Objective To investigate the early changes of left ventricular end-diastolic diameter (LVEDD) in patients with severe aortic valve stenosis (AS) after transcatheter aortic valve replacement (TAVR) and the effect of the changes on the prognosis of TAVR. Methods A single-center retrospective cohort study was performed on 113 severe AS patients undergoing TAVR treatment in our hospital from December 2017 to December 2021.When the improvement of postoperative to preoperative LVEDD ≥1.8 mm was defined as early LVEDD improvement by echocardiography, the patients were divided into improvement group and non-improvement group.After the patients were followed up in 1 year after TAVR through clinic or telephone visits, their clinical data on cardiac ultrasound, electrocardiogram, and surgery-related complications were collected.The endpoints were major adverse cardiovascular events (MACE), including 1-year all-cause mortality, myocardial infarction or angina, and heart failure-related hospitalization. Results The average age of the patients was 71.2±6.5 years, and 59(52.2%) of them were female.The postoperative (4 d after TAVR on average) LVEDD was 48.9±6.5 mm, significantly shorter than that preoperatively (50.7±7.3 mm, P < 0.001).There were 53 patients obtaining early improvement of LVEDD before discharge, accounting for 46.9% of the discharged patients.Univariate Cox regression analysis found that preoperative diabetes (HR: 2.635, 95%CI: 1.013~6.858, P=0.047) and postoperative pacemaker implantation (HR: 3.518, 95%CI: 1.336~9.263, P=0.011) were risk factors for MACE at 1 year, and early improvement of LVEDD was a protective factor (HR: 0.176, 95%CI: 0.052~0.601, P=0.006).Multivariate Cox analysis indicated that early LVEDD improvement was still an independent protective factor for MACE at 1 year (HR: 0.231, 95%CI: 0.062~0.857, P=0.029). Conclusion LVEDD can be improved to various degrees in the early stage after TAVR, and the cumulative risk of developing MACE at 1 year in patients with early improvement of LVEDD is lower than that of patients without improvement.

Background Scarce data exist regarding the occurrence of mitral valve interference after transcatheter aortic valve replacement (TAVR) with Venus-A valve implantation. Several case reports have noted that the anterior mitral leaflet (AML) is mechanically affected by the prosthesis frame, particularly when implanted in a low position. This study aimed to investigate the potential factors influencing the clinical outcomes of AML interference after Venus-A valve implantation.Methods We retrospectively included 20 severe aortic valve stenosis patients who had undergone TAVR and had been implanted with the Venus-A valve at our hospital between October 2020 and June 2021. Pre- and post-procedural CT scans were used for the FEops HEARTguide simulation. Anatomically influencing factors were measured using the 3mensio software and derived from the FEops HEARTguide. The prosthesis-AML interference (PAI) was defined when it met both of two criteria:1) significant interference and limited AML movement shown by transthoracic or transoesophageal echocardiography, and 2) more than half cell intersection between the simulated Venus-A valve and the reconstructed AML revealed by the FEops HEARTguide. Anatomical factors and clinical outcomes were compared between the PAI and non-PAI groups.Results Nine PAI patients and 11 non-PAI cases were identified. PAI was associated with shorter mitral-aortic annulus distance (2.7±1.7 mm vs 5.0±2.2 mm, P = 0.019), larger prosthesis valve size ( P = 0.013), deeper implantation (12.2±3.3 mm vs 6.2±2.9 mm at non-coronary cusp side, P < 0.001) and less calcification of non-coronary cusp (median calcification score, 52.2 mm3 vs 156.0 mm3, P = 0.046). Regarding the clinical impact, PAI was associated with a higher rate of moderate or severe perivalvular leakage before discharge than those associated with the absence of PAI, with no difference in haemodynamic parameters and incidence of adverse events at the 30-day and 12-month follow-ups between the groups.Conclusions Interference between the Venus-A prosthesis valve and AML after TAVR was associated with a shorter mitral-aortic annulus distance, larger prosthesis usage, greater implantation depth, and less calcification of the non-coronary cusp. However, further studies are required to explore its long-term clinical impact.### Competing Interest StatementNic Debusschere and Giorgia Rocatello are employees of Feops NV. Sihang Cheng is an employee of Venus Medtech. The other authors report no disclosures of competing interest.### Funding StatementThis work was funded by the Chongqing Talents Project (Jin Jun) and Young Doctor Incubation Program of Xinqiao Hospital (2022YQB094).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Research Ethics Committee of the Second Affiliated Hospital (Xinqiao Hospital) of the Army Military Medical University, and the requirement for informed consent was waived because of its retrospective design.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

