Evaluating omadacycline dosing regimens against drug-resistant pathogens including Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various dosing regimens of omadacycline against main drug-resistant pathogens in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to calculate cumulative fractions of response (CFRs) in terms of drug area under the concentration curve/minimum inhibition concentration targets.CFR ≥ 90% was considered optimal for a dosage regimen. CFR of any approved oral/intravenous regimen with loading-dose was ≥ 90% against methicillin-resistant Staphylococcus aureus (MRSA) for ABSSSI and penicillin-resistant Streptococcus pneumonia, tetracycline-resistant Streptococcus pneumonia, MRSA and ß-lactamase positive Haemophilus influenzae for CABP. In conclusion, approved oral/intravenous loading and maintenance doses of omadacycline showed enough efficacy in the treatment of ABSSI and CABP caused by the main drug-resistant pathogens.

Factors associated with immune-related thyroid dysfunction induced by PD-1/PD-L1 inhibitors in cancer patients: an observational study.

This study aimed to identify the potential factors associated with immune thyroid dysfunction caused by programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in cancer patients. We conducted a retrospective study of thyroid immune-related adverse events (irAEs) in cancer patients treated with PD-1/PD-L1 inhibitors at Tianjin First Central Hospital from January 2020 to March 2023. Thyroid irAEs were characterized as hypothyroidism, hyperthyroidism and thyrotoxicosis followed by hypothyroidism. A total of 175 patients were screened in the study, of whom 48 patients (27%) developed thyroid irAEs (including 24 hypothyroidism, 11 hyperthyroidism and 13 thyrotoxicosis followed by hypothyroidism) following PD-1/PD-L1 inhibitors treatment. Multivariate logistic regression analysis showed that combination therapy with PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (lenvatinib/regorafenib) and high baseline anti-TPO level were associated with the development of thyroid irAEs caused by PD-1/PD-L1 inhibitors. The nomogram models showed good discriminant ability and could bring net benefits for more patients according to the decision curve analysis. However, the model needs to be further validated in other large cohorts.

Supratherapeutic posaconazole concentrations associated with hyperlipidemia in a patient with HSCT.

Posaconazole is a potent, extended-spectrum triazole antifungal used for the treatment and prophylaxis of serious fungal infections. Previous reports have demonstrated hyperlipidemia resulted in significant changes in posaconazole pharmacokinetics and tissue distribution in rats. However, the effect of hyperlipidemia on the pharmacokinetics of posaconazole in patients has not yet been reported. We report a case of a 34-year-old woman who experienced a supratherapeutic posaconazole trough concentration (PTC) associated with hyperlipidemia after haploidentical hematopoietic stem cell transplantation (HSCT). The patient was admitted 13 months after HSCT for recurrent cough and sputum. She was treated with caspofungin due to developing invasive fungal infection of Candida tropicalis. After 10 days, caspofungin was discontinued due to the poor therapeutic efficacy and replaced with amphotericin B. Afterwards, the condition of the patient improved significantly and she was switched to daily oral posaconazole tablet. Therapeutic drug monitoring (TDM) of posaconazole showed a PTC was 3.2 mg/L. After discharge, she continued to receive posaconazole tablet as antifungal treatment. Two months later, laboratory tests at outpatient showed her blood lipid levels were significantly elevated and PTC was increased to 9.38 mg/L. Therefore, the posaconazole tablet was discontinued and she received lipid-lowering therapy. A few days later, the PTC was down to 5.22 mg/L. No medication errors and significant drug interactions were found. Hence, supratherapeutic PTC for this patient may be caused by hyperlipidemia which altered pharmacokinetics of posaconazole. Our findings highlight the need for close TDM in order to avoid supratherapeutic PTC if hyperlipidimia occurs during posaconazole use.

Ileus induced by the combination of vinca alkaloids and posaconazole in a patient with acute lymphoblastic leukemia: a case report and literature review.

