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The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19., COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.

Background The aim of this study is to explore the characteristics of Kawasaki disease (KD) and concurrent pathogens due to a stay-at-home isolation policy during coronavirus disease 2019 (COVID-19) epidemic. Methods All patients with KD admitted between February and April in 2015–2020, were classified into before (group 1, in 2015–2019) and after (group 2, in 2020) isolation groups. A total of 4742 patients [with KD (n = 98) and non-KD (n = 4644)] referred to Mycoplasma pneumoniae (MP) and virus detection were analyzed in 2020. Clinical characteristics, laboratory data, and 13 pathogens were analyzed retrospectively. Results Group 2 had a significantly increased incidence of KD (0.11%) with 107 patients compared to that of group 1 (0.03%) with 493 patients. The comparisons of oral mucosal change, strawberry tongue, desquamation of the fingertips, cervical lymphadenopathy and neutrophil percentage decreased in group 2 compared to group 1. The infection rate of MP increased significantly in group 2 (34.7%) compared to group 1 (19.3%), while the positive rate of viruses decreased significantly in group 2 (5.3%) compared to group 1 (14.3%). In 2020, the positive rate of MP infection increased significantly in patients with KD compared to the increase in patients with non-KD. The infection rate of MP for younger children aged less than 3 years old was higher in group 2 than in group 1. Conclusion Compared with the characteristics of KD from 2015 to 2019 years, the incidence of KD was increased in 2020 and was accompanied by a high incidence of MP infection, especially in younger children (less than 3 years old) during the isolation due to COVID-19 pandemic.

Background Sepsis is a common disease in intensive care units, with high morbidity and mortality. Intestinal microecology plays a vital part in the development and progression of this disease, possibly because sepsis and its treatment cause specific changes in the composition of the intestinal flora. Aim To investigate the characteristics of intestinal flora disturbance in sepsis patients treated with antibiotics. Methods In this prospective comparative study, we enrolled ten patients with sepsis (sepsis group), hospitalized in the Department of Critical Care Medicine of the General Hospital, Ningxia Medical University, China (a class IIIa general hospital) from February 2017 to June 2017; ten patients without sepsis hospitalized in the same period (non-sepsis group) and ten healthy individuals (control group) were also enrolled. Fecal samples collected from the three groups were subjected to 16S rRNA gene sequencing and the intestinal flora diversity, structure, and composition were determined. Additionally, the dynamics of the intestinal flora diversity, structure, and composition in sepsis patients were investigated via 16S rRNA gene sequencing of samples collected 0 d, 3 d, and 7 d after admittance to the intensive care unit. Correlations between the serum levels of procalcitonin, endotoxin, diamine oxidase, and D-lactic acid and the intestinal flora composition of sepsis patients were also investigated. Results Compared with the healthy control group, sepsis and non-sepsis patients showed reduced intestinal flora α-diversity and a distinct flora structure, with Firmicutes as the dominant phylum, and significantly decreased proportions of Bacteroidetes, as well as Prevotella and Lachnospira, among other genera. Of note, the proportion of Enterococcus was significantly increased in the intestinal tract of sepsis patients. Interestingly, the α-diversity in the sepsis group decreased gradually, from days 1 to 7 of treatment. However, pairwise comparisons showed that both the diversity and structure of the intestinal flora were not significantly different considering the three different time points studied. Curiously, the serum levels of procalcitonin, endotoxin, diamine oxidase, and D-lactic acid in sepsis patients correlated with the prevalence of various bacterial genera. For example, the prevalence of Ruminococcus was positively correlated with serum procalcitonin, endotoxins, and diamine oxidase; similarly, the prevalence of Roseburia was positively correlated with serum procalcitonin, endotoxins, and D-lactic acid. Conclusion Sepsis patients in intensive care units show dysbiosis, lasting for at least 1 wk.

Background Liberal oxygen therapy might increase the mortality rate of patients. Non-rebreathing masks (NRM) are a high-flow, non-invasive oxygen device that can provide oxygen concentration up to 95%. This study aimed to determine the impact of using NRM in patients with respiratory failure. Methods This retrospective cohort study was conducted in four medical institutions in Taiwan from January 2010 to December 2016. The association between mortality and NRM use before receiving ventilator support in patients with respiratory failure in the emergency department was analyzed. Patients were divided into the NRM treatment and no NRM treatment groups. A 1:4 propensity score matching was conducted. Regarding the duration of NRM use, treatments were grouped as 0 h, 0–1 h, 1–2 h, and >2 h. Results A total of 18,749 patients were included, with 1074 using NRM. After propensity score matching, 1028 patients using NRM (0–1 h: 508, 1–2 h: 193, and >2 h: 327) and 4112 patients not using NRM were analyzed. The 30-day mortality rates were 29.1%, 28.5%, 27.5%, and 35.5% in the 0 h, 0–1 h, 1–2 h, and >2 h treatment groups, respectively. Patients with respiratory failure due to pulmonary disease using NRM over 2 h had a higher mortality rate than patients not using NRM (hazard ratio: 1.3, 95% CI: 1.01–1.66). Conclusions Prolonged use of NRM in patients with respiratory failure due to pulmonary disease possibly increases mortality.

To examine to what degree guidelines for PET and PET/CT used systematic review evidence. The latest version of guidelines for PET, PET/CT or PET/MRI published in English in PubMed until December 2019 was analysed in two categories: (1) for indications, if mainly discussing the appropriate use of PET in diverse conditions; (2) for procedures, if providing step-by-step instructions for imaging. We surveyed the general characteristics and the use of systematic review evidence for developing recommendations across all guidelines, and surveyed the citation of evidence for five recommendation topics in guidelines for procedures. Forty-seven guidelines, published between 2004 and 2020, were included. Guidelines for indications were developed mainly on systematic reviews (13 of 19, 68.4%). Among those, 12 (63.2%) reported the level of evidence, 4 (21.1%) reported the strength of recommendations, 3 (15.8%) described external review and 7 (36.8%) involved methodologists. Guidelines for procedures were seldom developed on systematic reviews (1 of 27, 3.7%). Among those, 1 (3.7%) reported the level of evidence, 1 (3.7%) reported the strength of recommendations, 3 (11.1%) described external review and 1 (3.7%) involved methodologists. Systematic review evidence was cited by 2 (7.4%) procedure guidelines per recommendation topic in median. The use of systematic review evidence for developing recommendations among PET or PET/CT guidelines was suboptimal. While our survey is an icebreaking attempt to explore a key element (i.e. use of systematic review evidence) for developing nuclear medicine guidelines, assessments of other domains of guideline quality may help capture the entire picture. • The use of systematic review evidence for developing recommendations among guidelines for PET or PET/CT was suboptimal. • Only 13 (68.4%) guidelines for indications and 1 (3.7%) guideline for procedures systematically reviewed the literature during guideline development. • For each recommendation topic we examined, only a median of 2 (7.4%) procedure guidelines cited systematic review evidence.

Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial arteriopathy characterized by recurrent lacunar stroke, migraine, and depression. The mechanism of cognitive dysfunction in CADASIL is still uncertain. The aim of this study was to use tract-based spatial statistics (TBSS) to map voxelwise the spatial distribution of brain microstructural change revealed by DTI-derived indices in patients with CADASIL to further study the underlying neuropsychopathological mechanism of CADASIL. Method Twelve patients with CADASIL and 11 age-, sex-matched healthy controls underwent magnetic resonance imaging at 3 T. Then we evaluated DTI-derived indices (fractional anisotropy [FA], mode of anisotropy [MO], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) of brain white matter (WM) between CADASIL patients and healthy subjects through TBSS. Results Compared with healthy controls, patients with CADASIL showed extensive decreased FA, MO and increased RD, AD, and MD throughout the entire brain (mainly the WM of the temporal poles, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, uncinate fasciculus, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and Scheltens scores. Decreased FA values and MO values were positively correlated with Montreal Cognitive Assessment scores in CADASIL patients. Increased AD, RD, and MD values were significantly negatively correlated with Montreal Cognitive Assessment scores. Conclusions Widespread WM abnormalities were clearly shown in CADASIL by using TBSS. Severity of microstructural changes correlates significantly with extension of T2 hyperintensity. Moreover, WM microstructural damage and cognitive impairment were significantly correlated. This study indicated that WM tract damage plays an important role in cognitive impairment in CADASIL.

