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The remote forcing from land surface changes in the Sahara is hypothesized to play a pivotal role in modulating the intensity of the East Asian summer monsoon (EASM) through ocean-atmospheric teleconnections. This modu-lation has far-reaching consequences, particularly in facilitating societal shifts documented in northern China. Here, we present a well-dated lake-level record from the Daihai Lake Basin in northern China, providing quantitative assessments of Holocene monsoonal precipitation and the consequent mi-grations of the northern boundary of the EASM. Our reconstruction, informed by a water-and-energy balance model, indicates that annual precipitation reached -700 mm during 8-5 ka, followed by a rapid decline to -550 mm be-tween 5 and 4 ka. This shift coherently aligns with a significant -300 km northwestward movement of the EASM northern boundary during the Middle Holocene (MH), in contrast to its current position. Our findings underscore that these changes cannot be entirely attributed to orbital forcing, as corrob-orated by simulation tests. Climate model simulations deployed in our study suggest that the presence of the Green Sahara during the MH significantly strengthened the EASM and led to a northward shift of the monsoon rainfall belt. Conversely, the Sahara's reversion to a desert landscape in the late Ho-locene was accompanied by a corresponding southward retraction of monsoon influence. These dramatic hydroclimate changes during -5-4 ka likely triggered or at least contributed to a shift in Neolithic cultures and societal transformation in northern China. With decreasing agricultural pro-ductivity, communities transitioned from millet farming to a mixed rainfed agriculture and animal husbandry system. Thus, our findings elucidate not only the variability of the EASM but also the profound implications of a remote forcing, such as surface transformations of the Sahara, on climatic changes and cultural evolution in northern China.

Objective: There is limited study from low-and-middle income countries on the effect of perinatal exposure to air pollution and the risk of infection in infant. We assessed the association between perinatal exposure to traffic related air pollution and the risk of infection in infant during their first six months of life. Methods: A prospective cohort study was performed in Jakarta, March 2016–September 2020 among 298 mother-infant pairs. PM2.5, soot, NOx, and NO2 concentrations were assessed using land use regression models (LUR) at individual level. Repeated interviewer-administered questionnaires were used to obtain data on infection at 1, 2, 4 and 6 months of age. The infections were categorized as upper respiratory tract (runny nose, cough, wheezing or shortness of breath), lower respiratory tract (pneumonia, bronchiolitis) or gastrointestinal tract infection. Logistic regression models adjusted for covariates were used to assess the association between perinatal exposure to air pollution and the risk of infection in the first six months of life. Results: The average concentrations of PM2.5 and NO2 were much higher than the WHO recommended levels. Upper respiratory tract infections (URTI) were much more common in the first six months of life than diagnosed lower respiratory tract or gastro-intestinal infections (35.6%, 3.5% and 5.8% respectively). Perinatal exposure to PM2.5 and soot suggested increase cumulative risk of upper respiratory tract infection (URTI) in the first 6 months of life per IQR increase with adjusted OR of 1.50 (95% CI 0.91; 2.47) and 1.14 (95% CI 0.79; 1.64), respectively. Soot was significantly associated with the risk of URTI at 4–6 months age interval (aOR of 1.45, 95%CI 1.02; 2.09). All air pollutants were also positively associated with lower respiratory tract infection, but all CIs include unity because of relatively small samples. Adjusted odds ratios for gastroint

It is unclear whether cancers of the upper aerodigestive tract (UADT) and gastric cancer are related to air pollution, due to few studies with inconsistent results. The effects of particulate matter (PM) may vary across locations due to different source contributions and related PM compositions, and it is not clear which PM constituents/sources are most relevant from a consideration of overall mass concentration alone. We therefore investigated the association of UADT and gastric cancers with PM 2.5 elemental constituents and sources components indicative of different sources within a large multicentre population based epidemiological study. Cohorts with at least 10 cases per cohort led to ten and eight cohorts from five countries contributing to UADT- and gastric cancer analysis, respectively. Outcome ascertainment was based on cancer registry data or data of comparable quality. We assigned home address exposure to eight elemental constituents (Cu, Fe, K, Ni, S, Si, V and Zn) estimated from Europe-wide exposure models, and five source components identified by absolute principal component analysis (APCA). Cox regression models were run with age as time scale, stratified for sex and cohort and adjusted for relevant individual and neighbourhood level confounders. We observed 1139 UADT and 872 gastric cancer cases during a mean follow-up of 18.3 and 18.5 years, respectively. UADT cancer incidence was associated with all constituents except K in single element analyses. After adjustment for NO 2, only Ni and V remained associated with UADT. Residual oil combustion and traffic source components were associated with UADT cancer persisting in the multiple source model. No associations were found for any of the elements or source components and gastric cancer incidence. Our results indicate an association of several PM constituents indicative of different sources with UADT but not gastric cancer incidence with the most robust evidence for traffic and residual oil combust

Meng Wei,1,2,* Xiaobo Wang,1,2,* Yunhai Mo,1,2,* Cunqing Kong,3 Mengqi Zhang,2,4 Guanhua Qiu,2,5 Zhihong Tang,1,2 Jie Chen,1,2 Feixiang Wu1,2 1Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 2Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education/Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, 530021, People’s Republic of China; 3Medical Imaging Center, Affiliated Taihe Hospital, Hubei University of Medicine, Hubei, 442000, People’s Republic of China; 4Department of Interventional Therapy, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 5Department of Ultrasound, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Chen; Feixiang Wu, Email jiechen185@163.com; wufx2013@163.comIntroduction: Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth.Methods: We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (I

Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption, allowing for longer treatment intervals similar to intravenous immunoglobulin (up to once monthly). fSCIG 10% is indicated in the USA for treating adults and children aged ≥ 2 years with primary immunodeficiency diseases (PIDs). This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from November 2015 to October 2021 to assess the long-term safety of fSCIG 10% in routine clinical practice. Patients with PIDs aged ≥ 16 years who were prescribed and/or had started fSCIG 10% treatment were enrolled. In total, 253 patients were enrolled and included (full analysis set). Participants received fSCIG 10% treatment for a median (interquartile range) of 10.0 (3.5-11.8) months, with the majority of infusions administered every 4 weeks (54.4% [1197/2201 infusions]) and at home (62.6% [1395/2230 infusions]). Overall, 98.5% of infusions were administered without rate reduction, interruption, or discontinuation due to adverse events (AEs). Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Development of antibodies against rHuPH20 was uncommon; 14/196 patients (7.1%) tested positive for binding antibodies (titer ≥ 1:160) with no neutralizing antibodies detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated self-administration of fSCIG 10% was well tolerated in US clinical practice by patients with PIDs.

Accurate positioning in space is an important foundation for ensuring the stability of autonomous flight and successful mapping and navigation of unmanned aerial vehicles (UAVs). At present, the SLAM algorithm based on the Cartographer algorithm for real-time positioning and mapping is widely used in fields such as robot navigation and autonomous driving. However, in the context of UAV applications, this algorithm has a high dependence on the amount of point cloud information in the surrounding environment, and cannot achieve precise positioning in open spaces with insufficient lighting and fewer feature points, resulting in significant mapping errors. In order to solve the problem of low positioning estimation accuracy in the Cartographer algorithm in above environment, this paper proposes a precise positioning algorithm for UAVs that integrates VIO and Cartographer. This algorithm can continuously output more accurate position estimation information during UAV flight, compensating for the problem of inaccurate position estimation caused by partial feature loss or coordinate system drift in point clouds. In addition, this algorithm ensures navigation obstacle avoidance in narrow spaces by improving positioning accuracy and mapping accuracy, making it more applicable in the field of UAVs. Finally, the effectiveness of the proposed positioning algorithm was verified through experimental analysis of the Cartographer dataset and practical testing of UAVs in real scenarios.

Chromatin marks are associated with transcriptional regulatory activities. However, very few lncRNAs have been characterized with the role in regulating epigenetic marks, largely due to the technical difficulty in identifying chromatin-associating RNA. Current methods are largely limited by the availability of ChIP-grade antibody and the crosslinking, which generates high noise. Here, we developed a method termed Chrom-seq to efficiently capture RNAs associated with various chromatin marks in living cells. Chrom-seq jointly applies highly specific chromatin mark reader with APEX2, which catalyzes the oxidation of biotin-aniline to label the adjacent RNAs for isolation by streptavidin-coated beads. Using the readers of mCBX7/dPC, mCBX1, and mTAF3, we detected RNA species significantly associated with H3K27me3, H3K9me3, and H3K4me3, respectively. We demonstrated that Chrom-seq outperformed other equivalent methods in terms of sensitivity, efficiency, and cost of practice. It provides an antibody-free approach to systematically map RNAs at chromatin marks with potential regulatory roles in epigenetic events.

BACKGROUND: The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. METHODS: We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. RESULTS: We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01x10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. CONCLUSIONS: Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smok

The control of the polymer structure is a pivotal factor in imparting a wide range of desirable properties to polymers. However, existing methods often entail harsh conditions and laborious procedures. In this study, we demonstrate that solvent and water play a crucial role in the facile regulation of cyclic imidazolidine and linear dienamine units in the polymer chains produced by the facile polymerization of imidazolines and ester alkynes, which was triggered by the spontaneous imine-yne click reaction. Notably, when carried out in acetonitrile, the yielded polymers predominantly feature cyclic imidazolidine structures (up to 96%), whereas those synthesized in chloroform in the presence of water are predominantly characterized by linear dienamine structures (up to 91%). These structural variances give rise to diverse properties in the polymers, including variations in glass transition temperatures, Raman signals, nontraditional luminescence, refractive indices, etc. Moreover, the reaction mechanism was unambiguously proposed based on model reaction studies, shedding light on the underlying chemical processes driving these distinct results. The ability to control polymer structure through solvents and water offers a promising avenue for tailoring polymer properties, unlocking new opportunities for advanced materials design. © 2024 American Chemical Society.

Fire hazards are a primary concern in aircraft accidents, and controlling combustible materials is pivotal in managing cabin fire risks. This work aims to elucidate the impact of widespread measures that introduce phosphorus-based flame retardants (PFRs) on the fire safety of carbon fiber epoxy composites (CF/EP). Firstly, the hazardous indicators for flame retardant CF/EP composites exhibit two categories of optimization and degradation, which are caused by the intrinsic feature, pyrolysis characteristics and chemical valence states of PFRs. Secondly, the fire hazards of composites are assessed by fusing the analytic network process and information weights guided by Nash Equilibrium theory. The method combines the merits of subjective and objective weights from dimensions of intrinsic hazards, interrelationships and data dispersion of indicators. Finally, the assessed fire hazard rankings under 35 and 65 kW/m2 both are EP > CF/EP16%DOPO-HQ > CF/EP > CF/EP7%DPO. In conclusion, DOPO-HQ (+1) primarily increases the fire hazard of CF/EP due to gas-phase flame-retardant effects, while DPO (+3) predominantly reduces the fire hazard of CF/EP by contributing to condensed-phase effects. This work highlights the contradictory effects of PFRs on the fire safety of CF/EP composites due to structure and thermal stability. The proposed ANP and IW hybridization method provides a theoretical foundation for selecting flame retardants and assessing material fire hazards comprehensively. © 2024 Elsevier Ltd

