Mendelian randomization analysis demonstrates the causal effects of IGF family members in diabetes.

Background: Observational studies have consistently shown significant associations between the IGF family and metabolic diseases, including diabetes. However, these associations can be influenced by confounding factors and reverse causation. This study aimed to assess the causal relationship between the IGF family and diabetes using Mendelian randomization (MR). Methods: We conducted a two-sample MR analysis to investigate the causal effects of the IGF family on diabetes. Instrumental variables for the IGF family and diabetes were derived from summary-level statistics obtained from genome-wide association studies. Horizontal pleiotropy was assessed using MR-Egger regression and the weighted median method. We applied the inverse-variance weighted method as part of the conventional MR analysis to evaluate the causal impact of the IGF family on diabetes risk. To test the robustness of the results, we also employed MR-Egger regression, the weighted median method, and a leave-one-out analysis. Results: Our study revealed that IGF-1 causally increases the risk of Type 2 Diabetes (T2D), while IGFBP-6, adiponectin and INSR decreases the risk (IGF-1, OR 1.02 [95% CI 1-1.03], p = 0.01; IGFBP-6, OR 0.92 [95% CI 0.87-0.98], p = 0.01; Adiponectin, OR 0.837 [95% CI 0.721-0.970], p = 0.018; INSR, OR 0.910 [95% CI 0.872-0.950], p = 1.52 × 10-5). Additionally, genetically lower levels of IGF-1 and IGFBP-5, along with higher levels of IGFBP-7, were associated with an increased risk of Type 1 Diabetes (T1D) (IGF-1, OR 0.981 [95% CI 0.963-0.999], p = 0.037; IGFBP-5, OR 0.882 [95% CI 0.778-0.999], p = 0.049; IGFBP-7, OR 1.103 [95% CI 1.008-1.206], p = 0.033). Conclusion: In summary, our investigation has unveiled causal relationships between specific IGF family members and T1D and T2D through MR analysis. Generally, the IGF family appears to reduce the risk of T1D, but it presents a more complex and controversial role in the context of T2D. These findings provide compelling evidence that T2D is intricately linked with developmental impairment. Our study results offer fresh insights into the pathogenesis and the significance of serum IGF family member concentrations in assessing diabetes risk.

PandaOmics: An AI-Driven Platform for Therapeutic Target and Biomarker Discovery.

PandaOmics is a cloud-based software platform that applies artificial intelligence and bioinformatics techniques to multimodal omics and biomedical text data for therapeutic target and biomarker discovery. PandaOmics generates novel and repurposed therapeutic target and biomarker hypotheses with the desired properties and is available through licensing or collaboration. Targets and biomarkers generated by the platform were previously validated in both in vitro and in vivo studies. PandaOmics is a core component of Insilico Medicine's Pharma.ai drug discovery suite, which also includes Chemistry42 for the de novo generation of novel small molecules, and inClinico─a data-driven multimodal platform that forecasts a clinical trial's probability of successful transition from phase 2 to phase 3. In this paper, we demonstrate how the PandaOmics platform can efficiently identify novel molecular targets and biomarkers for various diseases.

The relationship of exercise and cancer-related fatigue in patients with advanced liver cancer: a cross-sectional study.

There is increasing interest in understanding exercise as a potential treatment for cancer-related fatigue (CRF); however, rarely research has been conducted on more aggressive cancers with short survival, such as liver cancer. The purpose of this study was to provide educational ideas for insufficient exercise and provide clues for the design of effective and safe exercise intervention programs with high compliance in patients of advanced liver cancer in the future. Participants were recruited from a tertiary cancer hospital using convenience sampling. All participants were asked to complete self-report questionnaires that assessed their medical and demographic variables, exercise habits and CRF during their hospitalization in the interventional department. Spearman's correlation analysis and Nonparametric test was used to explore correlations between exercise subgroups and CRF. The Baron and Kenny's Approach was used to investigate the mediating effect of exercise index between P-EX and CRF. 207 out of 255 participants were enrolled in this study, with an average age of 55.4 years. The CRF score was 33 (28, 36), and 93.2% had insufficient exercise. Exercise frequency (≥ 3 Times/week) (Z = 4.34, p = 0.037) and maintaining exercise trend (Z = 15.85, p = 0.001) had a positive effect on CRF. P-EX had a great impact on exercise index and affecting CRF directly. Participants in the study showed serious fatigue and insufficient exercise. Exercise education can be initiated earlier, particularly those without regular exercise experience. Sustained light exercise, compliant with exercise habits and interests, three times a week may be a practical way to reduce the risk of CRF in advanced liver cancer.

