The Changing Faces of Leadership in Surgery: Study on Presidents of Major Surgical Organizations.

INTRODUCTION: To gain an understanding of the changing faces of leadership in surgery, we examined trends in the demographics, additional degrees pursued, and scientific publication characteristics of the past presidents of three major surgery organizations. METHODS: We queried the BoardCertifiedDocs and Web of Science databases for the demographics, as well as the quantity and quality of publications, of the past presidents of the Association for Academic Surgery, Society of University Surgeons, and American College of Surgeons from 1970 to 2020. Data were analyzed by decade to identify any trends. RESULTS: We identified a total of 140 presidents from the organizations. The proportion of female presidents significantly increased from the 1990s to the 2010s (10% versus 33%, P < 0.05). The percentage of non-White presidents increased from the 1970s to the 2010s (3.33% versus 21.2%, P = 0.024). The percentage of presidents with additional degrees also increased from the 1970s to the 2010s (10.0% versus 48.8%, P = 0.039). During this same time period, the most common area of expertise of presidents shifted from cardiothoracic surgery to surgical oncology. The ratio of presidents' postinduction to preinduction publications was significantly increased among all three organizations in the 2010s compared to the 1970s (P < 0.05). Co-cluster analysis revealed a research topic change from the 1970s to the 2010s. CONCLUSIONS: The faces of surgical leadership have changed in terms of gender equality, racial diversity, surgical subspecialty, and additional degrees held. Such a transformation mirrors evolving diversity, equity, and inclusion initiatives, and it further highlights the adaptability of surgical leadership to the ever-changing landscape of surgery.

Effect of Tacrolimus Time in Therapeutic Range on Postoperative Recurrence in Patients Undergoing Liver Transplantation for Liver Cancer.

BACKGROUND AND OBJECTIVE: Liver cancer is the second highest cause of cancer-related deaths worldwide. It is commonly treated with liver transplantation, where tacrolimus is typically used as an antirejection immunosuppressant. The purpose of this study was to evaluate the effect of tacrolimus time in therapeutic range (TTR) on liver cancer recurrence in liver transplant recipients and to compare the performance of TTRs calculated according to the target ranges recommended in published guidelines. METHODS: A total of 84 patients who underwent liver transplantation for liver cancer were retrospectively included. Tacrolimus TTR was calculated using linear interpolation from the date of transplantation until recurrence or the last follow-up according to target ranges recommended in the Chinese guideline and international expert consensus. RESULT: Twenty-four recipients developed liver cancer recurrence after liver transplantation. The CTTR (TTR calculated according to the Chinese guideline) for the recurrence group was significantly lower than that of the nonrecurrence group (26.39% vs. 50.27%, P < 0.001), whereas the ITTR (TTR calculated according to the international consensus) was not significantly different between the two groups (47.81% vs. 56.37%, P = 0.165). Multivariate survival analysis revealed that age, microvascular invasion, hepatocellular carcinoma, CTTR, and mean tacrolimus trough concentration were independent predictors of liver cancer recurrence after liver transplantation. CONCLUSIONS: TTR predicts liver cancer recurrence in liver transplant recipients. The range of tacrolimus concentrations recommended in the Chinese guideline was more beneficial than that recommended in the international consensus for Chinese patients undergoing liver transplantation for liver cancer.

HIV-1-related factors interact with p53 to influence cellular processes.

Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). Long terminal repeats (LTRs) in thegenome regulate integration, duplication, and expression of viral gene. The permissibility of HIV-1 infection hinges on the host cell cycle status. HIV-1 replicates by exploiting various cellular processes via upregulation or downregulation of specific cellular proteins that also control viral pathogenesis. For example, HIV-1 regulates the life cycle of p53, which in turn contributes significantly to HIV-1 pathogenesis. In this article, we review the interaction between HIV-1-associated factors and p53, providing information on their regulatory and molecular mechanisms, hinting possible directions for further research.

FGFR2 alteration as a potential therapeutic target in poorly cohesive gastric carcinoma.

BACKGROUND: Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. METHODS: Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. RESULTS: Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. CONCLUSIONS: FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.

Longitudinal K-means approaches to clustering and analyzing EHR opioid use trajectories for clinical subtypes.

