Loss-of-function/gain-of-function polymorphisms of the ATP sensitive P2X7R influence sepsis, septic shock, pneumonia, and survival outcomes.

Introduction: Extracellular ATP (eATP) released from damaged cells activates the P2X7 receptor (P2X7R) ion channel on the surface of surrounding cells, resulting in calcium influx, potassium efflux and inflammasome activation. Inherited changes in the P2X7R gene (P2RX7) influence eATP induced responses. Single nucleotide polymorphisms (SNPs) of P2RX7 influence both function and signaling of the receptor, that in addition to ion flux includes pathogen control and immunity. Methods: Subjects (n = 105) were admitted to the ICU at the University Hospital Ulm, Germany between June 2018 and August 2019. Of these, subjects with a diagnosis of sepsis (n = 75), were also diagnosed with septic shock (n = 24), and/or pneumonia (n = 42). Subjects with pneumonia (n = 43) included those without sepsis (n = 1), sepsis without shock (n = 29) and pneumonia with septic shock (n = 13). Out of the 75 sepsis/septic shock patients, 33 patients were not diagnosed with pneumonia. Controls (n = 30) were recruited to the study from trauma patients and surgical patients without sepsis, septic shock, or pneumonia. SNP frequencies were determined for 16 P2RX7 SNPs known to affect P2X7R function, and association studies were performed between frequencies of these SNPs in sepsis, septic shock, and pneumonia compared to controls. Results: The loss-of-function (LOF) SNP rs17525809 (T253C) was found more frequently in patients with septic shock, and non-septic trauma patients when compared to sepsis. The LOF SNP rs2230911 (C1096G) was found to be more frequent in patients with sepsis and septic shock than in non-septic trauma patients. The frequencies of these SNPs were even higher in sepsis and septic patients with pneumonia. The current study also confirmed a previous study by our group that showed a five SNP combination that included the GOF SNPs rs208294 (C489T) and rs2230912 (Q460R) that was designated #21211 was associated with increased odds of survival in severe sepsis. Discussion: The results found an association between expression of LOF P2RX7 SNPs and presentation to the ICU with sepsis, and septic shock compared to control ICU patients. Furthermore, frequencies of LOF SNPs were found to be higher in sepsis patients with pneumonia compared to those without pneumonia. In addition, a five SNP GOF combination was associated with increased odds of survival in severe sepsis. These results suggest that P2RX7 is required to control infection in pneumonia and that inheritance of LOF variants increases the risk of sepsis when associated with pneumonia. This study confirms that P2RX7 genotyping in pneumonia may identify patients at risk of developing sepsis. The study also identifies P2X7R as a target in sepsis associated with an excessive immune response in subjects with GOF SNP combinations.

The impact of physical therapy intervention of dysphagia on preventing pneumonia in acute stroke patients: A randomized controlled trial.

BACKGROUND AND OBJECTIVES: Dysphagia is a common complication following stroke. It corresponds to the development of pneumonia, which is always associated with bad prognosis, longer hospital stays and increased mortality. The aim of the study was to assess the impact of physical therapy intervention of dysphagia on preventing pneumonia in acute stroke patients. METHODS: A single-blind randomized controlled trial was carried out on 70 ischemic stroke patients with oropharyngeal dysphagia, age ranged from 49 to 65 years. They were randomly assigned to two groups (control and study) of equal number. Patients in the control group received oral care and nasogastric tube feeding, while patients in the study group received the same program in addition to the designed physical therapy program (exercises and neuromuscular electrical stimulation). The intervention program was applied for 40 min/session, 1 session/day, and 5 days/week for 4 weeks. Gugging swallowing screen (GUSS), and stroke associated pneumonia (SAP) control and prevention criteria were used to assess dysphagia and incidence of pneumonia at baseline, after two and 4 weeks of intervention for both groups. RESULTS: Before treatment, all patients were susceptible to pneumonia after two and 4 weeks of intervention; there were a significant increase in GUSS score in both groups with more improvement in favor of the study group (p < 0.05) and a statistically significant increase in incidence of SAP after 2 weeks of intervention only in the control group (p < 0.05). The results also showed a significant negative correlation between GUSS score and SAP (r = - 0.3662, p = 0.0018) IMPLICATIONS FOR PHYSIOTHERAPY PRACTICE: adding physical therapy (exercise therapy and neuromuscular electrical stimulation) to oral care and nasogastric tube feeding is effective in improving oropharyngeal dysphagia and decreasing the incidence of aspiration pneumonia in acute ischemic stroke patients.

Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation.

Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRß, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRß as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.

Differences in the risk of immune-related pneumonitis between PD-1 and PD-L1 inhibitors: a meta-analysis according to the new mirror-principle and PRISMA guidelines.

PURPOSE: To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. METHOD: The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines. RESULTS: A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84)). CONCLUSION: Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.

Risk factors for postoperative pneumonia in patients after lung resection for non-small cell lung cancer - results of a cohort study.

Postoperative pneumonia is the most common complication in patients after lung resection for non-small cell lung cancer (NSCLC). The tolerable incidence of this complication ranges from 5 to 8 %. The aim of this study was to evaluate the influence of initial risk factors on the incidence of postoperative pneumonia in patients undergoing lung resection for NSCLC. A retrospective cohort study was conducted at the University Hospital Ostrava between January 1, 2016, and December 31, 2022. All adult patients who underwent pulmonary lobectomy for primary NSCLC during the study period were included in the study. A total of 350 patients were included in the study. The incidence of postoperative pneumonia was 10.9%. Analysis of baseline risk factors did not show a statistically significant association with the incidence of this complication. The only statistically significant finding was a longer hospital stay in patients with postoperative pneumonia. The risk of postoperative pneumonia in patients undergoing lung resection for non-small cell lung cancer cannot be clearly explained by the initial risk factors examined alone. The complex nature of this risk also requires a comprehensive approach to prevention, including both patient-centred measures and improved postoperative care.

Serum C-reactive protein to albumin ratio as a potential risk indicator of pneumonia caused by Chlamydia psittaci: a multicenter retrospective study.

Introduction: The aim of the study was to describe psittacosis pneumonia and to assess the predictive value of the C-reactive protein/albumin ratio in psittacosis pneumonia for severity. Methods: Data on psittacosis pneumonia cases diagnosed using metagenomic sequencing were collected from three hospitals in Shanghai, China from Oct. 2019 to Oct. 2022. Serum levels of C-reactive protein and albumin were measured and the C-reactive protein to albumin ratio (CAR) was calculated. Spearman's correlation analysis, ordered logistic regression analysis, and receiver operating characteristic curve analysis were conducted to examine the correlation and predictive ability of the three indicators on the severity of the disease. Results: A total of 27 patients with psittacosis pneumonia were enrolled, with an average age of 62 years and 70.4% being male. 44.4% of patients had a clear history of contact with poultry or birds. The predominant symptom was fever (100%). Patients treated in the respiratory intensive care unit (RICU) had a higher likelihood of experiencing wheezing (88.9% versus 33.3%, P=0.013) and chest tightness (88.9% vs. 33.3%, P=0.013) than those in the general ward (Non-RICU). The proportion of patients with pleural effusion was significantly higher in the RICU compared to the Non-RICU (88.9% vs. 38.9%, P=0.019). The RICU group had a significantly higher CAR than the Non-RICU group (9.41 vs. 4.05, P=0.017). This result was accompanied by higher intubation and ventilator support (33.3% vs. 0.0%, P=0.029), higher PCT and CRP levels and lower albumin and PaCO2 levels in the RICU than in the Non-RICU. Logistic regression analysis indicated that CAR (OR 1.49; 95% CI 1.07-2.06, P=0.017) was risk factor for prolonged hospitalization (> 14 days). Discussion: Elevated serum CAR levels were found to be associated with a greater risk of severe psittacosis pneumonia. Consequently, it may serve as an uncomplicated and useful diagnostic tool for clinicians to promptly and precisely ascertain the severity of psittacosis pneumonia, ultimately aiding them in devising the most optimal therapeutic plan.

Impact of Toll-like receptor 2 (rs5743708) gene polymorphism in pediatric pneumonia: risk and severity.

