Understanding the etiology of mental health problems in postrehabilitation COVID-19 patients:Insights and strategies for effective intervention

In this editorial,we comment on an article by Alhammad et al that was published in a recent issue of the World Journal of Clinical Cases(Manuscript No.:91134).We specifically focus on the mental health problems caused by coronavirus disease 2019(COVID-19),their mechanisms,and targeted rehabilitation strategies.Severe acute respiratory syndrome coronavirus 2,via its spike protein,binds to angiotensin-converting enzyme 2 and other receptors prior to infiltrating diverse cells within the central nervous system,including endothelial cells,neurons,astrocytes,and oligodendrocytes,thereby contributing to the development of mental illnesses.Epidemiological data from 2020 underscored the global upsurge in major depressive and anxiety disorders by 27.6%and 25.6%,respectively,during the pandemic.The commented research show that 30%of post-intensive care unit discharge patients with COVID-19 in the Arabic region exhibited Hospital Anxiety and Depression Scale scores that were indicative of anxiety and depression.While acknowledging psychosocial factors,such as grief and loss,it is crucial to recognize the potential neurological impact of the virus through various mechanisms.Accordingly,interventions that encompass dietary measures,health supplements,and traditional Chinese medicine with neuroprotective properties are necessary.This editorial underscores the urgency to implement comprehensive rehabilitation approaches to address the intricate interplay between COVID-19 and mental well-being.

Human Milk Oligosaccharides Enhance Innate Immunity to Respiratory Syncytial Virus and Influenza <i>in Vitro</i>

Human milk oligosaccharides (HMO) contribute to innate immunity by enhancing growth of beneficial bacteria, epithelial cell maturation and mucosal barrier integrity. They have immunomodulatory effects and can block pathogen binding to host cell surface glycans or receptors. We investigated the effects of 2’-fucosyllactose (2’FL), 6’-sialyllactose (6’SL), 3’-sialyllactose (3’SL) and lacto-N-neoTetraose (LNnT) on human respiratory epithelial cell lines or peripheral blood mononuclear cells (PBMCs) following respiratory viral infectionin vitro. Expression of cytokines and viral load were monitored in infected cells. These biomarkers of innate immunity were selected since viral load and cytokine levels (IP-10, MIP-1α, IL-6, IL-8, TNF-α) have been correlated with disease severity in respiratory syncytial virus (RSV) and influenza (IAV) virus infectionin vivo. 2’FL significantly decreased RSV viral load and cytokines associated with disease severity (IL-6, IL-8, MIP-1α) and inflammation (TNF-α, MCP-1) in airway epithelial cells. LNnT and 6’SL significantly decreased IAV viral load in airway epithelial cells. 6’SL dose-dependently down-regulated IP-10 and TNF-α in RSV infected PBMCs. HMO at or below levels found in breast milk enhance innate immunity to respiratory viruses in vitro and may interact directly with cells to modulate biomarkers of innate immunity.

呼吸道合胞病毒感染断奶鼠右心注射辣椒素可延长呼吸暂停反应

目的:观察呼吸道合胞病毒(RSV)感染是否影响动脉血气及RSV感染后断奶鼠对辣椒素致呼吸暂停反应的影响。方法:采用麻醉下自主呼吸断奶鼠,分别给于鼻腔内滴入RSV病毒或无病毒的培养液(0.7 ml/kg)。在RSV感染后2 d,右心房内注射辣椒素(4、16、64μg/kg)后,观察动脉血气、通气等变化。结果:RSV感染组呼吸频率较对照组显著增加,对动脉血气影响不显著。RSV感染组最长呼吸暂停反应、呼吸暂停次数和呼吸暂停总时间均较对照组有显著增加(P<0.05),死亡率为50%。结论:RSV感染增加了呼吸频率,并强化辣椒素致呼吸暂停反应。

Relationship of Intracellular Free Ca^(2+) Concentration and Calcium-activated Chloride Channels of Pulmonary Artery Smooth Muscle Cells in Rats under Hypoxic Conditions

