A ratiometric nanoprobe for the in vivo bioimaging of hypochlorous acid to detect drug-damaged liver and kidneys.

As the organs responsible for toxin transformation and excretion in the body, damage to the liver and kidneys induced by inevitable drug toxicity is the main cause of acute liver and kidney injury. P-Acetamidophenol overdose leads hypochlorous acid (HClO) to accumulate in the mitochondria of tissues, ultimately resulting in acute liver and kidney injury in humans, despite its clinical use as an antipyretic medicine. Herein, we report an HClO-activatable self-assembling ratiometric nanoprobe NRH-800-PEG for screening the upregulation of HClO by colocalization in mitochondria while monitoring the changes in the endogenous HClO levels in cells with ratiometric signals. Furthermore, NRH-800-PEG was constructed to evaluate injury by fluorescence ratio imaging in the tissues of inflammatory mice. Our strategy offers a novel tool for assessing disease progression during drug-induced liver and kidney injury.

Deep vein thrombosis in acute respiratory distress syndrome caused by bacterial pneumonia.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by acute hypoxaemia, and few studies have reported the incidence of deep vein thrombosis (DVT) in direct ARDS caused by bacterial pneumonia. We performed a study to evaluate the prevalence, risk factors, prognosis and potential thromboprophylaxis strategies of DVT in these patients. METHODS: Ninety patients were included. Demographic, and clinical data, laboratory data and outcome variables were obtained, and comparisons were made between the DVT and non-DVT groups. RESULTS: Of the 90 patients, 40 (44.4%) developed lower extremity DVT. Compared with non-DVT patients, DVT patients had higher systemic inflammatory response syndrome (SIRS) scores, lower serum creatinine levels, higher D-dimer levels, and higher rates of sedative therapy and invasive mechanical ventilation (IMV). Multivariate analysis showed an association between the SIRS score (OR 3.803, P = 0.027), level of serum creatinine (OR 0.988, P = 0.001), IMV (OR 5.822, P = 0.002) and DVT. The combination of SIRS score, serum creatinine level and IMV has a sensitivity of 80.0% and a specificity of 74.0% for screening for DVT. The survival rate within 28 days after ARDS in the DVT group was significantly lower than that in the non-DVT group (P = 0.003). There was no difference in the prevalence of DVT between the 41 patients who received thromboprophylaxis and the 49 patients who did not receive thromboprophylaxis (41.5% vs 46.9%; P = 0.603). CONCLUSIONS: The prevalence of DVT is high in hospitalized patients with direct ARDS caused by bacterial pneumonia and may be associated with adverse outcomes. The current thromboprophylaxis strategies may need to be further optimized.

Alkaline Phosphatase Activated Near-Infrared Frequency Upconversion Photosensitizers for Tumor Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising anticancer method due to its noninvasive features, high efficiency, and superior accuracy. The activated near-infrared upconversion photosensitizer has a high tissue penetration depth and could be explicitly released with minimal side effects. Therefore, we designed and synthesized a series of Br-substituted compounds (NFh-Br) based on the near-infrared upconversion hemicyanine dye. The heavy atomic effect improves the generation of 1O2 and upconversion luminous efficiency. Especially, NFh-Br11 exhibited an excellent 1O2 generation rate under 808 nm excitation and effectively killed tumor cells in vitro, and the alkaline phosphatase (ALP)-activatable photosensitizer (NFh-ALP) was obtained by modifying the NFh-Br11. NFh-ALP could be activated by ALP and release NFh-Br11, which induces apoptosis of tumor cells and has outstanding anticancer effects in vitro and in vivo. This work could provide a strategy for designing activatable upconversion photosensitizers.

