass spectra can be explained solely by feed-down, which substantially softens the spectra of K− mesons. Hence, in contrast to the commonly adapted argumentation in literature, the different slopes do not necessarily imply diverging freeze-out temperatures of K+ and K− mesons caused by different couplings to baryons.
We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions.
In this letter we report the first multi-differential measurement of correlated pion-proton pairs from 2 billion Au+Au collisions at sNN=2.42 GeV collected with HADES. In this energy regime the population of Δ(1232) resonances plays an important role in the way energy is distributed between intrinsic excitation energy and kinetic energy of the hadrons in the fireball. The triple differential d3N/dMπ±pdpTdy distributions of correlated π±p pairs have been determined by subtracting the πp combinatorial background using an iterative method. The invariant-mass distributions in the Δ(1232) mass region show strong deviations from a Breit-Wigner function with vacuum width and mass. The yield of correlated pion-proton pairs exhibits a complex isospin, rapidity and transverse-momentum dependence. In the invariant mass range 1.1<Minv(GeV/c2)<1.4, the yield is found to be similar for π+p and π−p pairs, and to follow a power law 〈Apart〉α, where 〈Apart〉 is the mean number of participating nucleons. The exponent α depends strongly on the pair transverse momentum (pT) while its pT-integrated and charge-averaged value is α=1.5±0.08st±0.2sy.
The production of Σ0 baryons in the nuclear reaction p (3.5 GeV) + Nb (corresponding to sNN=3.18 GeV) is studied with the detector set-up HADES at GSI, Darmstadt. Σ0s were identified via the decay Σ0→Λγ with subsequent decays Λ→pπ− in coincidence with a e+e− pair from either external (γ→e+e−) or internal (Dalitz decay γ⁎→e+e−) gamma conversions. The differential Σ0 cross section integrated over the detector acceptance, i.e. the rapidity interval 0.5<y<1.1, has been extracted as ΔσΣ0=2.3±(0.2)stat±(−0.6+0.6)sys±(0.2)norm mb, yielding the inclusive production cross section in full phase space σΣ0total=5.8±(0.5)stat±(−1.4+1.4)sys±(0.6)norm±(1.7)extrapol mb by averaging over different extrapolation methods. The Λall/Σ0 ratio within the HADES acceptance is equal to 2.3±(0.2)stat±(−0.6+0.6)sys. The obtained rapidity and momentum distributions are compared to transport model calculations. The Σ0 yield agrees with the statistical model of particle production in nuclear reactions. Keywords: Hyperons, Strangeness, Proton, Nucleus.
We present the results of two-pion production in tagged quasi-free np collisions at a deutron incident beam energy of 1.25 GeV/c measured with the High-Acceptance Di-Electron Spectrometer (HADES) installed at GSI. The specific acceptance of HADES allowed for the first time to obtain high-precision data on π+π− and π−π0 production in np collisions in a region corresponding to large transverse momenta of the secondary particles. The obtained differential cross section data provide strong constraints on the production mechanisms and on the various baryon resonance contributions (∆∆, N(1440), N(1520), ∆(1600)). The invariant mass and angular distributions from the np → npπ+π −and np → ppπ−π0 reactions are compared with different theoretical model predictions.
We present first data on sub-threshold production of Ks0 mesons and Λ hyperons in Au+Au collisions at sNN=2.4 GeV. We observe an universal 〈Apart〉 scaling of hadrons containing strangeness, independent of their corresponding production thresholds. Comparing the yields, their 〈Apart〉 scaling, and the shapes of the rapidity and the pt spectra to state-of-the-art transport model (UrQMD, HSD, IQMD) predictions, we find that none of them can simultaneously describe these observables with reasonable χ2 values.
We investigate identical pion HBT intensity interferometry in central Au+Au collisions at 1.23A GeV. High-statistics π−π− and π+π+ data are measured with HADES at SIS18/GSI. The radius parameters, derived from the correlation function depending on relative momenta in the longitudinally comoving system and parametrized as three-dimensional Gaussian distribution, are studied as function of transverse momentum. A substantial charge-sign difference of the source radii is found, particularly pronounced at low transverse momentum. The extracted source parameters agree well with a smooth extrapolation of the center-of-mass energy dependence established at higher energies, extending the corresponding excitation functions down towards a very low energy.
