Abstract Introduction: Propofol is a widely used anesthetic and its dose is closely related to aging. Telomere length (TL) is a unique heritable trait, and emerging as a biomarker of aging, health and disease. Telomerase RNA component (TERC) plays an important role in maintaining TL. We proposed a hypothesis that propofol dose in general anesthesia can be predicted by measuring TL before operation, which greatly reduced the risk of anesthesia, especially the elderly. Methods: The association between the propofol dose in anesthesia induction and: TL in the DNA of peripheral blood leukocytes; body weight; sex; difference of the Bispectral Index (BIS) before and after anesthesia induction in patients was evaluated by multivariable linear regression analyses. The mutation at the 5’end or 3’end of TERC was detected. We recruited 100 patients of elective surgery. Results: We found that propofol dose in anesthesia induction was clearly correlated significantly with TL (r = 0.78, p < 0.001), body weight (r = 0.84, p = 0.004), sex (r = 0.83, p= 0.84, p = 0.004), sex (r = 0.83, p = 0.004), and difference of BIS before and after anesthesia induction (r = 0.85, p = 0.029). By comparing the absolute values of standardized regression coefficients (0.58, 0.21, 0.19, and 0.12) of the four variables, it can be seen that TL contributes the most to the propofol dose in anesthesia induction. However, the mutation at the 5’ end or 3’ end of TERC was not found. Conclusions: These findings provide preliminary evidence that the propofol dose in anesthesia induction was clearly correlated with genetically determined TL. TL may be a promising predictor of the propofol dose, which is beneficial to improve the safety of anesthesia and reduce perioperative complications.

Objectives: The present study analyzed the reciprocal relationships between four common pediatric ophthalmic diseases (i.e., hyperopia, myopia, astigmatism, and strabismus) and attention‐deficit/hyperactivity disorder (ADHD) in children. Methods: This study enrolled 86,028 children with ADHD and 1,798,673 children without ADHD in the Taiwan Maternal and Child Health Database who were born at any time from 2004 to 2017. Cox proportional hazards regression models were used to estimate the bidirectional relationships of the four ophthalmic diseases with ADHD in children after adjusting for age, sex, and gestational age at birth. Survival curves for time-to-event variables were estimated using the Kaplan-Meier method, and the log-rank test was used to compare the curves. Results: The results indicated that ADHD significantly predicted the occurrence of hyperopia, myopia, astigmatism, and strabismus. Furthermore, hyperopia, myopia, astigmatism, and strabismus significantly predicted the occurrence of ADHD. The time between enrollment and ADHD diagnosis was shorter for patients with ophthalmic diseases than for the control group, and the time between enrollment and ophthalmic disease diagnosis was also shorter for ADHD patients than for the control group. Sex differences were found in the associations between ADHD and ophthalmic diseases. Conclusion: Clinicians should monitor children with ADHD for hyperopia, myopia, astigmatism, and strabismus to ensure appropriate treatment, and vice versa.

Abstract Objectives: To screen the COL1A1 and COL1A2 gene mutation sites in a family with type I osteogenesis imperfecta (OI)/hearing loss and analyze the characteristics and recovery of hearing loss in patients with osteogenesis imperfecta. Methods: The basic clinical data of Ol proband and her parents were collected, and the COL1A1 and COL1A2 genes were detected in peripheral blood by PCR amplification and generation Sanger sequencing. Literature of stapedial surgery in patients with osteogenesis imperfecta was collected. Results: The heterozygous mutation of the 26 exon c.1922_1923 ins C in the Ol progenitor COL1A1 gene led to the amino acid frameshift mutation of p.Pro 601FS, which was not detected in the phenotypic parents. The homozygous of exon 28 c.1782>G in COL1A2 was detected in the proband and her parents, resulting in changes in the protein p.Pro 549Ala. Conclusion: The clinical symptoms of the Ol proband is caused by heterozygous mutation of the 26 exon c.1922_1923 ins C in COL1A1 gene. Stapedial surgery can provide short-term and long-term hearing benefits for Ol patients with hearing loss. Level of evidence: Level 4.