Screening and early warning system for chronic obstructive pulmonary disease with obstructive sleep apnoea based on the medical Internet of Things in three levels of healthcare: protocol for a prospective, multicentre, observational cohort study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are prevalent respiratory diseases in China and impose significant burdens on the healthcare system. Moreover, the co-occurrence of COPD and OSA exacerbates clinical outcomes significantly. However, comprehensive epidemiological investigations in China remain scarce, and the defining characteristics of the population affected by COPD and OSA, alongside their intrinsic relationship, remain ambiguous. METHODS AND ANALYSIS: We present a protocol for a prospective, multicentre, observational cohort study based on a digital health management platform across three different healthcare tiers in five sites among Chinese patients with COPD. The study aims to establish predicative models to identify OSA among patients with COPD and to predict the prognosis of overlap syndrome (OS) and acute exacerbations of COPD through the Internet of Things (IoT). Moreover, it aims to evaluate the feasibility, effectiveness and cost-effectiveness of IoT in managing chronic diseases within clinical settings. Participants will undergo baseline assessment, physical examination and nocturnal oxygen saturation measuring. Specific questionnaires screening for OSA will also be administered. Diagnostic lung function tests and polysomnography will be performed to confirm COPD and OSA, respectively. All patients will undergo scheduled follow-ups for 12 months to record the changes in symptoms, lung functions and quality of life. Primary outcomes include the prevalence and characteristics of OS, while secondary outcomes encompass OS prognosis and the feasibility of the management model in clinical contexts. A total of 682 patients with COPD will be recruited over 12-24 months. ETHICS AND DISSEMINATION: The study has been approved by Peking University Third Hospital, and all study participants will provide written informed consent. Study results will be published in an appropriate journal and presented at national and international conferences, as well as relevant social media and various stakeholder engagement activities. TRIAL REGISTRATION NUMBER: NCT04833725.

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

The Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infected a substantial proportion of Chinese population, and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment. We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles, plus viral, bacterial, and fungal content, as well as virulence factors and examined their relationships to 28-day mortality were examined. In addition, the bronchoalveolar lavage fluid (BALF) samples from invasive ventilated hospital/community-acquired pneumonia patients (HAP/CAP) sampled in 2019 were included for comparison. Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages, with no difference in 28-day mortality between them. Compared to HAP/CAP cohort, invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract; and in the COVID-19 non-survivors, we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane, higher abundance of opportunistic pathogens including bacterial Alloprevotella, Caulobacter, Escherichia-Shigella, Ralstonia and fungal Aspergillus sydowii and Penicillium rubens. Correlational analysis further revealed significant associations between host immune responses and microbial compositions, besides synergy within viral, bacterial, and fungal pathogens. Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients, providing the basis for future clinical treatment and reduction of fatality.

Activatable self-assembled organic nanotheranostics: Aspartyl aminopeptidase triggered NIR fluorescence imaging-guided photothermal/photodynamic synergistic therapy.

Phototherapy has developed as a powerful method for remedial modalities. The conventional photosensitizers are "always on" state and lack tumor targeting, which contributed to poor therapeutic effect and high toxicity. Therefore, we developed an aspartyl aminopeptidase (DNPEP) activated self-assembled organic nanoparticles (NRh-Asp NPs) with sensitive external irradiation-induced photothermal therapy and photodynamic therapy (PTT/PDT). NRh-Asp NPs can be activated to NRh-NH2 NPs by DNPEP, demonstrating strong near-infrared (NIR) fluorescence, and efficiently generating heat and singlet oxygen under the near-infrared laser. NRh-Asp NPs was successfully used for visualizing DNPEP in vitro and in vivo in NIR region, and demonstrated good synergistic anti-cancer efficacy of PDT and PTT. These results suggest that DNPEP-mediated NRh-Asp NPs are promising candidates for image-guided phototherapeutic of tumor.

Mitochondria targeted near-infrared chemodosimeter for upconversion luminescence bioimaging of hypoxia.

We report a mitochondria-targeted near-infrared probe (NRh-O) for frequency upconversion luminescence (FUCL) imaging of hypoxia. Under hypoxic conditions, NRh-O rapidly responds to release the FUCL product NRh (λex/em = 850/825 nm) with high sensitivity and selectivity in mitochondria. This highlights the potential application of a hypoxia-responsive probe in early clinical diagnosis.

Relationship Between Endogenous Hydrogen Sulfide and Pulmonary Vascular Indexes on High-Resolution Computed Tomography in Patients with Chronic Obstructive Pulmonary Disease.

