Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.

Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function, and molecular pathways between mammalian podocytes and Drosophila nephrocytes are highly conserved, therefore we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes of high-sucrose diet flies showed significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocytes filtration structure known as the slit diaphragm was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunction. Regulating mitochondrial dynamics by either genetic modification of the Pink1/Park (mammalian PINK1/PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1/Park-mediated mitophagy and associated control of mitochondrial dynamics, essential for function, in diabetic nephropathy; and demonstrate that targeting this pathway might provide therapeutic benefits in type 2 diabetic nephropathy.

A Drosophila model to screen Alport syndrome COL4A5 variants for their functional pathogenicity.

Alport syndrome is a hereditary chronic kidney disease, attributed to rare pathogenic variants in either of three collagen genes (COL4A3/4/5) with most localized in COL4A5. Trimeric type IV Collagen α3α4α5 is essential for the glomerular basement membrane that forms the kidney filtration barrier. A means to functionally assess the many candidate variants and determine pathogenicity is urgently needed. We used Drosophila, an established model for kidney disease, and identify Col4a1 as the functional homolog of human COL4A5 in the fly nephrocyte (equivalent of human podocyte). Fly nephrocytes deficient for Col4a1 showed an irregular and thickened basement membrane and significantly reduced nephrocyte filtration function. This phenotype was restored by expressing human reference (wildtype) COL4A5, but not by COL4A5 carrying any of three established pathogenic patient-derived variants. We then screened seven additional patient COL4A5 variants; their ClinVar classification was either likely pathogenic or of uncertain significance. The findings support pathogenicity for four of these variants; the three others were found benign. Thus, demonstrating the effectiveness of this Drosophila in vivo kidney platform in providing the urgently needed variant-level functional validation.

Design of ultrahigh-Q silicon microring resonators based on free-form curves.

A design method for ultrahigh-Q microring resonators (MRRs) based on Bezier free-form curves was proposed and demonstrated. An MRR consisting of a specially designed 180° waveguide bend, a directional coupler, and two low-loss multi-mode strip waveguides was designed. The free-form curves were used to increase the degree of freedom in the design, shaping the waveguide bend with a gradient width and curvature. This design effectively reduced the propagation loss caused by the roughness of waveguide sidewalls and the mode mismatch loss caused by the excitation of high order modes. The small effective radius of only 20µm enabled the MRR to have a large free spectral range (FSR) and a compact and flexible structure. The MRR was manufactured using a standard process provided by foundry and measured to have an ultrahigh loaded Q factor of 1.86 × 106 and a FSR of about 1 nm.

Artificial neural network assisted the design of subwavelength-grating waveguides for nanoparticles optical trapping.

In this work, we propose artificial neural networks (ANNs) to predict the optical forces on particles with a radius of 50 nm and inverse-design the subwavelength-grating (SWG) waveguides structure for trapping. The SWG waveguides are applied to particle trapping due to their superior bulk sensitivity and surface sensitivity, as well as longer working distance than conventional nanophotonic waveguides. To reduce the time consumption of the design, we train ANNs to predict the trapping forces and to inverse-design the geometric structure of SWG waveguides, and the low mean square errors (MSE) of the networks achieve 2.8 × 10-4. Based on the well-trained forward prediction and inverse-design network, an SWG waveguide with significant trapping performance is designed. The trapping forces in the y-direction achieve-40.39 pN when the center of the particle is placed 100 nm away from the side wall of the silicon segment, and the negative sign of the optical forces indicates the direction of the forces. The maximum trapping potential achieved to 838.16 kBT in the y-direction. The trapping performance in the x and z directions is also quite superior, and the neural network model has been further applied to design SWGs with a high trapping performance. The present work is of significance for further research on the application of artificial neural networks in other optical devices designed for particle trapping.

Aerobic fitness as a moderator of acute aerobic exercise effects on executive function.

