A therapeutic regimen of ceftazidime-avibactam for a critical patient receiving prolonged intermittent renal replacement therapy.

The present report firstly described a critically ill patient receiving a dosing regimen of ceftazidime-avibactam (CAZ-AVI) (1.875g q24h) to eliminate multidrug-resistant Klebsiella pneumoniae and a scheduled time for prolonged intermittent renal replacement therapy (PIRRT) every 48h (6h-session beginning 12h after the previous dosage on hemodialysis day). This dosing regimen for CAZ-AVI and a scheduled time for PIRRT allowed pharmacodynamic parameters of ceftazidime and avibactam to have little difference on hemodialysis and non-hemodialysis days so that we can maintain a relatively stable drug concentration. Our report highlighted not only the importance of dosing regimens in patients with PIRRT but also the significance of hemodialysis time points during the dosing interval. The innovative therapeutic plan proved to be suitable for patients infected with Klebsiella pneumoniae when on PIRRT according to the trough plasma concentrations of ceftazidime and avibactam which were maintained above the minimum inhibitory concentration during the dosing interval.

[The Effect of Exogenous Recombinant HMGB1 on Neural Stem Cells and Related Mechanism].

OBJECTIVES: To explore the effect of exogenous recombinant high mobility group protein box1 (rHMGB1) on proliferation and differentiation of neural stem cells (NSCs) and the related mechanism. METHODS: SD rat cerebral cortex cells were cultured in serum-free medium, extending the culture and purification of neural stem cells. NSCs were identified by detecting nestin-label with immunofluorescence method.The NSCs proliferation activity after adding different concentrations of rHMGB1 was determined by CCK-8 assay and the optimal concentration of rHMGB1 for the follow-up experiments was selected.The effect of rHMGB1 on NSCs differentiation was detected by immunofluorescence assay. The mRNA and protein expression of involved factors were studied by real-time PCR and Western blot separately. RESULTS: The neural cells isolated from the cortex of rat embryos showed the expression of nestin antigen and the neural stem cells purity could reach more than 99% when cultured to the third generation. Under the stimulation of 10 ng/mL rHMGB1, neural stem cells proliferation activity were the highest, therefore, 10 ng/mL rHMGB1 was selected to treat the experimental group. The expression of TUJ1 in the experimental group was higher than that in the control group (P<0.05). Real-time PCR and Western blot confirmed rHMGB1 could improve the expression of receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), matrix metalloproteinase 9 (MMP-9) and nerve growth factor(NGF) respectively at the level of mRNA and protein expression. CONCLUSIONS: Exogenous rHMGB1 promoted rat NSCs proliferation and differentiation into neuronsin vitro by activating RAGE, TLRs, MMP-9 signaling.

Long survival in a pancreatic carcinoma patient with multi-organ toxicities after sintilimab treatment: A case report.

Pancreatic carcinoma is the leading cause of death among digestive malignancies in China. In particular, there is no breakthrough in prolonging the survival of pancreatic cancer patients with chemical and targeted therapies. Tumor immunotherapy brings opportunities and progress for the treatment of pancreatic cancer. Sintilimab is an innovative PD-1 inhibitor which was reported certain clinical benefits in multi-line treatments of advanced pancreatic cancer with gemcitabine. The combination therapy of PD-1 with gemcitabine plus high-intensity focused ultrasound (HIFU) in pancreatic cancer has not been reported. Here we report a case of a Chinese old patient diagnosed with metastatic pancreatic cancer. Two months after sintilimab treatment, the patient occurred severe immune colitis. The patient was diagnosed with immune ureteritis after 8 months of treatment. The immue-related adverse events (irAEs) refined after timely recognition and correct intervention by the clinician and clinical pharmacist. After first-line treatment of sintilimab plus gemcitabine combined with pancreatic HIFU, the patient achieved a remarkable benefit of 11-month progression-free survival (PFS) and 20-month overall survival (OS). The first-line treatment of sintilimab plus gemcitabine combined with HIFU demonstrates a potential therapeutic effect on metastatic pancreatic carcinoma with tolerable adverse reactions.

Prevalence and Predictors of Hemorrhagic Foci on Long-term Follow-up MRI of Recent Single Subcortical Infarcts.

