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Background: Acute-on-chronic liver failure (ACLF) is a common clinical type of liver failure, and patients with acute-on-chronic liver failure are prone to fungal infections, especially the increasing incidence of invasive pulmonary aspergillosis(IPA). Voriconazole is recommended as the first-line antifungal agent in the treatment of invasive aspergillosis, however, no recommendation has been given for patients with severe liver cirrhosis (Child-Pugh C) and liver failure. This trial aims to examine the therapeutic effects and safety of voriconazole in the treatment of IPA in patients with liver failure.Methods: This study is a non-double-blind randomized controlled trial. The 96 eligible acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis will be randomly assigned to receive either the optimized voriconazole regimen or the recommended voriconazole regimen for patients with mild to moderate liver cirrhosis (Child-Pugh A and B), at a 1:1 ratio, with an 8-week follow-up period. The antifungal efficacy of voriconazole will be the primary outcome measure. Plasma voriconazole concentration; the laboratory examination(CRP, PCT, ESR, etc.); chest CT; adverse events; and mortality at week 4 and 8 will be the secondary outcome measures.Discussion: This trial aims to demonstrate the efficacy and safety of voriconazole in the treatment of IPA in patients with liver failure, which is expected to provide a reference for scientific optimization of voriconazole regimens and a realistic basis for the standardized treatment of acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis.Trial registration: The trial was registered with the Chinese Clinical Trial Registry, ChiCTR2100048259. Registered on 5 July 2021.

Background: To investigate the clinical features and risk factors of ventriculoperitoneal shunt (VPS) associated surgical site infections (SSIs) in HIV-negative patients with cryptococcal meningitis (CM).Methods: We retrospectively reviewed the medical records of HIV-negative patients with CM underwent VPS operation admitted to The Third Affiliated Hospital of Sun Yat-sen University in Southwest China over the past 7 years.Results: 193 patients were included, of whom 25 (12.95%) had SSIs in 6 (median duration, 1-48 days) days after operation. Compared with patients without SSIs, patient with SSIs tended to be shorter preoperative preparation time. 52% patients in SSIs group and 25% patients in no-SSIs group underwent VPS operations within 3 days after admission (p=0.017). Although body temperature and infectious indicators slightly elevated postoperative in both groups. The patients with SSIs experienced more fever; more central nervous system symptoms; higher PCT value and lower cerebrospinal fluid (CSF) glucose in contrast to the no-SSIs group. Multivariate regression analysis found a 2.653 fold increase in the risk of infection for every 1℃ increase in postoperative body temperature. The most prevalent organisms were oxacillin resistant coagulase-negative Staphylococci (found in 33% of positive specimens).Conclusions: SSIs was one of the serious surgical complications after VPS operation. High body temperature, the occurrence of dizziness and headache, low postoperative hemoglobin are risk factors. Postoperative patients with high fever, high PCT and low CSF glucose should be paid more attention to.

Background To investigate the clinical features and risk factors of ventriculoperitoneal shunt (VPS) associated surgical site infections (SSIs) in HIV-negative patients with cryptococcal meningitis (CM). Methods We retrospectively reviewed the medical records of HIV-negative patients with CM underwent VPS operation admitted to The Third Affiliated Hospital of Sun Yat-sen University in Southwest China over the past 7 years. Results 193 patients were included, of whom 25 (12.95%) had SSIs in 6 (median duration, 1–48 days) days after operation. Compared with patients without SSIs, patient with SSIs tended to be shorter preoperative stay. 52% patients in SSIs group and 25% patients in no-SSIs group underwent VPS operations within 3 days after admission (p = 0.017). Although body temperature and infectious indicators slightly elevated postoperative in both groups. The patients with SSIs experienced more fever; more central nervous system symptoms; higher PCT value and lower cerebrospinal fluid (CSF) glucose in contrast to the no-SSIs group. Multivariate regression analysis found a 2.653 fold increase in the risk of infection for every 1 °C increase in postoperative body temperature. Among the 25 patients, 9 patients had positive culture results, three samples reported to be oxacillin resistant coagulase-negative Staphylococci. Conclusions SSIs was one of the serious surgical complications after VPS operation. High body temperature, the occurrence of dizziness and headache, low postoperative hemoglobin are risk factors. Postoperative patients with high fever, high PCT and low CSF glucose should be paid more attention to.

