The association between telomere length and diabetes mellitus: accumulated evidence from observational studies.

OBJECTIVE: In order to assess the associations between telomere length (TL) and diabetes mellitus (DM), especially type 2 diabetes (T2DM), we performed this systematic review and meta-analysis. METHODS: PubMed, Embase, and Web of Science were thoroughly searched up to July 11, 2023. The pooled standardized mean difference (SMD) and the 95% confidence interval (CI) were evaluated using the random-effects model. Age, sex, study design, duration of diabetes, region, sample size, and body mass index (BMI) were used to stratify subgroup analyses. RESULTS: A total of 37 observational studies involving 18,181 participants from 14 countries were included in the quantitative meta-analysis. In this study, patients with diabetes had shorter TL than the non-diabetic, whether those patients had T1DM (-2.70; 95% CI: -4.47, -0.93; P<0.001), T2DM (-3.70; 95% CI: -4.20, -3.20; P<0.001), or other types of diabetes (-0.71; 95% CI: -1.10, -0.31; P<0.001). Additionally, subgroup analysis of T2DM showed that TL was significantly correlated with age, sex, study design, diabetes duration, sample size, detection method, region, and BMI. CONCLUSION: A negative correlation was observed between TL and DM. To validate this association in the interim, more extensive, superior prospective investigations and clinical trials are required.

Racial and social-economic inequalities in systemic chemotherapy use among adult glioblastoma patients following surgery and radiotherapy.

Not all patients with glioblastoma multiforme (GBM) eligible for systemic chemotherapy after upfront surgery and radiotherapy finally receive it. The information on patients with GBM was retrieved from the surveillance, epidemiology, and end results database. Patients who underwent upfront surgery or biopsy and external beam radiotherapy between 2010 and 2019 were eligible for systemic chemotherapy. The available patient and tumor characteristics were assessed using multivariable logistic regression and chi-squared test. Out of the 16,682 patients eligible, 92.1% underwent systemic chemotherapy. The characteristics linked to the lowest systemic chemotherapy utilization included tumors of the brain stem/cerebellum (P = 0.01), former years of diagnosis (P = 0.001), ≥ 80 years of age (P < 0.001), Hispanic, Non-Hispanic Asian, Pacific Islander, or Black race (P < 0.001), non-partnered status (P < 0.001), and low median household income (P = 0.006). Primary tumor site, year of diagnosis, age, race, partnered status, and median household income correlated with the omission of systemic chemotherapy in GBM in adult patients.

Optimization research on multi-trip distribution of reverse logistics terminal for automobile scrap parts under the background of sustainable development strategy.

To effectively solve the reverse logistics distribution problem caused by the increasing number of scrapped parts in the automotive market, this study constructs a multi-trip green vehicle routing problem model with time windows by comprehensively considering the coordination between carbon dioxide emissions and cost efficiency. A hybrid adaptive genetic algorithm is proposed to solve this problem, featuring innovative improvements in the nearest neighbor rule based on minimum cost, adaptive strategies, bin packing algorithm based on the transfer-of-state equation, and large-scale neighborhood search. Additionally, to efficiently obtain location data for supplier factory sites in the distribution network, a coordinate extraction method based on image recognition technology is proposed. Finally, the scientific validity of this study is verified based on the actual case data, and the robust optimization ability of the algorithm is verified by numerical calculations of different examples. This research not only enriches the study of green vehicle routing problems but also provides valuable insights for the industry to achieve cost reduction, efficiency enhancement, and sustainable development in reverse logistics.

Prognostic significance of platelet­to­albumin ratio in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy: a retrospective study of 858 cases.

