[Advances in clinical studies of chronic cough].

Chronic cough is a common complaint in respiratory specialist clinics, with a significant impact on cough-specific quality of life and psychophysiological health. The diagnosis, treatment and management of chronic cough remains a major challenge. We summarized a series of recent advances from clinical studies in the epidemiology, diagnosis and management of chronic cough over the past year.

Cyclic di-AMP Rescues Porphyromonas gingivalis-Aggravated Atherosclerosis.

Growing evidence demonstrates the relationship between periodontitis and atherosclerotic cardiovascular diseases. The periodontal pathogen Porphyromonas gingivalis (Pg) has been shown to contribute to the progression of atherosclerosis. Cyclic diadenylate monophosphate (c-di-AMP) has been widely studied as an immune adjuvant for tumor immunotherapy, given its ability to activate the stimulator of interferon genes (STING) and regulate trained immunity. This study sought to elucidate the role of c-di-AMP in Pg-associated atherosclerosis. Periodontitis and atherosclerosis mouse models were established by ligature application around maxillary second molars and feeding ApoE knockout mice with a high-fat diet. We found that periodontitis and atherosclerosis were more severe in mice exposed to Pg than mice that underwent ligature placement only, while prophylactic treatment with c-di-AMP activated trained immunity and elicited significant alleviation of alveolar bone resorption, as well as reduced blood lipid levels and atherosclerotic plaque accumulation. After 3 mo of intervention, c-di-AMP limited the elevation of cytokines interleukin (IL)-6, IL-1ß, tumor necrosis factor α, and interferon ß; extracellular matrix remodeling enzymes MMP-2 and MMP-9; and adhesion molecules ICAM-1 and VCAM-1 gene expression. The mechanism underlying Pg-aggravated atherosclerosis may be attributed to changes in microbiota composition in oral and aortic plaques and excess inflammatory response, whereas c-di-AMP could prevent the effects of Pg infection due to its potential ability to activate trained immunity and regulate microecological balance. Our findings suggest a positive role of c-di-AMP in alleviating Pg-aggravated atherosclerosis by regulating the immune response and influencing the local microenvironment.

The Impact of Frailty on COVID-19 Outcomes: A Systematic Review and Meta-analysis of 16 Cohort Studies.

BACKGROUND: Frail patients are increasingly vulnerable to stress, which is mainly manifested by a reduced physiologic reserve in metabolic and immune systems and neuromuscular system. Several studies found a significant association of frailty with COVID-19 severity to support the evidence for the application of frailty assessment. However, there were contradictory results in other studies. Thus we conducted a systematic review and meta-analysis to synthesize the current studies to investigate impact of frailty on COVID-19 outcomes and provide evidence-based decisions in clinical practice. OBJECTIVE: We aimed to synthesize the current studies to investigate impact of frailty on COVID-19 outcomes and provide evidence-based decisions in clinical practice. DESIGN: A systematic review and Meta-analysis of 16 cohort studies. PARTICIPANTS: Patients with COVID-19. METHODS: A systematic retrieving for potential literature was conducted in several public electronic databases, including Medline(OvidSP), EMBASE, Pubmed and Chinese databases(China National Knowledge Infrastructure,Wanfang and Weipu) on August 1, 2020.The literature research was updated on October 26, 2020. Newcastle Ottawa Scale for cohort studies was used for quality assessment. RevMan (Version 5.3) and Stata 14.0 were used to synthesize the pooled effects. RESULTS: According to the predefined inclusion and exclusion criteria, sixteen studies of 4324 patients were included in the final analysis. Frailty was significantly associated with increased risk of all-cause mortality among patients with COVID-19, with pooled adjusted odds ratios of 1.81 (95% confidence intervals:1.48,2.21, I2=87.0%, P<0.001). The result was consistent in stratified analysis to according to age, patient source, definitions of frailty, study quality, and adjustment method. Frailty was significant associated with an increased risk of COVID-19 severity, admission to intensive care unit, application of invasive mechanical ventilation, long-length stay. CONCLUSIONS: In this meta-analysis, we found frailty was significantly associated with an increased risk of clinical adverse events (all- cause mortality, COVID-19 severity, admission to the intensive care unit, application of invasive mechanical ventilation, long-length stay). Given the epidemic of COVID-19 and shortage of medical resources, paying more attention to screening frailty would contribute to disease management and resource allocation among patients with COVID-19.