Pediatric pneumonia is a common respiratory infection that affects children and is thought to be a major source of mortality and morbidity worldwide, particularly in low- and middle-income nations. Toll-like receptor2 (TLR2) is an important receptor involved in the recognition of bacterial pathogens and the activation of the immune response. Genetic variability in TLR2 may partially explain individual differences in susceptibility to infections. The purpose of this study was to investigate the possible contribution of the TLR2 (rs5743708) variant to the risk and severity of pediatric pneumonia infection. The study included 100 pediatric patients diagnosed with pneumonia and 100 normal controls who were age and gender matched. Real-time polymerase chain reaction (PCR) was used to genotype participants for the TLR2 (rs5743708) variant. The analysis revealed that children with the TLR2 (rs5743708) (G/A) genotype showed a 2.52-fold greater risk of having pneumonia (OR: 2.52; 95% CI: 1.32-4.79; p = 0.005) in comparison with patients who have wild homozygous genotypes. Furthermore, we observed that the TLR2 (rs5743708) (A) allele is connected to a greater risk of pneumonia infection in children (OR: 1.612; 95% CI: 1.07-2.43; p = 0.023) but did not significantly influence infection severity. In conclusion, children with the TLR2 (rs5743708) mutant (G/A) genotype and (A) allele had a significantly higher risk of having pneumonia, but they were not at high risk for the severity of the infection.

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Veno-Arterial Extracorporeal Membrane Oxygenation in the Rat.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

Current Diagnostic Techniques for Pneumonia: A Scoping Review.

Community-acquired pneumonia is one of the most lethal infectious diseases, especially for infants and the elderly. Given the variety of causative agents, the accurate early detection of pneumonia is an active research area. To the best of our knowledge, scoping reviews on diagnostic techniques for pneumonia are lacking. In this scoping review, three major electronic databases were searched and the resulting research was screened. We categorized these diagnostic techniques into four classes (i.e., lab-based methods, imaging-based techniques, acoustic-based techniques, and physiological-measurement-based techniques) and summarized their recent applications. Major research has been skewed towards imaging-based techniques, especially after COVID-19. Currently, chest X-rays and blood tests are the most common tools in the clinical setting to establish a diagnosis; however, there is a need to look for safe, non-invasive, and more rapid techniques for diagnosis. Recently, some non-invasive techniques based on wearable sensors achieved reasonable diagnostic accuracy that could open a new chapter for future applications. Consequently, further research and technology development are still needed for pneumonia diagnosis using non-invasive physiological parameters to attain a better point of care for pneumonia patients.

Clinical risk factors and blood protein biomarkers of 10-year pneumonia risk.

BACKGROUND: Chronic inflammation may increase susceptibility to pneumonia. RESEARCH QUESTION: To explore associations between clinical comorbidities, serum protein immunoassays, and long-term pneumonia risk. METHODS: Framingham Heart Study Offspring Cohort participants ≥65 years were linked to their Centers for Medicare Services claims data. Clinical data and 88 serum protein immunoassays were evaluated for associations with 10-year incident pneumonia risk using Fine-Gray models for competing risks of death and least absolute shrinkage and selection operators for covariate selection. RESULTS: We identified 1,370 participants with immunoassays and linkage to Medicare data. During 10 years of follow up, 428 (31%) participants had a pneumonia diagnosis. Chronic pulmonary disease [subdistribution hazard ratio (SHR) 1.87; 95% confidence interval (CI), 1.33-2.61], current smoking (SHR 1.79, CI 1.31-2.45), heart failure (SHR 1.74, CI 1.10-2.74), atrial fibrillation/flutter (SHR 1.43, CI 1.06-1.93), diabetes (SHR 1.36, CI 1.05-1.75), hospitalization within one year (SHR 1.34, CI 1.09-1.65), and age (SHR 1.06 per year, CI 1.04-1.08) were associated with pneumonia. Three baseline serum protein measurements were associated with pneumonia risk independent of measured clinical factors: growth differentiation factor 15 (SHR 1.32; CI 1.02-1.69), C-reactive protein (SHR 1.16, CI 1.06-1.27) and matrix metallopeptidase 8 (SHR 1.14, CI 1.01-1.30). Addition of C-reactive protein to the clinical model improved prediction (Akaike information criterion 4950 from 4960; C-statistic of 0.64 from 0.62). CONCLUSIONS: Clinical comorbidities and serum immunoassays were predictive of pneumonia risk. C-reactive protein, a routinely-available measure of inflammation, modestly improved pneumonia risk prediction over clinical factors. Our findings support the hypothesis that prior inflammation may increase the risk of pneumonia.