This study aimed to investigate the moderating role of aerobic fitness on the effect of acute exercise on improving executive function from both behavioral and cerebral aspects. Thirty-four young individuals with motor skills were divided into high- and low-fitness groups based on their maximal oxygen uptake. Both groups completed 30 min of moderate-intensity aerobic exercise on a power bike. Executive function tests (Flanker, N-back, More-odd-shifting) were performed before and after exercise and functional near-infrared spectroscopy was used to monitor prefrontal cerebral blood flow changes during the tasks. The results indicated significant differences between the two groups regarding executive function. Participants with lower aerobic fitness performed better than their higher fitness counterparts in inhibitory control and working memory, but not in cognitive flexibility. This finding suggests that the aerobic fitness may moderate the extent of cognitive benefits gained from acute aerobic exercise. Furthermore, the neuroimaging data indicated negative activation in the frontopolar area and dorsolateral prefrontal cortex in response to three complex tasks. These findings underscore the importance of considering individual aerobic fitness when assessing the cognitive benefits of exercise and could have significant implications for tailoring fitness programs to enhance cognitive performance.

Application of three-dimensional technology in video-assisted thoracoscopic surgery sublobectomy.

Background: Due to the widespread use of imaging techniques, the detection rate of early-stage lung cancer has increased. Video-assisted thoracoscopic surgery (VATS) sublobectomy has emerged as a prominent alternative to lobectomy, offering advantages like reduced resection range, better preservation of lung function, and enhanced postoperative quality of life. However, sublobectomy is more intricate than lobectomy, necessitating a higher level of surgical proficiency and anatomical understanding. Methods: Three electronic databases were searched to capture relevant studies from January 2016 to March 2023, which related to the application of three-dimensional(3D) technology in VATS sublobectomy. Results: Currently, clinical departments such as orthopedics, hepatobiliary surgery, and urology have started using 3D technology. This technology is expected to be widely used in thoracic surgery in future. Now 3D technology assists in preoperative planning, intraoperative navigation and doctor-patient communication. Conclusion: 3D technologies, instrumental in locating pulmonary nodules and identifying variations in target lung segmental vessels and bronchi, play pivotal roles in VATS sublobectomy, especially in preoperative planning, intraoperative navigation, and doctor-patient communication. The limitations of 3D technology in clinical application are analyzed, and the future direction of existing 3D technology development is prospected.

HIV-1 Nef acts in synergy with APOL1-G1 to induce nephrocyte cell death in a new Drosophila model of HIV-related kidney diseases.

Background: People carrying two APOL1 risk alleles (RA) G1 or G2 are at greater risk of developing HIV-associated nephropathy (HIVAN). Studies in transgenic mice showed that the expression of HIV-1 genes in podocytes, and nef in particular, led to HIVAN. However, it remains unclear whether APOL1-RA and HIV-1 Nef interact to induce podocyte cell death. Method: We generated transgenic (Tg) flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. Results: We found that HIV-1 Nef acts in synergy with APOL1-G1 resulting in nephrocyte structural and functional defects. Specifically, HIV-1 Nef itself can induce endoplasmic reticulum (ER) stress (without affecting autophagy). Through a different pathway, Nef exacerbates the organelle acidification defects and reduced autophagy induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating ER stress, triggering nephrocyte dysfunction and ultimately cell death. Conclusions: A new Drosophila model of HIV-1-related kidney diseases identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high relevance between Drosophila nephrocytes and human podocytes, this finding suggests ER stress as a new therapeutic target for HIV-1 and APOL1-associated nephropathies.

Applying narrative medicine to prepare empathetic healthcare providers in undergraduate pharmacy education in Singapore: a mixed methods study.

