Mycobacterium bovis BCG Given at Birth Followed by Inactivated Respiratory Syncytial Virus Vaccine Prevents Vaccine-Enhanced Disease by Promoting Trained Macrophages and Resident Memory T Cells.

Respiratory syncytial virus (RSV) infects more than 60% of infants in their first year of life. Since an experimental formalin-inactivated (FI) RSV vaccine tested in the 1960s caused enhanced respiratory disease (ERD), few attempts have been made to vaccinate infants. ERD is characterized by Th2-biased responses, lung inflammation, and poor protective immune memory. Innate immune memory displays an increased nonspecific effector function upon restimulation, a process called trained immunity, or a repressed effector function upon restimulation, a process called tolerance, which participates in host defense and inflammatory disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) given at birth can induce trained immunity as well as heterologous Th1 responses. We speculate that BCG given at birth followed by FI-RSV may alleviate ERD and enhance protection through promoting trained immunity and balanced Th immune memory. Neonatal mice were given BCG at birth and then vaccinated with FI-RSV+Al(OH)3. BCG/FI-RSV+Al(OH)3 induced trained macrophages, tissue-resident memory T cells (TRM), and specific cytotoxic T lymphocytes (CTL) in lungs and inhibited Th2 and Th17 cell immune memory, all of which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented the innate tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. Therefore, BCG given at birth to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants. IMPORTANCE RSV is the leading cause of severe lower respiratory tract infection of infants. ERD, characterized by Th2-biased responses, inflammation, and poor immune memory, has been an obstacle to the development of safe and effective killed RSV vaccines. Innate immune memory participates in host defense and inflammatory disease. BCG given at birth can induce trained immunity as well as heterologous Th1 responses. Our results showed that BCG/FI-RSV+Al(OH)3 induced trained macrophages, TRM, specific CTL, and balanced Th cell immune memory, which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. BCG at birth as an adjuvant to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants.

Extracorporeal Membrane Oxygenation for Acute Lung Injury in Idiopathic Inflammatory Myopathies-A Potential Lifesaving Intervention.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) can present with acute IIM-related lung injury and respiratory failure, leading to a high mortality risk in intensive care units (ICU). Extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome can be lifesaving. We aimed to report a case series of IIM patients that received ECMO. METHODS: Patients with IIM from tertiary care centers in Belgium, Canada, Denmark, United States, and Sweden who underwent ECMO were reviewed to describe clinical characteristics, disease outcomes and hospitalization course. Clinical characteristics at admission and during ICU stay including ECMO complications and mortality causes were summarized. RESULTS: The study included 22 patients (50% female, mean±SD age at admission 47 ± 12 years) with anti-MDA5 positive dermatomyositis (68%), anti-synthetase syndrome (14%), polymyositis (9%), overlap myositis (5%) and non-MDA5 dermatomyositis (5%). Patients had low comorbidity scores and 46% had received immunosuppression before their ICU admission. Eight (36%) patients died in the ICU, six (27%) were bridged to recovery and eight (36%) were bridged to transplant. When comparing patients bridged to recovery and those who died in the ICU, those who died were older (p= 0.03) and had higher median Charlson comorbidity index scores (p= 0.05). Both groups had similar frequencies of ECMO-related complications (33% vs 50%, p= 0.94). CONCLUSION: In the patients exposed to ECMO in this case series, 14 were successfully bridged to recovery or transplant, while 8 died in the ICU. Large studies are needed to collect data on clinical outcomes in patients with IIM-ILD exposed to ECMO to identify the best candidates for the intervention.

Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality and immunosuppression response. METHODS: Patients with CTD-ILD had high-resolution chest computed tomography (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern (usual interstitial pneumonia [UIP]; non-specific interstitial pneumonia [NSIP]; organizing pneumonia [OP]; fibrotic hypersensitivity pneumonitis [fHP]; and other). Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. RESULTS: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and OP (HR 0.18, 95%CI 0.05, 0.57), but higher in fHP (HR 1.58, 95%CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95%CI 1.4, 2.8), with no change for UIP or fHP. CONCLUSION: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

Specificity protein 1/3 regulate T-cell acute lymphoblastic leukemia cell proliferation and apoptosis through ß-catenin by acting as targets of miR-495-3p.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic heterogeneous disease. This study explored the mechanism of specificity protein 1/3 (Sp1/3) in T-ALL cells through ß-catenin by acting as targets of miR-495-3p. Expression levels of miR-495-3p, Sp1, Sp3, and ß-catenin in the serum from T-ALL children patients, healthy controls, and the T-ALL cell lines were measured. The cell proliferation ability and apoptosis rate were detected. Levels of proliferation-related proteins proliferating cell nuclear antigen (PCNA)/cyclinD1 and apoptosis-related proteins B-cell lymphoma-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) were determined. The binding of Sp1/3 and ß-catenin promoter and the targeted relationship between miR-495-3p with Sp1/3 were analyzed. Sp1/3 were upregulated in CD4+ T-cells in T-ALL and were linked with leukocyte count and risk classification. Sp1/3 interference prevented proliferation and promoted apoptosis in T-ALL cells. Sp1/3 transcription factors activated ß-catenin expression. Sp1/3 enhanced T-ALL cell proliferation by facilitating ß-catenin expression. miR-495-3p targeted and repressed Sp1/3 expressions. miR-495-3p overexpression inhibited T-ALL cell proliferation and promoted apoptosis. Conjointly, Sp1/3, as targets of miR-495-3p limit apoptosis and promote proliferation in T-ALL cells by promoting ß-catenin expression.

The loss of function GBA1 c.231C > G mutation associated with Parkinson disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by bradykinesia, rigidity, and tremor. However, familial PD caused by single-gene mutations remain relatively rare. Herein, we described a Chinese family affected by PD, which associated with a missense heterozygous glucocerebrosidase 1 (GBA1) mutation (c.231C > G). Clinical data on the proband and her family members were collected. Brain MRI showed no difference between affected and unaffected family members. Whole-exome sequencing (WES) was performed to identify the pathogenic mutation. WES revealed that the proband carried a missense mutation (c.231C > G) in GBA1 gene, which was considered to be associated with PD in this family. Sanger sequencing and co-segregation analyses were used to validate the mutation. Bioinformatics analysis indicated that the mutation was predicted to be damaging. In vitro functional analyses were performed to investigated the mutant gene. A decrease in mRNA and protein expression was observed in HEK293T cells transfected with mutant plasmids. The GBA1 c.231C > G mutation caused a decreased GBA1 concentration and enzyme activity. In conclusion, a loss of function mutation (c.231C > G) in GBA1 was identified in a Chinese PD family and was confirmed to be pathogenic through functional studies. This study help the family members understand the disease progression and provide a new example for studying the pathogenesis of GBA1-associated Parkinson disease.

MNDR v3.0: mammal ncRNA-disease repository with increased coverage and annotation.

Many studies have indicated that non-coding RNA (ncRNA) dysfunction is closely related to numerous diseases. Recently, accumulated ncRNA-disease associations have made related databases insufficient to meet the demands of biomedical research. The constant updating of ncRNA-disease resources has become essential. Here, we have updated the mammal ncRNA-disease repository (MNDR, http://www.rna-society.org/mndr/) to version 3.0, containing more than one million entries, four-fold increment in data compared to the previous version. Experimental and predicted circRNA-disease associations have been integrated, increasing the number of categories of ncRNAs to five, and the number of mammalian species to 11. Moreover, ncRNA-disease related drug annotations and associations, as well as ncRNA subcellular localizations and interactions, were added. In addition, three ncRNA-disease (miRNA/lncRNA/circRNA) prediction tools were provided, and the website was also optimized, making it more practical and user-friendly. In summary, MNDR v3.0 will be a valuable resource for the investigation of disease mechanisms and clinical treatment strategies.