Objective: To explore the relationship between endogenous hydrogen sulfide (H2S) and high-resolution computed tomography (HRCT) indexes in pulmonary vascular remodeling. Methods: A total of 94 stable chronic obstructive pulmonary disease (COPD) patients were recruited for the study．Plasma H2S levels were measured using fluorescence probe. Fluorescence quantitative polymerase chain reaction was used to measure H2S synthase cystathionine-γ-lyase (CSE) mRNA and cystathionine-ß-synthesis enzyme (CBS) mRNA. The main pulmonary artery diameter (mPAD), axial diagonal mPAD, coronal mPAD, sagittal mPAD, right pulmonary artery diameter (RPAD), left pulmonary artery diameter (LPAD), and ascending aortic diameter (AAD) and the percentage of total cross-sectional area of vessels less than 5 mm2 of total lung area (%CSA <5) on HRCT were measured. Pulmonary arterial systolic pressure (PASP) of echocardiography, blood gas analysis, and routine blood tests were performed. Correlation analysis and multivariate linear regression were performed using SPSS 22.0. Results: H2S was negatively correlated with mPAD, axial diagonal mPAD, and sagittal mPAD (r = -0.25~-0.32) and positively correlated with PaO2 (r = 0.35). Relative expression of CSE mRNA was positively correlated with PASP, coronal mPAD, sagittal mPAD, white blood cell count (WBC), and neutrophil count (N) (r = 0.30~0.44). The relative expression of CBS mRNA was positively correlated with PASP, WBC, and N (r = 0.34~0.41). In separate models predicting pulmonary vascular indexes, a 1µmol/L increase in H2S predicted lower pulmonary artery diameter (for axial diagonal mPAD, 0.76mm lower; for mPAD/AAD, 0.68mm lower). All P values were less than 0.05. Conclusion: Endogenous H2S may be involved in pulmonary vascular remodeling, providing a new method for the diagnosis and treatment of COPD. The generation of H2S may be inhibited by hypoxia, inflammation, etc.

Phenotype and management of chronic obstructive pulmonary disease patients in general population in China: a nationally cross-sectional study.

This study aims to investigate the characteristics of the phenotype and management of chronic obstructive pulmonary disease (COPD) patients in the general population in China. We analyzed spirometry-confirmed COPD patients who were identified from a population-based, nationally representative sample in China. All participants were measured with airflow limitation severity based on post-bronchodilator FEV1 percent predicted, bronchodilator responsiveness, exacerbation history, and respiratory symptoms. Among a total of 9134 COPD patients, 90.3% were non-exacerbators, 2.9% were frequent exacerbators without chronic bronchitis, 2.0% were frequent exacerbators with chronic bronchitis, and 4.8% were asthma-COPD overlap. Less than 5% of non-exacerbators ever had pulmonary function testing performed. The utilization rate of inhaled medication in non-exacerbators, exacerbators without chronic bronchitis, exacerbators with chronic bronchitis, and asthma-COPD overlap was 1.4, 23.5, 29.5, and 19.4%, respectively. A comprehensive strategy for the management of COPD patients based on phenotype in primary care is urgently needed.

Hydrogen Sulfide Attenuates Particulate Matter-Induced Emphysema and Airway Inflammation Through Nrf2-Dependent Manner.

PURPOSE: To investigate whether hydrogen sulfide provide protective effects on atmosphere particulate matter (PM)-induced emphysema and airway inflammation and its mechanism. METHODS: Wild type C57BL/6 and Nrf2 knockout mice were exposed to PM (200 µg per mouse). Hydrogen sulfide or propargylglycine were administered by intraperitoneal injection respectively 30 min before PM exposure, mice were anesthetized 29th day after administration. Mice emphysema, airway inflammation, and oxidative stress were evaluated, the expression of NLRP3, active caspase-1, and active caspase-3 were detected. Alveolar epithelial A549 cells line were transfected with control small interfering RNA (siRNA) or Nrf2 siRNA and then incubated with or without hydrogen sulfide for 30 min before exposed to fine particulate matter for 24 h, cell viability, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) assay, the secretion of interleukin (IL)-1ß, ASC speck formation, the expression level of NLRP3, active caspase-1, and active caspase-3 were measured. RESULTS: PM significantly increased mice emphysema and airway inflammation measured by mean linear intercept, alveolar destroy index and total cell, neutrophil counts, cytokines IL-6, tumor necrosis factor (TNF)-α, CXCL1, IL-1ß in bronchoalveolar lavage fluid. PM-induced mice emphysema and airway inflammation was greatly attenuated by hydrogen sulfide, while propargylglycine aggravated that. PM-induced oxidative stress was reduced by hydrogen sulfide as evaluated by 8-OHdG concentrations in lung tissues. The expression of NLRP3, active caspase-1, and active caspase-3 enhanced by PM were also downregulated by hydrogen sulfide in mice lung. The protective effect of hydrogen sulfide on emphysema, airway inflammation, inhibiting oxidative stress, NLRP3 inflammasome formation, and anti-apoptosis was inhibited by Nrf2 knockout in mice. Similarly, hydrogen sulfide attenuated the secretion of IL-1ß, NLRP3 expression, caspase-1 activation, ASC speck formation, and apoptosis caused by fine particulate matter exposure in A549 cells but not in Nrf2 silenced cells. CONCLUSION: Hydrogen sulfide played a protect role in PM-induced mice emphysema and airway inflammation by inhibiting NLRP3 inflammasome formation and apoptosis via Nrf2-dependent pathway.