Hemorrhagic foci surrounding the lacune in the long-term evolution of recent single subcortical infarcts (RSSIs) remains largely unexplored. We aimed to determine the prevalence, characteristics, and predictors of hemorrhagic foci in patients with RSSI. From a prospective, longitudinal study of RSSIs, we recruited patients who underwent multimodal MRI assessments both at baseline and approximately one year after the stroke onset. Hemorrhagic foci were identified using susceptibility-weighted imaging (SWI). Among 101 patients with RSSI, nearly half (n = 45, 44.6%) had hemorrhagic foci within the index RSSI lesions on follow-up SWI. RSSIs with hemorrhagic foci formation were associated with a longer time to follow-up imaging (median 449 versus 401 days, P = 0.005) and higher likelihood of being located in the anterior circulation compared to those without hemorrhagic foci (88.9% versus 64.3%, P = 0.003). Hemorrhagic foci were also associated with larger lesion size (P < 0.001), a higher proportion of cavitation formation (P = 0.003), higher baseline NIHSS scores (P = 0.004), and poorer functional outcomes (P = 0.001). In the subset of RSSIs in the lenticulostriate artery (LSA) territory, after adjustment for covariates, larger initial lesion volume (OR 1.80, 95% CI 1.13-2.87; P = 0.014) and greater decreases in LSA total length (OR 0.59, 95% CI 0.36-0.96; P = 0.035) were independently associated with hemorrhagic foci formation. The extent of ischemia in the initial infarct is predictive of the presence of hemorrhagic residues. Our findings contribute to the current understanding of the mechanisms underlying the evolution of RSSIs.

Influence of continuous renal replacement therapy on the plasma concentration of tigecycline in patients with septic shock: A prospective observational study.

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing. Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group (n = 6) or non-CRRT group (n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t-test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model. Results: Peak concentration (Cmax) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs. 406.29 ± 108.00 ng/mL, p-value: 0.129). Trough concentration (Cmin) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs. 174.79 ± 33.15 ng/mL, p-value: 0.000, adjusted p-value: 0.000). In safety, Cmin was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, Cmin of all patients in CRRT group was lower than 474.8 ng/mL. Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only Cmin shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2000037475.

Sting mutation attenuates acetaminophen-induced acute liver injury by limiting NLRP3 activation.

Acetaminophen (N-acetyl-p-aminophenol; APAP), a widely used effective nonsteroidal anti-inflammatory drug, leads to acute liver injury at overdose worldwide. Evidence showed that the severity of liver injury associated with the subsequent involvement of inflammatory mediators and immune cells. The innate immune stimulator of interferon genes protein (STING) pathway was critical in modulating inflammation. Here, we show that STING was activated and inflammation was enhanced in the liver in APAP-overdosed C57BL/6J mice, and Sting mutation (Stinggt/gt) mice exhibited less liver damage. Multiplexing flow cytometry displayed that Sting mutation changed hepatic recruitment and replacement of macrophages/monocytes in APAP-overdosed mice, which was inclined to anti-inflammation. In addition, Sting mutation limited NLRP3 activation in the liver in APAP-overdosed mice, and inhibited the expression of inflammatory cytokines. Finally, MCC950, a potent and selective NLRP3 inhibitor, significantly ameliorated APAP-induced liver injury and inflammation. Besides, pretreatment of MCC950 in C57 mice resulted in changes of immune cells infiltration in the liver similar to Stinggt/gt mice. Our study revealed that STING played a crucial role in APAP-induced acute liver injury, possibly by maintaining liver immune cells homeostasis and inhibiting NLRP3 inflammasome activation, suggesting that inhibiting STING-NLRP3 pathway might be a potential therapeutic strategy for acute liver injury.

Association of compromised cerebral perfusion with lenticulostriate artery impairments in the subacute phase of branch atheromatous disease.

