Time to trimethoprim/sulfamethoxazole initiation among patients with rheumatic disease complicated by Pneumocystis jirovecii pneumonia: impact on 90-day mortality.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening disease with increasing prevalence in patients with rheumatic disease. Trimethoprim/sulfamethoxazole (TMP/SMX) is an effective treatment for patients with rheumatic disease hospitalized for PJP. This study aimed to describe the 90-day mortality of patients with rheumatic disease complicated by PJP and investigate whether the administration of TMP/SMX after 7 days from initial symptoms correlates with 90-day mortality. METHODS: We enrolled consecutive patients with rheumatic disease complicated with PJP in our center from August 2018 to August 2021. The participants were classified into two groups according to when TMP/SMX was initiated: early (within the first 7 days) and late (after 7 days). The primary outcome was 90-day PJP-related mortality. Multivariate cox regression and Kaplan-Meier survival analyses were conducted to identify the risk factors for mortality and examine differences in survival between early and late use of TMP/SMX. RESULTS: Thirty-seven patients with rheumatic disease (median age 50.1 years, 24.3% male) complicated by PJP were enrolled in our study, and 15 (40.5%) patients died at or before 90 days of follow-up. The most common comorbidity was systemic lupus erythematosus (14, 37.8%), followed by inflammatory myopathy (11, 27.9%). Patients in the early group were less likely to require mechanical ventilation (8/27, 29.6% vs. 9/10, 90.0%, P = 0.002), lower doses glucocorticoids (43.2 mg/d vs. 72.2 mg/d, P = 0.039) and had lower mortality (7/27, 25.9% vs. 8/10, 80.0%, P = 0.006) than those in the late group. In the Kaplan-Meier analysis, the survivor probability of the early group was notably higher than that of the late group (P = 0.007). Multivariate cox regression analysis showed that initiation of TMP/SMX after 7 days from admission (hazard ratio [HR]: 5.9, 95% confidence interval [CI]: 1.1-30.4; P = 0.034) and a higher level of lactate dehydrogenase (LDH; HR: 6.0, 95% CI: 1.1-31.8; P = 0.035) were associated with 90-day mortality in patients with rheumatic disease complicated by PJP. CONCLUSION: Patients with rheumatic disease complicated by PJP had poor prognoses, with mortality rates as high as 40.5%. TMP/SMX initiation after 7 days from initial symptoms and a higher level of serum LDH were significantly associated with increased 90-day mortality.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

SENP3 facilitates M1 macrophage polarization via the HIF-1α/PKM2 axis in lipopolysaccharide-induced acute lung injury.

M1/M2 macrophage polarization plays a pivotal role in the development of acute lung injury (ALI). The hypoxia-inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis, which functions upstream of macrophage polarization, has been implicated in this process. The function of HIF-1α is known to be tightly regulated by SUMOylation. Upregulation of SUMO-specific peptidase 3 (SENP3), a deSUMOylation enzyme, is induced by reactive oxygen species (ROS), which are abundantly produced during ALI. To explore the links between SENP3, macrophage polarization, and lung injury, we used mice with Senp3 conditional knockout in myeloid cells. In the lipopolysaccharide (LPS)-induced ALI model, we found that in vitro and in vivo SENP3 deficiency markedly inhibited M1 polarization and production of pro-inflammatory cytokines and alleviated lung injury. Further, we demonstrated that SENP3 deficiency suppressed the LPS-induced inflammatory response through PKM2 in a HIF-1α-dependent manner. Moreover, mice injected with LPS after PKM2 inhibitor (shikonin) treatment displayed inhibition of M1 macrophage polarization and reduced lung injury. In summary, this work revealed that SENP3 promotes M1 macrophage polarization and production of proinflammatory cytokines via the HIF-1α/PKM2 axis, contributing to lung injury; thus, SENP3 may represent a potential therapeutic target for ALI treatment.

Impact of Platelet Transfusion Thresholds on Outcomes of Patients With Sepsis: Analysis of the MIMIC-IV Database.

