Reassessment of Progression-Free Survival as a Surrogate End Point of Overall Survival

Progression-free survival (PFS) has been increasingly used as a surrogate endpoint for overall survival (OS) by FDA in cancer drug approval. However, whether PFS can fully represent OS has remained uncertain. Breast cancer is the most prevalent cancer among females, and PFS has been the most common endpoint in drug approval trials for decades. Nevertheless, studies have shown conflicting results on whether PFS correlates with OS among subtypes of breast cancer and across different treatments. This study aims to reassess the correlation between PFS and OS in breast cancer, and evaluate under what circumstances can we consider using PFS as a surrogate of OS.Doctor of Pharmac

Beneficial Effect of Consecutive Screening Mammography Examinations on Mortality from Breast Cancer: A Prospective Study

BackgroundPreviously, the risk of death from breast cancer was analyzed for women participating versus those not participating in the last screening examination before breast cancer diagnosis. Consecutive attendance patterns may further refine estimates.PurposeTo estimate the effect of participation in successive mammographic screening examinations on breast cancer mortality.Materials and MethodsParticipation data for Swedish women eligible for screening mammography in nine counties from 1992 to 2016 were linked with data from registries and regional cancer centers for breast cancer diagnosis, cause, and date of death (Uppsala University ethics committee registration number: 2017/147). Incidence-based breast cancer mortality was calculated by whether the women had participated in the most recent screening examination prior to diagnosis only (intermittent participants), the penultimate screening examination only (lapsed participants), both examinations (serial participants), or neither examination (serial nonparticipants). Rates were analyzed with Poisson regression. We also analyzed incidence of breast cancers proving fatal within 10 years.ResultsData were available for a total average population of 549 091 women (average age, 58.9 years ± 6.7 [standard deviation]). The numbers of participants in the four groups were as follows: serial participants, 392 135; intermittent participants, 41 746; lapsed participants, 30 945; and serial nonparticipants, 84 265. Serial participants had a 49% lower risk of breast cancer mortality (relative risk [RR], 0.51; 95% CI: 0.48, 0.55; P P ConclusionWomen participating in the last two breast cancer screening examinations prior to breast cancer diagnosis had the largest reduction in breast cancer death. Missing either one of the last two examinations conferred a significantly higher risk.Published under a CC BY 4.0 license.</p

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

Predicting the depletion of antioxidants in high density polyethylene (HDPE) under sunlight using the reciprocity law

Depletion of antioxidants in HDPE subjected to sunlight exposure was studied. Sunlight radiation was simulated using a laboratory xenon light weatherometer at three irradiation levels. Oxidative induction time (OIT) test was performed on different layers along the thickness of the test coupons to establish the antioxidant depletion throughout the exposure duration. The highest drop in OIT was obtained for the surface layer facing the radiation, followed by the backside layer which was exposed to indirect radiation reflected from the wall of the weatherometer. The core section showed a slower decrease under the same exposure conditions. Furthermore, the OIT depletion rate in the surface layer increased with radiation intensity. The study proved that the sunlight degradation of the tested polyethylene can be accelerated by increasing the irradiation intensity based on the reciprocity law

Insider trading law enforcement and gross spreads of ADR IPOs

Using American Depositary Receipt (ADR) IPOs from 34 countries during 1980-2004, we find that, on average, the enforcement of insider trading laws reduces the underwriter gross spread by 49-61 basis points, which is about 10-12% of the average gross spread for ADR IPOs. This relation is present regardless of whether issuers have a prior listing or whether issuers are from developed or emerging markets. The association becomes stronger for ADRs underwritten by less prestigious underwriters and for issuers that are involved in privatization. The political institutions in the issuers' home markets also affect gross spreads.American Depositary Receipts (ADRs) Gross spread Insider trading law enforcement Political rights Legal origin

Sunlight Degradation of Polymeric Detectable Warning Surface Products

Detectable warning surface (DWS) is a panel product installed at the edge of curb ramps to warn visually impaired pedestrians about the proximity of the roadway. Most DWS products are made of polymers and are subjected to outdoor weathering. Therefore, sunlight degradation is an important factor that affects their service life. In this study, the effects of sunlight on material degradation in four DWS products made from polyester, neopentylglycol (NPG), polyurethane, and polyolefin were evaluated by exposing DWS test coupons in a xenon weatherometer. The exposure conditions were largely based on ASTM D 2565 for a duration of 3,000 h. Color change induced by radiation was measured using a spectro-colorimeter. The fastest discoloration was measured in DWS made from polyurethane. The largest color change occurred between 500 and 1,000 h for polyurethane and between 1,000 and 3,000 h for other polymers. The changes of surface appearance observed under a digital microscope were consistent with the discoloration. The reinforcing fibers in DWS products made from polyester and polyurethane were revealed after 3,000 h exposure. Decrease in surface wear resistance was obtained in tested coupons that were exposed to the highest irradiance level. The product made from NPG exhibited the greatest decrease in wear resistance, while that made from polyolefin showed the least change