Objective: To investigate the association between monocyte to high-density lipoprotein cholesterol ratio (MHR) and periodontitis and to provide new epidemiologic evidence on the factors affecting periodontitis. Methods: Data on MHR, periodontitis, and other covariates were selected from the NHANES(National Health and Nutrition Examination) database for 3 cycles of subjects in 2009-2010, 2011-2012, and 2013-2014, and a total of 8 456 study subjects were included. The study participants were grouped according to the prevalence of periodontitis (presence or absence), and three regression models (unadjusted covariates, partially adjusted covariates, and fully adjusted covariates) were constructed to analyze the relationship between MHR and periodontitis by using a weighted logistic regression method with stepwise adjustment for confounders. MHR was divided into four groups from Q1 to Q4 according to quartiles from small to large for weighted trend analysis, and the nonlinear relationship between MHR (continuous) and periodontitis was analyzed using a restricted cubic spline with subgroup analysis and sensitivity analysis. Results: All three logistic regression models showed a positive association between MHR and periodontitis (OR = 2.92, 95%CI: 2.14-3.99, P<0.001 (not adjusted); OR = 1.97, 95%CI: 1.39-2.78, P<0.001 (partially adjusted); OR = 1.62, 95%CI: 1.10-2.39, P = 0.017 (fully adjusted)). Trend analysis showed a significantly higher risk of developing periodontitis in the Q4 group compared with the Q1 group in both single (OR = 1.92, 95% CI: 1.58-2.33, P<0.001) and multifactorial analyses (OR = 1.30, 95% CI: 1.03-1.64, P = 0.029). Restricted cubic spline results did not support a nonlinear relationship between MHR and periodontitis (P for nonlinear>0.05), subgroup analysis showed no significant interaction between the covariates and MHR (P>0.05), and sensitivity analysis also showed a positive correlation between MHR and periodontitis (OR = 1.67, 95%CI: 1.31-2.14, P<0.001). Conclusion MHR is positively associated with the risk of developing periodontitis.