BACKGROUND: The benefits of platelet thresholds for transfusion remain unclear. This study assessed the effect of two transfusion thresholds on the survival outcomes of patients with sepsis and thrombocytopenia. METHODS: In this retrospective cohort study, data of patients with sepsis admitted to an intensive care unit (ICU) and who had received platelet transfusion were extracted from the Medical Information Mart for Intensive Care IV database. Patients were classified into the lower-threshold group (below 20,000/µL) and higher-threshold group (20,000-50,000/µL), based on thresholds calculated from their pretransfusion platelet count. The endpoints included 28- and 90-day mortality, red blood cell (RBC) transfusion, ICU-free days, and hospital-free days. RESULTS: There were 76 and 217 patients in the lower-threshold and higher-threshold groups, respectively. The higher-threshold group had a higher rate of surgical ICU admission (35.0% vs. 9.2%) and lower quick Sequential Organ Failure Assessment (qSOFA) score than the lower-threshold group. In the higher-threshold group, 94 (43.3%) and 132 (60.8%) patients died within 28 and 90 days, compared to 51 (67.1%) and 63 (82.9%) patients in the lower-threshold group (adjusted odds ratio, 1.96; 95% confidence interval, 1.16 to 3.03; P = 0.012; adjusted odds ratio, 2.04; 95% confidence interval, 1.16 to 3.57; P = 0.012, respectively). After stratification by mortality risk, the subgroup analysis showed a consistent trend favoring higher-threshold transfusion but reached statistical significance only in the low-risk group. There were no differences in red blood cell transfusion, ICU-free days, and hospital-free days between the groups. The E-value analysis suggested robustness to unmeasured confounding. CONCLUSIONS: In patients with sepsis and thrombocytopenia, platelet transfusion at a higher threshold was associated with a greater reduction in the 28- and 90-day mortalities than that at a lower threshold.

Veno-Arterial Extracorporeal Membrane Oxygenation in the Treatment of Hemodynamically Unstable Lupus Myocarditis: A Retrospective Case Series Study.

Objective: The clinical manifestations and treatment of three patients with hemodynamically unstable lupus myocarditis (LM) were analyzed. Methods: The clinical data of three patients with LM with hemodynamic instability, who were admitted to the emergency ICU of the south hospital of the Renji Hospital, School of Medicine, Shanghai Jiao Tong University of Medicine from January 2018 to December 2021, were collected and analyzed, and relevant literatures were reviewed. Results: Two of the three patients had the first onset of systemic lupus erythematosus. The other patient had mixed connective tissue disease in the past, and lupus was the main manifestation of this disease. At the onset of the disease, all patients had chest tightness and shortness of breath; two patients had a fever, and the markers of myocardial injury increased. Cardiac color Doppler ultrasound indicated that left ventricular ejection fraction decreased significantly. Cardiac insufficiency with cardiogenic shock rapidly appeared as the main manifestation. Two patients immediately started veno-arterial extracorporeal membrane oxygenation (VA-ECMO), and ECMO was also started in one patient after a pacemaker placement was ineffective. For all three patients, high-dose hormones were given to control the primary disease, and then the ECMO machines were removed successfully. Conclusion: VA-ECMO treatment should be implemented in patients with hemodynamically unstable LM as soon as possible to maintain the patient's hemodynamics and help them overcome the crisis of cardiac dysfunction, allowing more time for primary disease treatment.

Opportunities and challenges of hepatocellular carcinoma organoids for targeted drugs sensitivity screening.

Hepatocellular carcinoma is one of the malignancies worldwide with a high mortality rate and an increasing incidence. Molecular Targeted agents are its common first-line treatment. Organoid technology, as a cutting-edge technology, is gradually being applied in the development of therapeutic oncology. Organoid models can be used to perform sensitivity screening of targeted drugs to facilitate the development of innovative therapeutic agents for the treatment of hepatocellular carcinoma. The purpose of this review is to provide an overview of the opportunities and challenges of hepatocellular carcinoma organoids in targeted drug sensitivity testing as well as a future outlook.

Performance of Procalcitonin to Distinguish Fungal from Bacterial Infections in Patients with Systemic Lupus Erythematosus.

PURPOSE: To evaluate the performance of serum procalcitonin (PCT) concentrations to diagnose fungal infection in patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: From January 2017 to October 2020, SLE patients hospitalized for serious infection with an identified single bacterial or fungal pathogen, as well as PCT measured within 24h after admission were included. The diagnostic performance of PCT was evaluated independently and in combination with the white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). The analysis included the sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and the crude and adjusted area under the receiver operating characteristic curve (AUROC). RESULTS: Sixty-nine patients were included; 26 had a fungal infection (38%) and 43 had a bacterial infection (22 gram-positive and 21 gram-negative). Fungal infection patients were mainly distributed in the respiratory group (88.5%), and bacterial infection distribution were more prevalent in respiratory group (44.2%) and abdominal/urinary group (23.3%). The PCT concentration was significantly lower in fungal infections than bacterial infections (fungal: 0.22 ng/mL, interquartile range [IQR], 0.09-0.44 vs bacterial: 0.60 ng/mL, IQR, 0.16-5.74; p = 0.016) and differed significantly between different infection sites (p = 0.022). PCT had better diagnostic performance for predicting fungal infection (AUROC = 0.731) than the WBC count (AUROC = 0.581), the CRP level (AUROC = 0.716), and ESR (AUROC = 0.583). PCT and ESR together had the best diagnostic performance, with 46.2% sensitivity and 88.4% specificity. Further, the AUROC increased compared to PCT alone but was statistically insignificant (p = 0.693). CONCLUSION: For SLE patients with serious infection, the PCT concentration had better diagnostic accuracy for predicting fungal infection than the WBC count, the CRP level, and ESR. Combining PCT and ESR obtained the highest AUROC and provided an acceptable discrimination performance.