Identification of patient subtypes from retrospective Electronic Health Record (EHR) data is fraught with inherent modeling issues, such as missing data and variable length time intervals, and the results obtained are highly dependent on data pre-processing strategies. As we move towards personalized medicine, assessing accurate patient subtypes will be a key factor in creating patient specific treatment plans. Partitioning longitudinal trajectories from irregularly spaced and variable length time intervals is a well-established, but open problem. In this work, we present and compare k-means approaches for subtyping opioid use trajectories from EHR data. We then interpret the resulting subtypes using decision trees, examining how each subtype is influenced by opioid medication features and patient diagnoses, procedures, and demographics. Finally, we discuss how the subtypes can be incorporated in static machine learning models as features in predicting opioid overdose and adverse events. The proposed methods are general, and can be extended to other EHR prescription dosage trajectories.

Teaching surgery novices and trainees advanced laparoscopic suturing: a trial and tribulations.

INTRODUCTION: The benefits of minimally invasive surgery are numerous; however, considerable variability exists in its application and there is a lack of standardized training for important advanced skills. Our goal was to determine whether participation in an advanced laparoscopic curriculum (ALC) results in improved laparoscopic suturing skills. METHODS AND PROCEDURES: Study design was a prospective, randomized controlled trial. Surgery novices and trainees underwent baseline FLS training and were pre-tested on bench models. Participants were stratified by pre-test score and randomized to undergo either further FLS training (control group) or ALC training (intervention group). All were post-tested on the same bench model. Tests for differences between post-test scores of cohorts were performed using least squared means. Multivariable regression identified predictors of post-test score, and Wilcoxon rank sum test assessed for differences in confidence improvement in laparoscopic suturing ability between groups. RESULTS: Between November 2018 and May 2019, 25 participants completed the study (16 females; 9 males). After adjustment for relevant variables, participants randomized to the ALC group had significantly higher post-test scores than those undergoing FLS training alone (mean score 90.50 versus 82.99, p = 0.001). The only demographic or other variables found to predict post-test score include level of training (p = 0.049) and reported years of video gaming (p = 0.034). There was no difference in confidence improvement between groups. CONCLUSIONS: Training using the ALC as opposed to basic laparoscopic skills training only is associated with superior advanced laparoscopic suturing performance without affecting improvement in reported confidence levels. Performance on advanced laparoscopic suturing tasks may be predicted by lifetime cumulative video gaming history and year of training but does not appear to be associated with other factors previously studied in relation to basic laparoscopic skills, such as surgical career aspiration or musical ability.

Investigation of photoassociation with full-dimensional thermal-random-phase wavefunctions.

By taking the femtosecond two-photon photoassociation (PA) of magnesium atoms as an example, we propose a method to calculate the thermally averaged population, which is transferred from the ground X1Σg + state to the target (1)1Πg state, based on the solution of full-dimensional time-dependent Schrödinger equation. In this method, named as method A, we use thermal-random-phase wavefunctions with the random phases expanded in both the vibrational and rotational degrees of freedom to model the thermal ensemble of the initial eigenstates. This method is compared with the other two methods (B and C) at different temperatures. Method B is also based on thermal-random-phase wavefunctions, except that the random-phase expansion is merely used for the vibrational degree of freedom. Method C is based on the independent propagation of every initial eigenstate, instead of the thermal-random-phase wavefunctions. Taking the (1)1Πg state as the target state, it is found that although these three methods can present the same population on the (1)1Πg state, the computation efficiency of method A increases dramatically with the increase in temperature. With this efficient method A, we find that the PA process at 1000 K can also induce rotational coherence, i.e., the molecular field-free alignment in the excited electronic states.

Effect of healthcare system reforms on job satisfaction among village clinic doctors in China.

