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The preservation of biosignatures on Mars is largely associated with extensive deposits of clays formed under mild early Noachian conditions (> 3.9 Ga). They were followed by widespread precipitation of acidic sulfates considered adverse for biomolecule preservation. In this paper, an exhaustive mass spectrometry investigation of ferric subsurface materials in the Rio Tinto gossan deposit (~ 25 Ma) provides evidence of well-preserved molecular biosignatures under oxidative and acidic conditions. Time of flight secondary ion mass spectrometry (ToF-SIMS) analysis shows a direct association between physical-templating biological structures and molecular biosignatures. This relation implies that the quality of molecular preservation is exceptional and provides information on microbial life formerly operating in the shallow regions of the Rio Tinto subsurface. Consequently, low-pH oxidative environments on Mars could also record molecular information about ancient life in the same way as the Noachian clay-rich deposits, (Grant No. ANR-15-IDEX-02), European Regional Development Fund (Grant No. RYC2018-023943-I), Horizon 2020 Framework Programme (Grant No. RYC-2014-19446)

Background Pulmonary fibrosis is a fatal lung disease with limited treatment options. Icaritin is the active ingredient derived from the traditional Chinese medical plant Epimedium and possesses many biomedical activities. This study aimed to investigate the effects and molecular mechanisms of icaritin on bleomycin-induced pulmonary fibrosis in mice. Methods To assess its preventative effects, bleomycin treated mice received 0, 0.04, 0.2, and 1 mg/kg of icaritin from day 1 onwards. To assess its therapeutic effects, bleomycin treated mice received 0 and 1 mg/kg of icaritin from day 15 onwards. Mice were sacrificed on day 21 and lung tissues were collected, stained with HE, Masson and immunohistochemistry. Q-PCR was used to measure Collagen I and Collagen III expression, western blotting was used to quantify α-SMA, Collagen I expression. Hydroxyproline content was measured using a biochemical method. NIH3T3 and HLF-1 cells were treated with TGF-β1with or without icaritin, and α-SMA, Collagen I were tested. PPARγ antagonist GW9662 and PPARγ-targeted siRNA were used to investigate the mechanism of icaritin in inhibiting myofibroblast differentiation. Results Both preventative and therapeutic administration of icaritin improved the histopathological changes, decreased Collagen and α-SMA, lowered hydroxyproline content in bleomycin-treated lung tissues. Icaritin decreased α-SMA and Collagen I expression in TGF-β1-stimulated NIH3T3 and HLF-1 cells. However, its effect in reducing α-SMA and Collagen I expression was suppressed when expression or activity of PPARγ was inhibited. Conclusions Icaritin has therapeutic potential against pulmonary fibrosis via the inhibition of myofibroblast differentiation, which may be mediated by PPARγ.

Purpose Uterine fibroids are benign gynecologic tumors and commonly occur in women by the age of 50. Women with symptomatic uterine fibroids generally receive surgical intervention, while they do not favor the invasive therapies. To evaluate the feasibility and safety of a novel magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) modality, ArcBlate, in the treatment of uterine fibroids. Methods Nine patients with uterine fibroids and one patient with adenomyosis were treated with ArcBlate MRgHIFU. Tumor size and quality of life were evaluated postoperatively at 1 and 3 months by magnetic resonance imaging (MRI) and the 36-Item Short Form Survey (SF-36), respectively. Results All patients completed the ArcBlate MRgHIFU procedure and there were no treatment-related adverse effects either during the procedure or during the 3 months of follow-up. Despite limiting the ablation volume to under 50% of the treated fibroid volume as a safety precaution, tumor volumes were markedly reduced in four patients by 15.78–58.87% at 3-month post-treatment. Moreover, SF-36 scale scores had improved at 3 months from baseline by 2–8 points in six patients, indicating relief of symptoms and improved quality of life. Conclusion This study evidence demonstrates the safety and feasibility of ArcBlate MRgHIFU and suggests its potential for treating uterine fibroids.

Background/purpose The orthodontic aligner becomes popular worldwide in orthodontic therapy as an esthetic alternative to fixed labial braces. This study evaluated orthodontic tooth movement behavior using different aligner materials and attachment shapes for the movement of a single tooth. Materials and methods First bicuspid extracted resin typodont models were printed with a 3D printer. Three type of attachments, an ellipsoid shape (thick and thin) and a bar, were designed to fit the canine crown surface. Three types of aligner materials, Polyethylene Terephthalate enhanced with glycol (BIOSTAR) Polyethylene Terephthalate (BenQ), and Thermoplastic polyurethanes (TPU) were used to fabricate different aligners. The typodonts with aligners were sunk in a water bath to simulate canine distal movement in vivo. The canine crown, root movement, and long axis angle changes in each step were calculated and recorded. The data were analysed using a oneway ANOVA statistical method. Results Comparing the three aligners, the changes the long axis of the canine showed that the BENQ group had a smaller change in the long axis angle. The BENQ group canine involved bodily movement, but the canine movement of the BIOSTAR and TPU group involved tipping. Comparing the three attachments, the bar type attachment had more canine crown tipping in the BIOSTAR and TPU groups. The thick and thin ellipsoid-shaped attachments showed no statistical differences in tooth movement. Conclusion Attachment shape or size had little influence on the bodily movement of the tooth. A high modulus material may thus be suitable for clinical applications.

Background/objectives To identify visual trajectories and examine their relationships with physical and cognitive function in older Chinese adults. Design Population-based longitudinal study. Setting The Chinese Longitudinal Healthy Longevity Survey. Participants A total of 16,151 participants aged ≥65 years. Measurements Visual, physical (including activities of daily living [ADL] and instrumental ADL [IADL]), and cognitive function were assessed at baseline and subsequently every 3 years. ADI disability and IADL disability were defined as needing any help in any item of the Katz scale and a modified Lawton's scale, respectively. Cognitive impairment was defined as a Chinese version of the Mini-Mental State Examination score below 24. A group-based trajectory model was used to determine visual trajectories adjusted for age, sex, and education. Associations of visual trajectories with ADL disability, IADL disability, and cognitive impairment were evaluated using generalized estimating equation models adjusted for potential confounders. Results This study identified three distinct visual trajectories, including no decline (32.4%), moderate decline (48.3%), and progressive decline (19.3%) during the follow-up period. Compared with the no decline trajectory, both the moderate decline (ADL disability: OR = 2.75, 95% CI: 2.30-3.28; IADL disability: OR = 3.01, 95% CI: 2.74-3.31; cognitive impairment: OR = 3.37, 95% CI: 3.02-3.76) and the progressive decline (ADL disability: OR = 8.50, 95% CI: 6.55-11.02; IADL disability: OR = 12.96, 95% CI: 9.95-16.87; cognitive impairment: OR = 10.84, 95% CI: 8.89-13.23) trajectories were significantly associated with an increased risk of functional impairment. Compared with the moderate decline trajectory, the progressive decline trajectory was significantly associated with an increased risk of ADL disability (OR = 3.09, 95% CI: 2.46-3.89), IADL disability (OR = 4.30, 95% CI: 3.29-5.61), and cognitive impairment (OR = 3.22, 95% CI:2.63-3.93). Conclusion Older Chinese adults exhibit three distinct visual trajectories and those with decline trajectories in vision have an increased risk of functional impairment than those with a trajectory of no decline in vision.

Background and objective Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. Anti-IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2-high SAA. The effects of anti-IgE therapy on fibrocyte activities were investigated in this study. Methods The expression of CCR7, CXCR4, ST2 and α-SMA (α-smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti-IgE therapy. Results Omalizumab effectively improved asthma control and pulmonary function in T2-high SAA, associated with a decline in serum levels of IL-33 and IL-13. Omalizumab down-regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α-SMA+ fibrocytes within the cultured non-adherent non-T (NANT) cells after 3-7 days of culture. The decrease in serum levels of IL-33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL-33/ST2 axis. The elevated IL-13 expression in SAA patients potentiated the effects of IL-33 by increasing ST2 expression. Conclusion Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α-SMA+ fibrocytes after 3-7 days of culture in SAA patients. IL-33 and IL-13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.

