Decoding cellular plasticity and niche regulation of limbal stem cells during corneal wound healing.

BACKGROUND: Dysfunction or deficiency of corneal epithelium results in vision impairment or blindness in severe cases. The rapid and effective regeneration of corneal epithelial cells relies on the limbal stem cells (LSCs). However, the molecular and functional responses of LSCs and their niche cells to injury remain elusive. METHODS: Single-cell RNA sequencing was performed on corneal tissues from normal mice and corneal epithelium defect models. Bioinformatics analysis was performed to confirm the distinct characteristics and cell fates of LSCs. Knockdown of Creb5 and OSM treatment experiment were performed to determine their roles of in corneal epithelial wound healing. RESULTS: Our data defined the molecular signatures of LSCs and reconstructed the pseudotime trajectory of corneal epithelial cells. Gene network analyses characterized transcriptional landmarks that potentially regulate LSC dynamics, and identified a transcription factor Creb5, that was expressed in LSCs and significantly upregulated after injury. Loss-of-function experiments revealed that silencing Creb5 delayed the corneal epithelial healing and LSC mobilization. Through cell-cell communication analysis, we identified 609 candidate regeneration-associated ligand-receptor interaction pairs between LSCs and distinct niche cells, and discovered a unique subset of Arg1+ macrophages infiltrated after injury, which were present as the source of Oncostatin M (OSM), an IL-6 family cytokine, that were demonstrated to effectively accelerate the corneal epithelial wound healing. CONCLUSIONS: This research provides a valuable single-cell resource and reference for the discovery of mechanisms and potential clinical interventions aimed at ocular surface reconstruction.

Comparison of Coagulation-Integrated Sand Filtration and Ultrafiltration for Seawater Reverse Osmosis Pretreatment.

The removal of dissolved organic matter (DOM) from seawater before the reverse osmosis (RO) processes is crucial for alleviating organic fouling of RO membranes. However, research is still insufficiently developed in the comparison of the effectiveness of integrating coagulation with ultrafiltration (UF) or sand filtration (SF) in the pretreatment stage of seawater reverse osmosis (SWRO) for the removal of DOM. In this study, we investigated the effect of pretreatment technologies on RO fouling caused by DOM in seawater, including the integration of coagulation and sand filtration (C-S pretreatment) and the integration of coagulation and ultrafiltration (C-U pretreatment). Both integrated pretreatments achieved comparable DOM removal rates (70.2% for C-U and 69.6% for C-S), and C-S exhibited enhanced removal of UV-absorbing compounds. Although C-U was more proficient in reducing the silt density index (below 2) compared to C-S (above 3) and improved the elimination of humic acid-like organics, it left a higher proportion of tyrosine-protein-like organics, soluble microbial by-product-like organics, and finer organics in the effluent, leading to the formation of a dense cake layer on RO membrane and a higher flux decline. Therefore, suitable technologies should be selected according to specific water conditions to efficiently mitigate RO membrane fouling.

Dehydration of Organic Solvents from Ternary Mixtures Containing Toluene/Methanol/Water by Pervaporation.

The separation of a toluene/methanol/water ternary mixture is a difficult task due to the toluene/water and toluene/methanol azeotropes. In this article, low-energy pervaporation is proposed for the separation of the ternary azeotrope toluene-methanol-water. This work investigates the effects of feed temperature, feed flow rate, and vacuum on pervaporation and compares the energy consumption of pervaporation with that of distillation. The results showed that at the optimized flow rate of 50 L/h and a permeate side vacuum of 60 kPa at 50 °C, the water and methanol content in the permeate was about 63.2 wt.% and 36.8 wt.%, respectively, the water/ methanol separation factor was 24.04, the permeate flux was 510.7 g/m2·h, the water content in the feed out was reduced from 2.5 wt.% to less than 0.66 wt.%, and the dehydration of toluene methanol could be realized. Without taking into account the energy consumption of pumps and other power equipment, pervaporation requires an energy consumption of 43.53 kW·h to treat 1 ton of raw material, while the energy consumption of distillation to treat 1 ton of raw material is about 261.5 kW·h. Compared to the existing distillation process, the pervaporation process consumes much less energy (about one-sixth of the energy consumption of distillation). There is almost no effect on the surface morphology and chemical composition of the membrane before and after use. The method provides an effective reference for the dehydration of organic solvents from ternary mixtures containing toluene/methanol/water.