VQ proteins are a class of plant-specific proteins containing the conserved motif FxxhVQxhTG（h denotes hydrophobic residues and x represents any amino acid）and are named VQ for the V and Q residues. By analyzing the structure of VQ members it was found that most VQ genes do not contain introns and the number of encoded amino acids is less than 300 aa. A majority of VQ proteins are located in the nucleus. Accumulated evidence has highlighted the importance of VQ proteins mainly participating in signal pathways through interacting with partners (eg. WRKYs and MAPKs) to regulate plant growth and development and respond to biotic and abiotic stresses. This review primarily focuses on the structure of VQ members in plant kingdom and the biological function and the mechanism of VQ protein action, and discusses recent advances in understanding the pivotal role of VQ-motif, which provides a solid foundation for further exploration on VQ proteins.

Aim: The aim is to study ANXA2 biomarkers for early diagnosis of cervical cancer. Materials & methods: The study used bioinformatics analysis and experimental verification of ANXA2 expression in cervical cancer. Results: ANXA2 expression was higher in cancer tissues than in non-cancer tissues (p = 0.002). ANXA2 was expressed in cell membranes of non-cancer tissues, whereas in cancer tissues it was expressed in both the cell membranes and the cytoplasm. Moreover, ANXA2 expression was more pronounced in squamous cell carcinomas. ANXA2 expression decreased overall survival of patients, and the data suggested that protein expression was associated with invasion and migration of tumors. Conclusion: ANXA2 has high specificity and sensitivity as a detection marker for cervical cancer and can assist in the diagnosis of cervical cancer.

Objective. In this study, we aimed to analyze thyroid function and related risk factors for thyroid dysfunction in 35 patients with Gitelman syndrome (GS). Methods. This study included 35 patients with GS who were referred to West China Hospital of Sichuan University from Aug 2013 to Jan 2018. General patient characteristics were collected, and thyroid function was assessed. To evaluate the potential contribution of hypokalemia to thyroid dysfunction, 636 patients who were clinically diagnosed with primary aldosteronism (PA) during the same period were included as the control group; these patients were divided into a hypokalemia group ( N = 528 ) and a normokalemia group ( N = 108 ). Logistic regression was used to screen for significant determinants of thyroid dysfunction in the GS patients. Results. Patients with GS had a significantly different prevalence of subclinical hypothyroidism, hypothyroidism, and hyperthyroidism than patients with hypokalemic PA and normokalemic PA (28.6%, 2.9%, and 11.4% vs. 15.5%, 6.1%, and 0.7% vs. 8.3%, 4.6%, and 2.8%, P < 0.001 ). No significant difference was observed in the distribution of thyroid function between the hypokalemic PA group and the normokalemic PA group ( P > 0.05 ). No significant differences were seen in the positive rates of thyrotropin receptor antibody (TRAb), thyroglobulin antibody (TGAb), and thyroid peroxidase antibody (TPOAb) among the three groups ( P > 0.05 ). In the logistic regression, only sex (OR, 7.4; 95% CI, 1.555-35.479; P = 0.012 ) was significantly correlated with thyroid dysfunction in GS patients. Conclusion. GS is complicated with a greater rate of thyroid dysfunction than primary aldosteronism. The risk of thyroid dysfunction in female patients with GS is higher than that in male patients.

Evaluating patients with chronic venous leg ulcers (CVLUs) is essential to find the underlying etiology. The basic tenets in managing CVLUs are to remove the etiological causes, to address systemic and metabolic conditions, to examine the ulcers and artery pulses, and to control wound infection with debridement and eliminating excessive pressure on the wound. The first-line treatments of CVLUs remain wound care, debridement, bed rest with leg elevation, and compression. Evidence to support the efficacy of silver-based dressings in healing CVLUs is unavailable. Hydrogen peroxide is harmful to the growth of granulation tissue in the wound. Surgery options include a high ligation with or without stripping or ablation of the GSVs depending on venous reflux or insufficiency. Yet, not all CVLUs are candidates for surgical treatment because of comorbidities. When standard care of wound for 4 wk failed to heal CVLUs effectively, use of advanced wound care should be considered based on the available evidence. Negative pressure wound therapy facilitates granulation tissue development, thereby helping closure of CVLUs. Autologous split-thickness skin grafting is still the gold standard approach to close huge CVLUs. Hair punch graft appears to have a better result than traditional hairless punch graft for CVLUs. Application of adipose tissue or placenta-derived mesenchymal stem cells is a promising therapy for wound healing. Autologous platelet-rich plasma provides an alternative strategy for surgery for safe and natural healing of the ulcer. The confirmative efficacy of current advanced ulcer therapies needs more robust evidence.

O-GlcNAc modification plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regulated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated transcription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O-GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear factor erythroid 2-related factor-1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress., Protein O-GlcNAcylation is involved in regulating gene expression and maintaining cellular homeostasis. Here, the authors develop a chemical reporter-based strategy for the proteomic profiling and genome-wide mapping of genotoxic stress-induced O-GlcNAcylated chromatin-associated proteins.

Porphyromonas gingivalis is a pathogen closely associated with periodontal and systemic infections. Recently, lysine acetylation (Kac) and lysine succinylation (Ksuc) have been identified in bacterial proteins with diverse biological and pathological functions. The Ksuc of P. gingivalis ATCC 33277 has been characterized in our previous work, and here, we report the systematic analysis of Kac and its crosstalk with Ksuc in this bacterium. A combination of the affinity enrichment by the acetyl-lysine antibody with highly sensitive LC-MS/MS was used to identify the lysine-acetylated proteins and sites in P. gingivalis ATCC 33277. A total of 1,112 lysine-acetylated sites matching 438 proteins were identified. These proteins involved in several cellular processes, especially those proteins related to protein biosynthesis and central metabolism had a high tendency to be lysine acetylated. Moreover, lysine sites flanked by tyrosine, phenylalanine, and histidine in the +1 position, as well as residue lysine in position +4 to +5, were the targets of Kac. Additionally, proteins involved in adhesins, gingipains, black pigmentation, and oxidative stress resistance were identified as substrates of Kac. Collectively, these results suggest Kac may play a critical role in the regulation of physiology and virulence of P. gingivalis. Furthermore, we discovered that, Ksuc and Kac were extensively overlapped in P. gingivalis ATCC 33277, especially in proteins related to ribosomes and metabolism. This study provides a significant beginning for further investigating the role of Kac and Ksuc in the pathogenicity of P. gingivalis.