Background Ferritin, the natural iron storage protein complex, self-assembles into a uniform cage-like structure. Human H-ferritin (HFn) has been shown to transverse the blood–brain barrier (BBB) by binding to transferrin receptor 1 (TfR1), which is abundant in endothelial cells and overexpressed in tumors, and enters cells via endocytosis. Ferritin is easily genetically modified with various functional molecules, justifying that it possesses great potential for development into a nanocarrier drug delivery system. Results In this study, a unique integrin α2β1-targeting H-ferritin (2D-HFn)-based drug delivery system was developed that highlights the feasibility of receptor-mediated transcytosis (RMT) for glioma tumor treatment. The integrin targeting α2β1 specificity was validated by biolayer interferometry in real time monitoring and followed by cell binding, chemo-drug encapsulation stability studies. Compared with naïve HFn, 2D-HFn dramatically elevated not only doxorubicin (DOX) drug loading capacity (up to 458 drug molecules/protein cage) but also tumor targeting capability after crossing BBB in an in vitro transcytosis assay (twofold) and an in vivo orthotopic glioma model. Most importantly, DOX-loaded 2D-HFn significantly suppressed subcutaneous and orthotopic U-87MG tumor progression; in particular, orthotopic glioma mice survived for more than 80 days. Conclusions We believe that this versatile nanoparticle has established a proof-of-concept platform to enable more accurate brain tumor targeting and precision treatment arrangements. Additionally, this unique RMT based ferritin drug delivery technique would accelerate the clinical development of an innovative drug delivery strategy for central nervous system diseases with limited side effects in translational medicine. Graphic Abstract

The basic helix-loop-helix (bHLH) families that act as transcription factors play a central role in regulating a wide range of physiological, metabolic, and developmental processes in higher organisms. Systematic identification and characterization of bHLH gene families has not yet been performed in sugarcane. In the present study, 37 SsbHLH genes (101 total alleles) were identified in Saccharum spontaneum (Ss), with 1–4 alleles each. Phylogenetic analysis indicated that these SsbHLH could be classified into 17 subfamilies according to bHLH domains. All of the SsbHLHs were localized on 20 chromosomes, and the SsbHLH member’s likely arose through gene duplication. Based on a sugarcane transcriptome dataset trigged by Acidovorax avenae subsp. avenae (Aaa) causing red stripe, SsbHLH27 and SsbHLH36 were significantly upregulated by 1.12- to 5.96-fold [log2(Fold Change)] in cultivar ROC22 (red stripe resistant), while both genes were significantly depressed in cultivar MT11-610 (red stripe susceptible) under Aaa infection. Based on another sugarcane transcriptome dataset trigged by Xanthomonas albilineans (Xa) causing leaf scald, four genes (SsbHLH03/04/36/37) were highly upregulated by 1.23- to 5.11-fold [log2(Fold Change)] in LCP85-384 (leaf scald-resistant), but downregulated or non-significantly changed in cultivar ROC20 (leaf scald-susceptible) under Xa infection. SsbHLH15/17 were positively induced by both Aaa and Xa stimuli, whereas SsbHLH30/33 were negatively regulated by both pathogens. Some genes, such as SsbHLH06/11, had different expression profiles under the two pathogens infections, showing increased expression after Aaa infection but reduced expression with Xa. These findings provide important candidate genes for further functional analyses in sugarcane in response to bacterial stress.

Cancer cachexia often occurs in malignant tumors and is a multifactorial and complex symptom characterized by wasting of skeletal muscle and adipose tissue, resulting in weight loss, poor life quality and shorter survival. The pathogenic mechanism of cancer cachexia is complex, involving a variety of molecular substrates and signal pathways. Advancements in understanding the molecular mechanisms of cancer cachexia have provided a platform for the development of new targeted therapies. Although recent outcomes of early-phase trials have showed that several drugs presented an ideal curative effect, monotherapy cannot be entirely satisfactory in the treatment of cachexia-associated symptoms due to its complex and multifactorial pathogenesis. Therefore, the lack of definitive therapeutic strategies for cancer cachexia emphasizes the need to develop a better understanding of the underlying mechanisms. Increasing evidences show that the progression of cachexia is associated with metabolic alternations, which mainly include excessive energy expenditure, increased proteolysis and mitochondrial dysfunction. In this review, we provided an overview of the key mechanisms of cancer cachexia, with a major focus on muscle atrophy, adipose tissue wasting, anorexia and fatigue and updated the latest progress of pharmacological management of cancer cachexia, thereby further advancing the interventions that can counteract cancer cachexia.

This study investigated healthcare utilization and expenditure for patients with type 2 diabetes mellitus and schizophrenia and associated factors. Healthcare utilization (outpatient visits and hospitalization) and expenditure (outpatient, inpatient, and total medical expenditure) between 2002 and 2013 of patients with T2DM with schizophrenia (case group) and without (control group) were examined using the Taiwan National Health Insurance Research Database. (1) The average total numbers of outpatient visits and hospital admissions of the case group were 35.14 outpatient visits and 1.09 hospital admissions significantly higher than those of the control group in the whole study period (based on every 3-year period). Nonpsychiatric outpatient visits and nonpsychiatric hospital admissions were significantly more numerous for the case group. (2) The total outpatient expenditure, total inpatient expenditure, and total medical expenditure of the case group were NT$65,000, NT$170,000, and NT$235,000 significantly higher than those of the control group, respectively. Nonpsychiatric outpatient expenditure was significantly lower for the case group, but the inpatient and total nonpsychiatric medical expenditure were similar between groups. (3) Patients who were elder of low income, with complications, and high diabetes mellitus complication severity index had higher total numbers of outpatient visits and hospitalizations and medical expenditure. (4) Women had a higher number of outpatient visits but a lower number of hospitalization and medical expenditure. Lower non-psychiatric outpatient expenditure despite more visits indicated non-psychiatrist may not understand schizophrenia patients and cannot communicate well with them, leading to neglect of medical evaluation and treatment that should be carried out.

Rationale: With over seven million infections and $25 billion treatment cost, chronic ischemic wounds are one of the most serious complications in the United States. The controlled release of bioactive factor enriched exosome from finbrin gel was a promising strategy to promote wound healing. Methods: To address this unsolved problem, we developed clinical-grade platelets exosome product (PEP), which was incorporate with injectable surgical fibrin sealant (TISSEEL), to promote chronic wound healing and complete skin regeneration. The PEP characterization stimulated cellular activities and in vivo rabbit ischemic wound healing capacity of TISSEEL-PEP were performed and analyzed. Results: PEP, enriched with transforming growth factor beta (TGF-β), possessed exosomal characteristics including exosome size, morphology, and typical markers including CD63, CD9, and ALG-2-interacting protein X (Alix). In vitro, PEP significantly promoted cell proliferation, migration, tube formation, as well as skin organoid formation. Topical treatment of ischemic wounds with TISSEEL-PEP promoted full-thickness healing with the reacquisition of hair follicles and sebaceous glands. Superior to untreated and TISSEEL-only treated controls, TISSEEL-PEP drove cutaneous healing associated with collagen synthesis and restoration of dermal architecture. Furthermore, PEP promoted epithelial and vascular cell activity enhancing angiogenesis to restore blood flow and mature skin function. Transcriptome deconvolution of TISSEEL-PEP versus TISSEEL-only treated wounds prioritized regenerative pathways encompassing neovascularization, matrix remodeling and tissue growth. Conclusion: This room-temperature stable, lyophilized exosome product is thus capable of delivering a bioactive transforming growth factor beta to drive regenerative events.

Early-life antibiotic use is associated with allergic diseases. The risk factors for the progression from atopic dermatitis (AD) to asthma or allergic rhinitis are still unknown. We aimed to investigate the association between exposure to different antibiotics and the risk of new-onset asthma in children with AD. By using the Longitudinal Health Insurance Database 2005, we selected AD patients less than 6 years old identified by ICD-9-CM code 691.8. The case group was defined as those having new-onset asthma, and the control group was defined as those without an asthma history. Information on antibiotic exposure in the 5 years prior to the index date was collected from drug prescription records. We estimated the adjusted odds ratio by using conditional logistic regression, adjusted for age, sex, index year, other potential risk factors and antibiotics. Antibiotic exposure was associated with the development of asthma in patients with AD (aOR = 3.68, 95% CI 2.13–6.36), particularly for patients less than 5 years old (aOR = 4.14, 95% CI 2.24–7.64) (p for trend

Maize yellow mosaic virus (MaYMV) hosted in various gramineous plants was assigned to the genus Polerovirus (family Luteoviridae) in 2018. However, little is known about its genetic diversity and population structure. In this study, 509 sugarcane leaf samples with mosaic symptoms were collected in 2017 to 2019 from eight sugarcane-growing provinces in China. Reverse-transcription PCR results revealed that four positive-sense RNA viruses were found to infect sugarcane, and the incidence of MaYMV among samples from Fujian, Sichuan, and Guangxi Provinces was 52.1, 9.8, and 2.5%, respectively. Based on 82 partial MaYMV sequences and 46 whole-genome sequences from different host plants, phylogenetic analysis revealed that MaYMV populations are very closely associated with their source geographical regions (China, Africa, and South America). Pairwise identity analysis showed significant variability in genome sequences among MaYMV isolates with genomic nucleotide identities of 91.1 to 99.9%. In addition to codon mutations, insertions or deletions also contributed to genetic variability in individual coding regions, especially in the readthrough protein (P3-P5 fusion protein). Low gene flow and significant genetic differentiation of MaYMV were observed among the three geographical populations, suggesting that environmental adaptation is an important evolutionary force that shapes the genetic structure of MaYMV. Genes in the MaYMV genome were subject to strong negative or purification selection during evolution, except for the movement protein (MP), which was under positive selection pressure. This finding suggests that the MP may play an important role in MaYMV evolution. Taken together, our findings provide basic information for the development of an integrated disease management strategy against MaYMV.

Background Adrenal hemangioma is a rare benign adrenal tumor that is usually misdiagnosed preoperatively. We here present a case of adrenal cavernous hemangioma that was successfully treated with retroperitoneal laparoscopic adrenalectomy. Case presentation A 67-year-old man with dull right back pain attended our clinic for examination of a mass on the right adrenal gland for 1 week. Pheochromocytoma was considered according to the preoperative computed tomography angiography + computed tomography urography findings and was subsequently corrected to adrenal gland hemangioma according to postoperative pathological findings. The patient showed no recurrence of adrenal hemangioma during the 1-year follow-up period after surgery. Conclusion Adrenal gland hemangioma is rare with a high rate of misdiagnosis, and it should be considered in imaging findings of adrenal tumors with typical hemangioma. Surgery is an effective treatment method.

Recently studies found that APEX1 was abnormally expressed in melanoma, indicating that it might be involved in the development of melanoma. However, the underlying mechanism and the interaction between APEX1 and LINC00470 in melanoma are not clear. Therefore, we aimed to investigate the role of LINC00470 in the development of melanoma in this work. We discovered that LINC00470 was overexpressed in melanoma tissues and cells compared with the adjacent normal tissues and cells by qPCR. The overexpression of LINC00470 promoted the proliferation and migration of melanoma cells. The functional investigation demonstrated that LINC00470 activated the transcription factor, ZNF131, to regulate the APEX1 expression, which finally promoted cell proliferation and migration. In contrast, knockdown of LINC00470 could significantly inhibit the melanoma cell proliferation and migration, and suppress the growth of tumor in vivo. Overexpression of APEX1 could reverse the impact of the silence of LINC00470 in melanoma cells. In summary, our studies revealed that LINC00470 promoted melanoma proliferation and migration by enhancing the expression of APEX1, which indicated that LINC00470 might be a therapeutic target for the treatment of melanoma.

Introduction: Information regarding availability of electronic healthcare databases in the Asia-Pacific region is critical for planning vaccine safety assessments particularly, as COVID-19 vaccines are introduced. This study aimed to identify data sources in the region, potentially suitable for vaccine safety surveillance. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE). Methods: Nineteen countries targeted for database reporting were identified using published country lists and review articles. Surveillance capacity was assessed using two surveys: a 9-item introductory survey and a 51-item full survey. Survey questions related to database characteristics, covariate and health outcome variables, vaccine exposure characteristics, access and governance, and dataset linkage capability. Other questions collated research/regulatory applications of the data and local publications detailing database use for research. Results: Eleven databases containing vaccine-specific information were identified across 8 countries. Databases were largely national in coverage (8/11, 73%), encompassed all ages (9/11, 82%) with population size from 1.4 to 52 million persons. Vaccine exposure information varied particularly for standardized vaccine codes (5/11, 46%), brand (7/11, 64%) and manufacturer (5/11, 46%). Outcome data were integrated with vaccine data in 6 (55%) databases and available via linkage in 5 (46%) databases. Data approval processes varied, impacting on timeliness of data access. Conclusions: Variation in vaccine data availability, complexities in data access including, governance and data release approval procedures, together with requirement for data linkage for outcome information, all contribute to the challenges in building a distributed network for vaccine safety assessment in the Asia-Pacific and globally. Common data models (CDMs) may help expedite vaccine safety research across the region. Refereed/Peer-reviewed

Diabetic nephropathy (DN) is the primary microvascular complication of diabetes mellitus and may result in end-stage renal disease. The overproduction of various inflammatory factors is involved in the pathogenesis of DN. Protein tyrosine phosphatase 1B (PTP1B) modulates the expression of a series of cytokines and nuclear factor kappa B (NF-κB) activity. cAMP response element-binding protein (CREB) and lysine methyltransferase 5A (KMT5A) have been reported to participate in the maintenance of a healthy endothelium. In the present study, we hypothesise that CREB associates with KMT5A to modulate PTP1B expression, thus contributing to high glucose-mediated glomerular endothelial inflammation. Our analyses revealed that plasma inflammatory factor levels, glomerular endothelial p65 phosphorylation and PTP1B expression were increased in DN patients and rats. In vitro, high glucose increased endothelial inflammatory factor levels and p65 phosphorylation by augmenting PTP1B expression in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose decreased CREB and KMT5A expression. CREB overexpression and KMT5A overexpression both inhibited high glucose-induced PTP1B expression, p65 phosphorylation and endothelial inflammatory factor levels. si-CREB- and sh-KMT5A-induced p65 phosphorylation and endothelial inflammatory factor levels were reversed by si-PTP1B. Furthermore, CREB was associated with KMT5A. Mechanistic research indicated that CREB and histone H4 lysine 20 methylation (H4K20me1, a downstream target of KMT5A) occupy the PTP1B promoter region. sh-KMT5A augmented PTP1B promoter activity and activated the positive effect of si-CREB on PTP1B promoter activity. Our in vivo study demonstrated that CREB and KMT5A were downregulated in glomerular endothelial cells of DN patients and rats. In conclusion, CREB associates with KMT5A to promote PTP1B expression in vascular endothelial cells, thus contributing to hyperglycemia-induced inflammatory factor levels in DN patients and rats.