To investigate the relationship between intracellular free Ca^2＋ concentration （[Ca^2＋ ]i ） and calcium-activated chloride （Clca） channels of pulmonary artery smooth muscle cells （PASMCs） in rats under acute and chronic hypoxic conditions, acute hypoxia-induced contraction was observed in rat pulmonary artery by using routine blood vascular perfusion in vitro. The fluorescence Ca^2＋ indicator Fura-2/AM was used to observe [Ca^2＋ ]i of rat PASMCs under normal and chronic hypoxic condition. The effect of Clca channels on PASMCs proliferation was assessed by MTT assay. The Clca channel blockers niflumic acid （NFA） and indaryloxyacetic acid （IAA-94） exerted inhibitory effects on acute hypoxia-evoked contractions in the pulmonary artery. Under chronic hypoxic condition, [Ca^2＋ ]i was increased. Under normoxic condition, [Ca^2＋ If was （123.634-18.98） nmol/ L, and in hypoxic condition, [Ca^2＋]i wag （281. 754-16.48） nmol/L （P〈0. 01）. Under normoxic condition, [Ca^2＋ ]i showed no significant change and no effect on Clca channels was observed （P〉 0. 05）. Chronic hypoxia increased [Ca^2＋ ]i which opened Clca channels. The NFA and IAA-94 blocked the channels and decreased [Ca^2＋ ]i from （281.75± 16.48） nmot/L to （117.66 ±15.36） nmol/L （P〈0.01）. MTT assay showed that under chronic hypoxic condition NFA and IAA-94 decreased the value of absorbency （A value） from 0. 459±0. 058 to 0. 224±0. 025 （P〈0. 01）. Hypoxia increased [Ca^2＋ ]i which opened Cl~ channels and had a positive-feedback in [Ca^2＋ ]i. This may play an important role in hypoxic pulmonary hypertension. Under chronic hypoxic condition, Clca channel may play a part in the regulation of proliferation of PASMCs.

High-frequency electrical stimulation of cervical vagi reduces airway response to methacholine

AIM: To test whether high-frequency electrical stimulation(HES) of the bilateral cervical vagus nerves reduces the airway responses to methacholine(MCh).METHODS: Guinea pigs were pretreated with saline(Sal, n = 9) or ovalbumin(Ova, n = 10) aerosol for two weeks(5 min/d, 5 d/wk) and subsequently anesthetized, paralyzed, tracheotomized and artificially ventilated. Both total lung resistance(RL) and dynamic pulmonary compliance(Cdyn) were recorded. In addition, the effects of vagal low-frequency electrical stimulation(LES, monophasic, 50 Hz) and HES(monophasic and biphasic, 1 and 2.5 kH z) for about 10 s or 2 min on the responses of RL and Cdyn to MCh aerosol-induced bronchoconstriction were compared in both groups of guinea pigs. In a few guinea pigs, the impact of bivagotomy on the RL responses to MCh was assessed.RESULTS: Before MCh challenge, LES, but not HES, significantly increased RL by about 30%(P < 0.01) and decreased Cdyn by about 20%(P < 0.01) similarly in both groups. MCh aerosol for 2 min elevated RL and diminished Cdyn more in Ova- than Sal-treated animals(RL: 313% ± 52% vs 113% ± 17%, P < 0.01; Cdyn:-56% ± 7% vs-21% ± 3%, P < 0.01). During MCh-induced airway constriction, LES further enhanced, but HES decreased RL and this decrease was greater in Ova-(about 45%) than Sal-treated animals(about 34%, P < 0.01) with little change in cardiovascular activity. On the other hand, LES further reduced whereas HES increased Cdyn more in Ova-(about 20%) than Sal-treated animals(about 13%, P < 0.01). In addition, bivagotomy almost eliminated the RL and Cdyn responses to MCh. CONCLUSION: We conclude that vagal HES is able to alleviate the bronchoconstriction induced by MCh in anesthetized guinea pigs, likely via reversible inhibition/blockade of vagal conduction.

Pharmacotherapy for Adult Patients with Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome （ARDS） is one of the leading death reasons in Intensive Care Unit （ICU）. It is frustrating that there is no pharmacotherapy effective enough to reduce the mortality of ARDS. The most important treatment of ARDS nowadays is supportive treatment, including mechanical ventilation （MV）, fluid management, and sedation. Successful trials of ARDS treatments usually aim to avoid further lung injury of ARDS patients, such as low tidal volume of MV and conservative fluid strategy. These strategies can only maintain the mortality around 40%.