Vinca alkaloid (VA)-induced ileus, a rare but severe autonomic neuropathy, can be enhanced by concomitant use of antifungal triazole agents. We herein present a case of VA-induced ileus in a 17-year-old girl who was diagnosed with B-cell acute lymphoblastic leukemia. On day 1, the patient received cyclophosphamide, vincristine, and methylprednisolone. On day 2, she began treatment with posaconazole oral suspension at 200 mg three times daily for prophylaxis against invasive fungal infection. On day 5, she began induction therapy consisting of vindesine, methylprednisolone, daunorubicin, and cyclophosphamide. The patient developed severe abdominal pain with marked constipation on day 11 and was diagnosed with incomplete ileus. After switching the antifungal agent to micafungin, performing gastrointestinal decompression, administering parenteral nutrition, and omitting the fourth dose of vindesine, the ileus symptoms were relieved. This case emphasizes the potential interaction between VAs and posaconazole. We also herein present a review of the literature on ileus caused by the combination of VAs and antifungal triazole agents. In clinical practice, physicians and pharmacists should be aware of the possibility of ileus caused by the use of VAs in combination with posaconazole. It is important to reduce complications during chemotherapy to improve patients' prognosis.

Assessment of micafungin dosage regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various micafungin dosing regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration targets of micafungin. Current standard clinical micafungin dosing regimens of 1 and 2 mg/kg/day were appropriate for the prevention and treatment of Candida glabrata infection in pediatric patients undergoing HSCT, respectively. Moreover, the high-dose prophylactic dosage (2 mg/kg/day) and therapeutic dosage (4 mg/kg/day) should be the preferred option to optimize efficacy against Candida albicans. However, none of the simulated regimens was effective against Candida parapsilosis in pediatric HSCT patients. These PK/PD-based simulations rationalize and optimize the micafungin dosing regimens against Candida spp. in pediatric patients undergoing HSCT.

Effects of dibutyl phthalate on lipid metabolism in liver and hepatocytes based on PPARα/SREBP-1c/FAS/GPAT/AMPK signal pathway.

Phateacid esters (PAEs), such as dibutyl phthalate (DBP), have been widely used and human exposure results into serious toxic effects; such as the development of fatty liver disease. In the present study, SD rat models for in vivo study (normal and fatty liver model group) and hepatocytes for in vitro study (normal and abnormal lipid metabolism model group) were established to determine the effects of DBP on liver function and discover the possible mechanisms. Meanwhile, the peroxisome proliferator activated receptor (PPARα) blocker, GW6471, with the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activator, AICAR, were applied in vitro study to clarify the role of PPARα/SREBP-1c/FAS/GPAT/AMPK signal pathway in the process. Results suggested that DBP could activate PPARα signaling pathway and affected the protein expression of SREBP, FAS and GPAT to cause hyperlipidemia and abnormal liver function. DBP also could inhibit the phosphorylation and activation of AMPK to inhibit the decomposition and metabolism of lipids. Interestingly, the effects of DBP could be alleviated by GW6471 and AICAR. Our experimental results provide reliable evidence that DBP exposure could further induce liver lipid metabolism disorder and other hepatic toxicity through PPARα/SREBP-1c/FAS/GPAT/AMPK signal pathway.

Evaluating posaconazole dosing regimens of the different formulations against Aspergillus spp. in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various posaconazole dosing regimens of the different formulations against Aspergillus spp. in adults. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) in terms of area under the concentration-time curve/minimum inhibition concentration (AUC/MIC) targets of posaconazole. According to the results of the PTA analysis, currently recommended clinical dosing regimens of the delayed-release tablet and intravenous (i.v.) solution were appropriate in prophylaxis against Aspergillus spp. with MICs ≤ 0.125 µg/mL. However, only high-dose regimens of the delayed-release tablet could achieve the target PTA in the treatment against Aspergillus spp. at an MIC of 0.125 µg/mL. Furthermore, the CFR was calculated for each dosing regimen. For the oral suspension, none of the simulated dosing regimens was effective against Aspergillus spp. For the delayed-release tablet and i.v. solution, the recommended dosing regimens were effective for prophylaxis of invasive fungal infections by four Aspergillus spp. (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans and Aspergillus terreus). However, these recommended dosing regimens were only effective for the treatment of A. terreus infection. Therefore, the high-dose regimen (200 mg oral every 12 h) of the delayed-release tablet should be recommended to achieve optimal therapeutic efficacy against four Aspergillus spp. (A. flavus, A. fumigatus, A. nidulans and A. terreus). These PK/PD-based simulations rationalise and optimise the dosing regimens of the different posaconazole formulations against Aspergillus spp. in adults.