Background Most evidence regarding the risk factors for early in-hospital mortality in patients with severe COVID-19 focused on laboratory data at the time of hospital admission without adequate adjustment for confounding variables. A multicenter, age-matched, case-control study was therefore designed to explore the dynamic changes in laboratory parameters during the first 10 days after admission and identify early risk indicators for in-hospital mortality in this patient cohort. Methods Demographics and clinical data were extracted from the medical records of 93 pairs of patients who had been admitted to hospital with severe COVID-19. These patients had either been discharged or were deceased by March 3, 2020. Data from days 1, 4, 7, and 10 of hospital admission were compared between survivors and non-survivors. Univariate and multivariate conditional logistic regression analyses were employed to identify early risk indicators of in-hospital death in this cohort. Results On admission, in-hospital mortality was associated with five risk indicators (ORs in descending order): aspartate aminotransferase (AST, >32 U/L) 43.20 (95% CI: 2.63, 710.04); C-reactive protein (CRP) greater than 100 mg/L 13.61 (1.78, 103.941); lymphocyte count lower than 0.6×109/L 9.95 (1.30, 76.42); oxygen index (OI) less than 200 8.23 (1.04, 65.15); and D-dimer over 1 mg/L 8.16 (1.23, 54.34). Sharp increases in D-dimer at day 4, accompanied by decreasing lymphocyte counts, deteriorating OI, and persistent remarkably high CRP concentration were observed among non-survivors during the early stages of hospital admission. Conclusions The potential risk factors of high D-dimer, CRP, AST, low lymphocyte count and OI could help clinicians identify patients at high risk of death early in the hospital admission. This might assist with rationalization of health care resources.

Oncogenic high-risk human papillomavirus (HR-HPV) infection causes a majority of cases of cervical cancer and pre-cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV-16/18-infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA-seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV-16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV-16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA-mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl-capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV-16 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer.

Targeted muscle reinnervation enables native muscles to send electromyographic signals to myoelectric receptors, which drive movements in a prosthesis. This system requires voluntary contracture of muscles for sequential control of powered prosthetic joints. This report describes a surgical solution for cases where the chest wall is depleted of muscle targets. A 13-year-old boy with left forequarter amputation and pectoralis major resection as a result of extended necrotizing facilities 8 years prior received a neurotized free Vertical Rectus Abdominus Mycocutaneous (VRAM) flap (28 × 10 cm) designed to produce myoelectric signals, reduce pain, and provide stability for prosthetic fitting. Five intercostal nerves from the VRAM were coapted to portions of the brachial plexus to create a myoelectric interface for targeted muscle reinnervation. The postoperative course was uneventful. At 39 months of follow-up, the patient gained control of the transferred VRAM and was able to operate a custom-fitted myoelectric prosthesis together with contraction of the ipsilateral infraspinatus muscle. The neurotized VRAM transfer created a neural interface in an area with depleted neuromuscular targets while decreasing pain and adding tissue bulk for proper prosthesis fitting. Such a surgical strategy may have applications in other areas of the body.

Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the utility of cerebrospinal fluid (CSF) as a medium for epidermal growth factor receptor (EGFR) mutation testing in clinical practice. We prospectively enrolled patients with EGFR-mutant NSCLC who underwent CSF sampling for suspected LM. The supernatant of CSF after routine cytology examination was collected. The diagnosis of LM was established according to EANO-ESMO criteria. CSF and plasma cell-free DNA (cfDNA) were retrieved for EGFR mutation testing. Fifty-one patients with a median age of 62.7 years were enrolled. The median duration from initial diagnosis to CSF sampling was 23.0 months and most patients (94.1%) had received at least one EGFR-tyrosine kinase inhibitor. Adenocarcinoma cells were found in 37 CSF samples (72.5%), and 48 (94.1%) patients had confirmed or probable LM. Thirty-five of these 48 patients (72.9%) had valid EGFR mutation-testing results using CSF cfDNA and tended to have higher white blood cell counts and positive cytology in their CSF compared to those with invalid mutation testing results. The overall detection rate of EGFR mutation in CSF cfDNA was 68.8%, and the T790M detection rate was 14.6%. In 37 patients with paired CSF and plasma samples, the concordance rate of the EGFR mutation results was 29.7%. For patients with EGFR-mutant NSCLC with LM, CSF supernatant is a valuable source for EGFR mutation testing and may provide important information.

Background Emerging evidence demonstrated dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, prevented various cardiovascular events. However, the detailed mechanisms underlying its cardioprotective properties remained largely unknown. Results In the present study, we sought to investigate the effects of DAPA on the cardiac ischemia/reperfusion (I/R) injury. Results from in vitro experiments showed that DAPA induced the phosphorylation of AMPK, resulting in the downregulation of PKC in the cardiac myoblast H9c2 cells following hypoxia/reoxygenation (H/R) condition. We demonstrated that DAPA treatment diminished the H/R-elicited oxidative stress via the AMPK/ PKC/ NADPH oxidase pathway. In addition, DAPA prevented the H/R-induced abnormality of PGC-1α expression, mitochondrial membrane potential, and mitochondrial DNA copy number through AMPK/ PKC/ NADPH oxidase signaling. Besides, DAPA reversed the H/R-induced apoptosis. Furthermore, we demonstrated that DAPA improved the I/R-induced cardiac dysfunction by echocardiography and abrogated the I/R-elicited apoptosis in the myocardium of rats. Also, the administration of DAPA mitigated the production of myocardial infarction markers. Conclusions In conclusion, our data suggested that DAPA treatment holds the potential to ameliorate the I/R-elicited oxidative stress and the following cardiac apoptosis via modulation of AMPK, which attenuates the cardiac dysfunction caused by I/R injury.

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Background This study aimed to evaluate the analgesic and sedative effects of remifentanil-based fast-track cardiac anesthesia in children undergoing transthoracic device closure of ventricular septal defects (VSDs). Methods A retrospective analysis was conducted on 62 children who underwent transthoracic device closure of VSDs from May 2019 to August 2019. The patients were divided into two groups based on the anesthesia methods: group F was given remifentanil-based fast-track cardiac anesthesia, and Group C was given conventional anesthesia. Patient-related clinical data, postoperative analgesia scores, and sedation scores were collected and analyzed. Results There was no significant difference in intraoperative hemodynamic changes, bispectral index values, postoperative analgesia scores, sedation scores, or the incidence of adverse events between the two groups. Compared with Group C, the duration of mechanical ventilation and the length of intensive care unit (ICU) and hospital stay in group F were significantly lower. Conclusion Remifentanil-based fast-track anesthesia can be safely applied in children undergoing transthoracic device closure of VSDs, with acceptable postoperative analgesia and sedation effects and shorter mechanical ventilation times and ICU and hospital stays compared with conventional anesthesia.

Protobothrops mucrosquamatus is one of the common venomous snakes in Southeast Asia. This retrospective cohort study conducted in six medical institutions in Taiwan aimed to obtain information on the optimal management strategies for P. mucrosquamatus snakebite envenomation. Data were extracted from the Chang Gung Research Database from January 2006 to December 2016. The association between early antivenom administration and patient demographics, pain requiring treatment with analgesic injections, and hospital length of stay was analyzed. A total of 195 patients were enrolled; 130 were administered antivenom within 1 hour after emergency department arrival (early group), whereas 65 were treated later than 1 hour after arrival (late group). No in-hospital mortality was identified. The difference in surgical intervention rates between the early and late groups was statistically insignificant (P = 0.417). Compared with the early group, the late group showed a higher rate of antivenom skin test performance (46.9% versus 63.1%, respectively, P = 0.033), longer hospital stay (42 ± 62 hours versus 99 ± 70 hours, respectively, P = 0.016), and higher rate of incidences of pain requiring treatment with analgesic injections (29.2% versus 46.2%, respectively, P = 0.019). After adjusting for confounding factors, early antivenom administration was associated with decreased pain requiring treatment with analgesic injections (adjusted odds ratio: 0.51, 95% CI: 0.260–0.985). Antivenom administration within 1 hour of arrival was associated with a decreased likelihood of experiencing pain and hospital length of stay in patients with P. mucrosquamatus snakebites. Antivenom skin testing was associated with delays in antivenom administration.

