The phase 1‐2 study CO‐338‐010 (Study 10; NCT01482715) is evaluating single‐agent rucaparib, a poly(ADP‐ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In ...the dose escalation phase (Part 1), we characterized the single‐dose and steady‐state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40‐500 mg; n = 16) or twice daily (BID; dose range, 240‐840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half‐life was approximately 17 hours, and median time to maximum concentration (tmax) ranged from 1.5 to 6.0 hours after a single dose and 1.5 to 4.0 hours following repeated dosing. The steady‐state accumulation ratio ranged from 1.60 to 2.33 following QD dosing and 1.47 to 5.44 following BID dosing. No effect of food on rucaparib pharmacokinetics was observed with a single dose of 40 mg (n = 3) or 300 mg (n = 6). In a phase 2 portion of the study (Part 3), the pharmacokinetic profile of rucaparib was further evaluated at the recommended phase 2 dose of 600 mg BID (n = 26). The mean (coefficient of variation) steady‐state maximum concentration (Cmax) and area under the concentration‐time curve from time zero to 12 hours (AUC0‐12h) were 1940 ng/mL (54%) and 16 900 ng ⋅ h/mL (54%), respectively. A high‐fat meal moderately increased rucaparib exposure. The fed‐to‐fasted geometric mean ratios (90% confidence interval CI) for AUC0‐24h and Cmax were 138% (117%‐162%) and 120% (99.1%‐146%); the median (90%CI) tmax delay was 2.5 (0.5‐4.4) hours.
Background Experimental studies have shown that vaccination can reduce viral replication to attenuate progression of influenza-associated lower respiratory tract illness (LRTI). However, clinical ...studies are conflicting, possibly due to use of non-specific outcomes reflecting a mix of large and small airway LRTI lacking specificity for acute lung or organ injury. Methods We developed a global ordinal scale to differentiate large and small airway LRTI in hospitalized adults with influenza using physiologic features and interventions (PFIs): vital signs, laboratory and radiographic findings, and clinical interventions. We reviewed the literature to identify common PFIs across 9 existing scales of pneumonia and sepsis severity. To characterize patients using this scale, we applied the scale to an antiviral clinical trial dataset where these PFIs were measured through routine clinical care in adults hospitalized with influenza-associated LRTI during the 2010–2013 seasons. Results We evaluated 12 clinical parameters among 1020 adults; 210 (21%) had laboratory-confirmed influenza, with a median severity score of 4.5 (interquartile range, 2–8). Among influenza cases, median age was 63 years, 20% were hospitalized in the prior 90 days, 50% had chronic obstructive pulmonary disease, and 22% had congestive heart failure. Primary influencers of higher score included pulmonary infiltrates on imaging (48.1%), heart rate ≥110 beats/minute (41.4%), oxygen saturation <93% (47.6%) and respiratory rate >24 breaths/minute (21.0%). Key PFIs distinguishing patients with severity < or ≥8 (upper quartile) included infiltrates (27.1% vs 90.0%), temperature ≥ 39.1°C or <36.0°C (7.1% vs 27.1%), respiratory rate >24 breaths/minute (7.9% vs 47.1%), heart rate ≥110 beats/minute (29.3% vs 65.7%), oxygen saturation <90% (14.3% vs 31.4%), white blood cell count >15,000 (5.0% vs 27.2%), and need for invasive or non-invasive mechanical ventilation (2.1% vs 15.7%). Conclusion We developed a scale in adults hospitalized with influenza-associated LRTI demonstrating a broad distribution of physiologic severity which may be useful for future studies evaluating the disease attenuating effects of influenza vaccination or other therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To identify the ability of multiple variables to predict prostate cancer specific mortality (PCSM) in a whole of population series of all radical prostatectomies (RP) performed in Victoria, ...Australia.
Materials & Methods
A total of 2154 open RPs were performed in Victoria between July 1995 and December 2000. Subjects without follow up data, Gleason grade, pathological stage were excluded as were those who had pT4 disease or received neoadjuvant treatment. 1967 cases (91.3% of total) met the inclusion criteria for this study. Tumour characteristics were collated via a central registry. We used competing hazards regression models to investigate associations.
