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The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
OBJECTIVE: The role of supraglottic airway devices in emergency airway management is highlighted in international airway management guidelines. We evaluated the application of the new generation laryngeal tube suction (LTS-II/LTS-D) in the management of in-hospital unexpected difficult airway and cardiopulmonary resuscitation.
METHODS: During a seven-year period, patients treated with a laryngeal tube who received routine anesthesia and had an unexpected difficult airway (Cormack Lehane Grade 3-4), who underwent cardiopulmonary resuscitation, or who underwent cardiopulmonary resuscitation outside the operating room and had a difficult airway were evaluated. Successful placement of the LTS II/LTS-D, sufficient ventilation, time to placement, number of placement attempts, stomach content, peripheral oxygen saturation/end-tidal carbon dioxide development (SpO2/etCO2) over 5 minutes, subjective overall assessment and complications were recorded.
RESULTS: In total, 106 adult patients were treated using an LTS-II/LTS-D. The main indication for placement was a difficult airway (75%, n=80), followed by cardiopulmonary resuscitation (25%, n=26) or an overlap between both (18%, n=19). In 94% of patients (n=100), users placed the laryngeal tube during the first attempt. In 93% of patients (n=98), the tube was placed within 30 seconds. A significant increase in SpO2 from 97% (0-100) to 99% (5-100) was observed in the whole population and in cardiopulmonary resuscitation patients. The average initial etCO2 of 39.5 mmHg (0-100 mmHg) decreased significantly to an average of 38.4 mmHg (10-62 mmHg) after 5 minutes. A comparison of cardiopulmonary resuscitation patients with non-cardiopulmonary resuscitation patients regarding gastric contents showed no significant difference.
CONCLUSIONS: LTS-D/LTS-II use for in-hospital unexpected difficult airway management provides a secure method for primary airway management until other options such as video laryngoscopy or fiber optic intubation become available.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
The relaxation of hot nuclear matter to an equilibrated state in the central zone of heavy-ion collisions at energies from AGS to RHIC is studied within the microscopic UrQMD model. It is found that the system reaches the (quasi)equilibrium stage for the period of 10-15 fm/c. Within this time the matter in the cell expands nearly isentropically with the entropy to baryon ratio S/A = 150 - 170. Thermodynamic characteristics of the system at AGS and at SPS energies at the endpoints of this stage are very close to the parameters of chemical and thermal freeze-out extracted from the thermal fit to experimental data. Predictions are made for the full RHIC energy square root s = 200$ AGeV. The formation of a resonance-rich state at RHIC energies is discussed.
Relativistic hadron-hadron collisions in the ultra-relativistic quantum molecular dynamics model
(1999)
Hadron-hadron collisions at high energies are investigated in the Ultra- relativistic-Quantum-Molecular-Dynamics approach. This microscopic trans- port model describes the phenomenology of hadronic interactions at low and intermediate energies ( s < 5 GeV) in terms of interactions between known hadrons and their resonances. At higher energies, s > 5 GeV, the excitation of color strings and their subsequent fragmentation into hadrons dominates the multiple production of particles in the UrQMD model. The model shows a fair overall agreement with a large body of experimental h-h data over a wide range of h-h center-of-mass energies. Hadronic reaction data with higher precision would be useful to support the use of the UrQMD model for relativistic heavy ion collisions.
Abstract: Local thermal and chemical equilibration is studied for central AqA collisions at 10.7 160 AGeV in the Ultrarelativis- . tic Quantum Molecular Dynamics model UrQMD . The UrQMD model exhibits strong deviations from local equilibrium at the high density hadron string phase formed during the early stage of the collision. Equilibration of the hadron resonance matter is established in the central cell of volume Vs125 fm3 at later stages, tG10 fmrc, of the resulting quasi-isentropic expansion. The thermodynamical functions in the cell and their time evolution are presented. Deviations of the UrQMD quasi-equilibrium state from the statistical mechanics equilibrium are found. They increase with energy per baryon and lead to a strong enhancement of the pion number density as compared to statistical mechanics estimates at SPS energies. PACS: 25.75.-q; 24.10.Lx; 24.10.Pa; 64.30.qt
Microscopic calculations of central collisions between heavy nuclei are used to study fragment production and the creation of collective flow. It is shown that the final phase space distributions are compatible with the expectations from a thermally equilibrated source, which in addition exhibits a collective transverse expansion. However, the microscopic analyses of the transient states in the reaction stages of highest density and during the expansion show that the system does not reach global equilibrium. Even if a considerable amount of equilibration is assumed, the connection of the measurable final state to the macroscopic parameters, e.g. the temperature, of the transient "equilibrium" state remains ambiguous.
We analyze the reaction dynamics of central Pb+Pb collisions at 160 GeV/nucleon. First we estimate the energy density pile-up at mid-rapidity and calculate its excitation function: The energy density is decomposed into hadronic and partonic contributions. A detailed analysis of the collision dynamics in the framework of a microscopic transport model shows the importance of partonic degrees of freedom and rescattering of leading (di)quarks in the early phase of the reaction for E >= 30 GeV/nucleon. The energy density reaches up to 4 GeV/fm 3, 95% of which are contained in partonic degrees of freedom. It is shown that cells of hadronic matter, after the early reaction phase, can be viewed as nearly chemically equilibrated. This matter never exceeds energy densities of 0.4 GeV/fm 3, i.e. a density above which the notion of separated hadrons loses its meaning. The final reaction stage is analyzed in terms of hadron ratios, freeze-out distributions and a source analysis for final state pions.
Local kinetic and chemical equilibration is studied for Au+Au collisions at 10.7 AGeV in the microscopic Ultrarelativistic Quantum Molecular Dynamics model (UrQMD). The UrQMD model exhibits dramatic deviations from equilibrium during the high density phase of the collision. Thermal and chemical equilibration of the hadronic matter seems to be established in the later stages during a quasiisentropic expansion, observed in the central reaction cell with volume 125 fm3. For t > 10 fm/c the hadron energy spectra in the cell are nicely reproduced by Boltzmann distributions with a common rapidly dropping temperature. Hadron yields change drastically and at the late expansion stage follow closely those of an ideal gas statistical model. The equation of state seems to be simple at late times: P = 0.12 Epsilon. The time evolution of other thermodynamical variables in the cell is also presented.