BackgroundTranscatheter aortic valve replacement (TAVR) in the treatment of patients with pure native aortic valve regurgitation (NAVR) has been based on the “off-label” indications, while the absence of aortic valve calcification and difficulty in anchoring was found to significantly increase the risk of prosthesis malposition. The aim of this study was to explore the anatomical predictors of severe prosthesis malposition following TAVR with the self-expandable Venus-A Valve among patients with NAVR.MethodsA total of 62 patients with NAVR who underwent TAVR with Venus-A Valve at four Chinese clinical centers were retrospectively observed. The clinical features, aortic multidetector computed tomography (MDCT) data, and clinical outcomes were compared between non-/mild malposition and severe malposition groups. Univariate logistic regression analysis was used to identify the risk factors of severe prosthesis malposition, and the receiver operating characteristic (ROC) curve was used to explore the predictive value of the risk factors.ResultsValve migration to ascending aortic direction occurred in 1 patient, and the remaining 61 patients (including 19 severe malposition cases and 42 non-/mild malposition cases) were included in the analysis. The diameter and height of the sinotubular junction (STJ) and STJ cover index (STJCI, calculated as 100%*STJ diameter/nominal prosthesis crown diameter) were all greater in the severe malposition group (all p < 0.05). Logistic regression showed that STJ diameter (OR = 1.23, 95% CI 1.04–1.47, p = 0.017), STJ height (OR = 1.24, 95% CI 1.04–1.47, p = 0.017), and STJCI (OR = 1.08, 95% CI 1.01–1.16, p = 0.032) were potential predictors for severe prosthesis malposition. The area under the ROC curve was 0.72 (95% CI 0.58–0.85, p = 0.008) for STJ diameter, 0.70 (95% CI 0.55–0.86, p = 0.012) for STJ height, and 0.69 (95% CI 0.55–0.83, p = 0.017) for STJCI, respectively. The cutoff value was 33.2 mm for STJ diameter (sensitivity was 84.2% and specificity was 65.8%), 24.1 mm for STJ height (sensitivity was 57.9% and specificity was 87.8%), and 81.0% for STJCI (sensitivity was 68.4% and specificity was 68.3%), respectively.ConclusionLarger and higher STJ, as well as greater STJ to valve crown diameter ratio, may help identify patients at high risk for severe prosthesis malposition among patients with NAVR undergoing TAVR with Venus-A prosthesis valve.

Background Ascending to high altitude (HA) contribute to the development of acute mountain sickness (AMS). The prevalence, clinical features and relative risks for AMS may dynamically evolve but has not been described. Methods A total of 1,629 healthy men aged from 16 to 45 years were enrolled. A fast ascent cohort (n=1283) ascended to 3700 m by airplane and further ascended to 4400 m by bus; a slow ascent cohort (n=346) ascended to 3450 m by bus and further ascended to 4100 m by bus. AMS was diagnosed by the Lake Louise Scoring (LLS) system. Results As diagnosed by the old LLS and new LLS, the prevalence of AMS was 68.4% and 56.1% at 3700 m, respectively, which decreased to 21.4% and 14.3% after further ascending to 4400 m in the fast ascent cohort; the prevalence of AMS was 30.3% and 25.7% at 3450 m, which increased to 36.6% and 32.2% after further ascending to 4100 m in the slow ascent cohort. Moreover, AMS-related symptoms, such as headache, dizziness and fatigue, were the leading symptoms except at 4400 m in the fast ascent cohort. Fast ascent protocol was a risk factor during the initial ascent but became a protective factor after a further ascent to a higher altitude. Conclusions Ascent protocol was the primary factor that affected the incidence of AMS and related symptoms. These findings imply a novel strategy for high altitude travels or work with a plan to ascend to a higher altitude.

