Effectiveness of nirmatrelvir-ritonavir versus azvudine for adult inpatients with severe or critical COVID-19.

BACKGROUND: In China, both nirmatrelvir-ritonavir (Paxlovid) and azvudine have been granted approval to treat adult SARS-CoV-2-infected patients with moderate symptoms. Information about the clinical effect of the two available agents among inpatients with severe or critical COVID-19 is scarce. PURPOSE: To compare the clinical outcomes of Paxlovid and azvudine among adult inpatients with severe or critical COVID-19. METHOD: We conducted a retrospective cohort study in two large medical centres after the epidemic control measures were lifted in China. A new propensity score matched-inverse probability of treatment weighting cohort was constructed to evaluate the in-hospital all-cause mortality, hospital length of stay, Sequential Organ Failure Assessment (SOFA) score and safety. RESULTS: A total of 955 individuals were in the cohort. The antiviral therapy strategies were decided by the senior physician and the supplies of the pharmacy. A total of 451 patients were in the Paxlovid group, and 504 patients were in the azvudine group. Compared with Paxlovid, the effects of azvudine on in-hospital all-cause mortality were not significantly different, and the OR (95% CI) was 1.084 (0.822 to 1.430), and the average hospital length of stay of patients discharged alive was also similar in the azvudine group, and the difference (day) and (95% CI) was 0.530 (-0.334 to 1.393). After 7 days of therapy, the degree of decline in the SOFA score was greater in the Paxlovid group than in the azvudine group (p<0.001). The change in glomerular filtration rate was not significantly different (p=0.824). CONCLUSION: Paxlovid and azvudine had similar effectiveness on in-hospital all-cause mortality and hospital length of stay. Compared with the azvudine group, after 7 days of therapy, the degree of decline in SOFA score was significantly higher in the Paxlovid group. These findings need to be verified in larger prospective studies or randomised controlled trials.

Dual-targeting tigecycline nanoparticles for treating intracranial infections caused by multidrug-resistant Acinetobacter baumannii.

Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is a formidable pathogen responsible for severe intracranial infections post-craniotomy, exhibiting a mortality rate as high as 71%. Tigecycline (TGC), a broad-spectrum antibiotic, emerged as a potential therapeutic agent for MDR A. baumannii infections. Nonetheless, its clinical application was hindered by a short in vivo half-life and limited permeability through the blood-brain barrier (BBB). In this study, we prepared a novel core-shell nanoparticle encapsulating water-soluble tigecycline using a blend of mPEG-PLGA and PLGA materials. This nanoparticle, modified with a dual-targeting peptide Aß11 and Tween 80 (Aß11/T80@CSs), was specifically designed to enhance the delivery of tigecycline to the brain for treating A. baumannii-induced intracranial infections. Our findings demonstrated that Aß11/T80@CSs nanocarriers successfully traversed the BBB and effectively delivered TGC into the cerebrospinal fluid (CSF), leading to a significant therapeutic response in a model of MDR A. baumannii intracranial infection. This study offers initial evidence and a platform for the application of brain-targeted nanocarrier delivery systems, showcasing their potential in administering water-soluble anti-infection drugs for intracranial infection treatments, and suggesting promising avenues for clinical translation.

Extracranial Germ Cell Tumors in Children: Ten Years of Experience in Three Children's Medical Centers in Shanghai.

OBJECTIVE: The aim was to describe the clinical features of extracranial germ cell tumors (GCTs) in pediatrics and study the clinical risk factors related to survival for malignant germ cell tumors (MGCTs) in order to optimize therapeutic options. METHODS: The clinical data of children with extracranial GCTs in three children's medical centers in Shanghai were retrospectively analyzed. RESULTS: In total, 1007 cases of extracranial GCTs diagnosed between 2010 and 2019 were included in this study, including teratomas (TERs) 706 (70.11%) and MGCTs 301 (29.89%). There were twice as many TER cases as MGCT cases. Approximately 50% of children with GCTs were <3 years old (43.39% for TERs, 67.13% for MGCTs). GCTs in children of different ages show differences in tumor anatomical locations and pathological subtypes. The 5-year event-free survival (EFS) and overall survival (OS) of all patients with MGCTs were 82.33% (95% CI, 77.32%, 86.62%) and 94.13% (95% CI, 90.02%, 96.69%), respectively. The multivariate Cox regression analysis identified a primary site in the mediastinum and alpha fetoprotein (AFP) levels ≥10,000 ng/mL as independent adverse prognostic factors (p < 0.0.0001, χ2 = 23.6638, p = 0.0225, χ2 = 5.2072.). There were no significant differences in OS among children receiving various chemotherapy regimens, such as the BEP, PEB, JEB and other regimens (VBP/VIP and AVCP/IEV) (p < 0.05). CONCLUSIONS: The clinical features of GCTs in Chinese pediatrics are similar to those reported in children in Europe and America. The age distribution of pathological types and primary sites in GCTs reflect the developmental origin of type I and type II GCTs transformed from mismigration primordial germ cells (PGCs). Optimizing the current platinum-based chemotherapy regimens and exploring the treatment strategies for MGCTs of the mediastinum are future research directions.

