Hepatic, biliary and pancreatic cancers are a diverse set of malignancies with poor prognoses. It is possible that common molecular mechanisms are involved in the carcinogenesis of these cancers. Here, we identified LINC01537 and seven protein‐coding genes by integrative analysis of transcriptomes of mRNAs, microRNAs and long non‐coding RNAs from cholangiocarcinoma, hepatocellular carcinoma and pancreatic adenocarcinoma cohorts in TCGA. A predictive model constructed from seven biomarkers was established to successfully predict the survival rate of patients, which was then further verified in external cohorts. Additionally, patients with high‐risk scores in our model were prone to epithelial–mesenchymal transition. Finally, activation of the biomarker PDE2A significantly attenuated migration and epithelial–mesenchymal transition in the HepG2 liver cancer cell line. ACSM5, ADRA1A, CCL14, DNASE1L3, LILRB5, PDE2A and RBP5 expression. Our prognostic model was predictive of patient survival in both TCGA test cohorts and in two independent validation cohorts.Hepatic, biliary and pancreatic cancers are a diverse set of malignancies with poor prognoses. Here, we established a prognostic model for hepatic–biliary–pancreatic cancers based on  The livPrimary liver cancer, including hepatocellular carcinoma (75–85% of cases) and intrahepatic cholangiocarcinoma (10–15% of cases), has become the sixth most commonly cancer and the fourth leading cause of cancer death worldwide . The 5‐yRecently, accumulating evidence has verified that mRNAs, microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs) participated in the initiation and progression of several tumor types, including hepatocellular carcinoma, cholangiocarcinoma and pancreatic adenocarcinoma , 12, 13.Genome‐wide transcriptomic studies have been performed in various cancers and provide an opportunity to systematically study the molecular mechanisms across different types of cancers . Here, whttps://portal.gdc.cancer.gov) [Systematic searches of the Cancer Genome Atlas (TCGA) database for the CHOL, LIHC and PAAD cohorts were performed. Level 3 RNA‐sequencing (RNA‐seq) count data  and miRNA‐sequencing (miRNA‐seq) count data (Illumina HiSeq miRNA‐Seq platform), as well as their corresponding clinical phenotypic data and survival information, were obtained from the GDC Data Portal (cer.gov) . For mRNEssential clinical information consisting of patient ID, gender, age, TNM staging, tumor histological grading, survival state and survival time was also extracted. We excluded cases from TCGA database according to the following criteria: (a) patients without survival statues and survival time information; (b) patients without their corresponding mRNA or miRNA expression data; (c) patients with a follow‐up time < 1 month. In total, 469 patients were selected in this project.https://portal.gdc.cancer.gov) [The mutation data for CHOL cohort, LIHC cohort and PAAD cohort were also downloaded from the GDC Data Portal (cer.gov) .https://dcc.icgc.org) and the data from GSE57495 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57495) were used as the external validation cohorts to further test the efficacy of the predictive accuracy of prognostic model.Additionally, the LIRI‐JP cohort downloaded from the International Cancer Genome Consortium  were utilized for subsequent experimental validation. All of the data were publicly available and there were no ethical issues involved.Finally, the data from GSE5203  in GEO ddeseq2 package [bioconductor was used to reveal the differentially expressed mRNAs (DEmRNAs), differentially expressed miRNAs (DEmiRNAs) and differentially expressed lncRNAs (DElncRNAs). The significant different thresholds are P < 0.05 and ¦log2 fold change ¦ ≥ 1. The GENCODE database was used for distinguish lncRNAs from mRNAs (https://www.gencodegenes.org). Simultaneously, the ‘GDC.h38 GENCODE v22 GTF’ file was download from GDC to annotate mRNA and lncRNA from RNA‐seq. Venn diagrams were performed to visualize the uniformly upregulated or downregulated DEmRNAs, DEmiRNAs and DElncRNAs.The  package  in biocofgsea package [r. To evaluate the potential functions of uniformly upregulated or downregulated genes of the cancers, Gene Ontology  and Kyoto Encyclopedia of Genes and Genomes  pathway enrichment analysis was performed using the clusterprofiler package in r [P < 0.05. To explore the significantly enriched gene sets between high‐risk and low‐risk groups, GSEA analysis was also performed as described above.Gene Set Enrichment Analysis (GSEA) against hallmark gene sets in MsigDb  was perf package  in r. Toage in r . The sigP < 0.05 and r ≤ −0.3 in each cohort were selected for ceRNA construction [ggalluvial r package [Co‐expression analysis was implemented using the Pearson correlation coefficient. Because co‐expression is one of the features of the ceRNA network, lncRNA–miRNA and miRNA–mRNA pairs with truction , 29. Nex package .P < 0.05 were selected for further analysis. Furthermore, Kaplan–Meier survival analysis of DEmRNAs and DElncRNA was performed using the survival package in r [P value was calculated utilizing a log‐rank test and DEmRNAs and DElncRNA with P < 0.05 were considered statistically significant.The relationship between mRNA expression level and overall survival (OS) of patients was evaluated by univariate Cox regression analysis. mRNAs with age in r . Patientn, Coef and Exp are the number of signature genes, the coefficient obtained from LASSO Cox regression and the expression of signature genes, respectively. Features, consisting of gender, age, TNM grading and tumor histological staging, were submitted and analyzed by multivariate Cox regression to determine factors related with prognosis. P < 0.05 was set as the threshold to identify independent prognostic factors.A risk score signature was constructed utilizing the most robust markers, which were selected by least absolute shrinkage and selection operator (LASSO) Cox regression. The risk score signature was then calculated using:regplot package in r [A nomogram model of independent factors was constructed and visualized using the age in r . To verihttps://zlab.bio/guide‐design‐resources). Synthesized sgRNA oligonucleotides were annealed, phosphorylated and cloned into the digested plenti‐sg‐mCherry vector. The sgRNA sequences targeted PDE2A are shown in Table sgRNAs targeting PDE2A promoter region were designed by publicly available online tools  and cultured in Dulbecco's modified Eagle's medium  containing 10% fetal bovine serum (BI), 1% penicillin/streptomycin (BI) at 37 °C in 5% COplenti‐sg‐mCherry‐vector, plenti‐sg‐mCherry‐PDE2A‐sg1 and plenti‐sg‐mCherry‐PDE2A‐sg2 were respectively co‐transfected with dCas9‐VP64‐puro  utilizing Lipofectamine 3000 . After 24 or 48 h, cells were collected for subsequent experiments.