Results
At median follow up of 10.3 years pT stage of RP (P < 0.001) and high Gleason score of the RP specimen (P < 0.001 for ≥8 Subhazard ratio (SHR) 11.19 and 4 + 3 = 7 SHR 7.10) compared with Gleason score 6 disease were strong predictors of progression to PCSM. Gleason score 3 + 4 = 7 was not at this time a significant predictor of PCSM (P = 0.08, SHR 1.84). Predictors of PCSM, independent of stage and grade, included rural residency (P = 0.003), primary surgeon contributing less than 40 cases (low‐volume) to the VRPR (P = 0.025) and the involvement of a trainee surgeon in the operation (P = 0.031).
Conclusion
The significant prediction of PCSM by pT cancer stage, Gleason score and primary Gleason pattern at RP in this whole of population study suggests a need to avoid understaging/grading in the process of cancer diagnosis and active surveillance protocols. Multi‐modality therapy is likely to have a greater impact on PCSM in higher stage and Gleason grade disease. Identification of increased PCSM with rural residency and with involvement of a trainee urologist, and reduction in PCSM with higher surgeon volume all suggest potential for improved PC outcomes to be achieved with changes to surgical training and service delivery.
Radiative transfer modelling of dust devils Mason, Jonathon P.; Patel, Manish R.; Lewis, Stephen R.
Icarus (New York, N.Y. 1962),
March 2013, 2013-03-00, 20130301, Letnik:
223, Številka:
1
Journal Article
Recenzirano
► We study light transmission through dust devils with a Monte Carlo scattering model. ► The scattered flux is highly dependent on the internal dust distribution. ► The direct flux is dependent on ...the total amount of dust present. ► A solar zenith angle bias acts on the asymmetry parameter in the scattered flux. ► Measurement of total and scattered flux is crucial for characterising dust devils.
Dust devils are particle laden convective vortices that form at the base of convective plumes. They are typically observed in dry desert climates on Earth and have been observed to form frequently on Mars. Meteorological measurements have also indicated that martian surface spacecraft have experienced numerous dust devil transits. To date, the characterisation of dust devils through the interpretation of spectral measurements of sunlight taken during a transit has yet to be investigated. Such measurements would provide valuable information of the physical size, dust load and internal structure of dust devils. A Monte Carlo Radiative Transfer (MCRT) model was developed to simulate the attenuation of sunlight through a dust devil and to investigate the observed spectral variation during such an event. The predicted transit signature resulting from a dust devil transit is highly dependent on the method of observation. The scattered light flux increases during the transit with the magnitude dependent on the dust concentration, making it sensitive to the internal dust distribution. This dependence is not observed for the total light flux which experiences a decrease and is strongly dependent on the total extinction through the vortex and insensitive to how the dust is distributed. The implication of this work is that separate in situ measurement of both the total and scattered flux is crucial for characterising dust devils and such measurements provide a powerful tool that could be exploited by future Mars missions.
BackgroundAdverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with ...improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order.MethodsWe analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity.Results295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions.ConclusionsPatients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab.Trial registration numbersNCT01772004 and NCT02155647.
More than a full Martian year of observations have now been made by the Nadir Occultation for MArs Discovery (NOMAD) instrument suite on-board the ExoMars Trace Gas Orbiter. Radiative transfer ...modeling of NOMAD observations taken in the nadir geometry enable the seasonal and global-scale variations of carbon monoxide gas in the Martian atmosphere to be characterized. These retrievals show the column-averaged volume mixing ratio of carbon monoxide to be about 800 ppmv, with significant variations at high latitudes caused by the condensation and sublimation of the background CO2 gas. Near summer solstice in each hemisphere, the CO volume mixing ratio falls to 400 ppmv in the south and 600 ppmv in the north. At low latitudes, carbon monoxide volume mixing ratio inversely follows the annual cycle of surface pressure. Comparison of our retrieved CO volume mixing ratio against that computed by the GEM-Mars general circulation model reveals a good match in their respective seasonal and spatial trends, and can provide insight into the physical processes that control the distribution of CO gas in the current Martian atmosphere.
•The global, seasonal distribution of CO gas is retrieved from NOMAD nadir observations.•Globally averaged CO abundance is ~800 ppm, but with strong seasonal variations.•GCM modeling can provide insight into physical processes behind retrieved abundances.
A new series of aurones 3a–x has been synthesized by aldol condensation of N-(Un)substituted quinolone-3-carbaldehydes 1a–h and (Un)substituted benzofuran-3(2H)-ones 2a–c in the presence of 10mol% ...NaOH in ethanol using a microwave irradiation method. All the aurone derivatives were screened for in vitro antimicrobial activity against a representative panel of bacterial and fungal pathogens using a broth microdilution method. The majority of the synthesized compounds elicited more or equipotent inhibitory action against all the tested bacterial and fungal strains. In vitro antioxidant activity was evaluated by the Ferric Reducing Antioxidant Power (FRAP) method. Compounds 3k and 3u displayed the highest antioxidant potential.
