Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

How to probe the microscopic onset of irreversibility with ultracold atoms.

The microscopic onset of irreversibility is finally becoming an experimental subject. Recent experiments on microscopic open and even isolated systems have measured statistical properties associated with entropy production, and hysteresis-like phenomena have been seen in cold atom systems with dissipation (i.e. effectively open systems coupled to macroscopic reservoirs). Here we show how experiments on isolated systems of ultracold atoms can show dramatic irreversibility like cooking an egg. In our proposed experiments, a slow forward-and-back parameter sweep will sometimes fail to return the system close to its initial state. This probabilistic hysteresis is due to the same non-adiabatic spreading and ergodic mixing in phase space that explains macroscopic irreversibility, but realized without dynamical chaos; moreover this fundamental mechanism quantitatively determines the probability of return to the initial state as a function of tunable parameters in the proposed experiments. Matching the predicted curve of return probability will be a conclusive experimental demonstration of the microscopic onset of irreversibility.

Vibrio coralliilyticus infection triggers a behavioural response and perturbs nutritional exchange and tissue integrity in a symbiotic coral.

Under homoeostatic conditions, the relationship between the coral Pocillopora damicornis and Vibrio coralliilyticus is commensal. An increase in temperature, or in the abundance of V. coralliilyticus, can turn this association pathogenic, causing tissue lysis, expulsion of the corals' symbiotic algae (genus Symbiodinium), and eventually coral death. Using a combination of microfluidics, fluorescence microscopy, stable isotopes, electron microscopy and NanoSIMS isotopic imaging, we provide insights into the onset and progression of V. coralliilyticus infection in the daytime and at night, at the tissue and (sub-)cellular level. The objective of our study was to connect the macro-scale behavioural response of the coral to the micro-scale nutritional interactions that occur between the host and its symbiont. In the daytime, polyps enhanced their mucus production, and actively spewed pathogens. Vibrio infection primarily resulted in the formation of tissue lesions in the coenosarc. NanoSIMS analysis revealed infection reduced 13C-assimilation in Symbiodinium, but increased 13C-assimilation in the host. In the night incubations, no mucus spewing was observed, and a mucus film was formed on the coral surface. Vibrio inoculation and infection at night showed reduced 13C-turnover in Symbiodinium, but did not impact host 13C-turnover. Our results show that both the nutritional interactions that occur between the two symbiotic partners and the behavioural response of the host organism play key roles in determining the progression and severity of host-pathogen interactions. More generally, our approach provides a new means of studying interactions (ranging from behavioural to metabolic scales) between partners involved in complex holobiont systems, under both homoeostatic and pathogenic conditions.

High-Throughput Sequencing of the T-Cell Receptor Beta Chain Gene Repertoire in Chronic Lymphocytic Leukemia.

High-throughput, next-generation sequencing (NGS) offers a unique opportunity for in-depth characterization of adaptive immune receptor repertoires. Nevertheless, limitations and pitfalls exist in every step of both the experimental and the analytical procedure, leading to discrepancies in the literature and incomprehensive and/or altogether misleading results. Thus, standardization of protocols in NGS immunogenetics is urgently needed.Here, we describe the experimental protocol that we developed for T-cell receptor beta chain (TRB) gene repertoire analysis in chronic lymphocytic leukemia, aiming to provide a reproducible and biologically meaningful output. Although optimized for TRBV-TRBD-TRBJ gene rearrangements, this protocol may be customized for other adaptive immune receptor sequences, as well.

Using NanoSIMS coupled with microfluidics to visualize the early stages of coral infection by Vibrio coralliilyticus.