Fine particulate matter components and interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Exposure to ambient fine particulate matter with an aerodynamic diameter <2.5 µg·m-3 (PM2.5) is a risk factor for pulmonary and systemic autoimmune diseases; however, evidence on which PM2.5 chemical components are more harmful is still scant. Our goal is to investigate potential associations between major PM2.5 components and interstitial lung disease (ILD) onset in rheumatoid arthritis (RA). METHODS: New-onset RA subjects identified from a US healthcare insurance database (MarketScan) were followed for new onset of RA-associated ILD (RA-ILD) from 2011 to 2018. Annual concentrations of ambient PM2.5 chemical components (i.e. sulfate, nitrate, ammonium, organic matter, black carbon, mineral dust and sea salt) were estimated by combining satellite retrievals with chemical transport modelling and refined by geographically weighted regression. Exposures from 2006 up to 1 year before ILD onset or end of study were assigned to subjects based on their core-based statistical area or metropolitan division codes. A novel time-to-event quantile-based g (generalised)-computation approach was used to estimate potential associations between RA-ILD onset and the exposure mixture of all seven PM2.5 chemical components adjusting for age, sex and prior chronic obstructive pulmonary disease (as a proxy for smoking). RESULTS: We followed 280 516 new-onset RA patients and detected 2194 RA-ILD cases across 1 394 385 person-years. The adjusted hazard ratio for RA-ILD onset was 1.54 (95% CI 1.47-1.63) per every decile increase in all seven exposures. Ammonium, mineral dust and black carbon contributed more to ILD risk than the other PM2.5 components. CONCLUSION: Exposure to components of PM2.5, particularly ammonium, increases ILD risk in RA.

Serologic phenotypes distinguish systemic lupus erythematosus patients developing interstitial lung disease and/or myositis.

OBJECTIVES: To determine if serologic phenotypes could be identified in systemic lupus erythematosus patients developing interstitial lung disease (ILD) and/or myositis. METHODS: Adult SLE patients (without myositis/ILD at baseline) had annual assessments and serum sampling between 2000 and 2017. New-onset ILD was identified using the SDI pulmonary fibrosis item. New-onset myositis was identified using the SLICC Damage Index muscle atrophy/weakness item, the SLEDAI-2K item for myositis, and annual creatinine kinase testing. Chart review confirmed ILD/myositis cases and randomly sampled SLE patients from baseline formed our sub-cohort (N = 72). Cases and sub-cohort were compared regarding myositis-related biomarkers at baseline and at a randomly selected follow-up between baseline and end of observation (date of ILD/myositis diagnosis or Dec. 31, 2017). Descriptive analyses and hazards ratios (HRs) were generated for ILD/myositis incidence, focusing on baseline serology and adjusting for sex, race/ethnicity, age at SLE diagnosis, and SLE duration. RESULTS: Fourteen SLE patients developed ILD (N = 9), myositis (N = 3), and/or both (N = 2). Thirteen of those (92.9%) developing ILD/myositis had at least one biomarker at baseline, versus 47 (65.3%) SLE patients who never developed myositis/ILD. The most common biomarkers in myositis/ILD were KL-6, anti-Ro52, and anti-Ku. Baseline biomarkers tended to remain positive in follow-up. In multivariate Cox regressions, SLE patients had higher risk of developing myositis/ILD with elevated baseline KL-6 (adjusted hazard ratio 3.66; 95% confidence interval 1.01, 13.3). When updating biomarkers over time, we also saw correlations between anti-Smith and ILD/myositis. CONCLUSIONS: Baseline myositis-related biomarkers were highly associated with ILD/myositis incidence. This is the first identification of biomarker phenotypes with ILD/myositis risk in SLE.

Association between chronic obstructive pulmonary disease, smoking, and interstitial lung disease onset in rheumatoid arthritis.

