Antivirals with common targets against highly pathogenic viruses.

Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics.

Developing pan-ß-coronavirus vaccines against emerging SARS-CoV-2 variants of concern.

The concurrent prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) raises the concern for the emergence of potential new ß-CoV clades via genetic recombination, bearing high SARS-CoV-2-like transmissibility and high MERS-CoV-like mortality rates. Therefore, we argue that there is an urgent need to develop pan-ß-CoV vaccines that can target not only current SARS-CoV-2 variants of concern, but also future putative SARS-CoV-3- or MERS-CoV-2-like coronavirus.

A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.

Cystic fibrosis (CF) is a genetic disease caused by the mutations of cystic fibrosis transmembrane conductance regulator (CFTR), the cystic fibrosis transmembrane conductance regulator gene. Cftr is a critical ion channel expressed in the apical membrane of mouse salivary gland striated duct cells. Although Cftr is primarily a Cl- channel, its knockout leads to higher salivary Cl- and Na+ concentrations and lower pH. Mouse experiments show that the activation of Cftr upregulates epithelial Na+ channel (ENaC) protein expression level and Slc26a6 (a 1Cl-:2[Formula: see text] exchanger of the solute carrier family) activity. Experimentally, it is difficult to predict how much the coregulation effects of CFTR contribute to the abnormal Na+, Cl-, and [Formula: see text] concentrations and pH in CF saliva. To address this question, we construct a wild-type mouse salivary gland model and simulate CFTR knockout by altering the expression levels of CFTR, ENaC, and Slc26a6. By reproducing the in vivo and ex vivo final saliva measurements from wild-type and CFTR knockout animals, we obtain computational evidence that ENaC and Slc26a6 activities are downregulated in CFTR knockout in salivary glands.NEW & NOTEWORTHY This paper describes a salivary gland mathematical model simulating the ion exchange between saliva and the salivary gland duct epithelium. The novelty lies in the implementation of CFTR regulating ENaC and Slc26a6 in a CFTR knockout gland. By reproducing the experimental saliva measurements in wild-type and CFTR knockout glands, the model shows that CFTR regulates ENaC and Slc26a6 anion exchanger in salivary glands. The method could be used to understand the various cystic fibrosis phenotypes.

Short-term culture for rapid identification by mass spectrometry and automated antimicrobial susceptibility testing from positive bottles.

BACKGROUND: Early and appropriate antibiotic treatment improves the clinical outcome of patients with sepsis. There is an urgent need for rapid identification (ID) and antimicrobial susceptibility testing (AST) of bacteria that cause bloodstream infection (BSI). Rapid ID and AST can be achieved by short-term incubation on solid medium of positive blood cultures using MALDI-TOF mass spectrometry (MS) and the BD M50 system. The purpose of this study is to evaluate the performance of rapid method compared to traditional method. METHODS: A total of 124 mono-microbial samples were collected. Positive blood culture samples were short-term incubated on blood agar plates and chocolate agar plates for 5 ∼ 7 h, and the rapid ID and AST were achieved through Zybio EXS2000 MS and BD M50 System, respectively. RESULTS: Compared with the traditional 24 h culture for ID, this rapid method can shorten the cultivation time to 5 ∼ 7 h. Accurate organism ID was achieved in 90.6% of Gram-positive bacteria (GP), 98.5% of Gram-negative bacteria (GN), and 100% of fungi. The AST resulted in the 98.5% essential agreement (EA) and 97.1% category agreements (CA) in NMIC-413, 99.4% EA and 98.9% CA in PMIC-92, 100% both EA and CA in SMIC-2. Besides, this method can be used for 67.2% (264/393) of culture bottles during routine work. The mean turn-around time (TAT) for obtaining final results by conventional method is approximately 72.6 ± 10.5 h, which is nearly 24 h longer than the rapid method. CONCLUSIONS: The newly described method is expected to provide faster and reliable ID and AST results, making it an important tool for rapid management of blood cultures (BCs). In addition, this rapid method can be used to process most positive blood cultures, enabling patients to receive rapid and effective treatment.

Oleic acid improves hepatic lipotoxicity injury by alleviating autophagy dysfunction.