Pharmacokinetic/Pharmacodynamic Analysis of Daptomycin Against Staphylococcus aureus and Enterococcus faecium in Pediatric Patients by Monte Carlo Simulation.

The objective of this study was to evaluate the efficacy of various daptomycin dosing regimens against Staphylococcus aureus and Enterococcus faecium in pediatric patients with proven/suspected gram-positive infection. Monte Carlo simulations (MCSs) were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. According to the results of the MCSs, currently approved pediatric dosage regimens were sufficient against Staphylococcus aureus with MIC ≤ 0.5 µg/mL for all pediatric patients, but poor when MIC ≥ 1 µg/mL except for adolescents (12-17 years) who need a dosage of ≥10 mg/kg/day at MIC = 1 µg/mL. For Enterococcus faecium with MIC ≤ 4 µg/mL, the recommended dosage of 8-12 mg/kg/day in adults was enough for adolescents, but not subjected to younger pediatric patients. Furthermore, based on MIC distributions obtained from the European Committee on Antimicrobial Susceptibility Testing, the approved high-dose regimen should be recommended for infants aged 3-12 months, children (2-11 years), and adolescents to achieve better clinical efficacy against methicillin-resistant Staphylococcus aureus. In addition, the dosage of 8-12 mg/kg/day was powerful against Enterococcus faecium for adolescents; however, only the highest dosage of 12 mg/kg/day was effective for infants aged 3-12 months and children. All the simulated regimens were not optimal for infants aged 13-24 months. These PK/PD-based simulations rationalize and optimize the dosage regimens of daptomycin against Staphylococcus aureus and Enterococcus faecium in pediatric patients.

The therapeutic effects of Jaceosidin on lipopolysaccharide-induced acute lung injury in mice.

Acute lung injury (ALI) results from various factors including uncontrolled pulmonary inflammation, oxidative damage and the over-activated complement with high mortality rates. Jaceosidin was a flavonoid compound with significant anti-complement activity. We aimed to investigate the therapeutic effects of Jaceosidin on ALI induced by lipopolysaccharide (LPS). Mice were orally administrated with Jaceosidin (15, 30 and 60 mg/kg) after LPS challenge. 24 h after LPS challenge, Jaceosidin could significantly decrease the lung wet-to-dry weight (W/D) ratio and the protein concentration in bronchoalveolar lavage fluid (BALF). Jaceosidin could down-regulate the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), together with up-regulation the levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) in BALF. Jaceosidin could significantly decrease the levels of myeloperoxidase (MPO), cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB), COX-2 mRNA and NF-κB p65 mRNA together with increasing the activity of catalase (CAT). Additionally, Jaceosidin attenuated lung histopathological changes, inhibited the expressions of COX-2 and NF-κB p65 and reduced complement deposition with decreasing the levels of complement 3 (C3) and complement 3c (C3c) in serum. These data suggest that Jaceocidin may dampen the inflammatory response and decrease the levels of complement together with the antioxidant activity following LPS-induced ALI.

miRNAome, mRNAome and degradome analysis of Tibetan minipigs anterior pituitary.

Tibetan minipig is an important animal model for human diseases. The anterior pituitary is the master gland responsible for growth, reproduction, and metabolism and is regulated by thousands of miRNAs/mRNAs molecules. However, little is known about miRNAs and their relationships with mRNAs in Tibetan minipig anterior pituitary. Using microarray and mRNA-Sequencing, we identified 203 miRNAs and 12,040 mRNA transcripts from the anterior pituitary of Tibetan minipigs. These miRNAs were corresponding to 194 hairpin precursors, 25 miRNA clusters and 24 miRNA families. In addition, 64 intragenic miRNAs were annotated. Using three bioinformatic algorithms (TargetScan, miRanda and RNAhybrid), 359,184 possible miRNA-mRNA interactions were predicted, and an integrated network of miRNAs and pituitary-specific mRNA transcripts was established. To validate the predicted results, the degradome sequencing was employed to confirm miRNA-mRNA interactions, totally, 30 miRNA-mRNA pairs were identified. The present study provided a general overview of miRNA and mRNA annotation in Tibetan minipig anterior pituitary and established a miRNA-mRNA interactions database at the whole genome scale, which helps shed light on the molecular mechanisms in the anterior pituitary of pigs even other mammals.

