Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

Explosion of research on psychopathology and social media use after COVID-19:A scientometric study

BACKGROUND Despite advances in research on psychopathology and social media use,no comprehensive review has examined published papers on this type of research and considered how it was affected by the coronavirus disease 2019(COVID-19)outbreak.AIM To explore the status of research on psychopathology and social media use before and after the COVID-19 outbreak.METHODS We used Bibliometrix(an R software package)to conduct a scientometric analysis of 4588 relevant studies drawn from the Web of Science Core Collection,PubMed,and Scopus databases.RESULTS Such research output was scarce before COVID-19,but exploded after the pandemic with the publication of a number of high-impact articles.Key authors and institutions,located primarily in developed countries,maintained their core positions,largely uninfluenced by COVID-19;however,research production and collaboration in developing countries increased significantly after COVID-19.Through the analysis of keywords,we identified commonly used methods in this field,together with specific populations,psychopathological conditions,and clinical treatments.Researchers have devoted increasing attention to gender differences in psychopathological states and linked COVID-19 strongly to depression,with depression detection becoming a new trend.Developments in research on psychopathology and social media use are unbalanced and uncoordinated across countries/regions,and more indepth clinical studies should be conducted in the future.CONCLUSION After COVID-19,there was an increased level of concern about mental health issues and a changing emphasis on social media use and the impact of public health emergencies.

Impact of Social Determinants of Health on Self-Perceived Resilience: An Exploratory Study of Two Cohorts of Adults with Congenital Heart Disease

Social determinants of health(SDOH)affect quality of life.We investigated SDOH impacts on self-perceived resilience among people with adult congenital heart disease(ACHD).Secondary analysis of data from two com-plementary studies:a survey study conducted May 2021–June 2022 and a qualitative study conducted June 2020–August 2021.Resilience was assessed through CD-RISC10 score(range 0–40,higher scores reflect greater self-perceived resilience)and interview responses.Sociodemographic and SDOH(education,employment,living situa-tion,monetary stability,financial dependency,area deprivation index)data were collected by healthcare record review and self-report.We used linear regression with robust standard errors to analyze survey data and performed a thematic analysis of interview data.Survey participants(N=127)mean age was 42±14 years;51%were female,87%white.ACHD was moderate(75%)or complex(25%);41%functional class C or D.Resilience(mean 30±7)varied by monetary stability:compared to people with difficulty paying bills,resilience was 15.0 points higher(95%CI:6.9–23.1,p<0.001)for people reporting having enough money and 14.2 points higher(95%CI:5.9–22.4,p=0.001)for those reporting just enough money.Interview participants’(N=25)mean age was 32 years(range 22–44);52%were female,72%white.ACHD was moderate(56%)or complex(44%);76%functional class C or D.Participants discussed factors affecting resilience aligned with each of the major SDOH,prominently,economic stability and healthcare access and quality.Financial stability may be important for supporting self-perceived resi-lience in ACHD.This knowledge can inform the development of resilience interventions for this population.

Respiratory Mechanics, Respiratory Muscle Strength, Control of Ventilation and Gas Exchange in Patients with Autoimmune Liver Disease