Data augmentation algorithms, such as back translation, have shown to be effective in various deep-learning tasks. Despite their remarkable success, there has been a hurdle to applying data augmentation algorithms to code-related tasks since code consists of discrete tokens with uniqueness and certainty. In this work, we propose FeaMix, a novel yet simple data augmentation approach designed for the feature mix with memory batch based on self-consistency learning. FeaMix has a couple of uniqueness. First, it specially selects the samples to be mixed by memory batch to guarantee that the generated features are in the same spatial distribution as the mixed features. Second, it extends the self-consistency learning technique to optimize the language model for code-related tasks. With extensive experiments, we empirically validate that our method outperforms several baseline models and traditional data augmentation methods on code generation and code translation. It is noteworthy that we achieve state-of-the-art results in the CoNaLa and CodeTrans benchmarks, with a significant improvement of 1.9% in the Exact Match accuracy metric for code translation tasks. IEEE

To generate dance that temporally and aesthetically matches the music is a challenging problem in three aspects. First, the generated motion should be beats-aligned to the local musical features. Second, the global aesthetic style should be matched between motion and music. And third, the generated motion should be diverse and non-self-repeating. To address these challenges, we propose ReChoreoNet, which re-choreographs high-quality dance motion for a given piece of music. A data-driven learning strategy is proposed to efficiently correlate the temporal connections between music and motion in a progressively learned cross-modality embedding space. The beats-aligned content motion will be subsequently used as autoregressive context and control signal to control a normalizing-flow model, which transfers the style of a prototype motion to the final generated dance. In addition, we present an aesthetically labelled music-dance repertoire (MDR) for both efficient learning of the cross-modality embedding, and understanding of the aesthetic connections between music and motion. We demonstrate that our repertoire-based framework is robustly extensible in both content and style. Both quantitative and qualitative experiments have been carried out to validate the efficiency of our proposed model. © Institute of Automation, Chinese Academy of Sciences and Springer-Verlag GmbH Germany, part of Springer Nature 2024.

Distribution of shrubs expanding in grasslands – shrubification – is ongoing worldwide in grasslands and is common on the Qinghai–Tibetan Plateau (QTP). But the consequences of shrubification for plant carbon (C) input and fate in soil are unclear. We used 13C pulse labelling in a meadow on the QTP to compare photosynthetic capacity and photosynthate distribution in shoots, roots, soil and microbial functional groups between herbaceous plants (herbs) and shrubby Potentilla fruticosa. During 3 h of labeling in 13CO2 atmosphere, the 13C amount assimilated by shrubs (0.81 g C/m−2) was only 38 % of that by herbs. Over 8 days after labeling, 13C amount respired jointly by roots and soil microorganisms under shrubs (0.049 g m−2) was less than half of that under herbs. The mean residence time of 13C for respiration jointly by roots and rhizosphere microorganisms was longer under shrubs (0.61 day) than under herbs (0.44 day). Within 22 days after labelling, 13C amounts in roots, soil, and microorganisms were consistently smaller under shrubs than those under herbs. Consequently, shrub P. fruticosa had not only smaller photosynthetic potential, but also allocated less photosynthate belowground and slowed down C cycling in soil compared with herbs. The distribution of total 13C in microbial functional groups indicated by PLFA analysis was similar between herbs and shrubs. Averaged over vegetation patch types, gram negative bacteria and AMF accounted for 22 % and 4 % of the total microbial PLFAs in the 0–20 cm, respectively, but these two functional groups took up 51 % and 23 % of the total 13C absorbed by microorganisms, respectively. This indicates that gram negative bacteria and AMF are major consumers of rhizodeposits. Concluding, shrubification leads to smaller C allocation belowground and slows down C cycling in the soil.

Variable-frequency air injection and extraction is critical for salt cavern compressed air energy storage (CAES) power plants to smoothly integrate electricity into the power grid, and the magnitude of its effect on the mechanical properties and damage progression of the salt cavern surrounding rock determines the operation scheme of CAES power plants. To examine the impact of variable frequency, a series of monotonic loading tests with different rates and variable-frequency fatigue (VFF) tests with different upper limit stresses were carried out. Dilatancy stresses have a positive power function relationship with loading rate and frequency, but the fatigue loading process weakens this nonlinear tendency. The rate of change (CR) or the exponent of the fitted function can express it. From the initial stage to the steady stage, the CR of dilatancy stress increases about three times, and the CR of residual volumetric strain decreases about five to eight times. Increased upper-limit stress weakens this trend of change. Both high speed and high-frequency loading shift the damage acceleration point forward (e.g., b value accelerates earlier). The damage rate correlation is significant in the later stages of the VFF tests, the rate correlation of damage is significant. Both the upper stress and the extension of the main fracture zone enhance the rate dependence of fracture types. Moreover, the effect of rate on crystal penetrating cracks is more pronounced in the high-stress interval. The number of fractures significantly affects the dilatancy, rather than the type of fracture. This study serves as a guide for the design of variable frequency programs in different CAES salt cavern operation stages, as well as subsequent research., Funder: National Natural Science Fund of China (No. 52274073, 51834003); China Postdoctoral Science Foundation (No. 2023M730427); Chongqing Postdoctoral Research Project (No. 2023CQBSHTB3139);Fulltext license: CC BY