BACKGROUND: Despite evidence supporting the high correlation of the novel platelet-to-albumin ratio (PAR) with survival in diverse malignancies, its prognostic relevance in nasopharyngeal carcinoma (NPC) remains underexplored. This study aimed to examine the link between PAR and overall survival (OS) in NPC and to establish a predictive model based on this biomarker. METHODS: We retrospectively assembled a cohort consisting of 858 NPC patients who underwent concurrent chemoradiotherapy (CCRT). Utilizing the maximally selected log-rank method, we ascertained the optimal cut-off point for the PAR. Subsequently, univariate and multivariate Cox proportional hazards models were employed to discern factors significantly associated with OS and to construct a predictive nomogram. Further, we subjected the nomogram's predictive accuracy to rigorous independent validation. RESULTS: The discriminative optimal PAR threshold was determined to be 4.47, effectively stratifying NPC patients into two prognostically distinct subgroups (hazard ratio [HR] = 0.53; 95% confidence interval [CI]: 0.28-0.98, P = 0.042). A predictive nomogram was formulated using the results from multivariate analysis, which revealed age greater than 45 years, T stage, N stage, and PAR score as independent predictors of OS. The nomogram demonstrated a commendable predictive capability for OS, with a C-index of 0.69 (95% CI: 0.64-0.75), surpassing the performance of the conventional staging system, which had a C-index of 0.56 (95% CI: 0.65-0.74). CONCLUSIONS: In the context of NPC patients undergoing CCRT, the novel nutritional-inflammatory biomarker PAR emerges as a promising, cost-efficient, easily accessible, non-invasive, and potentially valuable predictor of prognosis. The predictive efficacy of the nomogram incorporating the PAR score exceeded that of the conventional staging approach, thereby indicating its potential as an enhanced prognostic tool in this clinical setting.

A 5' UTR Language Model for Decoding Untranslated Regions of mRNA and Function Predictions.

The 5' UTR, a regulatory region at the beginning of an mRNA molecule, plays a crucial role in regulating the translation process and impacts the protein expression level. Language models have showcased their effectiveness in decoding the functions of protein and genome sequences. Here, we introduced a language model for 5' UTR, which we refer to as the UTR-LM. The UTR-LM is pre-trained on endogenous 5' UTRs from multiple species and is further augmented with supervised information including secondary structure and minimum free energy. We fine-tuned the UTR-LM in a variety of downstream tasks. The model outperformed the best known benchmark by up to 5% for predicting the Mean Ribosome Loading, and by up to 8% for predicting the Translation Efficiency and the mRNA Expression Level. The model also applies to identifying unannotated Internal Ribosome Entry Sites within the untranslated region and improves the AUPR from 0.37 to 0.52 compared to the best baseline. Further, we designed a library of 211 novel 5' UTRs with high predicted values of translation efficiency and evaluated them via a wet-lab assay. Experiment results confirmed that our top designs achieved a 32.5% increase in protein production level relative to well-established 5' UTR optimized for therapeutics.

Efficacy and Safety of Alprostadil in Microcirculatory Disturbances During Emergency PCI: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The clinical advantage of alprostadil [prostaglandin E1 (PGE1)] in the treatment of microcirculatory disturbances (defined as no-reflow or slow-flow) in acute percutaneous coronary intervention (PCI) is still disputed. The purpose of our study was to review the efficacy of PGE1 supplements in patients with acute myocardial infarction (AMI) who had urgent PCI. DESIGN: This study was a meta-analysis of randomized controlled trials. DATA SOURCES: PubMed, Embase, the Cochrane Library, Ovid, ProQuest, Scopus, the Chinese BioMedical Literature Database, China National Knowledge Internet, the China Science and Technology Journal Database, and the Wanfang Data Knowledge Service Platform were used as sources. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomized controlled trials including PGE1 for the treatment of intraoperative microcirculatory disorders and major cardiovascular adverse events in emergency PCI in people with AMI. Independent data extraction was conducted, and study quality was assessed. The meta-analysis was carried out by using random effects models to calculate the risk ratio (RR) of microcirculatory disorders between groups receiving PGE1 and those receiving placebo, nitroglycerin, or tirofiban. MAIN OUTCOME MEASURES: The primary endpoint of the study was the incidence of microcirculatory disturbances. Secondary outcomes included corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), the percentage of patients with TIMI myocardial perfusion grade 3 (TMPG3), and the percentage of patients with myocardial blush grade 3 (MBG3) as efficacy indicators. Additionally, major adverse cardiovascular events (MACE) at 30 days and 180 days were assessed as safety indicators. RESULTS: There were 18 trials involving a total of 1458 participants. PGE1 significantly reduced the occurrence of microcirculation disorders compared with conventional medications and placebo [risk ratio 0.48, 95% confidence interval (CI) 0.36-0.63, I2 = 46%; cTFC (RR -4.74, 95% -6.85 to -2.63, I2 93%); percentage of patients with TMPG3 (RR 1.34, 95% CI 1.07-1.68, I2 70%) or MBG3 (RR 1.33, 95% CI 1.19-1.49, I2 0%); major adverse cardiovascular events (MACEs) in 30 days (RR 0.48, 95% CI 0.27-0.86, I2 0%); and MACEs in 180 days (RR 0.41, 95% CI 0.28-0.60, I2 0%)]. CONCLUSIONS: We found that PGE1 decreased the occurrence of micro-circulation disturbance in AMI and enhanced the outcome of PCI. Additional studies should be conducted to confirm these findings.