Objectives: To assess respiratory elastance and resistive properties in patients with autoimmune liver disorders using the passive relaxation expiration technique and compare findings to a group of patients with non-autoimmune liver disease and control subjects. These findings were then related to control of ventilation and gas exchange. A secondary objective was to assess respiratory muscle strength and gas exchange and their relation to respiratory mechanics. Methods: Measurements included respiratory elastance and resistance using the passive relaxation method. Pulmonary function, gas exchange and control of ventilation were assessed using standard methods. Results: a) Compared to control subjects, Ers in patients with liver disease was on average 50% greater than in controls;b) mean respiratory resistance, expressed as the respiratory constants, K1 and K2 in the Rohrer relationship, Pao/V’ = K1 + K2V’, was not different from control resistance;c) mean maximal inspiratory and maximal expiratory pressures averaged 36% and 55% of their respective control values;d) inspiratory occlusion pressure in 0.1 sec (P0.1) was increased and negatively associated with FVC;and e) increases in P0.1, mean inspiratory flow (Vt/Ti) and presence of respiratory alkalosis confirmed the increase in ventilatory drive. Despite inspiratory muscle weakness in patients, P0.1/Pimax averaged 5-fold higher than in control subjects. Conclusions: Despite inspiratory muscle weakness and a V’E similar to that in normal subjects, central drive is increased in patients with chronic liver disease. The increase in ventilatory drive is related to smaller lung volumes and weakly associated with increase in respiratory elastance. Findings confirm that P0.1 is a reliable measure of central drive and is an approach that can be used in the evaluation of control of ventilation in patients with chronic liver disease.

Endovascular treatment of pulmonary embolism: Selective review of available techniques

Acute pulmonary embolism(PE) is the third most common cause of death in hospitalized patients. The development of sophisticated diagnostic and therapeutic modalities for PE, including endovascular therapy, affords a certain level of complexity to the treatment of patients with this important clinical entity. Furthermore, the lack of level I evidence for the safety and effectiveness of catheter directed therapy brings controversy to a promising treatment approach. In this review paper, we discuss the pathophysiology and clinical presentation of PE, review the medical and surgical treatment of the condition, and describe in detail the tools that are available for the endovascular therapy of PE, including mechanical thrombectomy, suction thrombectomy, and fibrinolytic therapy. We also review the literature available to date on these methods, and describe the function of the Pulmonary Embolism Response Team.

Role of peripheral eosinophilia in acute exacerbation of chronic obstructive pulmonary disease

BACKGROUND Eosinophil counts are a promising guide to systemic steroid administration for chronic obstructive pulmonary disease(COPD).AIM To study the role of peripheral eosinophilia in hospitalized patients with acute exacerbation of COPD(AECOPD).METHODS From January 2014 to May 2017,patients with AECOPD hospitalized in Taipei Tzu Chi Hospital were retrospectively stratified into two groups according to their peripheral eosinophil count:The EOS group(eosinophil count≥2%)and the non-EOS group(eosinophil count<2%).Demographics,comorbidities,laboratory data,steroid use,length of hospital stay,and COPD-related readmissions were compared between the groups.RESULTS A total of 625 patients were recruited,with 176 patients(28.2%)in the EOS group.The EOS group showed a lower prevalence of infection,lower cumulative doses of prednisolone equivalents,shorter length of hospital stay,and higher number of COPD-related readmissions than the non-EOS group.There were significantly linear correlations between eosinophil percentage and number of readmissions and between eosinophil percentage and length of hospital stay P<0.001,and a lower percent-predicted value of forced expiratory volume in one second(FEV1)were associated with shorter time to first COPD-related readmission[adjusted hazard ratio(adj.HR)=1.488,P<0.001;adj.HR=0.985,P<0.001,respectively].CONCLUSION The study findings suggest that the EOS group had the features of a shorter length of hospital stay,and lower doses of systemic steroids,but more frequent readmissions.The EOS group and lower percent-predicted FEV1 values were risk factors for shorter time to first COPD-related readmission.

Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: The role of inflammatory biomarkers

Pneumonia and acute respiratory distress syndrome are common and important causes of respiratory failure in the intensive care unit with a significant impact on morbidity, mortality and health care utilization despite early antimicrobial therapy and lung protective mechanical ventilation. Both clinical entities are characterized by acute pulmonary inflammation in response to direct or indirect lung injury. Adjunct anti-inflammatory treatment with corticosteroids is increasingly used, although the evidence for benefit is limited. The treatment decisions are based on radiographic, clinical and physiological variables without regards to inflammatory state. Current evidence suggests a role of biomarkers for the assessment of severity, and distinguishing sub-phenotypes (hyperinflammatory versus hypo-inflammatory) with important prognostic and therapeutic implications. Although many inflammatory biomarkers have been studied the most common and of interest are C-reactive protein, procalcitonin, and pro-inflammatory cytokines including interleukin 6. While extensively studied as prognostic tools (prognostic enrichment), limited data are available for the role of biomarkers in determining appropriate initiation, timing and dosing of adjunct anti-inflammatory treatment (predictive enrichment)