Lipotoxicity caused by excess free fatty acids, particularly saturated fatty acids (SFAs) such as palmitic acid (PA), is one of the most important pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, unsaturated fatty acids (UFAs), such as oleic acid (OA), are nontoxic and can combat SFA-induced toxicity through alleviation of cell apoptosis, endoplasmic reticulum stress (ER stress) and lipids metabolism disorder. However, whether OA is able to regulate autophagy is largely unknown. So, this study aims to investigate the mechanism underlying OA mediated modulation of autophagy in hepatocytes and mice with NAFLD. In vitro, human hepatoma cell line HepG2 cells, human normal liver cells L-02 and mouse normal liver cells AML12 were treated with palmitic acid (PA)/tunicamycin (TM) or/and OA for 48 h. In vivo, C57/BL6 mice were fed with high fat diet (HFD) to induce NAFLD. And the HFD was partial replaced by olive oil to observe the protective effects of olive oil. We demonstrated that PA/TM impaired cell viability and induced cellular apoptosis in HepG2 cells and L-02 cells. Moreover, PA/TM induced autophagy impairment by reducing the nuclear translocation of transcription factor EB (TFEB) and inhibiting the activity of CTSB. However, OA substantially alleviated PA/TM induced cellular apoptosis and autophagy dysfunction in hepatocytes. Additionally, restoring autophagy function is able to reduce ER stress. Similarly, HFD for 20 weeks successfully established NAFLD model in C57/BL6 mice, and significant autophagy impairment were observed in liver tissues. Noteworthily, 30% replacement of HFD with olive oil had profoundly reversed NAFLD. It significantly impoved steatosis, and reduced autophagy dysfunction, ER stress and apoptosis in liver tissue. Conclusively, these data demonstrated that OA is able to effectively impove autophagy dysfunction under the context of both PA and ER stress inducer induced lipotoxicity, and OA mediated regulation of lysosome dysfunction through TFEB plays an important role, suggesting that the regulation of ER stress-autophagy axis is a critical mechanism in OA driven protection in NAFLD.

Risk factors and predicting nomogram for the clinical deterioration of non-severe community-acquired pneumonia.

BACKGROUND: Currently, there remains insufficient focus on non-severe community-acquired pneumonia (CAP) patients who are at risk of clinical deterioration, and there is also a dearth of research on the related risk factors. Early recognition of hospitalized patients at risk of clinical deterioration will be beneficial for their clinical management. METHOD: A retrospective study was conducted in The First Affiliated Hospital of Wenzhou Medical University, China, spanning from January 1, 2018 to April 30, 2022, and involving a total of 1,632 non-severe CAP patients. Based on whether their condition worsened within 72 h of admission, patients were divided into a clinical deterioration group and a non-clinical deterioration group. Additionally, all patients were randomly assigned to a training set containing 75% of patients and a validation set containing 25% of patients. In the training set, risk factors for clinical deterioration in patients with non-severe CAP were identified by using LASSO regression analysis and multivariate logistic regression analysis. A nomogram was developed based on identified risk factors. The effectiveness of the nomogram in both the training and validation sets was assessed using Receiver Operating Characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: Age, body mass index (BMI), body temperature, cardiovascular comorbidity, respiratory rate, LDH level, lymphocyte count and D-dimer level were identified as risk factors associated with the clinical deterioration of non-severe CAP within 72 h of admission. The area under curve (AUC) value of the nomogram was 0.78 (95% CI: 0.74-0.82) in the training set and 0.75 (95% CI: 0.67-0.83) in the validation set. Furthermore, the calibration curves for both the training and validation sets indicated that the predicted probability of clinical deterioration aligned with the actual probability. Additionally, DCA revealed clinical utility for the nomogram at a specific threshold probability. CONCLUSION: The study successfully identified the risk factors linked to the clinical deterioration of non-severe CAP and constructed a nomogram for predicting the probability of deterioration. The nomogram demonstrated favorable predictive performance and has the potential to aid in the early identification and management of non-severe CAP patients at elevated risk of deterioration.

Associations amongst dynamic knee stiffness during gait, quadriceps stiffness, and the incidence of knee osteoarthritis over 24 months: a cohort study with a mediation analysis.