OBJECTIVES: In rheumatoid arthritis (RA), respiratory manifestations include chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). We assessed whether baseline COPD and smoking were associated with RA-ILD onset. METHODS: We identified new-onset ILD in incident RA subjects within the MarketScan Commercial Claims database, using physician and/or hospitalisation diagnostic codes. Smoking data (current, past, never) were available for a subset via a health questionnaire. Kaplan-Meier analyses assessed time to ILD onset, stratified by prior COPD and smoking. Multivariate Cox regression models were adjusted for age, sex, and (in the subset) smoking. Sensitivity analyses adjusted for past RA drugs. RESULTS: Among 373,940 new RA subjects, 6343 (1.7%) developed ILD (8.1 events per 1000 person-year, 95% CI 7.9, 8.3). ILD was more common among subjects with baseline COPD. Adjusting for age and sex, the hazard ratio (HR) between baseline COPD and incident ILD was 2.15, 95% CI 1.93, 2.39. We could not establish a clear relationship between current smoking and ILD; in the subset with smoking data, the HR point estimate for COPD was similar but the 95% CI was wider (due to fewer subjects) and included the null value. Adjusting for baseline RA drugs did not change results. CONCLUSIONS: Pre-existing COPD in incident RA subjects was associated with higher risk of future ILD. While a trend persisted after adjusting for smoking, we were limited by reduced sample size. Our study highlights the importance of ongoing assessments of potentially complicated relationships between smoking, COPD, and other factors in RA-associated ILD.

Clinical relevance of rheumatoid factor and anti-citrullinated peptides in fibrotic interstitial lung disease.

BACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is a frequent cause of interstitial lung disease (ILD); however, the impact of rheumatoid factor and anti-citrullinated peptide antibody seropositivity in ILD without connective tissue disease (CTD) is unclear. We examined the association of seropositivity with ILD progression, mortality and response to immunosuppression in non-CTD ILD. METHODS: A total of 1570 non-CTD patients (with idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, interstitial pneumonia with autoimmune features or unclassifiable ILD) and 181 RA-ILD patients were included from a prospective registry. Longitudinal forced vital capacity (FVC), transplant-free survival and incidence of progressive fibrosing-ILD (PF-ILD) were compared between seronegative non-CTD ILD (reference group), seropositive non-CTD ILD and RA-ILD using linear mixed-effect and Cox proportional hazards models adjusted for age, sex, smoking pack-years and baseline FVC. Interaction between seropositivity and immunosuppression on FVC decline was assessed in patients with ≥6 months of follow-up before and after the treatment. RESULTS: Two hundred and seventeen (13.8%) patients with seropositive non-CTD ILD had similar rates of FVC decline and transplant-free survival compared to seronegative non-CTD ILD, but more frequently met the criteria for PF-ILD (hazard ratio [HR] = 1.35, p = 0.004). RA-ILD had slower FVC decline (p = 0.03), less PF-ILD (HR = 0.75, p = 0.03) and lower likelihood of lung transplant or death (HR = 0.66, p = 0.01) compared to seronegative non-CTD ILD. No interaction was found between seropositivity and treatment on FVC decline in non-CTD ILD. CONCLUSION: Seropositivity in non-CTD ILD was not associated with improved outcomes or treatment response, highlighting the importance of other disease features in determining prognosis and predicting response to immunosuppression.

Myositis in systemic lupus erythematosus.