Indolent lung opacity: Ten years follow-up of pulmonary inflammatory pseudo-tumor

Inflammatory pseudotumor(IPT) has always been considered a diagnostic challenge. Its rarity and resemblance to other more common pathological entities imposes that neither clinical nor radiological characteristics can lead to a definitive diagnosis. The surgical excision of the lesion is the ultimate approach for accurate diagnosis and cure. Moreover the true nature of IPT, its origin as a neoplastic entity or an overreactive inflammatory reaction to an unknown trigger, has been a long debated matter. Surgery remains the treatment of choice. IPT is mostly an indolent disease with minimal morbidity and mortality. Local invasion and metastasis predict a poor prognosis. We hereby present a unique case of pulmonary IPT that was surgically excised, but recurred contralaterally, shortly thereafter. Despite no medical or surgical treatment for ten years, the lesion has remained stable in size, with neither symptoms nor extra-pulmonary manifestations.

Pulmonary sequestration infected with nontuberculous mycobacteria:a report of two cases and literature review

We report two cases of pulmonary sequestration infected with nontuberculous mycobacteria(NTM): Mycobacterium avium and Mycobacterium abscessus.Chest computed tomography showed pneumonic consolidation in the right lower lobe,which received a systemic blood supply from the descending aorta in both patients.Video-assisted thoracoscopic surgeries were successfully performed and pathologica]examinations revealed multiple caseating granulomas.A review of the literature revealed only seven previous case reports of pulmonary sequestration infected with NTM,and no case with Mycobacterium abscessus has been reported.

Pulmonary Arterial Hypertension Medical Management of the Adult Patient with Congenital Heart Disease

Congenital heart disease(CHD)-associated pulmonary arterial hypertension(PAH)includes a heterogeneous patient population that can be characterized by the underlying cardiac malformation.CHD-associated PAH has an estimated prevalence of 5– 10% in adult patients,with an increasing number of patients surviving to adulthood because of advances in the surgical management and the development of pulmonary arterial hypertension(PAH)-targeted pharmacotherapy.Although limited data exist,targeted PAH pharmacotherapy has proven to be benefi cial in patients with CHD-associated PAH,with observed improvement in functional class,increase in exercise capacity,and improvement in quality of life and cardiopulmonary hemodynamics.Additionally,there has been increasing interest in the“treat-to-close”strategy.PAH-targeted pharmacotherapy may be used to optimize cardiopulmonary hemodynamics so as to improve patients’operability in repairing the cardiac defect.Although there have been signifi cant advances in the management of this disease state in the past 2 decades,mortality remains high,and ongoing clinical trials are needed to better understand the treat-to-close strategy.

Effects of intrapulmonary percussive ventilation on airway mucus clearance: A bench model