Background Knee osteoarthritis (OA) is a common disease condition associated with aging and a frequent cause of primary care consultations. Few longitudinal studies have been conducted to investigate the incidence of symptomatic knee osteoarthritis (OA) and to identify its risk factors among the Chinese population. Methods The China Health and Retirement Longitudinal Study (CHARLS) is a nationwide longitudinal survey of persons aged ≥45 years. Symptomatic knee OA was diagnosed when both self-reported knee pain and self-reported physician-diagnosis arthritis existed. Using the national survey data collected from the CHARLS, we estimated the incidence of symptomatic knee OA, taking into account the complex survey design and response rate. We applied weighted logistic regression analysis to identify its risk factors. Results In the 4-year follow-up, the cumulative incidence of symptomatic knee OA among middle-aged and older Chinese adults was 8.5%; the incidence was higher among females (11.2%) than males (5.6%). Female (odds ratio (OR) 1.98 [95% confidence interval (CI) 1.65–2.37]), rural area (OR 1.32 [95% CI 1.08–1.60]), and West region (OR 2.33 [95% CI 1.89–2.87]) were associated with a higher risk of incident symptomatic knee OA. Physical activities (OR 0.47 [95% CI 0.29–0.76]) and high education level (OR 0.60 [95% CI 0.41–0.88]) was associated with a lower risk of incident symptomatic knee OA, while histories of heart disease (OR 1.40 [95% CI 1.07–1.82]), kidney disease (OR 1.80 [95% CI 1.35–2.39]), and digestive disease (OR 1.54 [95% CI 1.30–1.82]) were associated with a higher risk of incident symptomatic knee OA. Conclusion The cumulative incidence of symptomatic knee OA over 4 years was relatively high, and varied by province and region. Lack of physical activities was confirmed to be risk factors of incident symptomatic knee OA. The presence of heart disease, kidney disease, and digestive disease may be associated with a higher risk of incident symptomatic knee OA, further research need to confirm these findings.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP), in which exon open reading frame 15 (ORF15) of RPGR has been implicated to play a substantial role. We identified a novel hemizygous missense mutation E585K of RPGR from whole-exome sequencing of RP. RNA-Seq analysis and functional study were conducted to investigate the underlying pathogenic mechanism of the mutation. Our results showed that the mutation actually affected RPGR ORF15 splicing. RNA-Seq analysis of the human retina followed by validation in cells revealed a complex splicing pattern near the 3′ boundary of RPGR exon 14 in the ORF15 region, resulting from a variety of alternative splicing events (ASEs). The wildtype RPGR mini-gene expressed in human 293T cells confirmed these ASEs in vitro. In contrast, without new RNA species detected, the mutant mini-gene disrupted the splicing pattern of the ORF15 region, and caused loss of RPGR transcript heterogeneity. The RNA species derived from the mutant mini-gene were predominated by a minor out-of-frame transcript that was also observed in wildtype RPGR, resulting from an upstream alternative 5′ splice site in exon 14. Our findings therefore provide insights into the influence of RPGR exonic mutations on alternative splicing of the ORF15 region, and the underlying molecular mechanism of RP.

Introduction This study was to develop a simple model for predicting malignancy of peripheral pulmonary lesions (PPLs) based on endobronchial ultrasonography (EBUS) and clinical findings. Methods Patients who had EBUS for PPLs were analyzed and compared on the EBUS imaging characteristics and clinical data. The malignancy prediction model was established by the logistic equation of probability of malignant PPL based on the data of 135 patients. The model was tested on an additional 50 patients for efficiency. Results Among 135 prospectively enrolled patients, 77 (57%) patients had malignant and 58 (43%) had benign lesions with the size of 36.5±19.9 mm. Univariate analysis demonstrated a significant (P 0.05) difference in age (50 years as the cutoff value) and history of extra-thoracic malignancies. Logistic analysis of multiple factors showed that smoking history, serum CEA, borderline, air bronchogram, heterogeneous echo, and anechoic areas were significant (P

In this study, we sequenced the complete mitogenome of Gobiobotia meridionalis (Chen et Tsao, 1982). The genome is 16,609 base pair (bp) in length, encoding 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and 1 non-coding control region (D-loop). The nucleotide composition is A: 30.34%, T: 26.88%, G: 16.49%, and C: 26.29% (AT content: 55.22%). The complete mitogenome of G. meridionalis provides essential and important DNA molecular data for the genetic diversity conservation of this species.

Objective This study aimed to ascertain the minimum gadolinium dosage on contrast-enhanced (CE) T2 fluid-attenuated inversion recovery (FLAIR) at appropriate imaging time. Methods Different dosages of gadodiamide were imaged with a 3.0-T magnetic resonance scanner for T2-FLAIR and T1WI. Twenty glioma-induced rat models were randomly assigned into 4 groups (1/2, 1/4, 1/6, 1/8 of routine dosage) and imaged for T2-FLAIR and T1WI preinjection and postinjection of gadodiamide. Contrast-enhanced T2-FLAIR was acquired for 8 repetitions postinjection. Enhancement effects were assessed by calculating contrast-noise ratio and contrast ratio using Kruskal-Wallis and Mann-Whitney rank sum test. Results The in vitro experiment showed that gadodiamide at 1/4 of the T1WI dosage presented the best contrast on CE-T2-FLAIR. For in vivo study, the best enhancement effect on CE-T2-FLAIR was achieved at 1/2 of the routine dosage at 8 to 12 minutes of delayed scanning. Compared with CE-T1WI at routine dosage, CE-T2-FLAIR at 1/2 gadodiamide dosage presented similar enhancement effects with no statistical difference (P = 0.244 and 0.090 for contrast-noise ratio and contrast ratio, respectively). Conclusions Contrast-enhanced T2-FLAIR imaging with half of T1WI routine gadodiamide dosage can produce similar enhancement effects to CE-T1WI when characterizing brain gliomas. The cut-down of contrast agent dosage may help reduce gadolinium accumulation in certain tissues.

RNA silencing is a conserved mechanism in eukaryotic organisms to regulate gene expression. Argonaute (AGO), Dicer-like (DCL) and RNA-dependent RNA polymerase (RDR) proteins are critical components of RNA silencing, but how these gene families’ functions in sugarcane were largely unknown. Most stress-resistance genes in modern sugarcane cultivars (Saccharum spp.) were originated from wild species of Saccharum, for example S. spontaneum. Here, we used genome-wide analysis and a phylogenetic approach to identify four DCL, 21 AGO and 11 RDR genes in the S. spontaneum genome (termed SsDCL, SsAGO and SsRDR, respectively). Several genes, particularly some of the SsAGOs, appeared to have undergone tandem or segmental duplications events. RNA-sequencing data revealed that four SsAGO genes (SsAGO18c, SsAGO18b, SsAGO10e and SsAGO6b) and three SsRDR genes (SsRDR2b, SsRDR2d and SsRDR3) tended to have preferential expression in stem tissue, while SsRDR5 was preferentially expressed in leaves. qRT-PCR analysis showed that SsAGO10c, SsDCL2 and SsRDR6b expressions were strongly upregulated, whereas that of SsAGO18b, SsRDR1a, SsRDR2b/2d and SsRDR5 was significantly depressed in S. spontaneum plants exposed to PEG-induced dehydration stress or infected with Xanthomonas albilineans, causal agent of leaf scald disease of sugarcane, suggesting that these genes play important roles in responses of S. spontaneum to biotic and abiotic stresses.

To quantify the global and regional left ventricular (LV) myocardial strain in type 2 diabetes mellitus (T2DM) patients using cardiac magnetic resonance (CMR) tissue-tracking techniques and to determine the ability of myocardial strain parameters to assessment the LV deformation. Our study included 98 adult T2DM patients (preserved LV ejection fraction [LVEF], 72; reduced LVEF, 26) and 35 healthy controls. Conventional LV function, volume-time curve parameters and LV remodeling index were measured using CMR. Global and regional LV myocardial strain parameters were measured using CMR tissue tracking and compared between the different sub-groups. Receiver operating characteristic analysis was used to assess the diagnostic accuracy. Regression analyses were conducted to determine the relationship between strain parameters and the LV remodeling index. The results show that global radial peak strain (PS) and circumferential PS were not significantly different between the preserved-LVEF group and control group (P > 0.05). However, longitudinal PS was significantly lower in the preserved-LVEF group than in the control group (P = 0.005). Multivariate linear and logistic regression analyses showed that global longitudinal PS was independently associated (β = 0.385, P

Carfentrazone-ethyl and tribenuron-methyl, the two widely used herbicides for weed control in field crops, frequently cause phytotoxicity to wheat seedlings in the field. In this study, a total of 697 wheat accessions containing three panels were scanned using wheat 90 K and 660 K SNP arrays to identify important herbicide resistance loci. Genome-wide association study (GWAS) revealed 329 significant single-nucleotide polymorphisms (SNPs) with phenotypic variance explained (PVE) of 11.3% to 27.6%. Among these SNPs, 15 were detected in multiple environments and they were mainly distributed on chromosomes 1B, 2D, 5B, 5D, 6D, and 7D. Further analysis indicated that gHR-5B (467–587 Mb), gHR-7D (46–52 Mb), and gHR-1B (517–580 Mb) were important herbicide resistance loci in wheat. Linkage mapping in a bi-parental population detected one QTL (qHR-1B) with PVE of 7.44% to 8.28%. This is reliable locus because its physical position (554–566 Mb) overlapped with gHR-1B by GWAS in the genome of Chinese Spring. This study provided some herbicide-resistant germplasm and important genetic loci for identifying genes of common wheat.

