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The correlation between socio-economic status (SES) and bone-related diseases garners increasing attention, prompting a bidirectional Mendelian randomization (MR) analysis in this study. Genetic data on SES indicators (average total household income before tax, years of schooling completed, and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fractures (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses and multivariable MR were performed to enhance the robustness of our findings. Higher educational attainment exhibited associations with increased eBMD (β: .06, 95% confidence interval [CI]: 0.01-0.10, P = 7.24 × 10-3), and reduced risks of osteoporosis (OR: 0.78, 95% CI: 0.65-0.94, P = 8.49 × 10-3), spine fracture (OR: 0.76, 95% CI: 0.66-0.88, P = 2.94 × 10-4), femur fracture (OR: 0.78, 95% CI: 0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR: 0.79, 95% CI: 0.70-0.88, P = 2.05 × 10-5), foot fracture (OR: 0.78, 95% CI: 0.66-0.93, P = 5.92 × 10-3), and wrist-hand fracture (OR: 0.83, 95% CI: 0.73-0.95, P = 7.15 × 10-3). Material deprivation appeared to increase the risk of spine fracture (OR: 2.63, 95% CI: 1.43-4.85, P = 1.91 × 10-3). A higher FN-BMD level positively affected increased household income (β: .03, 95% CI: 0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index, type 2 diabetes, smoking initiation, and frequency of alcohol intake. The MR analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings provide valuable insights for health guideline formulation and policy development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Non-Hodgkin's lymphoma incidence rates vary between European and Asian populations. The reasons remain unclear. This two-sample two-step Mendelian randomisation (MR) study aimed to investigate the causal relationship between anthropometric indicators (AIs) and diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and the possible mediating role of basal metabolic rate (BMR) in Europe., Methods: We used the following AIs as exposures: body mass index (BMI), whole-body fat mass (WBFM), whole-body fat-free mass (WBFFM), waist circumference(WC), hip circumference(HC), standing height (SH), and weight(Wt). DLBCL and FL represented the outcomes, and BMR was a mediator. A two-sample MR analysis was performed to examine the association between AIs and DLBCL and FL onset. We performed reverse-MR analysis to determine whether DLBCL and FL interfered with the AIs. A two-step MR analysis was performed to determine whether BMR mediated the causality., Findings: WBFFM and SH had causal relationships with FL. A causal association between AIs and DLBCL was not observed. Reverse-MR analysis indicated the causal relationships were not bidirectional. Two-step MR suggested BMR may mediate the causal effect of WBFFM and SH on FL., Conclusions: We observed a causal relationship between WBFFM and SH and the onset of FL in Europeans, Which may explain the high incidence of follicular lymphoma in Europeans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates., Results: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals., Conclusions: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles., (© 2024. The Author(s).)

Aim: The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE-MI., Methods and Results: Overall, 23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South-East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of atrial fibrillation), type of myocardial infarction (more often ST-elevation myocardial infarction), and treatment (low rate of primary percutaneous coronary intervention). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (34.8%) and beta-blockers (65.5%) was low in SA, whereas mineralocorticoid receptor antagonist use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident heart failure varied two-fold among regions, with the lowest rate in SA (4.6/100 person-years) and the highest in LA (9.2/100 person-years). Rates of incident heart failure varied almost six-fold among regions, with the lowest rate in SA (1.0/100 person-years) and the highest in Northern Europe (5.9/100 person-years). The effect of sacubitril/valsartan was not modified by region., Conclusion: In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a 'real-world' unselected population may be limited, these findings underscore the importance of considering both regional and within-region differences when designing global clinical trials., (© 2023 European Society of Cardiology.)

Domesticated grapevines spread to Europe around 3,000 years ago. Previous studies have revealed genomic signals of introgression from wild to cultivated grapes in Europe, but the time, mode, genomic pattern, and biological effects of these introgression events have not been investigated. Here, we studied resequencing data from 345 samples spanning the distributional range of wild ( Vitis vinifera ssp. sylvestris ) and cultivated ( V. vinifera ssp. vinifera ) grapes. Based on machine learning-based population genetic analyses, we detected evidence for a single domestication of grapevine, followed by continuous gene flow between European wild grapes (EU) and cultivated grapes over the past ~2,000 y, especially from EU to wine grapes. We also inferred that soft-selective sweeps were the dominant signals of artificial selection. Gene pathways associated with the synthesis of aromatic compounds were enriched in regions that were both selected and introgressed, suggesting EU wild grapes were an important resource for improving the flavor of cultivated grapes. Despite the potential benefits of introgression in grape improvement, the introgressed fragments introduced a higher deleterious burden, with most deleterious SNPs and structural variants hidden in a heterozygous state. Cultivated wine grapes have benefited from adaptive introgression with wild grapes, but introgression has also increased the genetic load. In general, our study of beneficial and harmful effects of introgression is critical for genomic breeding of grapevine to take advantage of wild resources.

Culex tritaeniorhynchus is the primary vector of Japanese encephalitis (JE) and has a wide global distribution. However, the current and future geographic distribution maps of Cx. tritaeniorhynchus in global are still incomplete. Our study aims to predict the potential distribution of Cx. tritaeniorhynchus in current and future conditions to provide a guideline for the formation and implementation of vector control strategies all over the world. We collected and screened the information on the occurrence of Cx. tritaeniorhynchus by searching the literature and online databases and used ten algorithms to investigate its global distribution and impact factors. Cx. tritaeniorhynchus had been detected in 41 countries from 5 continents. The final ensemble model (TSS = 0.864 and AUC = 0.982) indicated that human footprint was the most important factor for the occurrence of Cx. tritaeniorhynchus . The tropics and subtropics, including southeastern Asia, Central Africa, southeastern North America and eastern South America, showed high habitat suitability for Cx. tritaeniorhynchus . Cx. tritaeniorhynchus is predicted to have a wider distribution in all the continents, especially in Western Europe and South America in the future under two extreme emission scenarios (SSP5-8.5 and SSP1-2.6). Targeted strategies for the control and prevention of Cx. tritaeniorhynchus should be further strengthened.

An improved understanding of global Urban Exposure to Flooding (UEF) is essential for developing risk-reduction strategies for sustainable urban development. This study is the first to assess the long-term historical global UEF at a fine spatial resolution (i.e., 30 m) and annual temporal frequency, with consideration of smaller urban areas in the exposure assessment compared to those using coarse resolution data. We assessed the UEF by investigating the spatially explicit urban expansion in the 100-year floodplain extents. The global UEF increased more than four-fold from 16,443 km 2 in 1985 to 92,233 km 2 in 2018 with accelerated temporal trends. The most notable growth in UEF occurred in Asia (74.1%), followed by Europe (11.6%), Northern America (8.7%), Africa (2.9%), Southern America (2.2%), and Australia (0.5%). Notably, China and US were the two countries with the largest UEF, accounting for about 61.5% of global growth in UEF. In addition, only 1.2% of global floodplains were occupied by urban expansion by 2018, whereas this percentage reached 20% in the basins of Western Europe, Eastern Asia, and Northeastern US. Moreover, although the floodplains only accounted for 5.5% of the global land areas, 12.6% of the urban expansion occurred in the floodplains from 1985 to 2018, with the most rapid increases in the basins in Southeastern and Eastern China. Our findings highlight that the trends of accelerated increasing urban exposure to flooding have been occurring for at least the past three decades., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding the genetic diversity of wheat is important for wheat breeding and improvement. However, there have been limited attempts to evaluate wheat diversity using fluorescence in situ hybridization (FISH). In this study, the chromosomal structures of 149 wheat accessions from 13 countries located between the latitudes of 30°N and 45°N, the principal growing region for wheat, were characterized using FISH with pTa535 and pSc119.2 probes. The ranges of the numbers of FISH types in the A-, B-, and D-genome chromosomes were 2-8, 3-7, and 2-4, respectively, and the average numbers in the A and B genomes were greater than in the D genome. Chromosomal translocations were detected by these probes, and previously undescribed translocations were also observed. Using the FISH, the genetic relationships among the 149 common wheat lines were divided into three groups (G1, G2, and G3). G1 mainly consisted of southern European lines, G2 consisted of most lines from Japan and some lines from western Asia, China, and Korea, and G3 consisted of the other lines from southern Europe and most of the lines from western Asia, China, and Korea. FISH karyotypes of wheat chromosomes distinguished chromosomal structural variations, revealing the genetic diversity among wheat varieties. Furthermore, these results provide valuable information for the further genetic improvement of wheat in China.

