Therapeutic drug monitoring of linezolid and exploring optimal regimens and a toxicity-related nomogram in elderly patients: a multicentre, prospective, non-interventional study.

BACKGROUND: The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. METHODS: In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. RESULTS: A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72 h and 26.1 (17.0, 38.1) mg/L at 5-10 days (P = 0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. CONCLUSIONS: Linezolid trough concentrations increased dramatically in the elderly, by about 10 mg/L in patients aged 65-80 years, followed by a further increase of 10 mg/L for every 10 years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.

Necessity for higher teicoplanin doses in older adults: a multicenter prospective observational study in China.

BACKGROUND: Many older adult patients receive low-dose teicoplanin with varied regimens, leading to a lack of clarity on its optimal regimens and toxicity profiles in China. This study aimed to clarify these aspects by analyzing teicoplanin treatment concentrations and toxicities. METHODS: We included older adult patients administered teicoplanin at four tertiary hospitals in Beijing from June 2021 to July 2023, targeting a trough concentration (Cmin) ≥ 10 mg/L. Teicoplanin concentrations and toxicities were monitored dynamically. RESULTS: From 204 patients, we obtained 632 teicoplanin concentrations. Most patients (83.3%) received low-dose regimens. Suboptimal concentrations were found in 66.4% of patients within 7 days of treatment and 17.0% after 15 days. Cmin gradually increased with treatment duration and was influenced initially by creatinine and by both body weight and creatinine from days 8 to 14. The target concentration was achieved in 53.1%, 33.9%, 15.6%, and 5.5% of patients at 3, ≤ 7, 8-14, and ≥ 15 days after withdrawal, respectively. Slow elimination was associated with average Cmin and eGFR. Nephrotoxicity, hepatotoxicity, and thrombocytopenia occurred in 12.5%, 4.1%, and 31.5% of patients, respectively, without significant differences between concentrations. CONCLUSIONS: Most older adult patients were underdosed, indicating a need for dose adjustment. Given the varied risk factors for suboptimal concentrations in different treatment stages, a one-size-fits-all regimen was ineffective. We recommend an initial dose of 400 mg at 12-h intervals for the first three days, with subsequent doses from days 4 to 14 adjusted based on creatinine and body weight; after day 14, a maintenance dose of 200 mg daily is advised. TRIAL REGISTRATION: ChiCTR2100046811; 28/05/2021.

Molecular epidemiological and clinical infection characteristics analysis of Ralstonia.

PURPOSE: This study was to clarify the molecular epidemiology and clinical infection characteristics of Ralstonia pickettii and establish sequence typing system. METHODS: 48 nonrepetitive Ralstonia pickettii strains were collected from January 2008 to December 2013 at the Chinese People's Liberation Army General Hospital (PLAGH) and were identified through a specific PCR experiment, 16 S rDNA experiment and VITEK 2 system to compare the identification accuracy. The sequence types of the strains were analyzed by multilocus sequence typing (MLST) method. The antibiotic sensitivity of these strains was determined with disc diffusion tests and broth microdilution method. The clinical data of Ralstonia pickettii infected patients were collected. RESULTS: All of the 48 strains were identified as Ralstonia pickettii by VITEK 2 system. 30 and 34 strains were identified as Ralstonia pickettii by PCR and 16 S rDNA experiment respectively. ST9 was the most sequence types (STs) in these 18 STs of 42 strains. 42 strains were divided into 2 groups (A and B) and 18 genotypes. Ralstonia pickettii was sensitive to some cephalosporins, ß-lactam/ß-lactamase inhibitor, levofloxacin and trimethoprim/sulfamethoxazole. Cough, sputum, shortness of breath and pulmonary rales were the common clinical symptoms of most Ralstonia pickettii infected patients. CONCLUSION: We established a sequence typing system with a relatively fine resolution and the PCR assay is a faster and more sensitive method for clinical identification of Ralstonia pickettii. ST9 is the most common sequence types of Ralstonia pickettii. The most common clinical characteristics of Ralstonia pickettii infected patients were cough, sputum, shortness of breath and pulmonary rales.

Antiviral effectiveness and survival correlation of azvudine and nirmatrelvir/ritonavir in elderly severe patients with COVID-19: a retrospective real-world study.

Background: Azvudine and nirmatrelvir/ritonavir are approved to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with a high risk for progression to severe infection. We sought to compare the antiviral effectiveness and clinical outcomes of elderly severe patients with COVID-19 receiving these two antiviral agents. Methods: In this observational study, we identified 249 elderly patients with severe COVID-19 infection who were admitted to the Second Medical Center of the People's Liberation Army General Hospital from December 2022 to January 2023, including 128 azvudine recipients, 66 nirmatrelvir/ritonavir recipients and 55 patients not received antiviral treatments. We compared the cycle threshold (Ct) value dynamic change of all three groups. The primary outcome was a composite outcome of disease progression, including all-cause death, intensive care unit admission, and initiation of invasive mechanical ventilation. The outcomes of all enrolled patients were followed up from the electronic medical record system. Kaplan-Meier and Cox risk proportional regression analyses were used to compare the clinical outcomes of all three groups. To more directly compare the effectiveness of the two antiviral drugs, we performed propensity-score matching between the two antiviral groups and compared antiviral efficacy and clinical outcomes in the matched population. Findings: Among 249 patients (mean age, 91.41 years), 77 patients died during the follow-up period. When compared to patients who did not receive any antivirals, neither nirmatrelvir/ritonavir nor azvudine demonstrated a survival benefit. The Cox analysis of the all-cause death of the three groups showed that the risk of death was 0.730 (0.423-1.262) in the azvudine group 0.802 (0.435-1.480) and in the nirmatrelvir/ritonavir group compared with the non-antiviral group. After propensity score matching, we included 58 azvudine recipients and 58 nirmatrelvir/ritonavir recipients. The fitted curve of the Ct value after matching illustrated that the rate of viral decline in the early stage of nirmatrelvir/ritonavir treatment seems to surpass that of azvudine, but there was no statistical significance. Azvudine was seemly associated with a lower risk of composite outcomes (HR:1.676, 95% CI:0.805-3.488) and short-term all-cause death (HR: 1.291, 95%CI: 0.546-3.051). Interpretation: Patients who received azvudine have a similar antiviral effectiveness and survival curve trend compared to nirmatrelvir/ritonavir. In this limited series, antiviral treatment was not associated with a significant clinical benefit. This lack of clinical benefit might be attributed to potential bias. Funding: This study was supported by the "National Key R&D Program of China" (Funding No. 2020YFC2008900) and the National Defense Science and Technology Innovation Special Zone Project (223-CXCY-N101-07-18-01).

Predicting ventilator-associated pneumonia in elderly patients requiring mechanical ventilation through the detection in tracheal aspirates.

OBJECTIVE: In this study, we evaluated the clinical utility of tracheal aspirates α-amylase (AM), pepsin, and lipid-laden macrophage index (LLMI) in the early diagnosis of ventilator-associated pneumonia (VAP) in elderly patients on mechanical ventilation. METHODS: Within 96 hours of tracheal intubation, tracheal aspirate specimens were collected from elderly patients on mechanical ventilation; AM, pepsin, and LLMI were detected, and we analyzed the potential of each index individually and in combination in diagnosing VAP. RESULTS: Patients with VAP had significantly higher levels of AM, pepsin, and LLMI compared to those without VAP (P < 0.001), and there was a positive correlation between the number of pre-intubation risk factors of aspiration and the detection value of each index in patients with VAP (P < 0.001). The area under a receiver operating characteristic (ROC) curve (AUC) of AM, pepsin, and LLMI in diagnosis of VAP were 0.821 (95% CI:0.713-0.904), 0.802 (95% CI:0.693-0.892), and 0.621 (95% CI:0.583-0.824), the sensitivities were 0.8815, 0.7632, and 0.6973, the specificities were 0.8495, 0.8602, and 0.6291, and the cutoff values were 4,321.5 U/L, 126.61 ng/ml, and 173.5, respectively. The AUC for the combination of indexes in diagnosing VAP was 0.905 (95% CI:0.812-0.934), and the sensitivity and specificity were 0.9211 and 0.9332, respectively. In the tracheal aspirate specimens, the detection rate of AM ≥ cutoff was the highest, while it was the lowest for LLMI (P < 0.001). The detection rates of AM ≥ cutoff and pepsin ≥ cutoff were higher within 48 hours after intubation than within 48-96 hours after intubation (P < 0.001). In contrast, the detection rate of LLMI ≥ cutoff was higher within 48-96 hours after intubation than within 48 hours after intubation (P < 0.001). The risk factors for VAP identified using logistic multivariate analysis included pre-intubation aspiration risk factors (≥3), MDR bacteria growth in tracheal aspirates, and tracheal aspirate AM ≥ 4,321.5 U/L, pepsin ≥ 126.61 ng/ml, and LLMI ≥ 173.5. CONCLUSION: The detection of AM, pepsin, and LLMI in tracheal aspirates has promising clinical utility as an early warning biomarker of VAP in elderly patients undergoing mechanical ventilation.

Nomogram prediction model called "ADPLCP" for predicting linezolid-associated thrombocytopenia in elderly individuals.