OBJECTIVES: Myositis is an infrequent feature of SLE and may often be overlooked. We aimed to estimate the incidence of myositis in SLE, and to determine demographic and clinical factors associated with it. METHODS: Within our lupus cohort, we identified potential myositis cases using the SLICC Damage Index for muscle atrophy or weakness, the SLEDAI-2K item for myositis, and annually measured serum creatinine kinase. Cases were confirmed through chart review. We performed descriptive analyses of prevalent myositis cases as of January 2000. From that point onward, we studies patients without myositis to determine risk of incident myositis, using cohort analyses adjusted for demographic variables (age, sex, race/ethnicity). RESULTS: As of January 2000, there were 5 prevalent myositis cases in our SLE cohort. Among 560 SLE patients with a study visit from January 2000 onward, with no history of myositis at baseline, 5 new cases (4 females, 1 male) were identified over an average follow-up of 8.5 years (incidence 1.05 cases per 1000 person-years). There was a higher proportion of Caucasians in the non-myositis group versus myositis group, with a trend for fewer females in the myositis cases. Arthritis, Raynaud's phenomenon, and anti-Smith antibodies were common pre-existing features, occurring in all incident myositis cases. In Cox regression analyses adjusting for age, race/ethnicity and sex, non-Caucasian patients had a markedly increased risk of developing myositis. CONCLUSION: We found a low incidence of myositis in our SLE cohort. A cluster of variables, particularly non-Caucasian race/ethnicity, arthritis, Raynaud's phenomenon, and anti-Smith antibodies were associated with risk of developing myositis in SLE. These variables may aid clinicians in identifying SLE patients at highest risk for this important complication.

Changes in skin score in early diffuse cutaneous systemic sclerosis are associated with changes in global disease severity.

OBJECTIVE: To determine whether skin score changes are associated with changes in overall disease severity, function and quality of life in early dcSSc patients. METHODS: A total of 154 and 128 dcSSc patients from the Canadian Scleroderma Research Group database with 1 and 2 year follow-up and a disease duration ⩽5 years without end-stage organ damage and/or significant comorbidity at the initial visit were included. Skin was assessed using the modified Rodnan skin score (mRSS) and disease severity by the summed Medsger disease severity score (DSS) (without skin domain), physician and patient global assessments, function [HAQ disability index (HAQ-DI)] and quality of life [36-item Short Form Health Survey (SF-36) physical component summary (PCS)]. Analyses were repeated in patients with a disease duration ⩽3 years. RESULTS: At 2 years, 64 (50%) patients had improved skin (mRSS decrease of ⩾5 points and/or ⩾25%). Skin improvers had improved summed DSS (P = 0.002); better physician global assessments of disease activity, severity and damage (all P ⩽ 0.003); better HAQ-DI (P = 0.001) and SF-36 PCS (P = 0.005). Changes in the mRSS were positively correlated with changes in summed DSS (P = 0.006) and other disease outcomes. In the 26 (20.3%) patients with worsened skin (mRSS increase of ⩾5 points and/or ⩾25%), the summed DSS and physician global assessments were worse (P = 0.01 and P ⩽ 0.009, respectively). In the subgroup with a disease duration ⩽3 years, similar associations were found. CONCLUSION: At 1 and 2 years, overall disease improvement parallels skin improvement in early dcSSc. This is important for prognosis and reflects the value of mRSS as an outcome measure in trials with these patients.

Skin improvement is a surrogate for favourable changes in other organ systems in early diffuse cutaneous systemic sclerosis.

OBJECTIVES: Skin improvement in diffuse cutaneous SSc (dcSSc), measured with modified Rodnan skin score (mRSS), is frequently used as a primary outcome in clinical trials, but it is uncertain whether mRSS changes reflect changes in other organ systems. This aim of this study was to explore if skin changes in early dcSSc over 1 and 2 years are associated with changes in severity of other organ involvement. METHODS: Canadian Scleroderma Research Group database patients with dcSSc, disease duration of ≤5 years, no evidence of initial end-stage organ damage and/or significant comorbidity who had 1 year (n = 154) and 2 years (n = 128) of follow-up data were included. mRSS changes of 25% and/or ≥5 points were considered significant. Organ involvement was assessed by Medsger Disease Severity Score and Canadian Scleroderma Research Group definitions using bivariate, chi-square, ANOVA, adjusted regression and longitudinal mixed effect model analyses. RESULTS: Improvement in mRSS was found in 41% of patients at 1 year and in 50% at 2 years. Improved patients showed less forced vital capacity decline (P = 0.012) and less frequent new cardiac involvement (P = 0.02) over 1 year, as well as better lung (by both Disease Severity Score, P = 0.006, and Δforced vital capacity%, P = 0.026), peripheral vascular (P = 0.006) and joint/tendon (P = 0.002) involvement over 2 years. mRSS worsening was consistently linked to less favourable lung outcomes at both 1- and 2-year follow-up visits, and more severe gastrointestinal disease at 2 years. CONCLUSION: Changes in lung function in early dcSSc closely parallel skin changes. mRSS improvement reflects better prognosis for visceral disease and may be a reliable outcome measure in clinical trials.

