Huaqin Pan

Evidence supporting the efficacy of adjunctive corticosteroid therapy in human immunodeficiency virus (HIV)-negative patients with Pneumocystis jirovecii pneumonia (PJP) who present with respiratory failure is increasing. However, the optimal dosing regimen remains uncertain. Our study aimed to evaluate the effectiveness of high-dose versus low-dose adjunctive corticosteroid therapy in this population. This retrospective cohort study included HIV-negative patients diagnosed with PJP who received adjunctive corticosteroid therapy in Zhongnan Hospital of Wuhan University from June 2018 to March 2023. Patients were categorized into high-dose group (≥1 mg/kg/day of prednisone equivalent) and low-dose group (<1 mg/kg/day). The risk was estimated by the time-dependent Cox regression analyses with inverse probability of treatment weighting (IPTW). Subgroup analysis focused on patients with respiratory failure. Ultimately, 120 HIV-negative PJP patients were included (high-dose, n=72; low-dose, n=48). The overall 30- and 90-day mortality rates were 30.8% and 41.7%, respectively. No significant differences were observed in 30-day mortality (P=0.80 before analysis; P=0.62 after analysis) and 90-day mortality (P=0.86 before analysis; P=0.97 after analysis) between the two groups before and after IPTW analysis. Results in the respiratory failure subgroup were consistent with the overall findings. In conclusion, low-dose adjunctive corticosteroid therapy may be adequate for treating HIV-negative PJP.

Sepsis‑induced liver injury increases mortality through inflammatory dysregulation. Although Radioprotective 105 (RP105) modulates inflammation, its role in septic liver injury remains unclear. The present study investigates the mechanism of RP105 in sepsis‑driven hepatic damage. Sepsis was induced in RP105 knockout (KO) and wild‑type (WT) mice via cecal ligation and puncture (CLP). Liver injury was assessed by serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), histology (H&E), inflammatory markers (anti‑myeloperoxidase, F4/80, IL‑1β, IL‑6 and TNF‑α) and apoptosis markers (Caspase‑3, BAX/BCL‑2 ratio, GADD45A and PUMA). RNA sequencing identified key differentially expressed genes. RP105‑suppressor of cytokine signaling (SOCS) 2 interaction was validated by co‑immunoprecipitation (Co‑IP) and JAK2/STAT3 pathway activity was measured by western blotting. Lipopolysaccharide‑stimulated RP105‑KO macrophages were used in vitro. RP105‑KO mice exhibited exacerbated liver injury post‑CLP, evidenced by significantly elevated ALT/AST (Pin vivo and in vitro (P<0.001). RP105 protects against septic liver injury by binding SOCS2 to inhibit JAK2/STAT3 signaling, thereby attenuating inflammation and apoptosis. The present study is the first to demonstrate the RP105‑SOCS2 interaction in septic liver injury, revealing the RP105/SOCS2 axis as a potential therapeutic target.

Liver transplant recipients face a higher risk of multidrug-resistant (MDR) infections because of preoperative comorbidities, extensive antibiotic use, immunosuppressive therapy, and prolonged mechanical ventilation. Carbapenem-resistant Acinetobacter baumannii (CRAB) remains one of the most challenging pathogens in this group. We report a case of a liver transplant recipient with OXA-23-producing Acinetobacter baumannii pneumonia. Initial treatment with polymyxin B and eravacycline produced unsatisfactory results and worsened renal dysfunction during treatment. Later, administration of sulbactam-durlobactam (SUL-DUR) combined with meropenem resulted in significant clinical improvement. Follow-up CT scans showed notable resolution, and the patient successfully recovered, with renal function restored and eventual discharge. This case highlights the difficulty of managing OXA-23-producing Acinetobacter baumannii in liver transplant patients, especially those with kidney impairment. SUL-DUR showed effective therapy with a much lower risk of nephrotoxicity compared to previously used agents.

Background: Liver cirrhosis is a chronic progressive disease caused by various liver injury mechanisms, characterized by irreversible fibrosis, hepatocyte degeneration and necrosis, and the formation of regenerative nodules, ultimately leading to liver failure and multiple severe complications, significantly increasing the risk of mortality. Methods: This study analyzes global and China-specific trends in liver cirrhosis incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021, focusing on various causes including hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). Data from the Global Burden of Disease (GBD) database were used to assess changes in liver cirrhosis statistics globally and in China. The study examined incidence, prevalence, mortality, and DALYs over the period from 1990 to 2021. Results: Global liver cirrhosis incidence reached 58.4 million in 2021, up from 36.9 million in 1990, primarily driven by NAFLD, which increased from 24.8 million in 1990 to 48.3 million in 2021. While HBV- and HCV-related cirrhosis declined, deaths from alcoholic cirrhosis rose. In China, NAFLD became the main cause, although alcohol-related cirrhosis and an aging population remain major challenges. Conclusions: The growth of NAFLD and alcohol-related cirrhosis undermines progress in controlling HBV and HCV. Targeted prevention and management strategies are needed, especially in regions with low and middle SDI, which show higher cirrhosis mortality. For China, early intervention for NAFLD and continued control of HBV and HCV are critical to reduce the cirrhosis burden.