Experience in the diagnosis and treatment of pneumonia caused by infection with Tropheryma whipplei: A case series.

Tropheryma whipplei (TW) is the root cause of Whipple's disease (WD), a rare infectious illness leading to multi-organ impairment. A prominent feature of WD is acute pneumonia, which can be exceedingly challenging to diagnose clinically due to the pathogen's surreptitious nature. However and significantly, with the advent of metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF), it offers clinicians a potent tool at their disposal to detect TW infections. The present study conducted a retrospective analysis of clinical data gleaned from five patients in Hunan Province in China. Findings in this study demonstrated the potential of BALF-mNGS in diagnosing pneumonia caused by TW infection.

Single cell RNA-seq resolution revealed CCR1+/SELL+/XAF+ CD14 monocytes mediated vascular endothelial cell injuries in Kawasaki disease and COVID-19.

INTRODUCTION: The COVID-19 pandemic provide the opportunities to explore the numerous similarities in clinical symptoms with Kawasaki disease (KD), including severe vasculitis. Despite this, the underlying mechanisms of vascular injury in both KD and COVID-19 remain elusive. To identify these mechanisms, this study employs single-cell RNA sequencing to explore the molecular mechanisms of immune responses in vasculitis, and validate the results through in vitro experiments. METHOD: The single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs) was carried out to investigate the molecular mechanisms of immune responses in vasculitis in KD and COVID-19. The analysis was performed on PBMCs from six children diagnosed with complete KD, three age-matched KD healthy controls (KHC), six COVID-19 patients (COV), three influenza patients (FLU), and four healthy controls (CHC). The results from the scRNA-seq analysis were validated through flow cytometry and immunofluorescence experiments on additional human samples. Subsequently, monocyte adhesion assays, immunofluorescence, and quantitative polymerase chain reaction (qPCR) were used to analyze the damages to endothelial cells post-interaction with monocytes in HUVEC and THP1 cultures. RESULTS: The scRNA-seq analysis revealed the potential cellular types involved and the alterations in genetic transcriptions in the inflammatory responses. The findings indicated that while the immune cell compositions had been altered in KD and COV patients, and the ratio of CD14+ monocytes were both elevated in KD and COV. While the CD14+ monocytes share a large scale of same differentiated expressed geens between KD and COV. The differential activation of CD14 and CD16 monocytes was found to respond to both endothelial and epithelial dysfunctions. Furthermore, SELL+/CCR1+/XAF1+ CD14 monocytes were seen to enhance the adhesion and damage to endothelial cells. The results also showed that different types of B cells were involved in both KD and COV, while only the activation of T cells was recorded in KD. CONCLUSION: In conclusion, our study demonstrated the role of the innate immune response in the regulation of endothelial dysfunction in both KD and COVID-19. Additionally, our findings indicate that the adaptive immunity activation differs between KD and COVID-19. Our results demonstrate that monocytes in COVID-19 exhibit adhesion to both endothelial cells and alveolar epithelial cells, thus providing insight into the mechanisms and shared phenotypes between KD and COVID-19.

Diagnostic significance of microRNAs in sepsis.