Background Purpose: Whether altered cerebral perfusion is associated with the pathogenesis of single subcortical infarctions (SSIs) in the lenticulostriate artery (LSA) territory remains unclear. Objective: We aimed to assess whether cerebral perfusion abnormalities are related to LSA impairments in the subacute phase of SSIs and then to examine their correlations with etiological subtypes of SSIs. Methods: A total of 110 patients with acute SSIs in the LSA territory were prospectively recruited between July 2017 and October 2021, and they underwent magnetic resonance perfusion-weighted imaging (PWI) and whole-brain vessel-wall imaging (VWI) within 7 days of stroke onset. Based on VWI, patients were assigned to one of two SSI subtypes: branch atheromatous disease (BAD, n = 78, 70.9%) or lacunar infarction related to cerebral small vessel disease (CSVD-related LI, n = 32, 29.1%). Perfusion maps and LSA morphology were also quantitatively assessed. Results: Based on PWI, 22 patients (20%) had hypoperfusion and 88 (80%) showed normal perfusion. Compared with normal individuals, patients with hypoperfusion showed shorter average LSA length (23.48 ± 4.81 mm versus 25.47 ± 3.74 mm, p = 0.037). Compared with patients with CSVD-related LI, patients with BAD had significantly lower relative cerebral blood flow [0.95 (IQR 0.81-1.12) versus 1.04 (IQR 0.92-1.22); p = 0.036] and cerebral blood volume [0.95 (IQR 0.84-1.15) versus 1.14 (IQR 0.97-1.27); p = 0.020] after adjusting for hypertension, number of LSA branches, and infarct volume. Conclusion: Compromised cerebral perfusion is associated with impairments in the LSA and with BAD pathogenesis. Perfusion magnetic resonance imaging can provide important insights into acute SSI pathophysiology, and it may be useful for determining the clinical significance of perfusion abnormalities in BAD occurrence.

Cognitive impairment in two subtypes of a single subcortical infarction.

BACKGROUND: Single subcortical infarction (SSI) is caused by two main etiological subtypes, which are branch atheromatous disease (BAD) and cerebral small vessel disease (CSVD)-related SSI. We applied the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ), the Shape Trail Test (STT), and the Stroop Color and Word Test (SCWT) to investigate the differences in cognitive performance between these two subtypes of SSI. METHODS: Patients with acute SSIs were prospectively enrolled. The differences of MoCA-BJ, STT, and SCWT between the BAD group and CSVD-related SSI group were analyzed. A generalized linear model was used to analyze the associations between SSI patients with different etiological mechanisms and cognitive function. We investigated the correlations between MoCA-BJ, STT, and SCWT using Spearman's correlation analysis and established cut-off scores for Shape Trail Test A (STT-A) and STT-B to identify cognitive impairment in patients with SSI. RESULTS: This study enrolled a total of 106 patients, including 49 and 57 patients with BAD and CSVD-related SSI, respectively. The BAD group performances were worse than those of the CSVD-related SSI group for STT-A (83 [60.5-120.0] vs. 68 [49.0-86.5], P = 0.01), STT-B (204 [151.5-294.5] vs. 153 [126.5-212.5], P = 0.015), and the number of correct answers on Stroop-C (46 [41-49] vs. 49 [45-50], P = 0.035). After adjusting for age, years of education, National Institutes of Health Stroke Scale and lesion location, the performance of SSI patients with different etiological mechanisms still differed significantly for STT-A and STT-B. CONCLUSIONS: BAD patients were more likely to perform worse than CSVD-related SSI patients in the domains of language, attention, executive function, and memory. The mechanism of cognitive impairment after BAD remains unclear.

[Construction of an indicator system for evaluating the protection efficacy of national nature reserves in China: A case study on terrestrial vertebrates (excluding migratory birds)].

The protection efficacy of nature reserves is a key element in achieving targets of biodiversity conservation. It is therefore very important to develop a scientific, systematic, and accurate index system for evaluating the protection efficacy of national nature reserves in China. Using methods of frequency statistics, expert consultation, analytic hierarchy process, and demonstration survey, we present a novel index system for evaluating the protection efficacy of Chinese national nature reserves for terrestrial vertebrates (excluding migratory birds) over a 10-year period. The indicator system included one target layer, two system layers, nine factor layers, and forty index layers. The system layer included ecological effectiveness evaluation (with a score of 60%) and management effectiveness evaluation (score of 40%). The ecological effectiveness evaluation was a comprehensive, dynamic evaluation of the target species, population, habitat, and ecological system. The management effectiveness evaluation was focused on the effectiveness of patrol and monitoring. The additional part aimed to analyze the impact of humans on the target species, population and nature resources of the nature reserve. This study combined the ecological effectiveness evaluation and the management effectiveness evaluation for the first time, highlighted the importance of time and space changes, distinguished the influence of natural factors from human factors, and integrated them into the evaluation results. By emphasizing quantifiable indicators, this evaluation index system could vastly assist the protection of nature reserves by improving management effectiveness, biodiversity conservation, and macroscopic decision-making.