This study aimed to examine the design, conduct, and analysis of systematic reviews assessing drug safety through a cross-sectional survey.We searched PubMed to identity systematic reviews published in the Cochrane Database of Systematic Reviews and Core Clinical Journals indexed in 2015 and randomly sampled systematic reviews assessing drug effects at a 1:1 ratio of Cochrane and non-Cochrane reviews. Teams of two investigators independently conducted study screening and collected data, using prespecified, standardized questionnaires. In addition to general information, we collected details about the planning and analyses of safety outcomes.We included 120 systematic reviews, including 60 Cochrane and 60 non-Cochrane reviews. Most reviews searched PubMed/MEDLINE (n = 117, 97.5%), EMBASE (n = 105, 87.5%), and Cochrane CENTRAL (n = 110, 91.7%) and conducted independent and duplicate study selection (n = 98, 81.7%), risk of bias assessment (n = 105, 87.5%), and data collection (n = 105, 87.5%). Only nine (7.5%) reviews clearly defined safety outcomes, and seven (5.8%) defined a primary safety outcome; none stated whether the primary safety outcome was predefined. Among the 80 reviews that pooled the primary dichotomous safety data across studies, less than half (41%, n = 33) conducted subgroup analysis to explore for sources of heterogeneity or reported a GRADE assessment for the overall quality of evidence. Cochrane reviews were more likely to provide a study protocol (100% vs. 23.3%; P 0.001), involve methodologists (53.3% vs. 20.0%; P 0.001), and report a GRADE assessment for the primary safety outcome (70.6% vs. 19.6%; P 0.001).Our findings highlighted areas for improved planning and analysis in the assessment of drug safety among systematic reviews. Cochrane reviews were superior to non-Cochrane reviews; however, most reviews did not prespecify their safety outcomes or methods for analysis, explore sources of heterogeneity among pooled effects, or assess the overall quality of evidence with the GRADE approach.

Black point is a common disease in wheat all over the world. The disease could downgrade wheat quality and cause human health problems. In this study, 406 wheat cultivars were used to investigate black point resistance. In the field tests, 20, 65.5, and 14.5% of the tested cultivars were resistant, moderately resistant, and susceptible, respectively, suggesting that improving black point resistance is necessary in Chinese wheat breeding. A genome-wide association study (GWAS) identified 386 single-nucleotide polymorphisms (SNPs) significantly related to black point resistance in the tested wheat cultivars, and they were located on all chromosomes. Linkage mapping in a biparental population identified three quantitative trait loci (QTL) for black point resistance—QBP.hau-3A, QBP.hau-6D, and QBP.hau-7D—with 6.76, 7.79, and 8.84% phenotypic variation explained, respectively. Based on both the GWAS and linkage analyses, QBP.hau-6D covered six significant SNPs from the GWAS, and the position of these SNPs indicated that this QTL is a new locus for black point resistance. This study provides valuable germplasm for breeding wheat cultivars with resistance to black point and information for further understanding of molecular and genetic basis of black point resistance.

This study aimed to investigate the association of obesity with adrenal gland volume (AGV) and the effects of weight loss on AGV. This study included obese patients (N = 25) who underwent sleeve gastrectomy and age- and sex-matched healthy volunteers (HVs) (N = 25) and overweight healthy volunteers (overweight-HVs) (N = 21). Thin-slice computed tomography was used to evaluate adrenal morphological changes. AGV was measured semiautomatically based on the digital imaging and communications in medicine (DICOM) image. The effects of weight loss on AGV and adrenal gland density were evaluated in patients for 1 year or more after sleeve gastrectomy. Left, right, and total AGV were 6.77 ± 0.36, 5.76 ± 0.31, and 12.53 ± 0.64 cm3 in obese patients, which were significantly higher than those in the overweight-HVs (3.88 ± 0.14, 3.09 ± 0.13, and 6.97 ± 0.24 cm3) and HVs (3.38 ± 0.23, 2.67 ± 0.15, and 6.04 ± 0.36 cm3). AGV was larger in overweight-HVs than in HVs, but no statistically significant difference was identified. Sleeve gastrectomy significantly reduced body weight (− 27.1 ± 2.5 kg), left AGV (− 0.80 ± 0.26 cm3), and right AGV (− 0.88 ± 0.20 cm2). The adrenal volume in five patients was not reduced, despite significant weight loss postsurgery. The mean density of adrenal glands was lower in obese patients (P = 0.025) but were not significantly increased postsurgery. Obesity leads to increased AGV, and in some cases, this effect seems to be irreversible. The clinical implication of obesity-induced adrenal morphological changes needs to be studied further.

Background The microvascular effects of obesity should be considered in diabetic individuals for elucidating underlying mechanisms and developing targeted therapies. This study aims to determine the effect of obesity on myocardial microvascular function in type 2 diabetes mellitus (T2DM) patients using cardiac magnetic resonance (CMR) first-pass perfusion imaging and assessed significant risk factors for microvascular dysfunction. Materials and methods Between September 2016 and May 2018, 120 patients with T2DM (45.8% women [55 of 120]; mean age, 56.45 ± 11.97 years) and 79 controls (44.3% women [35 of 79]; mean age, 54.50 ± 7.79 years) with different body mass index (BMI) scales were prospectively enrolled and underwent CMR examination. CMR-derived perfusion parameters, including upslope, time to maximum signal intensity (TTM), maximum signal intensity (MaxSI), MaxSI (-baseline), and SI (baseline), and T2DM related risk factors were analyzed among groups/subgroups both in T2DM patients and controls. Univariable and multivariable linear and logistic regression analyses were performed to assess the potential additive effect of obesity on microvascular dysfunction in diabetic individuals. Results Compared with controls with comparable BMIs, patients with T2DM showed reduced upslope and MaxSI and increased TTM. For both T2DM and control subgroups, perfusion function gradually declined with increasing BMI, which was confirmed by all perfusion parameters, except for TTM (all P P P P = 0.022) and glycated haemoglobin (β = − 0.184; 95% CI, − 0.281 to − 0.039; P = 0.010) were significantly associated with global upslope in the T2DM group. Multivariable logistic regression analysis indicated that T2DM was an independent predictor of microvascular dysfunction in normal-weight (odds ratio[OR], 6.46; 95% CI, 2.08 to 20.10; P = 0.001), overweight (OR, 7.19; 95% CI, 1.67 to 31.07; P = 0.008) and obese participants (OR, 11.21; 95% CI, 2.38 to 52.75; P = 0.002). Conclusions Myocardial microvascular function gradually declined with increasing BMI in both diabetes and non-diabetes status. T2DM was associated with an increased risk of microvascular dysfunction, and obesity exacerbated the adverse effect of T2DM.