Atrial natriuretic peptide (ANP) is a type of peptide hormone secreted by atrial cells, which has many important biological functions and roles. In the current study, we studied the effect of ANP on the activity of epidermal growth factor (EGF). Furthermore, we also explore the cellular properties of EGF in adult retinal pigment epithelial cell line-19 (ARPE-19). For this, we firstly analyzed the cellular properties of EGF on adult retinal pigment epithelial cell line-19 (ARPE-19), the results indicated that EGF/EGFR (epidermal growth factor receptor) internalized into the ARPE-19 cells in a time-dependent manner. In addition, we also found that EGF/EGFR can be transported into the cell nuclei of ARPE-19 in a time-dependent manner in ARPE-19 cells. Furthermore, we analyzed the effect of ANP on EGF's activity, and found that EGFR-mediated signaling was activated with EGF stimulation in a dose-dependent manner, but the intracellular signaling pathways were inhibited by ANP treatment. Additionally, we further analyzed the potential mechanism by which ANP affects the EGF signaling pathway, and the results showed that ANP alone has no effect on total EGFR expression by Western-blot assay. Next, we further evaluated the EGFR stability on the cell membrane, and the results indicated that membrane-localized EGFR expression was significantly down-regulated under ANP treatment, although the total EGFR expression was not changed. In short, the current research lays the foundation for studying the regulatory relationship between ANP and EGF.

BACKGROUND:The aims of this study were to explore the characteristics of left ventricular (LV) functional changes in subjects with or without acute mountain sickness (AMS) and their associations with AMS incidence.METHODS:A total of 589 healthy men were enrolled and took a trip from Chengdu (500 m, above sea level (asl)) to Lhasa (3700 m, asl) by airplane. Basic characteristics, physiological data, and echocardiographic parameters were collected both at Chengdu and Lhasa, respectively. AMS was identified by the Lake Louise Questionnaire Score.RESULTS:The oxygen saturation (SpO2), end-systolic volume index, end-diastolic volume index (EDVi), stroke volume index (SVi), E-wave velocity, and E/A ratio were decreased, whereas the heart rate (HR), ejection fraction, cardiac index (CI), and A-wave velocity were increased at the third day after arrival, as evaluated by an oximeter and echocardiography. However, AMS patients showed higher HR and lower EDVi, SVi, CI, E-wave velocity, and E/A ratio than AMS-free subjects. Among them, SVi, which is mainly correlated with the changes of EDVi and altered LV filling pattern, was the most valuable factor associated with AMS incidence following receiver-operator characteristic curves and linear and Poisson regression. Compared with subjects in the highest SVi tertile, subjects in the middle SVi tertile showed higher multivariable Incidence Rate Ratios (IRR) for AMS with higher incidences of mild headache and gastrointestinal symptoms, whereas subjects in the lowest SVi tertile showed even higher multivariable IRR with higher incidences of all the symptoms.CONCLUSIONS:This relatively large-scale case-control study revealed that the reduction of SVi correlated with the altered LV filling pattern was associated with the incidence and clinical severity of AMS.