BACKGROUND: Sepsis is a life-threatening condition that induce tens of million death each year, yet early diagnosis remains a formidable challenge. Many studies have focused on the diagnostic accuracy of microRNAs (miRNAs) for sepsis in recent years, particularly miR-155-5p, miR-21, miR-223-3p, miR-146a, and miR-125a. Thus, we conducted this meta-analysis to explore if miRNAs may be used as a biomarker for sepsis detection. METHODS: We searched PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, and China National Knowledge Infrastructure through May 12, 2022. This meta-analysis was conducted using Meta-disc 1.4 and STATA 15.1 in a fixed/random-effect model. RESULTS: The analysis included a total of 50 relevant studies. The overall performance of total miRNAs detection was: pooled sensitivity, 0.76 (95% confidence interval [CI], 0.75 to 0.77); pooled specificity, 0.77 (95%CI, 0.75 to 0.78); and area under the summary receiver operating characteristic curves value (SROC), 0.86. The subgroup analysis suggested that detection in miR-155-5p group had the highest area under the curve (AUC) of SROC among all miRNAs: pooled sensitivity, 0.71 (95%CI, 0.67 to 0.75); pooled specificity, 0.82 (95%CI, 0.76 to 0.86); and SROC, 0.85. MiR-21, miR-223-3p, miR-146a, and miR-125a had SROC values of 0.67, 0.78, 0.69, and 0.74, respectively. The specimen type was found to be a source of heterogeneity in the meta-regression study. The SROC of serum was higher than that of plasma (0.87 and 0.83, respectively). CONCLUSIONS: Our meta-analysis revealed that miRNAs, specifically miR-155-5p, could be useful biomarkers for detecting sepsis. A clinical serum specimen is also indicated for diagnostic purposes.

The runoff changes are controlled by combined effects of multiple regional environmental factors in the alpine hilly region of Northwest China.

The imbalance between the water supply and demand in arid and semiarid regions is becoming increasingly serious due to global warming and human activities. It is of great significance to reveal the variation characteristics of runoff and its main controlling factors for the sustainable management of regional water resources. However, few previous studies have considered the integrated effects of multiple control factors on runoff variation at different periodic scales. We collected meteorological and hydrological data from 1960 to 2019 in the Huangshui watershed and explored the correlation degree between runoff and regional environment factors such as precipitation (P), potential evaporation (ET0), mean temperature (T), normalized difference vegetation index (NDVI). The wavelet coherence indicates that there was a high degree of positive phase consistency between runoff changes and P, ET0, T and NDVI at an approximately 12-month period scale, with lag times of approximately 1, 2, 1 and 0 months, respectively. The P was the single factor most closely related to runoff, and its combined with ET0 dominated the runoff change during the whole study period. The Budyko frame combined with elastic coefficient analysis showed that the climate change were the main reasons for the increase in annual runoff in change period I (1981-1990), and changes in the underlying surface due to human activities and vegetation variation was the main reason for the decrease in runoff in change period II (1991-2019). The wetter climate brought more rainfall input but this did not make runoff appear an obvious upward trend. Therefore, for alpine regions with sensitive and fragile ecological environment, the balance between human water consumption, vegetation ecological water demand, and precipitation should be weighed. The combination of wavelet coherence analysis and Budyko framework is helpful to better determine the potential driving factors of regional runoff change.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated. AIM: In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF. METHODS: MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used. RESULTS: In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031). CONCLUSION: The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.

Controversial causal association between IGF family members and osteoporosis: a Mendelian randomization study between UK and FinnGen biobanks.