BACKGROUND: Narrative medicine demonstrated positive impact on empathy in medicine and nursing students. However, this pedagogical approach had not been evaluated in pharmacy education. This study sought to apply and evaluate the narrative medicine approach in extending empathy in Asian undergraduate pharmacy students. METHODS: Narrative medicine was applied through workshops which used narratives of people with different experiences and perspectives. First-year undergraduate pharmacy students who volunteered and attended these workshops formed the intervention group (N = 31) and the remaining first-year cohort formed the control group (N = 112). A sequential explanatory mixed methods approach was adopted in which quantitative methods were first used to measure impact on pharmacy students' empathy using the Jefferson Scale of Empathy- Health Professions Student (JSE-HPS), and qualitative methods (i.e. group interviews) were then used to assess pharmacy students' emotional responses to narratives, and the perspectives of pharmacy students and faculty of this pedagogical approach. RESULTS: There was no difference in JSE-HPS scores between intervention and control groups across baseline (i.e. upon matriculation), pre-intervention, and post-intervention timepoints. Pharmacy students in the intervention group had lower scores in Factor 3 ("Standing in People's Shoes") following the intervention. Five themes, guided by internal and external factors in cognition, emerged from the Group Interviews: (1) incongruence between students' motivation and faculty's perception, (2) learning context, (3) academic context, (4) cognitive system, and (5) affective system. Themes 1, 4 and 5 referred to internal factors such as students' motivation, perceived learnings, and feelings. Themes 2 and 3 referred to external factors including workshop materials, activities, content, and facilitation. CONCLUSION: This study is the first to demonstrate that pharmacy students engaged with the narrative medicine approach as narratives elicited emotional responses, exposed them to diverse perspectives, and deepened their appreciation of the importance of empathy and complexities of understanding patients' perspectives. Scaffolded educational interventions using narratives and real-life patient encounters, alongside longitudinal measurements of empathy, are necessary to bring about meaningful and sustained improvements in empathy.

Seven new triterpenoids from the roots of Adenophora tetraphylla (Thub.) Fisch.

Seven new triterpenoids, named Adeterpenoids A-G (1-7) and eight known compounds (8-15), were isolated from 70% ethanol extract of the roots of Adenophora tetraphylla (Thub.) Fisch. The compounds from it were separated by column chromatography techniques such as silica gel, ODS, and preparative liquid chromatography. Their structures were clarified based on extensive spectral analysis (1D, 2D-NMR, HR-ESI-MS, IR, UV, and CD) and comparison with the literature. At the same time, all compounds were evaluated for their cytotoxic activity against the LN229 (human glioma cell line). The results showed that compounds 2, 5, 6, 13, and 14 had a significant inhibitory effect on LN229 cells.

Apatinib Plus Toripalimab (Anti-PD1 Therapy) as Second-Line Therapy in Patients With Advanced Gastric or Esophagogastric Junction Cancer: Results From a Randomized, Open-Label Phase II Study.

BACKGROUND: This study aimed to assess the activity of apatinib plus toripalimab in the second line for patients with advanced gastric or esophagogastric junction cancer (GC/EGJC). METHODS: In this open-label, phase II, randomized trial, patients with advanced GC/EGJC who progressed after first-line chemotherapy were enrolled and received 250 mg apatinib per day plus 240 mg toripalimab on day 1 per 3 weeks (arm A) or physician's choice of chemotherapy (PC, arm B). The primary endpoint of this study was the 1-year survival rate. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed as secondary endpoints. RESULTS: Twenty-five patients received apatinib plus toripalimab while 26 were enrolled in arm B. The 1-year survival rates of the 2 groups were 43.3% and 42.3%, respectively (P = .903). The PFS was 2.77 versus 2.33 months (P = .660). The OS was 8.30 versus 9.88 months (P = .539). An objective response was reported in 20.0% of patients in arm A compared to 26.9% in arm B (P = .368), respectively. A total of 6 (24.0%) patients experienced adverse events of grade ≥ 3 in arm A, while 9 (34.6%) patients suffered from adverse events of grade ≥ 3 in arm B. No drug-related deaths occurred in either group. CONCLUSION: Toripalimab plus apatinib treatment in second-line therapy of advanced GC/EGJC showed manageable toxicity but did not improve clinical outcomes relative to PC treatment (ClinicalTrials.gov Identifier: NCT04190745).

Transcriptomic analysis and knockout experiments reveal the role of suhB in the biocontrol effects of Pantoea jilinensis D25 on Botrytis cinerea.