Determinants influencing health-promoting behaviors in individuals at high risks of stroke: a cross-sectional study.

Background: Quit smoking, moderate drinking, exercise, and healthy eating habits are all known to decrease the risk of stroke. As a result, understanding the health behaviors of high risk groups for stroke is crucial. Health behavior is influenced by knowledge, social environment, and health beliefs. However, little research has been done on these relationships. For a better grasp of the relationships mentioned above, consider using the COM-B model (capability, opportunity, motivation, and behavior). The purpose of this study was to investigate the variables related to health behavior and to test the mediating effect of health beliefs. Methods: The cross-sectional study was carried out at a physical examination center of a tertiary hospital in Shanghai, China. 986 high-risk populations of stroke have been tested using the Health Behavior Scale (HBS-SP), Stroke Knowledge Questionnaire (SKQ), Health Beliefs Questionnaire (HBS), and Multidimensional Scale of Perceived Social Support (MSPSS). The structural equation modeling was used in this study. Results: The scores for MSPSS, SKQ, HBS, and HBS-SP were 60.64 ± 13.72, 26.60 ± 9.77, 157.71 ± 34.34, and 2.46 ± 0.41, respectively. The revised model fits well (approximate root mean square error = 0.042; comparative fit index = 0.946). The health behavior was obviously and positively correlated to social Support, stroke knowledge, and health beliefs. Moreover, health belief has a mediating effect on the relation of social support, stroke knowledge, and health behavior. Conclusion: Chinese high risk groups for stroke have a mediate level of health behaviors. Factors associated with health behaviors are knowledge of stroke, health beliefs, and social support. The COM-B-based model can be used to explain the health behavior of individuals at risk of stroke and to guide the formulation of effective health management programs.

The role of evidence-based practice and empathy in shared decision-making attitudes among newly graduated nurses: A cross-sectional study.

AIM: Examine the levels of variables and explore drivers associated with shared decision-making attitudes among newly graduated nurses. DESIGN: This was a descriptive and cross-sectional study. METHODS: From August 2022 to October 2022, a cross-section of 216 newly graduated nurses from four comprehensive A-level hospitals in northern China was recruited using convenience sampling. Newly graduated nurses are generally defined as nurses with a service period of six months to one year. Data were collected using an online questionnaire support platform, including the Nursing Shared Decision-Making Attitude scale, Jefferson scale of Empathy-Health profession students and the Health Sciences Evidence-Based Practice questionnaire. All data were analysed descriptively, and correlational analysis and hierarchical regression were used to make identical connections between variables. RESULTS: Newly graduated nurses supported shared decision-making. Perceptions of shared decision-making were correlated with the experiences of empathy and evidence-based practice. Additionally, perspective-taking of empathy and beliefs, and the ability to search for and apply existing scientific findings of evidence-based practice had a significant impact on more positive attitudes. CONCLUSION: The survey showed that acceptance of shared decision-making was positive among newly graduated nurses. Clinical nursing managers and teachers should pay attention to cultivating the evidence-based practice and empathy of newly graduated nurses to adopt an optimistic attitude towards shared decision-making in the long term. IMPACT: The survey addresses attitudes of shared decision-making among newly graduated nurses and determines whether empathy and evidence-based practice has an impact on it. The main finding is that newly graduated nurses have an optimistic outlook on the implementation of shared decision-making. This survey showed that empathy and evidence-based practice competencies are associated with shared decision-making attitudes among newly graduated nurses. The results of this survey have an impact on educational institutions and hospitals in the form of recommendations. Several training programmes on empathy and evidence-based practice can help adopt the shared decision-making attitudes of newly graduated nurses. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study.