Sarcopenia as a Risk Factor for Future Hip Fracture: A Meta-Analysis of Prospective Cohort Studies.

OBJECTIVE: Our study aims to determine whether sarcopenia is a predictive factor of future hip fractures. DESIGN: Systematic review and meta-analysis. Set: We searched for potentially suitable articles in PubMed, Cochrane library, Medline and EMBASE from inception to March 2020. The quality of the research was assessed by the Newcastle-Ottawa Scale (NOS). Finally, a meta-analysis was conducted with the Stata software. PARTICIPANTS: Older community-dwelling residents. MEASUREMENTS: Hip fracture due to sarcopenia. RESULTS: We retrieved 2129 studies through our search strategy, and five studies with 23,359 individuals were analyzed in our pooled analyses. Sarcopenia increases the risk of future hip fractures with a pooled hazard ratio (HR) of 1.42 (95% CI: 1.18-1.71, P <0.001, I2 = 37.7%). In addition, in subgroup analyses based on different definitions of sarcopenia, sarcopenia was associated with the risk of future hip fractures with the Asian Working Group for Sarcopenia (AWGS) criteria with a pooled HR of 2.13(95% CI: 1.33-3.43). When subgroup analyses were conducted by sex, sarcopenia was associated with the risk for future hip fractures in females with pooled HRs of 1.69 (95% CI: 1.18-2.43). Sarcopenia was associated with the risk of future hip fractures in the group with a follow-up period of more than 5 years, with a pooled HR of 1.32 (95% CI: 1.08-1.61), and in the group with a follow-up period of less than 5 years, with a pooled HR of 2.13 (95% CI: 1.33-3.43). CONCLUSIONS: Sarcopenia could significantly increase the risk of future hip fracture in old people; thus, it is necessary to prevent hip fractures in individuals with sarcopenia.

Nosocomial infection by Klebsiella pneumoniae among neonates: a molecular epidemiological study.

BACKGROUND: Nosocomial infection by Klebsiella pneumoniae (Kp) and drug resistance of Kp among neonates is a major concern. Hypervirulent K. pneumoniae (hvKp) infections are gradually increasing worldwide. Carbapenem-resistant hvKp infection has brought challenges to clinical treatment. AIM: To evaluate the changes in drug resistance trends of Kp strains in neonatal intensive care unit (NICU) nosocomial infections, to analyse drug resistance genes and virulence genes of carbapenem-resistant K. pneumoniae (CRKP) and to identify whether these CRKP strains are hvKp. METHODS: A total of 80 neonates with Kp nosocomial infections from 2013 to 2018 were retrospectively studied. Drug susceptibility testing was performed on 80 Kp strains, among which the 12 CRKP strains were further studied. FINDINGS: Kp accounted for 26.9% of nosocomial infections in the NICU. CRKP strains accounted for 15.0%. Among the 80 nosocomial infection Kp strains, CRKP strains accounted for 33.3% and 53.3% in 2017 and 2018 respectively. One of the 12 CRKP strains was positive in the drawing test. The 12 CRKP strains were divided into four complete genome sequence types: cgST1 (N = 2), cgST2 (N = 1), cgST3 (N = 1), and cgST4 (N = 8). Among genes that mediated carbapenem resistance, strains of cgST4 carried NDM-5, strains of cgST2 and cgST3 carried NDM-1, and strains of cgST1 carried IMP-4. None of the 12 CRKP strains carried rmpA/rmpA2 (highly related with hvKp). CONCLUSION: Nosocomial infections of CRKP among neonates are becoming common, but no hvKp was found among the CRKP strains in this study.

Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies.

BACKGROUND: The mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, however the localized spatio-temporal effects of the drugs are less well understood. We explore the emergence of spatially preferential drug efficacy resulting from variations in mechanisms of cell-drug interactions. METHODS: 3D spheroids of HeLa-C3 cells were treated with drugs, cisplatin and paclitaxel. This was followed by sectioning and staining of the spheroids to track the spatio-temporal apoptotic effects of the drugs. A mechanistic drug-cell interaction model was developed and simulated to analyse the localized efficacy of these drugs. RESULTS: The outcomes of drug actions on a local cell population was dependant on the interactions between cell repair probability, intracellular drug concentration and cell's mitosis phase. In spheroids treated with cisplatin, drug induced apoptosis is found to be scattered throughout the volume of the spheroids. In contrast, effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis based on the scheduling strategy. CONCLUSIONS: The preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. The model simulations and experimental data show that treatments initiated with paclitaxel are more efficacious due to the cascading of spatial effects of the drugs.

Chewing lice from high-altitude and migrating birds in Yunnan, China, with descriptions of two new species of Guimaraesiella.

In total, 366 birds representing 55 species in 24 families and eight orders, were examined for chewing lice (Phthiraptera: Amblycera, Ischnocera) in two high-altitude localities in Yunnan Province, China. In Ailaoshan, almost all of the birds examined were resident passeriforms, of which 36% were parasitized by chewing lice. In Jinshanyakou, most birds were on migration, and included both passerine and non-passerine birds. Of the passerine birds caught in Jinshanyakou, only one bird (0.7%) was parasitized by chewing lice. The prevalence of Myrsidea and Brueelia-complex lice on birds caught in Ailaoshan was higher than in previous reports. Of the chewing lice identifiable to species level, three represent new records for China: Actornithophilus hoplopteri (Mjöberg, 1910), Maculinirmus ljosalfar Gustafsson & Bush, 2017 and Quadraceps sinensis Timmermann, 1954. In total, 17 new host records are included, of which we describe two as new species in the Brueelia-complex: Guimaraesiella (Cicchinella) ailaoshanensis sp. nov. ex Schoeniparus dubius dubius (Hume, 1874) and G. (C.) montisodalis sp. nov. ex Fulvetta manipurensis tonkinensis Delacour & Jabouille, 1930. This published work has been registered in ZooBank, http://zoobank.org/urn:lsid:zoobank.org:pub:9FC3D8EE-2CED-4DBE-A1DB-471B71260D27.

Evaluation of the effect of nickel clusters on the formation of incipient soot particles from polycyclic aromatic hydrocarbons via ReaxFF molecular dynamics simulations.

In the present study, the ReaxFF reactive molecular dynamics simulation method was applied to investigate the effect of a small nickel cluster (Ni13) on the formation of nascent soot from polycyclic aromatic hydrocarbon (PAH) precursors. A series of NVT simulations was performed for systems of a Ni13 cluster and various PAH monomers, namely, naphthalene, anthracene, pyrene, coronene, ovalene, and circumcoronene, at temperatures from 400 to 2500 K. At low temperatures, the PAHs form soot particles via binding and stacking around nickel clusters. Larger soot particles are formed due to the early initiation of clustering provided by nickel compared to those observed in homogenous PAH systems. At 1200-1600 K, the PAH monomers show a chemisorption tendency onto the nickel surface, which results in incipient soot particles. Chemical nucleation was observed at 2000 K where nickel-assisted dehydrogenation and chemisorption of PAH led to the growth of stable soot particles, which did not occur in the absence of Ni-clusters. At a high temperature (2500 K), nickel significantly accelerates the ring-opening and graphitization of PAH molecules and increases the size of the fullerene-type soot as compared to that of homogenous systems.

[Hospitalization burden of hand, foot and mouth disease in Anhua county of Hunan province, 2013-2016].