Hypervirulent Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae (hvKP), especially multidrug-resistant hvKP (MDR-hvKP) infections, are distributed globally, and lead to several outbreaks with high pathogenicity and mortality in immunocompetent individuals. This is usually characterized by a rapidly metastatic spread resulting in multiple pyogenic tissue abscesses. To date, even though the explanation of hypervirulent factors of hvKP has been identified, it still remains to be fully understood. The most common key virulence agents of hvKP included (1) siderophore systems for iron acquisition, (2) increased capsule production, (3) the colibactin toxin, (4) hypermucoviscosity, and so on. Several hypervirulence factors have been renewed, and the evolution of MDR-hvKP has been deeply explored recently. We aim to describe a chain of key virulence agents attributed to the lethality of hvKP and MDR-hvKP. In this review, recent advances in renewed factors in hypervirulence were summarized, and potential therapeutic targets are explored. Novel co-existence of hypervirulence agents and multidrug-resistant elements, even the superplasmid, was screened. Superplasmid simultaneously harbours hypervirulence and multidrug-resistant genes and can mobile autonomously by its complete conjugative elements. Research into related immunity has also gained traction, which may cause multiple invasive infections with higher mortality rates than classical ones, such as neutrophil- and complement-mediated activity. The evolution of virulence and multidrug resistance is accelerating. More reliable methods for identifying hvKP or MDR-hvKP must be investigated. Furthermore, it is critical to investigate innovative treatment targets in the future.

Targeted Antibiotics for Lower Respiratory Tract Infection with Corynebacterium striatum.

Purpose: To assess the impact of targeted antibiotic therapy on clinical outcomes of patients with lower respiratory tract (LRT) infection with Corynebacterium striatum (C. striatum). Methods: A new propensity score-inverse probability of treatment weighting (IPTW) cohort study was conducted by using 10-year data. The study included LRT infection patients with respiratory secretions cultured positive for C. striatum simultaneously. The primary outcome was all-cause hospital mortality; the secondary outcomes included hospital stay, ICU stay and ventilation time. The safety outcomes were drug-related serum creatinine (Cr) increase and thrombocytopenia. Results: A total of 339 patients were included in the cohort, and 84 (24.78%) initiated vancomycin or linezolid therapy. In the new IPTW cohort, targeted antibiotic therapy did not improve all-cause hospital mortality (P=0.632), and the OR (95% CI) was 0.879 (0.519-1.488). Moreover, targeted antibiotic therapy was not associated with hospital stay (P=0.415), ICU stay (P=0.945) or ventilation time (P=0.885). The side effects of drug-related higher serum Cr (P=0.044) and thrombocytopenic levels (P=0.038) cannot be ignored. Conclusion: Clinical benefits by vancomycin or linezolid targeted against LRT infection with C. striatum were limited and with drug-related side effects. A prospectively designed study is needed to further confirm the results.

Clinical efficacy and safety of linezolid in intensive care unit patients.