BACKGROUND: The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. METHODS: We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. RESULTS: We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01x10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. CONCLUSIONS: Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smok

Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. Methods: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. Results: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Lowdensity lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. 1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. Conclusion: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 x 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. Findings: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. Interpretation: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal disea

Background Coeliac disease (CeD) has been associated with a broad range of diseases in observational data; however, whether these associations are causal remains undetermined. We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to investigate the comorbidities of CeD. Methods Single nucleotide polymorphisms (SNPs) associated with CeD at the genome-wide significance threshold and without linkage disequilibrium (R2 <0.001) were selected from a genome-wide association study including 12,041 CeD cases as the instrumental variables. We first constructed a polygenic risk score for CeD and estimated its associations with 1060 unique clinical outcomes in the UK Biobank study (N = 385,917). We then used two-sample MR analysis to replicate the identified associations using data from the FinnGen study (N = 377,277). We performed a secondary analysis using a genetic instrument without extended MHC gene SNPs. Findings Genetic liability to CeD was associated with 68 clinical outcomes in the UK Biobank, and 38 of the associations were replicated in the FinnGen study. Genetic liability to CeD was associated with a higher risk of several autoimmune diseases (type 1 diabetes and its complications, Graves' disease, Sjögren syndrome, chronic hepatitis, systemic and cutaneous lupus erythematosus, and sarcoidosis), non-Hodgkin's lymphoma, and osteoporosis and a lower risk of prostate diseases. The associations for type 1 diabetes and non-Hodgkin's lymphoma attenuated when excluding SNPs in the MHC region, indicating shared genetic aetiology. Interpretation This study uncovers multiple clinical outcomes associated with genetic liability to CeD, which suggests the necessity of comorbidity monitoring among this population.

BACKGROUND: The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. METHODS: We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. RESULTS: We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01x10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. CONCLUSIONS: Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smok

Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. Methods: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. Results: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Lowdensity lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. 1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. Conclusion: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 x 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. Findings: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. Interpretation: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal disea

Background Coeliac disease (CeD) has been associated with a broad range of diseases in observational data; however, whether these associations are causal remains undetermined. We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to investigate the comorbidities of CeD. Methods Single nucleotide polymorphisms (SNPs) associated with CeD at the genome-wide significance threshold and without linkage disequilibrium (R2 <0.001) were selected from a genome-wide association study including 12,041 CeD cases as the instrumental variables. We first constructed a polygenic risk score for CeD and estimated its associations with 1060 unique clinical outcomes in the UK Biobank study (N = 385,917). We then used two-sample MR analysis to replicate the identified associations using data from the FinnGen study (N = 377,277). We performed a secondary analysis using a genetic instrument without extended MHC gene SNPs. Findings Genetic liability to CeD was associated with 68 clinical outcomes in the UK Biobank, and 38 of the associations were replicated in the FinnGen study. Genetic liability to CeD was associated with a higher risk of several autoimmune diseases (type 1 diabetes and its complications, Graves' disease, Sjögren syndrome, chronic hepatitis, systemic and cutaneous lupus erythematosus, and sarcoidosis), non-Hodgkin's lymphoma, and osteoporosis and a lower risk of prostate diseases. The associations for type 1 diabetes and non-Hodgkin's lymphoma attenuated when excluding SNPs in the MHC region, indicating shared genetic aetiology. Interpretation This study uncovers multiple clinical outcomes associated with genetic liability to CeD, which suggests the necessity of comorbidity monitoring among this population.

Introduction: Although digestive system disease affects gut microbiota and their metabolites associated with dementia risk, the association between digestive system diseases and incident dementia has not yet been established. Methods: This cohort analysis included 458,181 participants free of baseline dementia in the UK Biobank (2006–2021). The associations of 14 digestive system diseases with dementia incidence were examined in 2022 using Cox proportional hazards regression models. Analyses were performed to differentiate the associations for early-onset (age <65 years) and late-onset (age ≥65 years) dementia. Interaction and stratification analyses were performed for polygenic risk score and APOE. Results: During a median follow-up of 12.4 years, 6,415 incident dementia cases were diagnosed. Eleven digestive system diseases showed significant associations with an increased risk of dementia after controlling for covariates and multiple testing. Compared with hazard ratios for individuals without digestive system diseases, the hazard ratios of dementia increased from 1.15 (95% confidence interval=1.09, 1.23) for patients with intestinal diverticular disease to 2.31 (95% confidence interval=1.98, 2.70) for patients with cirrhosis. The associations were different between certain digestive system diseases and dementia by onset age. The associations appeared to be stronger for cirrhosis (Q=0.001), irritable bowel syndrome (Q<0.001), gastritis and duodenitis (Q=0.002), gastroesophageal reflux disease (Q<0.001), ulcerative colitis (Q=0.047), gallbladder disease (Q=0.012), and peptic ulcer (Q=0.030) with early-onset dementia. There were no interactions for polygenic risk score or APOE (p>0.05). Conclusions: These findings suggest an increased need for dementia prevention among patients with digestive system diseases.