The present work developed keratin-based pH-sensitive nanofibers and explored the kinetics of the controlled-release effect. Extracted from wool fibers, keratin was firstly synthesized with 5- fluorouracil (5-FU). Then 5-FU/keratin was blended with poly (L-Lactide) PLLA solution and electrospun altogether to fabricate a nanofibrous scaffold, for local tumor chemotherapy. 5-FU/keratin/PLLA nanofibrous scaffolds were characterized by Fourier transform infrared spectroscopy to confirm that 5-FU was loaded within the nanofibers successfully. Scanning electron microscopy and transmission electron microscope images indicated the smooth and uniform structure of the nanofibers. Thermo-gravimetric analysis differential scanning calorimeter and X-ray diffraction techniques indicated 5-FU particles distributed in nanofibers at a molecular level. Compared with 5-FU from pure drug and 5-FU/PLLA nanofibers without keratin, the dissolution results indicated that 5- FU/keratin/PLLA nanofibers had a pH-stimuli responsive character in the acidic environment. HCT-116 tumor cell line was applied to investigate the antitumor effect of the composite nanofibers. The MTS assay indicated that adding keratin into the system increased the inhabitation of tumor cells after 120 hours observation. Zeta potential analysis was introduced to analyze the interaction effect between 5-FU and keratin. The in vitro drug release kinetics analysis indicated that due to the electrostatic interaction between keratin and 5-FU molecules, the composite nanofibers can extend the release period of 5-FU in the acidic environment which suggested a longer effective inhibition in local tumor chemotherapy.

The present study aimed to establish a cellular model to test the hypothesis that oncogene-induced senescence (OIS) is triggered by aging-related activation of microglia. Primary microglia were incubated with phorbol 12-myristate 13-acetate (PMA), and β-galactosidase (β-Gal) staining was applied to subsequent assessment of cellular senescence. Moreover, flow cytometry was employed for examinations of cell cycle arrest and senescence-associated proteins, p53 and p21 were measured by western blotting. Furthermore, examination of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) were carried out with microglia supernatants undergoing age-related degenerative diseases in the nervous system, using ELISA. PC12 cells were co-cultured with microglia activated by aging-related alteration(s) to evaluate whether apoptosis was increased in PC12 cells. Cellular senescence-associated β-Gal staining showed that microglial β-Gal expression gradually increased with prolonged PMA stimulation. Microglia in the group receiving 72 h of PMA stimulation displayed the highest percentage of cells arrested in G0/G1, the highest amount of senescence-associated expression of p53 and p21, and the most prominent secretion of TNF-α and IL-1β. In comparison with controls, an increase of apoptotic PC12 cells was detected, which were co-cultured with aging microglia. Taken together, microglia tend to undergo senescence after PMA treatment, suggesting that microglial senescence is associated with inactivation of certain oncogenes.

The rapid development and application of molecular marker assays have facilitated genomic selection and genome-wide linkage and association studies in wheat breeding. Although PCR-based markers (e.g. simple sequence repeats and functional markers) and genotyping by sequencing have contributed greatly to gene discovery and marker-assisted selection, the release of a more accurate and complete bread wheat reference genome has resulted in the design of single-nucleotide polymorphism (SNP) arrays based on different densities or application targets. Here, we evaluated seven types of wheat SNP arrays in terms of their SNP number, distribution, density, associated genes, heterozygosity and application. The results suggested that the Wheat 660K SNP array contained the highest percentage (99.05%) of genome-specific SNPs with reliable physical positions. SNP density analysis indicated that the SNPs were almost evenly distributed across the whole genome. In addition, 229 266 SNPs in the Wheat 660K SNP array were located in 66 834 annotated gene or promoter intervals. The annotated genes revealed by the Wheat 660K SNP array almost covered all genes revealed by the Wheat 35K (97.44%), 55K (99.73%), 90K (86.9%) and 820K (85.3%) SNP arrays. Therefore, the Wheat 660K SNP array could act as a substitute for other 6 arrays and shows promise for a wide range of possible applications. In summary, the Wheat 660K SNP array is reliable and cost-effective and may be the best choice for targeted genotyping and marker-assisted selection in wheat genetic improvement.

Objective. The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of malignant PPGL. Methods. We retrospectively collected and analyzed surgical tumor tissue from 226 patients initially diagnosed with PPGL who underwent surgery from Jan. 2009 to Jan. 2016 at West China Hospital, Sichuan University. We observed and quantified the expression of Snail, galectin-3, and IGF1R in paraffin-embedded samples by immunohistochemical staining. Results. The significant difference in survival time among the three groups (benign PHEO, benign PGL, and potentially malignant PPGL) was compared by Kaplan-Meier survival analysis. The positive staining of Snail, galectin-3, and IGF1R in the benign PHEO group was significantly lower than that in the other three groups (P<0.001). The Kaplan-Meier survival plots indicated that the survival time of the patients with intense positive staining was significantly lower than that of the patients with weak positive staining. Conclusion. The intense expression of Snail, galectin-3, and IGF1R may be valuable indicators for the diagnosis of malignant PPGL.

Background Despite the growing concern about the safety of gadolinium-based contrast agents (GBCAs), they are still the most commonly used. Ferumoxytol, as an off-label alternative MRI contrast agent, cannot be administered by a rapid bolus for dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI). Purpose To assess the feasibility of iron sucrose (IS) as a contrast agent for MR angiography (MRA) and DSC-PWI. Study type Prospective animal model. Animal model Thirty-six normal rats (16 for MRA, 20 for biocompability tests) and 36 occlusion of the middle cerebral artery (MCAO) model rats. Field strength/sequence 3.0T; head and neck angiography, using a fast spoiled gradient-recalled-echo (FSPGR) sequence and DSC-MRI using echo planar imaging(EPI) sequence. Assessment MRA was performed on normal rats to examine the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of different doses of IS. DSC-PWI was performed on MCAO rats at 0, 24, 48, and 72 hours postreperfusion to investigate the lesion detectability of IS. Arterial spin labeling (ASL) and DSC-PWI enhanced by GBCAs were conducted on MCAO rats as controls. Statistical tests Kruskal-Wallis test was used to compare qualitative assessment. One-way analysis of variance (ANOVA) was used to compare the parametric data. Pearson's r values were evaluated between relative cerebral blood flow(rCBF)-ASL, rCBF-DSCIS , and rCBF obtained from DSC-PWI enhanced by GBCA. Results The mean SNR and CNR of the common carotid artery at doses of 10 mg Fe/kg of IS were comparable with the standard dose of GBCAs (SNR: 68.04 ± 12.55 vs. 67.72 ± 14.66; CNR: 23.78 ± 7.21vs. 21.63 ± 6.83). In MCAO rat models, rCBF and relative cerebral blood volume (rCBV) of ipsilateral striatum declined (0.72 ± 0.14, 0.86 ± 0.11) with prolonged relative mean transit time (rMTT) and relative time-to-peak (rTTP) (1.27 ± 0.24, 1.07 ± 0.03) following occlusion. Hyperperfusion was observed in all rats at 48 and 72 hours postreperfusion, in 4/6 rats at 24 hours postreperfusion for IS-mediated DSC-PWI. Data conclusion IS may be an effective contrast agent for both MRA and DSC-PWI in ischemic stroke models. Level of evidence 1 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:836-849.

The current corona virus disease 2019 outbreak caused by severe acute respiratory syndrome coronavirus 2 started in Wuhan, China in December 2019 and has put the world on alert. To safeguard Chinese citizens and to strengthen global health security, China has made great efforts to control the epidemic. Many in the global community have joined China to limit the epidemic. However, discrimination and prejudice driven by fear or misinformation have been flowing globally, superseding evidence and jeopardizing the anti-severe acute respiratory syndrome coronavirus 2 efforts. We analyze this phenomenon and its underlying causes and suggest practical solutions. CORE TIP: The acute respiratory syndrome coronavirus 2 outbreak is a global public health issue. Fear and stigma are growing due to misinformation and unfounded rumors. As a global community, we need solidarity instead of stigma to limit the spread of corona virus disease 2019. Open and transparent information on the outbreak to the global public, and administrative warning from authorities in every country are necessary to reduce fear and discrimination.