The low-temperature electrochemical corrosion behavior of aircraft 2024 aluminum alloy was investigated in different concentrations of potassium-acetate-type fluid, and the results showed that the corrosion medium initially impacted some corrosiveness on the 2024 aluminum alloy. However, the corrosion rate of the alloy decreased with prolonged immersion in the corrosion medium, and this was attributed to the protective effect of the corrosion products layer, which impeded the attack by the aggressive solution. Time-domain analysis of electrochemical noise measurements at -5 °C revealed the occurrence of uniform corrosion on the alloy at the initial stages of immersion, general corrosion at the middle stages of immersion, and a pitting-dominated corrosion type from the middle to late stages of immersion.

SUMMARY: At present, the anatomical relationship the mid-portion of popliteus tendon complex (PTC) and the surrounding tissues is still unclear, especially its relationship to the posterior cruciate ligament (PCL). It affected the anatomical reconstruction of the posterolateral complex (PLC) injury. A total of 30 cases of the adult human knee joint fixed with formalin were used. Sagittal sections were made in 14 knee joints by the P45 plastination technique and dissection of 16 cases of knee joints. The P45 section revealed that the popliteus muscle fascia ran superiorly over the posterior edge of the tibial intercondylar eminence, and turned forward to be integrated into the PCL. Laterally, near the posterior edge of the lateral tibial plateau, the popliteus tendon penetrates through the articular capsule (AC), where two dense fibrous bundles were given off upwards by the popliteus tendon: one was the ventral fiber bundle, which ran superiorly over the posterior edge of the tibial plateau and then moved forwards to connect with the lateral meniscus; the dorsal fibers bundle ascended directly and participated in the AC. Meanwhile, the popliteus muscle dissection showed that at the posterior edge of the platform of the lateral condyle of the tibia, at the tendon-muscle transition, the PTC and AC were anchored to PCL.

RESUMEN: En la actualidad, la relación anatómica entre la porción media del complejo tendinoso poplíteo (CTP) y los tejidos circundantes aún no está clara, especialmente su relación con el ligamento cruzado posterior (LCP). Esto afecta la reconstrucción anatómica de la lesión del complejo posterolateral (LCP). Se utilizaron un total de 30 casos de articulaciones de rodillas humanas de individuos adultos fijadas con formalina. Se realizaron cortes sagitales en 14 articulaciones de rodilla mediante la técnica de plastinación P45 y disección de 16 casos de articulaciones de rodilla. La sección P45 reveló que la fascia del músculo poplíteo discurría superiormente sobre el margen posterior de la eminencia intercondílea tibial y giraba hacia delante para integrarse en el LCP. Lateralmente, cerca del margen posterior de la platillo tibial lateral, el tendón poplíteo penetra a través de la cápsula articular (CA), donde el tendón poplíteo desprendió hacia arriba dos haces fibrosos densos: uno era el haz de fibras ventral, que corría superiormente sobre el margen posterior de la meseta tibial y luego se movió hacia adelante para conectar con el menisco lateral; el haz de fibras dorsales ascendía directamente y participaba en la CA. Por su parte, la disección del músculo poplíteo mostró que en el margen posterior del platillo del cóndilo lateral de la tibia, en la transición tendón-músculo, el CTP y el AC estaban anclados al LCP.

Abstract Experimental models that consider host-pathogen interactions are relevant for improving knowledge about oral candidiasis. The aim of this study was to assess the epithelial immune responses, Candida penetration of cell monolayers, and virulence during mixed species culture infections. Single species cultures of Candida albicans and mixed cultures (C. albicans, Streptococcus mutans, and Streptococcus sanguinis) were used to infect monolayers of HaCaT and FaDu ATCC HTB-43 cells for 12 h. After infection, IL-18 and IL-34 gene expression was measured to assess epithelial cell immune responses, and lactate dehydrogenase (LDH) activity was measured as an indicator of cell damage. Microscopy determined C. albicans morphology and penetration of fungal cells through the keratinocyte monolayer. Monolayers devoid of infection served as controls. Data were analyzed by an ANOVA one-way test followed by Tukey’s post-hoc test (α = 0.05). The results found that IL-18 and IL-34 gene expression and LDH activity were significantly (p < 0.05) upregulated for both cell lines exposed to mixed species cultures compared with C. albicans alone. Candida albicans yeast and hyphae were evident in C. albicans only infections. In contrast, monolayers infected by C. albicans, S. mutans, and S. sanguinis exhibited higher microbial invasion with several hyphal aggregates detected. The presence of streptococci in C. albicans infection enhances the virulence and pathogenicity of the fungus with associated increased immune responses and tissue damage. Extrapolation of these findings to oral infection would indicate the added potential benefit of managing bacterial components of biofilms during treatment.