−ΔΔCt method. Primers used for amplification are shown in Table Total RNA was extracted using Trizol reagent (Invitrogen) in accordance with the manufacturer's instructions. Two micrograms of RNA was used for cDNA synthesis . qPCR was performed using EvaGreen 2xqPCR MasterMix (Abm) and CFX96 Real‐time PCR Detection System . Each sample was determined with triplicate independent experiments. The relative target gene expression, as a fold change above control group after normalization to GAPDH, was calculated using the 25) were resuspended in 200 μL of fetal bovine serum‐free medium and placed in the upper chambers . Then, 600 μL of medium supplemented with 10% fetal bovine serum was added to the lower chambers. After 48 h of incubation at 37 °C, the cells were fixed with 4% paraformaldehyde , stained with 0.1% crystal violet (Solarbio) and imaged.Cells , E‐cadherin, N‐cadherin and Snail  with 1 : 1000 dilutions.r, version 4.0.3  and prism, version 8 . All data are presented as the mean ± SD. Pairwise comparisons were performed based on a two‐tailed Student's t‐test. P < 0.05 was considered statistically significant.Statistical analyses were performed using A brief overview of the screening strategy employed in the present study is shown in Fig. Aiming to explore the enriched gene sets of digestive glands malignances, GSEA was performed in different cancers. The GSEA results showed that 20 gene sets enriched in CHOL, consisting of ‘G2M checkpoint’, ‘E2F targets’ and ‘epithelial mesenchymal transition’, etc., followed by 15 terms in PAAD  and 14 terms in LIHC . Furthermore, ‘G2M checkpoint’, ‘E2F targets’ and ‘KRAS down signaling’ were enriched gene sets in CHOL, LIHC and PAAD Fig. , respectNext, we performed GO and KEGG enrichment analyses on the uniformly up‐regulated and down‐regulated DEmRNAs in the three types of tumor to gain insight with respect to the common biological functions of three digestive gland malignancies. Functional annotations of GO enrichment demonstrated that upregulated genes were significantly related with cell division, whereas downregulated genes were significantly associated with transport regulation and immune processes Fig. . The KEG2+/Mn2+ dependent 1 K (PPM1K) and retinol binding protein 5 (RBP5), among which PDE2A exhibited the strongest correlation with LINC01537 . It was suggested that LINC01537 and the eight protein‐coding genes may be interrelated in a miRNA independent manner in hepatic–biliary––pancreatic cancers.Given to that ‘microRNAs in cancer’ was enriched in upregulated genes in our analysis, we proposed that a common ceRNA network constructed by mRNAs–miRNA–lncRNAs may be universally involved in the digestive malignancies. To explore the potential ones, we first performed lncRNAs–miRNAs and miRNAs–mRNAs co‐expression analysis in CHOL, LIHC and PAAD, respectively. One hundred and twenty‐two lncRNAs, 19 miRNAs and 580 mRNAs were co‐expressed in the CHOL cohort; 25 lncRNAs, nine miRNAs and 181 mRNAs were co‐expressed in the LIHC cohort; and 28 lncRNAs, nine miRNAs and 245 mRNAs were co‐expressed in the PAAD cohort. We then obtained the intersection of co‐expression networks Fig. , but no 537 Fig. . InteresTo further investigate the importance of the above nine molecules (LINC01537 and eight mRNAs), we performed paired comparison analysis by examining their expression in tumor samples and the corresponding adjacent tissues 62 pairs). The expression of these nine molecules decreased in tumor tissues significantly compared to their matching para‐cancerous tissues . Moreover, the hazard ratios of these seven genes were all less than 1, demonstrating that they were protective factors. Considering the potential roles of these seven mRNAs in patient prognosis, we established a LASSO Cox regression model integrating these mRNAs to build a risk score signature . The area under the curve values of the entire TCGA cohorts were 0.69, 0.74 and 0.65 for 1‐, 3‐ and 5‐year survival rates, respectively.  and two independent external cohorts , it was significantly correlated with patient prognosis as a protective factor in LIHC  database. The fact that LINC01537 was not significantly correlated with the other two types of cancer might be a result of limited patient samples (LIHC : CHOL : PAAD ≈ 4 : 0.4 : 1.7). However, further functional studies are needed to investigate the specific effects of LINC01537 in carcinogenesis. Survival analysis demonstrated that the high expression of seven mRNAs  was associated with a significant survival advantage. Therefore, these seven mRNAs, similar to LINC01537, might be tumor suppressors in digestive glands.To better understand the common mechanism of digestive gland malignancies. LINC01537 and eight mRNAs  were finally screened out according to lncRNAs–miRNAs and miRNAs–mRNAs co‐expression analysis. LINC01537 is located on human chromosome 11q13.4. A previous study has demonstrated that LINC01537 was significantly associated with lung cancer survival, inhibiting tumor proliferation and metastasis, as well as enhanced cellular sensitivity to nilotinib through stabilized PDE2A protein . Anotheret al. [r = 0.73, P = 1.74 × 10–80). Therefore, we propose that LINC01537/PDE2A might repress the development of digestive gland malignancies as well, such as tumor proliferation, invasion and metastasis.ACSM5, as a protein‐coding gene, mainly participates in the cytochrome P450 pathway. GO annotations related to ACSM5 consist of GTP binding and butyrate‐CoA ligase activity . ACSM5 aet al.  reportedBased on these seven genes, we constructed a predictive model to evaluate the risk of patients’ malignancy. Multivariate Cox regression analysis demonstrated that both pathologic T and risk score were independent prognostic factors. In addition, the nomogram model composed of pathologic T and the risk group accurately predicted the malignancies, which might be helpful in clinics with respect to guiding the clinical practice of cancer prognosis. GSEA analysis further indicated that EMT might be a potential mechanism of poor outcome in the high‐risk group of patients. EMT is a critical step in cancer metastasis. Metastasis is the leading cause of cancer‐associated deaths . During In the present study, we identified risk score, comprising the expression of seven genes , and pathologic T, as robust and independent universal biomarkers of digestive gland malignancies. Our nomogram model based on these two independent prognostic factors could efficiently predict the prognosis of patients and probably also the occurrence of EMT. However, the clinical application of this nomogram model and the exact molecular mechanism require further research in digestive gland malignancies. The mechanism regarding the key molecules also needs further study, especially for LINC01537. We also found that PDE2A might play a role in the metastasis of hepatocellular carcinoma. In conclusion, the present study demonstrates a shared molecular mechanism underlying hepatic, biliary and pancreatic cancers. Meanwhile, it also improves our cognition of the heterogeneity and complexity in digestive gland malignancies, which require more effective diagnostic, prognostic and therapeutic approaches.The authors declare no conflict of interest.Design: JZ and CCW. Data collection and analysis: JZ, JX, YXW, XZ and JJC. Data interpretation: JZ. Manuscript writing: JZ and CCW. Final approval of manuscript: All authors. The first draft of the manuscript was written by JZ and all authors commented on previous versions of the manuscript. All authors have read and approved the final version of the manuscript submitted for publication.Fig. S1. Differences between normal and CHOL samples. Principal component analysis for lnRNAs (A), miRNAs (B) and mRNAs (C). The heatmap of differentially expressed lnRNAs (D), miRNAs (E) and mRNAs (F). The volcano plot of differentially expressed lnRNAs (G), miRNAs (H) and mRNAs (I).Fig. S2. Differences between normal and LIHC samples. The heatmap of differentially expressed lnRNAs (A), miRNAs (B) and mRNAs (C). The volcano plot of differentially expressed lnRNAs (D), miRNAs (E) and mRNAs (F).Fig. S3. Volcano plots of differentially expressed lnRNAs (A), miRNAs (B) and mRNAs (C) between normal and PAAD samples.Fig. S4. Survival analysis of LINC01537 in the TCGA‐LIHC cohort.Fig. S5. Mutation landscape of key molecules associated with patient prognosis in digestive gland malignancies. (A) TCGA‐CHOL cohort. (B) TCGA‐LIHC cohort. (C) TCGA‐PAAD cohort.Fig. S6. Key molecules expression levels in HepG2 cell line.Click here for additional data file.Table S1. The correlation between LINC01537 and eight mRNAs.Table S2. The significant genes contributing to patient prognosis by univariate Cox regression analysis.Table S3. The differentially expressed EMT markers between the high‐risk group and low‐risk group.Click here for additional data file.


Ammotragus lervia) populations in the United States are a product of multiple human‐mediated introductions. Two mitochondrial markers  and one nuclear gene  were used to determine: (1) genetic variation, (2) if genetic units correspond to taxonomic designations, (3) the number and geographic origin of translocations, and (4) divergence times. Three phylogenetic analyses  produced similar topologies with two clades (I and II). Clade I contained progeny of individuals resulting from introductions to Texas and Spain, and individuals from Algeria. Individuals in Clade II were progeny of past introductions to the United States and Europe, and northern Algeria. Clade II was subdivided into two subclades (A and B) representing two haplogroups. No genetic variation was detected in the PRNP sequences. Three haplogroups appeared to correspond to the subspecies A. l. lervia and A. l. sahariensis whose native distribution includes northwestern Africa. Network analyses assigned haplogroups to two major groups similar to those depicted in the phylogenetic analyses. Genetic distances ranged from 0.80% to 5.17% and 2.99% to 15.42% for cytb and D loop, respectively; and were higher than normally recovered for caprids, warranting a reexamination of subspecific status. Divergence dates indicated a major split between A. l. lervia and A. l. sahariensis circa 2.38 mya. Together, the high level of genetic divergences among US populations and apparent presence of two subspecies of aoudad in the United States support the hypothesis of multiple introductions from multiple sources.Translocation records indicate aoudad ( A. l. sahariensis and/or A. l. blainei and A. l. lervia. Two major clades were identified using phylogenetic, network, and divergence analyses, in which genetic distances ranged from 0.80% to 5.17% and from 2.99% to 15.42% for cytochrome b and displacement loop. Given the extensive number of free‐ranging aoudad currently in Texas, the manuscript provides baseline genetic data for future management and conservation plans being developed for a species that is considered “vulnerable” in its native range.This manuscript explains that human‐mediated translocations of aoudad into the United States were a result of multiple introductions with putative subspecies identification as  Little is known concerning genetic variation and phylogeographic patterns of diversity among these putative subspecies. In reviewing the taxonomy of Caprini, Groves and Grubb . To date, no genetic information is available for the other four subspecies, complicating the resolution of phylogenetic relationships among subspecies within their native range, as well as their role in determining source‐stock origins of introduced populations throughout the world.Aoudad, also known as barbary sheep or arrui  in the early 1900s, those that documented the movement/transfers of aoudad between zoos  were not always in agreement. Further, given that private ranches were not obligated to maintain source‐stock information or geographic history records, they generally did not provide point of origin data for imported aoudad. Consequently, the multiple imports and subsequent purchase or trading of zoo progeny by private individuals, coupled with a paucity of source/origin documentation, make it difficult to discern if more than one subspecies of aoudad was introduced into the United States during this time frame.Beyond the aforementioned zoo records and discussions presented in the Simpson,  and New s Ogren, , 1965, tOvis canadensis) , and displacement loop (D loop) and one nuclear gene  were used to determine the magnitude of genetic variation. The cytb marker is used widely as a proxy to measure genetic divergence among species and subspecies . The goals of this study were to: (1) assess genetic variation in free‐ranging populations of aoudad in Texas, California, and New Mexico, (2) determine if genetic units correspond to existing taxonomic designations, (3) ascertain the number and geographic source of introductions, and (4) provide estimates of approximate divergence times among haplogroups. Mitochondrial markers, cytochrome 22.1A total of 232 aoudad samples were collected between 2018 and 2021, these included 209 samples from free‐ranging individuals, 19 samples from pedigreed captive individuals from the Fossil Rim Wildlife Center (Texas), and four historic samples , and were used in this study  was extracted from 0.1 g ear clip, muscle, liver, or 100 µl blood (stored in standard collection tubes containing EDTA) using the Qiagen DNeasy blood and tissue extraction kit . The entire cytb gene  was amplified using the polymerase chain reaction (PCR) method . Cycle sequencing reactions were conducted with BigDye Terminator v3.1 (Applied Biosystems) using the following primers: LGL766 and LGL765  was amplified in select individuals based on resulting haplogroups identified from the cytb dataset. The differences in sequencing methods for D loop are described below. Primers utilized to amplify the full‐length D loop (1097 bp) were 2340‐4 . Primers used to amplify the complete PRNP gene (771 bp) were MD582F .Data obtained from the cytb and D loop datasets were used to direct selection of individuals to be examined for the prion protein exon 3 gene  and the nuclear gene (PRNP: n = 1) datasets were obtained from NCBI GenBank and included samples examined in Derouiche et al.  was designated as the outgroup species following Ropiquet and Hassanin  models were evaluated using jModelTest‐2.1.10  model  obtained from an estimation of divergence from the most recent common ancestor , nucleotide diversity (π), number of haplotypes (h), haplotype diversity (Hd), and Fu's test of neutrality were calculated for both the entire cytb and D loop dataset  using DNAsp v6  and heterozygous nucleotide base positions were visually determined using chromatograms. The program MEGA X . In particular, three codons known to be of importance  was obtained when identical sequences were removed. This final dataset was used for all subsequent analyses involving phylogenetics, genetic distances, and genetic indices. The three phylogenetic analyses  generated similar topologies in the cytb dataset; consequently, each analysis is discussed in detail below; however, only the topology obtained from the BI analysis is shown  of 249 individuals was used to assign haplotype affiliation of all individuals to the sampled localities . Clade I contained 52 individuals from western and southeastern Algeria; Black Gap WMA, Davis Mountains, Dolan Falls Preserve, Elephant Mountain WMA, Fawcett WMA, Fossil Rim Wildlife Center, Garza Co., Glass Mountains, Kerr WMA, Love Creek Preserve, Val Verde Co., and the Waddell Ranch (now Fawcett WMA) in Texas; Mansoura Zoo, Egypt and/or Niger; and Navalvillar de Pela region, Spain. Clade II was divided into two subclades (A and B); with Subclade II‐A being supported in the BI analysis (PPV ≥ 0.95). The three haplotypes representing the 191 individual sequences forming Subclade II‐B were not supported by the three analyses and instead formed an unresolved polytomy. Subclade II‐A contained 6 individuals from the Béchar Province, Algeria; Elephant Mountain WMA and Davis Mountains in Texas; National Museum of Natural History (MNHN), Paris, France; and Vincennes Zoo, Paris, France and/or Morocco and/or La Hoya Field Station, Almería, Spain. Subclade II‐B contained 191 individuals from northern Algeria; northern Algeria and/or La Hoya Field Station and/or Tunisia, Almería, Spain; Black Gap WMA, Caprock Canyons State Park, Carrizo Mountains, Chinati Mountains, Culberson Co., Davis Mountains, Dolan Falls Preserve, Elephant Mountain WMA, Fawcett WMA, Garza Co., Kerr WMA, Love Creek Preserve, Palo Duro Canyon State Park, Presidio Co., Scurry Co., Sierra Vieja Mountains, Van Horn Mountains, and Waddell Ranch in Texas; Cambria, California; Game Management Units near Lincoln National Forest, New Mexico; Thailand; and Tunisia.The ML analysis also produced a topology (not shown) that was nearly identical to the topology obtained from the BI analysis. The only difference between the BI and ML analyses involved nodal support for Subclade II‐A. In the ML analysis, Subclade II‐A was only moderately supported (BS = 65). Similar to the BI analysis, no support was obtained for the three haplotypes representing the 191 individual sequences forming Subclade II‐B and produced an unresolved polytomy. Bootstrap support values obtained from the ML analysis were superimposed onto the BI topology Figure .For the parsimony analysis, 379,908 equally, most parsimonious trees  were retrieved. A majority rule consensus tree was generated (not shown) that was similar in topology to the tree obtained in the BI analysis , there was no nodal support (BS < 65) for either Subclade A or B resulting in an unresolved polytomy containing seven haplotypes representing the 197 individual sequences. Bootstrap support values obtained from the parsimony analysis were superimposed onto the BI topology Figure . The 51 3.1.2n = 36) was obtained when identical sequences were removed. This final dataset then was used for all subsequent phylogenetic analyses, estimations of genetic distances, and other calculation of genetic indices. The three phylogenetic analyses  generated similar topologies; consequently, each analysis is discussed in detail below; however, only the topology obtained from the BI analysis is shown  of 70 aoudad samples was used to assign haplotype affiliation of all individuals to the sampled localities  of aoudad samples Figure . Clade IThe ML analysis of the D loop dataset also produced a topology (not shown) that was essentially identical to the topology obtained from the BI analysis. As in the BI analysis, strong support was recovered for Clades I and II  as was moderate support for Subclade II‐A and Subclade II‐B . Bootstrap support values obtained from the ML analysis were superimposed onto the BI topology  for the parsimony analysis of the D loop dataset, the heuristic search was terminated before the analysis could be completed. At the point of termination , 9,461,411 equally, most‐parsimonious trees  were retrieved. The parsimony analysis produced a topology (not shown) that was essentially identical to the topology of the BI analysis. Bootstrap support values obtained from the parsimony analysis were superimposed onto the BI topology , representing a total of 64 nucleotide substitutions, were detected in the D loop dataset Table . These i3.3Estimation of Kimura‐2 parameter Kimura,  genetic Genetic distances (see Table 3.4A. l. sahariensis) from Clade II (A. l. lervia) began approximately 2.38 mya. Radiation within A. l. sahariensis (Clade I) was estimated to have occurred at 0.99 mya. The major split between individuals assigned to Subclade II‐A and Subclade II‐B is estimated within the last 1.25 mya followed by radiation within Subclade II‐A and Subclade II‐B was estimated at 0.65 and 0.85 mya, respectively.A Molecular Clock Test  was 66, nucleotide diversity (π) was 0.01618, number of haplotypes (h) was 8, haplotype diversity (Hd) was 0.365, and Fu's test of neutrality was 42.287 for the entire cytb dataset (excluding sites with gaps or missing data) and within‐population indices are reported in Table s) was 116, nucleotide diversity (π) was 0.02296, number of haplotypes (h) was 5, haplotype diversity (Hd) was 0.182, and Fu's test of neutrality was 25.498 and within‐population indices are reported in Table p > .05) whereas Tajima's D for the D loop dataset was −1.3532 and was not significant (p = 0.068) using the program Arlequin . Given the similarity of the results of the cytb and D loop sequence analyses from all three studies, inferences from the smaller D loop dataset can be inferred using the larger cytb dataset. The PRNP gene provided negligible information relative to phylogenetic association and source‐stock determination; therefore, discussion was restricted solely to the basic description of the prion protein (PrP) genotype in aoudad.It is important to note that data used in this research were obtained from three independent studies: cytb only  produced a similar arrangement of individuals with two major clades identified . In addition, the genetic divergences of D loop observed between the two clades of aoudad (I and II) indicated a high level of genetic divergence compared to subspecies of Rupicapra  at 2.38 mya. Similar divergence estimates were reported for Ammotragus by Derouiche et al. (A. l. sahariensis (Clade I) was estimated to have occurred at 0.99 mya. The major split between individuals assigned to Subclade II‐A and Subclade II‐B was estimated to have occurred within the last 1.25 mya. Radiations within Subclade II‐A and Subclade II‐B were estimated at 0.65 and 0.85 mya, respectively. The divergence between Clades I and II and subsequent radiations within each clade were similar to that estimated for recognized subspecies of bovids  haplogroup was represented by individuals in Subclade II‐B. The second most common haplogroup represented by individuals in Clade I was restricted to populations in central and west‐central Texas. The third haplogroup (Subclade II‐A) was at a much lower frequency and was restricted to two localities in extreme western Texas.A. l. lervia, Cassinello, Based on the available information garnered from translocation records, state agencies, and scientific publications Barrett, , it appeAmmotragus lervia lervia. Second, although there are no translocation records  studbook indicated that individuals from their facility were obtained from the Khartoum Zoo, Sudan circa 1991 and therefore were most likely representative of the Kordofan subspecies, A. l. blainei . However, no samples clearly assignable to A. l. blainei were available for this study; therefore, the source‐stock at the Khartoum Zoo were not actually representative of A. l. blainei or that A. l. sahariensis and A. l. blainei are genetically identical based on the mtDNA dataset ; however, it most likely is either affiliated with A. l. lervia or one of the other subspecies that have yet to be genetically examined. Clearly, Clades I and II differ substantially in regard to levels of genetic divergence . However, when included with the D loop dataset herein, Haplotype Amle02 as well as Haplotype Amle03 grouped with samples from Algeria  contained in Clade II‐A. Additionally, Haplotype Amle01 was associated with Clade II‐B. This discrepancy suggests that Haplotype Amle04  most likely is representative of A. l. sahariensis as this haplotype groups with Clade I; whereas Haplotypes Amle01, Amle02, and Amle03 and other samples from Texas, are representative of A. l. lervia or one of the other subspecies that have yet to be genetically examined. These results imply that additional populations from Almería and surrounding regions should be examined to determine whether they are A. l. lervia or A. l. sahariensis or if they represent an undescribed genetic subspecies.Relative to Europe, Stipoljev et al.  postulat55.1n = 2) and Subclade II‐B (n = 1), respectively. Similarly, samples collected at this locality in 2020 indicated that both of these haplogroups persisted over the 40‐year interval . Third, the Dolan Falls Preserve population is highly skewed toward one haplogroup as only three individuals represented Clade I and 32 individuals were assigned to Subclade II‐B. Under this disproportional representation of haplotypes, over time, the haplogroup associated with Subclade II‐B may outcompete the haplogroup associated with Clade I, resulting in a local extinction of the second most common haplotype in United States. Fourth, if haplogroups are indicative of subspecies .Given the high level of genetic divergence ; Data curation (lead); Formal analysis (lead); Investigation (lead); Methodology (lead); Project administration (lead); Resources ; Validation ; Visualization ; Writing – original draft (lead); Writing – review & editing (lead). Rachael C. Wiedmeier: Data curation (supporting); Investigation (supporting); Resources (supporting); Writing  – review & editing (supporting). Emma K. Roberts: Data curation (supporting); Investigation (supporting); Methodology (supporting); Writing – review & editing (supporting). David R. Pipkin: Data curation (supporting); Resources (supporting); Writing – review & editing (supporting). Froylán Hernández: Data curation (supporting); Resources (supporting); Writing – review & editing (supporting). Joseph P. Bayouth: Data curation (supporting); Formal analysis (supporting); Writing – review & editing (supporting). Warren C. Conway: Conceptualization ; Data curation (supporting); Funding acquisition (lead); Project administration ; Resources ; Supervision ; Validation ; Visualization ; Writing – review & editing . Robert D Bradley: Conceptualization ; Data curation ; Formal analysis ; Funding acquisition ; Investigation ; Methodology ; Project administration ; Resources ; Software ; Supervision (lead); Validation ; Visualization (lead); Writing – original draft ; Writing – review & editing .Supplementary MaterialClick here for additional data file.


The effectiveness of emergency surgery vs. non‐emergency surgery strategies for emergency admissions with acute appendicitis, gallstone disease, diverticular disease, abdominal wall hernia or intestinal obstruction is unknown. Data on emergency admissions for adult patients from 2010 to 2019 at 175 acute National Health Service hospitals in England were extracted from the Hospital Episode Statistics database. Cohort sizes were: 268,144 (appendicitis); 240,977 ; 138,869 (diverticular disease); 106,432 (hernia); and 133,073 . The primary outcome was number of days alive and out of hospital at 90 days. The effectiveness of emergency surgery vs. non‐emergency surgery strategies was estimated using an instrumental variable design and is reported for the cohort and pre‐specified sub‐groups . Average days alive and out of hospital at 90 days for all five cohorts were similar, with the following mean differences (95%CI) for emergency surgery minus non‐emergency surgery after adjusting for confounding: −0.73 days (−2.10–0.64) for appendicitis; 0.60 (−0.10–1.30) for gallstone disease; −2.66 (−15.7–10.4) for diverticular disease; −0.07 (−2.40–2.25) for hernia; and 3.32 (−3.13–9.76) for intestinal obstruction. For patients with ‘severe frailty’, mean differences (95%CI) in days alive and out of hospital for emergency surgery were lower than for non‐emergency surgery strategies: −21.0 (−27.4 to −14.6) for appendicitis; −5.72 (−11.3 to −0.2) for gallstone disease, −38.9 (−63.3 to −14.6) for diverticular disease; −19.5 (−26.6 to −12.3) for hernia; and − 34.5 (−46.7 to −22.4) for intestinal obstruction. For patients without frailty, the mean differences (95%CI) in days alive and out of hospital were: −0.18 (−1.56–1.20) for appendicitis; 0.93 (0.48–1.39) for gallstone disease; 5.35 (−2.56–13.28) for diverticular disease; 2.26 (0.37–4.15) for hernia; and 18.2 (14.8–22.47) for intestinal obstruction. Emergency surgery and non‐emergency surgery strategies led to similar average days alive and out of hospital at 90 days for five acute conditions. The comparative effectiveness of emergency surgery and non‐emergency surgery strategies for these conditions may be modified by patient factors. EmergenFor acute conditions, such as acute diverticular disease, non‐emergency surgery strategies drawing on multidisciplinary expertise have been developed. These non‐emergency surgery strategies include: medical management; non‐surgical procedures ; or surgery deferred to the elective (planned) setting. Over the last 20 years, there has been an increase in the proportion of emergency general surgery admissions for patients over 75 years old, who are more likely to have multiple comorbidities