Variable-frequency air injection and extraction is critical for salt cavern compressed air energy storage (CAES) power plants to smoothly integrate electricity into the power grid, and the magnitude of its effect on the mechanical properties and damage progression of the salt cavern surrounding rock determines the operation scheme of CAES power plants. To examine the impact of variable frequency, a series of monotonic loading tests with different rates and variable-frequency fatigue (VFF) tests with different upper limit stresses were carried out. Dilatancy stresses have a positive power function relationship with loading rate and frequency, but the fatigue loading process weakens this nonlinear tendency. The rate of change (CR) or the exponent of the fitted function can express it. From the initial stage to the steady stage, the CR of dilatancy stress increases about three times, and the CR of residual volumetric strain decreases about five to eight times. Increased upper-limit stress weakens this trend of change. Both high speed and high-frequency loading shift the damage acceleration point forward (e.g., b value accelerates earlier). The damage rate correlation is significant in the later stages of the VFF tests, the rate correlation of damage is significant. Both the upper stress and the extension of the main fracture zone enhance the rate dependence of fracture types. Moreover, the effect of rate on crystal penetrating cracks is more pronounced in the high-stress interval. The number of fractures significantly affects the dilatancy, rather than the type of fracture. This study serves as a guide for the design of variable frequency programs in different CAES salt cavern operation stages, as well as subsequent research., Funder: National Natural Science Fund of China (No. 52274073, 51834003); China Postdoctoral Science Foundation (No. 2023M730427); Chongqing Postdoctoral Research Project (No. 2023CQBSHTB3139);Fulltext license: CC BY

BACKGROUND: The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. METHODS: We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. RESULTS: We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01x10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. CONCLUSIONS: Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smok

Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. Methods: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. Results: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Lowdensity lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. 1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. Conclusion: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 x 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. Findings: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. Interpretation: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal disea

Background Coeliac disease (CeD) has been associated with a broad range of diseases in observational data; however, whether these associations are causal remains undetermined. We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to investigate the comorbidities of CeD. Methods Single nucleotide polymorphisms (SNPs) associated with CeD at the genome-wide significance threshold and without linkage disequilibrium (R2 <0.001) were selected from a genome-wide association study including 12,041 CeD cases as the instrumental variables. We first constructed a polygenic risk score for CeD and estimated its associations with 1060 unique clinical outcomes in the UK Biobank study (N = 385,917). We then used two-sample MR analysis to replicate the identified associations using data from the FinnGen study (N = 377,277). We performed a secondary analysis using a genetic instrument without extended MHC gene SNPs. Findings Genetic liability to CeD was associated with 68 clinical outcomes in the UK Biobank, and 38 of the associations were replicated in the FinnGen study. Genetic liability to CeD was associated with a higher risk of several autoimmune diseases (type 1 diabetes and its complications, Graves' disease, Sjögren syndrome, chronic hepatitis, systemic and cutaneous lupus erythematosus, and sarcoidosis), non-Hodgkin's lymphoma, and osteoporosis and a lower risk of prostate diseases. The associations for type 1 diabetes and non-Hodgkin's lymphoma attenuated when excluding SNPs in the MHC region, indicating shared genetic aetiology. Interpretation This study uncovers multiple clinical outcomes associated with genetic liability to CeD, which suggests the necessity of comorbidity monitoring among this population.

BACKGROUND: The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. METHODS: We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. RESULTS: We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01x10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. CONCLUSIONS: Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smok

Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. Methods: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. Results: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Lowdensity lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. 1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. Conclusion: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 x 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. Findings: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. Interpretation: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal disea

Introduction: Although digestive system disease affects gut microbiota and their metabolites associated with dementia risk, the association between digestive system diseases and incident dementia has not yet been established. Methods: This cohort analysis included 458,181 participants free of baseline dementia in the UK Biobank (2006-2021). The associations of 14 digestive system diseases with dementia incidence were examined in 2022 using Cox proportional hazards regression models. Analyses were performed to differentiate the associations for early-onset (age <65 years) and late-onset (age ≥ 65 years) dementia. Interaction and stratification analyses were performed for polygenic risk score and APOE. Results: During a median follow-up of 12.4 years, 6,415 incident dementia cases were diagnosed. Eleven digestive system diseases showed significant associations with an increased risk of dementia after controlling for covariates and multiple testing. Compared with hazard ratios for individuals without digestive system diseases, the hazard ratios of dementia increased from 1.15 (95% confi- dence interval=1.09, 1.23) for patients with intestinal diverticular disease to 2.31 (95% confidence interval=1.98, 2.70) for patients with cirrhosis. The associations were different between certain digestive system diseases and dementia by onset age. The associations appeared to be stronger for cirrhosis (Q=0.001), irritable bowel syndrome (Q<0.001), gastritis and duodenitis (Q=0.002), gastroesophageal reflux disease (Q<0.001), ulcerative colitis (Q=0.047), gallbladder disease (Q=0.012), and peptic ulcer (Q=0.030) with early-onset dementia. There were no interactions for polygenic risk score or APOE (p>0.05). Conclusions: These findings suggest an increased need for dementia prevention among patients with digestive system diseases.