PURPOSE:To observe the clinicopathological, immunohistochemical, and molecular genetic features of epithelioid glioblastoma (E-GBM), and identify tumor-associated prognostic factors. PATIENTS AND METHODS:The clinical and radiological data of fifteen cases of E-GBM were collected, and their pathological, immunohistochemical, and molecular features were examined. A 1p/19q analysis via FISH, MGMT promoter methylation by MS-PCR, and IDH1 and BRAF V600E mutation analysis by HRM-PCR were performed. The level of EZH2 expression was valuated by immunohistochemistry in 15 E-GBM cases, and the prognostic factors were analyzed in E-GBM patients. Fifteen non-E-GBM cases were used as a control. RESULTS:The fifteen cases of E-GBM included twelve males and three females, with fourteen cases supratentorially located. Headache was the main symptom. Microscopy revealed that the tumors were composed of epithelioid cells and some rhabdoid cells. The epithelioid and rhabdoid cells displayed focal discohesion, scant intervening neuropil, a distinct cell membrane, eosinophilic cytoplasm, and a laterally positioned nucleus. Most tumors showed high mitosis, zonal necrosis, and microvascular hyperplasia. Immunohistochemical findings included epithelioid cells positive for GFAP, vimentin, nestin, S-100, and INI-1. The molecular findings included no deletions of 1p/19q, EGFR amplifications, or IDH1 mutations in any case, a methylated MGMT promoter in 46.7% (7/15) cases, and a BRAFV600E mutation in 46.7% (7/15) cases. EZH2 overexpression occurred in 60.0% (9/15) of E-GBM cases. E-GBM patients with OS (≤12 months) exhibited extensive necrosis (6/6), EZH2 overexpression (6/6), MGMT promoter unmethylation (5/6), BRAFV600E mutation (3/6), and treatment (surgery4/6). E-GBM patients with OS (>12 months) exhibited focal or limited necrosis, low or negative EZH2 expression, MGMT promoter methylation (2/3), BRAFV600E mutation (3/3), and treatment (surgery+radiotherapy/chemo-radiotherapy, 2/3). CONCLUSION:E-GBM was a rare variant of glioblastoma, with histological epithelioid features and poor prognosis. Extensive necrosis, MGMT promoter unmethylation, EZH2 overexpression, and lack of adjuvant chemo-radiotherapy may indicate a poor prognosis.

Background Notch signaling abnormalities are associated with the development of various tumors, including hematopoietic and epithelium-derived tumors. However, the role of Notch signaling in tumors originating from mesenchymal cells is unclear. The effect of Notch3 expression on the prognosis of osteosarcoma and its role and mechanism in osteosarcoma cells have never been reported. Materials and methods In this study, we performed a clinicopathological analysis of 70 cases of osteosarcoma, with primary focus on survival. Osteosarcoma cell lines MTH and U2OS were used. After knockdown of Notch3 by lentiviral transfection and siRNA, the cell cycle, cell viability, and wound healing capacity were assessed. Subsequently, the Transwell assay was performed, and the expression levels of hairy and enhancer of split-1 (Hes1) and matrix metalloproteinase 7 (MMP7) were detected by RT-PCR and Western blot assay. The expression of MMP7 was also detected after knockdown of Hes1. Animal experiments were performed by injecting the cell lines MTH of Notch3 knockdown into mice tail veins and comparing the development of lung metastasis with the control group. Results Comparison of survival curves showed that Notch3 expression significantly impacts patient survival. Additionally, multivariate analysis revealed that Notch3 is an independent prognostic factor for osteosarcoma. In in vivo experiments, osteosarcoma-associated pulmonary metastasis in nude mice was reduced after Notch3 silencing. The expression of downstream effector molecule, Hes1, and that of the invasion and metastasis-associated proteolytic enzyme, MMP7, were reduced, and MMP7 was further decreased by Hes1 knockdown in in vitro experiments. Conclusion Notch3 is a prognostic factor for osteosarcoma and might regulate its invasion and metastasis through the downstream target gene Hes1 and effector MMP7.

Myelolipomas are benign tumors, consisting of hematopoietic cells and mature adipose tissue, which mainly occur within the adrenal gland. Extra-adrenal myelolipomas are rare, and fewer than 60 cases have been reported in the literature. Here, we report a case of intrasplenic myelolipoma in a 42-year-old man with more than 1 month of abdominal pain. Computed tomography scanning revealed a giant, heterogeneous, well-demarcated mass in the spleen. Splenectomy was performed, and an intrasplenic giant mass was completely excised. The diagnosis of myelolipoma was made based on morphological examination. To the best of our knowledge, this is the third reported case of myelolipoma in the human spleen.