BACKGROUND: Decreased strength and increased stiffness of the quadriceps have been associated with a higher risk of developing knee osteoarthritis (OA) in elders. Dynamic joint stiffness (DJS) represents collective resistance from active and passive knee structures for dynamic knee motions. Elevated sagittal knee DJS has been associated with worsening of cartilage loss in knee OA patients. Altered quadriceps properties may affect DJS, which could be a mediator for associations between quadriceps properties and knee OA. Hence, this study aimed to examine whether DJS and quadriceps properties would be associated with the development of clinical knee OA over 24 months, and to explore the mediation role of DJS in associations between quadriceps properties and knee OA. METHODS: This was a prospective cohort study with 162 healthy community-dwelling elders. Gait analysis was conducted to compute DJS during the loading response phase. Quadriceps strength and stiffness were evaluated using a Cybex dynamometer and shear-wave ultrasound elastography, respectively. Knee OA was defined based on clinical criteria 24 months later. Logistic regression with generalized estimating equations was used to examine the association between quadriceps properties and DJS and incident knee OA. Mediation analysis was performed to explore the mediation role of DJS in associations between quadriceps properties and the incidence of knee OA. RESULTS: A total of 125 participants (65.6 ± 4.0 years, 58.4% females) completed the 24-month follow-up, with 36 out of 250 knees identified as clinical knee OA. Higher DJS (OR = 1.86, 95%CI: 1.33-2.62), lower quadriceps strength (1.85, 1.05-3.23), and greater quadriceps stiffness (1.56, 1.10-2.21) were significantly associated with a higher risk of clinical knee OA. Mediation analysis showed that the DJS was not a significant mediator for the associations between quadriceps properties and knee OA. CONCLUSIONS: Higher sagittal knee dynamic joint stiffness, lower quadriceps strength, and greater quadriceps stiffness are potential risk factors for developing clinical knee OA in asymptomatic elders. Associations between quadriceps properties and knee OA may not be mediated by dynamic joint stiffness. Interventions for reducing increased passive properties of the quadriceps and knee joint stiffness may be beneficial for maintaining healthy knees in the aging population.

Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury.

BACKGROUND: Flucloxacillin (FLX)-induced liver injury is immune-mediated and highly associated to HLA-B∗57:01 expression. Host factors leading to drug-induced liver injury are not yet well understood. OBJECTIVE: Characterize in vivo immune mechanisms determining the development of CD8+ T cells reactive to FLX in animals expressing the risk human leukocyte antigen (HLA) allotype. METHODS: HLA-B∗57:01 transgenic mice (Tg) or Tg strains with H2-KbDb knockout (Tg/KO) or H2-KbDb/PD-1 double knockout (Tg/DKO) were treated with drug and/or anti-CD4 antibody. Drug-induced liver injury was evaluated on the basis of liver enzyme and histologic changes at day 10 of treatment. FLX-reactive CD8+ T cells were characterized in vitro by release of effector molecules on drug restimulation, gene expression, and flow cytometry analysis, and functionality tested for hepatic cytotoxicity. RESULTS: CD8+ T-cell responses to FLX in Tg were dependent on both HLA and mouse major histocompatibility complex I presentation and in vivo priming. Eliminating H2-KbDb in Tg/KO to allow exclusive presentation of FLX by HLA resulted in a less robust drug-specific CD8+T-cell response unless CD4+ cells, including regulatory T cells, were depleted. Treatment of Tg/KO with anti-CD4 antibody and FLX led to subclinical liver inflammation associated with an increase in PD1+CD8+ T cells in the lymphoid organs and liver. Impaired PD-1 expression in Tg/DKO led to liver histopathologic and transcriptional alterations but without hepatic enzyme elevations. Moreover, effector lymphocytes accumulated in the liver and showed FLX-dependent hepatic cytotoxicity in vitro when tolerogenic liver cells were depleted. CONCLUSIONS: In our in vivo models, FLX primes CD8+ T cells to recognize drug presented by HLA-B∗57:01 and murine major histocompatibility complex I. HLA-B∗57:01-dependent CD8+ T-cell reaction to FLX is limited by the presence of CD4+ cells, presumably regulatory T cells, and PD-1 expression. Tolerogenic hepatic cells limit clinical disease through PD-L1 or additional unexplored mechanisms.

Translation and validation of the Chinese version of the menstrual distress questionnaire.

BACKGROUND: The Menstrual Distress Questionnaire (MDQ) is a commonly used questionnaire that assesses various symptoms and distress associated with the menstrual cycle in women. However, the questionnaire has not been completely translated into Chinese with rigorous reliability and validity testing. METHODS: This study translated the Menstrual Distress Questionnaire Form Cycle (MDQC) from English into Chinese: MDQCC in two stages. First, it was translated forward and backward using Jones' model; second, to test the validity and reliability, 210 Chinese-speaking women were recruited through online announcements and posters posted between June 2019 and May 2020. Expert validity, construct validity, convergent validity, and factorial validity were determined using content validity index (CVI), intraclass correlation coefficient (ICC), composite reliability (CR), and exploratory factor analysis, respectively. For concurrent criterion validity, MDQCC score was compared with three existing pain scales. Reliability was evaluated using internal consistency across items and two-week test-retest reliability over time. RESULTS: The CVI for content validity was .92. Item-CVI for expert validities among the 46 items ranged from .50 - 1; scale-CVI for the eight subscales, from .87 - 1; ICC, from .650 - .897; and CRs, from .303 - .881. Pearson correlation coefficients between MDQCC and short-form McGill pain questionnaire, present pain intensity, and visual analog scale scores were .640, .519, and .575, respectively. Cronbach's α for internal consistency was satisfactory (.932). ICC for test-retest reliability was .852 for the entire MDQCC. CONCLUSION: MDQCC was valid and reliable for Mandarin Chinese-speaking women. It can be used to evaluate female psychiatric symptoms related to the menstrual cycle in future work.

The Menstrual Distress Questionnaire has been used to evaluate menstrual distress, including dysmenorrhoea and premenstrual syndrome. This questionnaire has been translated into Persian, Korean, Japanese, and Cantonese, rendering it to be used more and more widely all over the world. The study translated all 46 items of the Menstrual Distress Questionnaire from English to Mandarin Chinese using a two-stage strategy. The Chinese version of this questionnaire developed by the present study was found to be a valid and reliable tool in Chinese Mandarin-speaking female populations. It could be used to evaluate women's physical and psychiatric symptoms related to the menstrual cycle in future works.

Structural and functional analysis of salivary intercalated duct cells reveals a secretory phenotype.

Currently, all salivary ducts (intercalated, striated and collecting) are assumed to function broadly in a similar manner, reclaiming ions that were secreted by the secretory acinar cells while preserving fluid volume and delivering saliva to the oral cavity. Nevertheless, there has been minimal investigation into the structural and functional differences between distinct types of salivary duct cells. Therefore, in this study, the expression profile of proteins involved in stimulus-secretion coupling, as well as the function of the intercalated duct (ID) and striated duct cells, was examined. Particular focus was placed on defining differences between distinct duct cell populations. To accomplish this, immunohistochemistry and in situ hybridization were utilized to examine the localization and expression of proteins involved in reabsorption and secretion of ions and fluid. Further, in vivo calcium imaging was employed to investigate cellular function. Based on the protein expression profile and functional data, marked differences between the IDs and striated ducts were observed. Specifically, the ID cells express proteins native to the secretory acinar cells while lacking proteins specifically expressed in the striated ducts. Further, the ID and striated duct cells display different calcium signalling characteristics, with the IDs responding to a neural stimulus in a manner similar to the acinar cells. Overall, our data suggest that the IDs have a distinct role in the secretory process, separate from the reabsorptive striated ducts. Instead, based on our evidence, the IDs express proteins found in secretory cells, generate calcium signals in a manner similar to acinar cells, and, therefore, are likely secretory cells. KEY POINTS: Current studies examining salivary intercalated duct cells are limited, with minimal documentation of the ion transport machinery and the overall role of the cells in fluid generation. Salivary intercalated duct cells are presumed to function in the same manner as other duct cells, reclaiming ions, maintaining fluid volume and delivering the final saliva to the oral cavity. Here we systematically examine the structure and function of the salivary intercalated duct cells using immunohistochemistry, in situ hybridization and by monitoring in vivo Ca2+ dynamics. Structural data revealed that the intercalated duct cells lack proteins vital for reabsorption and express proteins necessary for secretion. Ca2+ dynamics in the intercalated duct cells were consistent with those observed in secretory cells and resulted from GPCR-mediated IP3 production.

Phase Separation Microparticles as a Three-Dimensional Cell Culture System To Promote Stem Cell Expansion.

Stem cell therapy is developing rapidly, but existing expansion techniques are insufficient for the use of a large number of cells. The surface chemistry and surface morphology characteristics of materials play a critical role in cellular behaviors and functions and have guiding significance for the design of biomaterials. Many studies have proven that these factors are essential to affect cell adhesion and growth. How to design a suitable biomaterial interface is the focus of recent studies. Here, the mechanosensing of human adipose-derived stem cells (hASC) on a set of materials and materials with various porosity is systematically studied. Guided by the mechanism discoveries, three-dimensional (3D) microparticles with optimized hydrophilicity and morphology are designed via liquid-liquid phase separation technology. The microparticles support scalable stem cell culture and extracellular matrix (ECM) collection, exhibiting great potential for stem cell applications.

A novel variant in the tropomyosin 3 gene presenting as an adult-onset distal myopathy - a case report.

BACKGROUND: We report a patient with a novel c.737 C > T variant (p.Ser246Leu) of the TPM3 gene presenting with adult-onset distal myopathy. CASE PRESENTATION: A 35-year-old Chinese male patient presented with a history of progressive finger weakness. Physical examination revealed differential finger extension weakness, together with predominant finger abduction, elbow flexion, ankle dorsiflexion and toe extension weakness. Muscle MRI showed disproportionate fatty infiltration of the glutei, sartorius and extensor digitorum longus muscles without significant wasting. Muscle biopsy and ultrastructural examination showed a non-specific myopathic pattern without nemaline or cap inclusions. Genetic sequencing revealed a novel heterozygous p.Ser246Leu variant (c.737C>T) of the TPM3 gene which is predicted to be pathogenic. This variant is located in the area of the TPM3 gene where the protein product interacts with actin at position Asp25 of actin. Mutations of TPM3 in these loci have been shown to alter the sensitivity of thin filaments to the influx of calcium ions. CONCLUSION: This report further expands the phenotypic spectrum of myopathies associated with TPM3 mutations, as mutations in TPM3 had not previously been reported with adult-onset distal myopathy. We also discuss the interpretation of variants of unknown significance in patients with TPM3 mutations and summarise the typical muscle MRI findings of patients with TPM3 mutations.

Fluorescence sensing and glycosidase inhibition effect of multivalent glycosidase inhibitors based on Naphthalimide-deoxynojirimycin conjugates.

Synthetic glycoconjugates as chemical probes have been widely developed for the detection of glycosidase enzymes. However, the binding interactions between iminosugar derivatives and glycosidases were limited, especially for the binding interactions between multivalent glycosidase inhibitors and α-glycosidases. In this paper, three naphthalimide-DNJ conjugates were synthesized. Furthermore, the binding interactions and glycosidase inhibition effects of them were investigated. It was found that the strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase. Moreover, the lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities with multisource glycosidases. Compound 13 with six carbons between the DNJ moiety and triazole ring showed the stronger binding interactions and better glycosidase inhibition activities against α-mannosidase (jack bean) and α-glucosidase (aspergillus niger). In addition, compound 13 showed an effective PBG inhibition effect in mice with 51.18 % decrease in blood glucose at 30 min. This result opens a way for detection of multivalent glycosidase inhibition effect by a fluorescent sensing method.

Comprehensive analysis of lncRNA expression profiles in postmenopausal osteoporosis.

To explore the key lncRNAs affecting postmenopausal osteoporosis (PMOP) progression, the transcriptome sequencing of peripheral blood mononuclear cells from fifteen early postmenopausal women, according to bone mineral density, were divided into groups of osteoporosis, osteopenia and normality, in each of which the expression profiles of lncRNAs was investigated. From the results we observed nine candidates of lncRNAs, which were to be compared with miRBase, and found that MIR22HG as one candidate of lncRNA was most likely to be directly used as miRNA precursor. Based on the KEGG annotation and lncRNA-miRNA-mRNA-KEGG network, we analyzed the potential role of candidate lncRNAs. The results showed that the expression profiles of lncRNAs could help identify the novel ones involved in the progression of PMOP, and that MIR22HG could serve as a miRNA precursor to regulate FoxO signaling pathway in bone metabolism. Our findings can be of great help in predicting and diagnosing early PMOP.

Folate ameliorates homocysteine-induced osteoblast dysfunction by reducing endoplasmic reticulum stress-activated PERK/ATF-4/CHOP pathway in MC3T3-E1 cells.

INTRODUCTION: Homocysteine (Hcy) is considered a newly identified risk factor for osteoporosis. Nevertheless, the underlying mechanism of folate (FA), a key factor in the metabolism of Hcy, in protection against osteoblast dysfunction remains unclear. The purpose of this study was to investigate the mechanism by which FA attenuates Hcy-induced osteoblast damage. MATERIALS AND METHODS: The Hcy-induced MC3T3-E1 cells were treated with different concentrations of FA. Cell morphology, cell density, cell proliferation ability, alkaline phosphatase (ALP) activity and mineralization capacity were observed and determined; the gene expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX) and ERS-associated factors, including glucose-regulated protein 78 (GRP-78), activating transcription factor 4 (ATF-4) and growth arrest and DNA damage inducible gene 153 (CHOP/GADD153), were assessed by RT-PCR; and protein levels of GRP-78 and ATF-4 were analyzed by western blotting. RESULTS: Hcy suppressed the proliferation, differentiation and mineralization ability of MC3T3-E1 cells in a concentration-dependent manner and activated the ERS signaling pathway. After intervention with different concentrations of FA, the cell viability and density, ALP activity, number of mineralized nodules, calcium content and Bcl-2 gene expression were all significantly increased, whereas the gene expression of GRP-78, CHOP/GADD153, ATF-4 and Bax was markedly downregulated, and protein levels of GRP-78 and ATF-4 were also markedly decreased. CONCLUSION: The adverse effects of Hcy on osteoblast differentiation are dose dependent. FA not only protects against osteoblasts apoptosis but also has a direct osteogenic effect on Hcy-induced osteoblasts, which could be partially mediated by inhibition of the PERK-activated ERS pathway.

Are Proton Pump Inhibitors More Effective Than Histamine-2-Receptor Antagonists for Stress Ulcer Prophylaxis in Critically Ill Patients? A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: Histamine-2-receptor antagonists (H2RAs) have been largely replaced by proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) despite the inconclusive evidence concerning comparative effectiveness. OBJECTIVE: To compare the effectiveness of PPIs and H2RAs on SUP in real-world setting. METHODS: PubMed, Embase, and the Cochrane Library were searched from inception to September 19, 2021. We included cohort studies comparing PPIs with H2RAs in critically ill adult patients and explicitly reporting the outcome of gastrointestinal (GI) bleeding or mortality. Newcastle-Ottawa Scale was used to assess potential risk of bias. We conducted a random-effects meta-analysis and only the studies with adjusted effect estimates were pooled. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of the evidence. RESULTS: Thirteen cohort studies (N = 145 149) were eligible and 11 of them available for full texts were of low to moderate risk of bias. Meta-analysis of adjusted effect estimates indicated that PPIs were associated with a significantly higher risk of GI bleeding, compared with H2RAs (8 studies, odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.30-3.01, low certainty). Post hoc pooling analysis also suggested that PPIs were associated with a slightly higher risk of mortality in comparison with H2RAs (7 studies, OR = 1.27, 95% CI = 1.13-1.42, low certainty). CONCLUSION AND RELEVANCE: The systematic review of cohort studies showed that PPIs were associated with higher risks of GI bleeding and mortality, although the certainty of evidence was low. Overall, we suggest not excluding H2RAs for SUP, while further studies are essential for elucidating the risk stratification, optimal regimen, and specific duration.

A Mathematical Model of Salivary Gland Duct Cells.

Saliva is produced in two stages in the salivary glands: the secretion of primary saliva by the acinus and the modification of saliva composition to final saliva by the intercalated and striated ducts. In order to understand the saliva modification process, we develop a mathematical model for the salivary gland duct. The model utilises the realistic 3D structure of the duct reconstructed from an image stack of gland tissue. Immunostaining results show that TMEM16A and aquaporin are expressed in the intercalated duct cells and that ENaC is not. Based on this, the model predicts that the intercalated duct does not absorb Na[Formula: see text] and Cl[Formula: see text] like the striated duct but secretes a small amount of water instead. The input to the duct model is the time-dependent primary saliva generated by an acinar cell model. Our duct model produces final saliva output that agrees with the experimental measurements at various stimulation levels. It also shows realistic biological features such as duct cell volume, cellular concentrations and membrane potentials. Simplification of the model by omission of all detailed 3D structures of the duct makes a negligible difference to the final saliva output. This shows that saliva production is not sensitive to structural variation of the duct.

Diagnostic performance of the metagenomic next-generation sequencing in lung biopsy tissues in patients suspected of having a local pulmonary infection.

