Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis

Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log10 CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log10 CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log10 CFU/g, while the burdens were 4.64, 7.16, and 1.44 log10 CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was -0.66 log10 CFU/mL/day, decreasing from an average of 4.75 log10 CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of -0.4 log10 CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (-0.33 log10 CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC0-24) of 25 to 50 mg · h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM. IMPORTANCE Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Here, we demonstrated the efficacy of APX2039, the second member of the gepix class, in rabbit and mouse models of cryptococcal meningitis. We also analyzed the drug levels in the blood and cerebrospinal fluid in the highly predictive rabbit model and built a mathematical model to describe the behavior of the drug with respect to the elimination of the fungal pathogen. We demonstrated that the oral administration of APX2039 resulted in a rapid decrease in the CSF fungal burden, with an effective fungicidal activity of -0.66 log10 CFU/mL/day, comparing favorably with good clinical outcomes in humans associated with reductions of -0.4 log10 CFU/mL/day. The drug APX2039 had good penetration of the central nervous system and is an excellent candidate for future clinical testing in humans for the treatment of CM

Selection of the silicon sensor thickness for the Phase-2 upgrade of the CMS Outer Tracker

During the operation of the CMS experiment at the High-Luminosity LHC the silicon sensors of the Phase-2 Outer Tracker will be exposed to radiation levels that could potentially deteriorate their performance. Previous studies had determined that planar float zone silicon with n-doped strips on a p-doped substrate was preferred over p-doped strips on an n-doped substrate. The last step in evaluating the optimal design for the mass production of about 200 m$^{2}$ of silicon sensors was to compare sensors of baseline thickness (about 300 μm) to thinned sensors (about 240 μm), which promised several benefits at high radiation levels because of the higher electric fields at the same bias voltage. This study provides a direct comparison of these two thicknesses in terms of sensor characteristics as well as charge collection and hit efficiency for fluences up to 1.5 × 10$^{15}$ n$_{eq}$/cm$^{2}$. The measurement results demonstrate that sensors with about 300 μm thickness will ensure excellent tracking performance even at the highest considered fluence levels expected for the Phase-2 Outer Tracker

The CMS Phase-1 pixel detector upgrade

The CMS detector at the CERN LHC features a silicon pixel detector as its innermost subdetector. The original CMS pixel detector has been replaced with an upgraded pixel system (CMS Phase-1 pixel detector) in the extended year-end technical stop of the LHC in 2016/2017. The upgraded CMS pixel detector is designed to cope with the higher instantaneous luminosities that have been achieved by the LHC after the upgrades to the accelerator during the first long shutdown in 2013–2014. Compared to the original pixel detector, the upgraded detector has a better tracking performance and lower mass with four barrel layers and three endcap disks on each side to provide hit coverage up to an absolute value of pseudorapidity of 2.5. This paper describes the design and construction of the CMS Phase-1 pixel detector as well as its performance from commissioning to early operation in collision data-taking.Peer reviewe

YOU'RE FAT. HOW'S THAT MY PROBLEM? PREDICTING THE LIFETIME 3RD PARTY DIRECT COSTS OF OBESITY AMONG LATE ADOLESCENT MINORITIES WITH A RACE-SPECIFIC AGE-RELATED WEIGHT GAIN CURVE

There exists enormous variation in estimates of the lifetime cost of obesity by race. In order to justify policy measures to reduce obesity rates nationally, we must first discern the cost of doing nothing, so this question remains imperative and unresolved. Although several researchers have sought to quantify obesity’s true cost stratified by race, none have produced a race-specific age-related weight gain curve, a vital component in producing an accurate estimate. This paper employs a Markov model of BMI category state changes separately for black and white males and females from ages 18 to 75 applied to updated estimates of obesity’s costs and effect on mortality to quantify the median lifetime cost of obesity at age 18. It finds lower lifetime costs than previously, due largely to the staggering gain in weight among normal weight individuals, particularly among black males, that occurs in early adulthood

Supplementary Data from: Responsible antibiotic use labeling and consumers’ willingness to buy and pay for fluid milk

These files contain data along supporting all results reported in Schell et al 2021 Responsible antibiotic use labeling and consumers’ willingness to buy and pay for fluid milk.This study was supported by USDA-NIFA’ Federal Formula Funds under Accession # 1014331 and Multistate Research Funds accession number #1016738 awarded to Renata Ivanek

ERCC1 and RRM1 in the International Adjuvant Lung Trial by Automated Quantitative in Situ Analysis

The excision repair cross completing group 1 gene product (ERCC1) and the regulatory subunit of ribonucleotide reductase (RRM1) have been reported as being prognostic of outcome and predictive of therapeutic efficacy in patients with non–small cell lung cancer. Routinely processed surgical specimens from 784 patients from the International Adjuvant Lung Trial were arrayed as tissue microarrays. In situ protein levels were scored with an automated, quantitative analysis system, dichotomized into high and low marker categories, and analyzed for associations with patients' characteristics, survival, and benefit from adjuvant chemotherapy. Scores for both markers were significantly associated with contributing center (P < 0.001) and skewed, with the bulk of scores being low. High scores were more frequent in women for ERCC1 and RRM1 and in older patients and those with adenocarcinoma for RRM1. Low ERCC1 scores indicated significant benefit from adjuvant chemotherapy [hazard ratio (HR) = 0.73 for chemotherapy versus control, P = 0.02]. Although all other survival associations were not statistically significant, low RRM1 scores trended to indicate benefit from adjuvant chemotherapy (HR = 0.84, P = 0.25), and ERCC1 scores were marginally prognostic of survival (HR = 0.77 for high versus low scores, P = 0.10). We conclude that contributing center and specimen quality substantially affect the levels of both markers. Future trials should incorporate the collection and processing of tumor specimens prospectively on standardized protocols to better reveal the impact of biomarkers on clinically relevant outcomes

The <i>Bal des Ardents</i> (1393), Thomas of Woodstock (1397) and Richard II (1400): Three Medieval Conspiracy Rumours and the Scots’ Mine Play (1608).

Assassination vehicles in Elizabethan and Jacobean tragedies sometimes involve meta-theatrical court festival massacres: court performances embedded within full-length drama, resulting in violent death or trauma to characters in the play. During his career as a playwright (c. 1600–08), John Marston pioneered the masquerade-within as a popular sub-category of court festival massacre. Were such underhand festival appropriations wholly inspired by stage precedents? Or did they also occur in real life? Whether its deaths were accidental or resulted from a botched assassination plot, the 1393 Bal des Ardents was hugely culturally and politically influential. Its continuing cultural afterlives bear witness to the geographical, chronological and social shockwaves of a medieval event whose impact illuminates the persistent collective trauma generated by extreme modern assassinations. My researches identify the conspiracy rumours encouraged in the wake of the 1393 Paris disaster and two English conspiracies of 1397 and 1400 linked to court festivals, as key to a fresh approach to the meta-theatrical court festival massacre, and to interpretation of two plays traditionally discussed together, which refer to these English conspiracies, Shakespeare’s Richard II and the anonymous Thomas of Woodstock. My analysis supports a post-Elizabethan dating of Woodstock, and encourages the hypothesis that it could be the so-called Scots’ Mine Play of 1608, the lost Jacobean play thought by some to have ended Marston’s career as a playwright