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The Small and Large Magellanic Clouds are the only galaxies outside our own in which radio pulsars have been discovered to date. The sensitivity of the MeerKAT radio interferometer offers an opportunity to search for a population of more distant extragalactic pulsars. The TRAPUM (TRansients And PUlsars with MeerKAT) collaboration has performed a radio-domain search for pulsars and transients in the dwarf star-forming galaxies Sextans A and B, situated at the edge of the Local Group 1.4 Mpc away. We conducted three 2-h multibeam observations at L band (856–1712 MHz) with the full array of MeerKAT. No pulsars were found down to a radio pseudo-luminosity upper limit of 7.9 |$\pm$| 0.4 Jy kpc |$^{2}$| at 1400 MHz, which is 28 times more sensitive than the previous limit from the Murriyang telescope. This luminosity is 30 per cent greater than that of the brightest known radio pulsar and sets a cut-off on the luminosity distributions of the entire Sextans A and B galaxies for unobscured radio pulsars beamed in our direction. A fast radio burst was detected in one of the Sextans A observations at a dispersion measure (DM) of 737 pc cm |$^{-3}$|⁠. We believe this is a background event not associated with the dwarf galaxy due to its large DM and its signal-to-noise ratio being strongest in the wide-field incoherent beam of MeerKAT. [ABSTRACT FROM AUTHOR]

Galactic plane radio surveys play a key role in improving our understanding of a wide range of astrophysical phenomena. Performing such a survey using the latest interferometric telescopes produces large data rates necessitating a shift towards fully or quasi-real-time data analysis with data being stored for only the time required to process them. We present here the overview and set-up for the 3000-h Max-Planck-Institut für Radioastronomie (MPIfR)–MeerKAT Galactic Plane Survey (MMGPS). The survey is unique by operating in a commensal mode, addressing key science objectives of the survey including the discovery of new pulsars and transients and studies of Galactic magnetism, the interstellar medium and star formation rates. We explain the strategy coupled with the necessary hardware and software infrastructure needed for data reduction in the imaging, spectral, and time domains. We have so far discovered 78 new pulsars including 17 confirmed binary systems of which two are potential double neutron star systems. We have also developed an imaging pipeline sensitive to the order of a few tens of micro-Jansky (⁠|$\mu{\rm Jy}$|⁠) with a spatial resolution of a few arcseconds. Further science operations with an in-house built S-band receiver operating between 1.7 and 3.5 GHz are about to commence. Early spectral line commissioning observations conducted at S-band, targeting transitions of the key molecular gas tracer CH at 3.3 GHz already illustrate the spectroscopic capabilities of this instrument. These results lay a strong foundation for future surveys with telescopes like the Square Kilometre Array (SKA). [ABSTRACT FROM AUTHOR]

We present new radio continuum images of the edge-on starburst galaxy NGC 5775, from LOFAR (140 MHz) and the Karl G. Jansky Very Large Array CHANG-ES survey (1500 MHz). We trace the non-thermal radio halo up to 13 kpc from the disc, measuring the non-thermal spectral index and estimating the total equipartition magnetic field strength (≈13  |$\mu$| G in the disc and ≈7  |$\mu$| G above the plane). The radio halo has a similar extent at both frequencies, displays evidence for localized cosmic ray streaming coinciding with prominent H α filaments and vertical extensions of the regular magnetic field, and exhibits a boxy morphology especially at 140 MHz. In order to understand the nature of the disc–halo flow, we extend our previous model of cosmic ray propagation by implementing an iso-thermal wind with a tunable 'flux tube' (approximately hyperboloidal) geometry. This updated model is successful in matching the vertical distribution of non-thermal radio emission, and the vertical steepening of the associated spectral index, in a consistent conceptual framework with few free parameters. Our new model provides the opportunity to estimate the mass outflow driven by the star formation process, and we find an implied rate of |$\dot{M}\approx 3$| – |$6\, \mathrm{M_{\odot }\, yr^{-1}}$| (≈40–80 per cent of the star formation rate) if the escape velocity is reached, with substantial uncertainty arising from the poorly understood distribution of interstellar medium material entrained in the vertical flow. The wind may play a role in influencing the vertical gradient in rotational velocity. [ABSTRACT FROM AUTHOR]

