Structural optimization of lead compounds is a crucial step in drug discovery. One optimization strategy is to modify the molecular structure of a scaffold to improve both its biological activities and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. One of the deep molecular generative model approaches preserves the scaffold while generating drug-like molecules, thereby accelerating the molecular optimization process. Deep molecular diffusion generative models simulate a gradual process that creates novel, chemically feasible molecules from noise. However, the existing models lack direct interatomic constraint features and struggle with capturing long-range dependencies in macromolecules, leading to challenges in modifying the scaffold-based molecular structures, and creates limitations in the stability and diversity of the generated molecules. To address these challenges, we propose a deep molecular diffusion generative model, the three-dimensional (3D) equivariant diffusion-driven molecular generation (3D-EDiffMG) model. The dual strong and weak atomic interaction force-based long-range dependency capturing equivariant encoder (dual-SWLEE) is introduced to encode both the bonding and non-bonding information based on strong and weak atomic interactions. Additionally, a gate multilayer perceptron (gMLP) block with tiny attention is incorporated to explicitly model complex long-sequence feature interactions and long-range dependencies. The experimental results show that 3D-EDiffMG effectively generates unique, novel, stable, and diverse drug-like molecules, highlighting its potential for lead optimization and accelerating drug discovery.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Objective: To evaluate the preventive effect of implementing the free influenza vaccination policy on school absence among primary and secondary school students, so as to provide a reference for formulating and adjusting vaccination strategies. Methods: Among primary and secondary school students aged 6 to 18 in Longgang District, Shenzhen, they were divided into a vaccinated group (265 996 students) and an unvaccinated group (122 513 students) according to their influenza vaccination history during November 2023. Propensity score matching was used to conduct a 1∶1 match between the two groups to balance covariates. The number of absences per month was set as the dependent variable to construct a difference in differences model, and Poisson regression was employed to analyze the overall and multi time point effects. Results: Vaccination against influenza was associated with low rate of absenteeism among primary and secondary school students, with an overall preventive effect of 26.52% (95% CI = 23.47% -29.45%). The preventive effects in November (the month of vaccination) and December 2023, January and March 2024 were 42.12%, 40.12%, 30.33% and 20.91%, respectively. The preventive effect of the influenza vaccine on absenteeism among primary school students (26.39%) was not significantly different from that among secondary school students ( 27.97% ) ( P >0.05). The regression coefficient for class vaccination rates ranged from 0.998 to 0.999 ( P <0.01), indicating that for every 10% increase in influenza vaccination rates, absenteeism could be reduced by 1.5% to 2.2%. Conclusion Implementing free influenza vaccination for primary and secondary school students might help to reduce the risk of absenteeism, yielding significant socioeconomic benefits.

Objective To evaluate the cost-effectiveness of roxadustat and darbepoetin alfa on treating renal anemia in dialysis-dependent chronic kidney disease(DD-CKD)patients,thus providing health economics reference for treatment of renal anemia.Methods A Markov model simulating the development and treatment of anemia in DD-CKD patients in a lifetime horizon(20 years)was constructed.Total costs of roxadustat and darbepoetin alfa injection were estimated from the perspective of Chinese healthcare system,with health outcomes converted into quality-adjusted life year(QALY).The incremental cost-effectiveness ratio(ICER)was used to describe the results.The willingness-to-pay(WTP)threshold was set at 257 094 yuan,which was three times China's gross domestic product(GDP)per capita in 2023.Sensitivity analyses were performed to test the uncertainties of the results.Results The total treatment costs of roxadustat and darbepoetin alfa injection were 111 902.41 yuan and 52 927.92 yuan respectively,corresponding to QALY values of 4.76 and 4.74 life-years.The incremental cost-effectiveness(ICER)was 2 654 912.45 yuan/QALY,which exceeded 3 times GDP per capita.Therefore,compared with darbepoetin alfa injection,roxadustat has no cost-effectiveness for patients with DD-CKD.Conclusion In the context of current economic development in China,darbepoetin alfa injection is more cost-effective than roxadustatin for treating anemia in DD-CKD patients.

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility.

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility.

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility.

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility.

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility.

Objective To investigate the medical expense control model of rational drug use based on the China healthcare security diagnosis related groups(CHS-DRG)simulation in Beijing in 2021.Methods By analyzing the simulated operation data from January to March 2021 before the intervention,the groups with rational drug management improving potential among the top three surgical disease groups in terms of the number of cases enrolled in the surgical department were selected.Then,the targeted intervention and guidance were implemented to the selected disease groups.Finally,the analysis was obtained by comparing the changes in several key indicators such as the average drug cost,average antibacterial drug cost,average surplus and average length of stay during June to August 2021.Moreover,the differences in antimicrobial drug use intensity and hospital infection reporting of the department as a whole where the problematic groups were located were also investigated.Results Before the intervention,the otolaryngology related groups(including DD29 and DE19),urology surgery related groups(including LD19 and LJ13)could be improved in antibacterial drug use during the perioperative period.Meanwhile,the chest surgery related group(including EB19)had space to be improved in auxiliary medication.After the intervention,the five groups'average drug cost and average antibacterial drug cost in the otolaryngology and urology surgery departments are all decreased.The antibiotics use intensity is also declined in otolaryngology and urology surgery departments.The average surplus of otolaryngology and urology surgery related groups are increased,with the DE19 disease group in ENT also achieving a profit turnaround.As for the indicators related to the quality of care,there were no significant differences in the groups'average length of stay and nosocomial infection reporting of these departments.Conclusion The hospital operation based on CHS-DRG payment is both an opportunity and a challenge.The all-inclusive payment model has prompted hospitals to take the initiative in controlling costs,and the exploration of a rational medication management and cost-control model related to disease groups has begun to show results in terms of cost reductions without affecting the quality of medical care.The research can also provide a solid foundation for the CHS-DRG actual payment and sustainable development of medical insurance fund.