Meta analysis of studies on epidemiology of hypertension in college and university teachers and staff / 中华医学图书情报杂志

Objective To more effectively prevent hypertension and provide better health care for college and university teachers and staff by keeping abreast with the epidemiology of hypertension. Methods The data were extracted from the selected Chinese and English papers on epidemiology of hypertension, which was followed by a meta-analysis of the prevalence, awareness rate, cure rate, and control rate of hypertension in college and university teachers and staff of China. Results A total of 73 papers were included in this study. The total prevalence of hypertension was 23. 3% (95%CI=21. 1%-25. 6%), the prevalence of hypertension was 27. 2% (95%CI=24. 4%-30. 0%) in male hypertensive teachers and staff and was 18. 6% (95%CI=16. 6%-20. 6%) in female hypertensive teachers and staff. The prevalence of hypertension increased with the increasing age and tended to increase with the year of investigation in college and university teachers and staff of China, and was the lowest in East China followed by Central China and West China. The awareness rate, cure rate and control rate of hypertension were 68. 3% (95%CI=59 . 7%-76 . 8%) , 63 . 7% ( 95%CI=55 . 5%-71 . 9%) , and 37 . 7% ( 95%CI=28 . 0%-47 . 5%) respec-tively in college and university teachers and staff of China. Conclusion The prevalence of hypertension is different in college and university teachers and staff of China due to different sexes, ages and areas.

Meta analysis of studies on epidemiology of hypertension in college and university teachers and staff / 中华医学图书情报杂志

Objective To more effectively prevent hypertension and provide better health care for college and university teachers and staff by keeping abreast with the epidemiology of hypertension. Methods The data were extracted from the selected Chinese and English papers on epidemiology of hypertension, which was followed by a meta-analysis of the prevalence, awareness rate, cure rate, and control rate of hypertension in college and university teachers and staff of China. Results A total of 73 papers were included in this study. The total prevalence of hypertension was 23. 3% (95%CI=21. 1%-25. 6%), the prevalence of hypertension was 27. 2% (95%CI=24. 4%-30. 0%) in male hypertensive teachers and staff and was 18. 6% (95%CI=16. 6%-20. 6%) in female hypertensive teachers and staff. The prevalence of hypertension increased with the increasing age and tended to increase with the year of investigation in college and university teachers and staff of China, and was the lowest in East China followed by Central China and West China. The awareness rate, cure rate and control rate of hypertension were 68. 3% (95%CI=59 . 7%-76 . 8%) , 63 . 7% ( 95%CI=55 . 5%-71 . 9%) , and 37 . 7% ( 95%CI=28 . 0%-47 . 5%) respec-tively in college and university teachers and staff of China. Conclusion The prevalence of hypertension is different in college and university teachers and staff of China due to different sexes, ages and areas.

Priming of anti-herbivore defense in tomato by arbuscular mycorrhizal fungus and involvement of the jasmonate pathway.

Mycorrhizas play a vital role in soil fertility, plant nutrition, and resistance to environmental stresses. However, mycorrhizal effects on plant resistance to herbivorous insects and the related mechanisms are poorly understood. This study evaluated effects of root colonization of tomato (Solanum lycopersicum Mill.) by arbuscular mycorrhizal fungi (AMF) Glomus mosseae on plant defense responses against a chewing caterpillar Helicoverpa arimigera. Mycorrhizal inoculation negatively affected larval performance. Real time RT-PCR analyses showed that mycorrhizal inoculation itself did not induce transcripts of most genes tested. However, insect feeding on AMF pre-inoculated plants resulted in much stronger defense response induction of four defense-related genes LOXD, AOC, PI-I, and PI-II in the leaves of tomato plants relative to non-inoculated plants. Four tomato genotypes: a wild-type (WT) plant, a jasmonic acid (JA) biosynthesis mutant (spr2), a JA-signaling perception mutant (jai1), and a JA-overexpressing 35S::PS plant were used to determine the role of the JA pathway in AMF-primed defense. Insect feeding on mycorrhizal 35S::PS plants led to higher induction of defense-related genes relative to WT plants. However, insect feeding on mycorrhizal spr2 and jai1 mutant plants did not induce transcripts of these genes. Bioassays showed that mycorrhizal inoculation on spr2 and jai1 mutants did not change plant resistance against H. arimigera. These results indicates that mycorrhizal colonization could prime systemic defense responses in tomato upon herbivore attack, and that the JA pathway is involved in defense priming by AMF.