In this paper we present recent Low Frequency Array observations of the pulsar J1740+1000. We confirm that its spectrum has a turnover at 260 MHz, which is unusual for a typical pulsar. We argue that in this case interferometric imaging provides more accurate pulsar flux estimates than other, more traditional, means such as beamformed observations. We conclude that existing calibration and imaging techniques can be used for a more comprehensive study of the influence of the interstellar medium on the point-like sources at very low frequencies in the near future. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries. [ABSTRACT FROM AUTHOR]

Aims. The shape of low-frequency radio continuum spectra of normal galaxies is not well understood, the key question being the role of physical processes such as thermal absorption in shaping them. In this work we take advantage of the LOFAR Multifrequency Snapshot Sky Survey (MSSS) to investigate such spectra for a large sample of nearby star-forming galaxies. Methods. Using the measured 150 MHz flux densities from the LOFAR MSSS survey and literature flux densities at various frequencies we have obtained integrated radio spectra for 106 galaxies characterised by different morphology and star formation rate. The spectra are explained through the use of a three-dimensional model of galaxy radio emission, and radiation transfer dependent on the galaxy viewing angle and absorption processes. Results. Our galaxies' spectra are generally flatter at lower compared to higher frequencies: the median spectral index αlow measured between ≈50 MHz and 1.5 GHz is −0.57 ± 0.01 while the high-frequency one αhigh, calculated between 1.3 GHz and 5 GHz, is −0.77 ± 0.03. As there is no tendency for the highly inclined galaxies to have more flattened low-frequency spectra, we argue that the observed flattening is not due to thermal absorption, contradicting the suggestion of Israel & Mahoney (1990, ApJ, 352, 30). According to our modelled radio maps for M 51-like galaxies, the free-free absorption effects can be seen only below 30 MHz and in the global spectra just below 20 MHz, while in the spectra of starburst galaxies, like M 82, the flattening due to absorption is instead visible up to higher frequencies of about 150 MHz. Starbursts are however scarce in the local Universe, in accordance with the weak spectral curvature seen in the galaxies of our sample. Locally, within galactic disks, the absorption effects are distinctly visible in M 51-like galaxies as spectral flattening around 100–200 MHz in the face-on objects, and as turnovers in the edge-on ones, while in M 82-like galaxies there are strong turnovers at frequencies above 700 MHz, regardless of viewing angle. Conclusions. Our modelling of galaxy spectra suggests that the weak spectral flattening observed in the nearby galaxies studied here results principally from synchrotron spectral curvature due to cosmic ray energy losses and propagation effects. We predict much stronger effects of thermal absorption in more distant galaxies with high star formation rates. Some influence exerted by the Milky Way's foreground on the spectra of all external galaxies is also expected at very low frequencies. [ABSTRACT FROM AUTHOR]