BACKGROUND: Village clinic doctors (VCDs) are part of the health service force in rural China. VCDs' job satisfaction (JS) is important to the stability of the three-tiered health service system. Since 2009, the Chinese government launched a new health care system reform (NHCSR) which affected VCDs significantly. This study aimed to analysing the effect of NHCSR on JS among VCDs. METHODS: All the data came from three surveys in Shandong Province conducted in 2012, 2015 and 2018. In 2012, an originally designed questionnaire was used to conduct a baseline survey of 405 VCDs from 27 townships in nine counties. In 2015 and 2018, 519 and 223 VCDs in the same counties were surveyed with the same questionnaire. Descriptive analysis and ANOVA were used to analyse the level and changes in VCDs' JS. RESULTS: The mean scores of VCDs' total JS were 2.664 ± 1.069, 3.121 ± 0.931 and 2.676 ± 1.044 in 2012, 2015 and 2018, respectively, with a significant difference (F = 28.732, P < 0.001). The mean scores of the medical practice environment and the job itself showed a continuous downward trend. The trends of the mean scores for job reward, internal work environment and organizational management were consistent with the trend for total JS. CONCLUSION: The NHCSR had a partly negative impact on VCDs' JS. Policy-makers should pay more attention to VCDs' job reward and medical practice environment. With the implementation of new reform policies, VCDs' JS should be the subject of more systematic and detailed research.

COVID-19 Information Dissemination Using the WeChat Communication Index: Retrospective Analysis Study.

BACKGROUND: The COVID-19 outbreak has tremendously impacted the world. The number of confirmed cases has continued to increase, causing damage to society and the economy worldwide. The public pays close attention to information on the pandemic and learns about the disease through various media outlets. The dissemination of comprehensive and accurate COVID-19 information that the public needs helps to educate people so they can take preventive measures. OBJECTIVE: This study aimed to examine the dissemination of COVID-19 information by analyzing the information released by the official WeChat account of the People's Daily during the pandemic. The most-read COVID-19 information in China was summarized, and the factors that influence information dissemination were studied to understand the characteristics that affect its dissemination. Moreover, this was conducted in order to identify how to effectively disseminate COVID-19 information and to provide suggestions on how to manage public opinion and information governance during a pandemic. METHODS: This was a retrospective study based on a WeChat official account. We collected all COVID-19-related information, starting with the first report about COVID-19 from the People's Daily and ending with the last piece of information about lifting the first-level emergency response in 34 Chinese provinces. A descriptive analysis was then conducted on this information, as well as on Qingbo Big Data's dissemination index. Multiple linear regression was utilized to study the factors that affected information dissemination based on various characteristics and the dissemination index. RESULTS: From January 19 to May 2, 2020, the People's Daily released 1984 pieces of information; 1621 were related to COVID-19, which mainly included headline news items, items with emotional content, and issues related to the pandemic's development. By analyzing the dissemination index, seven information dissemination peaks were discerned. Among the three dimensions of COVID-19 information-media salience, content, and format-eight factors affected the spread of COVID-19 information. CONCLUSIONS: Different types of pandemic-related information have varying dissemination power. To effectively disseminate information and prevent the spread of COVID-19, we should identify the factors that affect this dissemination. We should then disseminate the types of information the public is most concerned about, use information to educate people to improve their health literacy, and improve public opinion and information governance.

Development of an Interactive Remote Basic Surgical Skills Mini-Curriculum for Medical Students During the COVID-19 Pandemic.

Introduction. Teaching surgical skills has historically been a hands-on activity, with instructors and learners in close physical proximity. This paradigm was disrupted by the COVID-19 pandemic, requiring innovative solutions to surmount the challenges of teaching surgical skills remotely. In this work, we describe our institution's path and early results of developing an interactive remote surgical skills course for medical students in the surgical clerkship. Methods. 31 third-year medical students were distributed a set of surgical equipment and 3D printed phone dock. Each participant completed a baseline questionnaire and underwent 3 structured interactive remote sessions on surgical instruments, knot tying, and suturing techniques. Students were instructed on sharing their first-person viewpoint and received real-time feedback on their knot tying and suturing techniques from the course instructor. Pre- and post-session surveys were conducted and analyzed. Results. All students were able to complete the remote surgical skills course successfully, as defined by visually demonstrating successful two-handed knot and simple suture techniques. Students' aggregate confidence score in their knot tying ability (pretest mean 7.9, SD 0.7 vs posttest mean 9.7, SD 0.9, t-statistic -2.3, P = .03) and suturing ability (pretest mean 8.0, SD 1.3 vs posttest mean 13.8, SD 0.9 t-statistic -5.5, P < .001) significantly improved after the intervention. Qualitative feedback from the students underscored the utility of the first-person perspective for teaching surgical technique. Conclusion. This study demonstrates that remote teaching of knot tying and simple suturing to medical students can be effectively implemented using a remote learning curriculum that was well received by the learners.