Objectives: Osteoporosis, a prevalent skeletal disorder characterized by reduced bone strength, is closely linked to the IGF system, crucial for skeletal metabolism. However, the precise nature of this relationship remains elusive. In this study, we employed Mendelian randomization (MR) to unravel the associations between genetically predicted serum IGF system member levels and osteoporosis. Methods: A two-sample MR approach was employed to investigate these causal associations based on two individual datasets. Predictions of 14 serum levels of IGF system members were made using 11,036,163 relevant Single Nucleotide Polymorphisms (SNPs) within a cohort of 4,301 individuals of European descent. Genetic association estimates for osteoporosis were derived from two publicly available GWAS consortia: the Finnish consortium from the FinnGen biobank, comprising 212,778 individuals of Finnish descent (3,203 cases and 209,575 controls), and the UK consortium from the UK Biobank, including 337,159 individuals of European descent (5,266 cases and 331,893 controls). Results: According to the UK dataset, IGF-1 levels were associated with a reduced risk of osteoporosis, as indicated by the weighted median method (Odds Ratio [OR] = 0.998, 95% CI = 0.997-1.000, P = 0.032). Additionally, higher levels of IGFBP-3 were linked to a decreased risk of osteoporosis using the Inverse-Variance Weighted (IVW) method (OR = 0.999, 95% CI = 0.998-1.000, P = 0.019), and CTGF levels exhibited a negative association with osteoporosis, as determined by the weighted median method (OR = 0.998, 95% CI = 0.996-0.999, P = 0.004). In the FinnGen dataset, IGF-1 and IGFBP-3 were not identified to be associated with osteoporosis. While, IGF-LR1 levels displayed a negative association with osteoporosis, according to the MR-Egger method (OR = 0.886, 95% CI = 0.795-0.987, P = 0.036), while CYR61 was linked to an increased risk of osteoporosis based on both the weighted median and IVW methods (OR = 1.154, 95% CI = 1.009-1.319, P = 0.037, and OR = 1.115, 95% CI = 1.022-1.215, P = 0.014, respectively). Conclusion: This study provides compelling evidence that certain IGF family members play a role in the pathogenesis of osteoporosis between different datasets, indicating population specific causal effects between IGF family and osteoporosis. Although the results from both datasets demonstrated that IGF family involved in the pathogenesis of osteoporosis, but the responding key molecules might be various among different population. Subsequent research is warranted to evaluate the potential of these biomarkers as targets for osteoporosis prevention and treatment in specific population.

Anti-Helicobacter pylori activity of potential probiotic Lactiplantibacillus pentosus SLC13.

BACKGROUND: Here, we aimed to evaluate and compare the anti-Helicobacter pylori activity of potential probiotic Lactiplantibacillus pentosus SLC13 to Lactobacillus gasseri BCRC 14619 T and Lacticaseibacillus rhamnosus LGG. Phenotypic assays including growth curve, cell adhesion, and cellular cytotoxicity were performed to characterize SLC13. Anti-H. pylori activity of lactobacilli was determined by the disk diffusion method and co-culture assay. Exopolysaccharide (EPS) was extracted from lactobacilli to test its immune modulation activity, and IL-8 expression in AGS and GES-1 was determined by RT-qPCR. RESULTS: All three lactobacilli strains were tolerant to the simulated gastrointestinal conditions. SLC13 showed the highest adhesion ability to AGS and GES-1 cells, compared to LGG and BCRC 14619 T. The coculture assays of SLC13, LGG, and BCRC 14619 T with cells for 4 h showed no significant cytotoxic effects on cells. All tested strains exhibited an inhibitory effect against H. pylori J99. The cell-free supernatant (CFS) of three strains showed activity to inhibit H. pylori urease activity in a dose-dependent manner and the CFS of SLC13 had the highest urease inhibitory activity, compared to LGG and BCRC 14619 T. Only the treatment of AGS cells with SLC13 EPS significantly decreased the IL-8 expression induced by H. pylori infection as compared to cells treated with LGG and BCRC 14619 T EPS. CONCLUSIONS: SLC13 possesses potent antimicrobial activity against H. pylori growth, infection, and H. pylori-induced inflammation. These results suggest that SLC13 and its derivatives have the potential as alternative agents against H. pylori infection and alleviate inflammatory response.

Safety of a Novel ESAT6-CFP10 skin test compared with tuberculin skin test in a double-blind, randomized, controlled study.

BACKGROUND: ESAT6-CFP10 (EC) skin test has been reported accurate and safe in identifying tuberculosis infection. We aimed to demonstrate the safety of EC skin test compared with tuberculin skin test (TST) in university freshmen. METHODS: We conducted a double-blind, randomized, controlled clinical study in a university freshmen population with 16,680 participates in China, and finally 14,579 completed the study. About a half received an EC skin test and the others received TST. Adverse reactions were evaluated. RESULTS: Out of the 14,579 participants, 48.2% (7029/14,579) were males. The average age was 18.1 ± 0.8 years and the average BMI was 20.9 ± 3.1 kg/m2. 50.4% (7351/14,579) participants received EC skin test and 49.6% (7228/14,579) received TST. The EC group had significantly less adverse reactions compared with the TST group (21.3%, 1565/7351 vs. 34.6%, 2499/7228, P = 0.000). The most common adverse reactions for EC were bleeding (5.63%, 414), dermatodyschroia (4.27%, 314), induration (3.90%, 287), swelling (2.49%, 183), pain (1.59%, 117) and pruritus (1.48%, 109). Bleeding, dermatodyschroia, swelling and erythema were significantly less in EC group (P < 0.05), while others were similar to those of TST. CONCLUSION: the EC skin test was safe in our cohort. And its incidence of total adverse drug reactions (ADRs) is less than that of TST. Most adverse reactions were mild or moderate, lasting less than 48 h and self-limiting. Considering the satisfactory diagnostic accuracy in identifying tuberculosis infection, the cost and safety, the EC skin test might be a potential candidate for replacing TST in high burden countries or those with routine BCG vaccination. CLINICAL TRIALS REGISTRATION: ChiCTR2000038622, Safety of the EC skin test to screen tuberculosis infection in two universities, compared with the tuberculin skin test: a double-blind, randomized, controlled trial. registered on 26/09/2020 at http://www.chictr.org.cn .

Differential proteomic analysis of plasma-derived exosomes as diagnostic biomarkers for chronic HBV-related liver disease.

Hepatitis B virus (HBV) infection is still a major public health problem worldwide. We aimed to identify new, non-invasive biomarkers for the early diagnosis of chronic HBV-related diseases, reveal alterations in the progression of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Here, exosomes were isolated and characterized through size exclusion chromatography and nanoparticle tracking analysis. Profiles of differentially expressed proteins (DEPs) were analyzed through liquid chromatography-tandem mass spectrometry (LC-MS/MS), Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. Results showed that the DEPs, including CO9, LBP, SVEP1, and VWF levels in extracellular vesicles (EVs) were significantly higher in CHB than in healthy controls (HCs). VWF expression levels in EVs were significantly lower in CHB than in those with LC. KV311 expression levels in EVs were significantly higher, whereas LBP levels were significantly lower in patients with CHB than in those with HCC. All biomarkers seemed to exhibit a high diagnostic capacity for HBV-related liver disease. Patients with HBV-induced chronic liver disease exhibit characteristic protein profiles in their EVs. Thus, serum exosomes may be used as novel, liquid biopsy biomarkers to provide useful clinical information for the diagnosis of HBV-related liver diseases at different stages.

The effect of BCG vaccination and risk factors for latent tuberculosis infection among college freshmen in China.

OBJECTIVES: In this study, we aimed to verify whether Bacillus Calmette-Guérin (BCG) can protect first-year college students against Mycobacterium tuberculosis (MTB) infection by the recombinant fusion protein ESAT6-CFP10 skin test (ECST) or the tuberculin skin test (TST). METHODS: We conducted a cross-sectional study to assess risk factors for latent tuberculosis infection (LTBI). Vaccine effectiveness of BCG against LTBI, measured by ECST and TST separately, was assessed using multivariable logistic regression. RESULTS: A total of 7351 college freshmen accepted ECST, whereas 7228 accepted TST. A total of 263 (3.58%) tested positive with ECST and 581 (8.04%) tested positive with TST. BCG was significantly associated with LTBI (ECST: adjusted odds ratio (aOR) = 0.26; 95% CI 0.09 to 0.73; TST: aOR = 0.25; 95% CI 0.13 to 0.49). The BCG protective effect on freshmen living in rural areas (ECST: aOR = 0.16; 95% CI 0.04 to 0.55; TST: aOR = 0.12; 95% CI 0.04 to 0.33) is better than that of freshmen living in cities (ECST: aOR = 0.53; 95% CI 0.07 to 4.03; TST: aOR = 0.44; 95% CI 0.17 to 1.16). CONCLUSIONS: Protection against LTBI was strongly associated with BCG vaccination. A novel skin test (ECST) may underestimate the protective effects of BCG in college freshmen. BCG has better protection in areas with a slightly higher incidence of LTBI.