Background: Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships. Methods: Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables' (IVs) assumptions. Results: Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], p = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy. Conclusion: Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.

An Au bipyramids@CuZn MOF core-shell nanozyme enables universal SERS and a colorimetric dual-model bioassay.

In this study, a new type of gold nano-bipyramids@CuZn bimetallic organic framework (AuNBPs@CuZn MOF) nanozyme with high peroxidase (POD)-like activity and surface enhanced Raman scattering (SERS) activity was constructed with a special core-shell structure, which can catalyze the oxidation of TMB (colourless and Raman-inactive) into ox-TMB (blue and Raman-active). An AuNBPs@CuZn MOF-enabling universal SERS and colorimetric dual-model bioassay was thus developed for biomolecules with excellent performance, and has promising application prospects in the biosensing fields.

Surface Modification of Polyimide Aerogel by Thermoplastic Polyurethane for Enhanced Mechanical Strength and Thermal Insulation Performance.

Polyimide (PI) aerogel is a good thermal insulation material with the highest temperature resistance in practical application. But the mechanical strength of PI aerogels prepared by freeze-drying or thermoimide methods is weak. In this research, TPU was selected as an aging solution to solve the problem of the low mechanical strength of PI aerogel prepared by the freeze-drying method. Previous work has certified that the coupling of PI and thermoplastic polyurethane (TPU) can enhance the mechanical strength of PI aerogel to a certain extent due to the flexibility of TPU. But excessive TPU will change the PI structure in the cross-linking process and decrease the mechanical strength of the aerogel. Thus, a new kind of PI gel modification method was provided by using TPU as an aging solution, and the mechanical strength of PI aerogel is improved to 3.06 MPa. Furthermore, the shrinkage, specific surface area, waterproof angle, and thermal conductivity all show good performance, thus enabling PI aerogel to be used in many aspects. Specially, the method is simple and can be used to prepare some other high-strength aerogels.

Mesenchymal stem cell-derived extracellular vesicles relieve endothelial cell senescence via recovering CTRP9 upon repressing miR-674-5p in atherosclerosis.

Background: The senescence of endothelial cells is of great importance involving in atherosclerosis (AS) development. Recent studies have proved the protective role of mesenchymal stem cell-derived extracellular vesicles in AS, herein, we further desired to unvei their potential regulatory mechanisms in endothelial cell senescence. Methods: Senescence induced by H2O2 in primary mouse aortic endothelial cells (MAECs) was evaluated by SA-ß-gal staining. Targeted molecule expression was detected by qRT-PCR and Western blotting. The biological functions of MAECs were determined by CCK-8, flow cytometry, transwell, and tube formation assays. Oxidative injury was assessed by LDH, total and lipid ROS, LPO and MDA levels. The proliferation of adipose-derived mesenchymal stem cell (ADSCs) was analyzed by EdU assay. Effect of ADSCs-derived extracellular vesicles (ADSC-EVs) on AS was investigated in HFD-fed ApoE-/- mice. Results: miR-674-5p was up-regulated, while C1q/TNF-related protein 9 (CTRP9) was down-regulated in H2O2-induced senescent MAECs. CTRP9 was demonstrated as a target gene of miR-674-5p. miR-674-5p inhibition restrained senescence, oxidative stress, promoted proliferation, migration, and angiogenesis of H2O2-stimulated MAECs via enhancing CTRP9 expression. Moreover, treatment with ADSC-EVs inhibited H2O2-induced senescence and dysfunction of MAECs through regulating miR-674-5p/CTRP9 axis. In the in vivo AS mouse model, ADSC-EVs combination with miR-674-5p silencing slowed down AS progression via up-regulation of CTRP9. Conclusion: ADSC-EVs repressed endothelial cell senescence and improved dysfunction via promotion of CTRP9 expression upon miR-674-5p deficiency during AS progression, which might provide vital evidence for ADSC-EVs as a promising therapy for AS.