Impact of preoperative inflammatory indices and postoperative pneumonia on postoperative atrial fibrillation in patients with non-small cell lung cancer: a retrospective study.

BACKGROUND: This study aimed to evaluate the impact of preoperative inflammatory indices and postoperative pneumonia (POP) on postoperative atrial fibrillation (POAF) in non-small cell lung cancer (NSCLC) patients. METHODS: All consecutive patients who underwent pulmonary resection at our hospital (January 2016-October 2019) were enrolled. Preoperative inflammatory indices, demographic data, surgical details, and postoperative conditions were analyzed. Univariate and multivariate analyses of risk factors associated with POAF were also conducted. RESULTS: Among the 382 patients included in the study, 32 (8.38%) developed POAF. Compared to non-POAF patients, POAF patients had greater incidence of POP (P = 0.09). Approximately 31 patients (96.9%) developed atrial fibrillation within three days after surgery. The POAF group had a significantly greater mean age (68.94 years) than did the non-POAF group (63 years) (P = 0.002). Additionally, compared to non-POAF patients, POAF patients exhibited an increased number of resected mediastinal lymph nodes (P < 0.001) and mediastinal lymph node stations (P < 0.001).The POAF group also had a greater intraoperative blood volume (P = 0.006), longer surgical duration (P = 0.022), and greater drainage volume (P = 0.003). IA/B stage (P < 0.001) and IIIA/B stage(P < 0.001), and lobectomy resection (P = 0.008) and wedge resection (P = 0.023) were also associated with POAF. Compared to those in the non-POAF group, the POAF group had longer postoperative hospital stays (10.54 days vs. 9 days; P = 0.001) and longer drainage times (7 days vs. 5 days; P = 0.004). Multivariate analysis revealed age, POP, and stage IIIA/B as independent influencing factors of POAF in NSCLC patients. CONCLUSION: Preoperative inflammatory indices were not significantly associated with POAF, but age, POP, and stage IIIA/B were identified as independent influencing factors. Advanced-stage NSCLC patients may have a greater susceptibility to POAF than early-stage patients, although further validation is needed. Additionally, POAF was linked to a longer postoperative hospital stay.

Clinical characteristics and risk factors for mortality in pneumonia-associated acute respiratory distress syndrome patients: a single center retrospective cohort study.

Background: Pathogenic diversity may have contributed to the high mortality of pneumonia-associated acute respiratory distress syndrome (p-ARDS). Metagenomics next-generation sequencing (mNGS) serves as a valuable diagnostic tool for early pathogen identification. However, its clinical utility in p-ARDS remains understudied. There are still limited researches on the etiology, clinical characteristics and risk factors for 28-day mortality in p-ARDS patients. Methods: A single center retrospective cohort study of 75 p-ARDS patients was conducted. Patients were categorized into survival and deceased groups based on their 28-day outcomes. A comprehensive clinical evaluation was conducted, including baseline characteristics, laboratory indicators, outcomes and pathogen identification by mNGS and traditional microbiological testing. We then evaluated the diagnostic value of mNGS and identified clinical characteristics and risk factors for 28-day mortality in p-ARDS. Result: The overall ICU mortality was 26.67%, and the 28-day mortality was 57.33%, with 32 cases (42.67%) in the survival group, and 43 cases (57.33%) in the deceased group. Patients in the deceased group were older than those in the survival group (68(59,73) years vs. 59(44,67) years, P=0.04). The average lengths of ICU and hospital stay were 9(5,13) days and 14(7,21) days, respectively. The survival group had longer lengths of ICU and hospital stay (ICU: 11(7,17) days and hospital: 17(9,27) days) compared to the deceased group (ICU: 8(4,11) days and hospital: 12(6,19) days) (P<0.05). Survival patients exhibited lower Acute Physiology and Chronic Health Evaluation (APACHE) II score on the 3rd and 7th days, higher lymphocyte counts, higher CD3+ and CD8+ T cell counts compared to deceased patients (P<0.05). Multivariate logistic regression analysis identified age, APACHE II scores on 3rd and 7th days, CD8+ T cell count and length of ICU as independent risk factors for 28-day mortality in p-ARDS patients. mNGS demonstrated a significantly higher overall pathogen detection rate (70/75, 93.33%) compared to the traditional method (50/75, 66.67%, P=0.022). The average turnaround time (TAT) for mNGS was significantly shorter at 1(1,1) day compared to 4(3,5) days for the traditional method (P<0.001). Conclusion: Metagenome next-generation sequencing can be used as a valuable tool for identifying pathogens in p-ARDS, reducing diagnostic time and improving accuracy. Early application of mNGS alongside traditional methods is recommended for p-ARDS. Furthermore, older age, higher APACHE II scores, lower lymphocyte counts and lymphocyte subset counts were associated with increased mortality in p-ARDS patients, highlighting the importance of timely assessment of immune status and disease severity, especially in elderly.