Objectives The current study aimed to investigate the value of the computed tomography-based left-versus-right adrenal gland volume ratio (L/Rv) in screening patients with unilateral primary aldosteronism. Methods The current study recruited 114 patients who underwent successful adrenal venous sampling (AVS) and adrenal computed tomography at West China Hospital of Sichuan University. The patients were divided into three groups according to the AVS results: AVS-left, AVS-bilateral, and AVS-right primary aldosteronism. The volumes of the left and right adrenal glands were semiautomatically calculated. The L/Rv of each patient was computed, and its value in identifying unilateral primary aldosteronism was analyzed. Results The mean value of the L/Rv was larger in AVS-left patients and smaller in AVS-right patients than that in AVS-bilateral patients. In AVS-left primary aldosteronism patients, the cutoff value of the L/Rv with the highest Youden index was 1.344 [area under the curve (AUC) 0.851, sensitivity 80.0%, specificity 78.1%]. The optimal cutoff value was 1.908, of which 46.0% (23/50) of AVS-left primary aldosteronism patients could be identified (specificity 100.0%). In AVS-right primary aldosteronism patients, the cutoff value of the L/Rv with the highest Youden index was 1.267 (AUC 0.868, specificity 72.8%, sensitivity 87.9%). The optimal cutoff value was 0.765, of which 27.3% (9/33) of AVS-right primary aldosteronism patients could be identified (specificity 100.0%). Patients with L/Rv more than 1.908 or less than 0.765 had higher complete success rate postsurgery. Conclusion Although not perfect, the L/Rv is an applicable index to screen unilateral primary aldosteronism patients for surgery. Primary aldosteronism patients, even those aged more than 35 years, with an L/Rv more than 1.908 or less than 0.765 can be spared AVS before surgery.

Objective Aim of the study was to evaluate the clinical efficacy and safety of major uterine wall resection and reconstruction of the uterus (MURU) combined with a levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of adenomyosis. Methods Ninety patients diagnosed with adenomyosis were enrolled in this study. All participants were examined by transvaginal ultrasound (TVU) or magnetic resonance imaging (MRI). Serum levels of cancer antigen 125 (CA 125) were quantitatively measured. All patients underwent MURU in combination with LNG-IUS. The therapeutic safety of MURU was assessed during surgery and the patientsʼ stay in hospital. The clinical efficacy was evaluated by comparatively analyzing changes in dysmenorrhea, volume of menstrual blood, uterine volume and serum levels of CA 125 before, and at 3, 6 and 12 months following MURU. Results All 90 patients enrolled in the study were successfully treated with MURU combined with LNG-IUS. No significant complications were observed during surgery and hospital stay. The mean operation time, intraoperative blood loss and length of hospital stay were 82.4 ± 13.8 min, 53.3 ± 20.3 ml, and 4.3 ± 0.8 days, respectively. Dysmenorrhea completely disappeared in all patients. Uterine volume and serum levels of CA 125 were restored to normal ranges. No recurrence of adenomyosis was observed during postoperative follow-up. Conclusion MURU combined with LNG-IUS is an efficacious and safe treatment for severe adenomyosis. This combined technique is not only effective to manage severe adenomyosis but also preserves as much of the uterus as possible.

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs' characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.

Background The initial episode of angioedema in children can be potential life-threatening due to the lack of prompt identification and treatment. We aimed to analyze the factors predicting the severity and outcomes of the first attack of acute angioedema in children. Methods This was a retrospective study with 406 children ( Result In total, 109 (26.8%) children had severe angioedema, and the majority of those children were male (65.1%). Most of the children were of preschool age (56.4%), and only 6.4% were adolescents. The co-occurrence of pyrexia or urticaria, etiologies of the angioedema related to medications or infections, the presence of respiratory symptoms, and a history of allergies (asthma, allergic rhinitis) were predictors of severe angioedema (all p p Conclusion The co-occurrence of pyrexia or urticaria, etiologies related to medications or infections, the presence of respiratory symptoms, and a history of allergies were predictors of severe angioedema. More importantly, short-term POU observation and prompt treatment might be benefit for patients who did not require hospital admission.

Background Adrenal venous sampling (AVS) is the gold standard for preoperative differentiation between unilateral and bilateral primary aldosteronism (PA). However, results are sometimes vitiated by failing to access the right adrenal vein. Materials and methods The present study assumed that clinical decisions can be made with incomplete AVS data, by comparing aldosterone/cortisol (A/C) ratio in both left and right adrenal veins with that in the inferior vena cava (LAV/IVC and RAV/IVC). Receiver operation characteristic (ROC) curve and scatterplot were used to certify the upper and lower cutoffs and to analyze the significance of discrimination. One hundred and sixty patients diagnosed with PA from April 2017 to June 2018 underwent AVS in the Urology Department of West China Hospital, Chengdu, China. One hundred and eleven with complete AVS data were divided into 3 groups: left-sided (N = 40), right-sided (N = 29) and bilateral (N = 42). We also collected patients from September 2018 to April 2019 in our department as validation cohort to test our hypothesis. Results On the basis of LAV/IVC, RAV/IVC and diagnostic category, upper cutoff was 1.14 (50% sensitivity and 100% specificity) and lower cutoff 0.07 (27.5% sensitivity and 100% specificity) for LAV/IVC, and 1.04 (55% sensitivity and 100% specificity) and 0.08 (40% sensitivity and 100% specificity), respectively, for RAV/IVC. Conclusion The diagnostic model in this study contributes to clinical decision-making in patients with only partial PA with incomplete AVS data.

8-oxoguanine (8-oxoG) is one of the most prevalent genotoxic lesions, and it is generated in DNA attacked by reactive oxygen species (ROS). Adenine misincorporated opposite to 8-oxoG during replication is excised by MutY homolog (MUTYH), an important protein of the base excision repair (BER) system. Mutyh plays an important role in the maintenance of genomic integrity, but the functional consequences of Mutyh deficiency are not fully understood. In the current study, we investigated the histological and functional changes of five tissues (hippocampus, heart, liver, kidney and lung) and their molecular basis in Mutyh-/- and wild-type mice exposed to D-galactose (D-gal). Our data indicated that Mutyh deficiency hindered the weight gain of experimental mice and induced substantial alterations of 8-oxoG content and superoxide dismutase (SOD) activity, but no significant histological and functional impairment appeared in the investigated tissues of Mutyh- deficient mice without D-gal exposure. Under low-dose D-gal exposure, Mutyh deficiency altered expression of genes involved in mitochondrial unfolded protein response (UPRmt) in the heart, liver and lung, and caused an enhanced expression of mitochondrial dynamics proteins (MDPs) in hippocampus and liver. The stress responses could maintain mitochondrial proteostasis and function. However, such responses were not noted when experiencing excessive damage burden induced by high-dose D-gal exposure, in which Mutyh deficiency increased accumulation of 8-oxoG and aggravated mitonuclear protein imbalance, as well as histological lesions in heart, liver and kidney. A higher sensitivity to ROS-induced cardiotoxicity with high-dose D-gal exposure was noticed in Mutyh-/- mice. However, no differences in learning and memory impairments were observed between Mutyh-/- and wild-type mice with high-dose D-gal exposure. In conclusion, our data demonstrated that Mutyh deficiency has different impacts on various tissues based on the degree of oxidative stress.

Identifying more missing proteins (MPs) is an important mission of C-HPP. With the number of identified MPs being attenuated year by year (2,949 to 2,129 MPs from 2016 to 2019), we have realized that the difficulty of exploring the remaining MPs is a challenge in technique. Herein, we propose a comprehensive strategy to effectively enrich, separate, and identify proteins with low molecular weights, aiming at the discovery of MPs. Basically, a protein extract from human placenta was passed through a C18 SPE column, and the bound proteins that were eluted were further separated with an SDS-PAGE gel or a 50 kDa cutoff filter. The separated proteins were subjected to trypsin digestion, and the MS/MS signals were searched against data sets with two different digestion modes (full-trypsin and semitrypsin). The strategy was adopted, resulting in the identification of 4 MPs with 8 unique peptides (≥2 non-nested unique peptides with ≥9 amino acids). Importantly, the identification of 6 out of 8 of the unique peptides derived from the MPs was further supported by parallel reaction monitoring, which confirmed the identification of 3 MPs from human placenta tissues (Q6NT89: TMF-regulated nuclear protein 1; A0A183: late cornified envelope protein 6A; and Q6UWQ7: insulin growth factor-like family member 2, mapped to chromosomes 1, 1, and 19, respectively). The three proteins ranged in length from 80 aa to 227 aa. The study not only establishes a feasible strategy for analyzing proteins with low molecular weights but also fills a small part of a large gap in the list of MPs. The data obtained in this study are available via ProteomeXchange (PXD014083) and PeptideAtlas (PASS01389).