BACKGROUND: Global warming has triggered an increase in the prevalence and severity of coral disease, yet little is known about coral/pathogen interactions in the early stages of infection. The point of entry of the pathogen and the route that they take once inside the polyp is currently unknown, as is the coral's capacity to respond to infection. To address these questions, we developed a novel method that combines stable isotope labelling and microfluidics with transmission electron microscopy (TEM) and nanoscale secondary ion mass spectrometry (NanoSIMS), to monitor the infection process between Pocillopora damicornis and Vibrio coralliilyticus under elevated temperature. RESULTS: Three coral fragments were inoculated with 15N-labeled V. coralliilyticus and then fixed at 2.5, 6 and 22 h post-inoculation (hpi) according to the virulence of the infection. Correlative TEM/NanoSIMS imaging was subsequently used to visualize the penetration and dispersal of V. coralliilyticus and their degradation or secretion products. Most of the V. coralliilyticus cells we observed were located in the oral epidermis of the fragment that experienced the most virulent infection (2.5 hpi). In some cases, these bacteria were enclosed within electron dense host-derived intracellular vesicles. 15N-enriched pathogen-derived breakdown products were visible in all tissue layers of the coral polyp (oral epidermis, oral gastrodermis, aboral gastrodermis), at all time points, although the relative 15N-enrichment depended on the time at which the corals were fixed. Tissues in the mesentery filaments had the highest density of 15N-enriched hotspots, suggesting these tissues act as a "collection and digestion" site for pathogenic bacteria. Closer examination of the sub-cellular structures associated with these 15N-hotspots revealed these to be host phagosomal and secretory cells/vesicles. CONCLUSIONS: This study provides a novel method for tracking bacterial infection dynamics at the levels of the tissue and single cell and takes the first steps towards understanding the complexities of infection at the microscale, which is a crucial step towards understanding how corals will fare under global warming.

Neurological deficit is predicted by S100B in children after cardiac surgery.

INTRODUCTION: Children undergoing cardiac surgery may suffer from brain injuries after surgery and develop neurological deficit. Early diagnosis of brain injury after surgery would enable early therapeutic interventions. The aim of the study is to test whether S100B can serve as a biomarker for brain injury after cardiac surgery. METHODS: Seventy-five patients were enrolled in the study. Serum S100B was collected at the beginning of the surgery, and 6, 12, 24 h after surgery. S100B z-scores were calculated based on norms for age. Neurological evolutions were done before surgery and at discharge by the Pediatric Stroke Outcome Measure (PSOM). New neurological deficit (NND) was defined as a 1 point increase on the PSOM scale. RESULTS: Twenty patients had an NND after cardiac surgery. Medical background was similar between the groups with and without NND. S100B z-scores were significantly higher in the NND group at all time points after surgery. Using a cut-off of 3 z-score at 6 h after surgery, the positive predictive value was 79% and the negative predictive value was 90%. CONCLUSIONS: S100B is a potent early biomarker for brain injury after cardiac surgery. Hopefully, S100B could be used to prevent progression of brain injuries after cardiac surgery.

Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements.

Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.

Bosonic amplification of noise-induced suppression of phase diffusion.

We study the effect of noise-induced dephasing on collisional phase diffusion in the two-site Bose-Hubbard model. Dephasing of the quasimomentum modes may slow down phase diffusion in the quantum Zeno limit. Remarkably, the degree of suppression is enhanced by a bosonic factor of order N/logN as the particle number N increases.

[Circumcision and HIV]. / Circoncision et VIH.

The idea that circumcision decreases the risk of sexual transmission of HIV was first proposed in the 1980s, at the time of the worldwide emergence of HIV infection. Many descriptive studies have subsequently been conducted to confirm this effect. Over the last two years, three experimental studies have provided scientific proof of the protective effect of circumcision, evaluated to be about 60%. These studies were recently validated by the WHO. The underlying mechanism of this protective effect remains unclear, but appears to be related more to the number of CD4+ lymphocytes on the mucosal surface of the prepuce in uncircumcised men than to keratinisation of the glans in circumcised men. Paradoxically, the practical implications are unclear, as large-scale prophylactic circumcision, depending on the country, would raise problems of acceptability, material feasibility and even efficacy if the population, considering itself to be protected, abandons conventional safe sex precautions which remain essential.

Anisotropic solitons in dipolar bose-einstein condensates.

Starting with a Gaussian variational ansatz, we predict anisotropic bright solitons in quasi-2D Bose-Einstein condensates consisting of atoms with dipole moments polarized perpendicular to the confinement direction. Unlike isotropic solitons predicted for the moments aligned with the confinement axis [Phys. Rev. Lett. 95, 200404 (2005)10.1103/PhysRevLett.95.200404], no sign reversal of the dipole-dipole interaction is necessary to support the solitons. Direct 3D simulations confirm their stability.