Sepsis-associated acute kidney injury (SA-AKI) is a critical condition characterized by high morbidity and mortality rates, particularly in intensive care settings. This study focuses on RP105, a pattern recognition receptor, exploring its role in moderating the mechanisms of oxidative stress and ferroptosis during SA-AKI, offering insights into its potential as a therapeutic target. SA-AKI model was established using RP105 knockout (KO) and wild-type (WT) mice through cecal ligation and puncture (CLP). Comprehensive evaluations included the assessment of ferroptosis markers and the expression levels of pro-inflammatory cytokines. RP105 expression was markedly reduced in the kidneys following CLP induction, correlating with worsened renal outcomes. Compared to the Sham group, RP105^−/− mice displayed heightened renal damage, increased levels of oxidative stress markers, and enhanced lipid peroxidation. Notably, the deficiency of RP105 led to increased macrophage infiltration and a shift towards pro-inflammatory phenotypes, which further potentiated ferroptosis and exacerbated renal tissue damage. By influencing macrophage behavior and mitigating inflammatory responses. RP105 deficiency exacerbates macrophage-induced inflammation, oxidative stress, and ferroptosis, forming a vicious cycle that leads to more severe renal injury. These findings underscore the pivotal role of RP105 in mitigating oxidative stress and suppressing ferroptosis in the context of SA-AKI through regulation of the HO-1/SLC7A11/GPX4 axis. By preventing macrophage polarization toward a pro-inflammatory phenotype, RP105 alleviates inflammatory responses and tissue damage, highlighting its potential as a therapeutic target. Thus, RP105 emerges as a promising therapeutic candidate for mitigating sepsis-induced renal damage.

Background: Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated infectious diarrhea. A major clinical challenge is recurrent CDI (rCDI) without effective standard drug-based therapy. Additionally, a comprehensive comparison of various therapy effectiveness in rCDI patients is still under investigation.Methods: A Bayesian network meta-analysis (NMA) of randomized control trials up to March 2024 was performed to investigate the efficacy of rCDI interventions.Results: Seventeen trials were included, comprising 4,148 CDI patients with ten interventions, including fecal microbiota transplantation (FMT) by lower gastrointestinal (LGI), FMT by upper gastrointestinal (UGI), Autologous FMT (AFMT), vancomycin + FMT, vancomycin, placebo, fidaxomicin, Vowst (SER109), Rebyota (RBX2660), and monoclonal antibody. NMA showed that FMT by LGI had the highest efficacy in treating rCDIs with an odds ratio (95% confidence interval) of 32.33 (4.03, 248.69) compared with placebo. FMT by UGI also showed high efficacy, whereas the efficacy comparison between FMT by LGI and UGI was not statistically significant (ORs) (95% CI), 1.72 (0.65, 5.21). The rankogram and surface under the cumulative ranking curve (SUCRA) also showed FMT by LGI ranked at the top and FMT by UGI ranked second in the curative effect.Conclusion: NMA demonstrates FMT’s significant efficacy in rCDI management, regardless of administration route (lower or upper gastrointestinal). Despite its significant benefits, FMT’s safety is a concern due to the lack of standardized FDAcompliant manufacturing and oversight. Microbiota-based therapies also exhibit potential. However, limited research mandates further clinical exploration. Antibiotics, in contrast, display comparatively reduced efficacy in rCDI, potentially linked to disruptions in native gut microflora balance.Systematic Review: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=368435, Identifier CRD42022368435.

Purpose: Ferroptosis plays essential roles in the development of COPD. We aim to identify the potential ferroptosis-related genes of COPD through bioinformatics analysis. Methods: The RNA expression profile dataset GSE148004 was obtained from the GEO database. The ferroptosis-related genes were obtained from the FerrDb database. The potential differentially expressed ferroptosis-related genes of COPD were screened by R software. Then, protein–protein interactions (PPI), correlation analysis, gene-ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied for the differentially expressed ferroptosis-related genes. Finally, hub gene-microRNA(miRNA), hug gene-transcription factor interaction networks were constructed by miRTarBase v8.0 and JASPAR respectively, and hub gene drugs were predicted by the Enrichr database. Results: A total of 41 differentially expressed ferroptosis-related genes (22 up-regulated genes and 19 down-regulated genes) were identified between 7 COPD patients and 9 healthy controls. The PPI results demonstrated that these ferroptosis-related genes interacted with each other. The GO and KEGG enrichment analyses of differentially expressed ferroptosis-related genes indicated several enriched terms related to ferroptosis, central carbon metabolism in cancer, and the HIF-1 signaling pathway. The crucial miRNAs and drugs associated with the top genes were identified. Conclusion: We identified 41 potential ferroptosis-related genes in COPD through bioinformatics analysis. HIF1A, PPARG, and KRAS may affect the development of COPD by regulating ferroptosis. These results may expand our understanding of COPD and might be useful in the treatment of COPD.