Context. The new generation of broad-band radio continuum surveys will provide large data sets with polarization information. New algorithms need to be developed to extract reliable catalogs of linearly polarized sources that can be used to characterize those sources and produce a dense rotation measure (RM) grid to probe magneto-ionized structures along the line of sight via Faraday rotation. Aims. The aim of the paper is to develop a computationally efficient and rigorously defined source-finding algorithm for linearly polarized sources. Methods. We used a calibrated data set from the LOw Frequency ARray (LOFAR) at 150 MHz centered on the nearby galaxy M 51 to search for polarized background sources. With a new imaging software, we re-imaged the field at a resolution of 18″ × 15″ and cataloged a total of about 3000 continuum sources within 2.5° of the center of M 51. We made small Stokes Q and U images centered on each source brighter than 100 mJy in total intensity (201 sources) and used RM synthesis to create corresponding Faraday cubes that were analyzed individually. For each source, the noise distribution function was determined from a subset of the measurements at high Faraday depths where no polarization is expected; the peaks in polarized intensity in the Faraday spectrum were identified and the p-value of each source was calculated. Finally, the false discovery rate method was applied to the list of p-values to produce a list of polarized sources and quantify the reliability of the detections. We also analyzed sources fainter than 100 mJy but that were reported as polarized in the literature at at least another radio frequency. Results. Of the 201 sources that were searched for polarization, six polarized sources were detected confidently (with a false discovery rate of 5%). This corresponds to a number density of one polarized source per 3.3 square degrees, or 0.3 source per square degree. Increasing the false discovery rate to 50% yields 19 sources. A majority of the sources have a morphology that is indicative of them being double-lobed radio galaxies, and the ones with literature redshift measurements have 0.5 < z < 1.0. Conclusions. We find that this method is effective in identifying polarized sources, and is well suited for LOFAR observations. In the future, we intend to develop it further and apply it to larger data sets such as the LOFAR Two-meter Survey of the whole northern sky, LOTSS, and the ongoing deep LOFAR observations of the GOODS-North field. [ABSTRACT FROM AUTHOR]

With Low-Frequency Array (LOFAR) observations, we have discovered a diverse assembly of steep spectrum emission that is apparently associated with the intracluster medium (ICM) of the merging galaxy cluster Abell 2034. Such a rich variety of complex emission associated with the ICM has been observed in few other clusters. This not only indicates that Abell 2034 is a more interesting and complex system than previously thought but it also demonstrates the importance of sensitive and high-resolution, low-frequency observations. These observations can reveal emission from relativistic particles which have been accelerated to sufficient energy to produce observable emission or have had their high energy maintained by mechanisms in the ICM. The most prominent feature in our maps is a bright bulb of emission connected to two steep spectrum filamentary structures, the longest of which extends perpendicular to the merger axis for 0.5 Mpc across the south of the cluster. The origin of these objects is unclear, with no shock detected in the X-ray images and no obvious connection with cluster galaxies or AGNs. We also find that the X-ray bright region of the cluster coincides with a giant radio halo with an irregular morphology and a very steep spectrum. In addition, the cluster hosts up to three possible radio relics, which are misaligned with the cluster X-ray emission. Finally, we have identified multiple regions of emission with a very steep spectral index that seem to be associated with either tailed radio galaxies or a shock. [ABSTRACT FROM AUTHOR]

BACKGROUND In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. [ABSTRACT FROM AUTHOR]

BACKGROUND Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progressionfree survival and safety. RESULTS Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [Cl], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-Ll-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% Cl, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% Cl, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-Ll-positive population (hazard ratio, 0.56; 95% Cl, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432). [ABSTRACT FROM AUTHOR]

A Deep Learning Multi-output regression model is employed to correctly model the relationships between optical design parameters of an asymmetric Twin Elliptical Core Photonic Crystal Fiber (TEC-PCF) and its sensing performances. TEC-PCF acts as a biosensor to detect the blood glucose level taking hemoglobin components into account. Since asymmetric TEC-PCF uses a dual elliptical core, four super modes have to be evaluated to analyze the sensing performance in terms of effective index difference, transmission spectrum, coupling length, and sensor sensitivity. The dataset used in this work is of the optical design parameters of the sensor and Finite Element Method (FEM) results with effective indices of four super modes obtained from the COMSOL Multiphysics by varying hemoglobin concentration to 120 g/L, 140 g/L, and 160 g/L. Gretel.ai's free open-source synthetic data library is used to augment the dataset to make the training more efficient. Explainable AI (XAI) feature analysis using Shapley Additive Explanations (SHAP) framework is used for two purposes: feature selection and to know the feature's effect on prediction. The former led to the development of an optimal model with much fewer computational demands and the latter made the model interpretable. The proposed model can predict the accurate super modes when given input specifications with wavelength ranging from 1.27- [Formula: see text] and for various glucose concentrations under the influence of hemoglobin much faster compared to the other numerical simulations which are computationally expensive. Computation time taken by the proposed Artificial Neural Network (ANN) model, the proposed model with XAI and FEM is also being compared.

Antimicrobial resistance (AMR) is a global health concern. Targetting AMR, we present an in situ lactonization mechanism generating 4-nitroisobenzofuran-1(3 H )-one (IITK2020), an exclusive S. aureus inhibitor at 2-4 μg mL -1 MIC including multidrug-resistant S. aureus clinical strains, that prevents peptidoglycan biosynthesis.

Pancreatic lipase is a digestive enzyme involved in the hydrolysis of dietary fats. Orlistat, a potent pancreatic lipase inhibitor, is widely prescribed for long-term obesity treatment. Nevertheless, orlistat is reported for severe adverse effects including hepatotoxicity and pancreatitis. In the present study, a novel series of 11 benzyloxy substituted indole glyoxylamides were designed, synthesized and evaluated for in vitro pancreatic lipase inhibitory activity. Three analogues, 10b , 11b and 11c , exhibited potent activity (IC 50 ≤ 2.5 µM), with 11b exhibiting a potent IC 50 of 1.68 µM comparable to orlistat (IC 50 = 0.99 µM). Further, 11b exhibited reversible competitive inhibition with an inhibitory constant value of 0.98 μM. Molecular docking of these analogues was in agreement with in vitro results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity (Pearson's r  = 0.7122). A 50 ns molecular dynamics simulation of 11b- pancreatic lipase complex confirmed the role of extended alkyl interactions along with π-π stacking and π-cation interactions, in stabilizing the ligand (Maximum RMSD ≈ 3 Å) in the active site. Gastro-intestinal absorption and toxicity prediction of the three potent analogues highlighted the suitability of 11b for in vivo experiments. 11b at a dose of 20 mg/kg exhibited anti-obesity efficacy comparable to orlistat (10 mg/kg), wherein the serum triglycerides were found to be 94.95 and 83.85 mg/dL, respectively. Further, faecal triglyceride quantification indicated 11b to act through pancreatic lipase inhibition similar to orlistat. The present study identified a novel pancreatic lipase inhibitory benzyloxy substituted bis(indolyl) glyoxylamide 11b, with promising anti-obesity activity.Communicated by Ramaswamy H. Sarma.

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome., Objective: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium., Design, Setting, and Participants: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC., Outcome Measurements and Statistical Analysis: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility., Results and Limitations: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology., Conclusions: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy., Patient Summary: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Phase-III randomized control trial evidence suggests intermittent androgen deprivation therapy (IADT) is not significantly inferior to continuous androgen deprivation therapy (ADT) for patients with prostate cancer (PC). However, clinical practice and guidelines differ in their recommendations. We evaluate real-world utilization and practice patterns of IADT., Materials and Methods: Ontario men ≥65 years of age with PC who initiated ADT for ≥3 months were identified (1997-2017). Lapses in ADT ≥6 months (initial gap) and ≥3 months (subsequent gaps) were used to classify IADT. Neoadjuvant/adjuvant therapy was excluded. Disease stage adjustment was completed for patients with likely metastatic disease based on de novo presentation with ADT. Patient and physician predictors of IADT were analyzed using multivariable logistic regression., Results: We identified 8,544 patients with 1,715 having previously received local therapy. Among all patients, 16.4% received IADT. This ranged from 11.4%-24.8% across health-planning regions and increased to 26.6% in those with previous local therapy. Mean followup was 8.3 years. Patients with prior local therapy (OR 1.85, 95% CI 1.59-2.17, p <0.001) and those in the highest income quintile (OR 1.32, 95% CI 1.08-1.60, p=0.005) had increased odds of receiving IADT. Radiation oncologists were more likely to use IADT than urologists (OR 1.99, 95% CI 1.59-2.50, p <0.001), as were physicians with more experience (≥10 years in practice: OR 1.44, 95% CI 1.11-1.88, p=0.007). In specialty-stratified analyses, case volume was significantly associated with IADT for radiation oncologists (highest quartile: OR 1.73, 95% CI 1.14-2.62, p=0.009)., Conclusions: IADT remains underutilized for patients with PC who ≥65 years of age with only 1 in 4 to 1 in 6 eligible patients receiving this form of care. Clinical, sociodemographic and physician characteristics play an important role in treatment selection.