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
Rhodopsin-based voltage imaging tools for use in muscles and neurons of Caenorhabditis elegans
(2019)
Genetically encoded voltage indicators (GEVIs) based on microbial rhodopsins utilize the voltage-sensitive fluorescence of all-trans retinal (ATR), while in electrochromic FRET (eFRET) sensors, donor fluorescence drops when the rhodopsin acts as depolarization-sensitive acceptor. In recent years, such tools have become widely used in mammalian cells but are less commonly used in invertebrate systems, mostly due to low fluorescence yields. We systematically assessed Arch(D95N), Archon, QuasAr, and the eFRET sensors MacQ-mCitrine and QuasAr-mOrange, in the nematode Caenorhabditis elegans ATR-bearing rhodopsins reported on voltage changes in body wall muscles (BWMs), in the pharynx, the feeding organ [where Arch(D95N) showed approximately 128% ΔF/F increase per 100 mV], and in neurons, integrating circuit activity. ATR fluorescence is very dim, yet, using the retinal analog dimethylaminoretinal, it was boosted 250-fold. eFRET sensors provided sensitivities of 45 to 78% ΔF/F per 100 mV, induced by BWM action potentials, and in pharyngeal muscle, measured in simultaneous optical and sharp electrode recordings, MacQ-mCitrine showed approximately 20% ΔF/F per 100 mV. All sensors reported differences in muscle depolarization induced by a voltage-gated Ca2+-channel mutant. Optogenetically evoked de- or hyperpolarization of motor neurons increased or eliminated action potential activity and caused a rise or drop in BWM sensor fluorescence. Finally, we analyzed voltage dynamics across the entire pharynx, showing uniform depolarization but compartmentalized repolarization of anterior and posterior parts. Our work establishes all-optical, noninvasive electrophysiology in live, intact C. elegans.
Matrix metalloproteinases (MMPs) play crucial roles in tissue homeostasis and pathologies by remodeling the extracellular matrix. Previous studies have demonstrated the biological activities of MMP-derived cleavage products. Furthermore, specific fragments can serve as biomarkers. Therefore, an in vitro cleavage assay to identify substrates and characterize cleavage patterns could provide important insight in disease-relevant mechanisms and the identification of novel biomarkers. In the pathogenesis of osteoarthritis (OA), MMP-2, -8, -9 and -13 are of vital importance. However, it is unclear which protease can cleave which matrix component. To address this question, we established an in vitro cleavage assay using recombinantly expressed MMPs and the two cartilage matrix components, COMP and thrombospondin-4. We found a time- and concentration-dependent degradation and an MMP-specific cleavage pattern for both proteins. Cleavage products can now be enriched and purified to investigate their biological activity. To verify the in vivo relevance, we compared the in vitro cleavage patterns with serum and synovial fluid from OA patients and could indeed detect fragments of similar size in the human samples. The cleavage assay can be adapted to other MMPs and substrates, making it a valuable tool for many research fields.
n this paper we report on the investigation of baryonic resonance production in proton-proton collisions at the kinetic energies of 1.25 GeV and 3.5 GeV, based on data measured with HADES. Exclusive channels npπ+ and ppπ0 as well as ppe+e− were studied simultaneously in the framework of a one-boson exchange model. The resonance cross sections were determined from the one-pion channels for Δ(1232) and N(1440) (1.25 GeV) as well as further Δ and N* resonances up to 2 GeV/c2 for the 3.5 GeV data. The data at 1.25 GeV energy were also analysed within the framework of the partial wave analysis together with the set of several other measurements at lower energies. The obtained solutions provided the evolution of resonance production with the beam energy, showing a sizeable non-resonant contribution but with still dominating contribution of Δ(1232)P33. In the case of 3.5 GeV data, the study of the ppe+e− channel gave the insight on the Dalitz decays of the baryon resonances and, in particular, on the electromagnetic transition form-factors in the time-like region. We show that the assumption of a constant electromagnetic transition form-factors leads to underestimation of the yield in the dielectron invariant mass spectrum below the vector mesons pole. On the other hand, a comparison with various transport models shows the important role of intermediate ρ production, though with a large model dependency. The exclusive channels analysis done by the HADES collaboration provides new stringent restrictions on the parameterizations used in the models.
his contribution aims to give a basic overview of the latest results regarding the production of resonances in different collision systems. The results were extracted from experimental data collected with HADES that is a multipurpose detector located at the GSI Helmholtzzentrum, Darmstadt. The main points discussed here are: the properties of the strange resonances Λ(1405) and Σ(1385), the role of Δ’s as a source of pions in the final state, the production dynamics reflected in form of differential cross sections, and the role of the ϕ meson as a source for K− particles.
Snapshots of acetyl-CoA synthesis, the final step of CO₂ fixation in the Wood-Ljungdahl pathway
(2024)
In the ancient microbial Wood-Ljungdahl pathway, CO2 is fixed in a multi-step process with acetyl-CoA synthesis at the bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). Here, we present catalytic snapshots of the CODH/ACS from the gas-converting acetogen Clostridium autoethanogenum, characterizing the molecular choreography of the overall reaction including electron transfer to the CODH for CO2 reduction, methyl transfer from the corrinoid iron-sulfur protein (CoFeSP) partner to the ACS active site and acetyl-CoA production. Unlike CODH, the multidomain ACS undergoes large conformational changes to form an internal connection to the CODH active site, accommodate the CoFeSP for methyl transfer and protect the reaction intermediates. Altogether, the structures allow us to draw a detailed reaction mechanism of this enzyme crucial for CO2 fixation in anaerobic organisms.
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.