or frailty , 12, whiThe lack of relevant evidence about the relative effectiveness of emergency surgery vs. non‐emergency surgery strategies for patients with common acute conditions is a major barrier to improving the quality of emergency general surgery services. There is variation in emergency surgery rates across NHS hospitals in England for emergency admissions with common acute conditions . Patient2The emergency surgery or not (ESORT) study used Hospital Episodes Statistics data to define patient cohorts admitted as emergencies to 175 NHS acute hospitals for five common acute conditions: appendicitis; symptomatic gall bladder disease; symptomatic diverticular disease; abdominal wall hernia; and intestinal obstruction  . The patwww.lshtm.ac.uk/research/centres‐projects‐groups/esort). Full details of the original study design are available from a previous publication [The research project was approved by the London School of Hygiene and Tropical Medicine ethics committee. The present study involved the secondary analyses of existing pseudo‐anonymised data and did not require UK National Ethics Committee approval. The design and proposed analysis of the ESORT study were informed by a patient and public advisory group during two online workshops held in July 2020 [lication  and fromlication .For patients aged 18 years old or older, hospital admissions were eligible if a finished consultant episode within the admission met all the following criteria: occurred between April 2010 and December 2019; included a main diagnosis with an International Classification of Diseases, tenth revision (ICD‐10) diagnosis code judged relevant according to the consensus of a clinical panel ; sex, ethnicity; index of multiple deprivation (a socio‐economic measure); diagnostic subcategories; number of comorbidities; and frailty. The Charlson comorbidity index  and secoThe primary outcome measure was the number of days alive and out of hospital (DAOH) at 90 days. Days alive and out of hospital is a composite measure, which encompasses mortality and total length of hospital stay (LOS) including re‐admissions for re‐interventions. It has been recommended as a standardised patient‐centred outcome measure and a core outcome measure for clinical effectiveness trials in peri‐operative medicine . This ouAn instrumental variable analysis  and difference in means (continuous measures) between the comparison groups. The instrumental variable analysis estimated the relative effectiveness of emergency surgery vs. non‐emergency surgery for each individual and fully accounted for heterogeneity of effects as well as confounding  to 9053 , vs. the requirement that they exceed 10  in DAOH at 90 days associated with emergency surgery strategies was lower for patients with acute appendicitis (−12.55 (−23.61 to −1.49)); higher for patients with intestinal obstruction (26.37 (8.71–44.02)); and similar between the comparison groups for the other three conditions.For patients with severe frailty, the mean DAOH at 90 days following emergency surgery was lower than after non‐emergency surgery strategies, with mean differences (95%CI) for appendicitis of −21.0 (−27.4 to −14.6); gallstone disease −5.72 (−11.3 to −0.2); diverticular disease −38.9 (−63.3 to −14.6); hernia −19.5 (−26.6 to −12.3); and intestinal obstruction −34.5 (−46.7 to −22.4). For patients without frailty, the mean difference (95%CI) in DAOH favoured emergency surgery for hernia (2.26 (0.37–4.15)) and intestinal obstruction (18.2 (14.8–22.47)).For patients with severe frailty, there was an increase in 90‐day mortality following emergency surgery vs. non‐emergency surgery strategies for all conditions apart from hernia . The ability of this study to draw causal inference from a retrospective cohort study rests on the instrumental variable approach to deal with unmeasured confounding and may be undermined if the requisite assumptions do not hold. However, the finding that the instrumental variable balanced important case‐mix measures, such as frailty and comorbidity, provides assurance that it would also ensure that indicators of disease severity that are not available in the database were also similar between the emergency surgery and non‐emergency surgery groups.This study highlights various areas for further research. For patients with abdominal wall hernia, the ESORT study found similar rates of emergency vs. non‐emergency surgery strategies, and outcomes for most sub‐groups were similar for patients who had emergency surgery vs. those who did not. Hence, the ESORT study findings suggest that a RCT contrasting emergency with non‐emergency surgery strategies could be warranted for patients with abdominal wall hernia, which draws on related research examining health‐related quality of life and complications for patients following acute symptomatic hernia .In conclusion, this study finds that for patients presenting as emergency hospital admissions with common acute abdominal conditions, emergency and non‐emergency surgery strategies lead to similar average DAOH at 90 days. For patients with severe levels of frailty, emergency surgery strategies may lead to worse outcomes than non‐emergency surgery strategies for each of the five acute conditions. For non‐frail patients, emergency surgery strategies may be more effective for patients with hernia and intestinal obstruction. Further research to inform how best to optimise emergency general surgery provision should recognise that factors such as the patient's frailty level may modify the comparative effectiveness of emergency surgery and non‐emergency surgery strategies.AppendixS1. Section 1. Clinical panel defined inclusion and exclusion criteria.Section 2. Clinical panel definition of emergency surgery.Section 3. Tendency to operate as an instrumental variable.Section 4. Person‐level instrumental variable approach.Section 5. Proxies for the quality of acute care.Section 6. Sensitivity analysis.Click here for additional data file.Table S1. Application of ESORT study inclusion and exclusion criteria for emergency admissions to 175 acute NHS hospitals in England April 2010–December 2019.Table S2. Diagnostic subcategories.Table S3. Instrumental variable strength for the hospital‐level tendency to operate within the HES data (2009–19) for emergency admissions that met the ESORT study inclusion criteria for each of the five conditions.Table S4. Clinical management for the emergency surgery and non‐emergency surgery groups in and after (up to 30 days) the time window for emergency surgery.Click here for additional data file.Figure S1. Tendency to operate variation.Click here for additional data file.Figure S2. Balance plots.Click here for additional data file.Figure S3. Kaplan–Meier plots.Click here for additional data file.Figure S4. Mortality forest plots.Click here for additional data file.Figure S5. LOS forest plots.Click here for additional data file.Figure S6. Sensitivity analysis.Click here for additional data file.


Accurate assessment of volume responsiveness in elderly patients is important as it may reduce the risk of post-operative complications and enhance surgical recovery. This study evaluated the utility of two Doppler ultrasound-derived parameters, the carotid corrected flow time (FTc) and respirophasic variation in carotid artery blood flow peak velocity (ΔVpeak), to predict volume responsiveness in elderly patients under general anaesthesia.A total of 97 elderly patients undergoing elective abdominal surgery under general anaesthesia were enrolled in this prospective observational study. After entering the operating room, all patients underwent radial artery puncture connected with a LiDCO device to measure stroke volume variation (SVV), and fluid therapy was performed after anaesthesia induction. Patients were classified as responders if SVV ≥ 13% before fluid challenge and nonresponders if SVV < 13%. The FTc, ΔVpeak, SVV and haemodynamic data were measured by ultrasound at baseline (T0) and before (T1) and after (T2) fluid challenge. The correlations between the Doppler ultrasound-derived parameters and SVV were analysed, and the receiver operating characteristic (ROC) curves was computed to characterize both FTc and ΔVpeak as measures of volume responsiveness in elderly patients.r = -0.77; P < 0.01), and ΔVpeak was positively correlated with SVV . FTc and ΔVpeak predicted SVV ≥ 13% after general anaesthesia in elderly patients, with areas under the receiver operating characteristic curves (AUROCs) of 0.811  and 0.781 , respectively. The optimal cut-off values of FTc and ΔVpeak to predict SVV ≥ 13% were 340.74 ms  and 11.69% , respectively.Forty-one (42.3%) patients were fluid responders. Carotid FTc before fluid challenge was negatively correlated with SVV before fluid challenge ; registered 23 March 2020. The perioperative management of elderly patients is challenging for anaesthesiologists due to the functional decline of various organ systems and comorbidities; therefore, fluid management is critical . Fluid oStroke volume variation (SVV) is a dynamic indicator based on heart–lung interactions that is now widely used in fluid management . Howeverwww.chictr.org.cn; ChiCTR2000031193). All methods were carried out in accordance with Declaration of Helsinki. After written informed consent was obtained from the participants, 100 patients were assessed, and 97 patients were enrolled in this prospective observational study between May 2021 and November 2021. Elderly patients (age 65 or older) of either sex with American Society of Anesthesiologists physical status ( ASA PS) I-III, cardiac function class I-II, and body mass index (BMI) 18–30 kg/m2 who underwent elective gastrointestinal surgery under general anaesthesia after fasting for at least 6 to 8 h were recruited for this study. Exclusion criteria were as follows: systolic blood pressure (SBP) ≥ 180 mmHg or diastolic blood pressure (DBP) ≥ 