Background Coeliac disease (CeD) has been associated with a broad range of diseases in observational data; however, whether these associations are causal remains undetermined. We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to investigate the comorbidities of CeD. Methods Single nucleotide polymorphisms (SNPs) associated with CeD at the genome-wide significance threshold and without linkage disequilibrium (R2 <0.001) were selected from a genome-wide association study including 12,041 CeD cases as the instrumental variables. We first constructed a polygenic risk score for CeD and estimated its associations with 1060 unique clinical outcomes in the UK Biobank study (N = 385,917). We then used two-sample MR analysis to replicate the identified associations using data from the FinnGen study (N = 377,277). We performed a secondary analysis using a genetic instrument without extended MHC gene SNPs. Findings Genetic liability to CeD was associated with 68 clinical outcomes in the UK Biobank, and 38 of the associations were replicated in the FinnGen study. Genetic liability to CeD was associated with a higher risk of several autoimmune diseases (type 1 diabetes and its complications, Graves' disease, Sjögren syndrome, chronic hepatitis, systemic and cutaneous lupus erythematosus, and sarcoidosis), non-Hodgkin's lymphoma, and osteoporosis and a lower risk of prostate diseases. The associations for type 1 diabetes and non-Hodgkin's lymphoma attenuated when excluding SNPs in the MHC region, indicating shared genetic aetiology. Interpretation This study uncovers multiple clinical outcomes associated with genetic liability to CeD, which suggests the necessity of comorbidity monitoring among this population.

Metagenomic binning is an essential technique for genome-resolved characterization of uncultured microorganisms in various ecosystems but hampered by the low efficiency of binning tools in adequately recovering metagenome-assembled genomes (MAGs). Here, we introduce BASALT (Binning Across a Series of Assemblies Toolkit) for binning and refinement of short- and long-read sequencing data. BASALT employs multiple binners with multiple thresholds to produce initial bins, then utilizes neural networks to identify core sequences to remove redundant bins and refine non-redundant bins. Using the same assemblies generated from Critical Assessment of Metagenome Interpretation (CAMI) datasets, BASALT produces up to twice as many MAGs as VAMB, DASTool, or metaWRAP. Processing assemblies from a lake sediment dataset, BASALT produces ~30% more MAGs than metaWRAP, including 21 unique class-level prokaryotic lineages. Functional annotations reveal that BASALT can retrieve 47.6% more non-redundant opening-reading frames than metaWRAP. These results highlight the robust handling of metagenomic sequencing data of BASALT.

INTRODUCTION: Inflammatory bowel disease (IBD) is a relative contraindication to external beam radiation therapy (EBRT) for prostate cancer patients due to fear of increased risk of gastrointestinal (GI) toxicity. High-dose-rate (HDR) brachytherapy, capable of minimizing radiation dose to surrounding tissues, is a feasible alternative. Given limited data, this study examined the safety profile of HDR brachytherapy in this setting. MATERIAL AND METHODS: We conducted a retrospective review of patients with localized prostate cancer and IBD treated with HDR brachytherapy at the University of California San Francisco (UCSF), between 2010 and 2022. Eligibility criteria included biopsy-proven prostate cancer, no distant metastases, absence of prior pelvic radiotherapy, IBD diagnosis, and at least one follow-up visit post-treatment. RESULTS: Eleven patients were included, with a median follow-up of 28.7 months. The median dose administered was 2700 cGy (range, 1500-3150 cGy) over 2 fractions (range, 1-3 fractions). Two patients also received EBRT. Rectal spacers (SpaceOAR) were applied in seven patients. All patients experienced acute genitourinary (GU) toxicity, ten of which were grade 1 and one was grade 2. Eight patients experienced late grade 1 GU toxicity, and three patients had late grade 2 GU toxicity. GI toxicities were similarly low-grade, with six grade 1 acute toxicity, no grade 2 or higher acute toxicity, six grade 1 late toxicity, and one late grade 2 GI toxicity. No grade 3 or higher acute or late GI or GU toxicities were reported. CONCLUSIONS: HDR brachytherapy appears to be a safe and tolerable treatment modality for patients with prostate cancer and IBD, with minimal acute and late GI and GU toxicity. These findings warrant multi-institutional validation due to small sample size.

Neutron star (NS) binaries can be potentially intriguing gravitational wave (GW) sources, with both high- and low-frequency radiations from the possibly aspherical individual stars and the binary orbit, respectively. The successful detection of such a dual-line source could provide fresh insights into binary geometry and NS physics. In the absence of electromagnetic observations, we develop a strategy for inferring the spin-orbit misalignment angle using the tight dual-line double NS system under the spin-orbit coupling. Based on the four-year joint detection of a typical dual-line system with LISA and Cosmic Explorer, we find that the misalignment angle and the NS moment of inertia can be measured with sub-percentage and 5% accuracy, respectively., Comment: 8 pages, 3 figures. Accepted by PRD