Thyroid Carcinoma: Phenotypic Features, Underlying Biology and Potential Relevance for Targeting Therapy.

Thyroid carcinoma consists a group of phenotypically heterogeneous cancers. Recent advances in biological technologies have been advancing the delineation of genetic, epigenetic, and non-genetic factors that contribute to the heterogeneities of these cancers. In this review article, we discuss new findings that are greatly improving the understanding of thyroid cancer biology and facilitating the identification of novel targets for therapeutic intervention. We review the phenotypic features of different subtypes of thyroid cancers and their underlying biology. We discuss recent discoveries in thyroid cancer heterogeneities and the critical mechanisms contributing to the heterogeneity with emphases on genetic and epigenetic factors, cancer stemness traits, and tumor microenvironments. We also discuss the potential relevance of the intratumor heterogeneity in understanding therapeutic resistance and how new findings in tumor biology can facilitate designing novel targeting therapies for thyroid cancer.

Characterization of tea tree essential oil and large-ring cyclodextrins (CD9 -CD22 ) inclusion complex and evaluation of its thermal stability and volatility.

BACKGROUND: Although the structure and physicochemical properties of large ring cyclodextrins (LR-CDs) exhibit unique characteristics, and also possess very strong water solubility and high safety, little is known about the embedding performance of macrocyclodextrin. Encapsulation refers to a complex of tea tree oil (TTO) with the wall material, protecting the core material or changing its properties from adverse external factors, controlling its release rate against the evaporation and degradation of essential oils. In the present study, LR-CDs complexed with TTO were prepared by co-precipitation methods. RESULTS: The mass ratio of LR-CDs-TTO was six and the maximum complexation efficiency was 86.23%. Fourier-transform infrared spectroscopy analysis presented the loss of characteristic peaks related to TTO in the complex and no other additional peaks were observed. X-ray diffraction examination demonstrated several sharp peaks and intensity peaks at the diffraction angle of the TTO-LR-CDs complex. 1 H-NMR indicated a chemical shift as a result of the interaction between the molecules in the inclusion complex. Moreover, the thermal stability and aqueous solubility of TTO were enhanced after synergy with LR-CDs; particularly, the solubility of the complex was increased by 329-fold. The volatile characteristics of the encapsulated and original TTO were identical. CONCLUSION: The results of the present study show that TTO was efficaciously complexed with LR-CDs and exhibited enhanced solubility and thermal stability. © 2020 Society of Chemical Industry.

An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies.

BACKGROUND: Incorporation of next-generation sequencing (NGS) technology into clinical utility in targeted and immunotherapies requires stringent validation, including the assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) status by NGS as important biomarkers for response to immune checkpoint inhibitors. MATERIALS AND METHODS: We designed an NGS assay, Cancer Sequencing YS panel (CSYS), and applied algorithms to detect five classes of genomic alterations and two genomic features of TMB and MSI. RESULTS: By stringent validation, CSYS exhibited high sensitivity and predictive positive value of 99.7% and 99.9%, respectively, for single nucleotide variation; 100% and 99.9%, respectively, for short insertion and deletion (indel); and 95.5% and 100%, respectively, for copy number alteration (CNA). Moreover, CSYS achieved 100% specificity for both long indel (50-3,000 bp insertion and deletion) and gene rearrangement. Overall, we used 33 cell lines and 208 clinical samples to validate CSYS's NGS performance, and genomic alterations in clinical samples were also confirmed by fluorescence in situ hybridization, immunohistochemistry, and polymerase chain reaction (PCR). Importantly, the landscape of TMB across different cancers of Chinese patients (n = 3,309) was studied. TMB by CSYS exhibited a high correlation (Pearson correlation coefficient r = 0.98) with TMB by whole exome sequencing (WES). MSI measurement showed 98% accuracy and was confirmed by PCR. Application of CSYS in a clinical setting showed an unexpectedly high occurrence of long indel (6.3%) in a cohort of tumors from Chinese patients with cancer (n = 3,309), including TP53, RB1, FLT3, BRCA2, and other cancer driver genes with clinical impact. CONCLUSION: CSYS proves to be clinically applicable and useful in disclosing genomic alterations relevant to cancer target therapies and revealing biomarkers for immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: The study describes a specially designed sequencing panel assay to detect genomic alterations and features of 450 cancer genes, including its overall workflow and rigorous clinical and analytical validations. The distribution of pan-cancer tumor mutational burden, microsatellite instability, gene rearrangement, and long insertion and deletion mutations was assessed for the first time by this assay in a broad array of Chinese patients with cancer. The Cancer Sequencing YS panel and its validation study could serve as a blueprint for developing next-generation sequencing-based assays, particularly for the purpose of clinical application.