Novel Compound Heterozygous PKLR Mutation Induced Pyruvate Kinase Deficiency With Persistent Pulmonary Hypertension in a Neonate: A Case Report.

Background: Pulmonary hypertension could be associated with pyruvate kinase deficiency (PKD). There are few reported cases of PPHN as the first clinical manifestation of PKD. Herein we report a rare case of PKD in which the patient exhibited persistent pulmonary hypertension in the neonate (PPHN), and genetic testing helped to rapidly identify an potential association. Case presentation: The patient was a newborn boy who suffered from severe dyspnea, extreme anemia, skin pallor, and hypoxemia. Repeated echocardiography indicated persistent severe pulmonary hypertension with a calculated pulmonary artery pressure of 75 mmHg, and right ventricular hypertrophy. The administration of nitric oxide significantly reduced the pulmonary artery pressure. Whole-exome sequencing revealed a compound heterozygous mutation consisting of c.707T > G and c.826_827insAGGAGCATGGGG. PolyPhen_2 and MutationTaster indicated that both the c.707T > G (probability 0.999) and c.826_827insAGGAGCATGGGG (probability 0.998) mutations were disease causing. PROVEAN protein batch analysis indicated that the associated p.L236R region was deleterious (score -4.71) and damaging (SIFT prediction 0.00), and this was also the case for p.G275_V276insEEHG (deleterious score -12.00, SIFT prediction 0.00). Substantial structural changes in the transport domain of the protein were predicted using SWISS-MODEL, and indicated that both mutations led to an unstable protein structure. Thus, a novel compound heterozygous mutation of PKLR-induced PKD with PPHN was diagnosed. Conclusion: The current study suggests that molecular genetic screening is useful for identifying PPHN, particularly in children with metabolic disorders. In patients exhibiting unexplained hyperbilirubinemia combined with severe pulmonary hypertension, PKD might be a potential possible alternative explanation. Genetic screening is helpful for identifying genetic causes of pulmonary hypertension, especially in patients with PPHN. This report expands the mutation spectrum of the PKLR gene, and contributes to the genotype-phenotype map of PKD.

Controversial molecular functions of CBS versus non-CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review.

BACKGROUND: PRKAG2 cardiac syndrome is a rare autosomal dominant genetic disorder caused by a PRKAG2 gene variant. There are several major adverse cardiac presentations, including hypertrophic cardiomyopathy (HCM) and life-threatening arrhythmia. Two cases with pathogenic variants in the PRKAG2 gene are reported here who presents different cardiac phenotypes. METHODS: Exome sequencing and variant analysis of PRKAG2 were performed to obtain genetic data, and clinical characteristics were determined. RESULTS: The first proband was a 9-month-old female infant (Case 1), and was identified with severe DCM and resistant heart failure. The second proband was a 10-year-old female infant (Case 2), and presented with HCM and ventricular preexcitation. Exome sequencing identified a de novo c.425C > T (p.T142I) heterozygous variant in the PRKAG2 gene for Case 1, and a c.869A > T (p.K290I) for Case 2. The mutated sites in the protein were labeled and identified as p.K290 in the CBS domain and p.T142 in the non-CBS domain. Differences in the molecular functions of CBS and non-CBS domains have not been resolved, and variants might lead to the different cardiomyopathy phenotypes. Single-cell RNA analysis demonstrated similar expression levels of PRKAG2 in cardiomyocytes and conductive tissues. These results suggest that the arrhythmia induced by the PRKAG2 variant was the primary change, and not secondary to cardiomyopathy. CONCLUSION: In summary, this is the first case report to describe a DCM phenotype with early onset in patients possessing a PRKAG2 c.425C > T (p.T142I) pathogenic variant. Our results aid in understanding the molecular function of non-CBS variants in terms of the disordered sequence of transcripts. Moreover, we used scRNA-seq to show that electrically conductive cells express a higher level of PRKAG2 than do cardiomyocytes. Therefore, variants in PRKAG2 are expected to also alter the biological function of the conduction system.

Mechanotransduction Regulates the Interplays Between Alveolar Epithelial and Vascular Endothelial Cells in Lung.

Mechanical stress plays a critical role among development, functional maturation, and pathogenesis of pulmonary tissues, especially for the alveolar epithelial cells and vascular endothelial cells located in the microenvironment established with vascular network and bronchial-alveolar network. Alveolar epithelial cells are mainly loaded by cyclic strain and air pressure tension. While vascular endothelial cells are exposed to shear stress and cyclic strain. Currently, the emerging evidences demonstrated that non-physiological mechanical forces would lead to several pulmonary diseases, including pulmonary hypertension, fibrosis, and ventilation induced lung injury. Furthermore, a series of intracellular signaling had been identified to be involved in mechanotransduction and participated in regulating the physiological homeostasis and pathophysiological process. Besides, the communications between alveolar epithelium and vascular endothelium under non-physiological stress contribute to the remodeling of the pulmonary micro-environment in collaboration, including hypoxia induced injuries, endothelial permeability impairment, extracellular matrix stiffness elevation, metabolic alternation, and inflammation activation. In this review, we aim to summarize the current understandings of mechanotransduction on the relation between mechanical forces acting on the lung and biological response in mechanical overloading related diseases. We also would like to emphasize the interplays between alveolar epithelium and vascular endothelium, providing new insights into pulmonary diseases pathogenesis, and potential targets for therapy.

Serum level of testosterone predicts disease severity of male COVID-19 patients and is related to T-cell immune modulation by transcriptome analysis.

BACKGROUND: Severe disease of COVID-19 and mortality occur more frequently in male patients than that in female patients may be related to testosterone level. However, the diagnostic value of changes in the level of testosterone in predicting severe disease of male COVID-19 patients has not been determined yet. METHODS: Sixty-one male COVID-19 patients admitted to the First Affiliated Hospital of Zhejiang University School of Medicine were enrolled. Serum samples at different stages of the patients after admission were collected and testosterone levels were detected to analyze the correlation between testosterone level and disease severity. Transcriptome analysis of PBMC was performed in 34 patients. RESULTS: Testosterone levels at admission in male non-ICU COVID-19 patients (3.7 nmol/L, IQR: 1.5 âˆ¼ 4.7) were significantly lower than those in male ICU COVID-19 patients (6.7 nmol/L, IQR: 4.2 âˆ¼ 8.7). Testosterone levels in the non-ICU group increased gradually during the progression of the disease, while those in the ICU group remained low. In addition, testosterone level of enrolled patients in the second week after onset was significantly correlated with the severity of pneumonia, and ROC curve showed that testosterone level in the second week after onset was highly effective in predicting the severity of COVID-19. Transcriptome studies have found that testosterone levels of COVID-19 patients were associated with immune response, including T cell activation and regulation of lymphocyte activation. In addition, CD28 and Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) were found positively correlated with testosterone. CONCLUSIONS: Serum testosterone is an independent risk factor for predicting the severity of COVID-19 in male patients, and the level of serum testosterone in the second week after onset is valuable for evaluating the severity of COVID-19. Testosterone level is associated with T cell immune activation. The monitoring of serum testosterone should be highlighted in clinical treatment and the related mechanism should be further studied.

Baseline Quantitative Hepatitis B Core Antibody Titer Is a Predictor for Hepatitis B Virus Infection Recurrence After Orthotopic Liver Transplantation.

Objective: Hepatitis B virus (HBV) reinfection is a serious complication that arise in patients who undergo hepatitis B virus related liver transplantation. We aimed to use biomarkers to evaluate the HBV reinfection in patients after orthotopic liver transplantation. Methods: Seventy-nine patients who underwent liver transplantation between 2009 and 2015 were enrolled, and levels of biomarkers were analyzed at different time points. Cox regression and receiver operating characteristic (ROC) curves of different markers at baseline were used to analyze sustained hepatitis B surface antigen (HBsAg) loss. The Kaplan-Meier method was used to compare the levels of the biomarkers. Results: Among the 79 patients, 42 sustained HBsAg loss with a median time of 65.2 months (12.0-114.5, IQR 19.5) after liver transplantation and 37 patients exhibited HBsAg recurrence with a median time of 8.8 (0.47-59.53, IQR 19.47) months. In the ROC curve analysis, at baseline, 4.25 log10 IU/mL qHBcAb and 2.82 log10 IU/mL qHBsAg showed the maximum Youden's index values with area under the curves (AUCs) of 0.685and 0.651, respectively. The Kaplan-Meier method indicated that qHBsAg and quantitative antibody against hepatitis B core antigen (qHBcAb) levels in the two groups were significantly different (p = 0.031 and 0.006, respectively). Furthermore, the Cox regression model confirmed the predictive ability of qHBcAb at baseline (AUC = 0.685). Conclusion: Lower pretransplantation qHBcAb is associated with HBV infection. The baseline concentration of qHBcAb is a promising predictor for the recurrence of HBV in patients undergoing liver transplantation and can be used to guide antiviral treatment for HBV infection.

Meta-analysis and systematic review of electronic bronchoscopy in refractory pneumonia.

BACKGROUND: A systematic review and meta-analysis were performed to explore the adoption value of electronic bronchoscopy (EBS) in the diagnosis and treatment of refractory pneumonia and to provide a theoretical basis for the clinical bronchoscopy treatment of patients. METHODS: Randomized controlled trials of treatment-resistant pneumonia searched on PubMed, Embase, and other websites before December 31, 2020 were collected. Literature was selected by inclusion and exclusion criteria. Bias risk was assessed using Cochrane intervention system Review manual 5.0.2 and Review Manager 5.3. RESULTS: A total of 6 articles meeting the requirements were included, comprising 796 participants. The results of meta-analysis showed that the clinical efficacy [odds ratio (OR) =3.8; 95% confidence interval (CI): 1.11-12.99; Z=2.13; P =0.03] and white blood cell counts [mean difference (MD) =0.55; 95% CI: -0.57 to 1.67; Z=0.96; P=0.34] of patients both increased. The mortality rate (OR =0.7; 95% CI: 0.3-1.63; Z=0.82; P=0.41), the incidence of infection (OR =0.84; 95% CI: 0.5-1.39; Z=0.69; P=0.49), ICU hospitalization days (OR =0.59; 95% CI: 0.36-0.98; Z=2.04; P=0.04), days of antibiotic use (OR =0.39; 95% CI: 0.18-0.84; Z=2.41; P=0.02), body temperature (MD =-0.2; 95% CI: -0.24 to 0.16; Z=9.5; P<0.0001), and the PaO2:FIO2 ratio (MD =-9.96; 95% CI: -13.31 to -6.61; Z=5.83; P<0.0001) of patients in the experimental group were lower than those of the control group. Differences in white blood cell count, mortality rate, and incidence of infection of patients in the experimental group were not statistically significant compared with those in the control group. DISCUSSION: EBS adopted in the diagnosis and treatment of refractory pneumonia can reduce the occurrence of postoperative adverse reactions, reduce the infection rate, and effectively improve the clinical symptoms. It is therefore suitable for the treatment of this disease.