It is unclear whether cancers of the upper aerodigestive tract (UADT) and gastric cancer are related to air pollution, due to few studies with inconsistent results. The effects of particulate matter (PM) may vary across locations due to different source contributions and related PM compositions, and it is not clear which PM constituents/sources are most relevant from a consideration of overall mass concentration alone. We therefore investigated the association of UADT and gastric cancers with PM2.5 elemental constituents and sources components indicative of different sources within a large multicentre population based epidemiological study. Cohorts with at least 10 cases per cohort led to ten and eight cohorts from five countries contributing to UADT- and gastric cancer analysis, respectively. Outcome ascertainment was based on cancer registry data or data of comparable quality. We assigned home address exposure to eight elemental constituents (Cu, Fe, K, Ni, S, Si, V and Zn) estimated from Europe-wide exposure models, and five source components identified by absolute principal component analysis (APCA). Cox regression models were run with age as time scale, stratified for sex and cohort and adjusted for relevant individual and neighbourhood level confounders. We observed 1139 UADT and 872 gastric cancer cases during a mean follow-up of 18.3 and 18.5 years, respectively. UADT cancer incidence was associated with all constituents except K in single element analyses. After adjustment for NO2, only Ni and V remained associated with UADT. Residual oil combustion and traffic source components were associated with UADT cancer persisting in the multiple source model. No associations were found for any of the elements or source components and gastric cancer incidence. Our results indicate an association of several PM constituents indicative of different sources with UADT but not gastric cancer incidence with the most robust evidence for t, It is unclear whether cancers of the upper aerodigestive tract (UADT) and gastric cancer are related to air pollution, due to few studies with inconsistent results. The effects of particulate matter (PM) may vary across locations due to different source contributions and related PM compositions, and it is not clear which PM constituents/sources are most relevant from a consideration of overall mass concentration alone. We therefore investigated the association of UADT and gastric cancers with PM2.5 elemental constituents and sources components indicative of different sources within a large multicentre population based epidemiological study. Cohorts with at least 10 cases per cohort led to ten and eight cohorts from five countries contributing to UADT- and gastric cancer analysis, respectively. Outcome ascertainment was based on cancer registry data or data of comparable quality. We assigned home address exposure to eight elemental constituents (Cu, Fe, K, Ni, S, Si, V and Zn) estimated from Europe-wide exposure models, and five source components identified by absolute principal component analysis (APCA). Cox regression models were run with age as time scale, stratified for sex and cohort and adjusted for relevant individual and neighbourhood level confounders. We observed 1139 UADT and 872 gastric cancer cases during a mean follow-up of 18.3 and 18.5 years, respectively. UADT cancer incidence was associated with all constituents except K in single element analyses. After adjustment for NO2, only Ni and V remained associated with UADT. Residual oil combustion and traffic source components were associated with UADT cancer persisting in the multiple source model. No associations were found for any of the elements or source components and gastric cancer incidence. Our results indicate an association of several PM constituents indicative of different sources with UADT but not gastric cancer incidence with the most robust evidence for traffic and

Meilan Xian,1,2,&ast; Jiaoyuan Xu,1,3,&ast; Yamei Zheng,4 Lei Zhang,4 Jie Zhao,4 Jie Chen,1 Siguang Li,1 Lingsang Lin,1 Yi Zhong,4 Zehua Yang,4 Tian Xie,4 Linhui Huang,4 Yipeng Ding1,4 1Department of General Practice, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China; 2Department of General Diseases, Hainan Chengmei Hospital, Haikou, Hainan, 570300, People’s Republic of China; 3Department of General Clinic, Longbo Health Hospital, Lingao County, Hainan, 571800, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yipeng Ding; Linhui Huang, Department of General Practice, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, No. 19, Xiuhua Road, Xiuying District, Haikou, Hainan, 570311, People’s Republic of China, Email ypding@yeah.net; rochelle-11@163.comBackground: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder in pulmonology. Chuanbeimu (CBM) is a traditional Chinese medicinal herb for treating COPD and has been widely utilized in clinical practice. However, the mechanism of CBM in the treatment of COPD remains incompletely understood. This study aims to investigate the underlying therapeutic mechanism of CBM for COPD using network pharmacology and experimental approaches.Methods: Active ingredients and their targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database. COPD-associated targets were retrieved from the GeneCards database. The common targets for CBM and COPD were identified through Venn diagram analysis. Protein-protein interaction (PPI) networks and disease-herb-ingredient-target networks were constructed. Subseq

The lower Yangtze is one of the regions of origin of rice agriculture but it is unclear if environmental change drove the transition from hunting-gathering to agriculture. Long-term and continuous lacustrine records of anthropogenic fire are a more effective means of addressing this problem than the fragmentary terrestrial records available for the lower Yangtze region. We constructed a Holocene fire history revealed by records of black carbon content (BCC) and grain size of the sediments of Lake Nanyi in the lower Yangtze. Our results show the following: 1) Peaks in fire activity occurred during ∼8400–6500 (fire peak P1) and ∼ 1100–0 cal BP (fire peak P2), while weaker fire activity occurred during ∼6500–1100 cal BP (S2). 2) This temporal pattern of fire activity, with a double peak (P1-S2-P2), was asynchronous from east to west across the lower Yangtze. The warm and humid climate would not have caused intense fires and the reduction of forest during ∼8400–6500 and ∼ 1100–0 cal BP. Therefore, we suggest that anthropogenic ignitions, corresponding to pronounced population fluctuations after 8400 cal BP, dominated the regional fire activity. Combined with archaeological evidence, the inverse relationship between the agricultural and population levels and fire intensity during the mid-Holocene suggests that fire intensity at this time was the result of the diversity of landscape types associated with prehistoric subsistence patterns, rather than the magnitude of anthropogenic activity. Combined with sea level, rainfall and archaeological evidence, we propose a mechanism whereby asynchronous water-level rise during ∼8400–6500 cal BP forced the migration of humans to the foothills where they often used fire to modify the landscape as part of a broad-spectrum subsistence pattern. Whereas, water-level fall after 6500 cal BP expanded the area of open ground for human settlement, and in this less diverse landscape, less use was made of fire in agricultural subsistence. O