Background: To characterize the population of critically ill patients and infections treated with linezolid in the intensive care unit (ICU), and to evaluate the clinical efficacy and safety of linezolid therapy. Methods: This multi-center, observational, real-world study was conducted across 52 hospitals between June 9, 2018, and December 28, 2019. Patients who met the following inclusion criteria were included: (1) admitted to the ICU, (2) of any age group, and (3) having a clinical or laboratory diagnosis of a Gram-positive bacterial infection. Clinical efficacy was categorized as success (cured or improved), failed, or non-evaluable. Adverse events and serious adverse events were recorded during treatment. Results: A total of 366 ICU patients who met the inclusion criteria were evaluated. Linezolid was used as second- and first-line treatment in 232 (63.4%) and 134 (36.6%) patients, respectively. The most common isolated strain was Staphylococcus aureus (methicillin-resistant Staphylococcus aureus: n=37/119, 31.1%; methicillin-susceptible Staphylococcus aureus: n=15/119, 12.6%); this was followed by Enterococci (vancomycin-resistant Enterococci: n=8/119, 6.7%; vancomycin-susceptible Enterococci: n=11/119, 9.2%) and Streptococcus pneumoniae (multidrug-resistant: n=4/119, 3.4%; non-multidrug resistant: n=2/119, 1.7%). The main infection sites where pathogens were detected included the lung (n=216/366, 59.6%), skin and soft tissue (n=104/366, 28.4%), and blood (n=50/366, 13.7%). Clinical success was achieved in 301 (82.2%) patients; 34 (9.3%) were cured and 267 (73.0%) improved; treatment failure and non-evaluable outcomes were observed in 29 (7.9%) in 36 (9.8%) patients, respectively. Linezolid-related adverse events were reported in 8 (2.2%) patients. No treatment-related serious adverse events were reported. Conclusions: Based on real-world results, linezolid was found to be effective and safe in the treatment of Gram-positive bacterial infections in critically ill patients.

The effect of sex inequality on solid organ transplantation: A systematic review and meta-analysis.

BACKGROUND: Sex disparities are related to biological differences, which may have significant impact on patient and allograft outcomes. The aim was to investigate the impact of sex on clinical and safety outcomes after solid organ transplantation (SOT). METHODS: A systematic review and meta-analysis was performed. Observational studies comparing females vs. males after SOT were considered for inclusion after a systematic search of the Pubmed, Cochrane Library, and Web of Science databases conducted from 2016 to 2021. Primary outcome was mortality. PROSPERO register number: CRD42021282615. RESULTS: After retrieving 1103 studies, 22 observational studies (1,045,380 subjects) were finally deemed eligible for inclusion. Females accounted 36.3% of SOT recipients, but presented significantly lower mortality (odds ratio (OR): 0.87, 95% confidence interval (CI): 0.83-0.92, I2=78%). In subgroup analyses, mortality was significantly lower in females undergoing liver (OR: 0.89 95%CI: 0.86-0.92, I2=0%) or kidney transplantation (OR: 0.82 95%CI: 0.76-0.89, I2=72%). Male sex was consistently reported as a protective factor against hospital readmission. Among the outcomes, allograft dysfunction was influenced by a combination of donor-recipient sex and age. Data on overall infections were inconclusive. Several reports suggest a higher risk of malignancy among males. CONCLUSIONS: Females represent one-third of SOT recipients but have higher survival rates than males after liver and kidney transplantation. The impact on graft dysfunction was heterogeneous. While further research is warranted, our findings should encourage clinicians and researchers to consider sex as a factor when taking decisions regarding SOT management.

The emerging roles and therapeutic potential of B cells in sepsis.

Sepsis is a life-threatening syndrome caused by anomalous host response to infection. The pathogenesis of sepsis is complex, and immune dysfunction is the central link in its occurrence and development. The sepsis immune response is not a local and transient process but a complex and continuous process involving all major cell types of innate and adaptive immunity. B cells are traditionally studied for their ability to produce antibodies in the context of mediating humoral immunity. However, over the past few years, B cells have been increasingly recognized as key modulators of adaptive and innate immunity, and they can participate in immune responses by presenting antigens, producing cytokines, and modulating other immune cells. Recently, increasing evidence links B-cell dysfunction to mechanisms of immune derangement in sepsis, which has drawn attention to the powerful properties of this unique immune cell type in sepsis. Here, we reviewed the dynamic alterations of B cells and their novel roles in animal models and patients with sepsis, and provided new perspectives for therapeutic strategies targeting B cells in sepsis.

Targeted next-generation sequencing identifies a novel nonsense mutation in ANK1 for hereditary spherocytosis: A case report.

BACKGROUND: Hereditary spherocytosis (HS) is characterized by anemia, jaundice, splenomegaly, and cholelithiasis, and is caused by abnormal genes encoding red blood cell membrane components. The most common mutations found in HS are in the ANK1 gene. CASE SUMMARY: A 4-mo-old girl was admitted to our hospital with pallor that had lasted for more than 2 mo. She presented with jaundice, anemia and splenomegaly. A heterozygous mutation of ANK1 (exon23: c.G2467T:p.E823X) was identified, and the mutation was determined to be autosomal dominant. This mutation is linked to the relatively serious anemia she had after birth; this anemia improved with age. CONCLUSION: The utilization of next-generation sequencing may assist with the accurate diagnosis of HS, especially in atypical cases.

