Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract

[[abstract]]Both gemcitabine and weekly 24-h infusion of high-dose 5-fluorouracil/leucovorin (HDFL) have shown promising antitumour activity for patients with locally advanced or metastatic carcinoma of the biliary tract (CBT). From April 1999 through December 2002, 30 patients with inoperable CBT were treated with gemcitabine 800 mg m(-2), intravenous infusion for 30 min, followed by 5-FU, 2000 mg m(-2) and leucovorin, 300 mg m(-2), intravenous infusion for 24 h, on day 1, 8 and 15, every 4 weeks. A total of 166 cycles were given (median of four cycles per patient, range 1-24 cycles). Response was evaluable in 28 patients and toxicity in 29 patients. Partial response was obtained in six patients, stable disease in 13, while progressive disease occurred in nine. The objective response rate was 21.4% (95% CI: 5.2-37.6%). The most common grade 3 or 4 toxicity was infection (nine patients). Other types of grade 3 or 4 toxicity included leucopenia (four patients), thrombocytopenia (three patients), anaemia (three patients), nausea/vomiting (two patients) and elevation of liver transaminases (three patients). As of 30 September 2003, the median progression-free survival was 3.7 months (95% CI: 2.8-4.6 months) and the median overall survival was 4.7 months (95% CI: 0.8-8.6 months). Our data suggest that weekly gemcitabine plus HDFL is modestly active with acceptable treatment-related toxicity for patients with advanced CBT

Effect of plasma shaping on performance in the National Spherical Torus Experiment

The National Spherical Torus Experiment (NSTX) has explored the effects of shaping on plasma performance as determined by many diverse topics including the stability of global magnetohydrodynamic (MHD) modes (e.g., ideal external kinks and resistive wall modes), edge localized modes (ELMs), bootstrap current drive, divertor flux expansion, and heat transport. Improved shaping capability has been crucial to achieving Βt ∼40%. Precise plasma shape control has been achieved on NSTX using real-time equilibrium reconstruction. NSTX has simultaneously achieved elongation κ∼2.8 and triangularity δ∼0.8. Ideal MHD theory predicts increased stability at high values of shaping factor S≡ q95 Ip (a Bt), which has been observed at large values of the S∼37 [MA (m·T)] on NSTX. The behavior of ELMs is observed to depend on plasma shape. A description of the ELM regimes attained as shape is varied will be presented. Increased shaping is predicted to increase the bootstrap fraction at fixed Ip. The achievement of strong shaping has enabled operation with 1 s pulses with Ip =1 MA, and for 1.6 s for Ip =700 kA. Analysis of the noninductive current fraction as well as empirical analysis of the achievable plasma pulse length as elongation is varied will be presented. Data are presented showing a reduction in peak divertor heat load due to increasing in flux expansion. © 2006 American Institute of Physics

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD

Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology

Latent class analysis of sexual health markers among men and women participating in a British probability sample survey.

BACKGROUND: Despite known associations between different aspects of sexual health, it is not clear how patterning of adverse sexual health varies across the general population. A better understanding should contribute towards more effective problem identification, prevention and treatment. We sought to identify different clusters of sexual health markers in a general population, along with their socio-demographic, health and lifestyle correlates. METHODS: Data came from men (N = 5113) and women (N = 7019) aged 16-74 who reported partnered sexual activity in the past year in Britain's third National Survey of Sexual Attitudes and Lifestyles, undertaken in 2010-2012. Latent class analysis used 18 self-reported variables relating to adverse sexual health outcomes (STI and unplanned pregnancy, non-volitional sex, and sexual function problems). Correlates included socio-demographics, early debut, alcohol/drug use, depression, and satisfaction/distress with sex life. RESULTS: Four classes were found for men (labelled Good Sexual Health 83%, Wary Risk-takers 4%, Unwary Risk-takers 4%, Sexual Function Problems 9%); six for women (Good Sexual Health 52%, Wary Risk-takers 2%, Unwary Risk-takers 7%, Low Interest 29%, Sexual Function Problems 7%, Highly Vulnerable 2%). Regardless of gender, Unwary Risk-takers reported lower STI/HIV risk perception and more condomless sex than Wary Risk-takers, but both were more likely to report STI diagnosis than Good Sexual Health classes. Highly Vulnerable women reported abortion, STIs and functional problems, and more sexual coercion than other women. Distinct socio-demographic profiles differentiated higher-risk classes from Good Sexual Health classes, with depression, alcohol/drug use, and early sexual debut widely-shared correlates of higher-risk classes. Females in higher-risk classes, and men with functional problems, evaluated their sex lives more negatively than those with Good Sexual Health. CONCLUSIONS: A greater prevalence and diversity of poor sexual health appears to exist among women than men in Britain, with more consistent effects on women's subjective sexual well-being. Shared health and lifestyle characteristics of higher-risk groups suggest widespread benefits of upstream interventions. Several groups could benefit from tailored interventions: men and women who underestimate their STI/HIV risk exposure, women distressed by low interest in sex, and women experiencing multiple adverse outcomes. Distinctive socio-demographic profiles should assist with identification and targeting