Hao Guo,1,&ast; Li-Heng Li,2,&ast; Xiao-Hong Lv,1,&ast; Feng-Zhi Su,1,&ast; Jie Chen,1,&ast; Fei Xiao,1,3 Min Shi,1 Yu-Bo Xie1,3 1Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Anesthesiology, The Guilin Municipal Hospital of Traditional Chinese Medicine, Guangxi, People’s Republic of China; 3Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu-Bo Xie, Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, No. 22 Shuangyong Road, Nanning, 530000, People’s Republic of China, Tel +86 13977121557, Email xybdoctor@163.comPurpose: Postoperative sleep disturbance, characterized by diminished postoperative sleep quality, is a risk factor for postoperative delirium (POD); however, the association between pre-existing sleep disturbance and POD remains unclear. This study aimed to evaluate the association between preoperative sleep disturbance and POD in elderly patients after non-cardiac surgery.Patients and methods: This retrospective cohort study was conducted at a single center and enrolled 489 elderly patients who underwent surgery between May 1, 2020, and March 31, 2021. Patients were divided into the sleep disorder (SD) and non-sleep disorder (NSD) groups according to the occurrence of one or more symptoms of insomnia within one month or sleep- Numerical Rating Scale (NRS)≥ 6 before surgery. The primary outcome was the incidence of POD. Propensity score matching analysis was performed between the two groups. Multiple logistic regression analysis was performed to identify the risk factors for POD.Results: In both the unmatched cohort (16.0% vs 6.7%, P=0.003) and the matched cohort (17.0% vs 6.2%, P=0.023), the

Yanxu Zhong,1,2 Huan Lu,3 Xiaodan Lu,4 Zhini He,4 Yuyan Jiang,1 Jie Chen,1 Tippawan Liabsuetrakul2 1Food Safety Monitoring and Evaluation Department, Guangxi Zhuang Autonomous Region Centre for Disease Control and Prevention, Nanning, Guangxi Region, 530000, People’s Republic of China; 2Department of Epidemiology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand; 3Infectious Diseases Department, the Fourth People’s Hospital of Nanning, Nanning, Guangxi Region, 530000, People’s Republic of China; 4Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaCorrespondence: Tippawan Liabsuetrakul, Department of Epidemiology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand, Tel +66 74 451165, Fax +66 74 281166, Email tippawan.l@psu.ac.thBackground: Cooking oil and dietary foods are easily contaminated by aflatoxins (AFs) in Guangxi, China where low birth weight and preterm birth were prevalent. However, there are no data on AF exposure in pregnant women or their impact on newborn birth outcomes. This study aims to measure the levels and correlations of AFs in cooking oil, estimated dietary intake (EDI) of AFs in dietary foods, and serum AFB1 albumin adducts (AFB1-alb) with newborn birthweight and gestational age at birth.Methods: A prospective study was conducted among 126 pregnant women in Guangxi, China. All recruited women were interviewed for demographic data and behavior and obstetric information and then followed up until giving birth. AF measurements were obtained from cooking oil, dietary foods, maternal serum, and cord blood and the correlations of AF levels with newborn birthweight and gestational age at birth were tested using correlation analysis.Results: The median EDI of AFs in cooking oil was 2.61 ng/kg.bw/day and in dietary foods 2.95 ng/kg.bw/day. High

Yunpeng Feng,1 Shifeng Qiao,1 Jie Chen,1 Xin Wen,2 Yanlei Chen,3 Xiaoyu Song,1 Jiaxin Xu,1 Xiucheng Qiao,1 Jing Yang,2 Shenshen Zhang,1 Yang Feng,1 Yu Gao4 1The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China; 3The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of ChinaCorrespondence: Yu Gao, School of Basic Medical Sciences, Jinzhou Medical University, No. 40, Section 3 Songpo Road, Jinzhou, Liaoning, 121000, People’s Republic of China, Tel +86 15904161717, Email jzykdxgy@163.comPurpose: This research explored the association between CD163-labeled M2-type macrophages and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of 38 colorectal cancer (CRC) liver metastases. In addition, we investigated the correlation differences between M2-type macrophages and CAFs in the tumor microenvironments of 38 primary colorectal cancer patients with confirmed liver metastases and 946 colorectal cancer patients, as well as possible mechanisms of action between the two cells.Methods: The Immunohistochemistry (IHC) method was applied to detect the expression levels of M2-type macrophages and CAFs in the tissues of 984 cases of CRC and to analyze the correlation between M2-type macrophages and CAFs in colorectal cancer tissues. The IHC method was also applied to detect the expression levels of M2-type macrophages and CAFs in the liver metastases of 38 cases of CRC in the experimental group and to analyze the correlation between the two cells in liver metastases.Results: 1. M2-type macrophages and CAFs expression were significantly higher in 38 primary co

Yue Wang,1 Jie Chen,1 Han Dong,2 Rui-Lin Ma,1 Ying Zou,3 Wei Wang,4 Qingmei Zheng,5 Ying Feng,6 Zhangyun Tan,7 Xiaoqin Zeng,8 Yinqing Zhao,7 Yan Deng,1 Yanfang Wang,1 Bei Gu,9 Aijun Sun1,10 1National Clinical Research Center for Obstetric & Gynecologic Diseases Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China; 2Department of Obstetrics and Gynecology, Women and Children’s Hospital of Jinzhou, Jinzhou, Liaoning, 121000, People’s Republic of China; 3Department of Obstetrics and Gynecology, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, 410008, People’s Republic of China; 4Department of Reproductive Medicine, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 5Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266500, People’s Republic of China; 6Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 7Department of Obstetrics and Gynecology, Xinhui Maternity and Children’s Hospital, Nanning, Guangxi, 529100, People’s Republic of China; 8Department of Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou, Guangdong, 510000, People’s Republic of China; 9Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Peking University Ninth School of Clinical Medicine, Beijing, 100038, People’s Republic of China; 10Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, 100010, People’s Republic of ChinaCorrespondence: Aijun Sun, Email saj@pumch.cnBackground: The basic medical education stage is not enough to support physicians to fully diagnose and evaluate polycystic ovary syndrome (PCOS). The study ai