Gut microbiota in preterm infants with late-onset sepsis and pneumonia: a pilot case-control study.

BACKGROUND: Late-onset sepsis (LOS) and pneumonia are common infectious diseases, with high morbidity and mortality in neonates. This study aimed to investigate the differences in the gut microbiota among preterm infants with LOS, or pneumonia, and full-term infants. Furthermore, this study aimed to determine whether there is a correlation between intestinal pathogenic colonization and LOS. METHODS: In a single-center case‒control study, 16 S rRNA gene sequencing technology was used to compare gut microbiota characteristics and differences among the LOS group, pneumonia group, and control group. RESULTS: Our study revealed that the gut microbiota in the control group was more diverse than that in the LOS group and pneumonia group (P < 0.05). No significant differences in diversity were detected between the LOS and pneumonia groups (P > 0.05). Compared with the control group, the abundances of Akkermansia, Escherichia/Shigella, and Enterococcus increased, while the abundances of Bacteroides and Stenotrophomonas decreased in the LOS and pneumonia groups. The pathogenic bacteria in infants with LOS were consistent with the distribution of the main bacteria in the intestinal microbiota. An increase in Escherichia/Shigella abundance may predict a high risk of LOS occurrence, with an area under the curve (AUC) of 0.773. CONCLUSION: Changes in the gut microbiota composition were associated with an increased risk of LOS and pneumonia. The dominant bacteria in the gut microbiota of the LOS group were found to be associated with the causative pathogen of LOS. Moreover, preterm infants exhibiting an elevated abundance of Escherichia/Shigella may be considered potential candidates for predicting the onset of LOS.

MMP-3 mediates copper oxide nanoparticle-induced pulmonary inflammation and fibrosis.

BACKGROUND: The increasing production and usage of copper oxide nanoparticles (Nano-CuO) raise human health concerns. Previous studies have demonstrated that exposure to Nano-CuO could induce lung inflammation, injury, and fibrosis. However, the potential underlying mechanisms are still unclear. Here, we proposed that matrix metalloproteinase-3 (MMP-3) might play an important role in Nano-CuO-induced lung inflammation, injury, and fibrosis. RESULTS: Exposure of mice to Nano-CuO caused acute lung inflammation and injury in a dose-dependent manner, which was reflected by increased total cell number, neutrophil count, macrophage count, lactate dehydrogenase (LDH) activity, and CXCL1/KC level in bronchoalveolar lavage fluid (BALF) obtained on day 3 post-exposure. The time-response study showed that Nano-CuO-induced acute lung inflammation and injury appeared as early as day 1 after exposure, peaked on day 3, and ameliorated over time. However, even on day 42 post-exposure, the LDH activity and macrophage count were still higher than those in the control group, suggesting that Nano-CuO caused chronic lung inflammation. The Nano-CuO-induced pulmonary inflammation was further confirmed by H&E staining of lung sections. Trichrome staining showed that Nano-CuO exposure caused pulmonary fibrosis from day 14 to day 42 post-exposure with an increasing tendency over time. Increased hydroxyproline content and expression levels of fibrosis-associated proteins in mouse lungs were also observed. In addition, Nano-CuO exposure induced MMP-3 overexpression and increased MMP-3 secretion in mouse lungs. Knocking down MMP-3 in mouse lungs significantly attenuated Nano-CuO-induced acute and chronic lung inflammation and fibrosis. Moreover, Nano-CuO exposure caused sustained production of cleaved osteopontin (OPN) in mouse lungs, which was also significantly decreased by knocking down MMP-3. CONCLUSIONS: Our results demonstrated that short-term Nano-CuO exposure caused acute lung inflammation and injury, while long-term exposure induced chronic pulmonary inflammation and fibrosis. Knocking down MMP-3 significantly ameliorated Nano-CuO-induced pulmonary inflammation, injury, and fibrosis, and also attenuated Nano-CuO-induced cleaved OPN level. Our study suggests that MMP-3 may play important roles in Nano-CuO-induced pulmonary inflammation and fibrosis via cleavage of OPN and may provide a further understanding of the mechanisms underlying Nano-CuO-induced pulmonary toxicity.