OBJECTIVES:The rearrangement of echinoderm microtubule-associated protein-like 4-analplastic lymphoma kinase (EML4-ALK) in non-small cell lung cancer (NSCLC) cells might be a promising therapeutic target. However, the low positive rate seeks a reliable and cost-effective method for ALK rearrangement prescreening. This study aimed to evaluate the application of a novel primary antibody 1A4 for routine ALK immunohistochemistry (IHC) test. MATERIALS AND METHODS:Primary antibody 1A4 and D5F3 were used for the screening of 595 formalin-fixed, paraffin-embedded tissues of consecutive patients with lung adenocarcinoma for ALK-positive candidates. Ventana detection system and fluorescence in-situ hybridization (FISH) were used as reference methods. RESULTS:Among 595 cases, the protein expression statuses of 1A4 were 3+ (18), 2+ (50), 1+ (153), and 0+ (374), and those of D5F3 were 3+ (17), 2+ (18), 1+ (20), and 0+ (540). Ventana detection system and FISH test results were successfully obtained from 482 cases. A total of 298 specimens with 1A4 (-) showed 100% concordance with standard FISH results. All 58 FISH (+) cases were identified by antibody 1A4. Meanwhile, 14 and 5 were missed by antibody D5F3 with routine IHC and Ventana system, respectively. 1A4 with routine IHC had better sensitivity (100%, 75.9%, and 91.4%, respectively), but lower specificity (70.3%, 99.8%, and 100%, respectively), than D5F3 with routine IHC and Ventana system. CONCLUSION:The novel antibody 1A4 used as a prescreening method may help to reduce the false-negative rearranged ALK status if FISH or reverse transcription polymerase chain reaction results were used for validation.

Recent genome-wide association studies identified the common genetic variants in 9p21 were associated with the coronary artery disease (CAD). However, whether this locus could predict the severity of CAD in Chinese Han population is unclear. 499 CAD patients who underwent coronary angiography (CAG) have been enrolled for this study. The single-nucleotide polymorphisms rs2383207 and rs2383206 in 9p21 were genotyped in 499 CAG cases and 1519 controls in Chinese Han population. The gene dosage of 9p21 was stratified by the degree of vascular lesions and tested for association with the severity of CAD. Rs2383207 and rs2383206 demonstrated significant associations with 2-vessel and 3-vessel disease (P = 2.0×10(-3) and 1.9×10(-4) , respectively). GG genotypes of rs2383206 occurred higher proportion of left main trunk (LM) disease (P = 6.0×10(-3) ). GG genotypes of rs2383207 occurred higher proportion of left anterior descending artery disease (LAD) and right CAD (RCA) (P = 2.7×10(-6) and 1.6×10(-4) , respectively). The risk allele G of rs2383207 was associated with severity of CAD estimated by the Gensini score (P = 3.6×10(-5) ). Rs2383207 may strongly influence the development of CAD in Chinese Han population. The gene dosage in 9p21 could predict the severity of CAD.

Objective—Recent genome-wide association studies have identified that genetic variants in the SLC22A3-LPAL2-LPA gene cluster influence plasma lipoprotein(a) [Lp(a)] concentration. However, the association between this gene cluster and the severity of coronary artery disease (CAD), especially the potential underlying mechanism, remains unclear. The purpose of this study was to investigate the association between variation in the SLC22A3-LPAL2-LPA gene cluster and CAD. Approach and Results—We performed 2-stage case–control studies in a Chinese Han population. The variant genotypes were examined for their association with both Lp(a) level and severity of CAD. Putative mechanisms were also evaluated. One single nucleotide polymorphism, rs3088442, in the SLC22A3-LPAL2-LPA gene cluster was significantly associated with both plasma Lp(a) levels and CAD severity. The gene dosage of the risk allele at rs3088442 indicated a robust association with left main trunk disease (P=0.046), number of vascular lesions (P=4.5×10–3), and Gensini scores (P=0.012) in patients with CAD. Reporter gene analysis indicated that the rs3088442 G allele might suppress miR-147a binding to the 3′ untranslated region of SLC22A3, resulting in altered SLC22A3 and LPA gene expression (P=0.015 and 9.2×10–6, respectively), possibly explaining the increased plasma Lp(a) levels and risk of CAD. Conclusions—The genotype of rs3088442 within the SLC22A3-LPAL2-LPA gene cluster may contribute to regulation of plasma Lp(a) levels and possibly to the severity of CAD in a Chinese Han population.