Deep reinforcement learning identifies personalized intermittent androgen deprivation therapy for prostate cancer.

The evolution of drug resistance leads to treatment failure and tumor progression. Intermittent androgen deprivation therapy (IADT) helps responsive cancer cells compete with resistant cancer cells in intratumoral competition. However, conventional IADT is population-based, ignoring the heterogeneity of patients and cancer. Additionally, existing IADT relies on pre-determined thresholds of prostate-specific antigen to pause and resume treatment, which is not optimized for individual patients. To address these challenges, we framed a data-driven method in two steps. First, we developed a time-varied, mixed-effect and generative Lotka-Volterra (tM-GLV) model to account for the heterogeneity of the evolution mechanism and the pharmacokinetics of two ADT drugs Cyproterone acetate and Leuprolide acetate for individual patients. Then, we proposed a reinforcement-learning-enabled individualized IADT framework, namely, I$^{2}$ADT, to learn the patient-specific tumor dynamics and derive the optimal drug administration policy. Experiments with clinical trial data demonstrated that the proposed I$^{2}$ADT can significantly prolong the time to progression of prostate cancer patients with reduced cumulative drug dosage. We further validated the efficacy of the proposed methods with a recent pilot clinical trial data. Moreover, the adaptability of I$^{2}$ADT makes it a promising tool for other cancers with the availability of clinical data, where treatment regimens might need to be individualized based on patient characteristics and disease dynamics. Our research elucidates the application of deep reinforcement learning to identify personalized adaptive cancer therapy.

Design, synthesis and biological evaluation of quinazoline and pyrrolo[3,2-d]pyrimidine derivatives as TLR7 agonists for antiviral agents.

Pattern recognition receptors (PRRs) play a critical role in the innate immune response, and toll-like receptor 7 (TLR7) is an important member of PRRs. Although several TLR7 agonists are available, most of them are being tested clinically, with only one available on the market. Thus, it is imperative to develop new TLR7 agonists. In this study, we designed and synthesized three kinds of quinazoline derivatives and five kinds of pyrrolo[3,2-d]pyrimidine derivatives targeting TLR7. The antiviral efficacy of these compounds was evaluated in vitro and in vivo. Our findings indicated that four kinds of compounds showed exceptional antiviral activity. Furthermore, molecular docking studies confirmed that compound 11 successfully positioned itself in the pocket of the TLR7 guanosine loading site with a binding energy of -4.45 kcal mol-1. These results suggested that these compounds might be potential antiviral agents.

Effect of Intraorbital Mechanical Compression on Retinal Microvascular Perfusion in Quiescent Thyroid-Associated Ophthalmopathy Based on Ocular Biomechanics Measured by Corvis ST.

INTRODUCTION: To analyze the correlation between orbital compliance and retinal vessel density (VD) based on dynamic Scheimpflug analyzer (Corvis ST) and optical coherence tomographic angiography (OCT-A). METHODS: In this prospective observational study, 65 eyes of 44 patients with thyroid-associated ophthalmopathy (TAO) in quiescent stage were included (15 males and 29 females). The whole eye movement (WEM) was detected by Corvis ST. The superficial capillary plexus VD (SCP-VD) and deep capillary plexus VD (DCP-VD) were obtained by scanning the 3 × 3 mm area around the fovea using OCT-A, while the peripapillary vessel density (ppVD) was obtained by scanning the 4.5 × 4.5 mm area around the optic disk. Covariances including biomechanically corrected intraocular pressure (bIOP), axial length, age and gender were adjusted during data analysis. RESULTS: The mean WEM of the participants was 0.235 ± 0.066 mm. The mean SCP-VD and DCP-VD in whole image were 46.20% ± 3.77% and 50.51% ± 3.96%; the mean whole pp-VD was 49.75% ± 2.01%. WEM was positively correlated with SCP-VD (r = 0.327, p = 0.01) and the whole pp-VD (r = 0.394, p < 0.01) after adjusting by gender, axial length (AL), age and bIOP, but it was not significantly correlated with DCP-VD (r = 0.072 p = 0.581). CONCLUSION: Increase in orbital pressure might reduce retinal microvascular perfusion. Our data suggest orbital mechanical compression may be an important cause of retinal VD changes in quiescent patients with TAO.

