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Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma
No full textNasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulktranscriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC. Copyright
From macro-, through meso- to micro-scale: Densification behavior, deformation response and microstructural evolution of selective laser melted Mg-RE alloy
No full textTo clarify the densification behavior, deformation response and strengthening mechanisms of selective laser melted (SLM) Mg-RE alloys, this study systematically investigates a representative WE43 alloy via advanced material characterization techniques. A suitable laser output mode fell into the transition mode, allowing for the fabrication of nearly full-density samples (porosity = 0.85 ± 0.021 %) with favorable mechanical properties (yield strength=351 MPa, ultimate tensile strength = 417 MPa, the elongation at break = 6.5 % and microhardness = 137.9 ± 6.15 HV0.1) using optimal processing parameters (P = 80 W, v = 250 mm/s and d = 50 µm). Viscoplastic self-consistent analysis and transmission electron microscopy observations reveal that the plastic deformation response of the SLM Mg-RE alloys is primarily driven by basal and prismatic slips. Starting from a random texture before deformation (maximum multiple of ultimate density, Max. MUD = 3.95), plastic stretching led the grains to align with the Z-axis, finally resulting in a {0001} texture orientation after fracture (Max. MUD = 8.755). Main phases of the SLM state are mainly composed of α-Mg, Mg24Y5 and β’-Mg41Nd5, with an average grain size of only 4.27 µm (about a quarter of that in the extruded state), resulting in a favorable strength-toughness ratio. Except for the nano-β’ phase and semi-coherent Mg24Y5 phase (mismatch = 16.12 %) around the grain boundaries, a small amount of nano-ZrO2 and Y2O3 particles also play a role in dispersion strengthening. The high mechanical properties of the SLM state are chiefly attributed to precipitation hardening (44.41 %), solid solution strengthening (34.06 %) and grain boundary strengthening (21.53 %), with precipitation hardening being predominantly driven by dislocation strengthening (67.77 %). High-performance SLM Mg-RE alloy components were manufactured and showcased at TCT Asia 2024, receiving favorable attention. This work underscores the significant application potential of SLM Mg-RE alloys and establishes a strong foundation for advancing their use in the biomedical fields.</p
Cannabis Use Disorder Emergency Department Visits and Hospitalizations and 5-Year Mortality
No full textImportance: Cannabis use disorders (CUD) are associated with adverse health effects, including mental disorders and motor vehicle collision-related injuries. However, little is known about whether CUDs are associated with increased mortality risk. Objective: To examine whether individuals receiving incident hospital-based care (an emergency department visit or hospitalization) for a CUD is associated with increased risk of death. Design, Setting, and Participants: This population-based retrospective cohort study included all individuals aged 15 to 105 years living in Ontario, Canada, between 2006 and 2021 (n = 11622571 individuals). Overall and cause-specific mortality were compared between individuals with incident hospital-based CUD care and age- and sex-matched members of the general population or individuals with hospital-based care for other substance use disorders using cause-specific hazard models adjusted for comorbid mental health, substance use, and chronic health conditions. Statistical analysis was performed from September to December 2024. Exposure: Incident hospital-based CUD care. Main Outcomes and Measures: Overall and cause-specific mortality identified using vital statistics. Results: The matched analysis included 527972 individuals (mean [SD] age, 29.9 [13.6] years; 330034 [62.5%] female) with a median (IQR) follow-up of 5 (3-9) years; 106994 had incident CUD. Within 5 years of incident hospital-based CUD care, 3770 individuals (3.5%) died compared with 3770 (0.6%) of matched general population members. After adjusting for comorbid conditions, individuals with incident hospital-based CUD care were at increased risk of death relative to the general population (adjusted hazard ratio [aHR], 2.79 [95% CI, 2.62-2.97]). Individuals with hospital-based CUD care were at increased risk of all investigated types of death and particularly elevated risk of death by suicide (aHR, 9.70 [95% CI, 6.04-15.57]), trauma (aHR, 4.55 [95% CI, 3.55-5.82]), opioid poisoning (aHR, 5.03 [95% CI, 2.86-8.84]), other drug poisonings (aHR, 4.56 [95% CI, 3.11-6.68]), and lung cancer (aHR, 3.81 [95% CI, 2.39-6.07]) relative to the general population. Compared with an individual with hospital-based care for CUD, individuals with hospital-based care for alcohol (aHR, 1.30 [95% CI, 1.26-1.34]), stimulants (aHR, 1.69 [95% CI, 1.62-1.75]), and opioids (aHR, 2.19 [95% CI, 2.10-2.27]) were at relatively increased risk of death within 5 years. Conclusions and Relevance: In this cohort study of all residents of Ontario, Canada, individuals with incident hospital-based CUD care were at markedly increased risk of death compared with the general population. These findings suggest important clinical and policy implications, given global trends toward cannabis legalization and market commercialization accompanied by increasing cannabis use and CUDs.</p