Objective To investigate the effect of treprostinil on the early postoperative prognosis of patients with severe left heart valvular disease combined with severe pulmonary hypertension (PAH). Methods A retrospective study including 55 patients with severe left heart valvular disease combined with severe PAH who underwent left heart valve replacement in our hospital between January 2019 and May 2019 was conducted. Patients were divided into two groups (treprostinil group and control group), and the clinical data of patients in the two groups were compared and analyzed. Results Compared with the preoperative status, the mean postoperative pulmonary artery pressure (mPAP) in both groups was significantly lower. Compared with the control group, the treprostinil group had a significantly lower mPAP. Moreover, the postoperative mechanical ventilation time, intensive care unit (ICU) stay, and hospital stay of the treprostinil group were significantly shorter than those of the control group. There were no serious drug-related side effects in either group. Conclusions Treprostinil can improve the early postoperative prognosis of patients with severe left heart valvular disease combined with severe PAH undergoing prosthetic valve replacement.

Ephrin type-A receptor 10 (EPHA10) has been implicated as a potential target for breast and prostate cancer therapy. However, its involvement in oral squamous cell carcinoma (OSCC) remains unclear. We demonstrated that EPHA10 supports in vivo tumor growth and lymphatic metastasis of OSCC cells. OSCC cell migration, epithelial mesenchymal transition (EMT), and sphere formation were found to be regulated by EPHA10, and EPHA10 was found to drive expression of some EMT- and stemness-associated transcription factors. Among EPHA10 ligands, exogenous ephrin A4 (EFNA4) induced the most OSCC cell migration and sphere formation, as well as up-regulation of SNAIL, NANOG, and OCT4. These effects were abolished by extracellular signal-regulated kinase (ERK) inhibition and NANOG knockdown. Also, EPHA10 was required for EFNA4-induced cell migration, sphere formation, and expression of NANOG and OCT4 mRNA. Our microarray dataset revealed that EFNA4 mRNA expression was associated with expression of NANOG and OCT4 mRNA, and OSCC patients showing high co-expression of EFNA4 with NANOG or OCT4 mRNA demonstrated poor recurrence-free survival rates. Targeting forward signaling of the EFNA4-EPHA10 axis may be a promising therapeutic approach for oral malignancies, and the combination of EFNA4 mRNA and downstream gene expression may be a useful prognostic biomarker for OSCC.

Background/purpose: Maxillary posterior teeth have close anatomical proximity to the maxillary sinus floor. The aim of this retrospective study was to evaluate the associations between maxillary sinus membrane thickening and the adjacent teeth health by cone-beam computed tomography (CBCT). Materials and methods: CBCT images were collected from 235 Taiwanese patients. The sinus mucosal thickening >2 mm is considered a pathologic sinus membrane. Demographic data such as sex, age, the thickness of sinus membrane, and the adjacent teeth health were recorded, graded, and analyzed. Results: A total prevalence of maxillary sinus membrane thickening of 36.6% (86/235) was found in this study. The sinus membrane thickening was significantly associated with periodontal bone loss (p

Background To evaluate the use of a human fibrin glue (Tisseel) for minor bleeding control and approximation of ovarian defect during transvaginal natural orifice ovarian cystectomy (TNOOC) of benign and non-endometriotic ovarian tumors. Methods A total of 125 women with benign and non-endometriotic ovarian tumors who underwent TNOOC between May 2011 and January 2020: 54 with the aid of Tisseel and 71 with traditional suture for hemostasis and approximation of ovarian defect. Surgical outcomes such as length of surgery, operative blood loss, postoperative pain score, and postoperative hospital stay were recorded. Before and immediately (10 days) and at 6 months after the procedure, serum anti-Müllerian hormone (AMH) levels were also determined. Results Complete hemostasis and approximation of ovarian defect were achieved in all cases. No significant difference was noted in the operating time, operative blood loss, postoperative pain scores after 12, 24 and 48 h, length of postoperative stay, and baseline AMH levels between the two groups. The operation did not have a negative effect on the immediate and 6-month postoperative AMH levels in the suture group. However, the decline in the AMH levels was significant immediately after surgery in the Tisseel group, nevertheless, no significant difference was noted in the AMH levels at 6 months (3.3 vs. 1.7 mg/mL; p = 0.042, adjusted p = 0.210). Conclusion The use of Tisseel in TNOOC of benign and non-endometriotic ovarian tumors without suturing the ovarian tissue is clinically safe and feasible.

Background/Purpose Population aging and unequal accessibility of health care are increasingly important in developed countries. One strategy to overcome these issues is utilizing telemedicine, which is recently made possible technologically by the advancement of internet speed, high speed zooming cameras, and the information storages. In Taiwan, the telemedicine is granted legally by the amendment for Taiwan's Physician Act in 2018. Methods Kaohsiung Chang Gung Memorial Hospital (Kaohsiung CGMH) is the first hospital in Taiwan to provide the telemedicine service connecting to Cheng Kung Branch of Taitung Hospital since Nov 2018. Consultation services from Dermatology, ENT, and Ophthalmology have been delivered in the live-interactive and face to face module every week. Results Dermatology consultation comprises the majorities. In the first year, there were totally 426 dermatology consultation services. Eczema, fungal infections, and scabies infestation were the three most common diseases in the beginning. The disease diagnosis became more diverse after several months, including some ready-to-treat diseases pending correct diagnosis, such as pediculosis, psoriasis, and urticaria. Coupled with dermoscopic images, diseases such as hair loss, pediculosis capitis, skin tumor, and scabies, were diagnosed promptly. The subjective patient improvement rate was more than 75% year-round and the case closure rate was more than 85% year-round. Conclusion Teledermatology is a promising approach to serve the remote medical-underprivileged regions. The teledermatology is anticipated to help underserved regions, nursing homes, prisons, and in situations with severe pandemic infections, such as COVID-19.

Objective: The purpose of this study was to explore the clinical effect of preoperative health education based on the WeChat platform for parents of children with simple congenital heart disease. Methods: In this study, participants were randomly divided into an intervention group (WeChat group, n=40) and a control group (leaflet group, n=40) in our center. All parents were required to complete the Family Caregiver Task Inventory (FCTI) on the first visit and the Zarit Burden Interview (ZBI) and FCTI before the operation. Clinical, family and relevant data from children and parents were collected and subsequently analyzed. Results: Before the operation, the FCTI score and the ZBI score in the WeChat group were significantly lower than those in the control group (P=0.010, P=0.027, respectively). Compared to the FCTI score on the first visit, the preoperative status score was significantly lower in the WeChat group (P=0.008). The rate of loss to follow-up and complications in the WeChat group was also significantly lower than in the control group (P=0.003). Conclusion: Preoperative health education assisted by the WeChat platform for parents of children with simple congenital heart disease can effectively improve the parents' care ability and reduce the burden of care, preoperative complications and the rate of loss to follow-up.

Objective To explore the health-related quality of life (HRQoL) of children and adolescents with simple congenital heart defects before and after the transcatheter intervention. Methods The Pediatric Quality of Life Inventory 4.0 scale was used to assess the quality of life of 78 children and adolescents before and after the transcatheter intervention and to evaluate the parents' perception of their children's quality of life. Results In all, 76 patients were completed the study. The results showed that the scores of the four dimensions and the total score for the quality of life of the patients significantly improved 1 month after the intervention. At 6 months after treatment, the scores in all dimensions continued to improve. From the parents' perspective, the scores of the patients in all dimensions improved significantly at 1 month and 6 months after treatment. In terms of the quality of life assessment, the self-assessment results of the patients were more positive than those of their parents. Conclusions The results showed that the quality of life of children and adolescents with simple congenital heart defects can be positively affected by the transcatheter intervention. Moreover, this improvement is not transient and seems to increase over time.