Resumo O objetivo deste estudo foi avaliar a resposta epithelial imune, a colonização da Candida albicans em monocamadas celulares e sua virulência em resposta a infecções de culturas de biofilme multiespécie. Culturas de biofilme monoespécie de C. albicans e culturas mistas (C. albicans, Streptococcus mutans e Streptococcus sanguinis) foram utilizadas para infectar monocamadas de células HaCaT e FaDu por 12 h. Após a infecção, a expressão dos genes IL-18 e IL-34 foi medida para avaliar as respostas imunes das células epiteliais. A atividade da lactato desidrogenase (LDH) foi medida como um indicador de dano celular. A microscopia determinou a morfologia de C. albicans e a penetração das células fúngicas através da monocamada de queratinócitos. Monocamadas em que não houve infecção serviram como controles. Os dados foram analisados por um teste ANOVA one-way seguido pelo teste post-hoc de Tukey (α = 0,05). Os resultados demonstraram que a expressão gênica de IL-18 e IL-34 e a atividade de LDH foram (p < 0,05) reguladas positivamente para ambas as linhagens de células expostas a culturas de espécies mistas em comparação com C. albicans isoladamente. Leveduras de C.albicans e hifas foram evidentes em infecções apenas por C. albicans. Entretanto, monocamadas infectadas por C. albicans, S. mutans e S. sanguinis exibiram maior invasão microbiana com vários agregados de hifas detectados. Dessa maneira, a presença de estreptococos na infecção por C. albicans aumentou a virulência e a patogenicidade do fungo com respostas imunes aumentadas associadas a danos nos tecidos. A extrapolação desses achados para a infecção oral indicaria o potencial benéfico do controle dos componentes bacterianos em biofilmes durante a terapia da candidíase

Abstract Objective MicroRNA-29a-3p has been reported in a variety of cancers, but its role in hypopharyngeal cancer remains unclear. This study was to determine the role of microRNA-29a-3p in the occurrence and development of hypopharyngeal cancer. Methods 40 patients with hypopharyngeal cancer who underwent surgery in the Affiliated Hospital of Jining Medical University from April 2013 to November 2017 were selected for this study. The cancer tissue samples of the patients were collected, and the patients were followed up for three years. The expression of microRNA-29a-3p in tissue samples was detected by in situ hybridization with fluorescent probe, and the relationships among microRNA-29a-3p and clinicopathological factors, postoperative recurrent-metastasis, survival time were studied. Immunohistochemical was used to detect the expression of Ki67 and E-cadherin in tissue samples. Results Combined with HE staining results showed that microRNA-29a-3p expression was relatively high in non-cancer tissue cells (red blood cells and fibroblasts in tumor interstitial vessels), but was relatively low in cancer tissue and cells. According to the follow-up data of 40 patients with hypopharyngeal cancer, tumor size, T-stage, tumor differentiation, postoperative recurrent-metastasis of hypopharyngeal cancer patients were significantly negatively correlated with microRNA-29a-3p (p< 0.05). Immunohistochemica results further confirmed that microRNA-29a-3p was negatively correlated with the expression of Ki67 and E-cadherin. The survival time of patients positively related with microRNA-29a-3p expression (p< 0.05). Moreover, ROC curve analysis showed that the area under the curve of the combined detection of miRNA-29a-3p+Ki67+E-cadherin was larger than that of the single detection of the three indexes. Conclusions The expression of microRNA-29a-3p is closely related to the occurrence, development and prognosis of hypopharyngeal cancer, and it affects the proliferation and invasion. This indicates that microRNA-29a-3p serves as a therapeutic target for the occurrence and development of hypopharyngeal cancer. The evidence of study designs of this study is IV using “Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence”.

Abstract Objectives To determine whether tinnitus negatively impacts the accuracy of sound source localization in participants with normal hearing. Methods Seventy-five participants with tinnitus and 74 without tinnitus were enrolled in this study. The accuracy of sound source discrimination on the horizontal plane was compared between the two participant groups. The test equipment consisted of 37 loudspeakers arranged in a 180° arc facing forward with 5° intervals between them. The stimuli were pure tones of 0.25, 0.5, 1, 2, 4, and 8 kHz at 50 dB SPL. The stimuli were divided into three groups: low frequency (LF: 0.25, 0.5, and 1 kHz), 2 kHz, and high frequency (HF: 4 and 8 kHz) stimuli. Results The Root Mean Square Error (RMSE) score of all the stimuli in the tinnitus group was significantly higher than that in the control group (13.45 ± 3.34 vs. 11.44 ± 2.56, p = 4.115, t < 0.001). The RMSE scores at LF, 2 kHz, and HF were significantly higher in the tinnitus group than those in the control group (LF: 11.66 ± 3.62 vs. 10.04 ± 3.13, t = 2.918, p = 0.004; 2 kHz: 16.63 ± 5.45 vs. 14.43 ± 4.52, t = 2.690, p = 0.008; HF: 13.42 ± 4.74 vs. 11.14 ± 3.68, t = 3.292, p = 0.001). Thus, the accuracy of sound source discrimination in participants with tinnitus was significantly worse than that in those without tinnitus, despite the stimuli frequency. There was no difference in the ability to localize the sound of the matched frequency and other frequencies (12.86 ± 6.29 vs. 13.87 ± 3.14, t = 1.204, p = 0.236). Additionally, there was no correlation observed between the loudness of tinnitus and RMSE scores (r = 0.096, p = 0.434), and the Tinnitus Handicap Inventory (THI) and RMSE scores (r = −0.056, p = 0.648). Conclusions Our present data suggest that tinnitus negatively impacted sound source localization accuracy, even when participants had normal hearing. The matched pitch and loudness and the impact of tinnitus on patients’ daily lives were not related to the sound source localization ability. Level of evidence 4.

Abstract Objective To explore whether Cyclic Adenosine Monophosphate (cAMP)-Epac1 signaling is activated in 1-Desamino-8-D-arginine-Vasopressin-induced Endolymphatic Hydrops (DDAVP-induced EH) and to provide new insight for further in-depth study of DDAVP-induced EH. Methods Eighteen healthy, red-eyed guinea pigs (36 ears) weighing 200-350 g were randomly divided into three groups: the control group, which received intraperitoneal injection of sterile saline (same volume as that in the other two groups) for 7 consecutive days; the DDAVP-7d group, which received intraperitoneal injection of 10 mg/mL/kg DDAVP for 7 consecutive days; and the DDAVP-14d group, which received intraperitoneal injection of 10 μg/mL/kg DDAVP for 14 consecutive days. After successful modeling, all animals were sacrificed, and cochlea tissues were collected to detect the mRNA and protein expression of the exchange protein directly activated by cAMP-1 and 2 (Epac1, Epac2), and Repressor Activator Protein-1 (Rap1) by Reverse Transcription (RT)-PCR and western blotting, respectively. Results Compared to the control group, the relative mRNA expression of Epac1, Epac2, Rap1A, and Rap1B in the cochlea tissue of the DDAVP-7d group was significantly higher (p< 0.05), while no significant difference in Rap1 GTPase activating protein (Rap1gap) mRNA expression was found between the two groups. The relative mRNA expression of Epac1, Rap1A, Rap1B, and Rap1gap in the cochlea tissue of the DDAVP-14d group was significantly higher than that of the control group (p< 0.05), while no significant difference in Epac2 mRNA expression was found between the DDAVP-14d and control groups. Comparison between the DDAVP-14d and DDAVP-7d groups showed that the DDAVP-14d group had significantly lower Epac2 and Rap1A (p< 0.05) and higher Rap1gap (p < 0.05) mRNA expression in the cochlea tissue than that of the DDAVP-7d group, while no significant differences in Epac1 and Rap1B mRNA expression were found between the two groups. Western blotting showed that Epac1 protein expression in the cochlea tissue was the highest in the DDAVP-14d group, followed by that in the DDAVP-7d group, and was the lowest in the control group, showing significant differences between groups (p< 0.05); Rap1 protein expression in the cochlea tissue was the highest in the DDAVP-7d group, followed by the DDAVP-14d group, and was the lowest in the control group, showing significant differences between groups (p< 0.05); no significant differences in Epac2 protein expression in the cochlea tissue were found among the three groups. Conclusion DDAVP upregulated Epac1 protein expression in the guinea pig cochlea, leading to activation of the inner ear cAMP-Epac1 signaling pathway. This may be an important mechanism by which DDAVP regulates endolymphatic metabolism to induce EH and affect inner ear function. Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Level 5.