Laser powder bed fusion processed LaCe(Fe, Mn, Si)₁₃ lattices for magnetic refrigeration: Process optimization, microstructure, and magnetocaloric performance
No full textIn this study, the optimal laser powder bed fusion (LPBF) processing parameters for fabricating fully dense LaCe(Fe,Mn,Si)13 thin walls have been identified through a machine-learning approach based on the Gaussian process regression (GPR) model. All the specimens and components were fabricated using a continuous laser source. The relationship between the defect fraction of the fabricated thin wall and the line energy density (EL) and hatch (h) is established. The measured defect fraction of specimens fabricated using the validation data sets was very well in agreement with the predicted values of the GPR model, with an error of less than 1%. The microstructure of as-fabricated lattices is contained by α-Fe phases, LaFeSi phases, NaZn13-type phases, and the La/Ce/Si rich phases, which has an amorphous matrix embedded with nanocrystalline. The microstructure of the HTHed lattices presents the α-Fe phases, LaFeSi phases, and NaZn13-type phases. The diamond lattice has high heat exchange efficiency among the four lattices because of its large surface area (1577.1 mm2) and excellent thermal conductivity. Although the LPBF parameters are the same, the maximum isothermal magnetic entropy change (ΔSm) and Tc of the four samples differ. The X-ray powder diffraction test confirms that the HTHed Tube exhibits the highest volume of the NaZn13-type phase. The HTHed Tube saw ΔSm, about 1.63 J kg−1K−1 at 264.5 K. The ΔSm of HTHed Diamond around Tc (1.13 J kg−1K−1 at 219.5 K) is slightly higher than HTHed Gyroid (0.99 J kg−1K−1 at 250.5 K). Essentially, our work accelerates the search for optimal process parameters and guides the direction for lattice design of LaCe(Fe,Mn,Si)13.</p
Trifluridine/Tipiracil (FTD/TPI) in Metastatic Colorectal Cancer in Hong Kong: A Territory-Wide Cohort Study
No full textIntroduction: Randomized phase III trials showed that using trifluridine/tipiracil (FTD/TPI) in patients with pre-treated metastatic colorectal cancer (mCRC) conferred survival benefit versus placebo. Here, we investigated the effectiveness and safety of FTD/TPI and sought to identify prognostic factors among the mCRC population in Hong Kong. Methods: A non-interventional, retrospective, multicenter cohort study enrolled patients with mCRC who received FTD/TPI in seven public hospitals in Hong Kong between 2016 and 2020. Overall survival (OS) was the primary endpoint; treatment duration and occurrence of neutropenia were secondary endpoints. We also performed a post hoc analysis to identify factors influencing OS and treatment duration. Results: Overall, 456 patients were included (median age, 64.0 years; 57.5% men). Approximately half (225/456; 49.3%) had RAS wild-type tumors; the median treatment duration was 12.4 weeks (95% confidence interval [CI] 11.1–13.1). Median OS was 7.59 months (95% CI 7.00–8.21). Overall, 289 (63.4%) patients developed neutropenia of any grade and 159 (34.9%) developed grade ≥ 3 neutropenia. Neutropenia at 1 month occurred in 193 (43.1%) patients. The use of granulocyte colony-stimulating factor for neutropenia was reported for 42 (9.2%) patients. The development of neutropenia, absolute neutrophil count decrease of ≥ 2 grades in 1 month, absence of liver metastasis, and RAS wild-type status were associated with significantly longer OS and, except for RAS wild-type status (not analyzed), longer treatment duration (p < 0.05 for all comparisons). Conclusion: Our data show that treatment with FTD/TPI offers survival benefits in patients with refractory mCRC in Hong Kong consistent with randomized controlled trials and other real-world studies. Furthermore, the prognosis in patients receiving FTD/TPI appears to be significantly better in those who develop neutropenia, with RAS wild-type status, or those without liver metastases, despite a higher rate of dose reduction in the real-world setting.</p
Distinct moiré exciton dynamics in WS2/WSe2 heterostructure
No full textThis letter reports a time resolved pump-probe reflectance spectroscopic study on moiré excitons in a twisted monolayer WS2/WSe2 heterostructure. By probing at the resonant energies of intralayer excitons, we observed their distinct temporal tracks under the influence of interlayer excitons, which we attribute to the discrepancy in spatial distribution of the intralayer excitons in different layers. We also observed that intralayer moiré excitons in WSe2 layer differ at decay rate, which reflects different locations of Wannier-like and charge-transfer intralayer excitons in a moiré cell. We concluded that the interlayer moiré excitons form within a few picoseconds and have the lifetime exceeding five nanoseconds. Our results provide insights into the nature of moiré excitons and the strain’s significant impact on their behaviour in twisted heterostructures, which could have important implications for the development of novel optoelectronic devices.</p
Effect of bar diameter and cover thickness on bond behavior of steel bar in high-strength SHCC under pull-out condition: Experimental study and efficient finite element modeling