Purpose: Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha ( PDGFRA ) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST., Patients and Methods: VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression., Results: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%)., Conclusion: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST., Competing Interests: Yoon-Koo KangConsulting or Advisory Role: DAEHWA Pharmaceutical, Bristol Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, Macrogenics, Surface Oncology, Blueprint Medicines Suzanne GeorgeStock and Other Ownership Interests: Abbott LaboratoriesConsulting or Advisory Role: Blueprint Medicines, Deciphera, Bayer, Lilly, UpToDate, Research to Practice, MORE Health, Daiichi, KayotheraResearch Funding: Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks TherapeuticsPatents, Royalties, Other Intellectual Property: UptoDateExpert Testimony: BayerOther Relationship: Research to Practice, WCG Robin L. JonesConsulting or Advisory Role: Lilly, Immune Design, Merck Serono, Adaptimmune, Daiichi Sankyo, Eisai, Morphotek, TRACON Pharma, Immodulon Therapeutics, Deciphera, PharmaMar, Blueprint Medicines, Clinigen Group, Epizyme, Boehringer Ingelheim, Bayer, Karma Oncology, UpToDateResearch Funding: GlaxoSmithKlineTravel, Accommodations, Expenses: PharmaMar Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeakers' Bureau: Pfizer, Novartis, LillyResearch Funding: Novartis, Roche, Bristol Myers SquibbTravel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Olivier MirStock and Other Ownership Interests: Transgene, Amplitude Surgical, IpsenHonoraria: RocheConsulting or Advisory Role: Lilly, Pfizer, Roche, Lundbeck, JanssenSpeakers' Bureau: Lilly, Roche, PfizerResearch Funding: Ipsen, AstraZeneca, Blueprint MedicinesTravel, Accommodations, Expenses: Roche, Pfizer Shreyaskumar PatelConsulting or Advisory Role: Novartis, Immune Design, MaxiVax, Epizyme, Janssen, Lilly, Daiichi Sankyo, Bayer, Dova Pharmaceuticals, DecipheraResearch Funding: Blueprint Medicines, Hutchinson Med Pharma Margaret von MehrenConsulting or Advisory Role: Deciphera, ExelixisResearch Funding: ArQule, Novartis, Blueprint Medicines, Deciphera, Gradalis, Springworks Therapeutics, Lilly, Arog, Genmab, ASCOTravel, Accommodations, Expenses: Deciphera Pharmaceuticals, NCCNOther Relationship: NCCN Peter HohenbergerHonoraria: Roche, AstraZeneca, GlaxoSmithKline, BLUMedicine, NovartisConsulting or Advisory Role: Nanobiotix, PfizerResearch Funding: Novartis, Siemens Healthcare DiagnosticsTravel, Accommodations, Expenses: PharmaMar Victor VillalobosEmployment: Janssen OncologyConsulting or Advisory Role: Janssen, Lilly, Novartis, AbbVie, Ignyta, Agios, Epizyme, Blueprint Medicines, Springworks Therapeutics, NanoCarrier, Daiichi SankyoTravel, Accommodations, Expenses: Lilly, Janssen, Xencor, GenMab, Epizyme Mehdi BrahmiExpert Testimony: BayerTravel, Accommodations, Expenses: PharmaMar, Mundipharma William D. TapLeadership: Certis Oncology Solutions, Atropos, Innova TherapeuticsStock and Other Ownership Interests: Certis Oncology Solutions, AtroposConsulting or Advisory Role: EMD Serono, Lilly, Daiichi Sankyo, Blueprint Medicines, Agios, NanoCarrier, Deciphera, C4 Therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceutical, Servier, AbMaxBioResearch Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, DecipheraPatents, Royalties, Other Intellectual Property: Companion Diagnostic for CDK4 inhibitors—14/854,329, Enigma and CDH18 as companion Diagnostics for CDK4 inhibition—SKI2016-021-03 Jonathan TrentConsulting or Advisory Role: Novartis, Lilly, Janssen, Blueprint Medicines, Deciphera, Daiichi Sankyo, Epizyme, Agios, C4 Therapeutics, Bayer Patrick SchöffskiHonoraria: Deciphera, Blueprint Medicines, Boehringer IngelheimConsulting or Advisory Role: Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Deciphera, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital, Studiecentrum voor KernenergieResearch Funding: CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMarTravel, Accommodations, Expenses: MSD, Ipsen, Boehringer Ingelheim Kevin HeEmployment: Blueprint Medicines, AgiosStock and Other Ownership Interests: Blueprint Medicines, Agios, Incyte Paggy HewEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint MedicinesTravel, Accommodations, Expenses: Blueprint Medicines Kate NewberryEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint Medicines Maria RocheEmployment: Blueprint Medicines, EpizymeStock and Other Ownership Interests: Blueprint Medicines, Epizyme Michael C. HeinrichStock and Other Ownership Interests: MolecularMDHonoraria: NovartisConsulting or Advisory Role: MolecularMD, Novartis, Blueprint Medicines, Deciphera, Theseus PharmaceuticalsPatents, Royalties, Other Intellectual Property: Patent on treatment of GIST-licensed to NovartisExpert Testimony: Novartis Sebastian BauerHonoraria: Novartis, Pfizer, Bayer, Pharmamar, GlaxoSmithKlineConsulting or Advisory Role: Blueprint Medicines, Bayer, Lilly, Deciphera, Nanobiotix, Daiichi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, GlaxoSmithKlineResearch Funding: Blueprint Medicines, Novartis, IncyteTravel, Accommodations, Expenses: PharmamarNo other potential conflicts of interest were reported.

Objective: To study how demographic differences impact disease manifestation of sarcoidosis using the WASOG tool in a large multicentric study., Methods: Clinical data regarding 1445 patients with sarcoidosis from 14 clinical sites in 10 countries were prospectively reviewed from Feb 1, 2020 to Sep 30, 2020. Organ involvement was evaluated for the whole group and for subgroups differentiated by sex, race, and age., Results: The median age of the patients at diagnosis was 46 years old; 60.8% of the patients were female. The most commonly involved organ was lung (96%), followed by skin (24%) and eye (22%). Black patients had more multiple organ involvement than White patients (OR = 3.227, 95% CI: 2.243-4.643) and females had more multiple organ involvement than males (OR = 1.238, 95% CI: 1.083-1.415). Black patients had more frequent involvement of neurologic, skin, eye, extra thoracic lymph node, liver and spleen than White and Asian patients. Women were more likely to have eye (OR = 1.522, 95%CI: 1.259-1.838) or skin involvement (OR = 1.369, 95%CI: 1.152-1.628). Men were more likely to have cardiac involvement (OR = 1.326, 95%CI: 1.096-1.605). A total of 262 (18.1%) patients did not receive systemic treatment for sarcoidosis. Therapy was more common in Black patients than in other races., Conclusion: The initial presentation and treatment of sarcoidosis was related to sex, race, and age. Black and female individuals are found to have multiple organ involvement more frequently. Age at diagnosis<45, Black patients and multiple organ involvement were independent predictors of treatment., (Copyright © 2021. Published by Elsevier Ltd.)

Streptococcus suis, a ubiquitous bacterial colonizer in pigs, has recently extended host range to humans, leading to a global surge of deadly human infections and three large outbreaks since 1998. To better understand the mechanisms for the emergence of cross-species transmission and virulence in human, we have sequenced 366 S. suis human and pig isolates from 2005 to 2016 and performed a large-scale phylogenomic analysis on 1,634 isolates from 14 countries over 36 years. We show the formation of a novel human-associated clade (HAC) diversified from swine S. suis isolates. Phylogeographic analysis identified Europe as the origin of HAC, coinciding with the exportation of European swine breeds between 1960s and 1970s. HAC is composed of three sub-lineages and contains several healthy-pig isolates that display high virulence in experimental infections, suggesting healthy-pig carriers as a potential source for human infection. New HAC-specific genes are identified as promising markers for pathogen detection and surveillance. Our discovery of a human-associated S. suis clade provides insights into the evolution of this emerging human pathogen and extend our understanding of S. suis epidemics worldwide., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Vegetation phenology in spring has substantially advanced under climate warming, consequently shifting the seasonality of ecosystem process and altering biosphere-atmosphere feedbacks. However, whether and to what extent photoperiod (i.e., daylength) affects the phenological advancement is unclear, leading to large uncertainties in projecting future phenological changes. Here we examined the photoperiod effect on spring phenology at a regional scale using in situ observation of six deciduous tree species from the Pan European Phenological Network during 1980-2016. We disentangled the photoperiod effect from the temperature effect (i.e., forcing and chilling) by utilizing the unique topography of the northern Alps of Europe (i.e., varying daylength but uniform temperature distribution across latitudes) and examining phenological changes across latitudes. We found prominent photoperiod-induced shifts in spring leaf-out across latitudes (up to 1.7 days per latitudinal degree). Photoperiod regulates spring phenology by delaying early leaf-out and advancing late leaf-out caused by temperature variations. Based on these findings, we proposed two phenological models that consider the photoperiod effect through different mechanisms and compared them with a chilling model. We found that photoperiod regulation would slow down the advance in spring leaf-out under projected climate warming and thus mitigate the increasing frost risk in spring that deciduous forests will face in the future. Our findings identify photoperiod as a critical but understudied factor influencing spring phenology, suggesting that the responses of terrestrial ecosystem processes to climate warming are likely to be overestimated without adequately considering the