Xuebijing alleviates LPS-induced acute lung injury by downregulating pro-inflammatory cytokine production and inhibiting gasdermin-E-mediated pyroptosis of alveolar epithelial cells

Acute lung injury/acute respiratory distress syndrome(ALI/ARDS)is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response.Regrettably,the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition.Xuebijing(XBJ),a traditional Chinese medicine recognized for its potent anti-inflammatory properties,exhibits promise as a potential therapeutic agent for ALI/ARDS.This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism.To this end,we established an LPS-induced ALI model and treated ALI mice with XBJ.Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%.Moreover,XBJ substantially suppressed the production of TNF-α,IL-6,and IL-1βin the lung tissue.Subsequently,we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses.Furthermore,we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-αproduction.Therefore,this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-αrelease.

Metatranscriptome of human lung microbial communities in a cohort of mechanically ventilated COVID-19 Omicron patients

The Omicron variant of the severe acute respiratory syndrome coronavirus 2(SARS‑CoV‑2)infected a substantial proportion of Chinese population,and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment.We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles,plus viral,bacterial,and fungal content,as well as virulence factors and examined their relationships to 28-day mortality were examined.In addition,the bronchoalveolar lavage fluid(BALF)samples from invasive ventilated hospital/community-acquired pneumonia patients(HAP/CAP)sampled in 2019 were included for comparison.Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages,with no difference in 28-day mortality between them.Compared to HAP/CAP cohort,invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract;and in the COVID-19 non-survivors,we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane,higher abundance of opportunistic pathogens including bacterial Alloprevotella,Caulobacter,Escherichia-Shigella,Ralstonia and fungal Aspergillus sydowii and Penicillium rubens.Correlational analysis further revealed significant associations between host immune responses and microbial compositions,besides synergy within viral,bacterial,and fungal pathogens.Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients,providing the basis for future clinical treatment and reduction of fatality.

Molecular mechanisms and roles of pyroptosis in acute lung injury

Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS),which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli,can result in severe respiratory failures.The morbidity and mortality of patients remain high because the major treatments for ALI/ARDS are mainly supportive due to the lack of effective therapies.Numerous studies have demonstrated that the aggravation of coronavirus disease 2019(COVID-19)leads to severe pneumonia and even ARDS.Pyroptosis,a biological process identified as a type of programed cell death,is mainly triggered by inflammatory caspase activation and is directly meditated by the gasdermin protein family,as well as being associated with the secretion and release of pro-inflammatory cytokines.Clinical and experimental evidence corroborates that pyroptosis of various cells in the lung,such as immune cells and structural cells,may play an important role in the pathogenesis of“cytokine storms”in ALI/ARDS,including those induced by COVID-19.Here,with a focus on ALI/ARDS and COVID-19,we summarized the recent advances in this field and proposed the theory of an inflammatory cascade in pyroptosis to identify new targets and pave the way for new approaches to treat these diseases.

Analysis of Serum Metabolic Profile by Ultra-performance Liquid Chromatography-mass Spectrometry for Biomarkers Discovery： Application in a Pilot Study to Discriminate Patients with Tuberculosis

Background：Tuberculosis （TB） is a chronic wasting inflammatory disease characterized by multisystem involvement,which can cause metabolic derangements in afflicted patients.Metabolic signatures have been exploited in the study of several diseases.However,the serum that is successfully used in TB diagnosis on the basis of metabolic profiling is not by much.Methods：Orthogonal partial least-squares discriminant analysis was capable of distinguishing TB patients from both healthy subjects and patients with conditions other than TB.Therefore,TB-specific metabolic profiling was established.Clusters of potential biomarkers for differentiating TB active from non-TB diseases were identified using Mann-Whitney U-test.Multiple logistic regression analysis of metabolites was calculated to determine the suitable biomarker group that allows the efficient differentiation of patients with TB active from the control subjects.Results：From among 271 participants,12 metabolites were found to contribute to the distinction between the TB active group and the control groups.These metabolites were mainly involved in the metabolic pathways of the following three biomolecules：Fatty acids,amino acids,and lipids.The receiver operating characteristic curves of3D,7D,and 11D-phytanic acid,behenic acid,and threoninyl-γ-glutamate exhibited excellent efficiency with area under the curve （AUC） values of 0.904 （95% confidence interval [CI]：0.863-0.944）,0.93 （95% CI：0.893-0.966）,and 0.964 （95% CI：0.941-0.988）,respectively.The largest and smallest resulting AUCs were 0.964 and 0.720,indicating that these biomarkers may be involved in the disease mechanisms.The combination of lysophosphatidylcholine （18∶0）,behenic acid,threoninyl-γ-glutamate,and presqualene diphosphate was used to represent the most suitable biomarker group for the differentiation of patients with TB active from the control subjects,with an AUC value of 0.991.Conclusion：The metabolic analysis results identified new serum biomarkers that can distinguish TB from non-TB diseases.The metabolomics-based analysis provides specific insights into the biology of TB and may offer new avenues for TB diagnosis.

Long-term Follow-up of 5 Survivors after the First Outbreak of Human Infections with Avian Influenza A（H7N9） Virus in Shanghai, China

At the end of March 2013, the first case of human infection with avian influenza A（H7N9） virus was confirmed in Shanghai. From April to May 2013, 18 patients with avian influenza A（H7N9） virus infection were hospitalized in Shanghai Public Health Clinical Center, and finally, 12 of them survived. The short-term prognosis of these patients had been described previously, but the long-term prognosis remained unclear.

RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells

LIN28B is an evolutionarily conserved RNA-binding protein that regulates mRNA translation and miRNA let-7 maturation in embryonic stem cells and developing tissues.Increasing evidence demonstrates that LIN28B is activated in cancer and serves as a critical oncogene.However,the underlying molecular mechanisms of LIN28B function in tumorigenesis are still largely unknown.Here we report that LIN28B was expressed in over half of the patients with epithelial ovarian cancer who were examined(n=584).Functional experiments demonstrated that LIN28B inhibited ovarian cancer cell apoptosis.Furthermore,we showed that the proapoptotic factor BIM played an essential role in the antiapoptotic function of LIN28B.RNA-IP microarray analysis suggested that LIN28B binds to mRNAs that are associated with the DNA damage pathway,such as AKT2,in ovarian cancer cells.By binding to AKT2 mRNA and enhancing its protein expression,LIN28B regulated FOXO3A protein phosphorylation and decreased the transcriptional level of BIM,which antagonized the antiapoptosis activity of LIN28B.Taken together,these results mechanistically linked LIN28B and the AKT2/FOXO3A/BIM axis to the apoptosis pathway.The findings may have important implications in the diagnosis and therapeutics of ovarian cancer.

Improving the quality of pediatric clinical practice guidelines in China:a long way to go

Children’s health is one of the key health issues receiving increasing attention worldwide and it is also an important measure of a country’s social progress and economic development.[1]However,the development of pediatrics in China also faces many problems,such as the enormous contradiction between medical health resources and medical needs and the unbalanced development in various regions.[2]Although clinical practice guidelines(CPGs)play an important and positive role in solving medical health problems,[3]previous studies suggested that the methodological quality of some CPGs might be inadequate.It is important and necessary to investigate the current status of the pediatric CPGs in China and systematically evaluate their methodological quality.This paper investigated and analyzed the current status of the CPGs for pediatric in China,using the Appraisal of Guidelines for REsearch&Evaluation II(AGREE II)instrument to evaluate the methodological quality of evidence-based guidelines for pediatrics in China.The aim of this study was to appraise the methodological quality of the evidence-based guidelines for pediatrics published in China from 2010 to 2017 using the AGREE II instrument to provide a reference and guidance for guideline developers and users.

A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants

The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants.Here we show that the bivalency of an affinity maturated fully human singledomain antibody(n3113.1-Fc)exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus,and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2(ACE2)humanized mice.The crystal structure of n3113 in complex with the receptor-binding domain(RBD)of SARS-CoV-2,combined with the cryo-EM structures of n3113 and spike ecto-domain,reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2.The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion,expanding our recognition of neutralization by antibodies against SARS-CoV-2.Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2)for n3113.1-Fc with Y58L mutation,demonstrating the potential of n3113.1-Fc(Y58L)as a promising candidate for clinical development to treat COVID-19.