Sequential use of midazolam and dexmedetomidine for long-term sedation may reduce weaning time in selected critically ill, mechanically ventilated patients: a randomized controlled study.

BACKGROUND: Current sedatives have different side effects in long-term sedation. The sequential use of midazolam and dexmedetomidine for prolonged sedation may have distinct advantages. We aimed to evaluate the efficacy and safety of the sequential use of midazolam and either dexmedetomidine or propofol, and the use of midazolam alone in selected critically ill, mechanically ventilated patients. METHODS: This single-center, randomized controlled study was conducted in medical and surgical ICUs in a tertiary, academic medical center. Patients enrolled in this study were critically ill, mechanically ventilated adult patients receiving midazolam, with anticipated mechanical ventilation for ≥ 72 h. They passed the spontaneous breathing trial (SBT) safety screen, underwent a 30-min-SBT without indication for extubation and continued to require sedation. Patients were randomized into group M-D (midazolam was switched to dexmedetomidine), group M-P (midazolam was switched to propofol), and group M (sedation with midazolam alone), and sedatives were titrated to achieve the targeted sedation range (RASS - 2 to 0). RESULTS: Total 252 patients were enrolled. Patients in group M-D had an earlier recovery, faster extubation, and more percentage of time at the target sedation level than those in group M-P and group M (all P < 0.001). They also experienced less weaning time (25.0 h vs. 49.0 h; HR1.47, 95% CI 1.05 to 2.06; P = 0.025), and a lower incidence of delirium (19.5% vs. 43.8%, P = 0.002) than patients in group M. Recovery (P < 0.001), extubation (P < 0.001), and weaning time (P = 0.048) in group M-P were shorter than in group M, while the acquisition cost of sedative drug was more expensive than other groups (both P < 0.001). There was no significant difference in adverse events among these groups (all P > 0.05). CONCLUSIONS: The sequential use of midazolam and dexmedetomidine was an effective and safe sedation strategy for long-term sedation and could provide clinically relevant benefits for selected critically ill, mechanically ventilated patients. TRIAL REGISTRATION: NCT02528513 . Registered August 19, 2015.

Impairment of antigen-presenting function of peripheral γδ T cells in patients with sepsis.

Impairment of antigen-presenting functions is a key mechanism contributing to sepsis-induced immunosuppression. Recently, γδ T cells have been demonstrated as professional antigen-presenting cells (APCs); however, their role in sepsis remains unknown. In this in vitro study, the APC function of human peripheral γδ T cells was assessed using samples collected from 42 patients with sepsis and 27 age-matched healthy controls. The APC-related markers HLA-DR, CD27, CD80, and CCR7 on fresh γδT cells were significantly higher in patients with sepsis compared with matched controls; however, they responded poorly to 4-hydroxy-3-methyl-2-butenyl pyrophosphate (HMBPP) stimulation, characterized by the deactivation of these APC markers and impaired proliferation. Furthermore, the adhesion function of γδ T cells, essential for antigen presentation, was greatly reduced in patients with sepsis; for instance, in co-cultures with green fluorescent protein-expressing Escherichia coli, HMBPP-activated γδT cells from healthy individuals adhered to E. coli efficiently, whereas no such phenomenon was observed with respect to γδT cells from patients with sepsis. In line with these results, in co-cultures with isolated CD4+ αß T cells, HMBPP-activated γδT cells of healthy individuals promoted the efficient proliferation of CD4+ αß T cells, whereas γδT cells from patients with sepsis did not do so. In conclusion, our findings show that the antigen-presenting function of γδT cells is severely impaired in patients with sepsis and the mechanisms behind need further study.

Female representation in intensive care medicine: Challenges and perspectives from China.

The gender gap in the practice of intensive care medicine has increasingly been recognized as a problem in recent years. Despite limited information, the available data suggest that representation of women in the physician workforce, academic positions, and leadership roles in intensive care is inadequate globally. In this article, we describe the situation of female intensive care unit (ICU) physicians from the perspective of Chinese intensivists. The proportion of female ICU physicians in China has been increasing in recent years. The biggest challenges faced by female ICU physicians include balance of work and life, difficulties in career planning, and lack of academic influence. More attention and policy support should be provided to help them play a better role in intensive care medicine.

Severe Adaptive Immune Suppression May Be Why Patients With Severe COVID-19 Cannot Be Discharged From the ICU Even After Negative Viral Tests.

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the "dysregulated host response" to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.

