Summary
The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re‐evaluated after a median ...observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow‐up, investigator‐assessed complete response (CR) rate (21·0% vs 10·8%), median progression‐free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non‐responders. However, patients with objective response or a CR experienced a significantly longer OS than non‐responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first‐line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.
Perinatal mood disorders are a tremendous burden to childbearing families and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants is increasingly common. Exposure to SSRIs ...may affect serotonin signaling and ultimately, microbes that live in the gut. Health of the gut microbiome during pregnancy, lactation, and early infancy is critical, yet there is limited evidence to describe the relationship between SSRI exposure and gut microbiome status in this population. The purpose of this Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA)‐compliant scoping review is to assess evidence and describe key concepts regarding whether SSRI exposure affects the maternal and infant gut microbiome. Sources were collected from PubMed, Web of Science, and Scopus databases, and an additional gray literature search was performed. Our search criteria returned only three sources, two rodent models and one human subjects research study. Results suggest that fluoxetine (SSRI) exposure may affect maternal gut microbiome dynamics during pregnancy and lactation. There were no available sources to describe the relationship between perinatal SSRI exposure and the infant gut microbiome. There is a significant gap in the literature regarding whether SSRI antidepressants affect the maternal and infant gut microbiome. Future studies are required to better understand how SSRI antidepressant exposure affects perinatal health.
Background and Purpose
Itch is associated with several pathologies and is a common drug‐induced side effect. Chloroquine (CQ) is reported to induce itch by activating the Mas‐related G ...protein‐coupled receptor MrgprA3 and subsequently TRPA1. In this study, we demonstrate that CQ employs at least two MrgprA3‐independent mechanisms to activate or sensitize TRPA1 and TRPV1.
Experimental Approach
Patch clamp and calcium imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK 293T cells.
Key Results
In calcium imaging, CQ induces a concentration‐dependent but MrgprA3‐independent activation of TRPA1 and TRPV1. Although CQ itself inhibits TRPA1 and TRPV1 in patch clamp recordings, co‐application of CQ and ultraviolet A (UVA) light evokes membrane currents through both channels. This effect is inhibited by the reducing agent dithiothreitol (DTT) and is reduced on mutants lacking cysteine residues accounting for reactive oxygen species (ROS) sensitivity. The combination of CQ and UVA light triggers an accumulation of intracellular ROS, removes fast inactivation of voltage‐gated sodium currents and activates TRPV2. On the other hand, CQ is a weak base and induces intracellular alkalosis. Intracellular alkalosis can activate TRPA1 and TRPV1, and CQ applied at alkaline pH values indeed activates both channels.
Conclusion and Implications
Our data reveal novel pharmacological properties of CQ, allowing activation of TRPA1 and TRPV1 via photosensitization as well as intracellular alkalosis. These findings add more complexity to the commonly accepted dogma that CQ‐induced itch is specifically mediated by MrgprA3 coupling to TRPA1.
Understanding process parameter interactions and their effects on mammalian cell cultivations is an essential requirement for robust process scale-up. Furthermore, knowledge of the relationship ...between the process parameters and the product critical quality attributes (CQAs) is necessary to satisfy quality by design guidelines. So far, mainly the effect of single parameters on CQAs was investigated. Here, we present a comprehensive study to investigate the interactions of scale-up relevant parameters as pH,
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on CHO cell physiology, process performance and CQAs, which was based on design of experiments and extended product quality analytics. The study used a novel control strategy in which process parameters were decoupled from each other, and thus allowed their individual control at defined set points. Besides having identified the impact of single parameters on process performance and product quality, further significant interaction effects of process parameters on specific cell growth, specific productivity and amino acid metabolism could be derived using this method. Concerning single parameter effects, several monoclonal antibody (mAb) charge variants were affected by process
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and pH.
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-glycosylation analysis showed positive correlations between mAb sialylation and high pH values as well as a relationship between high mannose variants and process pH. This study additionally revealed several interaction effects as process pH and
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interactions on mAb charge variants and
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-glycosylation pattern. Hence, through our process control strategy and multivariate investigation, novel significant process parameter interactions and single effects were identified which have to be taken into account especially for process scale-up.
The understanding of how microbiomes assemble, function, and evolve requires metagenomic tools that can resolve microbiota compositions at the strain level. However, the identification and tracking ...of microbial strains in fecal metagenomes is challenging and available tools variably classify subspecies lineages, which affects their applicability to infer microbial persistence and transfer.
We introduce SameStr, a bioinformatic tool that identifies shared strains in metagenomes by determining single-nucleotide variants (SNV) in species-specific marker genes, which are compared based on a maximum variant profile similarity. We validated SameStr on mock strain populations, available human fecal metagenomes from healthy individuals and newly generated data from recurrent Clostridioides difficile infection (rCDI) patients treated with fecal microbiota transplantation (FMT). SameStr demonstrated enhanced sensitivity to detect shared dominant and subdominant strains in related samples (where strain persistence or transfer would be expected) when compared to other tools, while being robust against false-positive shared strain calls between unrelated samples (where neither strain persistence nor transfer would be expected). We applied SameStr to identify strains that are stably maintained in fecal microbiomes of healthy adults over time (strain persistence) and that successfully engraft in rCDI patients after FMT (strain engraftment). Taxonomy-dependent strain persistence and engraftment frequencies were positively correlated, indicating that a specific core microbiota of intestinal species is adapted to be competitive both in healthy microbiomes and during post-FMT microbiome assembly. We explored other use cases for strain-level microbiota profiling, as a metagenomics quality control measure and to identify individuals based on the persisting core gut microbiota.
SameStr provides for a robust identification of shared strains in metagenomic sequence data with sufficient specificity and sensitivity to examine strain persistence, transfer, and engraftment in human fecal microbiomes. Our findings identify a persisting healthy adult core gut microbiota, which should be further studied to shed light on microbiota contributions to chronic diseases. Video abstract.
•Frequency dependent hyperpolarizability of atomic systems surrounded by Debye plasma is reported taking H atom as a prototype.•Time dependent variation perturbation theory with Slater basis is used ...to study nonlinear response of plasma embedded H atom.•Two photon absorption in such systems is observed as an outcome of the present calculation.•The accidental degeneracy of H atom is systematically removed in presence of plasma.
Frequency dependent dipole hyperpolarizability of hydrogen atom confined under classical plasma is estimated using nonlinear response theory under a monochromatic electromagnetic field. The screened Coulomb potential is used to model the classical plasma. Time-dependent variation perturbation theory with Slater basis is applied for the first time for such an analysis. As an offshoot, two photon excitations are obtained from the poles of frequency dependent hyperpolarizability. We have specifically studied two photon excited states 2s,3s/3d and 4s/4d from the ground 1s state of H atom. The positions and radial density profiles of two photon excited states of free H atom are in excellent agreement with experimental and analytical results. The accidental degeneracy above principal quantum number n=2 is lifted systematically with respect to increased screening parameters. The results are expected to be important for different nonlinear optical processes like the Kerr effect, degenerate four wave mixing, harmonic generation etc. under external confinement.
Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart defect with limited data on long-term outcomes after surgical intervention.
We conducted a retrospective ...review of all children (N = 42) who underwent surgical repair of ALCAPA between 1980 and 2014 at the Royal Children's Hospital, Melbourne.
Twenty-nine (69% 29 of 42) patients underwent coronary reimplantation, 12 (29% 12 of 42) had intrapulmonary baffle (Takeuchi) repair, and 1 (2% 1 of 42) patient had ligation of the anomalous coronary artery. Nine (21%, 9 of 42) patients had concomitant mitral valve (MV) repair at the time of ALCAPA repair. A left ventricular assist device (LVAD) was used in 36% (15 of 42) of patients. Early mortality was 2.4% (1 of 42 patients). Median follow-up was 14 years (mean, 13 years; range, 4 months-31 years). There were no late deaths. Survival was 98% at 20 years. Freedom from reoperation was 81%, 81%, and 76% at 5, 10, and 20 years after operation, respectively. Eight patients underwent late MV repair or replacement at a median of 3 years (mean, 8 years; range, 2 months-25 years) after operation. Freedom from late MV repair or replacement was 86% at 5 and 10 years and 81% at 20 years after operation. Eleven (26% 11 of 42) patients had severe mitral regurgitation (MR) preoperatively. Of those 11 patients, 5 (45% 5 of 11) had concomitant MV repair at the time of ALCAPA repair, 3 (27% 3 of 11) had late MV repair or replacement, and the remaining 3 (27% 3 of 11) patients had mild MR at last follow-up. Thirty-six (90% 36 of 41) patients had normal left ventricular function and 4 (10% 4 of 41) patients had mildly reduced left ventricular (LV) function at last follow-up.
ALCAPA can be operated on with good outcomes. Persistent MR and a moderate rate of late MV repair warrants close follow-up.
•Comparison of full continuum solutions using four fundamentally different numerical approaches.•Analysis of different rise regimes providing reference data for liquid rising between plates ...(available online).•General derivation for the case of critical dampening for the classical rise equation.
The rise of liquid in capillaries, or between two parallel plates as the 2D variant thereof, represents a challenging test case for two-phase flow solvers without a full analytic solution. Four different numerical approaches are compared for the rise of liquid, also providing reference data being of high relevance for capillarity-dominated wetting processes. The used methods are an Arbitrary Lagrangian–Eulerian method (OpenFOAM solver interTrackFoam), a geometric Volume of Fluid code (FS3D), an algebraic Volume of Fluid method (OpenFOAM solver interFoam), and a level-set based extended discontinuous Galerkin discretization (BoSSS).
While the transient rise height shows excellent agreement between the different implementations, the velocity fields at the interface demonstrate a different level of local accuracy of the available approaches. Reducing the slip length reduces the overall dynamics of the system, thus yielding a qualitative change in the rise behavior – a behavior that is not covered by simplified ODE models. The obtained rise height results are vailable online: http://dx.doi.org/10.25534/tudatalib-173
Our objectives were to (1) compare the effect on pregnancies per artificial insemination (P/AI) of presynchronization of the estrous cycle with human chorionic gonadotropin (hCG) 7d before ...resynchronization of ovulation (Resynch) initiated 25d after timed artificial insemination (TAI) and compare the presynchronization treatment with the Double-Ovsynch (DO) protocol, and (2) evaluate whether hCG for presynchronization could be replaced with GnRH. In experiment 1, lactating Holstein cows were blocked by parity and were randomly assigned to receive (1) Resynch-25 (D25), the Resynch protocol (GnRH-7 d-PGF2α-56h-GnRH-16h-TAI) initiated 25d after TAI (n=418); (2) HGPG, presynchronization with hCG (2,000IU of Chorulon) 7d before D25 (n=450); and (3) DO (Pre-Resynch, GnRH-7 d-PGF2α-72h-GnRH; Breeding-Resynch, GnRH-7 d-PGF2α-56h-GnRH-16h-TAI) initiated 22d after TAI (n=405). At 29d after TAI, cows in the HGPG (37.3%) and DO (35.8%) groups had more P/AI than did cows in the D25 group (28.0%), and cows in the HGPG and DO groups continued to have more P/AI than did cows in the D25 group at 53d after TAI. Presynchronization with hCG induced ovulation in 76% of the cows, which increased the percentage of HGPG cows with a corpus luteum at the initiation of Resynch compared with cows in the D25 group. In experiment 2, the D25 (n=368) and HGPG (n=338) treatments described in experiment 1 were compared in addition to a third treatment (GGPG; n=351), in which the hCG injection 18d after TAI was replaced with a GnRH injection (200µg of gonadorelin). At 32d after TAI, cows in the HGPG group had more P/AI than did cows in the D25 group (33.7 vs. 25.5%), whereas cows in the GGPG group had intermediate P/AI (31.6%). At 53d after TAI, P/AI tended to be greater for cows in the HGPG group than for those in the D25 group, whereas P/AI for cows in the GGPG group did not differ from that for cows in the D25 group. Treatment with hCG and GnRH 18d after TAI induced ovulation in 58.8 and 48.2% of cows, respectively, but did not increase the percentage of cows with a corpus luteum at the initiation of Resynch. More cows in the HGPG and GGPG groups had their estrous cycles synchronized after the resynchronization protocols compared with cows in the D25 group. We conclude that presynchronization with hCG increased fertility by increasing synchronization to the Resynch protocol, whereas presynchronization with GnRH improved synchronization to the Resynch protocol but did not improve fertility when compared with no presynchronization or presynchronization with hCG.
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