Interplay between pulmonary epithelial stem cells and innate immune cells contribute to the repair and regeneration of ALI/ARDS.

Mammalian lung is the important organ for ventilation and exchange of air and blood. Fresh air and venous blood are constantly delivered through the airway and vascular tree to the alveolus. Based on this, the airways and alveolis are persistently exposed to the external environment and are easily suffered from toxins, irritants and pathogens. For example, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common cause of respiratory failure in critical patients, whose typical pathological characters are diffuse epithelial and endothelial damage resulting in excessive accumulation of inflammatory fluid in the alveolar cavity. The supportive treatment is the main current treatment for ALI/ARDS with the lack of targeted effective treatment strategies. However, ALI/ARDS needs more targeted treatment measures. Therefore, it is extremely urgent to understand the cellular and molecular mechanisms that maintain alveolar epithelial barrier and airway integrity. Previous researches have shown that the lung epithelial cells with tissue stem cell function have the ability to repair and regenerate after injury. Also, it is able to regulate the phenotype and function of innate immune cells involving in regeneration of tissue repair. Meanwhile, we emphasize that interaction between the lung epithelial cells and innate immune cells is more supportive to repair and regenerate in the lung epithelium following acute lung injury. We reviewed the recent advances in injury and repair of lung epithelial stem cells and innate immune cells in ALI/ARDS, concentrating on alveolar type 2 cells and alveolar macrophages and their contribution to post-injury repair behavior of ALI/ARDS through the latest potential molecular communication mechanisms. This will help to develop new research strategies and therapeutic targets for ALI/ARDS.

A Clinical Bacterial Dataset for Deep Learning in Microbiological Rapid On-Site Evaluation.

Microbiological Rapid On-Site Evaluation (M-ROSE) is based on smear staining and microscopic observation, providing critical references for the diagnosis and treatment of pulmonary infectious disease. Automatic identification of pathogens is the key to improving the quality and speed of M-ROSE. Recent advancements in deep learning have yielded numerous identification algorithms and datasets. However, most studies focus on artificially cultured bacteria and lack clinical data and algorithms. Therefore, we collected Gram-stained bacteria images from lower respiratory tract specimens of patients with lung infections in Chinese PLA General Hospital obtained by M-ROSE from 2018 to 2022 and desensitized images to produce 1705 images (4,912 × 3,684 pixels). A total of 4,833 cocci and 6,991 bacilli were manually labelled and differentiated into negative and positive. In addition, we applied the detection and segmentation networks for benchmark testing. Data and benchmark algorithms we provided that may benefit the study of automated bacterial identification in clinical specimens.

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.

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.

Single-cell landscape of immunological responses in elderly patients with sepsis.

Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.

Sleep deprivation induces corneal endothelial dysfunction by downregulating Bmal1.

BACKGROUND: Sleep deprivation (SD) is a common public health problem that contributes to various physiological disorders and increases the risk of ocular diseases. However, whether sleep loss can damage corneal endothelial function remains unclear. This study aimed to determine the effect and possible mechanism of SD on the corneal endothelium. METHODS: Male C57BL/6J mice were subjected to establish SD models. After 10 days, quantitative RT-PCR (qRT-PCR) and western blot or immunostaining for the expression levels of zonula occludens-1 (ZO-1), ATPase Na+/K + transporting subunit alpha 1 (Atp1a1), and core clock genes in the corneal endothelium were evaluated. Reactive oxygen species staining and mitochondrial abundance characterized the mitochondrial function. The regulatory role of Bmal1 was confirmed by specifically knocking down or overexpressing basic helix-loop-helix ARNT like 1 protein (Bmal1) in vivo. In vitro, a mitochondrial stress test was conducted on cultured human corneal endothelial cells upon Bmal1 knockdown. RESULTS: SD damaged the barrier and pump functions of mouse corneal endothelium, accompanied by mitochondrial dysfunction. Interestingly, SD dramatically downregulated the core clock gene Bmal1 expression level. Bmal1 knockdown disrupted corneal endothelial function, while overexpression of Bmal1 ameliorated the dysfunction induced by SD. Mitochondrial bioenergetic deficiency mediated by Bmal1 was an underlying mechanism for SD induced corneal endothelial dysfunction. CONCLUSION: The downregulation of Bmal1 expression caused by SD led to corneal endothelial dysfunction via impairing mitochondrial bioenergetics. Our findings offered insight into how SD impairs the physiological function of the corneal endothelium and expanded the understanding of sleep loss leading to ocular diseases.

Reverse Osmosis with Intermediate Chemical Demineralization: Scale Inhibitor Selection, Degradation, and Seeded Precipitation.

Two-stage reverse osmosis (RO) processes with intermediate concentrate demineralization (ICD) provide an efficient strategy to treat brines with high CaSO4 contents and reduce concentrate discharge. In this paper, an SRO concentrate is treated using ICD to remove CaSO4 and then mixed with a PRO concentrate for further desalination in SRO, thereby reducing the discharge of the concentrate. We investigate the selection and degradation of scale inhibitors, as well as seeded precipitation in the two-stage RO process with ICD, to achieve a high water recovery rate. A scale inhibitor is added to restrain CaSO4 crystallization on the membrane surface, and the optimized scale inhibitor, RO-400, is found to inhibit calcium sulfate scaling effectively across a wide range of the saturation index of gypsum (SIg) from 2.3 to 6. Under the optimized parameters of 40 W UV light and 70 mg/L H2O2, UV/H2O2 can degrade RO-400 completely in 15 min to destroy the scale inhibitor in the SRO concentrate. After scale inhibitor degradation, the SRO concentrate is desaturated by seeded precipitation, and the reaction degree of CaSO4 reaches 97.12%, leading to a concentrate with a low SIg (1.07) for cyclic desalination. Three UVD-GSP cycle tests show that the reused gypsum seeds can also ensure the effect of the CaSO4 precipitation process. This paper provides a combined UVD-GSP strategy in two-stage RO processes to improve the water recovery rate for CaSO4-contained concentrate.

Association between the triglyceride-glucose index and all-cause and CVD mortality in the young population with diabetes.

BACKGROUND: Although studies have demonstrated the value of the triglyceride-glucose (TyG) index for cardiovascular disease (CVD) and cardiovascular mortality, however, few studies have shown that the TyG index is associated with all-cause or CVD mortality in young patients with diabetes. This study aimed to investigate the association between the TyG index and all-cause and CVD mortality in young patients with diabetes in the United States. METHODS: Our study recruited 2440 young patients with diabetes from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Cox regression modeling was used to investigate the association between TyG index and mortality in young patients with diabetes. The nonlinear association between TyG index and mortality was analyzed using restricted cubic splines (RCS), and a two-segment Cox proportional risk model was constructed for both sides of the inflection point. RESULTS: During a median follow-up period of 8.2 years, 332 deaths from all causes and 82 deaths from cardiovascular disease were observed. Based on the RCS, the TyG index was found to have a U-shaped association with all-cause and CVD mortality in young patients with diabetes, with threshold values of 9.18 and 9.16, respectively. When the TyG index was below the threshold value (TyG index < 9.18 in all-cause mortality and < 9.16 in CVD mortality), its association with all-cause and CVD mortality was not significant. When the TyG index was above the threshold (TyG index ≥ 9.18 in all-cause mortality and ≥ 9.16 in CVD mortality), it showed a significant positive association with all-cause mortality and CVD mortality (HR 1.77, 95% CI 1.05-2.96 for all-cause mortality and HR 2.38, 95% CI 1.05-5.38 for CVD mortality). CONCLUSION: Our results suggest a U-shaped association between TyG index and all-cause and CVD mortality among young patients with diabetes in the United States, with threshold values of 9.18 and 9.16 for CVD and all-cause mortality, respectively.

Cell Cross-Talk in Alveolar Microenvironment: From Lung Injury to Fibrosis.

Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions among these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and the development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. In addition, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aim to reveal new insights into the molecular mechanisms that drive lung injury toward fibrosis and identify potential targets for therapeutic intervention.

Single-Nuclei Characterization of Lacrimal Gland in Scopolamine-Induced Dry Eye Disease.

Purpose: The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq). Methods: Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining. Results: The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells. Conclusions: Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.

Polystyrene microplastic-induced endoplasmic reticulum stress contributes to growth plate endochondral ossification disorder in young rat.

BACKGROUND: Previous studies on the effects of microplastics (MPs) on bone in early development are limited. This study aimed to investigate the adverse effects of MPs on bone in young rats and the potential mechanism. METHODS: Three-week-old female rats were orally administered MPs for 28 days, and endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) and ER stress agonist tunicamycin (TM) were added to evaluate the effect of ER stress on toxicity of MPs. The indicators of growth and plasma markers of bone turnover were evaluated. Tibias were analyzed using micro-computed tomography (micro-CT). Histomorphological staining of growth plates was performed, and related gene expression of growth plate chondrocytes was tested. RESULTS: After exposure of MPs, the rats had decreased growth, shortened tibial length, and altered blood calcium and phosphorus metabolism. Trabecular bone was sparse according to micro-CT inspection. In the growth plate, the thickness of proliferative zone substantial reduced while the thickness of hypertrophic zone increased significantly, and the chondrocytes were scarce and irregularly arranged according to tibial histological staining. The transcription of the ER stress-related genes BIP, PERK, ATF4, and CHOP dramatically increased, and the transcription factors involved in chondrocyte proliferation, differentiation, apoptosis, and matrix secretion were aberrant according to RT-qPCR and western blotting. Moreover, the addition of TM showed higher percentage of chondrocyte death. Administration of SAL alleviated all of the MPs-induced symptoms. CONCLUSION: These results indicated that MPs could induce growth retardation and longitudinal bone damage in early development. The toxicity of MPs may attribute to induced ER stress and impaired essential processes of the endochondral ossification after MPs exposure.

A novel therapeutic outlook: Classification, applications and challenges of inhalable micron/nanoparticle drug delivery systems in lung cancer (Review).

Lung cancer represents a marked global public health concern. Despite existing treatment modalities, the average 5­year survival rate for patients with patients with lung cancer is only ~20%. As there are numerous adverse effects of systemic administration routes, there is an urgent need to develop a novel therapeutic strategy tailored specifically for patients with lung cancer. Non­invasive aerosol inhalation, as a route of drug administration, holds unique advantages in the context of respiratory diseases. Nanoscale materials have extensive applications in the field of biomedical research in recent years. The present study provides a comprehensive review of the classification, applications summarized according to existing clinical treatment modalities for lung cancer and challenges associated with inhalable micron/nanoparticle drug delivery systems (DDSs) in lung cancer. Achieving localized treatment of lung cancer preclinical models through inhalation is deemed feasible. However, further research is required to substantiate the efficacy and long­term safety of inhalable micron/nanoparticle DDSs in the clinical management of lung cancer.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

Real-world effectiveness of nirmatrelvir-ritonavir versus azvudine in hospitalized patients with COVID-19 during the omicron wave in Beijing: a multicenter retrospective cohort study.

BACKGROUND AND AIM: Two oral antivirals (Nirmatrelvir- ritonavir and Azvudine) are widely used in China practice during the Omicron wave of the pandemic. However, little evidence regarding the real-world effectiveness of these two oral antivirals in in-hospital patients. We aimed to evaluate the clinical effectiveness of nirmatrelvir-ritonavir versus azvudine among adult hospitalized patients with COVID-19. METHODS: This retrospective cohort study used data from three Chinese PLA General Hospital medical centres. Hospitalized patients with COVID-19 treated with azvudine or nirmatrelvir-ritonavir from Dec 10, 2022, to February 20, 2023, and did not require invasive ventilation support on admission were eligible for inclusion. RESULTS: After exclusions and propensity-score matching, the final analysis included 486 azvudine recipients and 486 nirmatrelvir-ritonavir recipients. By 28 days of initiation of the antivirus treatment, the crude incidence rate of all-cause death was similar in both types of antivirus treatment (nirmatrelvir-ritonavir group 2.8 events 1000 person-days [95% CI, 2.1-3.6] vs azvudine group 3.4 events/1000 person-days [95% CI, 2.6-4.3], P = 0.38). Landmark analysis showed that all-cause death was lower in the nirmatrelvir-ritonavir (3.5%) group than the azvudine (6.8%, P = 0.029) within the initial 10-day admission period, while no significant difference was observed for results between 10 and 28 days follow-up. There was no significant difference between the nirmatrelvir-ritonavir group and the azvudine group in cumulative incidence of the composite disease progression event (8.6% with nirmatrelvir-ritonavir vs. 10.1% with azvudine, HR, 1.22; 95% CI 0.80-1.86, P = 0.43). CONCLUSION: Among patients hospitalized with COVID-19 during the omicron wave in Beijing, similar in-hospital clinical outcomes on 28 days were observed between patients receiving nirmatrelvir-ritonavir and azvudine. However, it is worth noticing that nirmatrelvir-ritonavir appears to hold an advantage over azvudine in reducing early mortality. Further randomized controlled trials are needed to verify the efficacy of those two antivirus medications especially in early treatment.

Nosocomial surveillance of multidrug-resistant Acinetobacter baumannii: a genomic epidemiological study.

Acinetobacter baumannii is a major opportunistic pathogen causing hospital-acquired infections, and it is imperative to comprehend its evolutionary and epidemiological dynamics in hospitals to prevent and control nosocomial transmission. Here, we present a comprehensive genomic epidemiological study involving the genomic sequencing and antibiotic resistance profiling of 634 A. baumannii strains isolated from seven intensive care units (ICUs) of a Chinese general hospital over 2 consecutive years. Our study reveals that ST2 is highly dominant (90.54%) in the ICUs, with 98.90% of the ST2 exhibiting multidrug resistant or extensively drug resistant. Phylogenetic analyses of newly sequenced genomes and public data suggest that nosocomial isolates originated outside the hospital but evolved inside. The major lineages appear to be stable, with 9 of the 28 identified nosocomial epidemic clones infecting over 60% of the affected patients. However, outbreaks of two highly evolved clones have been observed in different hospitals, suggesting significant inter-hospital transmission chains. By coupling patient medical records and genomic divergence of the ST2, we found that cross-ward patient transfer played a crucial role in pathogen's nosocomial transmission. Additionally, we identified 831 potential adaptive evolutionary loci and 44 associated genes by grouping and comparing the genomes of clones with different prevalence. Overall, our study provides a comprehensive and contemporary survey on the epidemiology and genomic evolution of A. baumannii in a large Chinese general hospital. These findings shed light on the nosocomial evolution and transmission of A. baumannii and offers valuable information for transmission prevention and antibiotic therapy.IMPORTANCEThis study delved into the genomic evolution and transmission of nosocomial Acinetobacter baumannii on a large scale, spanning both an extended time period and the largest sample size to date. Through molecular epidemiological investigations based on genomics, we can directly trace the origin of the pathogen, detecting and monitoring outbreaks of infectious diseases in a timely manner, and ensuring public health safety. In addition, this study also collects a large amount of genomic and antibiotic resistance detection data, which is helpful for phenotype prediction based on genomic sequencing. It enables patients to receive personalized antibiotic treatment quickly, helps doctors select antibiotics more accurately, and contributes to reducing the use of antibiotics and lowering the risk of antibiotic resistance development.