Aims To predict the effects of perfect adherence to the French alcohol consumption guidelines, a maximum of 10 standard alcoholic drinks per week with no more than two standard alcoholic drinks per day, during a 36-year period (2014–50). Design This simulation study is an adaption of the Sheffield Alcohol Policy Model. The dose–response relationship between alcohol consumption and alcohol-attributable cancer risks was defined by cancer site-specific risk functions, each modelled as a continuous risk. These estimates were used to compute the potential impact fraction (PIF) associated with alcohol consumption by cancer site. Setting The French general adult population during a 36-year period (2014–50). Participants For the baseline scenario, the current distribution of consumption levels, the counterfactual scenario and perfect adherence to the French alcohol consumption guidelines, we generated for each gender and age group 1000 randomly distributed alcohol consumption values from calibrated group-specific gamma distribution. Measurements The predicted number of new cancer cases among men and women in France between 2015 and 2050 that could have been prevented by following the French government's alcohol consumption guidelines. Findings The simulation predicted that perfect adherence to the French government's alcohol consumption guidelines would prevent, on average, an estimated 15 952 cancer cases per year after the PIF reached its full effect, which would have represented 4.5% of new cancer cases in 2015. The number of averted cancer cases over the study period were highest for oral cavity, oropharynx and hypopharynx cancer (respectively, 118 462, 95% CI = 113 803–123 022 and 11 167, 95% CI = 10 149–12 229] for men and women; liver and intrahepatic bile ducts cancer (123 447, 95% CI = 112 581–133 404 and 2825, 95% CI = 2208,4095); colorectal cancer (89 859, 95% CI = 84 651–95 355 and 12 847, 95% CI = 11 545–14 245); and female breast cancer (61 649, 95% CI = 56 330–67 452). Conclusion This simulation study of the French general population predicted that perfect adherence to the French government's alcohol consumption guidelines (no more than 10 standard alcoholic drinks per week and two per day) would prevent almost 16 000 cancer cases per year.

Background The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Methods and findings Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5–29, 49–69 versus 70–82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI –1 to 31, 92–120 versus 113–129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6–36, 49–73 versus 74–90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. Conclusions In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies., Author summary Why was this study done? The cells around a tumor, also known as the tumor microenvironment (TME), can help a tumor grow by suppressing the immune system or fight a tumor by mounting an immune response. Most studies of multiple myeloma (MM) have focused on the tumor itself, rather than the bone marrow (BM) TME in which the tumor is growing. We hypothesized that the MM TME held clues that could help us better treat patients. What did the researchers do and find? We used a gene-expression–based computational technique to determine which cell types were present in patient BM. Patients with BM lacking a family of innate immune cells called granulocytes presented with worse outcomes compared to other patients. As MM progresses from a predisease to a cancerous state, the percentage of granulocytes decreases; the patients with the fewest granulocytes had more serious diseases. What do these findings mean? If granulocytes help myeloma patients respond to therapy, then addressing the decline in granulocytes may improve MM treatment. Patients with MM and few granulocytes in their BM should be watched for worse outcomes.

The segmentation of high-grade gliomas (HGG) using magnetic resonance imaging (MRI) data is clinically meaningful in neurosurgical practice, but a challenging task. Currently, most segmentation methods are supervised learning with labeled training sets. Although these methods work well in most cases, they typically require time-consuming manual labeling and pre-trained models. In this work, we propose an automatically unsupervised segmentation toolbox based on the clustering algorithm and morphological processing, named AUCseg. With our toolbox, the whole tumor was first extracted by clustering on T2-FLAIR images. Then, based on the mask acquired with whole tumor segmentation, the enhancing tumor was segmented on the post-contrast T1-weighted images (T1-CE) using clustering methods. Finally, the necrotic regions were segmented by morphological processing or clustering on T2-weighted images. Compared with K-means, Mini-batch K-means, and Fuzzy C Means (FCM), the Gaussian Mixture Model (GMM) clustering performs the best in our toolbox. We did a multi-sided evaluation of our toolbox in the BraTS2018 dataset and demonstrated that the whole tumor, tumor core, and enhancing tumor can be automatically segmented using default hyper-parameters with Dice score 0.8209, 0.7087, and 0.7254, respectively. The computing time of our toolbox for each case is around 22 seconds, which is at least 3 times faster than other state-of-the-art unsupervised methods. In addition, our toolbox has an option to perform semi-automatic segmentation via manually setup hyper-parameters, which could improve the segmentation performance. Our toolbox, AUCseg, is publicly available on Github. (https://github.com/Haifengtao/AUCseg).

Background: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer. Methods: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case–control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies. Results: The OR/mGy was 1.02 (95% confidence interval, 1.00–1.03). We found significant associations between DTC and rs7164173 in CHD2 (P = 5.79 × 10−5), rs6067822 in NFATc2 (P = 9.26 × 10−5), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses (P = 3.40 × 10−4). Conclusions: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk. Impact: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disease characterized with radiographically evident pulmonary infiltrates and extracellular matrix deposition with limited treatment options. We previously described that microcystin-LR (MC-LR) reduces transforming growth factor (TGF)-β1/Smad signaling and ameliorates pulmonary fibrosis in bleomycin (BLM)-induced rat models. In the present study, we further demonstrate that microcystin-RR (MC-RR), an MC congener with lower toxicity than MC-LR, exerted an anti-fibrotic effect on BLM-induced pulmonary fibrosis rodent models and compared it with MC-LR. Our data show that MC-RR treatment attenuated BLM-associated pulmonary inflammation and collagen deposition in both therapeutic and preventive models. MC-RR reduced the expression of fibrotic markers, including vimentin, α-smooth muscle actin, collagen 1α1, and fibronectin, in rat pulmonary tissues. Furthermore, the core features of BLM-induced pulmonary fibrotic lesions were better alleviated by MC-RR than by MC-LR. MC-RR treatment substantially decreased the number of pulmonary M2 macrophages. In vitro, MC-RR attenuated the epithelial-mesenchymal transition and fibroblast-myofibroblast transition triggered by M2 macrophages. Therefore, we highlight MC-RR as a promising molecule for developing therapeutic and prophylactic strategies against IPF, a refractory lung disease.

Clinical question What are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes? Current practice Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades. SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment. This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications’ glucose-lowering potential. Recommendations The guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes • Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists. • More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists. • Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists. • Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists. • For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1 receptor agonists. How this guideline was created An international panel including patients, clinicians, and methodologists created these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel applied an individual patient perspective. The evidence A linked systematic review and network meta-analysis (764 randomised trials included 421 346 participants) of benefits and harms found that SGLT-2 inhibitors and GLP-1 receptor agonists generally reduce overall death, and incidence of myocardial infarctions, and end-stage kidney disease or kidney failure (moderate to high certainty evidence). These medications exert different effects on stroke, hospitalisations for heart failure, and key adverse events in different subgroups. Absolute effects of benefit varied widely based on patients’ individual risk (for example, from five fewer deaths in the lowest risk to 48 fewer deaths in the highest risk, for 1000 patients treated over five years). A prognosis review identified 14 eligible risk prediction models, one of which (RECODe) informed most baseline risk estimates in evidence summaries to underpin the risk-stratified recommendations. Concerning patients’ values and preferences, the recommendations were supported by evidence from a systematic review of published literature, a patient focus group study, a practical issues summary, and a guideline panel survey. Understanding the recommendation We stratified the recommendations by the levels of risk for CVD and CKD and systematically considered the balance of benefits, harms, other considerations, and practical issues for each risk group. The strong recommendation for SGLT-2 inhibitors in patients with CVD and CKD reflects what the panel considered to be a clear benefit. For all other adults with type 2 diabetes, the weak recommendations reflect what the panel considered to be a finer balance between benefits, harms, and burdens of treatment options. Clinicians using the guideline can identify their patient’s individual risk for cardiovascular and kidney outcomes using credible risk calculators such as RECODe. Interactive evidence summaries and decision aids may support well informed treatment choices, including shared decision making.