Comprehensive Analysis of 11 Species of Euodia (Rutaceae) by Untargeted LC-IT-TOF/MS Metabolomics and In Vitro Functional Methods.

The Euodia genus comprises numerous untapped medicinal plants that warrant thorough evaluation for their potential as valuable natural sources of herbal medicine or food flavorings. In this study, untargeted metabolomics and in vitro functional methods were employed to analyze fruit extracts from 11 significant species of the Euodia genus. An investigation of the distribution of metabolites (quinolone and indole quinazoline alkaloids) in these species indicated that E. rutaecarpa (Euodia rutaecarpa) was the most widely distributed species, followed by E. compacta (Euodia compacta), E. glabrifolia (Euodia glabrifolia), E. austrosinensis (Euodia austrosinensis), and E. fargesii (Euodia fargesii). There have been reports on the close correlation between indole quinazoline alkaloids and their anti-tumor activity, especially in E. rutaecarpa fruits which exhibit effectiveness against various types of cancer, such as SGC-7901, Hela, A549, and other cancer cell lines. Additionally, the E. rutaecarpa plant contains indole quinazoline alkaloids, which possess remarkable antibacterial properties. Our results offer novel insights into the utilization of Euodia resources in the pharmaceutical industry.

Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

Microstructure Formation and Characterization of Long-Acting Injectable Microspheres: The Gateway to Fully Controlled Drug Release Pattern.

Long-acting injectable microspheres have been on the market for more than three decades, but if calculated on the brand name, only 12 products have been approved by the FDA due to numerous challenges in achieving a fully controllable drug release pattern. Recently, more and more researches on the critical factors that determine the release kinetics of microspheres shifted from evaluating the typical physicochemical properties to exploring the microstructure. The microstructure of microspheres mainly includes the spatial distribution and the dispersed state of drug, PLGA and pores, which has been considered as one of the most important characteristics of microspheres, especially when comparative characterization of the microstructure (Q3) has been recommended by the FDA for the bioequivalence assessment. This review extracted the main variables affecting the microstructure formation from microsphere formulation compositions and preparation processes and highlighted the latest advances in microstructure characterization techniques. The further understanding of the microsphere microstructure has significant reference value for the development of long-acting injectable microspheres, particularly for the development of the generic microspheres.

Compressive stress gradients direct mechanoregulation of anisotropic growth in the zebrafish jaw joint.

Mechanical stimuli arising from fetal movements are critical factors underlying joint growth. Abnormal fetal movements negatively affect joint shape features with important implications for joint health, but the mechanisms by which mechanical forces from fetal movements influence joint growth are still unclear. In this research, we quantify zebrafish jaw joint growth in 3D in free-to-move and immobilised fish larvae between four and five days post fertilisation. We found that the main changes in size and shape in normally moving fish were in the ventrodorsal axis, while growth anisotropy was lost in the immobilised larvae. We next sought to determine the cell level activities underlying mechanoregulated growth anisotropy by tracking individual cells in the presence or absence of jaw movements, finding that the most dramatic changes in growth rates due to jaw immobility were in the ventrodorsal axis. Finally, we implemented mechanobiological simulations of joint growth with which we tested hypotheses relating specific mechanical stimuli to mechanoregulated growth anisotropy. Different types of mechanical stimulation were incorporated into the simulation to provide the mechanoregulated component of growth, in addition to the baseline (non-mechanoregulated) growth which occurs in the immobilised animals. We found that when average tissue stress over the opening and closing cycle of the joint was used as the stimulus for mechanoregulated growth, joint morphogenesis was not accurately predicted. Predictions were improved when using the stress gradients along the rudiment axes (i.e., the variation in magnitude of compression to magnitude of tension between local regions). However, the most accurate predictions were obtained when using the compressive stress gradients (i.e., the variation in compressive stress magnitude) along the rudiment axes. We conclude therefore that the dominant biophysical stimulus contributing to growth anisotropy during early joint development is the gradient of compressive stress experienced along the growth axes under cyclical loading.

Decoding the spatiotemporal regulation of transcription factors during human spinal cord development.

The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10× Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.