The overexpression of ATP-binding cassette (ABC) transporters is one of the important mechanisms of multidrug resistance (MDR). Some tyrosine kinase inhibitors (TKIs) such as CM082 might be a potential ABC transporter inhibitor, thus potentially reversing MDR. We used a 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay to determine the cytotoxicity and reversal effect of CM082. A xenograft model was established to evaluate the reversal MDR efficacy in vivo. The intracellular accumulation and efflux of ABCG2 substrates were measured by flow cytometry. We investigated the binding sites of ABCG2 via photolabeling ABCG2 with [125I]-iodoarylazidoprazosin (IAAP). Quantitative real-time PCR and western blot were utilized to analyze mRNA and protein expression. We found that CM082 could enhance the efficacy of substrate in ABCG2-overexpressing cells both in vitro and in vivo. Furthermore, CM082 significantly increased intracellular accumulation of ABCG2 substrates by inhibiting the efflux activity. CM082 stimulated ABCG2 ATPase activity and competed with [125I]-IAAP photolabeling of ABCG2 in a concentration-dependent manner. However, CM082 did not alter ABCG2 expression at protein and mRNA levels or inhibit vascular endothelial growth factor (VEGF) downstream signaling of AKT and extracellular signal-regulated kinase (ERK). Further research is encouraged to confirm whether CM082 concomitant with anticancer drugs of ABCG2 substrates could improve the clinical outcomes of cancer treatment in cancer patients with ABCG2 overexpression. Keywords: CM082, multidrug resistance, ABCG2

Background Streptococcus suis is an emerging zoonotic pathogen that mainly causes meningitis, sepsis, arthritis, endocarditis, and endophthalmitis in human. To the best of our knowledge, Spinal canal infection caused by Streptococcus suis has rarely been reported. Case presentation Here we report a case of spinal canal infection caused by Streptococcus suis in a 50-year-old male patient. The patient had a history of close contact with sick pigs days before disease onset. Initially he presented with headache and fever. After admission, the patient began to experience lower back pain, which led physicians to perform a lumber puncture. Meta-genomic next generation sequencing helped identify Streptococcus suis in the cerebrospinal fluid. MRI imaging indicated a spinal canal infection caused by Streptococcus suis. Conclusions Spinal canal infection is an uncommon disease of Streptococcus suis infection. This case report indicates that people presented with fever, headache and lower back pain should also be suspected as Streptococcus suis infection, especially for those who have had a history of sick pig contact.

Carbapenem-resistant Enterobacteriaceae (CRE) are the highest priority pathogens of the World Health Organization, and their prevalence in end-stage liver disease (ESLD) patients is increasing. CRE colonization is an independent risk factor for CRE infections. We aimed to assess risk factors and explore the relationship between CRE colonization, infection, and prognosis in patients with ESLD. A total of 311 patients with ESLD were screened for CRE colonization by fecal swabs from October 2020 to January 2022. Antimicrobial susceptibility was tested using the broth microdilution method. Carbapenem resistance genes, multilocus sequence type, and capsular serotype were analyzed by polymerase chain reaction (PCR). Seventeen CRE strains were detected, among which the most common was Klebsiella pneumoniae. The CRE colonization rate was 5.5%. Artificial liver support was an independent risk factor for CRE colonization. Compared to the non-CRE colonization group, the colonization group had a higher incidence of CRE infection and a worse prognosis. Furthermore, these strains were not closely related, and all were sensitive to polymyxin and tigecycline. There was a high colonization rate in ESLD patients, and colonization strains were highly diverse. CRE colonization deserves attention in these patients, especially when treated with artificial liver support.

Several genetic studies have shown that the small GTPase Rab29 is involved in the pathogenesis of Parkinson's Disease (PD). It has also been shown that overexpression of Rab29 increases the activity of leucine-rich repeat kinase 2, a protein kinase often mutated in familial PD, although the mechanism underlying this activation remains unclear. Here, we employed biochemical analyses to characterize the localization of Rab29 and found that, unlike general Rab proteins, Rab29 is predominantly fractionated into the membrane fraction by ultracentrifugation. We also found that Rab29 is resistant to extraction from membranes by GDP-dissociation inhibitors (GDIs) in vitro. Furthermore, Rab29 failed to interact with GDIs, and its membrane localization was not affected by the knockout of GDIs in cells. We show that the knockout of Rab geranylgeranyltransferase decreased the hydrophobicity of Rab29, suggesting that Rab29 is geranylgeranylated at its carboxyl terminus as is with typical Rab proteins. Notably, we demonstrated that membrane-bound Rab29 retains some hydrophilicity, indicating that mechanisms other than geranylgeranylation might also be involved in the membrane localization of Rab29. Taken together, these findings uncover the atypical nature of Rab29 among Rab proteins, which will provide important clues for understanding how Rab29 is involved in the molecular pathomechanism of PD.

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.

Recent studies revealed that leucine-rich repeat kinase 2 (LRRK2) phosphorylates several Rab proteins under physiological conditions. Mutations linked with familial Parkinson's disease cause an abnormal increase in the Rab phosphorylation, which has not been elucidated in an in vitro kinase assays where artificial peptide substrates are often used. Here, we provide protocols for detecting the LRRK2 activity in tissues and cultured cells using Rab phosphorylation as a readout.