110 mmHg, arrhythmia, heart valve disease, peripheral vascular disease, chronic kidney disease, cerebrovascular disease, carotid artery stenosis > 50%, anatomical variation, history of previous neck surgery or neck trauma, chronic obstructive pulmonary disease, severe anaemia or hypotension, severe hypotension after anaesthesia induction (SBP less than 90 mmHg or vasoactive drugs used more than 3 times), and allergy to vasoactive drugs and colloids involved in the study.The study protocol was approved by the Institutional Ethics Committee of The First Affiliated Hospital of University of Science and Technology of China ( NO.2021KY096) and registered in the Chinese Clinical Trial Register , noninvasive blood pressure measurement, pulse oximetry, and bispectral index (BIS) recording were commenced. Intravenous infusion of lactated Ringer solution  at 4 mL/kg/h was done through the peripheral vein. Radial artery puncture was performed under local anaesthesia to invasively monitor blood pressure and connect the patient to the LiDCO  system to monitor SVV. Patients were placed in a supine position in a calm state, and baseline carotid FTc, ΔVpeak and haemodynamic data were measured before general anaesthesia (T0). General anaesthesia was induced with etomidate at 0.15–0.2 mg/kg and sufentanil at 0.4–0.5 µg/kg, and endotracheal intubation was facilitated by intravenous rocuronium at 0.8 mg/kg. The patients were ventilated using volume control with a tidal volume of 8 -10 ml/kg, respiratory rate 8–12 breaths/min, inspiratory-to-expiratory ratio 1:2, positive end-expiratory pressure 0 cmH2O, and maintenance of end-tidal carbon dioxide partial pressure at 35–45 mmHg. Anaesthesia was maintained with propofol, remifentanil, and sevoflurane to keep the BIS between 40 and 60. The SVV, carotid FTc, ΔVpeak and haemodynamic values were measured 5 min after tracheal intubation (T1). At this time, the patients were categorized according to their SVV value; SVV ≥ 13% was the responder group, and < 13% was the nonresponder group. After recording these data, the patients were administered a fluid challenge of 7 ml/kg ideal body weight of 6% hydroxyethyl starch 130/0.4  within 30 min. Five minutes after completion of the fluid challenge, the same haemodynamic parameters were measured again (T2). Measurements at T2 were divided into three cases: 1. Patients with an unopened abdomen and no pneumoperitoneum could be measured directly. 2. In patients with an established pneumoperitoneum, the pneumoperitoneum was released in collaboration with the surgeon, and the data were measured 5 min later. 3. If the patient's abdomen had been opened, the surgeon paused the abdominal operation and covered the incision with gauze before measuring.FTc and ΔVpeak were measured by carotid ultrasound in the right common carotid artery as described by Blehar et al.  and SongΔVpeak was measured the same way FTc was. The maximum and minimum systolic velocity peaks were obtained in a single respiratory cycle. The calculation method ofΔVpeak was as follows: ΔVpeak = (maximum peak velocity-minimum peak velocity)/ [(maximum peak velocity + minimum peak velocity)/2] × 100. Each examiner measured it twice, and the mean of the four values was used for analysis.Sample-size calculation was performed with the Tests for One ROC Curve module in PASS 11 software. Previous studies have reported that the area under the receiver operating characteristic (ROC) curve (AUROC) of the descending aortic FTc to predict fluid responsiveness was 0.82 , so we a2 test for categorical variables.Normality distribution was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Data are presented as the mean and standard deviation for normally distributed continuous variables and as absolute numbers or percentages for categorical variables. Nonnormally distributed variables are reported as medians and interquartile ranges. Responder and nonresponder groups were compared by the independent t test for normally distributed data, the Mann–Whitney U test for nonnormally distributed data, and the χP-value < 0.05 (two-tailed) was considered statistically significant.The Pearson correlation coefficient was calculated to assess the relationships between ultrasound parameters and SVV. ROC curve analysis was performed to assess the ability of the ultrasound-derived parameters FTc and ΔVpeak to predict SVV ≥ 13%. The best cut-off value was that which maximized the Youden index  and the n = 5), severe hypertension (n = 3), severe anaemia (n = 2), or refusal to participate (n = 2). One hundred subjects were eventually enrolled. During the study, 2 patients developed severe hypotension after anaesthesia, and 1 patient was allergic to colloids. After they were excluded, 97 patients were included in the final analysis  and nonresponders (n = 56) . However, the common carotid FTc was significantly lower (P < 0.001) and the ΔVpeak was significantly higher (P < 0.001) in the responder group.A total of 112 eligible patients were evaluated, of whom 12 were excluded due to arrhythmia  and 0.781 , respectively. The best cut-off value of FTc obtained from this study was 340.74 ms, with a sensitivity of 76.8% and specificity of 80.5%. The optimal cut-off value of ΔVpeak was 11.69%, with a sensitivity of 78% and specificity of 67.9%.The grey zone for FTc occurred between 331.44 and 345.90 ms and contained 47.4% of patients. The grey zone for ΔVpeak occurred between 9.97% and 13.42% and included 48.5% of patients.The ability of FTc and ΔVpeak to predict SVV ≥ 13% at T1 is shown in Fig. This study showed that ultrasound assessment of carotid artery FTc was a more accurate and reliable indicator of volume responsiveness in elderly patients under general anaesthesia. ΔVpeak could also predict SVV ≥ 13% well. The changes in FTc and ΔVpeak from before to after fluid treatment were opposite: FTc increased, while ΔVpeak decreased.The ability of carotid FTc to predict fluid responsiveness based on transoesophageal ultrasound measurement of descending aortic FTc has proven useful for volume optimization . Kim et In previous studies of carotid ultrasound, various hemodynamic measures were used as the reference standards to determine volume responsiveness. These included invasive monitoring, MAP and noninvasive ultrasound monitoring . Among tCuriously, FTc also increased more following fluid administration in the non-responsive group, which is inconsistent with the findings of Kimura A et al.  and Xu LΔVpeak also well predicted SVV ≥ 13% in mechanically ventilated elderly subjects, with an AUROCof 0.781 and a cut-off value of 11.69%. Compared with Song and colleagues' study  of patieIt is worth mentioning that the changes in haemodynamic parameters were different in the two groups. The FTc value of the responder group was lower than that of the nonresponder group, while the ΔVpeak value was significantly higher in the nonresponder group. After anaesthesia induction, the blood pressure and heart rate of the subjects in the two groups decreased, but the decrease in the responder group was pronounced. All of these results suggest that subjects in the responder group had volume deficits and were more prone to haemodynamic fluctuations due to the effects of anaesthetic drugs.Our study has some limitations. First, the type of surgery was divided into laparoscopic surgery and open surgery. Although the measurement time for patients with pneumoperitoneum was 5 min after the pneumoperitoneum was relieved, the pneumoperitoneum may still have affected the measurement results , 26. SecIn conclusion, we found that the carotid FTc and ΔVpeak of elderly patients have good correlations with SVV, so they perform moderately well at predicting volume responsiveness. Considering its higher AUROC, as well as its slightly smaller grey area, FTc could be a more feasible and reliable predictor of SVV ≥ 13% than ΔVpeak. Further studies are needed to identify its role in other types of surgery and high-risk patients, such as those with severe cardiovascular disease.


Studies concerning the impact of air temperature on esophagogastric variceal bleeding (EGVB) have yielded conflicting results. Our study aimed to evaluate the correlation between air temperature and EGVB.A time-stratified case-crossover study design was performed. Patients received emergency gastroscopic hemostasis for upper gastrointestinal bleeding between Jan 1, 2014, and Dec 31, 2018 in the Fifth Medical Center of PLA General Hospital were enrolled. Conditional logistic regression analysis was applied to determine the association between air temperature and EGVB for different lag structures.A total of 4204 cirrhotic patients diagnosed with EGVB and received emergency gastroscopic hemostasis were enrolled. The mean number of daily EGVB cases peaked in October (2.65 ± 1.69) and fell to the lowest level in July (1.86 ± 1.38), and was 2.38 ± 1.58 in spring, 2.00 ± 1.46 in summer, 2.37 ± 1.58 in autumn, and 2.45 ± 1.58 in winter, respectively (P < 0.0001). In conditional logistic regression analysis, no significant correlations between air temperature and EGVB were observed and no significant difference were found when stratified by age, sex, etiology, liver cancer status, and grade of varices.Emergency admission for EGVB showed significant monthly and seasonal fluctuations, while in conditional logistic regression analysis, no association between minimum temperature and emergency admission for EGVB were observed. Esophagogastric variceal bleeding (EGVB) is the most life-threatening complication of cirrhosis and occurs in 5–15% of Esophagogastric varices (EV) patients annually . The comMeteorological factors are closely related to human health, and the evidence is generally clear that air temperature is associated with higher incidence and mortality in patients with cardiorespiratory and cerebrovascular diseases –7. SeverOur study used a time-stratified