Introduction: Seed-based analysis has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can modulate the dysfunctional brain network in patients with major depressive disorder (MDD). However, the voxel-based neuropsychological mechanism of taVNS on patients with first-episode MDD is poorly understood. The objective of this study was to assess the effects of an 8-week course of taVNS on patients with first-episode MDD. Methods: Twenty-two patients with first-episode MDD accepted an 8-week course of taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment. Voxel-based analyses were performed to characterize spontaneous brain activity. Healthy controls (n=23) were recruited to minimize test-retest effects. Analysis of covariance (ANCOVA) was performed to ascertain treatment-related changes. Then, correlations between changes in brain activity and the Hamilton Depression Rating Scale (HAM-D)/Hamilton Anxiety Scale (HAM-A) remission rate were estimated. Results: Significant group-by-time interactions on voxel-based analyses were observed in the inferior ventral striatum (VSi) and precuneus. Post-hoc analyses showed that taVNS inhibited higher brain activity in the VSi, while upregulating it in the precuneus. Functional connectivity (FC) between the VSi and precuneus decreased. Positive correlations were found between the HAM-D remission rate and changes in brain activity in the VSi. Conclusion: taVNS reduced the FC between VSi and precuneus by normalizing the abnormal spontaneous brain activity of VSi in first-episode MDD patients.

ABSTRACT Introduction: According to the American Heart Association guideline for coronary artery bypass grafting (CABG), female patients undergoing on-pump CABG (ONCAB) are at higher risk of short-term adverse outcomes than male patients. However, whether off-pump CABG (OPCAB) can improve the short-term outcome of female patients compared to ONCAB remains unclear. Methods: We conducted a meta-analysis to study the effect of the female sex on short-term outcomes of OPCAB vs. ONCAB. A total of 31,115 patients were enrolled in 12 studies, including 20,245 females who underwent ONCAB and 10,910 females who underwent OPCAB. Results: The in-hospital mortality in female patients who underwent OPCAB was significantly lower than in those in the ONCAB group with (2.7% vs. 3.4%; odds ratio [OR] 0.76; 95% confidence interval [CI] 0.65-0.89) and without (OR 0.68; 95% CI 0.52-0.89) adjustment for cardiovascular risk factor. The incidence of postoperative stroke in female patients who underwent OPCAB was lower than in those in the ONCAB group (1.2% vs. 2.1%; OR 0.59; 95% CI 0.48-0.73) before cardiovascular risk factor adjustment but was not significant (OR 0.87; 95% CI 0,66-1.16) after adjustment. There was no significant difference in the incidence of postoperative myocardial infarction between women who underwent OPCAB and those in the ONCAB group (1.3% vs. 2.3%; OR 0.88; 95% CI 0.54-1.43). Conclusion: In contrast to the American Heart Association CABG guideline, female patients who had OPCAB don’t have unfavorable outcomes compared with the ONCAB group.

Resumo O objetivo deste estudo foi avaliar a eficácia dos antibióticos comuns contra diferentes microrganismos em bovinos aparentemente saudáveis na província de Shandong e seus subúrbios. Um total de 220 amostras de esfregaço nasal foi coletado e cultivado para avaliação bacteriológica. Todos os isolados de bactérias após identificação preliminar foram submetidos a estudos de antibiograma seguindo o método de difusão em disco. Verificou-se no estudo que E. coli é o isolado mais comumente associado (21%), seguido por Klebsiella spp. (18%), Pseudomonas aeruginosa (13%), Salmonella spp. (15%), Shigella spp (12%) e Proteus spp (11%). Enquanto os estudos de antibiograma revelaram que o maior número de isolados bacterianos apresentou resistência à Ampicilina (95%), seguido por Augmentin (91%), Cefuroxima (85%) e Tetraciclina (95%) de (Escherichia coli e Klebsiella spp). No caso de Pseudomonas spp. e Salmonella, a maior resistência foi apresentada pela Ampicilina (90%) seguida pela Amoxicilina + Ácido Clavulânico (80%), Cefixima (90%) e Eritromicina (80%). Em Shigella spp e Salmonella spp, a maior resistência foi demonstrada por Amoxicilina, Ceftazidima, Augmentina (60%) e Amoxicilina + Ácido Clavulânico (50%). Conclui-se que estudos de antibiograma in vitro de isolados bacterianos revelaram maior resistência para Ampicilina, Augmentina, Cefuroxima, Cefixima, Tetraciclina, Eritromicina e Amoxicilina + Ácido Clavulânico. Os altos índices de resistência a antibióticos múltiplos (MARI) observados em todos os isolados neste estudo variaram de 0,6 a 0,9. O valor MARI de > 0,2 sugere várias bactérias resistentes a antibióticos e indica a presença de bactérias altamente resistentes.