Inhibitory effect of circulating fibrocytes on injury repair in acute lung injury/acute respiratory distress syndrome mice model.

The study was aimed to explore the functions of circulating fibrocytes (CFs) on injury repair in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) mice model and its clinical value as a biomarker for ALI/ARDS. ALI/ARDS mice model was established by intratracheal instillation of lipopolysaccharide (LPS). Mononuclear cells were isolated from peripheral blood of ALI/ARDS model and flow cytometry was used to measure CFs defined as cells positive for CD45 and collagen-1. Histological changes of lung tissues were evaluated by H&E staining and Masson's trichrome staining. The correlations of CFs counts with damnification of lung tissue and the severity of pulmonary fibrosis were evaluated by Pearson correlation analyses. Western blot was used to detect the protein expression of collagen-1. ELISA was applied to determine cytokine CXCL12 concentration. Clinical relevance between CFs and ALI/ARDS was investigated. The greater number of CFs in the ALI/ARDS group implied higher degree of lung injury and more severe pulmonary fibrosis. The protein expression of collagen-1 and concentration of cytokine CXCL12 in ALI/ARDS group were higher than that in control group. Clinical and prognostic analysis revealed the higher injury degree and death rates in ALI/ARDS group than those in control group, and identified a greater severity and mortality for patients with ARDS than those with ALI. ROC curve analysis indicated the counts of CFs greater than 5.85% can predict death rates with AUC = 0.928. CFs had an inhibitory effect on injury repair in ALI/ARDS mice model. This might be unfavorable as a clinical marker for progression of ALI/ARDS.

CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs.

Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8+ lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs.IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and effective killed RSV vaccine. Using adjuvants to regulate innate and adaptive immune responses could be an effective method to prevent ERD. We evaluated the impact of TLR and Notch signaling on ERD by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling, during FI-RSV immunization. The data showed that treatment of TLR or Notch signaling alone did not suppress FI-RSV-enhanced airway inflammation, while CpG plus L685,458 markedly inhibited ERD. The mechanism appears to involve suppressing Th17 memory responses and promoting tissue-resident memory cells. Moreover, these results suggest that regulation of lung immune memory with adjuvant compounds containing more than one immune-stimulatory molecule may be a good strategy to prevent FI-RSV ERD.

Impact of mechanical ventilation on clinical outcomes in ICU-admitted Alzheimer's disease patients: a retrospective cohort study.