Comparative performance of growth, vertebral structure and muscle composition in diploid and triploid Paralichthys olivaceus.

Growth, skeletal structure and muscle composition of cold-shock-induced triploid olive flounder Paralichthys olivaceus were investigated. The average values of total length and total weight of triploids were higher than those of diploids from 5 to 11 months posthatch (mph). The growth difference disappeared after 11 mph. The skeletal structure of flounder at 11 mph was observed by X-ray imaging method. There are four kinds of vertebral deformity including vertebrae fusion, one-sided compression, two-sided compression and vertically shifted. The trunk region (V8-18) and tailing end of the vertebral column were the predominant locations of deformity. In general, the frequencies of vertebral deformities in triploids (60.0%) were higher than those in diploids (33.3%, p < 0.05). Both the number of fish with deformed vertebrae and the average frequencies of deformed vertebrae in triploids were significantly higher than those in diploids (p < 0.05). The muscle tissues of diploid and triploid flounder at 11 mph contain the same types of fatty acid and free amino acid profiles. The number of fatty acids with significant higher contents in diploids and triploids was one and ten, respectively (p < 0.05). The contents of free amino acids showed no difference between triploid and diploid fish.

CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells are positively correlated with levels of IL-21 in active and transitional cystic echinococcosis patients.

BACKGROUND: In our study, we investigated whether circulating T follicular helper (Tfh) and the related cytokines are involved in human cystic echinococcosis (CE). METHODS: A total of 64 patients with CE and 30 healthy controls were enrolled in this study. Percentages of CCR7(lo)PD-1(hi) cells within CXCR5(+) CD4(+) T cells (circulating Tfh cells) were detected by flow cytometry. Levels of IL-21 and IL-4 in peripheral blood were detected by cytometric bead array. The mRNA expression of IL-21, IL-4, Bcl-6, and Blimp-1 in peripheral blood mononuclear cells (PBMCs) were measured by real-time PCR. Levels of IgG1, IgG2, IgG3, and IgG4 in the patients' sera were measured using enzyme-linked immunosorbent assay. RESULTS: Percentages of circulating Tfh cells were significantly increased in the CE1, CE2, and CE3 groups (p < 0.05). The concentrations of IL-21 and IL-4 in the serum were significantly increased in CE1, CE2, and CE3 groups (p < 0.05). IL-21 was positively correlated with circulating Tfh cells in CE3 group (r = 0.779, p < 0.05). The mRNA levels of IL-21, IL-4, and Bcl-6 were increased in CE1, CE2, and CE3 groups. Levels of IgG1 and IgG4 in patients' sera were increased in CE1, CE2, and CE3 groups. Levels of IgG2 and IgG3 were increased in CE4-5 group. Additionally, after stimulation with hydatid fluid in vitro, the levels of circulating Tfh cells, IL-21 and IL-4 in PBMCs isolated from CE patients were significantly increased (p < 0.05). CONCLUSIONS: The levels of circulating Tfh and related cytokines were significantly increased in CE patients, suggesting that they are involved in human CE.

Mertk Reduces Blood-Spinal Cord Barrier Permeability Through the Rhoa/Rock1/P-MLC Pathway After Spinal Cord Injury.

Disruption of the blood-spinal cord barrier (BSCB) is a critical event in the secondary injury following spinal cord injury (SCI). Mertk has been reported to play an important role in regulating inflammation and cytoskeletal dynamics. However, the specific involvement of Mertk in BSCB remains elusive. Here, we demonstrated a distinct role of Mertk in the repair of BSCB. Mertk expression is decreased in endothelial cells following SCI. Overexpression of Mertk upregulated tight junction proteins (TJs), reducing BSCB permeability and subsequently inhibiting inflammation and apoptosis. Ultimately, this led to enhanced neural regeneration and functional recovery. Further experiments revealed that the RhoA/Rock1/P-MLC pathway plays a key role in the effects of Mertk. These findings highlight the role of Mertk in promoting SCI recovery through its ability to mitigate BSCB permeability and may provide potential targets for SCI repair.