Background The kinematic alignment (KA) technique in total knee arthroplasty (TKA) aims to restore the native alignment of pre-disease knee joint anatomy. Determining the individualized alignment targets is crucial for pre-operative planning, which can be set according to different original knee phenotypes. Five most common knee phenotypes have been categorized for KA-TKA alignment target setting in our previous study. The purpose of this study was to investigate the distribution of the five phenotypes in advanced OA knee patients and evaluate the clinical outcomes of this phenotype-oriented KA-TKA using the generic instrument, with particular emphasis on alignment strategy, surgical technique, survivorship, radiographic and functional outcomes. Methods The clinical data of 123 patients (88 women, 35 men) who had undergone 140 TKAs in our hospital were reviewed. All the TKAs were performed with alignment targets set according to the original phenotypes of the knee, with the KA method, using the generic total knee instrument. The patients’ demographics, preoperative and postoperative knee alignment angles, one-year postoperative range of motion (ROM), Oxford knee scores (OKS), Combined knee society score (CKSS) were collected and analyzed. Results The 3 years survivorship was 99.3% for all cause of revision, and 100% with revision other than infection as the endpoint. The preoperative phenotypes of the knee were as follows: neutral alignment 20.1% (type 1: 3.6%, type 2: 16.5%), varus alignment 71.2% (type 3: 46.0%, type 4: 25.2%), and valgus alignment (type 5: 8.6%). Using our protocol, patients with different knee phenotypes could get similar great functional improvement though the postoperative alignment parameters were significantly different between the knee phenotypes (P Conclusion The early outcomes of this phenotype-oriented KA-TKA using generic total knee instruments are promising. Setting individualized alignment target according to original knee phenotype is rational and practical. The residual varus alignment did not cause any aseptic loosening in the 3 years follow-up. Long-term survivorship and functional outcomes need to be evaluated in future studies.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2–M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. Significance: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.

This study investigates the effects of Phyllanthus amarus extract (PAE) on immune responses, growth, and resistance to Vibrio alginolyticus in white shrimp (Litopenaeus vannamei). In vitro PAE treatment did not alter the cell viability of haemocytes and significantly enhanced immune parameters such as phenoloxidase (PO) activity, phagocytic activity, and superoxide anion (O2−) production. We conducted two feeding trials to examine the effects of PAE on the growth, disease resistance, and innate immune parameters of white shrimp. In the first in vivo trial, shrimps (4.01 ± 0.03 g) were fed a diet containing 0 g (control), 10 g (PAE10), 20 g (PAE20), or 40 g (PAE40) of PAE per kilogram of feed for 56 days. After the feeding period, the PAE20 group showed a significantly higher weight gain and specific growth rate than shrimp fed the control diet. Furthermore, after challenge with V. alginolyticus, shrimp fed a diet containing PAE showed significantly higher survival than those fed the control diet. The second in vivo trial (28 days) was performed to identify the mechanisms of enhanced immunity in PAE-fed shrimp. Shrimp fed the PAE20 diet generally had the highest total haemocyte count, PO activity, phagocytic activity, and O2− production, followed by the PAE40 and PAE10 groups. Thus, our results suggest that administration of 20 g of PAE per kilogram of feed can enhance immunity, growth, and resistance to V. alginolyticus in white shrimp.

Background Diabetes foot self-care is one of the self-management behaviors of diabetic patients leading to a reduction in the incidence of pressure ulcers and amputation. Having a valid, reliable, simple and comprehensive tool is essential in measuring the self-care behavior of diabetic patients. The aim of this study was to evaluate the psychometric properties of the Farsi version of the diabetes foot self-care bahavior scale (DFSBS) in Iran. Methods In this cross-sectional and methodological study, 500 patients with type 2 diabetes were recruited by convenience sampling. Construct validity was assessed by exploratory factor analysis (over 300 patients) and confirmatory factor analysis (over 200 patients). Internal consistency was calculated by Cronbach’s alpha coefficient and its stability was calculated by intraclass correlation coefficient (ICC). Results In the exploratory factor analysis, two self-care factors related to feet and shoes were extracted which had specific values of 38.49 and 1.24, respectively, and were able to account for 56.22% of the total self-care variance of diabetes foot. Confirmatory factor analysis had excellent fit model. The internal consistency and ICC of the whole instrument were 0.83 and 0.791 (95% CI: 0.575–0.925; P Conclusions The Farsi version of DFSBS (F-DFSBS) has good validity and reliability, and due to its appropriate psychometric properties, this tool can be used in future studies.

Purpose Progestin resistance is a critical obstacle for endometrial conservative therapy. Therefore, studies to acquire a more comprehensive understanding of the mechanisms are urgent. However, the pivotal molecules are still unexplored. Materials and methods We downloaded GSE121367 from the GEO database. The "limma" R language package was applied to identify differentially expressed genes (DEGs). We conducted Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Protein-protein interaction was constructed by STRING and visualized in Cytoscape. The tumor immune microenvironment was explored by the TISIDB database. Methylation validation and overall survival analysis were conducted by the TCGA database. In addition, the upstream modulators of hub genes were predicted by miRTarBase and Network Analyst databases. The expression levels of candidate genes were validated by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemical assay (IHC). Cell growth, clone formation, migration, invasion, and wound healing assays were studied to explore the role of MSX1 in progestin resistance in vitro. Results A total of 3,282 DEGs were identified and they were mostly enriched in the cell adhesion pathway. We screened out ten hub genes whose genomic alteration rates were low based on the current endometrial carcinoma sample sets. Has-miR-335-5p, has-miR-124-3p, MAZ, and TFDP1 were the most prominent upstream regulators. The methylation status of CDH1, JAG1, EPCAM, and MSX1 was decreased, corresponding to their high protein expression, which also predicted better overall survival. The homeobox protein of MSX1 showed significant tissue specificity and better prognostic value and its knockdown inhibited epithelial-mesenchymal transitions (EMT) and enhanced progesterone efficacy. Conclusion Our study identified that the gene of MSX1 promised to be the specific indicator and therapeutic target for progestin resistance. This would shed new light on the underlying biological mechanism to overcome progestin resistance of endometrial cancer.

A longstanding focus of perceptual learning research is learning specificity, the difficulty for learning to transfer to tasks and situations beyond the training setting. Previous studies have focused on promoting transfer across stimuli, such as from one sound frequency to another. Here we examined whether learning could transfer across tasks, particularly from fine discrimination of sound features to speech perception in noise, one of the most frequently encountered perceptual challenges in real life. Separate groups of normal-hearing listeners were trained on auditory interaural level difference (ILD) discrimination, interaural time difference (ITD) discrimination, and fundamental frequency (F0) discrimination with non-speech stimuli delivered through headphones. While ITD training led to no improvement, both ILD and F0 training produced learning as well as transfer to speech-in-noise perception when noise differed from speech in the trained feature. These training benefits did not require similarity of task or stimuli between training and application settings, construing far and wide transfer. Thus, notwithstanding task specificity among basic perceptual skills such as discrimination of different sound features, auditory learning appears readily transferable between these skills and their “upstream” tasks utilizing them, providing an effective approach to improving performance in challenging situations or challenged populations.

To investigate the associations between vision impairment (VI), vision correction (VC), and cognitive function.We included 20,677 participants aged ≥45 years from the China Health and Retirement Longitudinal Study (2011-2015). Participants were grouped into no VI, distance VI (DVI) only, near VI (NVI) only, or both distance and near VI (DNVI), and VI(+)/VC(-), VI(+)/VC(+), VI(-)/VC(-), or VI(-)/VC(+) further at baseline. Cognitive function at baseline and subsequently every two years was applied as a dependent variable in a generalized estimating equation model.DVI only, NVI only, and DNVI had significantly worse cognitive function over time than no VI (allCognitive function was worse in middle-aged and older Chinese with VI, especially in those with DNVI. VC was associated with better cognitive function over time regardless of the status of vision.