Objective: To estimate the serotype and age-specific hospitalization burden associated with hand, foot and mouth disease (HFMD) in Anhua county of Hunan province, between October 2013 and September 2016. Methods: We collected hospitalization records of HFMD patients from 6 virological surveillance hospitals, and reimbursement records through new rural cooperative medical system from 23 township health centers to estimate the age-specific hospitalization burden of HFMD in Anhua. Combined with the results of virological surveillance, the serotype-specific hospitalization burden of HFMD in Anhua, was estimated. Results: During the three years, it was estimated that 3 541 clinical diagnosed HFMD cases, including 3 146 laboratory-confirmed HFMD cases, were hospitalized in Anhua, but only one was diaguosed as being severe. The estimated average hospitalization rate was 723/100 000(95%CI: 699/100 000-747/100 000) for clinical diagnosed HFMD and 642/100 000 (95%CI: 620/100 000-665/100 000) for laboratory-confirmed HFMD between October 2013 and September 2016. The cases caused by Cox A16 (208/100 000) and Cox A6 (202/100 000) had higher hospitalization rates compared with the cases caused by EV71 (130/100 000), Cox A10 (38/100 000) and other enterovirus (64/100 000), and the difference was statistically significant (P<0.001). HFMD-associated hospitalization rates peaked in children aged 1 year (3 845/100 000), and then decreased with age. Compared with the hospitalized HFMD caused by EV71 and Cox A16, Cox A6-associated hospitalizations mainly occurred in younger age groups (P<0.001). Conclusion: Our study revealed a substantial hospitalization burden associated with mild HFMD caused by EV71, Cox A16, Cox A6 and Cox A10, especially in young children, in Anhua.

Tuning the electrical and optical anisotropy of a monolayer black phosphorus magnetic superlattice.

We investigate theoretically the effects of modulated periodic perpendicular magnetic fields on the electronic states and optical absorption spectrum in monolayer black phosphorus (phosphorene). We demonstrate that different phosphorene magnetic superlattice (PMS) orientations can give rise to distinct energy spectra, i.e. tuning the intrinsic electronic anisotropy. Rashba spin-orbit coupling (RSOC) develops a spin-splitting energy dispersion in this phosphorene magnetic superlattice. Anisotropic momentum-dependent carrier distributions along/perpendicular to the magnetic strips are demonstrated. The manipulations of these exotic electronic properties by tuning superlattice geometry, magnetic field and the RSOC term are addressed systematically. Accordingly, we find bright-to-dark transitions in the ground-state electron-hole pair transition rate spectrum and the PMS orientation-dependent anisotropic optical absorption spectrum. This feature offers us a practical way of modulating the electronic anisotropy in phosphorene by magnetic superlattice configurations and detecting this modulation capability by using an optical technique.

SRGN-TGFß2 regulatory loop confers invasion and metastasis in triple-negative breast cancer.

Patients with triple-negative breast cancers (TNBC) are at a high risk for a recurrent or metastatic disease, and the molecular mechanisms associated with this risk are unclear. Proteoglycan serglycin (SRGN) proteins are involved in tumor metastasis, but their role in TNBC has not yet been elucidated. This study investigates the SRGN gene expression and how it regulates TGFß2 and the downstream signaling of TGFß2 in TNBC cells and tissues. Our results show that SRGN mRNA and protein expression levels were significantly higher in TNBC cell lines and tumor tissues than that in non-TNBC cells and tissues. We inhibited SRGN expression and protein secretion using shRNA and we observed this inhibited the invasive motility of TNBC cancer cells in vitro and metastasis of TNBC cancer cells in vivo. SRGN protein treatment increased the expression and secretion of transforming growth factor-ß2 (TGFß2) by activating CD44/CREB1 signaling and promoted epithelial-to-mesenchymal transition in TNBC cells. Moreover, TGFß2 treatment increased the mRNA and protein expression of the SRGN gene by activating Smad3 to target the SRGN relative promoter domain in TNBC cells. Our findings demonstrate that SRGN interacts with TGFß2 which regulates TNBC metastasis via the autocrine and paracrine routes. SRGN could serve as a potential target for development of agents or therapeutics for the TNBC.

Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury.

An inhibitor of sodium glucose co-transporter type 2 (SGLT-2) is recommended in type 2 diabetes mellitus (DM) but its use is still undetermined in tacrolimus (TAC)-induced DM. We evaluated the effect of empagliflozin (Em) on TAC-induced pancreatic islet dysfunction and renal injury in an experimental model of TAC-induced DM and in vitro. TAC induced a twofold increase in SGLT-2 expression, while Em decreased SGLT-2 expression and further increased urinary glucose excretion compared to the TAC group. Em reduced hyperglycemia and increased plasma insulin level, pancreatic islet size, and glucose-stimulated insulin secretion compared to the TAC group. In kidney, Em alleviated TAC-induced renal dysfunction and decreased albumin excretion and histological injury compared with the TAC group. Increased oxidative stress and apoptotic cell death by TAC was remarkably decreased with Em in serum and pancreatic and renal tissues. In in vitro study, TAC decreased cell viability and increased reactive oxygen species (ROS) production in both insulin-secreting beta-cell derived (INS-1) and human kidney-2 (HK-2) cell lines. Addition of Em increased cell viability and decreased ROS production in HK-2 but not in INS-1 cell lines. This suggests that Em is effective in controlling TAC-induced hyperglycemia and has direct protective effect on TAC-induced renal injury.

Dynamics and kinetics of reversible homo-molecular dimerization of polycyclic aromatic hydrocarbons.

Physical dimerization of polycyclic aromatic hydrocarbons (PAHs) has been investigated via molecular dynamics (MD) simulation with the ReaxFF reactive force field that is developed to bridge the gap between the quantum mechanism and classical MD. Dynamics and kinetics of homo-molecular PAH collision under different temperatures, impact parameters, and orientations are studied at an atomic level, which is of great value to understand and model the PAH dimerization. In the collision process, the enhancement factors of homo-molecular dimerizations are quantified and found to be larger at lower temperatures or with smaller PAH instead of size independent. Within the capture radius, the lifetime of the formed PAH dimer decreases as the impact parameter increases. Temperature and PAH characteristic dependent forward and reverse rate constants of homo-molecular PAH dimerization are derived from MD simulations, on the basis of which a reversible model is developed. This model can predict the tendency of PAH dimerization as validated by pyrene dimerization experiments [H. Sabbah et al., J. Phys. Chem. Lett. 1(19), 2962 (2010)]. Results from this study indicate that the physical dimerization cannot be an important source under the typical flame temperatures and PAH concentrations, which implies a more significant role played by the chemical route.

Cip2a promotes cell cycle progression in triple-negative breast cancer cells by regulating the expression and nuclear export of p27Kip1.

Triple-negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets; as a consequence, TNBC exhibits poor clinical outcome. In this study, we showed that cancerous inhibitor of protein phosphatase 2A (Cip2a) represents a promising target in TNBC because Cip2a was highly expressed in TNBC cells and tumor tissues, and its expression showed an inverse correlation with overall survival in patients with TNBC. We found that inhibition of Cip2a in TNBC cells induced cell cycle arrest at the G2/M phase, inhibited cell proliferation and delayed tumor growth in the xenograft model. Moreover, Cip2a markedly decreased the expression and nuclear localization of p27Kip1 and this is critical for the ability of Cip2a to promote TNBC progression. Mechanistically, our studies showed that Cip2a promoted p27Kip1 phosphoration at Ser10 via inhibiting Akt-associated PP2A activity, which seems to relocalize p27Kip1 to the cytoplasm in TNBC cells. On the other hand, Cip2a also recruited c-myc to mediate the transcriptional inhibition of p27Kip1. Notably, we observed negative correlation between Cip2a and p27Kip1 expression in TNBC specimens. In addition, our data showed that Cip2a depletion could sensitize TNBC to PARP inhibition. Collectively, these data suggested that Cip2a effectively promotes TNBC cell cycle progression and tumor growth via regulation of PP2A/c-myc/p27Kip1 signaling, which could serve as a potential therapeutic target for TNBC patients.