Abstract The objective of this study was to evaluate the effectiveness of common antibiotics against different microorganisms in apparently healthy cattle in Shandong province and its suburb. A total of 220 nasal swab samples were collected and cultured for bacteriological evaluation. All the bacteria isolates after preliminary identification were subjected to antibiogram studies following disc diffusion method. It was found in the study that E. coli is the most commonly associated isolate (21%), followed by Klebsiella spp. (18%), Pseudomonas aeruginosa (13%), Salmonella spp. (15%), Shigella spp (12%), and Proteus spp (11%). While the antibiogram studies reveled that highest number of bacterial isolates showed resistance to Ampicillin (95%), followed by Augmentin (91%), Cefuroxime (85%) and Tetracycline (95%) of (Escherichia coli and Klebsiella spp). In the case of pseudomonas spp. and Salmonella the highest resistance was showed by Ampicillin (90%) followed by Amoxicillin + Clavulanic Acid (80%), Cefixime (90%), and Erythromycin (80%). In Shigella spp and Salmonella spp highest resistance was showed by Amoxicillin, Ceftazidime, Augmentin (60%), and Amoxicillin + Clavulanic Acid (50%). It is concluded that in vitro antibiogram studies of bacterial isolates revealed higher resistance for Ampicillin, Augmentin, Cefuroxime, Cefixime, Tetracycline, Erythromycin, and Amoxicillin + Clavulanic Acid. The high multiple Antibiotics resistance indexes (MARI) observed in all the isolates in this study ranging from 0.6 to 0.9. MARI value of >0.2 is suggests multiple antibiotic resistant bacteria and indicate presence of highly resistant bacteria.

Diet is the most direct way to affect the rumen microbial community. The objective of this study was to examine the effects of different diets on ruminal methanogen composition in cashmere goats. Twenty-four cashmere goats were randomly divided into four groups that were fed alfalfa hay (AH), alfalfa hay plus concentrate (AHC), corn stalks (CS), and corn stalks plus concentrate (CSC). The concentration of ammonia-N for the group fed AHC was substantially higher than in the other groups. The concentrations of total VFAs, acetate, and propionate in AH and AHC groups were higher than in the CS and CSC groups. The abundance of archaea was markedly different among different groups based on a high-throughput sequencing method. The abundance of Cand;'datus_Methanomethylophilus was 21.28% in the AH group, which was higher than the other groups. (Unclassified_c_ Thermoplasmata was the dominant methanogen in the AH and AHC groups, with abundances of 48.09% and 44.97%, respectively; Methanobrevibacter was the dominant methanogen in the CS and CSC groups, with abundances of 41.22% and 20.73%, respectively. A positive correlation was identified between pH and Methanosphaera; a negative relationship was observed between acetate and (Unclassified_o_Thermoplasmatales. In conclusion, the methanogen communities in cashmere goats varied on different diets. In the alfalfa hay-based diets, the Methanomassiliicoccales-affiliated groups were the dominant methanogens in the rumen of the goats. However, when fed the corn stalk-based diets, Methanobrev;bacter was the dominant methanogen in the rumen fluid. The results were related to dietary composition, especially crude protein content.

Abstract The innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS); however, no drug has been proven to be beneficial in the management of ARDS. Therefore, the aim of this study was to investigate the effects of using combined sedatives on systemic inflammatory responses in patients with ARDS. A total of 90 patients with ARDS and an intubation time of > 120 h were randomly divided into the propofol group (group P), midazolam group (group M), and combined sedation group (group U). Patients in groups P and M were sedated with propofol and midazolam, respectively, whereas patients in group U were sedated with a combination of propofol, midazolam, and dexmedetomidine. The dosage of sedatives and vasoactive drugs, duration of mechanical ventilation, and incidence of sedative adverse reactions were documented. The dosage of sedatives and vasoactive drugs, as well as the incidence of sedative adverse reactions in group U, was significantly lower than those in groups P and M. Similarly, the duration of mechanical ventilation in group U was significantly shorter than that in groups P and M. Hence, inducing sedation through a combination of multiple drugs can significantly reduce their adverse effects, improve their sedative effect, inhibit systemic inflammatory responses, and improve oxygenation in patients with ARDS.

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.