Arterio-esophageal fistula (AEF) is a rare life-threatening cause of upper gastrointestinal bleeding. Realizing the risk factors and clinical presentations of AEF will enable us to provide timely diagnosis, efficient treatment, and better outcome. We present a 43-year-old Taiwanese man who had histories of destructive lung, innominate artery-trachea fistula, and received bilobectomy. He was admitted to our hospital with fresh blood drainage from nasogastric tube. He was diagnosed as right fifth intercostal artery esophageal fistula by computed tomography angiography and transcatheter arterial embolization was performed. The bleeding stopped and the patient was discharged uneventfully. The risk factors of AEF include esophageal foreign body, vascular surgery, thoracic arterial malformations, and concurrent chemoradiotherapy in T4-esophageal cancer. Computed tomography angiography may be the most sensitive diagnostic test. Transcatheter arterial embolization or endovascular stent grafting may be considered as the first-line treatment of AEF in the future.

Background This study was intended to investigate the epidemiological characteristics of COVID-19 clusters and the severity distribution of clinical symptoms of involved cases in Sichuan Province, so as to provide information support for the development and adjustment of strategies for the prevention and control of local clusters. Methods The epidemiological characteristics of 67 local clusters of COVID-19 cases in Sichuan Province reported as of March 17, 2020 were described and analyzed. Information about all COVID-19 clusters and involved cases was acquired from the China Information System for Disease Control and Prevention and analyzed with the epidemiological investigation results taken into account. Results The clusters were temporally and regionally concentrated. Clusters caused by imported cases from other provinces accounted for 73.13%; familial clusters accounted for 68.66%; the average attack rate was 8.54%, and the average secondary attack rate was 6.11%; the median incubation period was 8.5 d; a total of 28 cases met the criteria for incubation period determination, and in the 28 cases, the incubation period was > 14 d in 21.43% (6/28). a total of 226 confirmed cases were reported in the 67 clusters. Ten cases were exposed before the confirmed cases they contacted with developed clinical symptoms, and the possibility of exposure to other infection sources was ruled out; two clusters were caused by asymptomatic carriers; confirmed cases mainly presented with fever, respiratory and systemic symptoms; a gradual decline in the severity of clinical symptoms was noted with the increase of the case generation. Conclusions Population movement and gathering restrictions and strict close contact management measures will significantly contribute to the identification and control of cases. Transmission during the incubation period and asymptomatic infections have been noted. Studies on the pathogenicity and transmissibility in these populations and on COVID-19 antibody levels and protective effects in healthy people and cases are required.

Purpose To evaluate the noninvasive prenatal testing (NIPT) results of 36,913 cases in Jiangxi province of central China and explore its application value in prenatal screening and diagnosis. Methods This retrospective analysis included 36,913 singleton pregnant women who underwent NIPT because of moderate-/high-risk pregnancy or voluntary requirements between January 2017 and December 2019 in our hospital. Chromosomal abnormalities such as trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs) were judged by standard Z-score analysis. Positive NIPT results were confirmed by amniocentesis and karyotyping. Pregnancy outcomes were followed up via telephone interview. Results A total of 1.01% (371/36,913) positive cases were detected by NIPT, comprising 137, 46, 31, and 157 cases of T21, T18, T13, and SCAs, respectively. A total of 116 of T21, 27 of T18, 13 of T13, and 51 of SCAs were confirmed to be true positive; all normal cases that had been followed up were verified to be true negative. The NIPT sensitivity in T21, T18, T13, and SCAs was 100.00% individually, whereas the specificity was 99.94% (36,488/36,509), 99.95% (36,579/36,598), 99.95% (36,594/36,612), and 99.72% (36,472/36,574), respectively. Furthermore, the negative predictive values of T21, T18, T13, and SCAs were all 100%, while the positive predictive values were 84.67%, 58.70%, 41.94%, and 33.33%, respectively. Conclusion NIPT is highly sensitive and has a low false positive rate in testing clinically significant fetal aneuploidies of general reproductive women. However, this technique cannot substitute for amniocentesis and karyotyping, and detailed genetic counseling is also essential for the high-risk group of NIPT.

MSstatsTMT implements a general statistical approach for relative protein quantification and tests for differential abundance in mass spectrometry-based experiments with TMT labeling. It is applicable to experiments with multiple conditions, multiple biological replicate runs and multiple technical replicate runs, and unbalanced designs. Evaluation on a controlled mixture, simulated datasets, and three biological investigations with diverse designs demonstrated that MSstatsTMT balanced the sensitivity and the specificity of detecting differentially abundant proteins, in large-scale experiments with multiple biological mixtures., Graphical Abstract Highlights • Statistical approach for differential abundance analysis for proteomic experiments with TMT labeling. • Applicable to large-scale experiments with complex or unbalanced design. • An open-source R/Bioconductor package compatible with popular data processing tools., Tandem mass tag (TMT) is a multiplexing technology widely-used in proteomic research. It enables relative quantification of proteins from multiple biological samples in a single MS run with high efficiency and high throughput. However, experiments often require more biological replicates or conditions than can be accommodated by a single run, and involve multiple TMT mixtures and multiple runs. Such larger-scale experiments combine sources of biological and technical variation in patterns that are complex, unique to TMT-based workflows, and challenging for the downstream statistical analysis. These patterns cannot be adequately characterized by statistical methods designed for other technologies, such as label-free proteomics or transcriptomics. This manuscript proposes a general statistical approach for relative protein quantification in MS- based experiments with TMT labeling. It is applicable to experiments with multiple conditions, multiple biological replicate runs and multiple technical replicate runs, and unbalanced designs. It is based on a flexible family of linear mixed-effects models that handle complex patterns of technical artifacts and missing values. The approach is implemented in MSstatsTMT, a freely available open-source R/Bioconductor package compatible with data processing tools such as Proteome Discoverer, MaxQuant, OpenMS, and SpectroMine. Evaluation on a controlled mixture, simulated datasets, and three biological investigations with diverse designs demonstrated that MSstatsTMT balanced the sensitivity and the specificity of detecting differentially abundant proteins, in large-scale experiments with multiple biological mixtures.

Seed vigor is crucial for crop early establishment in the field and is particularly important for forage crop production. Oat (Avena sativa L.) is a nutritious food crop and also a valuable forage crop. However, little is known about the genetics of seed vigor in oats. To investigate seed vigor-related traits and their genetic architecture in oats, we developed an easy-to-implement image-based phenotyping pipeline and applied it to 650 elite oat lines from the Collaborative Oat Research Enterprise (CORE). Root number, root surface area, and shoot length were measured in two replicates. Variables such as growth rate were derived. Using a genome-wide association (GWA) approach, we identified 34 and 16 unique loci associated with root traits and shoot traits, respectively, which corresponded to 41 and 16 unique SNPs at a false discovery rate < 0.1. Nine root-associated loci were organized into four sets of homeologous regions, while nine shoot-associated loci were organized into three sets of homeologous regions. The context sequences of five trait-associated markers matched to the sequences of rice, Brachypodium and maize (E-value < 10−10), including three markers matched to known gene models with potential involvement in seed vigor. These were a glucuronosyltransferase, a mitochondrial carrier protein domain containing protein, and an iron-sulfur cluster protein. This study presents the first GWA study on oat seed vigor and data of this study can provide guidelines and foundation for further investigations.