Vaccination-Route-Dependent Adjuvanticity of Antigen-Carrying Nanoparticles for Enhanced Vaccine Efficacy.

Vaccination-route-dependent adjuvanticity was identified as being associated with the specific features of antigen-carrying nanoparticles (NPs) in the present work. Here, we demonstrated that the mechanical properties and the decomposability of NP adjuvants play key roles in determining the antigen accessibility and thus the overall vaccine efficacy in the immune system when different vaccination routes were employed. We showed that soft nano-vaccines were associated with more efficient antigen uptake when administering subcutaneous (S.C.) vaccination, while the slow decomposition of hard nano-vaccines promoted antigen uptake when intravenous (I.V.) vaccination was employed. In comparison to the clinically used aluminum (Alum) adjuvant, the NP adjuvants were found to stimulate both humoral and cellular immune responses efficiently, irrespective of the vaccination route. For vaccination via S.C. and I.V. alike, the NP-based vaccines show excellent protection for mice from Staphylococcus aureus (S. aureus) infection, and their survival rates are 100% after lethal challenge, being much superior to the clinically used Alum adjuvant.

Inhibition of brain tumor growth by intravenous poly (ß-L-malic acid) nanobioconjugate with pH-dependent drug release [corrected].

Effective treatment of brain neurological disorders such as Alzheimer's disease, multiple sclerosis, or tumors should be possible with drug delivery through blood-brain barrier (BBB) or blood-brain tumor barrier (BTB) and targeting specific types of brain cells with drug release into the cell cytoplasm. A polymeric nanobioconjugate drug based on biodegradable, nontoxic, and nonimmunogenic polymalic acid as a universal delivery nanoplatform was used for design and synthesis of nanomedicine drug for i.v. treatment of brain tumors. The polymeric drug passes through the BTB and tumor cell membrane using tandem monoclonal antibodies targeting the BTB and tumor cells. The next step for polymeric drug action was inhibition of tumor angiogenesis by specifically blocking the synthesis of a tumor neovascular trimer protein, laminin-411, by attached antisense oligonucleotides (AONs). The AONs were released into the target cell cytoplasm via pH-activated trileucine, an endosomal escape moiety. Drug delivery to the brain tumor and the release mechanism were both studied for this nanobiopolymer. Introduction of a trileucine endosome escape unit resulted in significantly increased AON delivery to tumor cells, inhibition of laminin-411 synthesis in vitro and in vivo, specific accumulation in brain tumors, and suppression of intracranial glioma growth compared with pH-independent leucine ester. The availability of a systemically active polymeric drug delivery system that passes through the BTB, targets tumor cells, and inhibits glioma growth gives hope for a successful strategy of glioma treatment. This delivery system with drug release into the brain-specific cell type could be useful for treatment of various brain pathologies.

Lower tacrolimus time in therapeutic range is associated with inferior outcomes in adult liver transplant recipients.

Previous studies on solid organ transplantation have reported that a low time in therapeutic range (TTR) of tacrolimus increases the risk of poor outcomes. However, the reproducibility of the findings in liver transplantation has not yet been confirmed. The TTR, coefficient of variation (CV) and standard deviation (SD) were calculated for 207 adult liver transplant patients from the date of transplantation until the first episode of acute rejection (AR), graft loss, acute kidney injury (AKI), biliary complications, infection or the last follow-up. Kaplan-Meier curves, log-rank tests and Cox regression analyses were performed. Sixty-one (29.5%) patients reached the composite endpoint of AR, biliary complications and graft loss. The log-rank test indicated that the low TTR group had an increased risk of the composite endpoint (P < 0.001), AKI (P < 0.001) and infection (P < 0.001). Multivariate Cox regression analyses revealed that a 10% decrease in TTR was associated with an increased hazard for composite endpoint (hazard ratio [HR]: 1.185, P = 0.010), AKI (HR: 1.355, P < 0.001) and infection (HR: 1.357, P < 0.001). Unexpectedly, SD and CV demonstrated no association with the above-mentioned inferior outcomes. Compared with SD and CV, the TTR of tacrolimus was more correlated with inferior outcomes and may be a novel indicator for predicting the prognosis of liver transplantation.