Prevention of potential errors in resuscitation medications orders by means of a computerised physician order entry in paediatric critical care.

INTRODUCTION: Computerised physician order entry with clinical decision support system (CPOE+CDSS) is an important tool in attempting to reduce medication errors. The objective of this study was to evaluate the impact of a CPOE+CDSS on (1) the frequency of errors in ordering resuscitation (CPR) medications and (2) the time for printing out the order form, in a paediatric critical care department (PCCD). SETTING: An 18-bed PCCD in a tertiary-care children's hospital. DESIGN: Prospective cohort study. MEASURES: Compilation and comparison of number of errors and time to fill in forms before and after implementation of CPOE+CDSS. Time to fill in conventional, simulated and CPOE forms was measured and compared. RESULTS: There were three reported incidents of errors among 13,124 CPR medications orders during the year preceding implementation of CPOE+CDSS. These represent errors that escaped the triple check by three independent staff members. There were no errors after CPOE+CDSS was implemented (100% error reduction for 46,970 orders). Time to completion of drug forms dropped from 14 min 42 s to 2 min 14s (p < 0.001). CONCLUSIONS: CPOE+CDSS completely eliminated errors in filling in the forms and significantly reduced time to completing the form.

Fiberoptic bronchoscopy and bronchoalveolar lavage for the evaluation of pulmonary disease in children with primary immunodeficiency and cancer.

BACKGROUND: Patients with childhood cancer or primary immunodeficiencies (PID) are at high risk for developing pulmonary infections and non-infectious complications. The broad differential diagnoses and the critical condition of these patients often drive physicians to start broad-spectrum antibiotic therapy before a definite diagnostic procedure is performed. A definite diagnosis may be achieved in these situations by fiberoptic bronchoscopy (FOB) and bronchoalveolar lavage (BAL). PATIENTS AND METHODS: The records of 58 PIDs and cancer (immunocompromised group) pediatric patients who underwent 62 fiberoptic bronchoscopies between 2000 and 2004 were retrospectively reviewed and compared to 158 non-cancer patients who underwent 182 fiberoptic bronchoscopies during the same period. RESULTS: The overall diagnostic rate achieved by macroscopic inspection of purulent secretions or hemorrhage, abnormal cell count, and infectious agent isolation in the immunocompromised patients was 84%. A definite organism was recovered in 53.2% of the patients. Probable infection defined as purulent secretions or abnormal cell count without infectious agent isolation was diagnosed in another 21% of the patients. The rate of complications was 30.6%. In the control group, the overall diagnostic rate was 76.9% (n.s) and an infectious agent was demonstrated in 12.1% (P < 0.001). Probable infection was diagnosed in 24.2% (n.s) while the rate of complications was lower (15%) (P < 0.01). CONCLUSIONS: Rapid and accurate diagnoses were achieved in most procedures performed on immunocompromised patients. Although the rate of complications was higher in the immunocompromised group, they were usually very mild with no mortality. Based on these results, broncoalveolar lavage should be considered as an initial diagnostic tool in pediatric immunocompromised patients with pulmonary complications.

Nonlinear adiabatic passage from fermion atoms to boson molecules.

We study the dynamics of an adiabatic sweep through a Feshbach resonance in a quantum gas of fermionic atoms. Analysis of the dynamical equations, supported by mean-field and many-body numerical results, shows that the dependence of the remaining atomic fraction Gamma on the sweep rate alpha varies from exponential Landau-Zener behavior for a single pair of particles to a power-law dependence for large particle number N. The power law is linear, Gamma is proportional to alpha, when the initial molecular fraction is smaller than the 1/N quantum fluctuations, and Gamma is proportional to alpha(1/3) when it is larger. Experimental data agree well with a linear dependence, but do not conclusively rule out the Landau-Zener model.

Incoherent matter-wave solitons and pairing instability in an attractively interacting Bose-Einstein condensate.