To evaluate the technical feasibility and safety of percutaneous endovascular thrombolysis for extremity deep venous thrombosis (DVT) in children < 24 months old.
A retrospective chart review of a ...clinical and imaging database was performed for pediatric patients who underwent endovascular therapy for DVT between January 2010 and July 2013. Indications, techniques, technical and clinical success, and complications were reviewed. Techniques for thrombolysis included catheter-directed therapy (CDT) using alteplase infusion via a multi-side hole catheter, mechanical thrombectomy, and angioplasty. Short-term outcomes were assessed using surgical and imaging follow-up examinations for patency of the targeted vessel. Patients included 11 children (mean age, 9 mo; range, 3 wk-23 mo) who consecutively underwent endovascular thrombolysis for upper extremity (n = 6) or lower extremity (n = 5) DVT. The most common indication was preservation of venous access for future cardiac surgery or medical therapy.
The most common risk factor was the presence of a central venous catheter (10 of 11 patients). All patients with upper extremity DVT had congenital heart disease. CDT and angioplasty were performed in all patients. Venous patency was established in all patients. A grade III (95%-100%) thrombolysis response was achieved in seven patients, and a grade II (50%-95%) thrombolysis response was achieved in four patients. A major complication of pulmonary embolism occurred in one patient with upper extremity thrombolysis and was managed by intravenous systemic alteplase and heparin. No recurrence of thrombosis was found on average follow-up of 11.8 months (range, 1-41 mo).
Percutaneous endovascular thrombolysis for extremity DVT is safe and technically feasible in children < 24 months old.
A library comprises diversely substituted novel 3,4′-bicarbostyril derivatives have been designed by molecular hybridization technique and synthesized via multi-component reaction . Compounds
G22
...(MIC = 12.5 µg/mL) and
G38
(MIC = 25 µg/mL) exhibited 99% inhibition against
Mycobacterium tuberculosis
, while compounds
G40
(IC
50
= 0.019 µg/mL) and
G20
(IC
50
= 0.028 µg/mL) found to have excellent activity against
Plasmodium falciparum
. Compounds
G37
(MIC = 25 µg/mL) and
G8
,
G18
, and
G38
(MIC = 50 µg/mL) elicited excellent antimicrobial activity compared to standard drugs. Biological results revealed that the potency of the title compounds strongly depends on the length and flexibility of various spacers at
N
−1, the electronic influence of substituent at R
1
and lipophilicity of CH
3
group at R
2
position on bicarbostyril system.
Graphical Abstract
Background
The Coronavirus disease of 2019 (COVID‐19) has impacted physician practices in many ways with some ENT clinics reporting around a 50% drop in completed scheduled ENT visits during the ...first wave of the pandemic compared to 2019.
Aims
This study surveyed first round PPP loan disbursement to otolaryngology practices in the United States in response to COVID‐19.
Methods
A cross‐sectional study was conducted using publicly available data published on PPP by the SBA. Otolaryngology clinics receiving loans greater than $0.15M were filtered using the following terms: “otolaryngology”, “otolaryngologist”,“sinus”, “head and neck”, “throat”, “ENT”, and “facial plastic”. 481 ENT clinics that received loans greater than $0.15 M from the Paycheck Protection Program (PPP) were identified. Loan amount, business type, geographicregion, owner race, owner gender, and the number of jobs per business were recorded for each clinic. Chi‐square analysis was performed to determine significance (P < 0.05) of each characteristic.
Results
Loan distribution was significantly different based on jobs reported (P < .001) and business type (P < .001). 100% of loans ranging from $0.15 M to $0.35 M went to micro and small practices whereas 33% of medium‐sized practices received loans greater than $1 M. Higher proportions of Subchapter corporations (60.00%) received smaller loans of $0.15 to $0.35 M than Limited Liability Companies (39.13%) and Corporations (51.69%) which generally employ more people.
Discussion
Loan distribution was significantly different between businesses based on jobs reported (P < 0.001), with micro/small practices recieving smaller loans than their medium counterparts. All large businesses recived loans in in excess of $2 M. This suggests proportional distribution of loans in accordance with jobs reported.
Conclusion
This study suggests PPP funding was objectively distributed to ENT clinics based on staff size.
Level of Evidence
Level 4.
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