A 70-year-old man was admitted to our hospital due to "liver cirrhosis; grade 3 hypertension; pulmonary infection". On May 27, 2019, during upper abdomen plain and enhanced magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP), the patient experienced anaphylactic shock, manifested as sudden unconsciousness and lack of response, after intravenous administration of gadobenate dimeglumine (Multihance®). Gadobenate dimeglumine is a paramagnetic contrast used during diagnostic MRI. It has hepatobiliary specificity with very good imaging performance. A small amount is absorbed by normal liver cells after intravenous injection and excreted via the bile ducts while maintaining the chemical structure of gadobenate dimeglumine. It allows the visualization of local angiogenesis and perfusion, which reflect the hepatic blood supply and recent liver function, thereby providing a reference for clinical diagnosis. Gadobenate dimeglumine intravenous injection may cause adverse reactions such as nausea, dizziness, and anaphylactic shock. Anaphylactic shock is a known serious adverse reaction of gadobenate dimeglumine injection. In this paper, we report a case of gadobenate dimeglumine-induced anaphylactic shock based on the temporal relationship between the onset of symptoms and the injection. The patient received chest compressions and balloon-assisted ventilation in addition to rehydration and volume expansion and vasoactive drugs to maintain blood pressure, etc. The patient died despite treatments. In the clinical, physicians, nurses, and clinical pharmacists should closely monitor patients and promptly discontinue drug administration and provide symptomatic care in case of adverse reactions.

Recent studies revealed that leucine-rich repeat kinase 2 (LRRK2) phosphorylates several Rab proteins under physiological conditions. Mutations linked with familial Parkinson's disease cause an abnormal increase in the Rab phosphorylation, which has not been elucidated in an in vitro kinase assays where artificial peptide substrates are often used. Here, we provide protocols for detecting the LRRK2 activity in tissues and cultured cells using Rab phosphorylation as a readout.

Background: Overexpression of ATP-binding cassette (ABC) transporters was one of the important mechanisms of multidrug resistance (MDR). Some tyrosine kinase inhibitors (TKIs) such as CM082 might be the potential ABC-transporter inhibitors due to their similar ATP binding sites to tyrosine kinase, which could potentially reverse MDR. Methods: MTT assay and H460/MX20 cell xenograft model were established to evaluate the reversal MDR efficacy in vitro and in vivo. Drug efflux assay, intracellular drug accumulation and cellular localization assay were measured by flow cytometry. Competition of CM082 for photolabeling of ABCG2 with [125I]- IAAP was performed to ascertain the binding sites. Vanadate-sensitive ATPase activity of ABCG2 was measured to evaluate the effect of CM082 on ATP hydrolysis. Western blotting and RT-PCR were employed to study the effect of CM082 on protein and mRNA expression levels. Findings: CM082 could enhance the efficacy of chemotherapeutic substrate in ABCG2-overexpressing MDR cancer cells both in vitro and in vivo. CM082 significantly increased ABCG2 substrates intracellular accumulation by inhibiting the efflux of ABCG2, stimulated ABCG2 ATPase activity and competed with [125I]-IAAP photolabeling of ABCG2. CM082 did neither alter ABCG2 expression at protein and mRNA levels nor inhibit ErbB downstream signaling of AKT and ERK. Interpretation: This study indicates that CM082 could enhanced the sensitivity of chemotherapeutic agents in vitro and in vivo by inhibiting the activity of ABCG2, suggests CM082 might be potential ABC modulator to overcome MDR. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interest: There are no conflicts of interest to disclose. Ethical Approval: The protocol obtained approval from the Institutional Animal Care and Use Committee of Sun Yat-Sen University Cancer Center.

Background: The accuracy of test results is closely related to the clinical diagnosis and treatment, while drugs may interfere with the test results. When the abnormal value of results occured, it is important to analyze the drug-related interferential factors. Objective: To remind clinicians and pharmacists to eliminate interference factors when finding abnormal results by recording the cause analysis process of a patient with abnormally elevated creatinine. Methods: In this case of an abnormally elevated creatinine in a patient treated with vancomycin, the clinical pharmacist analyzed the reasons of patients' creatinine elevation, especially vancomycin-associated kidney injury and other interfering factors of combination drugs in the tests. Results: The clinical pharmacist Clinical pharmacists found that acute kidney damage was not caused by vancomycin, the “real killer” was the etamsylate interference factors in laboratory test of creatinine value. This discovery enabled the patient's antibiotic treatment to proceed smoothly. Conclusions: As a clinical pharmacist, it is necessary to understand the medication situation of patients and be familiar with the common types of "drug interference detection". With these advantages in drug knowledge, clinical pharmacists can assist clinicians to identification and judgment of adverse drug reactions, and play an important role in the treatment of patients.