Thioamides antithyroid‐drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD‐induced agranulocytosis is important for clinical management. ...We performed a genome‐wide association study (GWAS) involving 20 patients with ATD‐induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single‐nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD‐induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8–103.7; P = 1.3 × 10‐24) and replication (OR = 37; 95% CI = 3.7–367.4; P = 9.6 × 10‐7). HLA‐B*38:02:01 was in complete linkage disequilibrium with rs185386680. High‐resolution HLA typing confirmed that HLA‐B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)‐induced agranulocytosis (OR = 265.5; 95% CI = 27.9–2528.0; P = 2.5 × 10‐14), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA‐B*38:02:01 in predicting CMZ/MMI‐induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
Background Current practice of adding concurrent–adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. ...However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. Methods Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m2) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m2) plus fluorouracil (1000 mg per m2 per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. Results The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). Conclusions Adding concurrent–adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.
The increasing severity of droughts/floods and worsening air quality from increasing aerosols in Asia monsoon regions are the two gravest threats facing over 60% of the world population living in ...Asian monsoon regions. These dual threats have fueled a large body of research in the last decade on the roles of aerosols in impacting Asian monsoon weather and climate. This paper provides a comprehensive review of studies on Asian aerosols, monsoons, and their interactions. The Asian monsoon region is a primary source of emissions of diverse species of aerosols from both anthropogenic and natural origins. The distributions of aerosol loading are strongly influenced by distinct weather and climatic regimes, which are, in turn, modulated by aerosol effects. On a continental scale, aerosols reduce surface insolation and weaken the land‐ocean thermal contrast, thus inhibiting the development of monsoons. Locally, aerosol radiative effects alter the thermodynamic stability and convective potential of the lower atmosphere leading to reduced temperatures, increased atmospheric stability, and weakened wind and atmospheric circulations. The atmospheric thermodynamic state, which determines the formation of clouds, convection, and precipitation, may also be altered by aerosols serving as cloud condensation nuclei or ice nuclei. Absorbing aerosols such as black carbon and desert dust in Asian monsoon regions may also induce dynamical feedback processes, leading to a strengthening of the early monsoon and affecting the subsequent evolution of the monsoon. Many mechanisms have been put forth regarding how aerosols modulate the amplitude, frequency, intensity, and phase of different monsoon climate variables. A wide range of theoretical, observational, and modeling findings on the Asian monsoon, aerosols, and their interactions are synthesized. A new paradigm is proposed on investigating aerosol‐monsoon interactions, in which natural aerosols such as desert dust, black carbon from biomass burning, and biogenic aerosols from vegetation are considered integral components of an intrinsic aerosol‐monsoon climate system, subject to external forcing of global warming, anthropogenic aerosols, and land use and change. Future research on aerosol‐monsoon interactions calls for an integrated approach and international collaborations based on long‐term sustained observations, process measurements, and improved models, as well as using observations to constrain model simulations and projections.
Key Points
The fast‐developing Asia has suffered severe air pollution problem
Aerosol affects the Asian monsoon
Aerosol‐monsoon interactions dictate the climate change in the region
Background
Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium‐derived thymic stromal lymphopoietin ...(TSLP), interleukin (IL)‐25, and IL‐33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma.
Methods
Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR‐mediated IL‐33, Il‐25, and TSLP synthesis and release.
Results
Primary bronchial epithelial cells exposed to DEP showed upregulation of IL‐33, IL‐25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL‐33, IL‐25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL‐33, IL‐25, and TSLP. These patients derived clinical benefit from anti‐IgE treatment.
Conclusion
Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL‐33, IL‐25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma.
Environmental diesel exhaust particles (DEP) exposed to airway epithelium ligate cytoplasmic aryl hydrocarbon receptor (AhR), translocate to the nucleus with aryl hydrocarbon receptor nuclear translocator (ARNT), and then transactivate IL‐33, Il‐25, and TSLP gene expression. Patients with high AhR nucleus translocation overexpressed IL‐33, Il‐25, and TSLP cytokines compared to those with low. Patients with high AhR nucleus translocation are more response to anti‐IgE therapy compared to those with low.
Highlights • The importance of patients' hand hygiene is increasingly recognized. • Directly observed patient hand hygiene for hospitalized patients is proposed. • Hand hygiene ambassadors are ...appointed to assist patient hand hygiene. • Ambassador-assisted patient hand hygiene achieves better compliance. • Empowerment of patients and ambassadors is equally important.
The density matrix quantum Monte Carlo (DMQMC) method is used to sample exact-on-average N-body density matrices for uniform electron gas systems of up to 10^{124} matrix elements via a stochastic ...solution of the Bloch equation. The results of these calculations resolve a current debate over the accuracy of the data used to parametrize finite-temperature density functionals. Exchange-correlation energies calculated using the real-space restricted path-integral formalism and the k-space configuration path-integral formalism disagree by up to ∼10% at certain reduced temperatures T/T_{F}≤0.5 and densities r_{s}≤1. Our calculations confirm the accuracy of the configuration path-integral Monte Carlo results available at high density and bridge the gap to lower densities, providing trustworthy data in the regime typical of planetary interiors and solids subject to laser irradiation. We demonstrate that the DMQMC method can calculate free energies directly and present exact free energies for T/T_{F}≥1 and r_{s}≤2.
The excellent cryogenic tensile properties of the CrMnFeCoNi alloy are generally caused by deformation twinning, which is difficult to achieve at room temperature because of insufficient stress for ...twinning. Here, we induced twinning at room temperature to improve the cryogenic tensile properties of the CrMnFeCoNi alloy. Considering grain size effects on the critical stress for twinning, twins were readily formed in the coarse microstructure by cold rolling without grain refinement by hot rolling. These twins were retained by partial recrystallization and played an important role in improving strength, allowing yield strengths approaching 1 GPa. The persistent elongation up to 46% as well as the tensile strength of 1.3 GPa are attributed to additional twinning in both recrystallized and non-recrystallization regions. Our results demonstrate that non-recrystallized grains, which are generally avoided in conventional alloys because of their deleterious effect on ductility, can be useful in achieving high-strength high-entropy alloys.
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