Metabolic pathways in cancer cells typically become reprogrammed to support unconstrained proliferation. These abnormal metabolic states are often accompanied by accumulation of high concentrations of ATP in the cytosol, a phenomenon known as the Warburg Effect. However, how high concentrations of ATP relate to the functional state of proteins is poorly understood. Here, we comprehensively studied the influence of ATP levels on the functional state of the human enzyme, uridine phosphorylase I (hUP1), which is responsible for activating the chemotherapeutic pro‐drug, 5‐fluorouracil. We found that elevated levels of ATP decrease the stability of hUP1, leading to the loss of its proper folding and function. We further showed that the concentration of hUP1 exerts a critical influence on this ATP‐induced destabilizing effect. In addition, we found that ATP interacts with hUP1 through a partially unfolded state and accelerates the rate of hUP1 unfolding. Interestingly, some structurally similar metabolites showed similar destabilization effects on hUP1. Our findings suggest that metabolites can alter the folding and function of a human protein, hUP1, through protein destabilization. This phenomenon may be relevant in studying the functions of proteins that exist in the specific metabolic environment of a cancer cell.

To describe the clinical outcomes of Descemet membrane endothelial keratoplasty combined with phacoemulsification/posterior chamber intraocular lens implantation (triple procedure) for treatment of corneal decompensation induced by a phakic anterior chamber intraocular lens (AC IOL) implantation. Ten patients (10 eyes) with corneal decompensation due to phakic AC IOL implantation that had undergone the triple procedure were included in this study. Among the 10 eyes, 5 eyes underwent explantation of AC IOL prior to the transplantation, and then underwent the triple procedure. The remaining 5 eyes with a phakic AC IOL in situ underwent the triple procedure with concurrent explantation of AC IOL. Corrected distance visual acuity (CDVA), subjective refraction, endothelial cell density (ECD), and complications were documented. The triple procedure was performed across all eyes without any adverse events. The average CDVA improved from 1.32 ± 0.24 preoperatively to 0.15 ± 0.05 logarithm of the minimum angle of resolution (logMAR), which represents an improvement in Snellen equivalent from 20/400 (0.05) preoperatively to 20/28 (0.71) at 12 months after surgery. At 12 months, all eyes reached a CDVA of 20/32 (0.63) or better, and 50% of eyes reached a CDVA of 20/25 (0.8) or better. The mean donor ECD±SD was 2868.7 ± 67.9 cells/mm2, which decreased to 1724.1 ± 84.6 cells/mm2 at 12 months, representing 39.9% of endothelial cell loss. Patients did not experience any severe adverse events. The triple procedure is a safe and effective option for corneal decompensation induced by a phakic AC IOL implantation, helping achieve a satisfactory visual rehabilitation with few complications.

Ventricular arrhythmia (VA) is related to inflammatory activity. Rhodiola crenulate (RC) and its main active component, salidroside, have been reported as anti-inflammatory agents. The aim of this study was to demonstrate the effect of RC and salidroside in preventing VA via the inhibition of IL-17 in an ischemic heart failure (HF) model. Rabbit HF models were established by coronary artery ligation for 4 weeks. These rabbits were treated with RC (125, 250, 500 mg/kg) and salidroside (9.5 mg/kg) once every 2 days for 4 weeks. WBC, serum biochemistry, ECG, and the expression of CD4+ T cells were measured every 2 weeks. The mRNA and protein expressions of IL-17 were measured by real time-PCR, ELISA, and Western blotting after RC and salidroside treatment for 4 weeks. Open-chest epicardial catheter stimulation was performed for VA provocation. After RC and salidroside treatment in HF left ventricle, (1) the levels of WBC and CD4+ T cells decreased, (2) the expression of IL-17 and its downstream target genes, IL-6, TNF-α, IL-1β, IL-8, and CCL20, reduced, (3) the level of NLRP3 inflammasome was decreased, (4) fibrosis and collagen production were significantly downregulated, (5) p38 MAPK and ERK1/2 phosphorylation were attenuated, (6) the inducibility of VA was decreased, and (7) the levels of Kir2.1, Nav1.5, NCX, PLB, SERCA2a and RyR were up-regulated. RC inhibited the expression of IL-17 and its downstream target genes that were mediated by activation of several MAPKs, which decreased the levels of fibrosis and apoptosis and suppressed VA.

Some studies showed patients with chronic urticaria have a higher rate of peptic ulcer disease (PUD). Whether PUD is a risk factor for chronic urticaria is unclear. The objective of this study was to evaluate the incidence of and risk factors for chronic urticaria in patients with PUD using the Taiwan National Health Insurance Research Database. We conducted a retrospective nationwide cohort study of the period 2000–2012 and involving 11,901 patients with PUD who underwent Helicobacter pylori (HP) therapy (PUD + HP group) and an equal number of matched patients without HP infection (PUD − HP group). Furthermore, we enrolled 23,802 patients without PUD for comparison (non-PUD group). The Cox proportional hazards regression model was used to analyze chronic urticaria risk after adjusting for potential confounding factors. The mean ages of the three groups were around 50 years. Approximately 42.6% were female. Chronic urticaria incidences in the PUD + HP and PUD − HP groups were both significantly higher than that in the non-PUD group. The hazard ratios of chronic urticaria in the PUD + HP group and the PUD − HP group were 1.34 (95% confidence interval 1.09–1.64) and 1.45 (95% confidence interval 1.19–1.79), respectively. The risk difference became significant 2 years after patients with PUD had the HP infection tests and persisted till the end of follow-up. The risk increase was significant in patients with PUD who were female or aged 40–64 years. There was no difference in the risk comparison between PUD + HP and PUD − HP groups. Peptic ulcer disease, independent of HP infection, is associated with an increased chronic urticaria risk. Patients with PUD who were female or aged 40–64 years are more likely to have chronic urticaria.

BET inhibitors (BETi) exert an excellent anti-cancer activity in breast cancer. However, the identification of new potential targets to enhance breast cancer sensitivity to BETi is still an enormous challenge. Both NR5A2 and NCOA3 are frequently involved in cancer cells resistance to chemotherapy, also associated with poor prognosis in breast cancer. However, the functions of NR5A2 and NCOA3 in BETi resistance remains unknown. In this study, we found that BETi JQ1 and I-BET151 exhibited anti-cancer effects in breast cancer by inducing ferroptosis. NCOA3 as a coactivator synergized with NR5A2 to prevent BETi-induced ferroptosis. Mechanistically, we identified NR5A2 synergized with NCOA3 to increase expression of NRF2, a transcription factor that controls the expression of many antioxidant genes. Moreover, inhibition of NR5A2 or NCOA3 using small molecule inhibitors enhanced anti-cancer effects of BETi against breast cancer in vivo and in vitro. Altogether, our findings illustrated NR5A2 synergized with NCOA3 to confer breast cancer cells resistance to BETi by induction of NRF2. Inhibition of NR5A2/NCOA3 combined with BETi might be a novel strategy for treatment of breast cancer.

Objective To investigate the effect of remifentanil-based fast-track anesthesia on analgesia and sedation after transthoracic device closure of ventricular septal defects (VSDs) in adult patients. Methods A retrospective analysis was performed on 59 patients aged 21–53 years who underwent transthoracic device closure of VSDs from January 2019 to September 2019. According to the different anesthesia strategies, the patients were divided into the R group (using remifentanil-based anesthesia, n = 33) and the S group (using sufentanil-based anesthesia, n = 26). Patient-related clinical data, postoperative analgesia, and sedation scores were collected and analyzed. Results There was no significant difference in age, gender, body weight, and operation time between the group R and the group S (P > 0.05). There was also no significant difference in intraoperative hemodynamic changes, BIS scores, postoperative analgesia, and sedation scores between the two groups (P > 0.05). The duration of mechanical ventilation, the length of ICU stay, and hospital stay in the group R were significantly lower than those in the group S (P Conclusion Remifentanil-based fast-track anesthesia is effective for adult patients undergoing transthoracic device closure of VSDs, which may shorten the mechanical ventilation duration, the ICU and hospital stay of patients.