Primary diffuse large B cell lymphoma (DLBCL) of the uterus is rare, and primary DLBCL arising from a uterine leiomyoma (collision tumor) has not been reported in the literature.

To investigated the objective indicators and potential genotypes for acute mountain sickness (AMS). 176 male subjects were evaluated for symptoms scores and physiological parameters at 3700 m. EPAS1 gene polymorphisms were explored and verified effects of potential genotypes on pulmonary function by inhaled budesonide. The incidence of AMS was 53.98% (95/176). The individuals who suffered from headache with anxiety and greater changes in heart rate (HR), the forced vital capacity (FVC), and mean flow velocity of basilar artery (Vm-BA), all of which were likely to develop AMS. The rs4953348 polymorphism of EPAS1 gene had a significant correlation with the SaO2 level and AMS, and a significant difference in the AG and GG genotype distribution between the AMS and non-AMS groups. The spirometric parameters were significantly lower, but HR (P = 0.036) and Vm-BA (P = 0.042) significantly higher in the AMS subjects with the G allele than those with the A allele. In summary, changes in HR (≥82 beats/min), FVC (≤4.2 Lt) and Vm-BA (≥43 cm/s) levels may serve as predictors for diagnosing AMS accompanied by high-altitude syndrome. The A allele of rs4953348 is a protective factor for AMS through HR and Vm-BA compensation, while the G allele may contribute to hypoxic pulmonary hypertension in AMS.

Myelolipomas are benign tumors, consisting of hematopoietic cells and mature adipose tissue, which mainly occur within the adrenal gland. Extra-adrenal myelolipomas are rare, and fewer than 60 cases have been reported in the literature. Here, we report a case of intrasplenic myelolipoma in a 42-year-old man with more than 1 month of abdominal pain. Computed tomography scanning revealed a giant, heterogeneous, well-demarcated mass in the spleen. Splenectomy was performed, and an intrasplenic giant mass was completely excised. The diagnosis of myelolipoma was made based on morphological examination. To the best of our knowledge, this is the third reported case of myelolipoma in the human spleen.

Background: Oral glucocorticoids can prevent acute mountain sickness (AMS). Whether inhaled budesonide (BUD) can prevent AMS remains unknown. Objective: Our aim was to investigate the effectiveness of BUD in AMS prevention. Methods: Eighty subjects were randomly assigned to receive budesonide (BUD, inhaled), procaterol tablet (PT), budesonide/formoterol (BUD/FM, inhaled), or placebo tablet (n = 20 in each group). Subjects were treated for 3 days before ascending from 500 m to 3700 m within 2.5 h by air. Lake Louis AMS questionnaire, blood pressure, heart rate, and oxygen saturation (SpO(2)) were examined at 20, 72, and 120 h after high- altitude exposure. Pulmonary function was measured at 20 h after exposure. Results: Compared with placebo, BUD significantly reduced the incidence of AMS (70% vs. 25% at 20 h, p < 0.05; both 10% vs. 5% at 72 and 120 h, both p > 0.05) without side effects. The relative risk was 0.357, and the risk difference was 0.45. Mean SpO(2) was higher in BUD, BUD/FM, and PT groups than in the placebo group at 20 h (p < 0.05). SpO(2) in all 80 subjects dropped after ascent (98.1% to 88.12%, p < 0.01) and increased gradually, but it was still lower at 120 h than at baseline (92.04% vs. 98.1%, p < 0.01). Pulmonary function did not differ among the four groups at 20 h. Conclusion: BUD can prevent AMS without side effects. The alleviation of AMS may be related to increased blood oxygen levels rather than pulmonary function. (C) 2015 Elsevier Inc.