case-crossover study which had been widely used to examine short-term environmental exposure factors on acute cardiovascular and cerebrovascular events –15. We aWe collected clinical characteristics  of patients received emergency gastroscopic hemostasis for upper gastrointestinal bleeding between Jan 1, 2014, and Dec 31, 2018 in the Fifth Medical Center of PLA General Hospital. All diseases were coded by International Classifications of Diseases version 10 (ICD-10). Patients with a diagnosis of EGVB (ICD-10-K74.609 + and I85.001) treated with endoscopic varices ligation, endoscopic injection sclerotherapy, histoacryl injection, and Sengstaken-Blakemore tube were included. We excluded patients with concomitant aetiologies of upper gastrointestinal bleeding including peptic ulcer bleeding , acute haemorrhagic gastritis and duodenitis , Mallory–Weiss tear (ICD-10-K22.601), Dieulafoy’s lesion with haemorrhage (ICD-10-K25.051). Meteorological data on daily minimum temperature, relative humidity (RH%) and atmospheric pressure (AP) between Jan 1, 2014, and Dec 31, 2018 were obtained from the China meteorological administration.Microsoft Excel  was used for data collection and analysis. Data were expressed as mean ± standard deviation or count number. General and clinical characteristics of all enrolled cases were described, and ANOVA methods were applied to assess the seasonal and monthly variations of daily emergency admission for EGVB.We then used conditional logistic regression to examine association between air temperature and emergency admission for EGVB for each lag day. Distributed lag non-linear models (DLNM) with three degrees of freedom in the natural cubic splines and a maximum lag of 7 days were used to adjust for the delayed and non-linear effects of temperature. To control for the effects of other meteorological factors on EGVB, we added RH% and AP to the models. The effects of public holidays were not included in the models for the “Green Channel” of emergency medical service for EGVB. We calculated the percentage changes on the risks of EGVB per interquartile range (IQR) increase in minimum temperature on different single lag day (lag0-lag7). The associations with mean minimum temperature (lag01-lag07) on different lag days were also calculated to avoid underestimating the effect of the minimum temperature measured by single lag day model. We analyzed the exposure response association between minimum temperature and emergency admission for EGVB in the event day (lag 0) and different lag days . We straWe carried out statistical analysis with R version 3.6.1 and SPSS version 20.0. All statistical tests were two-sided and P < 0.05 was considered statistically significant.A total of 4204 cirrhotic patients diagnosed with EGVB and received emergency gastroscopic hemostasis between Jan 1, 2014, and Dec 31, 2018 in the Fifth Medical Center of PLA General Hospital were enrolled in this study. The mean age was 53.32 ± 11.46 years, 3155 (75.1%) patients were male, 936 (22.3%) patients were diagnosed with liver carcinoma. Main aetiologies of cirrhosis in these patients were HBV infection , alcohol liver disease , HCV infection , primary biliary cirrhosis , autoimmune hepatitis , and drug induced liver injury , and approximately 5.5% (n = 233) were cryptogenic cirrhosis. 2820 patients were diagnosed as esophageal variceal bleeding, 777 patients were diagnosed as gastric variceal bleeding, 25 patients were diagnosed as isolated gastric variceal bleeding, and the others couldn’t find the definite location of hemorrhage.P < 0.0001 and P < 0.0001). In Fig. The mean number of daily emergency admission for EGVB showed significant monthly and seasonal fluctuations (p = 0.208) for a temperature of > 0 and <  = 10, 1.32  for a temperature of > 10 and <  = 20, and 1.35  for a temperature of > 20 after adjusted for RH% and AP  for a temperature of > − 10 and <  = 0 compared with a temperature <  = − 10, 1.34  Airdecrease –24. TherThere are some limitations in our study. First, most patients were first visit, we couldn’t get detailed information on the hepatic venous pressure gradient and Childs-Pugh score at baseline to further study the association between air temperature and EGVB in different disease stage. Secondly, not all patients requiring an emergency admission for EGVB in Beijing were included, while Fifth Medical Center of PLA General Hospital is the largest institution providing emergency gastroscopic hemostasis and a “Green Channel” of emergency medical service for EGVB patients in Beijing, and our study enrolled the majority of EGVB patients in Beijing. The last limitation was that we could not discriminate the indoor and outdoor air temperature; however, this is not highlighted as a major concern in most previous studies emphasizing the impact of air temperature on diseases.Emergency admission for EGVB showed significant monthly and seasonal fluctuations, while in conditional logistic regression analysis, no associations between air temperature and emergency admission for EGVB were observed.


Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favourable effects on cardiorenal outcomes in patients with mild‐to‐severe chronic kidney disease with increased albuminuria and type 2 diabetes.Two large, randomized trials have evaluated the effects of finerenone on clinical outcomes. The first trial (FIDELIO‐DKD) investigated renal outcomes, and the second (FIGARO‐DKD) cardiovascular outcomes.Patients in the two studies had a high intrinsic risk of hyperkalemia due to type 2 diabetes, treatment with optimized doses of an inhibitor of the renin‐angiotensin system, and, in some patients, their advanced chronic kidney disease. This was reflected in the incidence of hyperkalemia in the placebo group during the trials. Patients on finerenone had a significantly higher incidence of hyperkalemia compared with patients on placebo, but treatment discontinuation due to hyperkalemia was low, and no patients experienced death attributable to hyperkalemia. Structured routine potassium monitoring with temporary treatment interruption and dose reduction, as used in the two trials, should ensure the safe use of finerenone to protect the kidneys and cardiovascular system of patients with albuminuric chronic kidney disease and type 2 diabetes.The aim of this document is to highlight the routine potassium management required when using finerenone and to provide practical recommendations. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with mild to severe chronic kidney disease with increased albuminuria and type 2 diabetes. This article highlights the routine potassium management required when using finerenone and provides furthermore practical recommendations. Both studies showed increased serum potassium concentrations and hyperkalemia rates with finerenone treatment compared with placebo, with a maximum difference in mean serum potassium between groups of 0.16 mmol/L in FIDELIO‐DKD and 0.23 mmol/L in FIGARO‐DKD. The increase in risk of hyperkalemia leading to permanent treatment discontinuation (1.7% for finerenone and 0.6% for placebo) was small.In this article, we aim to highlight aspects of potassium management with finerenone that were applied in the two trials and that are of particular relevance to clinical practice. We believe that a simple strategy for the management of hyperkalemia is important among clinicians, when several renoprotective drugs  may cause increases in potassium concentrations. Consequently, there is a high risk of drug discontinuation, with an increased risk of progression towards end‐stage kidney disease (ESKD). This discontinuation can be avoided by applying simple protocols for potassium management. In this regard, we spotlight the fact that changes in patient's serum potassium concentrations were predictable and manageable with routine potassium monitoring throughout the entire finerenone trial program. This reliable routine may thereby serve as a basis for potassium management with finerenone in clinical practice.22.1Hyperkalemia can be classified as acute (as occurring in an emergent setting), chronic, or recurrent, depending on the onset and number of hyperkalemia episodes that have occurred.Although the European Society of Cardiology (ESC),The KDIGO controversies' conference report defines the severity of hyperkalemia by both serum potassium concentration and ECG changes.2.2Abnormal serum potassium concentrations represent one of the most important electrolyte disorders in clinical practice. In this regard, potassium plays a critical role in normal cell membrane electrophysiology, with both hyperkalemia and hypokalemia leading to electrophysiological perturbations.2 approximately doubled the risk of hyperkalemia.An international meta‐analysis of over 1.2 million patients with CKD from 27 different cohorts examined the risk factors leading to hyperkalemia. The risk of hyperkalemia correlated strongly with the estimated glomerular filtration rate (eGFR): a decrease in eGFR of 15 ml/min per 1.73 m33.12 and a history of diabetic retinopathy or severe albuminuria (UACR ≥300 but <5000 mg/g) and an eGFR ≥25 to ≤75 ml/min/1.73 m2.The FIDELIO‐DKDIn patients with CKD and T2D, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo.3.22 and a history of diabetic retinopathy or severe albuminuria (UACR ≥300 but <5000 mg/g) and an eGFR of at least 60 ml/min/1.73 m2. All patients were treated with RAS blockade at the maximum tolerated dose. The median follow‐up time was 3.4 years.The FIGARO‐DKD trial included 7437 patients with T2D and CKD.In patients with T2D and stage 2 to 4 CKD with moderately increased albuminuria or stage 1 or 2 CKD with severely increased albuminuria, finerenone improved cardiovascular outcomes compared with placebo.3.3p = .0018). The risk of composite kidney event, i.e., time to the first episode of kidney failure, sustained decrease in eGFR by ≥57% from