[Disease resistance signal transfer between roots of different tomato plants through common arbuscular mycorrhiza networks].

Common mycorrhizal networks (CMNs) are the underground conduits of nutrient exchange between plants. However, whether the CMNs can serve as the underground conduits of chemical communication to transfer the disease resistance signals between plants are unknown. By inoculating arbuscular mycorrhizal fungus (AMF) Glomus mosseae to establish CMNs between 'donor' and 'receiver' tomato plants, and by inoculating Alternaria solani, the causal agent of tomato early blight disease, to the 'donor' plants, this paper studied whether the potential disease resistance signals can be transferred between the 'donor' and 'receiver' plants roots. The real time RT-PCR analysis showed that after inoculation with A. solani, the AMF-inoculated 'donor' plants had strong expression of three test defense-related genes in roots, with the transcript levels of the phenylalanine ammonia-lyase (PAL), lipoxygenase (LOX) and chitinase (PR3) being significantly higher than those in the roots of the 'donor' plants only inoculated with A. solani, not inoculated with both A. solani and AMF, and only inoculated with AMF. More importantly, in the presence of CMNs, the expression levels of the three genes in the roots of the 'receiver' plants were significantly higher than those of the 'receiver' plants without CMNs connection, with the connection blocking, and with the connection but the 'donor' plants not A. solani-inoculated. Compared with the control (without CMNs connection), the transcript level of the PAL, LOX and PR3 in the roots of the 'receiver' plants having CMNs connection with the 'donor' plants was 4.2-, 4.5- and 3.5-fold higher, respectively. In addition, the 'donor' plants activated their defensive responses more quickly than the 'receiver' plants (18 and 65 h vs. 100 and 140 h). These findings suggested that the disease resistance signals produced by the pathogen-induced 'donor' tomato plant roots could be transferred to the 'receiver' plant roots through CMNs.

[Mechanism of tomato plants enhanced disease resistance against early blight primed by arbuscular mycorrhizal fungus Glomus versiforme].

Arbuscular mycorrhiza (AM) can not only improve host plants nutrient absorption, but also enhance their disease resistance. Taking the tomato (Lycopersicon esculentum) seedlings preinoculated with axbuscular mycorrhizal fungus (AMF) Glomus versiforme as test materials, this paper studied their protective enzyme activities and defense-related genes expression, and their resistance against a fungal pathogen Alternaria solani Sorauer which causes early blight. The seedlings pre-inoculated with AMF and later inoculated with A. solani showed significantly higher activities of superoxide dismutase (SOD) and peroxidase (POD) in leaves. The leaf SOD activity of the dually inoculated plants reached the maximum 18 h after pathogen inoculation, being 28.6%, 79.2% and 82.8% higher than that of the plants with G. versiforme inoculation alone, pathogen inoculation alone, and non-inoculation, and the Leaf POD activity reached the maximum 65 h after pathogen inoculation, being 762%, 18.3%, and 1710% higher, respectively. Real time RT-PCR analysis showed that dual inoculation with C. versiforme and A. solani strongly induced the expression of three defense-related genes. The transcript levels of pathogen-related protein (PR1), basic type beta-1,3-glucanase (PR-2), and chitinase (PR-3) in leaves were 9.67-, 8.54-, and 13.4-fold higher, as compared with the non-inoculation control, respectively. Bioassay showed that the disease incidence and disease index of the seedlings pre-inoculated with C. versiforme were reduced by 36.3% and 61.4%, respectively, as compared with the non-mycorrhizal control plants. These findings indicated that mycorrhizal colonization could induce stronger and quicker defense responses of host tomato plants, and priming could be an important mechanism of the enhanced disease resistance of mycorrhizal tomato plants.