photoperiod effect., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01, HLA-B*15:02, HLA-A*31:01, and HLA-B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing of HLA-B*57:01 in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA-B*15:02 is only cost-effective across most of East and South Asia, whereas HLA-A*31:01 testing is likely to be cost-effective globally. Testing of HLA-B*58:01 is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Bis(2-chloroethyl) ether (BCEE) has become one of the most frequently detected chlorinated ether contaminants in the US and Europe, and is classified as a B2 carcinogen. In this study, the degradation rate of BCEE by mercury lamps, xenon lamp and electromagnetic induction electrodeless lamp (EIEL) activated persulfate were compared, and EIEL activated persulfate was confirmed to have higher degradation capability and lower energy consumption. In this sense, the degradation kinetics and mechanism in EIEL system were further investigated. The degradation reaction followed pseudo first-order, and the removal rate of BCEE exceeded 95% in 60 min when the initial pH, the concentration of BCEE and Na 2 S 2 O 8 were 3, 4 mg L -1 and 15 mM, respectively. Presence of inorganic anions and humic acids would reduce the degradation rate constant. In accordance with the results of electron paramagnetic resonance and quenching experiments, SO 4 - · was dominant in the acidic regime and OH· was dominant in the alkaline regime. Meanwhile, OH· had higher degradation rate with BCEE when initial pH was 7. Seven degradation products were identified and the reaction pathways included OH· substitution and free radical coupling. Although the total organic carbon was eliminated slowly during the degradation of BCEE, the predicted toxicity of most degradation products to Fathead minnow, Daphnia magna and oral rat were lower than BCEE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pharmaceuticals and personal care products (PPCPs) are recognized as one emerging group of environmental contaminants, capturing worldwide attention. These chemicals, closely connected to anthropogenic activities, are mainly transported through aquatic environments and reach coastal areas, eventually entering ocean offshore. Thus, this study concentrated on the 30 PPCPs in coastal waters of the Yellow and Bohai seas (77 sites), a fast-growing area with intensive anthropogenic activities. In general, the total concentrations of PPCPs in Chinese coastal waters (0.880-1194 ng L -1 ) greatly varied and were relatively greater than those (9.91-442 ng L -1 ) in Korean coastal waters. Sulfamethoxazole, sulfamethazine, oxytetracycline, ofloxacin, roxithromycin, anhydro-erythromycin, and caffeine were the seven predominant PPCPs in the coastal waters of study area. Further, we established the Predicted PPCPs Contamination Indicator (PPCI) to address potential anthropogenic activities being associated with site-specific PPCPs contamination. Three anthropogenic factors to PPCPs contamination were proven as the most influential, including (1) quantity of wastewater discharge, (2) gross product of meat, poultry, eggs and milk, and (3) gross aquatic product. The relatively high PPCI values appeared in Tianjin, Dalian, Tangshan, Yantai, and Qingdao in China and Gyeonggi and Jeonbuk in South Korea, which exhibited fairly good consistency with the corresponding PPCPs concentrations. A mini-review of the global PPCPs distributions revealed that seven priority PPCPs found in this study distributed widely in Asia rather than Europe, North America, and Australia. In general, global PPCPs contamination also reflected site- and region-specific distributions, suggesting varying usages and sources cross the region and/or country. Finally, the risk assessment suggested that ofloxacin and anhydro-erythromycin, with 36.4% and 23.4% sites higher than medium risks respectively, posed relatively high risks to sensitive algal species, Microcystis aeruginosa and Selenastrum capricornutum. Overall, the ecological risks of exposure of PPCPs in the Yellow and Bohai seas were higher compared to other regions of the world, thus the bilateral management of PPCPs between China and South Korea needs an immediate attention., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The prognostic values of the AJCC staging system for gastric cancer (GC-AJCC), the AJCC staging system for gastric neuroendocrine tumours (NET-AJCC) and the European Neuroendocrine Tumor Society (ENETS) system for gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma (MA)NEC remain controversial., Methods: Data on patients with (MA)NEC from 21 centres in China were