COVID-19 and Pneumonia detection and web deployment from CT scan and X-ray images using deep learning.

During the COVID-19 pandemic, pneumonia was the leading cause of respiratory failure and death. In addition to SARS-COV-2, it can be caused by several other bacterial and viral agents. Even today, variants of SARS-COV-2 are endemic and COVID-19 cases are common in many places. The symptoms of COVID-19 are highly diverse and robust, ranging from invisible to severe respiratory failure. Current detection methods for the disease are time-consuming and expensive with low accuracy and precision. To address such situations, we have designed a framework for COVID-19 and Pneumonia detection using multiple deep learning algorithms further accompanied by a deployment scheme. In this study, we have utilized four prominent deep learning models, which are VGG-19, ResNet-50, Inception V3 and Xception, on two separate datasets of CT scan and X-ray images (COVID/Non-COVID) to identify the best models for the detection of COVID-19. We achieved accuracies ranging from 86% to 99% depending on the model and dataset. To further validate our findings, we have applied the four distinct models on two more supplementary datasets of X-ray images of bacterial pneumonia and viral pneumonia. Additionally, we have implemented a flask app to visualize the outcome of our framework to show the identified COVID and Non-COVID images. The findings of this study will be helpful to develop an AI-driven automated tool for the cost effective and faster detection and better management of COVID-19 patients.

Clinical application of targeted next-generation sequencing in severe pneumonia: a retrospective review.

BACKGROUND: The precise identification of the underlying causes of infectious diseases, such as severe pneumonia, is essential, and the development of next-generation sequencing (NGS) has enhanced the effectiveness of pathogen detection. However, there is limited information on the systematic assessment of the clinical use of targeted next-generation sequencing (tNGS) in cases of severe pneumonia. METHODS: A retrospective analysis was conducted on 130 patients with severe pneumonia treated in the ICU from June 2022 to June 2023. The consistency of the results of tNGS, metagenomics next-generation sequencing (mNGS), and culture with the clinical diagnosis was evaluated. Additionally, the results for pathogens detected by tNGS were compared with those of culture, mNGS, and quantitative reverse transcription PCR (RT-qPCR). To evaluate the efficacy of monitoring severe pneumonia, five patients with complicated infections were selected for tNGS microbiological surveillance. The tNGS and culture drug sensitisation results were then compared. RESULTS: The tNGS results for the analysis of the 130 patients showed a concordance rate of over 70% with clinical diagnostic results. The detection of pathogenic microorganisms using tNGS was in agreement with the results of culture, mNGS, and RT-qPCR. Furthermore, the tNGS results for pathogens in the five patients monitored for complicated infections of severe pneumonia were consistent with the culture and imaging test results during treatment. The tNGS drug resistance results were in line with the drug sensitivity results in approximately 65% of the cases. CONCLUSIONS: The application of tNGS highlights its promise and significance in assessing the effectiveness of clinical interventions and providing guidance for anti-infection therapies for severe pneumonia.

[Prediction of risk of in-hospital death in patients with chronic heart failure complicated by lung infections using interpretable machine learning].

OBJECTIVE: To predict the risk of in-hospital death in patients with chronic heart failure (CHF) complicated by lung infections using interpretable machine learning. METHODS: The clinical data of 1415 patients diagnosed with CHF complicated by lung infections were obtained from the MIMIC-IV database. According to the pathogen type, the patients were categorized into bacterial pneumonia and non-bacterial pneumonia groups, and their risks of in-hospital death were compared using Kaplan-Meier survival curves. Univariate analysis and LASSO regression were used to select the features for constructing LR, AdaBoost, XGBoost, and LightGBM models, and their performance was compared in terms of accuracy, precision, F1 value, and AUC. External validation of the models was performed using the data from eICU-CRD database. SHAP algorithm was applied for interpretive analysis of XGBoost model. RESULTS: Among the 4 constructed models, the XGBoost model showed the highest accuracy and F1 value for predicting the risk of in-hospital death in CHF patients with lung infections in the training set. In the external test set, the XGBoost model had an AUC of 0.691 (95% CI: 0.654-0.720) in bacterial pneumonia group and an AUC of 0.725 (95% CI: 0.577-0.782) in non-bacterial pneumonia group, and showed better predictive ability and stability than the other models. CONCLUSION: The overall performance of the XGBoost model is superior to the other 3 models for predicting the risk of in-hospital death in CHF patients with lung infections. The SHAP algorithm provides a clear interpretation of the model to facilitate decision-making in clinical settings.