Association between glucocorticoids treatment and viral clearance delay in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Evidence of glucocorticoids on viral clearance delay of COVID-19 patients is not clear. METHODS: In this systematic review and meta-analysis, we searched for studies on Medline, Embase, EBSCO, ScienceDirect, Web of Science, Cochrane Library, and ClinicalTrials.gov from 2019 to April 20, 2021. We mainly pooled the risk ratios (RRs) and mean difference (MD) for viral clearance delay and did subgroup analyses by the severity of illness and doses of glucocorticoids. RESULTS: 38 studies with a total of 9572 patients were identified. Glucocorticoids treatment was associated with delayed viral clearance in COVID-19 patients (adjusted RR 1.52, 95% CI 1.29 to 1.80, I2 = 52%), based on moderate-quality evidence. In subgroup analyses, risk of viral clearance delay was significant both for COVID-19 patients being mild or moderate ill (adjusted RR 1.86, 95% CI 1.35 to 2.57, I2 = 48%), and for patients of being severe or critical ill (adjusted RR 1.59, 95% CI 1.23 to 2.07, I2 = 0%); however, this risk significantly increased for patients taking high doses (unadjusted RR 1.85, 95% CI 1.08 to 3.18; MD 7.19, 95% CI 2.78 to 11.61) or medium doses (adjusted RR 1.86, 95% CI 0.96 to 3.62, I2 = 45%; MD 3.98, 95% CI 3.07 to 4.88, I2 = 4%), rather those taking low doses (adjusted RR 1.38, 95% CI 0.94 to 2.02, I2 = 59%; MD 1.46, 95% CI -0.79 to 3.70, I2 = 82%). CONCLUSIONS: Glucocorticoids treatment delayed viral clearance in COVID-19 patients of taking high doses or medium doses, rather in those of taking low doses of glucocorticoids.

Takotsubo cardiomyopathy following pericardiectomy: A case report.

BACKGROUND: Takotsubo cardiomyopathy (TC) is defined as a temporary and reversible systolic abnormality of the left ventricle's apical area resembling myocardial infarction in the nonexistence of coronary artery disease. Only a few cases have been reported after cardiac operations or after pericardiocentesis. AIM: To emphasize the need to be aware of the possibility of the occurrence of this potentially fatal complication after cardiac surgery. MATERIALS AND METHODS: A 66-year-old man underwent a pericardiectomy. He progressed to exacerbation of hemodynamic instability postoperatively and was diagnosed with TC, finally, he had to be supported by an intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO). RESULTS: Patient's left ventricle function recovered fully in 2 weeks. DISCUSSION: We discussed the pathogenesis and treatment of postoperative TC. CONCLUSION: TC has to be carefully considered in the differential diagnosis in case of acute left ventricle dysfunction following cardiac surgery.

The neutrophil to lymphocyte ratio is an independent predictor for severe COVID-19 : Evidence from a multicenter case-control study and meta-analyses.

PURPOSE: The aim of this study was to determine whether the neutrophil to lymphocyte ratio (NLR) can predict severe Coronavirus disease 2019 (COVID-19). PATIENTS AND METHODS: A multicenter case-control study was conducted to investigate whether the NLR can help predict the severity of COVID-19. Patients confirmed to have COVID-19 between 16 January 2020 and 15 March 2020 were enrolled. Furthermore, meta-analyses were conducted based on both previous studies and our case-control study. RESULTS: In the case-control study, 213 patients (severe: 81) were included. The results suggested that the NLR was an independent risk factor (odds ratio [OR], 1.155, 95% confidence interval [95% CI]: 1.043-1.279, P = 0.006) and a great predictor (the area under the ROC curve was 0.728, 95% CI: 0.656-0.800) for severe COVID-19. In total, 18 datasets from 16 studies combined with our case-control study (severe: 1211; non-severe: 5838) were included in the meta-analyses and the results showed that the NLR of the severe COVID-19 group was significantly higher than that of the non-severe group (SMD = 1.10, 95% CI: 0.90-1.31, P < 0.001). Based on the 2â€¯× 2 data from 6 studies, the SROC of NLR for predicting severe COVID-19 was 0.802, with a sensitivity of 0.67 (95% CI: 0.61-0.72) and a specificity of 0.75 (95% CI: 0.73-0.78). CONCLUSION: Based on a multicenter case-control study and a meta-analysis, we found that the initial NLR was a great predictor of severe COVID-19.

Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen.

BACKGROUND: Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. METHODS: Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. RESULTS: A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. CONCLUSIONS: Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.