PURPOSE: This study aims to evaluate the diagnostic application and performance of the metagenomic next-generation sequencing (mNGS) in patients suspected of local pulmonary infection by comparing it to the traditional pathogen detection methods in lung tissue specimens obtained by a computerized tomography-guided biopsy (CT-guided biopsy). METHODS: We retrospectively reviewed patients, admitted to the First Affiliated Hospital of Wenzhou Medical University, China from May 2018 to December 2020, who were suspected of local pulmonary infection. All cases received a CT-guided lung biopsy, tissue samples were sent both for conventional examinations (CE) and mNGS tests. The sensitivity and specificity of the two diagnostic approaches were compared. RESULTS: 106 patients enrolled, 76 patients were diagnosed with a pulmonary infection. Among 49 patients with identified pathogens, CE confirmed pathogenic infections in 32 cases. Mycobacterium spp. and fungi accounted for 37.5% (12/32) and 28.1% (9/32), respectively, with bacteria 34.4% (11/32). The mNGS examination detected extra pathogenic microorganisms in 22 patients that were consistent with the patients' clinical and radiographic pictures. The sensitivity of mNGS was 53.9% vs. 42.1% for the CE, while the specificity was 56.7% versus 96.7%. For detection rate, mNGS was significantly superior to CE in bacterial (96.3% vs. 40.7%, p < 0.05), and mixed infections (100% vs. 50%, p < 0.05), but inferior to CE in fungal (60% vs. 90%, p > 0.05) and Mycobacterium spp. infections (66.7% vs. 100%, p > 0.05) with no significant difference. Among 31 cases diagnosed with lung abscess, the diagnostic performance of the detection rate was 67.7% (21/31) in favour of mNGS compared to 29.0% (9/31) for CE (p < 0.05). Most polymicrobial infections were induced by anaerobic species that coexisted with Streptococcus constellatus. And Klebsiella pneumoniae was the most common isolated monomicrobial infection. CONCLUSIONS: The most commonly detected causative pathogens for local pulmonary infections were bacteria, Mycobacterium spp. and fungi. Compared with the CE, the advantages of mNGS in the pathogens detection lie in the discovery of bacterial and mixed infections, as well as in the detection of lung abscess. Conversely, mNGS is not good enough to be recommendable for the detection of Mycobacterium spp. and fungi.

The effect of gestational diabetes mellitus on fetal right heart growth in late-term pregnancy: A prospective study.

BACKGROUND: Gestational diabetes mellitus (GDM) is a complication of pregnancy strongly associated with an increased risk of structural fetal abnormalities. As the fetal heart grows quickly during the late-term pregnancy period, it is important to understand fetal heart growth before birth. This study explored how GDM affects fetal heart growth by evaluating basic echocardiography indicators during late pregnancy. METHODS: This prospective, longitudinal study included 63 GDM patients (GDM group) and 67 healthy pregnant women (control group). All subjects underwent fetal echocardiography scans at gestational weeks 28-32, 32-36, and 36-40. Twelve echocardiographic indicators were assessed at each observation and analyzed by using a mixed model. RESULTS: The left atrial diameter (LA) and left ventricular end-diastolic diameter (LV) similarly increased from the first to the third observation. The right ventricular end-diastolic diameter (RV) was significantly different between the groups, and a group × time interaction was detected. The tricuspid annular peak systolic velocity (s') increased more rapidly in the GDM than the control group during the first to second observations, and the group × time interaction was significant. The increase in the tricuspid annular plane systolic excursion (TAPSE) of the GDM group was "slow-fast", while that of the control group was "fast-slow", during three observations. After adjusting covariates, the group difference and interaction effect of TAPSE and RV remained significant. CONCLUSIONS: The differences in fetal right heart indicators between the GDM and control groups suggest that GDM may affect the structure and functional growth of the fetal right heart during late-term pregnancy.

Virus Entry Inhibitors: Past, Present, and Future.

The approval of enfuvirtide marked a milestone for the development of virus entry inhibitor-based antiviral therapeutics. Since then, more peptide-, small-molecule-, and protein-based entry inhibitors have been identified and approved for viral diseases. Here we reviewed the development of virus entry inhibitors and the advantages and disadvantages of peptide-, small-molecule-, and protein-based entry inhibitors, herein summarizing the future trend of these antivirals. Virus entry inhibitors take effect outside the host cell, making them good candidates for development as pre- and post-exposure prophylaxis, microbicides, and therapeutics. This chapter, as well as this book, provides more information on the development and modification of peptide-, small-molecule-, and protein-based virus entry inhibitors.