Two-year survival after scheduled extubation in patients with pneumonia or ARDS: a prospective observational study.

PURPOSE: To report two-year survival after scheduled extubation in patients with pneumonia or acute respiratory distress syndrome (ARDS). METHODS: This was a prospective observational study performed in a respiratory ICU of a teaching hospital. Pneumonia or ARDS patients who successfully completed a spontaneous breathing trial were enrolled. Data were collected before extubation. Patients were followed up to two years by phone every 3 months. RESULTS: A total of 230 patients were enrolled in final analysis. One-, 3-, 6-, 12-, and 24-month survival was 77.4%, 63.8%, 61.3%, 57.8%, and 47.8%, respectively. Cox regression shows that Charlson comorbidity index (hazard ratio: 1.20, 95% confidence interval: 1.10-1.32), APACHE II score before extubation (1.11, 1.05-1.17), cough peak flow before extubation (0.993, 0.986-0.999), and extubation failure (3.96, 2.51-6.24) were associated with two-year mortality. To predict death within two years, the area under the curve of receiver operating characteristic was 0.79 tested by Charlson comorbidity index, 0.75 tested by APACHE II score, and 0.75 tested by cough peak flow. Two-year survival was 31% and 77% in patients with Charlson comorbidity index ≥ 1 and < 1, 28% and 62% in patients with APACHE II score ≥ 12 and < 12, and 64% and 17% in patients with cough peak flow > 58 and ≤ 58 L/min, respectively. CONCLUSIONS: Comorbidity, disease severity, weak cough and extubation failure were associated with increased two-year mortality in pneumonia or ARDS patients who experienced scheduled extubation. It provides objective information to caregivers to improve decision-making process during hospitalization and post discharge.

Performance of risk scores in predicting mortality at 3, 6, and 12 months in patients diagnosed with community-acquired pneumonia.

BACKGROUND: Risk scores (RS) evaluate the likelihood of short-term mortality in patients diagnosed with community-acquired pneumonia (CAP). However, there is a scarcity of evidence to determine the risk of long-term mortality. This article aims to compare the effectiveness of 16 scores in predicting mortality at three, six, and twelve months in adult patients with CAP. METHODS: A retrospective cohort study on individuals diagnosed with CAP was conducted across two hospitals in Colombia. Receiver Operating Characteristic (ROC) curves were constructed at 3, 6, and 12 months to assess the predictive ability of death for the following scoring systems: CURB-65, CRB-65, SCAP, CORB, ADROP, NEWS, Pneumonia Shock, REA-ICU, PSI, SMART-COP, SMRT-CO, SOAR, qSOFA, SIRS, CAPSI, and Charlson Comorbidity Index (CCI). RESULTS: A total of 3688 patients were included in the final analysis. Mortality at 3, 6, and 12 months was 5.2%, 8.3%, and 16.3% respectively. At 3 months, PSI, CCI, and CRB-65 scores showed ROC curves of 0.74 (95% CI: 0.71-0.77), 0.71 (95% CI: 0.67-0.74), and 0.70 (95% CI: 0.66-0.74). At 6 months, PSI and CCI scores showed performances of 0.74 (95% CI: 0.72-0.77) and 0.72 (95% CI: 0.69-0.74), respectively. Finally at 12 months, all evaluated scores showed poor discriminatory capacity, including PSI, which decreased from acceptable to poor with an ROC curve of 0.64 (95% CI: 0.61-0.66). CONCLUSION: When predicting mortality in patients with CAP, at 3 months, PSI, CCI, and CRB-65 showed acceptable predictive performances. At 6 months, only PSI and CCI maintained acceptable levels of accuracy. For the 12-month period, all evaluated scores exhibited very limited discriminatory ability, ranging from poor to almost negligible.