Hemophagocytic lymphohistiocytosis (HLH) is an overwhelming immune system activation that manifests as hyperinflammation and life-threatening multiple organ failure. However, the clinical manifestations of the systemic inflammatory response in sepsis and fulminant cytokine storm caused by HLH macrophage activation are very similar and difficult to distinguish. HLH triggered by two novel gene defects manifesting with multiorgan dysfunction syndrome (MODS) and distributive shock has not been reported. A 14-year-old male patient was hospitalized with a high fever, his condition deteriorated rapidly, accompanied by cytopenia, shock, and MODS, and he was subsequently transferred to our intensive care unit (ICU) for symptomatic and organ-supportive treatments. Laboratory indicators of cytopenia, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia, high soluble CD25, low natural killer (NK) cell cytotoxicity, and hemophagocytosis in the bone marrow confirmed the diagnosis of HLH. Molecular genetic analysis revealed that two novel heterozygous gene mutations in AP3B1 (c.3197 C > T) and ATM (c.8077 G > T) might have accounted for the onset. After treatment, the patient’s condition successfully improved. This case report demonstrates the timely determination of underlying triggers and critical care supports (supportive and etiological treatment) of HLH related to the improved outcome.

Background: Previous studies demonstrate a reduced risk of thrombosis and mortality with anticoagulant treatment in patients with COVID-19 than in those without anticoagulation treatment. However, an open question regarding the efficacy and safety of therapeutic anticoagulation (T-AC) versus a lower dose, prophylaxis anticoagulation (P-AC) in COVID-19 patients is still controversial.Methods: We systematically reviewed currently available randomized clinical trials (RCTs) and observational studies (OBs) from January 8, 2019, to January 8, 2022, and compared prophylactic and therapeutic anticoagulant treatment in COVID-19 patients. The primary outcomes were risk of mortality, major bleeding, and the secondary outcomes included venous and arterial thromboembolism. Subgroup analysis was also performed between critically ill and non-critically ill patients with COVID-19 and between patients with higher and lower levels of D-dimer. Sensitivity analysis was performed to decrease the bias and the impact of population heterogeneity.Results: We identified 11 RCTs and 17 OBs fulfilling our inclusion criteria. In the RCTs analyses, there was no statistically significant difference in the relative risk of mortality between COVID-19 patients with T-AC treatment and those treated with P-AC (RR 0.95, 95% CI, 0.78–1.15,P = 0.60). Similar results were also found in the OBs analyses (RR 1.21, 95% CI, 0.98–1.49,P = 0.08). The pooling meta-analysis using a random-effects model combined with effect sizes showed that in the RCTs and OBs analyses, patients with COVID-19 who received T-AC treatment had a significantly higher relative risk of the major bleeding event than those with P-AC treatment in COVID-19 patients (RCTs: RR 1.76, 95% CI, 1.19–2.62,P = 0.005; OBs: RR 2.39, 95% CI, 1.56–3.68,P < 0.0001). Compared with P-AC treatment in COVID-19 patients, patients with T-AC treatment significantly reduced the incidence of venous thromboembolism (RR 0.51, 95% CI, 0.39–0.67,PP = 0.87). The subgroup analysis of OBs shows that the mortality risk significantly reduces in critically ill COVID-19 patients treated with T-AC compared with those with P-AC treatment (RR 0.58, 95% CI, 0.39–0.86,P = 0.007), while the mortality risk significantly increases in non-critically ill COVID-19 patients treated with T-AC (RR 1.56, 95% CI, 1.34–1.80,P < 0.00001). In addition, T-AC treatment does not reduce the risk of mortality in COVID-19 patients with high d-dimer levels in RCTs. Finally, the overall sensitivity analysis after excluding two RCTs studies remains consistent with the previous results.Conclusions: In our integrated analysis of included RCTs and OBs, there is no significant difference between the mortality of T-AC and P-AC treatment in unselected patients with COVID-19. T-AC treatment in COVID-19 patients significantly reduced the incidence of venous thromboembolism but showed a higher risk of bleeding than those with P-AC treatment. In addition, P-AC treatment was superior to T-AC treatment in non-critically ill COVID-19 patients, the evidence supporting the necessity for T-AC treatment in critically ill COVID-19 patients came only from OBs.Trial registration: Protocol registration: The protocol was registered at PROSPERO (CRD42021293294).Graphical