AIM To determine the ability of intrapulmonary percussive ventilation(IPV) to promote airway clearance in spontaneously breathing patients and those on mechanical ventilation.METHODS An artificial lung was used to simulate a spontaneously breathing patient(Group 1), and was then connected to a mechanical ventilator to simulate a patient on mechanical ventilation(Group 2). An 8.5 mm endotracheal tube(ETT) connected to the test lung, simulated the patient airway. Artificial mucus was instilled into the mid-portion of the ETT. A filter was attached at both ends of the ETT to collect the mucus displaced proximally(mouth-piece filter) and distally(lung filter). The IPV machine was attached to the proximal end of the ETT and was applied for 10-min each to Group 1 and 2. After each experiment, the weight of the various circuit components were determined and compared to their dry weights to calculate the weight of the displaced mucus.RESULTS In Group 1(spontaneously breathing model), 26.8% ± 3.1% of the simulated mucus was displaced proximally, compared to 0% in Group 2(the mechanically ventilated model) with a P-value of < 0.01. In fact, 17% ± 1.5% of the mucus in Group 2 remained in the mid-portion of the ETT where it was initially instilled and 80% ± 4.2% was displaced distally back towards the lung(P < 0.01). There was an overall statistically significant amount of mucusmovement proximally towards the mouth-piece in the spontaneously breathing(SB) patient. There was also an overall statistically significant amount of mucus movement distally back towards the lung in the mechanically ventilated(MV) model. In the mechanically ventilated model, no mucus was observed to move towards the proximal/mouth piece section of the ETT. CONCLUSION This bench model suggests that IPV is associated with displacement of mucus towards the proximal mouthpiece in the SB patient, and distally in the MV model.

A case report of acute pulmonary vein stenosis

Hemoptysis is a common emergency symptom for pulmonary embolism. It's important to differential diagnosis for this symptom. This article reports a case of pulmonary vein stenosis. The patient was transferred to a number of hospitals for medical treatment, but was misdiagnosed for 7 months. This article aims to improve clinician's ability to differentially diagnose hemoptysis, and to deepen the knowledge of pulmonary vein stenosis.

Constant daily hypoxia leads to different degrees of pulmonary hypertension in two different rat strains

Pulmonary diseases associated with diurnal hypoxemia are known to be associated with pulmonary hypertension in some patients. In this study we examined the effects of daily hypoxia (10% oxygen;8h/day for 14 days) on two strains of rats to simulate sleep related hypoxia in pulmonary diseases expecting to find differences in vascular responses, the develop-ment of right ventricular hypertrophy and pulmonary hypertension according to genetic background. In response to daily hypoxia, Sprague Dawley rats developed right ventricular hypertrophy while Brown Norway rats did not. Both strains developed pulmonary hypertension (elevated right ventricular pressure) although the increase was significantly greater in the Sprague Dawley strain. Pulmonary artery (first branch) vasoconstrictive responses to potassium chloride were increased equally in both strains and the subsequent vasodilation with acetylcholine were reduced equally with daily hypoxia in both strains. Taken together, these findings suggest that the genetic makeup of the rats contributed significantly to the development of right ventricular hypertrophy and the degree of pulmonary hypertension. Moreover, this response is not secondary to differences in the intralobar pulmonary vascular reactivity. Genetic background could explain why certain patients do worse with hypoxia inducing pulmonary vascular diseases.

The Benefits of Pulmonary Rehabilitation Program on Post-Tuberculosis Bronchiectasis

Pulmonary rehabilitation has emerged as a recommended standard of care for patients with chronic lung disease. As in chronic obstructive pulmonary disease (COPD), persons with other forms of chronic respiratory disease commonly experience deconditioning and decreased quality of life. The aim of this prospective study is to determine the effect of a 4-week pulmonary rehabilitation program (PRP) on patients diagnosed with post-pulmonary tuberculosis bronchiectasis in the Philippines. The participants were above 18 years of age, diagnosed to have stable Post-Pulmonary tuberculosis bronchiectasis with chest computerized tomography (CT) scan or chest radiograph showing bronchiectatic changes, consented to attend the PRP sessions and be included in the study. The subjects underwent PRP for 4 weeks with a total of 8 sessions and determination of Forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), quality of life determination using the Saint George Respiratory Disease Questionnaire (SGRQ), and exercise endurance using the 6-minute walking test (6 MWT), before and after the PRP. A total of fourteen patients, six males and eight females, aged from 28 - 72 years old, completed the 4-week pulmonary rehabilitation program. There were four ex-smokers and ten non-smokers with concomitant asthma and COPD in some patients. There was significant improvement in the 6-minute walk test and quality of life after 4 weeks of rehabilitation program among the subjects with p value for 6 MWT at p = 0.0001 and p = 0.008 for SGRQ. Conclusion: Pulmonary rehabilitation program led to a significant improvement in exercise capacity and health related quality of life among patients with post-pulmonary tuberculosis bronchiectasis.

A Novel Mutation in FOXF1 Gene Associated with a Delayed Presentation of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, fatal developmental lung disorder of neonates and infants, associated with severe persistent pulmonary hypertension unresponsive to treatment. We reported the case of a term newborn with delayed presentation of ACD/MPV and a novel mutation of FOXF1 gene that received supportive cardiopulmonary treatments, inhaled nitric oxide, oral sildenafil and nebulized iloprost with no clinical improvement. DNA sequence analysis of FOXF1 gene identified a novel heterozygous variant c.257G > C;p.R86P, in exon 1. At autopsy, lung histology showed the characteristic features of ACD/MPV. FOXF1 has been identified as one of the genes responsible for ACD/MPV associated with multiple congenital malformations. This is a report of a novel heterozygous variant c.257G > C;p.R86P, in the first exon of FOXF1, in a patient with delayed presentation of ACD/MPV.

Ineffective esophageal motility is associated with acute rejection after lung transplantation independent of gastroesophageal reflux

BACKGROUND Gastroesophageal reflux is associated with poorer outcomes after lung transplant,likely through recurrent aspiration and allograft injury.Although prior studies have demonstrated a relationship between impedance-pH results and transplant outcomes,the role of esophageal manometry in the assessment of lung transplant patients remains debated,and the impact of esophageal dysmotility on transplant outcomes is unclear.Of particular interest is ineffective esophageal motility(IEM)and its associated impact on esophageal clearance.AIM To assess the relationship between pre-transplant IEM diagnosis and acute rejection after lung transplantation.METHODS This was a retrospective cohort study of lung transplant recipients at a tertiary care center between 2007 and 2018.Patients with pre-transplant anti-reflux surgery were excluded.Manometric and reflux diagnoses were recorded from pre-transplant esophageal function testing.Time-to-event analysis using Cox proportional hazards model was applied to evaluate outcome of first episode of acute cellular rejection,defined histologically per International Society of Heart and Lung Transplantation guidelines.Subjects not meeting this endpoint were censored at time of post-transplant anti-reflux surgery,last clinic visit,or death.Fisher’s exact test for binary variables and student’s t-test for continuous variables were performed to assess for differences between groups.RESULTS Of 184 subjects(54%men,mean age:58,follow-up:443 person-years)met criteria for inclusion.Interstitial pulmonary fibrosis represented the predominant pulmonary diagnosis(41%).During the follow-up period,60 subjects(33.5%)developed acute rejection.The all-cause mortality was 16.3%.Time-to-event univariate analyses demonstrated significant association between IEM and acute rejection[hazard ratio(HR):1.984,95%CI:1.03-3.30,P=0.04],confirmed on Kaplan-Meier curve.On multivariable analysis,IEM remained independently associated with acute rejection,even after controlling for potential confounders such as the presence of acid and nonacid reflux(HR:2.20,95%CI:1.18-4.11,P=0.01).Nonacid reflux was also independently associated with acute rejection on both univariate(HR:2.16,95%CI:1.26-3.72,P=0.005)and multivariable analyses(HR:2.10,95%CI:1.21-3.64,P=0.009),adjusting for the presence of IEM.CONCLUSION Pre-transplant IEM was associated with acute rejection after transplantation,even after controlling for acid and nonacid reflux.Esophageal motility testing may be considered in lung transplant to predict outcomes.