The dynamics of matter-wave solitons in Bose-Einstein condensates (BEC) is considerably affected by the presence of a thermal cloud and the dynamical depletion of the condensate. Our numerical results, based on the time-dependent Hartree-Fock-Bogoliubov theory, demonstrate the collapse of the attractively interacting BEC via collisional emission of atom pairs into the thermal cloud, which splits the (quasi-one-dimensional) BEC soliton into two partially coherent solitonic structures of opposite momenta. These incoherent matter waves are analogous to optical random-phase solitons.

Conversion efficiency of ultracold fermionic atoms to bosonic molecules via Feshbach resonance sweep experiments.

We explain why the experimental efficiency observed in the conversion of ultracold Fermi gases of 40K and 6Li atoms into diatomic Bose gases is limited to 0.5 when the Feshbach resonance sweep rate is sufficiently slow to pass adiabatically through the Landau-Zener transition but faster than "the collision rate" in the gas, and increases beyond 0.5 when it is slower. The 0.5 efficiency limit is due to the preparation of a statistical mixture of two spin states, required to enable s-wave scattering. By constructing the many-body state of the system we show that this preparation yields a mixture of even and odd parity pair states, where only even parity can produce molecules. The odd parity spin-symmetric states must decorrelate before the constituent atoms can further Feshbach scatter, thereby increasing the conversion efficiency; "the collision rate" is the pair decorrelation rate.

Directional "superradiant" collisions: bosonic amplification of atom pairs emitted from an elongated Bose-Einstein condensate.

We study spontaneous directionality in the bosonic amplification of atom pairs emitted from an elongated Bose-Einstein condensate, an effect analogous to superradiant emission of atom-photon pairs. Using a simplified model, we make analytic predictions regarding directional effects for both atom-atom and atom-photon emission. These are confirmed by numerical mean-field simulations, demonstrating the feasibility of nearly perfect directional emission along the condensate axis. The dependence of the emission angle on the pump strength for atom-atom pairs is significantly different than for atom-photon pairs.

Bose-enhanced chemistry: amplification of selectivity in the dissociation of molecular Bose-Einstein condensates.

We study the photodissociation chemistry of a quantum degenerate gas of bosonic triatomic ABC molecules, assuming two open rearrangement channels ( AB+C or A+BC). The equations of motion are equivalent to those of a parametric multimode laser, resulting in an exponential buildup of macroscopic mode populations. By exponentially amplifying a small differential in the single-particle rate coefficients, Bose stimulation leads to a nearly complete selectivity of the collective N-body process, indicating a novel type of ultraselective quantum degenerate chemistry.

Acute respiratory distress syndrome in children with malignancy--can we predict outcome?

PURPOSE: The purpose of this study was to delineate early respiratory predictors of mortality in children with hemato-oncology malignancy who developed acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: We conducted a retrospective chart review of children with malignant and ARDS who needed mechanical ventilation and were admitted to a pediatric intensive care unit from January 1987 to January 1997. RESULTS: Seventeen children with ARDS and malignancy aged 10.5 +/- 5.1 years were identified. Six of the 17 children (35.3%) survived. Sepsis syndrome was present in 70.6% of all the children. Peak inspiratory pressure, positive end-expiratory pressure (PEEP), and ventilation index values could distinguish outcome by day 3. A significant relationship between respiratory data and outcome related to efficiency of oxygenation, as determined by PaO(2)/FIO(2) and P(A-a)O(2), was present from day 8 after onset of mechanical ventilation. CONCLUSIONS: Peak inspiratory pressure, PEEP, and ventilation index values could distinguish survivors from nonsurvivors by day 3. This may assist in early application of supportive nonconventional therapies in children with malignancy and ARDS.

Bose-Einstein condensates beyond mean field theory: quantum backreaction as decoherence.

We propose an experiment to measure the slow log(N) convergence to mean field theory (MFT) around a dynamical instability. Using a density matrix formalism instead of the standard macroscopic wave function approach, we derive equations of motion which go beyond MFT and provide accurate predictions for the quantum break time. The leading quantum corrections appear as decoherence of the reduced single-particle quantum state.