Tomato gray mold, caused by Botrytis cinerea, is an important disease in tomato. Pantoea jilinensis D25, isolated form tomato rhizosphere soil, can prevent B. cinerea infection in tomato. To determine the underlying biocontrol mechanism, the transcriptome of P. jilinensis D25 was assessed. Differential expression analysis revealed that 941 genes were upregulated and 997 genes were downregulated. Through transcriptome analysis, the suhB gene was knocked out. ΔPj-suhB exhibited lower swimming motility and colonization abilities than strain D25. After 4 days of co-cultivation, ΔPj-suhB could reduce the colony diameter, mycelial weight, and spore production of B. cinerea with the inhibitory rates of 31.72 %, 39.62 %, and 47.42 %, respectively, compared with control. However, the inhibitory rates of strain D25 were 52.91 %, 60.09 %, and 76.85 %, respectively, compared with control. Strain D25 could significantly downregulate pathogenesis-related genes in B. cinerea, whereas the expression level of these genes in B. cinerea was higher after treatment with ΔPj-suhB than after that with strain D25. In vitro experiments revealed that the lesion area and disease control efficacy were 1.520 and 0.038 cm2 and 68.7 % and 99.0 %, respectively, after ΔPj-suhB and strain D25 treatments. Pot experiments revealed that ΔPj-suhB and strain D25 could prevent tomato plants from B. cinerea infection with the disease reduction rate of 37.5 % and 75.0 %, respectively. Though the activities of defense-related enzymes and expression level of defense related genes in tomato plants were increased under ΔPj-suhB treatment, these effects were higher after strain D25 treatment. Thus, these results demonstrated that suhB was the key gene in strain D25 underlying its biocontrol effect and mobility.

Systems genetics analysis reveals the common genetic basis for pain sensitivity and cognitive function.

BACKGROUND: There is growing evidence of a strong correlation between pain sensitivity and cognitive function under both physiological and pathological conditions. However, the detailed mechanisms remain largely unknown. In the current study, we sought to explore candidate genes and common molecular mechanisms underlying pain sensitivity and cognitive function with a transcriptome-wide association study using recombinant inbred mice from the BXD family. METHODS: The pain sensitivity determined by Hargreaves' paw withdrawal test and cognition-related phenotypes were systematically analyzed in 60 strains of BXD mice and correlated with hippocampus transcriptomes, followed by quantitative trait locus (QTL) mapping and systems genetics analysis. RESULTS: The pain sensitivity showed significant variability across the BXD strains and co-varies with cognitive traits. Pain sensitivity correlated hippocampual genes showed a significant involvement in cognition-related pathways, including glutamatergic synapse, and PI3K-Akt signaling pathway. Moreover, QTL mapping identified a genomic region on chromosome 4, potentially regulating the variation of pain sensitivity. Integrative analysis of expression QTL mapping, correlation analysis, and Bayesian network modeling identified Ring finger protein 20 (Rnf20) as the best candidate. Further pathway analysis indicated that Rnf20 may regulate the expression of pain sensitivity and cognitive function through the PI3K-Akt signaling pathway, particularly through interactions with genes Ppp2r2b, Ppp2r5c, Col9a3, Met, Rps6, Tnc, and Kras. CONCLUSIONS: Our study demonstrated that pain sensitivity is associated with genetic background and Rnf20-mediated PI3K-Akt signaling may involve in the regulation of pain sensitivity and cognitive functions.

Lactiplantibacillus plantarum and Saccharomyces cerevisiae-Fermented Coconut Water Alleviates Dextran Sodium Sulfate-Induced Enteritis in Wenchang Chicken: A Gut Microbiota and Metabolomic Approach.

In order to investigate the potential mechanisms of probiotic-fermented coconut water in treating enteritis, this study conducted a comprehensive analysis of the effects of probiotic intervention on the recovery from Dextran Sodium Sulfate-induced acute enteritis in Wenchang chicks. The analysis encompassed the assessment of growth performance, serum indicators, intestinal tissue structure, and metagenomic and metabolomic profiles of cecal contents in 60 Wenchang chicks subjected to intervention. This approach aimed to elucidate the impact of probiotic intervention on the recovery process from acute enteritis at both the genetic and metabolic levels in the avian model. The results revealed that intervention with Saccharomyces cerevisiae Y301 improved the growth rate of chicks. and intervention with Lactiplantibacillus plantarum MS2c regulated the glycerophospholipid metabolism pathway and reshaped the gut microbiota structure in modeling chicks with acute enteritis, reducing the abundance of potentially pathogenic bacteria from the Alistipes and increasing the abundance of potentially beneficial species from the Christensenellaceae. This intervention resulted in the production of specific gut metabolites, including Gentamicin C and polymyxin B2, recognized for their therapeutic effects on acute enteritis. The combined intervention of S. cerevisiae Y301 and L. plantarum MS2c not only enhanced growth performance but also mitigated intestinal wall damage and increased the abundance of gut metabolites such as gentamicin C and polymyxin B2, thereby mitigating symptoms of enteritis. Furthermore, this combined intervention reduced the levels of serum immune markers, including IL-10, IL-6, TNF-α, IFN-γ, and D-lactic acid, thus mitigating intestinal epithelial cell damage and promoting acute enteritis recovery. This study provides crucial insights into the mechanisms of action of probiotics and probiotic-fermented coconut water in acute enteritis recovery, offering new perspectives for sustainable farming practices for Wenchang chicken.