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.

Biotransformation of the neo-clerodane diterpene, scutebarbatine F (1), by Streptomyces sp. CPCC 205437 was investigated for the first time, which led to the isolation of nine new metabolites, scutebarbatine F1–F9 (2–10). Their structures were determined by extensive high-resolution electrospray ionization mass spectrometry (HRESIMS) and NMR data analyses. The reactions that occurred included hydroxylation, acetylation, and deacetylation. Compounds 2–4 and 8–10 possess 18-OAc fragment, which were the first examples of 13-spiro neo-clerodanes with 18-OAc group. Compounds 7–10 were the first report of 13-spiro neo-clerodanes with 2-OH. Compounds 1–10 were biologically evaluated for the cytotoxic, antiviral, and antibacterial activities. Compounds 5, 7, and 9 exhibited cytotoxic activities against H460 cancer cell line with inhibitory ratios of 46.0, 42.2, and 51.1%, respectively, at 0.3 μM. Compound 5 displayed a significant anti-influenza A virus activity with inhibitory ratio of 54.8% at 20 μM, close to the positive control, ribavirin.

ObjectivePrimary adrenal lymphoma (PAL) is easily misdiagnosed as other adrenal masses, such as adrenocortical carcinoma and pheochromocytoma, but patients with PAL benefit little from surgery. The diagnostic method for PAL thus far is limited to adrenal biopsy. In our study, we aimed to develop a quick and efficient diagnostic method for PAL.Methods and ResultsAt the same institution, 505 patients (between 2009 and 2019) and 171 patients (between 2019 and 2020) were separately included in the primary and validation studies. Univariate and multivariate analyses were conducted to evaluate clinical manifestations, laboratory findings, and radiological characteristics. Four determinants (age, bilateral masses, high-density lipoprotein cholesterol, and lactate dehydrogenase) were selected and further incorporated into a regression model to screen PAL. Accordingly, the nomogram was developed for clinical practice. In the primary study, the nomogram showed good discrimination, with an area under the receiver operating characteristic (ROC) curve (AUC) of 95.4% (95% CI, 90.6%–100.0%). Further validation study verified the efficacy of the nomogram, with an AUC of 99.0% (95% CI, 96.9%–100.00%) and 100.0% in all patients and patients with bilateral masses, respectively, and a sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of 66.67%/99.40%/66.67%/99.40%, 66.67%/100%/100%/92.86%, 50%/99.20%/50%/99.20%, and 100%/100%/100%/100%, in all patients, patients with bilateral adrenal masses, patients with nonfunctional adrenal masses, and patients with positive catecholamine results, respectively. The validation study also revealed a diagnostic specificity of 99.35% and 100% for patients with a unilateral adrenal mass and functional PCC, respectively.ConclusionsThe presented nomogram is the first user-friendly diagnostic model for PAL that simplifies the complex diagnostic process into personalized numeric estimates. We deem that patients who score below 50 are less likely to have PAL. We suggest that clinicians should arrange adrenal biopsy and surgery for patients with nonfunctional tumors and overt catecholamine-secreting tumors, respectively, who receive a score of 50 points or higher to confirm the diagnosis as soon as possible.

A Case of Locally Transmitted SARS-CoV-2 in Taiwan The authors describe transmission of the novel coronavirus from a woman who had been living for several months in Wuhan, China, to her husband, af...

Background Hox transcript antisense intergenic RNA (HOTAIR) is upregulated and associated with a poor prognosis in many cancer types. Besides, it is involved in the invasion and metastasis of non-small-cell lung cancer and nasopharyngeal carcinoma. Objectives The aim of this study was to investigate the association between the expression of HOTAIR and the grades of gliomas, and to explore its possible mechanism, as well as to evaluate the value of HOTAIR applied in predicting the grades of gliomas. Material and methods A total of 123 patients undergoing glioma surgeries were enrolled. Patients with grade I and grade II-IV tumors were regarded as the control group (n = 36) and the case group (n = 87), respectively. The expression of HOTAIR, matrix metalloproteinase 7 (MMP-7), matrix metalloproteinase 9 (MMP-9), and vascular endothelial growth factor (VEGF) was detected with quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in glioma tissues and then compared between grade I and grades II-IV. The correlation between the relative expression of HOTAIR and that of MMP-7, MMP-9 and VEGF was analyzed. Multivariate analysis was performed to identify independent risk factors. Receiver operating characteristic (ROC) curve was employed to evaluate the predictive value. Results The relative expression of HOTAIR, MMP-7, MMP-9, and VEGF was lower in glioma tissues of grade I than in the case of grades II-IV, and the relative expression of HOTAIR was positively correlated with the relative expression of MMP-7, MMP-9 and VEGF. Multivariate analysis showed that the relative expression of HOTAIR was independently associated with the grades of gliomas, but the relative expression of MMP-7, MMP-9 and VEGF was not. Besides, multivariate analysis showed that the expression level of HOTAIR >0.40 was an independent risk factor for grades II-IV after classifying the relative expression of HOTAIR, and ROC analysis showed that the expression level of HOTAIR >0.40 had a moderate value when applied in predicting grades II-IV. Conclusions Hox transcript antisense intergenic RNA might promote the invasion of gliomas through upregulating the expression of MMP-7, MMP-9 and VEGF, and the expression level of HOTAIR >0.40 had a moderate value when applied in predicting grades II-IV.

Objective: This study investigated the characteristics of the adrenal limbs of primary aldosteronism (PA) patients and evaluated the value of the adrenal limb width measurement for the differentiation of unilateral PA from bilateral PA. Methods: A total of 122 PA patients (93 unilateral PA, ages ranged from 23 to 72 years; 29 bilateral PA, ages ranged from 30 to 68 years) who had undergone successful adrenal venous sampling (AVS) and adrenal gland computed tomography (CT) scan were retrospectively included. The maximum width of each adrenal gland limb (normal area on CT images) was measured, the left adrenal limb width to right adrenal limb width ratio (L/Rw) was calculated, and its potential value in the differentiation of unilateral PA and bilateral PA was analyzed. Results: The mean widths of the left adrenal limbs and the right adrenal limbs were 0.52 ± 0.10 cm and 0.43 ± 0.09 cm in unilateral PA patients, versus 0.52 ± 0.10 cm and 0.49 ± 0.12 cm in bilateral PA patients. The L/Rw ratio was 1.22 ± 0.24 in unilateral PA patients and 1.11 ± 0.23 in bilateral PA patients (P

Objective This study aimed to investigate the changes in inflammatory biomarkers between newly diagnosed type 2 diabetes (T2DM) patients under one-year acarbose treatments and those under metformin managements. Methods Seventy patients with newly diagnosed T2DM and 32 volunteers with normal glucose tolerance (normal controls, NCs) were enrolled. Seventy patients with T2DM were randomly assigned to two subgroups and treated with acarbose (n=34) or metformin (n=36) for 1 year. Blood glucose, insulin, glycosylated hemoglobin (A1C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and inflammatory biomarker levels (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and ferritin) were detected at 0, 6 and 12 months. Results After adjusting for sex, the waist-to-hip ratio (WHR) and body mass index (BMI), higher fasting plasma glucose (FPG), standard meal test 1/2 hr and 2 hr glucose, TG, TC, LDL-C, IL-6, TNF-α, IL-2 and ferritin levels were observed in T2DM group than in NCs (P