Background Air pollution and meteorological factors exert complex nonlinear effects on acute symptoms in the population, with intricate interactions among these factors. Traditional statistical methods struggle to simultaneously address complex nonlinear relationships and multicollinearity issues. Objective To delineate the dynamic effects of air pollutants and meteorological parameters on acute symptoms in three distinct populations with the multicollinearity being addressed and to generate reliable scientific evidence for prevention and control of health risk factors. Methods A time-series study design was employed to collect data on air pollution (daily mean temperature, daily precipitation, daily mean relative humidity, and daily mean wind speed), meteorological factors [Air Quality Index (AQI), fine particulate matter (PM_2.5), inhalable particulate matter (PM₁₀), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and 8-hour maximum ozone (O₃)], and acute symptoms such as fever, cough, and sore throat in Jinan from June to December 2023. Key variables were selected using least absolute shrinkage and selection operator (LASSO) regression, followed by generalized additive mixed modeling (GAMM) to analyze the health effects of combined environmental exposures to air pollution and meteorological factors. Linear variables were modeled using linear mixed-effects function, nonlinear variables were smoothed using thin-plate regression splines, and variables with interaction effects were smoothed using low-rank scale-invariant tensor product splines. Fluctuations in independent variables following a normal distribution were treated as sampling errors and incorporated as random effects in the GAMM. Results For fever, the daily mean temperature, daily mean relative humidity, daily mean wind speed, and ambient SO₂ were statistically significant (P<0.05), with daily mean wind speed being a linear influencing factor. When the daily mean temperature was below 3 °C, each 10 °C increase corresponded to a relative risk (RR) of 2.64 (95%CI: 2.50, 2.79). When the daily mean temperature was ≥3 °C, each 10 °C increase corresponded to an RR of 0.86 (95%CI: 0.83, 0.89). Each 10% increase in daily mean relative humidity was associated with an RR of 0.93 (95%CI: 0.89, 0.97). Each 1 m·s⁻¹ increase in daily mean wind speed corresponded to an RR of 1.06 (95%CI: 1.02, 1.10). Within the concentration ranges of <10 μg·m⁻³, 10–<12.5 μg·m⁻³, and ≥12.5 μg·m⁻³, each 1 μg·m⁻³ increase in ambient SO₂ corresponded to RR values of 1.01 (95%CI: 0.98, 1.05), 1.21 (95%CI: 1.17, 1.24), and 0.97 (95%CI: 0.94, 0.99), respectively. For cough, the daily mean temperature, daily mean relative humidity, PM₁₀, and SO₂ were statistically significant (P<0.001), with PM₁₀ being a linear influencing factor. When the daily mean temperature was below 1 °C, each 10 °C increase corresponded to an RR of 1.47 (95%CI: 1.42, 1.52). When the daily mean temperature was ≥1 °C, each 10 °C increase corresponded to an RR of 0.85 (95%CI: 0.82, 0.87). Each 10% increase in daily mean relative humidity was associated with an RR of 0.95 (95%CI: 0.92, 0.98). Each 50 μg·m⁻³ increase in PM₁₀ concentration corresponded to an RR of 1.05 (95%CI: 1.02, 1.08). Within the concentration ranges of <10 μg·m⁻³, 10–<12.5 μg·m⁻³, and ≥ 12.5 μg·m⁻³, each 1 μg·m⁻³ increase in ambient SO₂ corresponded to RR values of 1.00 (95%CI: 0.97, 1.03), 1.12 (95%CI: 1.09, 1.16), and 0.98 (95%CI: 0.95, 1.00), respectively. For sore throat, the daily mean temperature, daily mean relative humidity, daily mean wind speed, PM₁₀, and SO₂ were statistically significant (P<0.05), with daily mean wind speed and PM₁₀ being linear influencing factors. When the daily mean temperature was below 2 °C, each 10 °C increase corresponded to an RR of 1.82 (95%CI: 1.69, 1.96). When the daily mean temperature was ≥2 °C, each 10 °C increase corresponded to an RR of 0.81 (95%CI: 0.77, 0.87). Each 10% increase in daily mean relative humidity was associated with an RR of 0.94 (95%CI: 0.88, 1.00). Within the concentration ranges of <10 μg·m⁻³, 10–<12.5 μg·m⁻³, and ≥12.5 μg·m⁻³, each 1 μg·m⁻³ increase in ambient SO₂ corresponded to RR values of 1.02 (95%CI: 0.97, 1.08), 1.13 (95%CI: 1.08, 1.19), and 0.98 (95%CI: 0.94, 1.02), respectively. Each 1 m·s⁻¹ increase in daily mean wind speed and each 50 μg·m⁻³ increase in PM₁₀ concentration were associated with RR values of 1.06 (95%CI: 1.00, 1.12) and 1.04 (95%CI: 0.98, 1.10), respectively. An interaction effect was observed between daily mean wind speed and PM₁₀: increasing daily mean wind speed non-linearly reduced the impact of PM₁₀, on sore throat whereas PM₁₀ had no significant effect on wind speed. Conclusion This study, by combining LASSO and GAMM, largely eliminates the multicollinearity among selected variables. It reveals complex non-linear effects and interactions between air pollutants, meteorological factors, and acute symptoms in different population groups in Jinan. The symptoms like fever, cough, and sore throat are non-linearly associated with daily mean temperature and SO₂ concentration, while PM₁₀ and wind speed show a linear relationship or interactive effects. These findings provide a new basis for the precise prevention and control of health risk factors.

Algorithmic systems based on artificial intelligence(AI)and machine learning(ML)have undergone rapid advancement in recent years, demonstrating extensive application across diverse ophthalmic disorders. Owing to the public availability of multiple global databases, significant progress has been achieved in the training and development of AI-integrated algorithms utilizing multimodal ophthalmic imaging modalities, including fundus photography and optical coherence tomography(OCT). These advancements have established a foundation for precision medicine and efficient healthcare delivery. The diagnosis of macular diseases relies on the identification of subtle alterations in tissue anatomy, where AI demonstrated exceptional performance in detecting intraocular biomarkers and evaluating anatomical changes during disease progression, with particularly prominent utility in the field of macular pathologies. This article provides a comprehensive review of the current applications of AI in macular diseases, aiming to synthesize existing research achievements and current challenges, while proposing visionary prospects for the broader implementation of AI in ophthalmology and even systemic medicine in the future.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

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