The effect of dexmedetomidine post-treatment on the inflammatory response of astrocyte induced by lipopolysaccharide.

To explore the effect of dexmedetomidine (DEX) post-treatment on the inflammatory response of astrocyte induced by lipopolysaccharide (LPS). The astrocytes of neonatal mice were primarily cultured in vitro. After purification and identification, the cells were divided into five groups: group C: control group; group L: astrocytes were treated with 1 µg/ml LPS for 24 h; group D1, D2, and D3: astrocytes were pretreated with 1 µg/ml for 24 h LPS, and then cultured with low (0.1 µM), medium (1 µM), high (10 µM) concentration of DEX for 30 min, respectively. The cell survival rate was detected by cell counting kit. The expressions of inducible nitric oxide synthase (iNOS) mRNA, tumor necrosis gactor-α (TNF-α) mRNA, and interleukin-1ß (IL-1ß) mRNA were measured by RT-PCR in cell lysis solution of every group. The concentration of nitric oxide (NO) was detected by Griess method. The concentrations of IL-1ß and TNF-α were measured, respectively, by enzyme-linked immuno sorbent assay. Compared with the group C, the expressions of iNOS mRNA, TNF-α mRNA, and IL-1ßm RNA were significantly up-regulated, the release of NO, TNF-α, and IL-1ß was significantly increased in group L (P < 0.05). Compared with group L, mRNA levels of inflammation-related factors and release of inflammatory factors were significantly down-regulated in group D2 and D3 (P < 0.05). There was no statistical difference between group D1 and group L. Pre-treatment with medium and high concentration of DEX can inhibit the LPS-induced inflammatory response of astrocyte.

[Study of 8,665 cases of the 50 g oral glucose challenge test to screen the gestational diabetes mellitus].

OBJECTIVE: To study the cutoff value, the appropriate time of the 50 g oral glucose challenge test (GCT) to screen the gestational diabetes mellitus (GDM) and to study the importance of the maternal age and body weight of GDM. METHODS: The clinical data of 8 665 pregnant women who underwent the GCT from January 1995 to March 2001 in the Department of Obstetrics and Gynecology of the First Hospital of Beijing University were collected, and a retrospective study was made. RESULTS: (1) The 1 h average plasma glucose level of the GCT is (6.8 +/- 1.7) mmol/L. The abnormal rate of GCT was 25.2% using 7.8 mmol/L as the cutoff, 5.3% (17/321) of GDM were misdiagnosed. When the cutoff is 7.2 mmol/L, the abnormal rate is increased to 36.5%, and 2.8% (9/321) of GDM were more diagnosed. If a value of 8.3 mmol/L as threshold, there would be 15.9% (51/321) of GDM to misdiagnose. (2) When 1 h blood glucose is >or= 11.2 mmol/L, the incidence of GDM is 55.8% (92/165). Among them, 62.0% (57/92) GDM could be diagnosed according to the fasting blood glucose. (3) There were no difference in the rate of abnormal GCT when GCT underwent between 24 and 36 weeks of gestation. (4) The rate of abnormal GCT and the incidence of the GDM are obviously different among the different age groups. The incidence of GDM among the women younger than 25 years old without high risk factors is only 0.3%, obviously lower than the other groups. (5) The average body mass index (BMI) of the women between 26 to 28 weeks of gestation is (24.9 +/- 2.9) kg/m(2). When the BMI is >or= 27.8 (x +/- s), the rate of abnormal GCT and the incidence of the GDM were obviously higher than the other women. CONCLUSIONS: (1) 7.8 mmol/L as the cutoff of the GCT for the screening of GDM is appropriate. When the 1 h blood glucose level is >or= 11.2 mmol/L, fasting blood glucose should first be done to diagnose GDM. (2) It is necessary to screen GDM as soon as possible after 24 weeks of gestation, but for the women with obviously high risk factors GCT should be done before 24 weeks of gestation. (3) Age and obesity are the important risk factors for the GDM. It is not necessary to screen GDM among the pregnant women younger than 25 years old without high risk factors.