Background: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting., Patients and Methods: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks)., Results: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001)., Conclusions: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker., Competing Interests: Disclosures KNC reports honoraria and/or consulting fees from Astellas, AstraZeneca, Constellation Pharmaceuticals, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, Sanofi, and grants and research funding from Astellas, AstraZeneca, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi. AWW reports a commercial research grant from Janssen and honoraria from AstraZeneca, Astellas, Janssen, and Merck. AAA reports honoraria, consulting fees, and/or research funding from Astellas, AstraZeneca, Janssen, Novartis, Sanofi, Tolmar, Telix, Merck Serono, Bristol Myers Squibb (BMS), Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Aptevo Therapeutics, Glaxo Smith Kline, MedImmune, SYNthorx, Bionomics, Merck Sharpe Dome, and Sanofi Aventis. LAW reports serving on advisory boards (with no personal financial contribution) for Pfizer, EISAI, AstraZeneca, Merck, BMS, and Ipsen, and grants from Pfizer, Merck, AstraZeneca, Roche, and BMS. BT reports grants and personal fees from Amgen, AstraZeneca, BMS, Janssen, Pfizer, MDS, Ipsen and Bayer, grants from Astellas, and personal fees from Sanofi, Tolmar, Novartis, IQVIA, and Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared with traditional chemotherapy is crucial for clinical practice., Design: A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy [cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1)] with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs [fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism]. Paule-Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects., Results: Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm [OR = 0.26, 95% confidence interval (CI) 0.19-0.35, I 2  = 92%]. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28-0.44; I 2  = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39-0.78, I 2  = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46-0.98, I 2  = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy., Conclusions: Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs., (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Present work reports the synthesis of a novel Chitosan-Polytetrafluoroethylene composite membrane with solvent resistant property for efficient separation of methanol/toluene mixture by pervaporation. The composite was crossed with tetraethyl orthosilicate (TEOS) to prevent or reduce membrane swelling and improve the separation factor. The synthesized membranes were characterized by SEM, FTIR and DSC analysis. Molecular dynamics (MD) simulation and computational fluid dynamics were coupled to predict the structural and diffusive properties besides concentration profile inside the membrane. Diffusion coefficients of methanol and toluene were found to be 1.7 × 10 -9 and 1.8 × 10 -12  m 2 /s, respectively. The effect of crosslinking on process parameters such as flux and separation factor was analyzed. The study confirmed that increasing TEOS concentration reduced the methanol flux but enhanced separation factor with respect to this alcohol. The membranes exhibited a flux of 0.13 kg/m 2  h and separation factor of 58.4 for azeotropic feed composition of 68 wt% methanol., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz., methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively. Compound 11e exhibited potent PL inhibitory activity (IC 50 =4.81µM and X i50 =10.01, respectively in method A and B), comparable to that of the standard drug, orlistat (IC 50 =0.99µM and X i50 =3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking studies validated the rationale of pharmacophoric design and are in accordance to the in vitro results. Compound 11e exhibited a potential MolDock score of -153.349kcal/mol. Further, the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the hydrophobic lid domain. Moreover, the carbonyl group at 2 nd position of the TZD ring existed adjacent to Ser 152 (≈3Å) similar to that of orlistat. A 10ns molecular dynamics simulation of 11e-PL complex revealed a stable binding conformation of 11e in the active site of PL (Maximum RMSD≈3Å). The present study identified novel thiazolidinedione based leads with promising PL inhibitory activity. Further development of the leads might result in potent PL inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Submerged membrane bioreactor (SMBR) is a relatively advanced technology for waste water treatment that involves integrated aerobic and anaerobic biological processes with membrane filtration. In the present investigation, hydrophobic polyvinylidene fluoride (PVDF) and hydrophilic polyacrylonitrile (PAN) hollow fiber (HF) membranes were tested in an indigenously fabricated SMBR for dairy effluent treatment under aerobic conditions using mixed microbial consortia. Effect of operating parameters such as suction pressure, degree of aeration and trans-membrane pressure (TMP) on membrane performance in terms of flux, rejection of turbidity, BOD and COD besides fouling characteristics was investigated. The observed optimum permeabilities of PVDF and PAN HF membranes were approximately 108 and 115 LMH bar(-1) with high extent of impurity removal. The rejection of COD was found to be 93% for PVDF and 91% for PAN HF membranes whereas corresponding rejection of BOD was observed to be 92% and 86%. A two-dimensional comprehensive model was developed to predict the hydrodynamic profile inside the module. Regression analysis revealed that the simulation results agreed well with experimental data., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Based on the TAX 327 phase III trial, docetaxel-based chemotherapy is the standard first-line treatment for hormone-resistant prostate cancer (HRPC); however, there is some heterogeneity in the use of this agent in routine clinical practice. The aim of the present study was to examine the patterns of docetaxel use in routine clinical practice at our institution and to compare them with docetaxel use in the TAX 327 clinical trial., Methods: We conducted a retrospective chart review of HRPC patients treated with first-line docetaxel between 2005 and 2007 at the Princess Margaret Hospital., Results: In the first-line setting, 88 patients with HRPC received docetaxel. The main reasons for initiating docetaxel were rising prostate-specific antigen (PSA, 98%) and progressive symptoms (77%). The PSA response rate was 67%; median time to response was 1.5 months, and duration of response was 6.8 months. Median survival was 15.9 months (95% confidence interval: 12.4 to 20.5 months). Patients received a median of 7 cycles of treatment, and the main toxicities were fatigue (35%) and neuropathy (24%). Post docetaxel, 36 patients received second-line treatment with a 22% response rate., Conclusions: In routine clinical practice, HRPC patients received docetaxel mainly because of symptomatic disease progression. Overall response rates and toxicities were comparable to those in the TAX 327 trial. However, our patients received a median of only 7 cycles of treatment versus the 9.5 administered on trial, and survival was slightly shorter in our single-institution study. A larger prospective multicentre analysis, including performance status and quality-of-life parameters, may be warranted to determine if docetaxel performs as well in routine clinical practice as it does in the clinical trial setting.

Forty-nine patients with chronic left bundle branch block and a normal frontal axis were compared with 53 patients with left bundle branch block and left axis deviation. The following clinical variables were more frequent (P less than 0.05) in patients with left axis deviation: greater age, exertional angina, congestive heart failure, cardiomegaly, cardiac functional class II to IV, coronary artery disease and presence of organic heart disease. Absence of organic heart disease (primary conduction disease) was seen only in patients with a normal axis. Patients with left axis deviation had longer (P less than 0.05) mean P-R, A-H and H-V intervals and atrial and atrioventricular (A-V) nodal effective refractory periods. All patients were prospectifely followed up for 30 to 2,271 days with a mean +/- standard error of the mean follo-up period of 538 +/- 72 for the group with a normal axis and 604 +/- 72 days for the group with left axis deviation (difference not significant). A-V block developed in three patients (6 percent) with left axis deviation and in none of those with a normal axis. The cumulative 4 year mortality rate for the entire group approached 75 percent. The patients with left axis deviation had greater cardiovascular mortality (P less than 0.05). In conclusion, among patients with left bundle branch block, those with left axis deviation have a greater incidence of myocardial dysfunction, more advanced conduction desease and greater cardiovascular mortality than those with a normal axis.