Pre-Lung transplant reflux testing demonstrates high prevalence of gastroesophageal reflux in cystic fibrosis and reduces chronic rejection risk

BACKGROUND Gastroesophageal reflux(GER)has been associated with poor outcomes after lung transplantation for chronic lung disease,including increased risk of chronic rejection.GER is common in cystic fibrosis(CF),but factors influencing the likelihood of pre-transplant pH testing,and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown.AIM To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF.METHODS This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant.Patients with pretransplant anti-reflux surgery were excluded.Baseline characteristics(age at transplantation,gender,race,body mass index),self-reported GER symptoms prior to transplantation,and pre-transplant cardiopulmonary testing results,were recorded.Reflux testing consisted of either 24-h pH-or combined multichannel intraluminal impedance and pH monitoring.Post-transplant care included a standard immunosuppressive regimen,and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients.The primary outcome of chronic lung allograft dysfunction(CLAD)was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria.Statistical analysis was performed with Fisher’s exact test to assess differences between cohorts,and time-to-event Cox proportional hazards modeling.RESULTS After applying inclusion and exclusion criteria,a total of 60 patients were included in the study.Among all CF patients,41(68.3%)completed reflux monitoring as part of pre-lung transplant evaluation.Objective evidence of pathologic reflux,defined as acid exposure time>4%,was found in 24 subjects,representing 58%of the tested group.CF patients with pre-transplant reflux testing were older(35.8 vs 30.1 years,P=0.01)and more commonly reported typical esophageal reflux symptoms(53.7%vs 26.3%,P=0.06)compared to those without reflux testing.Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing.Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses(68%vs 85%,P=0.003).There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not,after controlling for confounders(Cox Hazard Ratio 0.26;95%CI:0.08-0.92).CONCLUSION Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD.Systematic reflux testing may enhance outcomes in this patient population.

Analysis of Serum Antibody Level after COVID-19 Vaccine and Side Effects after Vaccine

Background: COVID-19 has caused a large number of deaths, in the elderly. In this situation, vaccines have been considered the main strategy to combat COVID-19 and were developed worldwide in 2020. One problem with COVID-19 vaccination is side effects after vaccination. In this report, we identify the relationship between side effects and elevation of antibodies as determined by monitoring several kinds of antibodies against COVID-19. Objective: We investigated whether the antibody level changed depending on side effects after COVID-19 vaccination. Methods: Healthy volunteers, who received two vaccinations between 10 March and 7 May 2021, were collected for this study. Information including age, gender, smoking history, medical history including allergies and side reactions after vaccination was obtained by questionnaire. Serum levels of antibodies of IgG and IgM against each S1, SP, and NP antigens of COVID-19 were evaluated frequently for 3 - 4 months after the first vaccination. Result: Ten employees working at Iwate Medical University were evaluated in this study. Side effects were observed in 7 of 10 patients, and grade 2 side effects in all 3 patients with a history of allergic disease. Serum S1 and SP IgG were elevated sufficiently in all patients. In all patients, IgG antibody titers fell below the cutoff point in approximately 3 months. No cases had elevated NP antibodies. SP IgM was elevated in three cases;all three cases with elevated IgM had allergic disease and the degree of side effects was relatively higher. Subjects with long-lasting elevated SPIgM were observed. Conclusion: S1 IgG and SP IgG exceeded the cutoff in all subjects after vaccination but decreased below the cutoff in all subjects within 4 months, regardless of side effects or allergic history. On the other hand, elevated SPIgM was suspected to be related to side effects and history of allergies, and cases with persistent elevation of SPIgM were observed.

DNA of neutrophil extracellular traps promote NF-κBdependent autoimmunity via cGAS/TLR9 in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease(COPD)is characterised by persistent airway inflammation even after cigarette smoking cessation.Neutrophil extracellular traps(NETs)have been implicated in COPD severity and acute airway inflammation induced by short-term cigarette smoke(CS).However,whether and how NETs contribute to sustained airway inflammation in COPD remain unclear.This study aimed to elucidate the immunoregulatory mechanism of NETs in COPD,employing human neutrophils,airway epithelial cells(AECs),dendritic cells(DCs),and a long-term CS-induced COPD mouse model,alongside cyclic guanosine monophosphate-adenosine monophosphate synthase and toll-like receptor 9 knockout mice(cGAS-^(−/−)TLR9^(−/−));Additionally,bronchoalveolar lavage fluid(BALF)of COPD patients was examined.Neutrophils from COPD patients released greater cigarette smoke extract(CSE)-induced NETs(CSE-NETs)due to mitochondrial respiratory chain dysfunction.These CSE-NETs,containing oxidatively-damaged DNA(NETs-DNA),promoted AECs proliferation,nuclear factor kappa B(NF-κB)activation,NF-κB-dependent cytokines and type-I interferons production,and DC maturation,which were ameliorated/reversed by silencing/inhibition of cGAS/TLR9.In the COPD mouse model,blocking NETs-DNA-sensing via cGAS^(−/−)and TLR9^(−/−)mice,inhibiting NETosis using mitoTEMPO,and degrading NETs-DNA with DNase-I,respectively,reduced NETs infiltrations,airway inflammation,NF-κB activation and NF-κBdependent cytokines,but not type-I interferons due to IFN-α/βreceptor degradation.Elevated NETs components(myeloperoxidase and neutrophil elastase activity)in BALF of COPD smokers correlated with disease severity and NF-κB-dependent cytokine levels,but not type-I interferon levels.In conclusion,NETs-DNA promotes NF-κB-dependent autoimmunity via cGAS/TLR9 in long-term CS exposure-induced COPD.Therefore,targeting NETs-DNA and cGAS/TLR9 emerges as a potential strategy to alleviate persistent airway inflammation in COPD.

Bronchoalveolar lavage fluid metagenomic next-generation sequencing assay for identifying pathogens in lung cancer patients

Background:For patients with lung cancer,timely identification of new lung lesions as infectious or non-infectious,and accurate identification of pathogens is very important in improving OS of patients.As a new auxiliary examination,metagenomic next-generation sequencing(mNGS)is believed to be more accurate in diagnosing infectious diseases in patients without underlying diseases,compared with conventional microbial tests(CMTs).We designed this study tofind out whether mNGS has better performance in distinguishing infectious and non-infectious diseases in lung cancer patients using bronchoalveolar lavagefluid(BALF).Materials and Methods:This study was a real-world retrospective review based on electronic medical records of lung cancer patients with bronchoalveolar lavage(BAL)and BALF commercial mNGS testing as part of clinical care from 1 April 2019 through 30 April 2022 at The First Affiliated Hospital of Sun Yat-sen University.164 patients were included in this study.Patients were categorized into the pulmonary non-infectious disease(PNID)group(n=64)and the pulmonary infectious disease(PID)group(n=100)groups based onfinal diagnoses.Results:BALF mNGS increased the sensitivity rate by 60%compared to CMTs(81%vs.21%,p<0.05),whereas there was no significant difference in specificity(75%vs.98.4%,p>0.1).Among the patients with PID,bacteria were the most common cause of infection.Fungal infections occurred in 32%of patients,and Pneumocystis Yersini was most common.Patients with Tyrosine kinase inhibitors(TKIs)therapy possess longer overall survival(OS)than other anti-cancer agents,the difference between TKIs and immuno-checkpoint inhibitors(ICIs)was insignificant(median OS TKIs vs.ICIs vs.Anti-angiogenic vs.Chemo vs.Radiotherapy=76 vs.84 vs.61 vs.58 vs.60).Conclusions:our study indicates that BALF mNGS can add value by improving overall sensitivity in lung cancer patients with potential pulmonary infection,and was outstanding in identifying Pneumocystis infection.It could be able to help physicians adjust the follow-up treatment to avoid the abuse of antibiotics.