analysed. Different staging systems were evaluated by performing Kaplan-Meier survival analysis and calculating the concordance index (C-index) and Akaike information criterion (AIC). Based on three existing systems, a modified staging system (mTNM) was developed., Results: A total of 871 patients were included. In the GC-AJCC system, an overlap was noticed for pT2 and pT3 categories. Patients with stage IIIC disease had a similar prognosis to those with stage IV disease. The pT categories of the NET-AJCC system had a lower C-index and higher AIC than those of the other systems. In the ENETS system, there was a low proportion (0·2 per cent) of patients with stage IIIA and a high proportion (67·6 per cent) of stage IIIB disease. The mTNM system adopted the NET-AJCC pT and GC-AJCC pN and pM definitions, and was developed based on the ENETS stage definitions. The proportion of patients in each stage was better distributed and the mTNM system showed improved prognostic performance in predicting overall and disease-free survival., Conclusion: The mTNM system offers more accurate prognostic value for gastric (MA)NEC than the AJCC or ENETS staging systems., (© 2020 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as anticancer therapies, we have concluded (1) that measles is not protective against cancer and (2) that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits., (Copyright © 2017 American Society of Human Genetics. All rights reserved.)

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Objective: To evaluate the occupational safety climate in different types of enterprises and its relationship with occupational accidental injury., Methods: A cross-sectional survey based on self-report questionnaires was performed among 3311 front-line workers from 54 medium and small-sized manufacturing enterprises of different types in Zhongshan, China to investigate the socio-demographic characteristics, safety climate experience in workplace, and incidence of occupational accidental injury in the past year., Results: Analysis of the data revealed that employees in different types of companies perceived different levels of safety climate, according to the scores on four subscales; the European and American enterprises had significantly better safety climate than the Hong Kong and Chinese private enterprises (P < 0.01). The self-reported rates of occupational injury were 3.38%, 4.76%, and 6.72%, respectively, for European and American, Hong Kong, and Chinese private enterprises (χ(2) = 6.78, P < 0.05). After control of such factors as age, sex, income, education level, and marriage, the logistic regression analysis showed that the risk of occupational accidental injury in the European and American enterprises was significantly lower than that in the Chinese private enterprises (OR = 0.57, 95%CI = 0.35-0.91)., Conclusion: The type of enterprise influences the occupational safety climate and incidence of occupational injury among workers.

Purpose: Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and gastric cancer risk have reported conflicting results. Therefore, we conducted this meta-analysis to provide more precise evidence., Methods: We searched the databases Medline, PubMed, Embase, and China National Knowledge Infrastructure up to July 30, 2009. Thirty-six studies with 4,357 gastric cancer cases and 9,796 controls were selected. Odds ratio (OR) and 95% confidence intervals (CI) were calculated based on fixed- and random-effects models., Results: The combined results based on all studies showed there was a significant link between GSTT1 null genotype and gastric cancer risk (OR = 1.14, 95%CI = 1.01-1.28). In subgroup analysis stratified on the basis of ethnic group, we also observed positive association between GSTT1 polymorphism and gastric cancer risk among Caucasians (non-Europeans + non-Americans), but not among East Asians. When stratifying by control source, the overall ORs for population- and hospital-based studies were 1.09 (95%CI = 0.94-1.28) and 1.17 (95%CI = 1.03-1.34), respectively. Subjects with both GSTM1 and GSTT1 negative genotypes had increased gastric cancer risk compared with those who had nonnull genotypes of both GST genes. Subgroup analyses for Helicobacter pylori infection and smoking habit did not reveal any significant association between GSTT1 polymorphism and gastric cancer development., Conclusions: This meta-analysis suggests that GSTT1 gene polymorphism may be not associated with increased gastric cancer risk among Europeans, Americans, and East Asians. More large-scale studies based on the same racial group are needed.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.