A Respiratory Motion Prediction Method Based on LSTM-AE with Attention Mechanism for Spine Surgery.

Respiratory motion-induced vertebral movements can adversely impact intraoperative spine surgery, resulting in inaccurate positional information of the target region and unexpected damage during the operation. In this paper, we propose a novel deep learning architecture for respiratory motion prediction, which can adapt to different patients. The proposed method utilizes an LSTM-AE with attention mechanism network that can be trained using few-shot datasets during operation. To ensure real-time performance, a dimension reduction method based on the respiration-induced physical movement of spine vertebral bodies is introduced. The experiment collected data from prone-positioned patients under general anaesthesia to validate the prediction accuracy and time efficiency of the LSTM-AE-based motion prediction method. The experimental results demonstrate that the presented method (RMSE: 4.39%) outperforms other methods in terms of accuracy within a learning time of 2 min. The maximum predictive errors under the latency of 333 ms with respect to the x, y, and z axes of the optical camera system were 0.13, 0.07, and 0.10 mm, respectively, within a motion range of 2 mm.

How does air pollution threaten mental health? Protocol for a machine-learning enhanced systematic map.

INTRODUCTION: Air pollution exposure has influenced a broad range of mental health conditions. It has attracted research from multiple disciplines such as biomedical sciences, epidemiology, neurological science, and social science due to its importance for public health, with implications for environmental policies. Establishing and identifying the causal and moderator effects is challenging and is particularly concerning considering the different mental health measurements, study designs and data collection strategies (eg, surveys, interviews) in different disciplines. This has created a fragmented research landscape which hinders efforts to integrate key insights from different niches, and makes it difficult to identify current research trends and gaps. METHOD AND ANALYSIS: This systematic map will follow the Collaboration for Environmental Evidence's guidelines and standards and Reporting Standards for Systematic Evidence Syntheses guidelines. Different databases and relevant web-based search engines will be used to collect the relevant literature. The time period of search strategies is conducted from the inception of the database until November 2022. Citation tracing and backward references snowballing will be used to identify additional studies. Data will be extracted by combining of literature mining and manual correction. Data coding for each article will be completed by two independent reviewers and conflicts will be reconciled between them. Machine learning technology will be applied throughout the systematic mapping process. Literature mining will rapidly screen and code the numerous available articles, enabling the breadth and diversity of the expanding literature base to be considered. The systematic map output will be provided as a publicly available database. ETHICS AND DISSEMINATION: Primary data will not be collected and ethical approval is not required in this study. The findings of this study will be disseminated through a peer-reviewed scientific journal and academic conference presentations.

Development and external validation of MRI-based RAS mutation status prediction model for liver metastases of colorectal cancer.