Background: Linezolid-associated thrombocytopenia (LAT) leads to drug withdrawal associated with a poor prognosis. Some risk factors for LAT have been identified; however, the sample size of previous studies was small, data from elderly individuals are limited, and a simple risk score scale was not established to predict LAT at an early stage, making it difficult to identify and intervene in LAT at an early stage. Methods: In this single-center retrospective case-control study, we enrolled elderly patients treated with linezolid in the intensive care unit from January 2015 to December 2020. All the data of enrolled patients, including demographic information and laboratory findings at baseline, were collected. We analyzed the incidence and risk factors for LAT and established a nomogram risk prediction model for LAT in the elderly population. Results: A total of 428 elderly patients were enrolled, and the incidence of LAT was 35.5% (152/428). Age ≥80 years old (OR=1.980; 95% CI: 1.179-3.325; P=0.010), duration of linezolid ≥ 10 days (OR=1.100; 95% CI: 1.050-1.152; P <0.0001), platelet count at baseline (100-149×109/L vs. ≥200×109/L, OR=8.205, 95% CI: 4.419-15.232, P <0.0001; 150-199 ×109/L vs. ≥200×109/L, OR=3.067, 95% CI: 1.676-5.612, P <0.001), leukocyte count at baseline ≥16×109/L (OR=2.580; 95% CI: 1.523-4.373; P <0.0001), creatinine clearance <50 mL/min (OR=2.323; 95% CI: 1.388-3.890; P=0.001), and total protein <60 g/L (OR=1.741; 95% CI: 1.039-2.919; P=0.035) were associated with LAT. The nomogram prediction model called "ADPLCP" (age, duration, platelet, leukocyte, creatinine clearance, protein) was established based on logistic regression. The area under the curve (AUC) of ADPLCP was 0.802 (95% CI: 0.748-0.856; P <0.0001), with 78.9% sensitivity and 69.2% specificity (cut-off was 108). Risk stratification for LAT was performed based on "ADPLCP." Total points of <100 were defined as low risk, and the possibility of LAT was <32.0%. Total points of 100-150 were defined as medium risk, and the possibility of LAT was 32.0-67.5%. A total point >150 was defined as high risk, and the probability of LAT was >67.5%. Conclusions: We created the ADPLCP risk score scale to predict the occurrence of LAT in elderly individuals. ADPLCP is simple and feasible and is helpful for the early determination of LAT to guide drug withdrawal or early intervention.

Whole-genome metagenomic analysis of the oral microbiota in patients with obstructive sleep apnea.

PURPOSE: The oral microbiota is closely associated with systemic health, but few studies have investigated the oral microbiota in patients with obstructive sleep apnea (OSA). This study aimed to identify the variation of oral microbiota among patients with severe OSA, and the change of oral microbiota after treatment with continuous positive airway pressure (CPAP). METHODS: Participants were enrolled in the study from November 2020 to August 2021. Sleep parameters using full nocturnal polysomnography (PSG) were collected on healthy controls, patients with severe OSA, and patients with severe OSA after CPAP treatment for 3 months. Oral samples were also collected by rubbing disposable medical sterile swabs on the buccal mucosa. Routine blood tests and biochemical indicators were measured using the fully automated biochemical analyzer. Oral microbial composition of oral samples were determined using whole-genome metagenomic analysis in all participants. Correlations were analyzed between the oral microbiota and blood lipids. RESULTS: Study enrollment included 14 participants, 7 healthy controls and 7 patients with severe OSA. At the species level, the relative abundances of Prevotella, Alloprevotella, Bacteroides, Veillonella_tobetsuensis, Candidatus saccharimonas, and Leptotrichia in the groups with severe OSA were significantly lower than those in the healthy controls (P both < 0.05). The abundances of Capnocytophaga, Veillonella, Bacillus_anthracis, Eikenella, and Kingella were significantly higher whereas the abundances of Gordonia and Streptococcus were significantly lower in the group with severe OSA compared to the severe OSA-CPAP group (P < 0.05 for both). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), 4 pathways changed in the group with severe OSA compared with healthy controls (P both < 0.05). Pathways related to Novobiocin biosynthesis, 2-Oxocarboxylic acid metabolism, and Histidine metabolism were enriched in the patients with severe OSA. Nine pathways showed significant differences with regard to the relative abundances of phenylalanine metabolism; alanine, aspartate, and glutamate metabolism; one carbon pool by folate; monobactam biosynthesis; 2-oxocarboxylic acid metabolism; arginine biosynthesis and vitamin B6 metabolism; novobiocin biosynthesis; and arginine and proline metabolism, which were significantly higher in the group with severe OSA compared to the severe OSA-CPAP group (P both < 0.05). The Spearman correlation analysis between blood lipid parameters and oral microbiota components showed that negative correlations were observed between total cholesterol and Streptomyces (r = - 0.893, P = 0.007), and high-density lipoprotein cholesterol (HDL-C) and Gordonia (r = - 0.821, P = 0.023); positive correlations were observed between HDL-C and Candidatus saccharimonas (r = 0.929, P = 0.003), and low-density lipoprotein cholesterol (LDL-C) and Capnocytophaga (r = 0.893, P = 0.007). CONCLUSION: There was an apparent discrepancy of the oral microbiota and metabolic pathways between the group with severe OSA and controls, and CPAP significantly changed oral microbial abundance and metabolic pathways in patients with severe OSA. Correlation analysis showed that these oral bacteria were strongly correlated with the blood lipids level.