baseline over a period of ≥4 weeks, or death from kidney failure, was 23% lower with finerenone compared with placebo . A kidney‐related event occurred in 360 (5.5%) patients on finerenone and 465 (7.1%) on placebo.FIDELITY, a pooled‐analysis of more than 13,000 patients from the FIGARO‐DKD and FIDELIO‐DKD phase III trials, demonstrated cardiovascular and kidney benefits of finerenone in patients with CKD and T2D.42 and 2–3 times per year for patients with UACR 30–300 mg/g and eGFR 15–59 ml/min per 1.73 m2).In the FIDELIO‐DKD and the FIGARO‐DKD trials, hyperkalemia was reported using thresholds of >5.5 mmol/L for mild hyperkalemia and >6.0 to <6.5 mmol/L for moderate hyperkalemia, in accordance with the latest KDIGO guidance based on the protocol.2), the incidence of hyperkalemia with finerenone treatment was lower in the former (10.8% vs. 18.3%), despite the longer median follow‐up (3.4 vs. 2.6 years).Finerenone had a predictable impact on serum potassium concentrations in both trials with a maximum difference in mean serum potassium between groups of 0.23 mmol/L in FIDELIO‐DKD and 0.16 mmol/L in FIGARO‐DKD. Given the higher mean eGFR in the FIGARO‐DKD trial compared with the FIDELIO‐DKD trial . If serum potassium concentrations are >4.8‐≤ 5.5 mmol/L, the dose should be maintained at 10 mg daily or 20 mg daily.If serum potassium concentrations are ≤4.8 mmol/L, the dose should be continued or increased to 20 mg per day ”.4.2Patients at the highest risk of hyperkalemia are those with low eGFR and high baseline serum potassium concentrations. More frequent serum potassium monitoring may be required for higher‐risk patients, including those using medications that impair potassium excretion or increase serum potassium concentrations.Finerenone is a CYP3A4 substrate. Concomitant use with a CYP3A4 inhibitor increases finerenone exposure, which may increase the risk of adverse reactions.When combined with other potassium‐raising medications, the risk of hyperkalemia is increased.4.3If serum potassium is elevated with normal acid–base balance, dietary modification is recommended to reduce potassium intake from foods of lower nutritional value after other non‐nutritional causes such as medications have been considered and treated, if medically appropriate.In a study comparing high consumption of fruits and vegetables against sodium bicarbonate and control conditions, fruit and vegetable consumption was as effective as sodium bicarbonate in reducing acidosis and slowing the decline in eGFR without increasing serum potassium.Table The recommended protein intake for stable patients with CKD is 0.55–0.60 g/kg/day, which can be reduced to 0.28–0.43 g/kg/day if it is supplemented with 7–15 g/day of KAs and essential AAs.Patients should not provide breastfeeding while using finerenone and for 1 day after stopping treatment. Patients with severe hepatic impairment should not take finerenone. Patients with moderate hepatic impairment may require additional serum potassium monitoring.5Finerenone shows kidney and cardiovascular benefits across the spectrum of patients with chronic kidney disease and type 2 diabetes, and it is well tolerated. Finerenone was associated with a low absolute risk of clinically relevant hyperkalemia, with only a small proportion of patients discontinuing treatment due to hyperkalemia, and no deaths attributed to hyperkalemia. A validated protocol for potassium monitoring and hyperkalemia management should be applied to enhance safety and to enable successful management of CKD with finerenone.Christoph Wanner: Conceptualization (lead); writing – review and editing (lead). Paola Fioretto: Writing – review and editing . Csaba P Kovesdy: Writing – review and editing . Jolanta Malyszko: Writing – review and editing . Roberto Pecoits‐Filho: Writing – review and editing . Oliver Schnell: Writing ‐ review and editing . Patrick Rossignol Writing ‐ review and editing .The publication has been funded by an unrestricted Educational Grant from Bayer AG.https://www.dopps.org/AboutUs/Support.aspxDr. Wanner received consulting fees and honoraria for lecturing from AstraZeneca, Bayer, Boehringer‐Ingelheim, FMC, GILEAD, GSK, Lilly, MSD, Sanofi and Vivor. Dr. Fioretto received condultation fees from AstraZeneca, Bayer, Boehringer‐Ingelheim, Lilly, Mundipharma, NovoNordisk. Dr. Kovesdy received consulting fees from Abbott, Akebia, AstraZeneca, Bayer, CSL Behring, Boehringer Ingelheim, Rockwell and Vifor. Dr. Rossignol: consulting for AstraZeneca, Bayer, Boehringer‐Ingelheim, CinCor, G3P, Idorsia, KBP, Novartis, Novo Nordisk, Relypsa Inc., a Vifor Pharma Group Company, Roche, Sanofi, Sequana Medical, Servier, Tasso, Vifor Fresenius Medical Care Renal Pharma, Vifor; Cofounder: CardioRenal, a company developing potassium and creatinine sensors for home self‐monitoring. Dr. Malyszko received consulting fees from AstraZeneca, Bayer, Servier. Dr. Oliver Schnell is a founder and CEO of Sciarc GmbH. Dr. Pecoits‐Filho: Research grants from Fresenius Medical Care, National Council for Scientific and Technological Development, grants (paid to employer) from Astra Zeneca, Boehringer‐Lilly, Novo Nordisk, Akebia, Bayer for participation in advisory Boards and educational activities. RPF is employed by Arbor Research Collaborative for health, who runs the DOPPS studies. Global support for the ongoing DOPPS Programs is provided without restriction on publications by a variety of funders. Funding is provided to Arbor Research Collaborative for Health and not to Dr. Pecoits‐Filho directly. For details, see


Tumors in the fibroma–thecoma group are benign tumors, typically found in the ovaries of postmenopausal women and occasionally develop in the testes. These tumors are mostly treated with radical orchiectomy because preoperative diagnosis confirming the benign nature is difficult.A 40‐year‐old man was incidentally pointed out to have a right intrascrotal mass, measuring approximately 10 cm on computed tomography. Malignant testicular tumor was suspected based on the location and size of the tumor. The patient underwent right radical orchiectomy. Histologically, the tumor had no evidence of malignancy, and the diagnosis of tumors in the fibroma–thecoma group was made. The patient had no recurrence 8 months after surgery.Intrascrotal tumors in the fibroma–thecoma group are rare benign tumors and mostly treated with radical orchiectomy due to concerns about malignancies. Further investigation is needed for accurate preoperative diagnosis, and we should be aware of these rare tumors. AFPα‐fetoproteinBCL2B‐cell/CLL lymphoma 2CK AE1/AE3Cytokeratin AE1/AE3CTComputed TomographyHCGHuman chorionic gonadotropinKITCD117LDHLactate dehydrogenaseMRIMagnetic Resonance ImagingSMASmooth muscle actinSTAT6Signal transducer and activator of transcription 6Intrascrotal tumors in the fibroma–thecoma group are rare benign tumors. Radical orchiectomy is most often performed, and the prognosis is excellent.Tumors in the fibroma–thecoma group are benign tumors, typically found in the ovaries of postmenopausal women. They are classified as sex cord–stromal tumors and account for approximately 4–7% of all gonadal neoplasms. Surgical resection is the primary treatment and is usually curative. In men, tumors in the fibroma–thecoma group occasionally develop in the testes. These tumors are exceedingly rare and typically measure 0.5–8 cm .A 40‐year‐old man was incidentally pointed out to have a right intrascrotal mass measuring approximately 10 cm on computed tomography taken to follow up on bilateral hydronephrosis Fig. .Scrotal ultrasonography showed a hypoechoic solid mass Figure . TesticuMacroscopically, the tumor was a solid, elastic, yellow‐grayish, hard mass measuring 12 × 7×5 cm and continuous with the testicular tunica albuginea but not with the testis Fig.  and S2. Although most intrascrotal masses are testicular tumors, there is a subset of extratesticular tumors arising from paratesticular tissues, including the spermatic cord, testicular tunics, epididymis, and vestigial remnants. Paratesticular tumors are rare and account for approximately 5% of intrascrotal neoplasms. Of these, approximately 75% arise from the spermatic cord.In 1997, Jones et al.Typically, fibromas of the testicular tunics are well‐circumscribed, white‐tan, or yellow. Microscopically, tumors are of low‐to‐moderate cellularity and are generally composed of uniform, randomly arranged spindle cells. The stroma is myxoid or collagenous, and inflammatory infiltrates are absent. Mitotic activity, nuclear atypicality, and necrosis are not usually seen.In our case, the tumor was continuous with the testicular tunica albuginea but not with the testis. Although the possibility of testicular stromal origin cannot be completely ruled out, the negative expression of inhibin‐α and calretinin might exclude tumors of gonadal stromal origin. The differential diagnosis of this tumor includes solitary fibrous tumor and other sex cord‐stromal tumors.Paratesticular tumors in the fibroma–thecoma group are mostly treated with radical orchiectomy, and there have been no recurrent cases reported.Tsutomu Anraku: Conceptualization; Writing – original draft. Hideki Hashidate: Investigation; Supervision; Validation. Asa Nakahara: Validation; Visualization. Tomoyuki Imai: Conceptualization; Supervision. Yoshiaki Kawakami: Supervision.The authors declare no conflict of interest.Not applicable.Written informed consent was obtained from the patient for the publication of this case report.Not applicable.This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.Figure S1. Scrotal ultrasonography showed a hypoechoic solid mass.Click here for additional data file.Figure S2. Gross appearance of the tumor before formalin fixation.Click here for additional data file.Figure S3. Microscopic appearance of the tumor tissue composed of spindle‐shaped cells.Click here for additional data file.