No full textEngineered/Strain-Hardening Cementitious Composites (ECC/SHCC) are highly attractive for tensile/shear-critical regions in reinforced concrete structures due to their high tensile ductility and excellent crack control capacity. To ensure effective stress transfer, a sufficient bond between steel bars and SHCC is crucial, particularly for high-strength SHCC. This study experimentally and numerically investigates the bond behavior between deformed steel reinforcing bars and high-strength SHCC through a direct pull-out approach. Steel bars with different diameters (D = 20/25/32 mm) and cover thicknesses (1D, 1.5D and 2D) were examined, with a fixed bond length of 4D. The block materials included conventional concrete and high-strength SHCC with compressive strength of 112 MPa, tensile strength of 8.6 MPa and tensile strain capacity >5 %. The findings demonstrated that SHCC can prevent the propagation of cracks, thereby maintaining the integrity of the bond. The bar diameter itself does not significantly affect the bond strength, while increasing the cover thickness from 1D to 2D effectively increases the peak loads and bond strength. A relatively simple but efficient finite element model was established, and the simulation showed good agreement with test results. These findings improve the understanding of bond characteristics of deformed steel bars with high-strength SHCC and facilitate the design of reinforced SHCC members.</p
Heterogeneous effects of telework on job satisfaction across gender and employment precarity: Evidence from postpandemic Japan
No full textScholars have long investigated the impact of flexible work arrangements (FWA) on job satisfaction. However, in recent years, many workplaces have abruptly introduced telework as a form of FWA in response to the COVID-19 pandemic, only to later call workers back to offices as the pandemic subsides. This trend is particularly prevalent in societies with inflexible work cultures like Japan. Nevertheless, we know little about how telework affects job satisfaction unequally among workers during and after the pandemic. Using the nationwide survey dataset collected by the Government of Japan’s Cabinet Office from 2020 to 2023, this study examines heterogeneous associations between telework and job satisfaction. Propensity score matching analyses based on the counterfactual framework show that the average effect of telework is substantially positive in both 2020 and 2023, but its magnitude decreases by over two-thirds during this period. Nonetheless, female nonregular workers experienced a larger psychological return on telework in 2023 despite its null effect in 2020. Male nonregular workers also see a high telework effect on job satisfaction in 2020 and 2023, whereas the effect size among their regular counterparts declines to near zero. These findings suggest that, in postpandemic Japan, (1) regular workers, particularly men, do not gain psychological benefits from telework under the traditional work culture requiring them to be present in the office, but (2) telework underpins job satisfaction of relatively precarious workers with less job security and benefits; and thus (3) the expanded usage of telework may help mitigate labor stratification in worker well-being.</p
Earthquake-related evacuation transportation: Insights from Kerman, Iran
No full textThe crowding aftermath of an earthquake adversely affect the operation of rescue teams, fuel consumption, delay, queuing, and post-disaster situations. In Kerman (Iran), 456 people were surveyed as part of the case study. First step, examines how different factors affect the decision to evacuate or stay in a building after an earthquake. A second phase is devoted to evaluate the voluntary evacuation travel behaviour. The two steps involve the use of random forest and structural equation modeling. The findings suggest that earthquake intensity, time of occurrence, the number of family members, and familiarity with neighborhood streets play a significant role in determining whether people will evacuate or not after an earthquake. For the travel characteristics associated with the voluntary evacuation, media impact, gender, family size, familiarity with neighborhood streets, traffic congestion on neighborhood streets, magnitude of the earthquake, and previous experiences all play a major role. Based on these findings, transport planners and city policy makers can make cities more resilient. Social media is a good tool for managing evacuation decision, while transport management strategies such as contraflow operations, signal coordination, transit operations, shoulder lane use, barricades, moveable barriers, and arrow boards are useful for neighborhoods with fewer tall buildings
Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma
No full textImmune checkpoint inhibitors are not effective for metabolic dysfunction-associated fatty liver disease (MAFLD)-hepatocellular carcinoma (HCC) patients, and identifying the key gut microbiota that contributes to immune resistance in these patients is crucial. Analysis using 16S rRNA sequencing reveals a decrease in Akkermansia muciniphila (Akk) during MAFLD-promoted HCC development. Administration of Akk ameliorates liver steatosis and effectively attenuates the tumor growth in orthotopic MAFLD-HCC mouse models. Akk repairs the intestinal lining, with a decrease in the serum lipopolysaccharide (LPS) and bile acid metabolites, along with decrease in the populations of monocytic myeloid-derived suppressor cells (m-MDSCs) and M2 macrophages. Akk in combination with PD1 treatment exerts maximal growth-suppressive effect in multiple MAFLD-HCC mouse models with increased infiltration and activation of T cells. Clinically, low Akk levels are correlated with PD1 resistance and poor progression-free survival. In conclusion, Akk is involved in the immune resistance of MAFLD-HCC and serves as a predictive biomarker for PD1 response in HCC