BACKGROUND: The mutation status of rat sarcoma viral oncogene homolog (RAS) has prognostic significance and serves as a key predictive biomarker for the effectiveness of antiepidermal growth factor receptor (EGFR) therapy. However, there remains a lack of effective models for predicting RAS mutation status in colorectal liver metastases (CRLMs). This study aimed to construct and validate a diagnostic model for predicting RAS mutation status among patients undergoing hepatic resection for CRLMs. METHODS: A diagnostic multivariate prediction model was developed and validated in patients with CRLMs who had undergone hepatectomy between 2014 and 2020. Patients from Institution A were assigned to the model development group (i.e., Development Cohort), while patients from Institutions B and C were assigned to the external validation groups (i.e., Validation Cohort_1 and Validation Cohort_2). The presence of CRLMs was determined by examination of surgical specimens. RAS mutation status was determined by genetic testing. The final predictors, identified by a group of oncologists and radiologists, included several key clinical, demographic, and radiographic characteristics derived from magnetic resonance images. Multiple imputation was performed to estimate the values of missing non-outcome data. A penalized logistic regression model using the adaptive least absolute shrinkage and selection operator penalty was implemented to select appropriate variables for the development of the model. A single nomogram was constructed from the model. The performance of the prediction model, discrimination, and calibration were estimated and reported by the area under the receiver operating characteristic curve (AUC) and calibration plots. Internal validation with a bootstrapping procedure and external validation of the nomogram were assessed. Finally, decision curve analyses were used to characterize the clinical outcomes of the Development and Validation Cohorts. RESULTS: A total of 173 patients were enrolled in this study between January 2014 and May 2020. Of the 173 patients, 117 patients from Institution A were assigned to the Model Development group, while 56 patients (33 from Institution B and 23 from Institution C) were assigned to the Model Validation groups. Forty-six (39.3%) patients harbored RAS mutations in the Development Cohort compared to 14 (42.4%) in Validation Cohort_1 and 8 (34.8%) in Validation Cohort_2. The final model contained the following predictor variables: time of occurrence of CRLMs, location of primary lesion, type of intratumoral necrosis, and early enhancement of liver parenchyma. The diagnostic model based on clinical and MRI data demonstrated satisfactory predictive performance in distinguishing between mutated and wild-type RAS, with AUCs of 0.742 (95% confidence interval [CI]: 0.651─0.834), 0.741 (95% CI: 0.649─0.836), 0.703 (95% CI: 0.514─0.892), and 0.708 (95% CI: 0.452─0.964) in the Development Cohort, bootstrapping internal validation, external Validation Cohort_1 and Validation Cohort_2, respectively. The Hosmer-Lemeshow goodness-of-fit values for the Development Cohort, Validation Cohort_1 and Validation Cohort_2 were 2.868 (p = 0.942), 4.616 (p = 0.465), and 6.297 (p = 0.391), respectively. CONCLUSIONS: Integrating clinical, demographic, and radiographic modalities with a magnetic resonance imaging-based approach may accurately predict the RAS mutation status of CRLMs, thereby aiding in triage and possibly reducing the time taken to perform diagnostic and life-saving procedures. Our diagnostic multivariate prediction model may serve as a foundation for prognostic stratification and therapeutic decision-making.

Comparison of Vancomycin Trough-Based and 24-Hour Area Under the Curve Over Minimum Inhibitory Concentration (AUC/MIC)-Based Therapeutic Drug Monitoring in Pediatric Patients.

OBJECTIVES: Vancomycin 24-hour area under the curve over minimum inhibitory concentration (AUC/MIC) monitoring has been recommended over trough-based monitoring in pediatric patients. This study compared the proportion of target attainment between vancomycin AUC/MIC and trough-based methods, and identified risk factors for subtherapeutic initial extrapolated targets. METHODS: This was a retrospective, observational study conducted at KK Women's and Children's Hospital (KKH), Singapore. Patients aged 1 month to 18 years with stable renal function who received intravenous vancomycin between January 2014 and October 2017, with at least 2 vancomycin serum concentrations obtained after the first dose of vancomycin, were included. Using a pharmacokinetic software, namely Adult and Pediatric Kinetics (APK), initial extrapolated steady-state troughs and 24-hour AUC were determined by using a one-compartmental model. Statistical tests included Wilcoxon rank sum test, McNemar test, logistic regression, and classification and regression tree (CART) analysis. RESULTS: Of the 82 pediatric patients included, a significantly larger proportion of patients achieved therapeutic targets when the AUC/MIC-based method (24, 29.3%) was used than with the trough-based method (9, 11.0%; p < 0.01). Patients with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or with age <13 years had an increased risk of obtaining subtherapeutic targets. However, empiric vancomycin doses of 60 mg/kg/day would be sufficient to achieve serum therapeutic targets, using the AUC/MIC-based method. CONCLUSION: The AUC/MIC-based vancomycin monitoring may be preferred because a larger proportion of patients could achieve initial therapeutic targets. Future prospective studies with larger sample size will be required to determine the optimal vancomycin strategy for pediatric patients.

Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development.

Highly evolutionarily conserved multiprotein complexes termed Complex of Proteins Associated with Set1 (COMPASS) are required for histone 3 lysine 4 (H3K4) methylation. Drosophila Set1, Trx, and Trr form the core subunits of these complexes. We show that flies deficient in any of these three subunits demonstrated high lethality at eclosion (emergence of adult flies from their pupal cases) and significantly shortened lifespans for the adults that did emerge. Silencing Set1, trx, or trr in the heart led to a reduction in H3K4 monomethylation (H3K4me1) and dimethylation (H3K4me2), reflecting their distinct roles in H3K4 methylation. Furthermore, we studied the gene expression patterns regulated by Set1, Trx, and Trr. Each of the COMPASS core subunits controls the methylation of different sets of genes, with many metabolic pathways active early in development and throughout, while muscle and heart differentiation processes were methylated during later stages of development. Taken together, our findings demonstrate the roles of COMPASS series complex core subunits Set1, Trx, and Trr in regulating histone methylation during heart development and, given their implication in congenital heart diseases, inform research on heart disease.

[Research progress of rapid surgery for hip fracture in elderly patients].

Objective: To review the research progress of rapid surgery for hip fracture in elderly patients. Methods: The published studies, expert consensus, and guidelines at home and abroad were systematically summarized from the aspects of the characteristics of aging population, the benefits of rapid surgery, the disadvantages of delayed surgery, and the recommendations of current guidelines, so as to further guide clinical practice. Results: Hip fracture is a common fracture type in the elderly population. As elderly patients generally have poor physique and often have a variety of underlying diseases, such as hypostatic pneumonia, bedsore, lower limb vein thrombosis, and other complications in conservative treatment, its disability rate and mortality are high, so surgical treatment is the first choice. At present, most relevant studies and expert consensus and guidelines at home and abroad support rapid surgery, that is, preoperative examination should be started immediately after admission, and adverse factors such as taking anticoagulant drugs, serious cardiovascular diseases, and severe anemia should be clearly and actively corrected, and surgery should be completed within 48 hours after admission as far as possible. Rapid surgery can not only significantly reduce the mortality of patients, but also reduce the length of hospital stay and the incidence of perioperative cognitive impairment, which is conducive to the recovery of patients with pain during hospitalization and postoperative function, and improve the prognosis of patients. Conclusion: In order to avoid many problems caused by delayed surgery, the elderly patients with hip fracture should be operated as soon as possible under the condition of actively correcting the adverse factors. Comprehensive evaluation and preparation, the development of an individualized surgical plan, and the formation of a multidisciplinary medical team can reduce surgical risks and improve effectiveness.

APOL1-G2 accelerates nephrocyte cell death by inhibiting the autophagy pathway.

People of African ancestry who carry the APOL1 risk alleles G1 or G2 are at high risk of developing kidney diseases through not fully understood mechanisms that impair the function of podocytes. It is also not clear whether the APOL1-G1 and APOL1-G2 risk alleles affect these cells through similar mechanisms. Previously, we have developed transgenic Drosophila melanogaster lines expressing either the human APOL1 reference allele (G0) or APOL1-G1 specifically in nephrocytes, the cells homologous to mammalian podocytes. We have found that nephrocytes that expressed the APOL1-G1 risk allele display accelerated cell death, in a manner similar to that of cultured human podocytes and APOL1 transgenic mouse models. Here, to compare how the APOL1-G1 and APOL1-G2 risk alleles affect the structure and function of nephrocytes in vivo, we generated nephrocyte-specific transgenic flies that either expressed the APOL1-G2 or both G1 and G2 (G1G2) risk alleles on the same allele. We found that APOL1-G2- and APOL1-G1G2-expressing nephrocytes developed more severe changes in autophagic pathways, acidification of organelles and the structure of the slit diaphragm, compared to G1-expressing nephrocytes, leading to their premature death. We conclude that both risk alleles affect similar key cell trafficking pathways, leading to reduced autophagy and suggesting new therapeutic targets to prevent APOL1 kidney diseases.