Case report: Recurrent lung infections following treatment with pralsetinib for an elderly patient with RET-fusion positive NSCLC.

Patients with RET fusions represent 1-2% of all cases of non-small cell lung cancer (NSCLC), the majority of whom are younger, and are extremely rare in the elderly. As a selective RET inhibitor, pralsetinib has been shown to be efficacious and well-tolerated in patients with RET-fusion NSCLC. Nevertheless, there are currently insufficient data available for assessing the activity and safety of pralsetinib in elderly patients with NSCLC. Herein, we report an 81-year-old NSCLC patient with KIF5B-RET fusion, who achieved stable disease for more than 9 months at a low-dose of pralsetinib as second-line therapy. Of particular note, during pralsetinb therapy, his clinical course was complicated by cryptococcal pneumonia and staphylococcus aureus lung abscess. Our study demonstrates that pralsetinib is an effective therapeutic option that provides survival benefits for elderly NSCLC patients harboring RET fusion. However, during pralsetinb therapy, treating physicians should maintain particular vigilance for the increased risk of infection, especially in elderly patients.

RIPK3 Induces Cardiomyocyte Necroptosis via Inhibition of AMPK-Parkin-Mitophagy in Cardiac Remodelling after Myocardial Infarction.

Receptor-interacting protein 3- (RIPK3-) modulated necroptosis plays a critical role in cardiac remodelling after myocardial infarction (MI). However, the precise regulatory mechanism is not fully elucidated yet. In the present study, we showed that RIPK3 expression was upregulated in myocardial tissue after MI in a mouse model by coronary artery ligation, as well as in the cardiomyocytes following hypoxic injury in vitro. The increase of RIPK3 expression was found to be accompanied by severe cardiac remodelling, cardiac dysfunction, and higher mortality. Elevated RIPK3 expression subsequently abrogated the AMPK pathway that was accompanied by inhibition of Parkin-mediated mitophagy. Loss of mitophagy increased the opening of mitochondrial permeability transition pore (mPTP), which ultimately induced the cardiomyocyte necroptosis. In contrast, genetic ablation of Ripk3 induced the AMPK/Parkin-mitophagy pathway, favouring a prosurvival state that eventually inhibited mPTP opening and induced the necroptosis of cardiomyocytes in the post-MI cardiac remodelling. In conclusion, our results revealed a key mechanism by which necroptosis could be mediated by RIPK3 via the AMPK/Parkin-mitophagy/mPTP opening axis, which provides a potential therapeutic target in the management of heart failure after MI.

Incidence and Associated Risk Factors for Lactic Acidosis Induced by Linezolid Therapy in a Case-Control Study in Patients Older Than 85 Years.

Background: Serum lactic acid is considered a prognostic indicator in critically ill patients. However, studies on linezolid-induced lactic acidosis (LILA) are still limited. Individuals older than 85 years old (very elderly) have limited capacity for organ compensation, and LILA data from these patients are lacking. In this study, we evaluated the risk factors for LILA in patients older than 85 years and established a risk prediction model for geriatric practice. Methods: In this retrospective cohort study, blood gas analysis data and arterial lactate levels were monitored in patients older than 85 years during the use of teicoplanin or linezolid. After propensity score matching analyses, we compared the incidence of lactic acidosis between the teicoplanin and linezolid therapy groups and identified the risk factors of LILA. Results: The incidence of lactic acidosis was found to be much lower in the group receiving teicoplanin than those receiving linezolid therapy (0 vs. 35.7%; p < 0.0001). A duration of linezolid therapy ≥ 9 days [odds ratio (OR), 3.541; 95% confidence interval (CI), 1.161-10.793; p = 0.026], an arterial blood glucose level ≥ 8 mmol/L (OR, 4.548; 95% CI, 1.507-13.725; p = 0.007), and a high sequential organ failure assessment score (OR, 1.429; 95% CI, 1.213-1.685; p < 0.0001) were risk factors for LILA. The constructed risk model could be used to predict LILA (area under the curve, 0.849; specificity, 65.1%; sensitivity, 91.4%, with a negative predictive value of 93.2% and a positive predictive value of 59.3%). Conclusions: LILA can occur in patients older than 85 years after a relatively shorter duration of linezolid therapy. Therefore, close monitoring of blood gas and arterial lactate levels during linezolid therapy in the very elderly population is necessary.

Prediction of the Therapeutic Effects of Pembrolizumab and Nivolumab in Advanced Non-Small Cell Lung Cancer by Platelet-Derived Microparticles in Circulating Blood.

BACKGROUND: There are limited methods to predict the therapeutic effect of immune checkpoint inhibitors (ICIs). The purpose of this study was to explore the value of circulating microparticles (MPs) in predicting thetherapeutic effects of immunotherapy. METHODS: A prospective study was conducted at the cancer center of PLA general hospital, including all patients with advanced non-small cell lung cancer (NSCLC) who were treated with pembrolizumab or nivolumab from December 2018 to December 2019. The patients were divided into an immune-related objective response (iOR) group and an immune-related disease progression (iPD) group.The numbers of total MPs, platelet-derived microparticles (PMPs) and T-lymphocyte-derived microparticles (T-LyMPs) at baseline and after immunotherapy were detected using a flow cytometer. Univariate analysis and multivariate logistic regression analysis were used to determine the independent influencing factors. RESULTS: We identified 32 patients in the iOR group and 18 patients in the iPD group. No significant difference were found intotal MPs, PMPs and T-LyMPs at the baseline between the 2 groups. While total MPs, PMPs and T-LyMPs in the iPD group were significantly higher than those in the iOR group after immunotherapy(P < 0.05). In the multivariate logistic regression analysis, PMPs ≥80 events/µL after immunotherapy(OR, 7.270; 95% CI, 1.092-48.404, P = 0.04) were associated with disease progression in advanced NSCLC and could independently predict the therapeutic effect of immunotherapy. CONCLUSIONS: PMPs after immunotherapy independently predicted the therapeutic effects of ICIs, making it possible to monitor the therapeutic effect in real time and rapidly adjust treatment regimens. In addition, this study found for the first time that elevated circulating T-LyMPs were associated with disease progression in advanced NSCLC.

Association of Metabolic Syndrome With Long-Term Cardiovascular Risks and All-Cause Mortality in Elderly Patients With Obstructive Sleep Apnea.

BACKGROUND: Evidence suggests that an increased risk of major adverse cardiac events (MACE) and all-cause mortality is associated with obstructive sleep apnea (OSA), particularly in the elderly. Metabolic syndrome (MetS) increases cardiovascular risk in the general population; however, less is known about its influence in patients with OSA. We aimed to assess whether MetS affected the risk of MACE and all-cause mortality in elderly patients with OSA. METHODS: From January 2015 to October 2017, 1,157 patients with OSA, aged ≥60 years, no myocardial infarction (MI), and hospitalization for unstable angina or heart failure were enrolled at baseline and were followed up prospectively. OSA is defined as an apnea-hypopnea index of ≥5 events per hour, as recorded by polysomnography. Patients were classified on the basis of the presence of MetS, according to the definition of the National Cholesterol Education Program (NCEP). Incidence rates were expressed as cumulative incidence. Cox proportional hazards analysis was used to estimate the risk of all events. The primary outcomes were MACE, which included cardiovascular death, MI, and hospitalization for unstable angina or heart failure. Secondary outcomes were all-cause mortality, components of MACE, and a composite of all events. RESULTS: MetS was present in 703 out of 1,157 (60.8%) elderly patients with OSA. During the median follow-up of 42 months, 119 (10.3%) patients experienced MACE. MetS conferred a cumulative incidence of MACE in elderly patients with OSA (log-rank, P < 0.001). In addition, there was a trend for MACE incidence risk to gradually increase in individuals with ≥3 MetS components (P = 0.045). Multivariate analysis showed that MetS was associated with an incidence risk for MACE [adjusted hazard ratio (aHR), 1.86; 95% confidence interval (CI), 1.17-2.96; P = 0.009], a composite of all events (aHR, 1.54; 95% CI, 1.03-2.32; P = 0.036), and hospitalization for unstable angina (aHR, 2.01; 95% CI, 1.04-3.90; P = 0.039). No significant differences in the risk of all-cause mortality and other components of MACE between patients with and without MetS (P > 0.05). Subgroup analysis demonstrated that males (aHR, 2.23; 95% CI, 1.28-3.91, P = 0.05), individuals aged <70 years (aHR, 2.36; 95% CI, 1.27-4.39, P = 0.006), overweight and obese individuals (aHR, 2.32; 95% CI, 1.34-4.01, P = 0.003), and those with moderate-severe OSA (aHR, 1.81;95% CI: 1.05-3.12, P = 0.032) and concomitant MetS were at a higher risk for MACE. CONCLUSION: MetS is common in elderly patients with OSA in the absence of MI, hospitalization for unstable angina or heart failure. Further, it confers an independent, increased risk of MACE, a composite of all events, and hospitalization for unstable angina. Overweight and obese males, aged <70 years with moderate-severe OSA combined with MetS presented a significantly higher MACE risk.

[Early diagnostic value of circulating microparticles in super-elderly patients with infection].

OBJECTIVE: To investigate the level and changing trend of microparticles (MPs) in super-elderly infected patients, and explore its early warning effect on infection. METHODS: The infected patients ≥ 85 years old admitted to the Second Medical Center of Chinese PLA General Hospital from December 2018 to March 2019 were selected as the observation group, and the healthy volunteers ≥ 85 years old in the same period were selected as the control group. Venous blood samples were collected at the 2nd hour, the 2nd day and the 7th day after fever, and the inflammatory markers such as white blood cell count (WBC), neutrophil percentage (NEUT), C-reactive protein (CRP) and procalcitonin (PCT) were measured. The levels of MPs were determined by flow cytometry. Annexin V labeled CD11b positive MPs (Annexin V+/CD11b+ MPs) represented leukocyte microparticles (LMPs), and Annexin V labeled CD66b positive MPs (Annexin V+/CD66b+ MPs) represented neutrophil microparticle (NMPs). The differences of each index at different time points between the two groups were compared, and the predictive value of each index to the infection of elderly patients was analyzed by receiver operating characteristic (ROC) curve. RESULTS: A total of 38 subjects were enrolled, including 28 cases in the observation group and 10 cases in the control group. The levels of LMPs and NMPs in the observation group increased to the peak at the 2nd hour after fever, and were significantly higher than those in the control group [LMPs (cells/µL): 55.0 (28.8, 197.2) vs. 19.0 (13.5, 28.3), NMPs (cells/µL): 226.5 (123.3, 516.5) vs. 26.5 (22.0, 48.8), both P < 0.01]. With the control of the disease, LMPs and NMPs decreased gradually. The NMPs on the 2nd day was significantly lower than that at the 2nd hour of fever [cells/µL: 106.0 (40.0, 309.0) vs. 226.5 (123.3, 516.5), P < 0.05], and the LMPs and NMPs on the 7th day were significantly lower than those on the 2nd day [LMPs (cells/µL): 17.0 (12.5, 43.8) vs. 42.0 (13.0, 117.0), NMPs (cells/µL): 30.0 (15.8, 62.0) vs. 106.0 (40.0, 309.0), both P < 0.05]. There was no significant difference in the levels of LMPs and NMPs between the two groups on the 7th day. Among the inflammatory markers, the NEUT in the observation group was significantly higher than that in the control group at the 2nd hour of fever (0.70±0.09 vs. 0.59±0.04, P < 0.01), but there was no significant difference in WBC, CRP and PCT between the two groups. On the 2nd day, the inflammatory markers in the observation group reached the peak and were significantly higher than those in the control group [WBC (×109/L): 9.33±2.44 vs. 6.37±1.28, NEUT: 0.78±0.08 vs. 0.57±0.04, CRP (mg/L): 5.67±2.99 vs. 0.33±0.18, PCT (µg/L): 0.80±0.67 vs. 0.07±0.03, all P < 0.01]. On the 7th day, the inflammatory markers in the observation group decreased significantly, and there was no significant difference between the observation group and the control group. ROC curve analysis showed that the area under ROC curve (AUC) and 95% confidence interval (95%CI) of LMPs and NMPs on the day of fever were higher than those of WBC, NEUT, CRP and PCT [0.888 (0.763-1.000), 0.973 (0.931-1.000) vs. 0.679 (0.346-0.811), 0.829 (0.700-0.958), 0.607 (0.404-0.811), 0.554 (0.358-0.749)]. CONCLUSIONS: LMPs and NMPs are significantly increased in the early stage of fever, which can predict the incidence of infection in the super-elderly patients.

Pirfenidone alleviates lipopolysaccharide-induced lung injury by accentuating BAP31 regulation of ER stress and mitochondrial injury.

Pirfenidone has been widely used in the treatment of idiopathic pulmonary fibrosis (IPF). However, the role of pirfenidone in LPS-induced acute lung injury (ALI) remains unclear. This study aims to investigate the protective effects of pirfenidone in ALI and to explore its underlying mechanism. Pirfenidone clearly reduces LPS-triggered ALI as indicated by significant pathological alterations, reduced oxidative stress and inflammatory responses in vivo. Furthermore, pirfenidone also blocks apoptosis of LPS-induced alveolar epithelial type II (ATII) cells through inhibition of endoplasmic reticulum (ER) stress and mitochondrial injury in vivo and in vitro. A lower expression level of BAP31, an ER transmembrane protein, was found to be associated with ALI followed LPS challenge. The reintroduction of BAP31 blunted LPS induced ER stress and mitochondrial damage and therefore alleviated ATII cell apoptosis, which correlated with pirfenidone treatment. Knockdown of BAP31 expression in pirfenidone treated ATII cells re-activated ER stress, mitochondrial damage and followed cellular apoptosis. In summary, this study confirms the beneficial effect of pirfenidone on ER stress and mitochondrial dysfunction mediated apoptosis via upregulation of BAP31. Our results demonstrated that pirfenidone may be considered as a potential agent for the treatment of ALI in the future.

Genetic diversity of antigen 38 kDa in Mycobacterium tuberculosis strains from China.

We used 335 Mycobacterium tuberculosis strains from 2010 National Epidemiologic Survey for TB in China and performed comparative sequence analysis of 38 kDa gene after amplification. From the results, we found that there were 5.07% M.tuberculosis strains that demonstrated genetic diversity of 38 kDa in China, and 2.99% strains showed polymorphism of the 38 kDa antigen, and this may be the reason for changes in the antigen produced, which may in turn cause alterations of related functions, thereby allowing immune evasion.

Predictive value of α-amylase in tracheal aspirates for ventilator-associated pneumonia in elderly patients.

OBJECTIVE: This study aims to investigate the correlation between α-amylase in tracheal aspirates and risk factors of aspiration, as well as ventilator-associated pneumonia (VAP), in elderly patients undergoing mechanical ventilation and explore the clinical value of α-amylase for predicting VAP. METHODS: Tracheal aspirates were collected from elderly patients within 2 weeks after tracheal intubation in mechanical ventilation, and α-amylase was detected. Patients were grouped according to the presence of VAP. The correlation between α-amylase and risk factors of aspiration before intubation, as well as VAP, were analyzed. RESULTS: The sample of this study comprised 147 patients. The average age of these patients was 86.9 years. The incidence of VAP was 21% during the study period. Tracheal aspirate α-amylase level increased with the increase in the number of risk factors for aspiration before intubation, α-amylase level was significantly higher in the VAP group than in the non-VAP group, the area under the receiver operating characteristic curve (ROC) of the diagnostic value of α-amylase for VAP was 0.813 (95% CI: 0.721-0.896), threshold value was 4,681.5 U/L, sensitivity was 0.801 and specificity was 0.793. Logistic multivariate analysis revealed the following risk factors for VAP: a number of risk factors before intubation of ≥3, a Glasgow score of <8 points, the absence of continuous aspiration of subglottic secretion and a tracheal aspirate α-amylase level of >4681.5 U/L. CONCLUSION: Tracheal aspirate α-amylase can serve as a biomarker for predicting VAP in elderly patients undergoing mechanical ventilation.

[Clinical characteristics and risk factors affecting outcomes of elderly patients with non-small cell lung cancer complicated by chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the clinical features, treatment strategy and risk factors affecting the prognosis of elderly patients with non-small cell lung cancer (NSCLC) complicated by chronic obstructive pulmonary disease (COPD). METHODS: We retrospectively analyzed the data of elderly patietns (>60 years) with newly diagnosed NSCLC complicated by COPD at the Geriatric Institution of General Hospital of PLA between January, 2000 and June, 2015. The clinical data collected included history of smoking, pulmonary function test results, initial treatments, TNM stage, chief complaints, comorbidities and laboratory tests. The Cox proportional hazards regression model was used to explore the prognostic factors in these patients. RESULTS: A total of 200 NSCLC patients were reviewed, of which 107 (53.5%) patients had the co-morbidity of COPD as confirmed by spirometry using bronchodilator test. The median survival of the patients with NSCLC complicated by COPD was 45.8 months with 1-, 3-, 5-, and 10-year survival rates of 80.4%, 55.4%, 41.0% and 20.0%, respectively. Stratification analysis showed that patients with COPD Gold grades 1 and 2 had a significant longer median overall survival (51.7 and 43.1 months, respectively) than those with grade 3/4 (16.9 months; P=0.020 and 0.043, respectively). Univariate and multivariate analyses using Cox proportional hazards regression model showed that an older age, a higher Gold grade, advanced disease stage (stages III and IV), squamous cell carcinoma, nonsurgical initial treatment, coughing and an elevated serum CEA level were independent risk factors for shorter survival of the patients. CONCLUSION: Multiple prognostic factors can affect the outcomes of elderly patients with NSCLC complicated by COPD, and a higher COPD Gold grade that fails to respond to treatment within 3 months is the independent risk factor for survival of the patients.

Bmi-1 overexpression as an efficient prognostic marker in patients with nonsmall cell lung cancer.

BACKGROUND: The prognostic effect of B-cell-specific Moloney leukemia virus insertion site 1 (Bmi-1) in patients with nonsmall cell lung cancer (NSCLC) remains controversial. We thus performed a meta-analysis to reveal the correlation between Bmi-1 with clinical features and overall survival (OS) in NSCLC. METHODS: Relevant studies were searched through PubMed, Embase, and Web of Science. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) as well as odds ratios (ORs) and 95% CIs were calculated by using STATA version 12.0. RESULTS: Fourteen studies consisting of 1323 patients were included for quantitative analysis. The results showed that Bmi-1 was significantly associated with tumor size (n = 7, OR = 1.79, 95% CI = 1.19-2.71, P = .005, fixed effect), poor differentiation (OR = 1.61, 95% CI = 1.11-2.33, P = .011, fixed effect), and distant metastasis (n = 4, OR = 4.69, 95% CI = 1.52-14.41, P = .007, fixed effect). In addition, high Bmi-1 expression also predicted poor OS (HR = 1.62, 95% CI = 1.14-2.3, P < .001). There was no significant publication bias for any of the analyses. CONCLUSION: In conclusion, Bmi-1 overexpression was correlated with tumor size, poor differentiation, distant metastasis, and worse OS in NSCLC. Therefore, Bmi-1 could be recommended as an efficient prognostic marker for NSCLC.

Elevated CD147 expression is associated with shorter overall survival in non-small cell lung cancer.

A number of studies have reported on the prognostic role of CD147 expression in non-small cell lung cancer (NSCLC); however, the results remain controversial. This study aims to investigate the impact of CD147 on the prognosis of NSCLC by means of a meta-analysis. A literature search was performed for relevant studies published before October 29, 2016. The hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated as effective measures. Sensitivity analysis and publication bias examination were also conducted. Ten eligible studies with a total of 1605 patients were included in this meta-analysis. CD147 overexpression was correlated with poor overall survival (OS) (HR=1.59, 95% CI=1.32-1.91, p<0.001). Elevated CD147 expression was associated with the presence of lymph node metastasis (OR=2.31, 95% CI=1.74-3.07, p<0.001) and advanced TNM stage (OR=3.03, 95% CI=1.24-7.39, p=0.015). However, no significant association between CD147 and sex, age, differentiation, or histology was found. No evidence of significant publication bias was identified. This meta-analysis revealed that overexpression of CD147 was associated with shorter OS, the presence of lymph node metastasis and advanced TNM stage in NSCLC. Therefore, CD147 could serve as a potential prognostic marker for NSCLC.

Hospital-acquired pneumonia due to Achromobacter xylosoxidans in the elderly: A single-center retrospective study in Beijing.

INTRODUCTION: Achromobacter xylosoxidans has been reported in several countries; however, hospital-acquired pneumonia (HAP) due to this organism in elderly patients in China remains rare. METHODOLOGY: HAP due to Achromobacter xylosoxidans identified at the General Hospital of the People's Liberation Army in Beijing from January 2008 to October 2011 was studied. Detailed clinical manifestations were collected. To study the clinical risk factors for the imipenem-resistant strain, patients were divided into two groups: imipenem-resistant (21 cases) and imipenem-nonresistant (20 cases). Univariate and multivariate logistic regression were used. RESULTS: All patients were > 75 years of age, and 92.7% (38/41) were male. Nine patients died 30 days after infection. The mean acute physiology and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) were 23.66 ± 7.71 and 6.93 ± 2.47, respectively. Almost all strains were resistant to aminoglycosides. However, the strains showed significant sensitivity to minocycline (MIN), piperacillin-tazobactam (PTZ), and cefoperazone-sulbactam (SCF). Compared with the imipenem-nonresistant group, more patients with imipenem-resistant infection had the following characteristics: use of an intubation, use of a proton-pump inhibitor (PPI), chronic obstructive pulmonary disease (COPD), and coronary artery disease (CHD). Among the four risk factors, COPD and CHD remained independent risk factors in the multivariate analysis. CONCLUSIONS: HAP due to Achromobacter xylosoxidans occurred in severely ill elderly patients with a long-term indwelling catheter and many underlying diseases. Effective treatment of imipenem-resistant organisms is challenging. SCF, PTZ, and MIN may be useful for imipenem-resistant Achromobacter xylosoxidans.