Targeted sequencing of maternal plasma for haplotype-based non-invasive prenatal testing of spinal muscular atrophy.

Five pregnant women with a child affected by spinal muscular atrophy (SMA) were recruited between November 2014 and March 2015. Deletion of exons 7 and/or 8 in the SMN1 gene were identified by multiplex ligation-dependent probe amplification (MLPA), the current standard diagnostic test for SMA. Parental and fetal haplotypes of the SMN1 gene were determined in each family from haplotype-based non-invasive testing of blood samples and maternal plasma, respectively. Fetal haplotype was compared with the results of MLPA of fetal DNA obtained from amniotic fluid or chorionic villi. Parental haplotypes were constructed successfully in the five families. Assisted by the information on parental haplotype, non-invasive testing of maternal plasma identified one fetus with homozygous deletion of exons 7 and 8, two fetuses with heterozygous deletion of exons 7 and 8 and two normal fetuses. These results were consistent with the diagnosis by MLPA. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Direct observation of atomic-scale origins of local dissolution in Al-Cu-Mg alloys.

Atomistic chemical inhomogeneities are anticipated to induce dissimilarities in surface potentials, which control corrosion initiation of alloys at the atomic scale. Precise understanding of corrosion is therefore hampered by lack of definite information describing how atomistic heterogeneities regulate the process. Here, using high-angle annular dark-field (HAADF) scanning transmission electron microscope (STEM) and electron energy loss spectroscopy (EELS) techniques, we systematically analyzed the Al20Cu2Mn3 second phase of 2024Al and successfully observed that atomic-scale segregation of Cu at defect sites induced preferential dissolution of the adjacent zones. We define an "atomic-scale galvanic cell", composed of zones rich in Cu and its surrounding matrix. Our findings provide vital information linking atomic-scale microstructure and pitting mechanism, particularly for Al-Cu-Mg alloys. The resolution achieved also enables understanding of dealloying mechanisms and further streamlines our comprehension of the concept of general corrosion.

[Review of numerical simulation study of Stanford type B thoracic aortic dissection].

According to the previous studies, some key indicators such as the hemodynamic parameters (pressure, flow rate, shear stress, etc.) as well as the geometry and the location of tear are closely related to the development of aortic dissection but are hard to measure in vivo. With the help of computational fluid dynamic method, a promising way is just shown to investigate the mechanisms and treatment of aortic dissection from the perspective of hemodynamics by constructing a three-dimensional model to simulate blood flow. This paper presents a systematic review of the development of aortic dissection research and the major research progress of computational fluid dynamics applied to the analysis of aortic dissection.

[Preliminary application of Dx-pH monitoring system in laryngopharyngeal reflux disease].

Objective: To summarize the application and significance of Dx-pH monitoring system in laryngopharyngeal reflux disease. Methods: Fifty-four patients who had symptoms of laryngopharyngeal reflux disease in our department from February to December in 2015 were retrospectively analyzed in this study. All patients were evaluated with reflux symptoms index(RSI), flexible laryngoscope and reflux finding score(RFS), and larygopharygeal Dx-pH monitoring. Results: Among all 54 patients, there were 26 patients whose Ryan score were positive(48.2%). The positive Ryan score mainly emerged when the patients were upright(24/26, 92.3%). Among 22 patients whose symptoms could not alleviate well by 8 weeks proton pump inhibitors treatment, there were 13 patients(59.1%) with positive Ryan scores. The Ryan scores were not in good accordance with RSI and RFS(κ=-0.013). Conclusions: Although the results were not in good accordance with RSI/RFS, Dx-pH monitoring system could prove laryngopharyngeal reflux events in patients with laryngopharyngeal reflux disease and help physicians to diagnose.