Impact of obstructive sleep apnea on pulmonary hypertension in patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) syndrome are highly prevalent respiratory conditions. Their coexistence is referred to as the overlap syndrome. They are both related to pulmonary hypertension (PH) development. This study investigated the effects of OSA on PH in patients with COPD and the associated factors. METHODS: Consecutive patients with stable COPD were recruited for an observational cross-sectional study from September 2016 to May 2018 at Peking University Third Hospital. In total, 106 patients with COPD were enrolled and performed home portable monitoring and echocardiography. OSA was defined by an apnea hypopnea index (AHI) ≥10 events/h. Based on OSA absence or presence, patients were divided into the COPD with OSA and COPD without OSA groups. Factors affecting pulmonary artery pressure (PAP) and PH were identified using univariate analysis and logistic regression models. RESULTS: In the 106 patients with COPD, the mean age was 69.52 years, 91.5% were men, and the mean forced expiratory volume in 1 s (FEV1) percentage of predicted was 56.15%. Fifty-six (52.8%) patients with COPD were diagnosed with OSA, and 24 (22.6%) patients with COPD were diagnosed as PH. Compared with COPD without OSA group, the median PAP in COPD with severe OSA group increased by 5 mmHg (36.00 [26.00-50.00] mmHg vs. 31.00 [24.00-34.00] mmHg, P = 0.036). COPD with percent of night-time spent with oxygen saturation below 90% (T90) > 10% group had higher PAP than COPD with T90 ≤ 1% group (36.00 [29.00-50.00)] mmHg vs. 29.00 [25.50-34.00] mmHg, F = 7.889, P = 0.007). Univariate analysis revealed age, FEV1% predicted, T90, and Charlson index had statistically significant effects on PH. Multiple regression analysis showed a significant and independent effect of both FEV1% predicted (odds ratio [OR] = 3.46; 95% confidence interval [CI]: 1.15-10.46; P = 0.028) and AHI (OR = 3.20; 95% CI: 1.09-19.35; P = 0.034) on PH. CONCLUSIONS: Patients with COPD with OSA are more susceptible to PH, which is associated with declining lung function and increased severity of OSA. Thus, nocturnal hypoxemia and OSA in elderly patients with COPD should be identified and treated.

Serum Monounsaturated Triacylglycerol Predicts Steatohepatitis in Patients with Non-alcoholic Fatty Liver Disease and Chronic Hepatitis B.

Chronic liver disease is associated with lipid metabolic disruption. We carried out a study to determine serum lipidomic features of patients with non-alcoholic fatty liver disease (NAFLD) and active chronic hepatitis B (CHB) and explored the biomarkers for non-alcoholic steatohepatitis (NASH). Serum lipidomic profiles of healthy controls (n = 23) and of biopsy-proven NAFLD (n = 42), CHB with NAFLD (n = 22) and without NAFLD (n = 17) were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. There were distinct serum lipidome between groups of NAFLD and CHB without NAFLD. Most of the neutral lipids and ceramide were elevated in the NAFLD group but were decreased in the CHB without NAFLD group. Plasmalogens were decreased in both groups. Triacylglycerols (TAGs) with lower carbon numbers and double bonds were increased in subjects with NASH. Serum monounsaturated TAG was a significant predictor of NASH (OR = 3.215; 95%CI 1.663-6.331) and positively correlated with histological activity (r = 0.501; P < 0.001). It showed good predictability for NASH in the NAFLD group [area under the receiver operating characteristic curves (AUROC) = 0.831] and was validated in the CHB group (AUROC = 0.833); this characteristic was superior to that of cytokeratin-18 and alanine transaminase. The increase in monounsaturated TAG might be a specific marker for NASH in both NAFLD and CHB patients.

Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B.

AIM: To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). METHODS: A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. RESULTS: After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05). CONCLUSION: Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients.