Pulmonary Infection Research Articles

Cyclophostin and Cyclipostins analogues counteract macrolide-induced resistance mediated by erm(41) in Mycobacterium abscessus

BackgroundMycobacterium abscessus is an emerging pathogen causing severe pulmonary infections, particularly in individuals with underlying conditions, such as cystic fibrosis or chronic obstructive pulmonary disease. Macrolides, such as clarithromycin (CLR) or azithromycin (AZM), represent the cornerstone of antibiotherapy against the M. abscessus species. However, prolonged exposure to these macrolides can induce of Erm(41)-mediated resistance, limiting their spectrum of activity and leading to therapeutic failure. Therefore, inhibiting Erm(41) could thwart this resistance mechanism to maintain macrolide susceptibility, thus increasing the rate of treatment success. In our previous study, the Erm(41) methyltransferase was identified as a possible target enzyme of Cyclipostins and Cyclophostin compounds (CyC).MethodsHerein, we exploited this feature to evaluate the in vitro activity of CLR and AZM in combination with different CyC via the checkerboard assay on macrolide-susceptible and induced macrolide-resistant M. abscessus strains selected in vitro following exposure CLR and AZM.ResultsOur results emphasize the use of the CyC to prevent/overcome Erm(41)‑induced resistance and to restore macrolide susceptibility.ConclusionThis work should expand our therapeutic arsenal in the fight against a antibioticresistant mycobacterial species and could provide the opportunity to revisit the therapeutic regimen for combating M. abscessus pulmonary infections in patients, and particularly in erm(41)-positive strains.

Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma.

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. We therefore studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28 day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide was on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. The trial completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80) and the median number of prior lines was 3 (range 1-9); 25% had high risk FISH. Prior therapies included: pomalidomide (33%), daratumumab (25%), and isatuximab (4%). Best ORR was 56.3% and median PFS was 10 months. In patients with 1 prior line of therapy, ORR was 73.7% and median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple class exposed with prior anti-CD38 monoclonal antibody.

ANTIVIRAL IL-33-STUMULATED GROUP 2 INNATE LYMPHOID CELLS (CD-90 AND CD-117) FROM MOUSE LUNGS

This article represents not only a significant scientific value, but also a great teaching and instruction value for researchers and motivated students to improve the skill spectrum in flow cytometry. This article provides step-by- step procedure description and results based on in vivo studies on murine lung tissue, cell of interest isolation with dual protocols for flow cytometry method as well as IL-33 impact in dynamics. The newly described innate lymphoid cells of group 2 (ILC2) play an important role in type 2 immune reactions, epithelial repair in mucosal tissue and metabolic homeostasis. ILC2 releases large amounts of type 2 cytokines such as interleukin 4 (IL-4), IL-5 and IL-13, which stimulate type 2 immunity, such as protection against worms. However, without strict regulation, the level of ILC2 can cause undesirable type 2 immune pathologies, including allergic inflammation of the respiratory tract, hypersensitivity of the respiratory tract and atopic dermatitis. Viral infections of the respiratory tract, which are typical triggers of type 1 immune reactions, often lead to type 2 pulmonary immune pathologies, such as asthma and its exacerbations. Interestingly, pulmonary virus infections induce the release of IL-33 with subsequent induction of ILC2-mediated type 2 pulmonary immunopathology, which is independent of the adaptive immune system.

Analysis of prognosis of neurological sequelae in children with carbon monoxide poisoning

This study retrospectively analyzed children admitted to the Fourth Affiliated Hospital of Guangxi Medical University for CO (carbon monoxide) poisoning from January 2018 to December 2022 and followed up on their neurological sequelae for a long time. The study was approved by the Ethics Committees of the Fourth Affiliated Hospital of Guangxi Medical University (the identification code was KY2023131) and informed consent was obtained from all participants and/or their legal guardians. The study complied with the Declaration of Helsinki. Through Global Deterioration Scale [GDS], we further compared the differences between children with and without cognitive impairment, and identified some risk factors for long-term cognitive impairment in children after CO poisoning. The GDS score of the patient was based on the follow-up score, and we only conducted one follow-up and recorded the GDS score throughout the entire study period. The follow-up time interval is defined as the time from the first discharge of the patient to our follow-up. A total of 113 children were encompassed in the study, with an average follow-up of 3.6 years (3.6 ± 1.5 years). Among them, 13 children (11.5%, 13/113) had cognitive abnormalities. The utilization of gas water heaters in enclosed bathrooms (101 cases, 89.4%) constituted the most frequent cause of CO poisoning among children in this study, followed by heating with fire (11 cases, 9.7%). Furthermore, one child was left by his father in a running car, thereby resulting in poisoning. The clinical manifestations of CO poisoning in children were mainly consciousness disorders (67 cases, 59.3%), dizziness or headache (37 cases, 32.7%), and other manifestations including irritability, crying, vomiting, limb weakness, and limb twitching, a total of 9 cases. The duration of consciousness disorders in children with cognitive abnormalities was mostly more than one day, with a median of 5 days, and the hospitalization time was longer. Children with cognitive abnormalities had higher C-reactive protein (CRP) levels, higher D-dimer levels, and higher liver enzyme levels. The most common imaging change after CO poisoning in children was cerebral edema, with two cases of subarachnoid hemorrhage observed and one case of demyelinating changes observed. For children with coma time less than one hour, there were few abnormal changes in cranial imaging. Children with cognitive abnormalities were more likely to develop epilepsy (38.5%, 5/13) and other system damage (53.8%, 7/13) during hospitalization, including pulmonary infection (3 cases), stressful gastrointestinal bleeding (2 cases), electrolyte imbalance (2 cases), dysfunction of liver, kidney or myocardial (3 cases), and some children had multiple system damage at the same time. There were statistical differences in the admission CO hemoglobin level, fibrinogen, D-dimer, high-sensitivity CRP, neuron enolase, alanine aminotransferase or aspartate aminotransferase (ALT or AST), lactate dehydrogenase, length of hospital stay, discharge and admission Glasgow Coma Scale (GCS), seizure frequency, duration of consciousness disorders more than one day, cranial imaging changes, use of ventilators, presence of other system damage, the number of hyperbaric oxygen (HBO) treatments, and whether the patients were transferred to another hospital between the two groups of children. Multivariate logistic regression analysis showed that head imaging changes and consciousness disorders lasting for more than a day were statistical differences. For children with unconsciousness lasting for more than one hour, it is advisable to contemplate conducting a head imaging examination as soon as possible within 3 days after CO exposure to guide the treatment during the acute phase.Characteristic alterations in cranial imaging and a longer duration of consciousness disorders (exceeding one day) might be correlated with subsequent neurological sequelae. For children with CO poisoning presenting these characteristics, active treatment can be implemented, encompassing but not restricted to HBO treatments, to minimize subsequent damage to the greater extent possible. So, for children who were unconscious for more than one day or presented characteristic changes in cranial imaging, long-term follow-up should be carried out to determine whether delayed encephalopathy or subsequent cognitive impairment occurs.

Palmitoleic acid inhibits Pseudomonas aeruginosa quorum sensing activation and protects lungs from infectious injury

BackgroundUnsaturated fatty acids targeting quorum sensing (QS) system have shown potential application in reducing bacterial virulence. We aim to investigate the effect of palmitoleic acid (PMA) on P. aeruginosa QS activation, and its impact on infection-induced lung injury.MethodsThe influence of PMA on QS signaling molecule (3OC12-HSL and C4-HSL) concentrations, pyocyanin production, and QS gene transcription levels were examined in wildtype PAO1 culture. The roles of PMA in reducing infection-induced injury were assessed in human bronchial epithelial BEAS-2B cells and mouse lung infection models, respectively. PMA levels and QS signaling molecule concentrations were tested in the bronchoalveolar lavage fluid (BALF) of bronchiectasis patients with first-time detection of P. aeruginosa infection.ResultsPMA administration dose-dependently suppressed the expression of QS signaling molecules, pyocyanin, and QS genes during the logarithmic stage of bacterial growth. In BEAS-2B cells, PMA-treated PAO1 filtrates significantly reduced cell apoptosis and expression of IL-8 and IL-6. In mouse lung infection models, prophylactically oral administration of PMA significantly downregulated the expression of P. aeruginosa QS signals and QS genes (lasR, rhlR, rhlI, lasB, rhlA, phzA1, phnA) in lungs, and relieved neutrophilic airway inflammation. Finally, PMA levels were negatively correlated with the concentrations of both 3OC12-HSL and C4-HSL in BALF of bronchiectasis patients, and positively correlated with their forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1.0).ConclusionOur findings show that PMA inhibits P. aeruginosa QS activation and protects lungs from injury caused by bacterial virulence. Hence, PMA may serve as a potential anti-QS agent against P. aeruginosa infection and would help to alleviate lung injury in bronchiectasis patients.

Transcriptomic Profiling Reveals Altered Expression of Genes Involved in Metabolic and Immune Processes in NDV-Infected Chicken Embryos

Objective: The poultry industry is significantly impacted by viral infections, particularly Newcastle Disease Virus (NDV), which leads to substantial economic losses. It is essential to comprehend how the sequence of development affects biological pathways and how early exposure to infections might affect immune responses. Methods: This study employed transcriptome analysis to investigate host–pathogen interactions by analyzing gene expression changes in NDV-infected chicken embryos’ lungs. Result: RNA-Seq reads were aligned with the chicken reference genome (Galgal7), revealing 594 differentially expressed genes: 264 upregulated and 330 downregulated. The most overexpressed genes, with logFC between 8.15 and 8.75, included C8A, FGG, PIT54, FETUB, APOC3, and FGA. Notably, downregulated genes included BPIFB3 (−4.46 logFC) and TRIM39.1 (−4.26 logFC). The analysis also identified 29 novel transcripts and 20 lncRNAs that were upregulated. Gene Ontology and KEGG pathways’ analyses revealed significant alterations in gene expression related to immune function, metabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. Key metabolic genes, such as ALDOB (3.27 logFC), PRPS2 (2.66 logFC), and XDH (2.15 logFC), exhibited altered expression patterns, while DCK2 (−1.99 logFC) and TK1 (−2.11 logFC) were also affected. Several immune-related genes showed significant upregulation in infected lung samples, including ALB (6.15 logFC), TLR4 (1.86 logFC), TLR2 (2.79 logFC), and interleukin receptors, such as IL1R2 (3.15 logFC) and IL22RA2 (1.37 logFC). Conversely, genes such as CXCR4 (−1.49 logFC), CXCL14 (−2.57 logFC), GATA3 (−1.51 logFC), and IL17REL (−2.93 logFC) were downregulated. The higher expression of HSP genes underscores their vital role in immune responses. Conclusion: Comprehension of these genes’ interactions is essential for regulating viral replication and immune responses during infections, potentially aiding in the identification of candidate genes for poultry breed improvement amidst NDV challenges.

The ataxia-telangiectasia disease protein ATM controls vesicular protein secretion via CHGA and microtubule dynamics via CRMP5

The autosomal recessive disease ataxia-telangiectasia (A-T) presents with cerebellar degeneration, immunodeficiency, radiosensitivity, capillary dilatations, and pulmonary infections. Most symptoms outside the nervous system can be explained by failures of the disease protein ATM as a Ser/Thr-kinase to coordinate DNA damage repair. However, ATM in adult neurons has cytoplasmic localization and vesicle association, where its roles remain unclear. Here, we defined novel ATM protein targets in human neuroblastoma cells, and filtered initial pathogenesis events in ATM-null mouse cerebellum. Profiles of global proteome and phosphoproteomics - both direct ATM/ATR substrates and overall phosphorylation changes - confirmed previous findings for NBN, MRE11, MDC1, CHEK1, EIF4EBP1, AP3B2, PPP2R5C, SYN1 and SLC2A1. Even stronger downregulation of ATM/ATR substrate phosphopeptides after ATM-depletion was documented for CHGA, EXPH5, NBEAL2 and CHMP6 as key factors of protein secretion and endosome dynamics, as well as for CRMP5, DISP2, PHACTR1, PLXNC1, INA and TPX2 as neurite extension factors. Prominent effects on semaphorin-CRMP5-microtubule signals and ATM association with CRMP5 were validated. As a functional consequence, microtubules were stabilized, and neurite retraction ensued. The impact of ATM on secretory granules confirms previous ATM-null cerebellar transcriptome findings. This study provides the first link of A-T neural atrophy to growth cone collapse and aberrant microtubule dynamics.

Use of ultrasonography in the diagnosis of pneumonia in intensive care patients

Aims: A significant portion of respiratory system infections seen in intensive care units is ventilator-associated pneumonia, which has a high mortality rate and diagnosis may be delayed. Bedside lung ultrasonography offers the advantages of standard diagnostic methods as chest radiography or thorax tomography. We aim to evaluate the bedside lung ultrasonography correlation with the chest radiography or thorax tomography Methods: It was conducted prospectively on 60 patients between the ages of 18-85 who were admitted to intensive care with respiratory failure within an 8-month period. Anterioposterior chest radiographs were taken on the first day of mechanical ventilation for the patients included in the study. Ultrasonographic (USG) examination was performed separately for both hemithoraxes and recorded digitally. Simultaneously with the ultrasonographic examination, PEEP, FiO2, blood gas examination results and the highest body temperatures in the last 24 hours were recorded. The quality and quantity of tracheal secretions were evaluated, and sampling was performed for complete blood examination and tracheal aspirate culture-antibiogram. Lung injury score (LIS) and pulmonary infection score (CPIS) were calculated from the data obtained. In this process, independent of the research, the same day examination results of patients who required thorax tomography (CT) for diagnosis and treatment planning were evaluated together with USG and chest radiography. Tomographic examinations were evaluated by a radiologist. Results: In the examination of 120 hemithoraxes of 60 patients we included in the study, we were able to detect 74.17% of the pathological images obtained with chest radiography and ultrasonographic examination with bedside ultrasonography and 70.84% with chest radiography. Of the 20 patients who underwent tomographic evaluation, pathology was observed in 40 hemithoraxes in 92.5% by tomography, in 85% by ultrasonography, and in 75% by chest radiography. While isolated consolidation was detected equally on USG and CT imaging, there was a high false-positive rate of 48% on chest radiography. 58.8% of the patients with consolidation detected by CT, we observed that there was growth in the tracheal aspirate of 56.2% of the patients whose ultrasonographic examination revealed consolidation. Conclusion: Bedside lung ultrasonography is a fast, non-invasive, repeatable and reliable diagnostic method in patients followed in intensive care, and is compatible with traditionally used laboratory and clinical parameters. This reveals that USG, which is known to have other advantages such as cost, applicability, and not using radiopaque, will become an indispensable examination for ICU.

Determination of Ideal Factors for Early Adoption and Standardization of Metagenomic Next-generation Sequencing for Respiratory System Infections.

Metagenomic next-generation sequencing (mNGS) demonstrates great promise as a diagnostic tool for determining the cause of pathogenic infections. The standard diagnostic procedures (SDP) include smears and cultures and are typically viewed as less sensitive and more time-consuming when compared to mNGS. There are concerns about the logistics and ease of transition from SDP to mNGS. mNGS lacks standardization of collection processes, databases, and sequencing. Additionally, there is the burden of training clinicians on interpreting mNGS results. Until now, few studies have explored factors that could be used as early adoption candidates to ease the transition between SDP and mNGS. This study evaluated 123 patients who had received both SDP and mNGS and compared several variables across a diagnostic test evaluation. The diagnostic test evaluation observed metrics such as sensitivity, specificity, positive and negative likelihood ratios (PLR, NLR), positive and negative predictive values (PPV, NPV), and accuracy. Factors included various sample sources such as bronchoalveolar lavage fluid (BALF), lung tissue, and cerebral spinal fluid (CSF). An additional factor observed was the patient's immune status. Pathogen detection was found to be significantly greater for mNGS for total patients, BALF sample source, CSF sample source, and non-immunocompromised patients (p<0.05). Pathogen detection was found to be insignificant for lung tissue sample sources and immunocompromised patients. Sensitivity, PLR, NLR, PPV, NPV, and accuracy appeared to be higher with mNGS for the total patients, BALF sample source, and non-immunocompromised patients when compared with SDP (p<0.05). With higher metrics in sensitivity, specificity, PLR, NLR, PPV, NPV, and accuracy for overall patients, mNGS may prove a better diagnostic tool than SDP. When addressing sample sources, mNGS for BALF-collected samples appeared to have higher scores than SDP for the same metrics. When patients were in a non-immunocompromised state, mNGS also demonstrated greater diagnostic benefits to BALF and overall patients compared to SDP. This study demonstrates that using BALF as a sample source and selecting non-immunocompromised patients may prove beneficial as early adoption factors for mNGS standard protocol. Such a study may pave the road for mNGS as a routine clinical method for determining the exact pathogenic etiology of lung infections.

Phage-derived polysaccharide depolymerase potentiates ceftazidime efficacy against Acinetobacter baumannii pneumonia via low-serum-dependent mechanisms

The emergence of multidrug-resistant Acinetobacter baumannii (MDR-AB), which most commonly manifests as pneumonia, has posed significant clinical challenges and called for novel treatment strategies. Phage depolymerases, which degrade bacterial surface carbohydrates, have emerged as potential antimicrobial agents. However, their preclinical application is limited to systemic infections due to their dependency on serum-mediated bacterial killing. To extend the treatment paradigm of depolymerase to low-serum lung infections, we explored the feasibility of applying phage depolymerase to potentiate antibiotic efficacy in controlling MDR-AB pneumonia. Using a model depolymerase, Dpo71, we observed that it could effectively potentiate antibiotic efficacy against MDR-AB2 bacteria in low-serum conditions mimicking lung milieu but showed no adjuvant effect in serum-free conditions. Unprecedentedly, we reported this low-serum-dependent mechanism that polysaccharide-degrading enzyme Dpo71 exposed bacteria to serum-induced membrane permeabilization and oxidative phosphorylation pathway inhibition, leading to a weakened ATP-dependent efflux pump and strengthened ROS-induced membrane permeabilization. These joint effects facilitated antibiotic (ceftazidime, CFZ) binding, ultimately exerting bactericidal effects. Resultantly, the bacterial load in the lungs of the Dpo71-CFZ combination group was significantly reduced compared with the Dpo71-alone and CFZ-alone groups. Overall, this study unravels the low-serum-dependent mechanisms by which depolymerase potentiated antibiotic efficacy, highlighting its potential as a novel strategy to enhance antibiotic activity against severe pneumonia.

Surfactant Protein-C Regulates Alveolar Type 2 Epithelial Cell Lineages via the CD74 Receptor.

Deficiency of surfactant protein-C (SPC) increases susceptibility to lung infections and injury, and suppressed expression of SPC has been associated with the severity of acute respiratory distress syndrome (ARDS). Alveolar type 2 epithelial cells (AT2) are critical for maintenance and repair of the lung. However, the role of the SPC in the regulation of AT2 cell lineage and the underlying mechanisms are not completely understood. This study aimed to investigate the mechanisms by which SPC regulates AT2 lineages. Sftpc-/- mice were used to model the SPC deficiency in ARDS patients. We utilized three-dimensional (3D) organoids to compare AT2 lineage characteristics between wild type (WT) and Sftpc-/- mice by analyzing AT2 proliferation, alveolar type 1 cells (AT1) differentiation and CD74 expression, using colony-formation assay, immunofluorescence, flow cytometry, and immunoblots. The results showed that Sftpc-/- mice demonstrated a reduced AT2 cell population. Influenza A virus subtype H1N1 (H1N1) infected Sftpc-/- mice demonstrated reduced AT2 proliferation and AT1 differentiation. Western blot indicated elevated levels of CD74 protein in AT2 cells of Sftpc-/- mice. Colony-forming efficiency was significantly attenuated in AT2 cells isolated from Sftpc-/- mice compared to the WT controls. Podoplanin (PDPN, a marker of AT1 cells) expression and transient cell count significantly increased in Sftpc-/- organoids. Moreover, siRNA-mediated gene silencing of CD74 in AT2 cells significantly increased AT2 proliferation and AT1 differentiation in Sftpc-/- organoids. This study suggests that SPC regulates AT2 lineage in vitro and in vivo. The SPC might influence AT2 lineage during the lung epithelium repair by activating signaling mechanism involving CD74 receptor.

Prevention of Aspiration: Oral Care, Antibiotics, Others.

Patients with aspiration pneumonia often develop this lung infection due to poor oral health or because the contents of the digestive tract or upper airway enter the lower airway traversing the larynx through different mechanisms. Prevention of this condition is directed at the mechanism by which it occurs. The elderly are the most likely to suffer from aspiration pneumonia, occasionally due to issues related to poor dental health, but more frequently due to abnormal swallowing, which may appear after a stroke, a functional impairment related to aging, or may be part of a specific disease such as Parkinson's disease or some other nervous system condition. People with dysphagia complicated by pneumonia have limited feeding and become debilitated, and aspiration pneumonia in these individuals has a high mortality rate at 90 days. Dietary modifications, assistance with feeding, use of postures that facilitate a normal deglutition, rehabilitation, and use of medications to improve swallowing defects are the tools of medicine to overcome the obstacles to swallowing normally and prevent the development of aspiration pneumonia and its consequences.

Pneumonia stage analyzes through image processing

A physical examination and diagnostic imaging techniques including lung biopsies, ultrasounds, and chest X-rays are typically used to make the diagnosis of pneumonia infection, an infectious disease that has the potential to be life-threatening. The objective of this research is to categorize the stages of pneumonia through image processing methods. Before that, an ensemble model for diagnosing pneumonia infections is created utilizing the transfer learning algorithms ResNet50V2 and DenseNet201. The 5,857 images were taken from the PAUL MOONEY dataset for this research. The proposed ensemble averaging model recognizes lung infection appropriately and accurately. By applying a contour detection approach, the left and right chests are separated and the affected pixels from there to analyze the stage of pneumonia. It is very crucial to identify the stage for treatment purposes.

Identification of mRNA biomarkers in extremely early hypertensive intracerebral hemorrhage (HICH)

IntroductionHypertensive intracerebral hemorrhage (HICH) stands out as a critical complication of primary hypertension. Consequently, investigating messenger RNA (mRNA) biomarkers becomes imperative, offering potential targets. This study is conducted for elucidating the expression profile of blood mRNA biomarkers in HICH.MethodsTwenty-five HICH patients were constituted the HICH group.Twenty-two healthy volunteers recruited and comprised the control group. Peripheral blood cells were extracted to identify candidate mRNA. The identified differential expressions of genes between the two groups were validated, and the potential associations between these differentially expressed genes and adverse events were analyzed. GO and KEGG enrichment of DEGs, Weighted Gene Co-expression Network and Protein Interaction Network were established. target mRNA was screened.ResultsThe study identified 3163 differentially expressed genes in HICH. 8 candidate mRNA (SPI1, HK3, HCK, SYK, CD14, FCER1G, CYBB, FGR) were pinpointed. Associations with pathways affecting HICH development included HIF-1 signaling, NF-kappa B signaling, and C-type lectin receptor signaling. In the HICH group, higher expressions of HK3, HCK, SYK, CD14, FCER1G, CYBB, and FGR, and lower SPI1 expression compared to the control group. HICH patients experienced high rates of complications: pulmonary infection (84%), epilepsy (16%), enlarged hematoma (20%), gastrointestinal bleeding (48%), malnutrition (84%), and lower limb deep vein thrombosis (DVT) (12%). Factors contributing to pulmonary infection included age and elevated expression of HCK, SYK, CD14, and FGR. SPI1 was associated with epilepsy, while its lower expression correlated with hematoma enlargement. Gastrointestinal bleeding was linked to increased cerebral hemorrhage. Malnutrition was associated with higher age, and expressions of HK3, HCK, SYK, CD14, FCER1G, CYBB, and FGR. Patients with lower limb DVT had elevated expressions of the identified genes.ConclusionIn hypertensive intracerebral hemorrhage, there are elevated expressions of HK3, HCK, SYK, CD14, FCER1G, CYBB, and FGR, along with reduced expression of SPI1. Furthermore, age, along with elevated expressions of HCK, SYK, CD14, and FGR, serves as influencing factors contributing to pulmonary infection in patients.

Muco-adhesive chitosan-coated polyphenol nanoparticle for treatment of infectious acute pneumonia through sustained pulmonary delivery of polymyxin B

Infectious acute pneumonia caused by bacteria has been a great challenge to human health for long time, and the rapid clearance of aerosolized antibiotics in the lungs restricts their clinical application. The development of nanoformulations with facile preparation and mucoadhesive properties for the pulmonary delivery of antibiotics is thus significant for the treatment of infectious acute pneumonia. In this study, FDA (Food and Drug Administration)-approved tannic acid (TA) was used to construct mucoadhesive nanoformulations through the facile coating of chitosan (CS) to achieve long-lasting anti-infection effects against infectious acute pneumonia. Using an antibacterial peptide, polymyxin B (PB), as the model drug, the flash nanocomplexation technique was used to prepare CS-coated TA/poly(vinyl alcohol) (PVA)/PB nanoparticles (TPBC NPs) through non-covalent interactions of each component. Investigation on acute pneumonia mice model demonstrated that, through the strong electrostatic interaction between positively charged chitosan and negatively charged mucin in the trachea, the release of polymyxin B retained in the lung for at least 24 h-post inhalation of TPBC NPs, thereby inhibiting pulmonary infection within 3 days. Combined with their great biocompatibility, mucoadhesive TPBC NPs prepared by a facile and reproducible procedure may provide a new strategy for the pulmonary delivery of antibiotics to treat infectious acute pneumonia.

Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC)

BackgroundAndrographolide is a medicinal compound which possesses anti-SARS-CoV-2 activity. A number of cellular targets of andrographolide have been identified by target predictions and computational studies. PurposeHowever, a potential cellular target of andrographolide has never been explored in SARS-CoV-2 infected lung epithelial cells. We aimed to identify cellular pathways involved in andrographolide-mediated anti-SARS-CoV-2 activity. MethodsThe viral infection was determined by immunofluorescence staining, enzyme-linked immunosorbent assay and focus-forming assay. Proteomic analysis was employed to identify cellular pathways and key proteins controlled by andrographolide in the human lung epithelial cells Calu-3 infected by SARS-CoV-2. Immunofluorescence staining was used to test protein expression and localization. Western blot and realtime PCR were utilized to elucidate gene expression. Cellular glutathione level was examined by a reduced/oxidized glutathione assay. An ectopic gene expression was delivered by plasmid transfection. ResultsGene ontology analysis indicates that proteins involved in nuclear factor erythroid 2-related factor 2 (NRF2)-regulated pathways were differentially expressed by andrographolide. Notably, andrographolide increased expression and nuclear localization of the transcription factor NRF2. In addition, transcriptional expression of GCLC and glutamate-cysteine ligase modifier subunit (GCLM), which are NRF2 target genes, were induced by andrographolide. We further find that infection of SARS-CoV-2 resulted in a reduction of glutathione level in Calu-3; the effect that was rescued by andrographolide. Moreover, andrographolide also induced expression of the glutathione producing enzyme GCLC in SARS-CoV-2 infected lung epithelial cells. Importantly, an ectopic over-expression of GCLC or treatment of N-acetyl-L-cysteine in Calu-3 cells led to a decrease in SARS-CoV-2 infection. ConclusionCollectively, our findings suggest the interplay between GCLC-mediated glutathione biogenesis induced by andrographolide and the anti-SARS-CoV-2 activity. The glutathione biogenesis and recycling pathways should be further exploited as a targeted therapy against SARS-CoV-2 infection.

Stenotrophomonas maltophilia bacteremia in adult patients with hematological diseases: clinical characteristics and risk factors for 28-day mortality.

Patients with hematological diseases are at high risk for Stenotrophomonas maltophilia (SM) bacteremia. This study retrospectively analyzed the clinical characteristics and risk factors for 28-day mortality among 140 adult hematological patients diagnosed with SM bacteremia from January 2012 to July 2023. he overall 28-day mortality was 31.43% (44/140), with a median age of 44 years. The median hospital stay before SM bacteremia onset was 25 days, and 69.29% of patients had unresolved neutropenia. All patients had received broad-spectrum antibiotics in the past month, and 69.29% developed breakthrough bacteremia during carbapenem therapy. Independent risk factors for mortality included a Sequential Organ Failure Assessment (SOFA) score ≥5, tigecycline exposure, age ≥60, and pulmonary infection. Patients with ≥2 risk factors were stratified into the high-risk group, with a significantly higher 28-day mortality compared with the low-risk group (56.52% vs 7.04%, P < 0.001). Treatment with trimethoprim-sulfamethoxazole (TMP/SMX) (P = 0.008) or TMP/SMX combined with cefoperazone/sulbactam (CSL) (P = 0.005) was associated with survival benefits among high-risk patients. Overall, SM bacteremia usually occurs in hematological patients with prolonged hospitalization, unresolved neutropenia, and extensive use of broad-spectrum antibiotics, especially carbapenems. Patients with high SOFA scores, advanced age, pulmonary infection, or recent tigecycline exposure are at higher risk of mortality. The preferred treatment is TMP/SMX rather than fluoroquinolones, with combination therapy of TMP/SMX and CSL considered a feasible treatment option.IMPORTANCEThis study, representing the largest cohort of adult hematological patients with SM bacteremia to date, strengthens the validity of existing findings and provides new insights into its clinical management. We identify risk factors for 28-day mortality, revealing that patients with two or more risk factors experience particularly high mortality rates. This highlights the importance of early identification and targeted management of high-risk individuals. Our findings also demonstrate that TMP/SMX is superior to fluoroquinolones and suggest that combining TMP/SMX with CSL may offer additional survival benefits.

Current Analytical Methods and Challenges for the Clinical Diagnosis of Invasive Pulmonary Aspergillosis Infection

In the last decade, pulmonary fungal infections such as invasive pulmonary aspergillosis (IPA) have increased in incidence due to the increased number of immunocompromised individuals. This increase is especially problematic when considering mortality rates associated with IPA are upwards of 70%. This high mortality rate is due to, in part, the length of time it takes to diagnose a patient with IPA. When diagnosed early, mortality rates of IPA decrease by as much as 30%. In this review, we discuss current technologies employed in both medical and research laboratories to diagnose IPA, including culture, imaging, polymerase chain reaction, peptide nucleic acid–fluorescence in situ hybridization, enzyme-linked immunosorbent assay, lateral flow assay, and liquid chromatography mass spectrometry. For each technique, we discuss both promising results and potential areas for improvement that would lead to decreased diagnosis time for patients suspected of contracting IPA. Further study into methods that offer increased speed and both analytical and clinical sensitivity to decrease diagnosis time for IPA is warranted.

Prognostic Factors Associated With Survival Distribution of Admission to Delayed Rapid Response Team Activation Among Deteriorating Patients: A Retrospective Study.

To investigate the prevalence of rapid response team delays, survival distribution of admission to rapid response team delay and its prognostic factors. A retrospective single-centre study. Data on rapid response team activations from 1 January 2018 to 31 December 2022 were retrieved from electronic medical records at a tertiary hospital in Hangzhou, China. All patients who met the eligibility criteria were included. Multivariable Cox regression analysis was conducted to analyse the data. Out of 636 patients included, 18.4% (117) experienced a delay, with a median (interquartile range) of 8.5 (12) days from admission to rapid response team activation. Six significant prognostic factors were found to be associated with the higher hazard ratio of rapid response team delay, including call time (05:01 PM and 7:59 AM), emergency admission, a higher Modified Early Warning Score, an admission diagnosis of infection, a comorbidity of respiratory failure/Acute Respiratory Distress Syndrome and the absence of lung infection. The prevalence of rapid response team delays was lower, and the days from admission to rapid response team delay was longer than in previous studies. Healthcare providers are suggested to prioritise the care of high-risk patient groups and provide proactive monitoring to ensure timely identification and management. Implementing artificial intelligence in continuous monitoring systems for high-risk patients is recommended. The findings help nurses anticipate potential delays in rapid response team activation, enabling better preparedness. The study highlights the prevalence of rapid response team delays, timing from admission to rapid response team activation and six prognostic factors influencing delays. It could shape patient care and inform future research. Hospital administrators should review staffing, especially during night shifts, to minimise delays. Further qualitative research is needed to explore why nurses may delay rapid response team activation. The STROBE checklist was adhered to when reporting this study. 'No patient or public contribution'.

Primary lung tumour stereotactic body radiotherapy followed by concurrent mediastinal chemoradiotherapy and adjuvant immunotherapy for locally advanced non-small-cell lung cancer: a multicentre, single-arm, phase 2 trial

Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve 2 mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 29·5 months (IQR 14·9-47·1). 1-year progression-free survival was 62·7% (90% CI 51·2-73·2; one-sided p=0·39, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Although this study did not meet the primary endpoint, activity and safety profiles of primary lung tumour SBRT followed by concurrent mediastinal chemoradiotherapy were favourable compared with other modern trials treating locally advanced NSCLC with chemoradiotherapy. These findings serve as the basis for the ongoing randomised phase 3 study NRG Oncology LU008 (NCT05624996). AstraZeneca and Atrium Health Levine Cancer Institute.