Background: Alzheimer's disease (AD) is increasingly recognized as a pressing global public health issue, demanding urgent development of scientific AD management strategies. In recent years, the proportion of AD patients in Intensive Care Units (ICU) has been on the rise. Simultaneously, the use of mechanical ventilation (MV) is becoming more prevalent among this specific patient group. Considering the pathophysiological characteristics of AD, the application of MV in AD patients may lead to different outcomes. However, due to insufficient research data, the significant impact of MV on the prognosis of AD patients in the ICU remains unclear. Therefore, we conducted this study to comprehensively evaluate the potential influence of MV on the survival rate of AD patients in the ICU. Methods: We obtained data from the MIMIC-IV database for patients diagnosed with AD. Using propensity score matching (PSM), we paired patients who received MV treatment with those who did not receive treatment. Next, we conducted Cox regression analysis to evaluate the association between MV and in-hospital mortality, 7-day mortality, 28-day mortality, 90-day mortality, 4-year mortality, length of hospital stay, and ICU stay. Results: The data analysis involved a cohort of 641 AD patients spanning from 2008 to 2019, inclusive. Following a 1:2 propensity score matching (PSM) procedure, 300 patients were successfully paired, comprising 123 individuals who underwent MV treatment and 177 who did not. MV demonstrated an association with an elevated risk of in-hospital mortality (HR 5.782; 95% CI 2.981-11.216; p < 0.001), 7-day mortality (HR 6.353; 95% CI 3.014-13.392; p < 0.001), 28-day mortality (HR 3.210; 95% CI 1.977-5.210; p < 0.001), 90-day mortality (HR 2.334; 95% CI 1.537-3.544; p < 0.001), and 4-year mortality (HR 1.861; 95% CI 1.370-2.527; p < 0.001). Furthermore, it was associated with a prolonged length of ICU stay [3.6(2.2,5.8) vs. 2.2(1.6,3.7); p = 0.001]. In the subgroup analysis, we further confirmed the robustness of the results obtained from the overall population. Additionally, we observed a significant interaction (p-interaction <0.05) between age, admission type, aspirin use, statin use, and the use of MV. Conclusion: In patients with AD who are receiving treatment in the ICU, the use of MV has been linked to higher short-term, medium-term, and long-term mortality rates, as well as prolong ICU stays. Therefore, it is crucial to break away from conventional thinking and meticulously consider both the medical condition and personal preferences of these vulnerable patients. Personalized treatment decisions, comprehensive communication between healthcare providers and patients, formulation of comprehensive treatment plans, and a focus on collaboration between the ICU and community organizations become imperative.

Association between acetaminophen administration and clinical outcomes in patients with sepsis admitted to the ICU: a retrospective cohort study.

Background: Sepsis, affecting over 30 million people worldwide each year, is a key mortality risk factor in critically ill patients. There are significant regional discrepancies in its impact. Acetaminophen, a common over-the-counter drug, is often administered to control fever in suspected infection cases in intensive care units (ICUs). It is considered generally safe when used at therapeutic levels. Despite its widespread use, there's inconsistent research regarding its efficacy in sepsis management, which creates uncertainties for ICU doctors about its possible advantages or harm. To address this, we undertook a retrospective cohort study utilizing the MIMIC-IV database to examine the correlation between acetaminophen use and clinical outcomes in septic patients admitted to the ICU. Methods: We gathered pertinent data on sepsis patients from the MIMIC-IV database. We used propensity score matching (PSM) to pair acetaminophen-treated patients with those who were not treated. We then used Cox Proportional Hazards models to examine the relationships between acetaminophen use and factors such as in-hospital mortality, 30-day mortality, hospital stay duration, and ICU stay length. Results: The data analysis involved 22,633 sepsis patients. Post PSM, a total of 15,843 patients were matched; each patient not receiving acetaminophen treatment was paired with two patients who received it. There was a correlation between acetaminophen and a lower in-hospital mortality rate (HR 0.443; 95% CI 0.371-0.530; p < 0.001) along with 30-day mortality rate (HR 0.497; 95% CI 0.424-0.583; p < 0.001). Additionally, it correlated with a decrease in the duration of hospitalization [8.4 (5.0, 14.8) vs. 9.0 (5.1, 16.0), p < 0.001] and a shorter ICU stay [2.8 (1.5, 6.0) vs. 3.1 (1.7, 6.5); p < 0.05]. Conclusion: The use of acetaminophen may lower short-term mortality in critically ill patients with sepsis. To confirm this correlation, future research should involve multicenter randomized controlled trials.

Helicobacter pylori CagA-mediated ether lipid biosynthesis promotes ferroptosis susceptibility in gastric cancer.

Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.