Optimizing Management of Patients With Barrett's Esophagus and Low-Grade or No Dysplasia Based on Comparative Modeling

Background & Aims: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. Methods: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). Results: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling$5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to$17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio,$36,045/QALY). Conclusions: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women

Real-time online monitoring of insect cell proliferation and baculovirus infection using digital differential holographic microscopy and machine learning

Real-time, detailed online information on cell cultures is essential for understanding modern biopharmaceutical production processes. The determination of key parameters, such as cell density and viability, is usually based on the offline sampling of bioreactors. Gathering offline samples is invasive, has a low time resolution, and risks altering or contaminating the production process. In contrast, measuring process parameters online provides more safety for the process, has a high time resolution, and thus can aid in timely process control actions. We used online double differential digital holographic microscopy (D3HM) and machine learning to perform non-invasive online cell concentration and viability monitoring of insect cell cultures in bioreactors. The performance of D3HM and the machine learning model was tested for a selected variety of baculovirus constructs, products, and multiplicities of infection (MOI). The results show that with online holographic microscopy insect cell proliferation and baculovirus infection can be monitored effectively in real time with high resolution for a broad range of process parameters and baculovirus constructs. The high-resolution data generated by D3HM showed the exact moment of peak cell densities and temporary events caused by feeding. Furthermore, D3HM allowed us to obtain information on the state of the cell culture at the individual cell level. Combining this detailed, real-time information about cell cultures with methodical machine learning models can increase process understanding, aid in decision-making, and allow for timely process control actions during bioreactor production of recombinant proteins

Whole Earth Telescope observations of BPM 37093 : a seismological test of crystallization theory in white dwarfs

BPM 37093 is the only hydrogen-atmosphere white dwarf currently known which has sufficient mass (~1.1 Mʘ) to theoretically crystallize while still inside the ZZ Ceti instability strip (Teff ~ 12 000 K). As a consequence, this star represents our first opportunity to test crystallization theory directly. If the core is substantially crystallized, then the inner boundary for each pulsation mode will be located at the top of the solid core rather than at the center of the star, affecting mainly the average period spacing. This is distinct from the “mode trapping” caused by the stratified surface layers, which modifies the pulsation periods more selectively. In this paper we report on Whole Earth Telescope observations of BPM 37093 obtained in 1998 and 1999. Based on a simple analysis of the average period spacing we conclude that a large fraction of the total stellar mass is likely to be crystallized

Whole Earth Telescope observations of BPM 37093 : a seismological test of crystallization theory in white dwarfs

BPM 37093 is the only hydrogen-atmosphere white dwarf currently known which has sufficient mass (~1.1 Mʘ) to theoretically crystallize while still inside the ZZ Ceti instability strip (Teff ~ 12 000 K). As a consequence, this star represents our first opportunity to test crystallization theory directly. If the core is substantially crystallized, then the inner boundary for each pulsation mode will be located at the top of the solid core rather than at the center of the star, affecting mainly the average period spacing. This is distinct from the “mode trapping” caused by the stratified surface layers, which modifies the pulsation periods more selectively. In this paper we report on Whole Earth Telescope observations of BPM 37093 obtained in 1998 and 1999. Based on a simple analysis of the average period spacing we conclude that a large fraction of the total stellar mass is likely to be crystallized

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology