Objective　To analyze the monitoring data of SARS-CoV-2 variants from local cases in Hainan Province between January 2023 and March 2024, and to understand the predominant variants epidemic situation and population characteristics of SARS-CoV-2 in Hainan Province, providing scientific guidance for the prevention and control strategies formulation, early warning of the risk of SARS-CoV-2 infection. Methods　The variation surveillance data submitted by five sentinel monitoring hospitals in Hainan Province from January 2023 to March 2024 were collected, and general descriptive analysis was conducted on the dynamic epidemic trend of the dominant clade, population characteristics, and disease severity. Results　From January 2023 to March 2024, a total of 2 600 local cases clade information in Hainan Province were collected, all of which were Omicron variant strains involving 115 evolutionary branches. The three phases identified include: the co-dominance of BA.5.2.48 and BF.7 from the first week of 2023 to the 13th week of 2024; the prevalence of XBB and its subclades from the 16th to the 52nd week of 2023; and the predominance of BA.2.86 and its subclades from the first to the 13th week of 2024, with Omicron BA.2.75 causing small-scale sporadic outbreaks. Among all the age groups of branch infection cases, individuals aged >18~60 years constituted the largest group, while those under 4 years were the smallest, with no significant gender differences. The severity of the clinical disease was mainly asymptomatic and mild. Conclusions　Different dominant evolutionary clades of SARS-CoV-2 showed sequential replacement characteristics, and the clinical severity of illnesses has gradually decreased. In the future, the focus should be on individuals aged >60 years and above and those aged >18~60 years with underlying conditions, along with continuous enhancement of variant monitoring and analysis. This will ensure a timely understanding of the dynamic epidemic trend of dominant evolutionary clades in time, and focus on the immunogenicity of the new variant branch and changes in immunogenicity and vaccine protection of new variant clades, providing scientific guidance for the vaccine research, clinical treatment, and immunization strategy formulation.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

Osteoporosis(OP) is a metabolic bone disorder characterized by reduced bone mass and degenerative bone tissue. Osteoporotic pain(OPP) is its most common clinical symptom, significantly affecting the quality of life of patients. With the limitations of modern medical treatments and the intensification of aging, it is imperative to explore more cost-effective interventions for OPP. This paper, based on databases such as China National Knowledge Infrastructure(CNKI), VIP, Wanfang, BioMed, and Web of Science, uncovered the connection between the pathogenesis of OPP in traditional Chinese medicine(TCM) and modern medical mechanisms and retrospectively summarized the basic and clinical research methods and evidence of TCM prescriptions in the treatment of OP and related pain diseases. Studies have shown that TCM prescriptions, focusing on treatments such as nourishing the kidney, strengthening the spleen, and activating blood circulation to remove blood stasis, can significantly improve pain symptoms, increase bone mineral density(BMD), and adjust bone metabolic indicators such as C-terminal telopeptide of type Ⅰ collagen(CTX), serum bone Gla-protein(S-BGP), and alkaline phosphatase(ALP). The mechanisms of action of TCM prescriptions in treating OP and improving OPP symptoms were related to signaling pathways such as Wnt/β-catenin, nuclear factor kappa-B(NF-κB), mitogen-activated protein kinase(MAPK), phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt), and the osteoprotegerin(OPG)/receptor activator of NF-κB(RANK)/receptor activator of NF-κB ligand(RANKL) axis. Further strengthening the accumulation and analysis of clinical data, rigorously designing and conducting randomized controlled trials of TCM treatments for OPP with large sample sizes, standardizing outcome measures in basic and clinical research by using methods such as the core outcome set(COS), and incorporating mass spectrometry and omics approaches to uncover more potential active components and mechanisms may contribute to a deeper exploration of the advantages and essence of TCM prescriptions in the treatment of OPP.
Humans ; Osteoporosis/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Retrospective Studies ; Bone Density/drug effects* ; Medicine, Chinese Traditional ; Pain/metabolism* ; Animals

Objective:To investigate the protective effect of lovastatin on liver injury in the rats induced by hyperlipidemia,and to elucidate its possible mechanism.Methods:Fifteen SD rats were randomly divided into control group,hyperlipidemia model group,and lovastatin group,with 5 rats in each group.The rats in control group were fed with standard diet,while the rats in hyperlipidemia model group and lovastatin group were fed high-fat diet for 12 weeks.Starting from the 8th week,the rats were administered treatments via gavage once a day for 4 weeks:the rats in lovastatin group received 2 mng·kg-1 lovastatin,while the rats in control group and hyperlipidemia model group received an equal volume of normal saline.The body weights of the rats in various groups were measured at weeks 1,8,9,10,11,and 12 after the experiment began;the histopathology of liver tissue of the rats in various groups was observed using HE staining;the serum levels of total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),malondialdehyde(MDA),as well as the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),and the levels of interleukin-2(IL-2),interleukin-6(IL-6),interleukin-12(IL-12),and tumor necrosis factor-a(TNF-α)of the rats in various groups were detected using commercial kits;the composition of the gut microbiota of the rats in various groups was analyzed by 16S rRNA sequencing.Results:Compared with control group,the body weight of the rats in hyperlipidemia model group was significantly increased from the 8th week of high-fat diet feeding(P＜0.05 or P＜0.01 or P＜0.001).Compared with hyperlipidemia model group,the body weight of the rats in lovastatin group was significantly decreased at weeks 11 and 12(P＜0.05).Compared with control group,the livers of the rats in hyperlipidemia model group appeared rough,pale,enlarged,with blunt edges,and had a granular and greasy texture.Compared with hyperlipidemia model group,the livers of the rats in lovastatin group were light brownish-red,soft,with slightly blunt edges,reduced volume,and less granularity and greasiness.Compared with control group,the liver cells of the rats in hyperlipidemia model group were swollen and disorganized,with pyknotic nuclei,extensive inflammatory cell infiltration,and numerous vacuolar degenerations.Compared with hyperlipidemia model group,the rats in lovastatin group showed significantly reduced hepatocyte swelling and degeneration,more orderly and intact liver cell arrangement,decreased inflammatory cell infiltration,and reduced vacuolar degeneration.Compared with control group,the serum levels of TC,TG,and LDL-C of the rats in hyperlipidemia model group were significantly increased(P＜0.05),and the serum HDL-C level was decreased(P＜0.05).Compared with hyperlipidemia model group,the serum levels of TC,TG,and LDL-C of the rats in lovastation group were significantly decreased(P＜0.05),and the serum HDL-C level was increased(P＜0.05).Compared with control group,the serum MDA levels and the ALT and AST activities of the rats in hyperlipidemia model group were significantly increased(P＜0.05),and the SOD and GSH-Px activities were significantly decreased(P＜0.05).Compared with hyperlipidemia model group,the serum MDA levels and ALT and AST activities of the rats in lovastatin group were decreased(P＜0.05),and the SOD and GSH-Px activities were increased(P＜0.05).Compared with control group,the serum levels of IL-2,IL-6,IL-12,and TNF-α of the rats in hyperlipidemia model group were significantly increased(P＜0.05).Compared with hyperlipidemia model group,the serum levels of IL-2,IL-6,IL-12,and TNF-α of the rats in lovastatin group were significantly decreased(P＜0.05).Compared with control group,the ACE and Chao1 indexes of the rats in hyperlipidemia model group were significantly decreased(P＜0.05).Compared with hyperlipidemia model group,the ACE and Chao1 indexes of the rats in lovastatin group were significantly increased(P＜0.05 or P＜0.01).Compared with control group,the relative abundances of Firmicutes and Proteobacteria of the rats in hyperlipidemia model group were significantly increased(P＜0.001),and the relative abundances of Bacteroidetes and Actinobacteria were decreased(P＜0.001).Compared with hyperlipidemia model group,the relative abundances of Firmicutes and Proteobacteria of the rats in lovastatin group were significantly decreased(P＜0.05 or P＜0.01),while the relative abundances of Bacteroidetes and Actinobacteria showed no significant changes.Compared with control group,the relative abundance of Lactobacillus of the rats in hyperlipidemia model group was significantly decreased(P＜0.001),and the relative abundances of Bacteroides,Desulfovibrio,and Clostridium were significantly increased(P＜0.01 or P＜0.001).Compared with hyperlipidemia model group,the relative abundance of Lactobacillus of the rats in lovastatin group showed no significant change but the relative abundances of Bacteroides,Desulfovibrio,and Clostridium were significantly decreased(P＜0.05 or P＜0.01 or P＜0.001).Conclusion:Lovastatin ameliorates liver injury induced by hyperlipidemia,and the mechanism may be related to its ability to improve gut microbiota composition and inhibit oxidative stress and inflammatory damage.

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*

It is believed that the root cause of vascular dementia lies in insufficient primal yang and weakness in the circulation of blood. The key pathological factors are the mutual stagnation of phlegm and blood stasis， and the obstruction of blood vessels. The general treatment principle is to tonify qi and promote yang， expel pathogenic factors， and unblock yang. This involves supplementing the innate and acquired yang qi of the spleen and kidneys， removing pathogenic factors like phlegm， turbidity， and blood stasis， in order to restore the function of yang qi and promote the circulation of blood and qi. The basic prescription for tonifying qi and promoting yang includes Heishunpian （Lycium Ruthenicum）， Zhichuanwu （Aconitum Carmichaelii）， Guizhi （Cinnamomum Cassia）， Renshen （Panax Ginseng）， and Huangqi （Astragalus Membranaceus）. Depending on the type of pathogenic excess， the treatment can be modified with Tongqiao Huoxue Decoction （通窍活血汤）， adding Yujin （Curcuma Longa） and Xiangfu （Cyperus Rotundus） to invigorate blood and promote yang， or with Fabanxia （Pinellia Ternata）， Chenpi （Citrus Reticulata）， Zhishi （Citrus Aurantium） plus Sijunzi Decoction （四君子汤） to resolve phlegm and promote yang. Both the root and branch are treated simultaneously. When yang qi is activated， blood and qi are nourished， and when pathogenic excess is expelled， the blood vessels are unblocked. This approach aims to provide a treatment strategy for vascular dementia.

Image 1.

Objective:To investigate ⅰ)the therapeutic effects of different doses of recombinant human prourokinase(rh-proUK)on patients with ST segment elevation myocardial infarction(STEMI)undergoing percutaneous coronary inter-vention(PCI),and ⅱ)its impact on peripheral blood P-selectin(CD62p)and Adropin levels.Methods:This randomized control study enrolled 132 STEMI patients undergoing PCI in Weinan Second Hospital between June 2020 and June 2023.Patients were randomly divided into control group(n=44,routine medication),low dose group(n=44,10 mg rh-proUK therapy)and high dose group(n=44,20 mg rh-proUK therapy).Therapeutic effective rate,myocardial perfu-sion immediate after operation,cardiac function,peripheral blood CD62p and Adropin levels,incidence of major adverse cardiovascular events(MACE)within 1 month after operation were compared among three groups.Results:Compared to patients in control group,those in high dose group had significantly higher total effective rate(95.5％vs.54.6％),pro-portions of TIMI myocardial perfusion grade(TMPG)grade 3(86.4％vs.25.0％)and ST segment resolution above 30％(∑STR≥30％)(88.6％vs.59.1％),stroke volume(SV)[(76.81±24.47)ml vs.(61.89±14.84)ml]and cardiac output(CO)[(6.48±1.45)L/min vs.(5.48±1.98)L/min],and significantly lower corrected TIMI frame count(CT-FC)[(31.80±6.32)frames vs.(52.39±7.14)frames],CD62p[(70.52±9.54)％vs.(82.42±12.44)％],Adropin[(82.48±9.55)pg/ml vs.(94.48±10.53)pg/ml]and total incidence of MACE(9.1％vs.38.6％)(P＜0.05 or＜0.01).Compared to those in low dose group,patients in high dose group had significantly higher total effective rate,pro-portions of TMPG grade 3 and ∑STR≥30％,SV and CO,and significantly lower CTFC,CD62p,Adropin and total inci-dence of MACE(P＜0.05 or＜0.01).Conclusion:The therapeutic effect of 20 mg rh-proUK on STEMI patients under-going PCI is significantly better than that of 10 mg,which could improve cardiac function,reduce CD62p,Adropin levels,and incidence of major adverse cardiovascular events.

Objective:To explore the value of metanephrine, normetanephrine, and some steroid hormones in the assessment of adrenal venous sampling (AVS).Methods:This retrospective study enrolled 101 patients with primary aldosteronism who underwent AVS at Peking Union Medical College Hospital between June 1, 2021, and October 1, 2024. Multiple hormones, including aldosterone, cortisol, metanephrine, normetanephrine and steroid hormone profiles, were measured in samples from the inferior vena cava and bilateral adrenal veins during AVS. Selectivity index and lateralization index were calculated based on the levels of different hormones to determine successful AVS cannulation (selectivity index≥2) and aldosterone hypersecretion lateralization (lateralization index≥2). Patients who underwent unilateral adrenalectomy were followed for at least 6 months. Clinical and biochemical outcomes were assessed according to the Primary Aldosteronism Surgical Outcome (PASO) criteria, with biochemical remission defined as achieving complete or partial biochemical remission postoperatively. The efficacy of different hormones relative to cortisol for calculating selectivity index and lateralization index was evaluated for subtype classification.Results:The age at diagnosis of the enrolled patients was (50.5±9.6) years, including 77 males. Regarding the selectivity index, five hormones including metanephrine, normetanephrine, androstenedione, 17α-hydroxypregnenolone, and dehydroepiandrosterone demonstrated significantly higher selectivity index compared to cortisol (all P<0.05). Based on the cortisol-derived selectivity index, AVS cannulation was unsuccessful in 8 patients; using the five indices, unsuccessful cannulation occurred in 2, 2, 3, 4, and 5 patients, respectively. Based on postoperative follow-up, 55 patients were identified as having unilateral surgically relievable primary aldosteronism. In identifying these patients, the performance of metanephrine, normetanephrine, androstenedione, 17α-hydroxypregnenolone, and dehydroepiandrosterone was non-inferior to cortisol, correctly identifying 95% (52/55), 93% (51/55), 91% (50/55), 87% (48/55), and 89% (49/55) of cases, respectively. However, among these patients, there were no statistically significant differences in the success rate of intubation in AVS and the ability to identify patients with unilateral primary aldosteronism between the five indicators and cortisol (all P>0.05). Using cortisol-based lateralization as the reference standard, androstenedione and dehydroepiandrosterone both achieved an accuracy of 90% (84/93) for determining the lateralized side, while 17α-hydroxypregnenolone, normetanephrine, and metanephrine achieved accuracies of 89% (83/93), 81% (74/93), and 80% (73/93), respectively. Conclusion:Metanephrine, normetanephrine, androstenedione, 17α-hydroxypregnenolone and dehydroepiandrosterone could increase the success rate of intubation in AVS, with a high ability to identify patients with unilateral primary aldosteronism, and are expected to replace cortisol as new indicators of AVS.

This study analyzed the genetic evolutionary characteristics of sandflies and their effects on the spread of kala-azar in various environments in endemic provinces in China,to provide a scientific basis for kala-azar disease prevention and control.Sand-flies were collected in kala-azar endemic areas such as southern Xinjiang,the large hilly areas of southern Gansu,the northern Sich-uan and Taihang Mountains,and surrounding small hills.The cytochrome c oxidase subunit I and cytochrome b gene fragments of mito-chondrial DNA were amplified to identify sandfly species.The COI and Cytb gene sequences of sandflies from southern Xinjiang and Si-chuan recorded in NCBI were also collected.The intraspecific and interspecific genetic differences of sandflies were calculated in MEGA11.0,and a phylogenetic tree was constructed through the neighbor-joining method,for analysis of the genetic and evolutionary characteristics of sandfly populations and their effects on disease transmission.A total of 155 sandflies were collected from nine sam-pling sites in seven provinces of China;the species included Phlebotomus chinensis,Phlebotomus wui,and Sergentomyia squamirostris.Five sandfly species belonging to two genera were collected:P.chinensis,P.wui,and Phlebotomus alexandri in the genus Phleboto-mus,and S.squamirostris in the genus Sergentomyia.Genetic evolution analysis based on COI and Cytb gene sequences indicated intra-specific genetic distances of 0-0.062 and 0-0.056,respectively,and interspecific genetic distances of 0.126-0.176 and 0.110-0.171,respectively.The phylogenetic tree indicated that P.wui,P.alexandri,Phlebotomus longiductus,and S.squamirostris clus-tered into one branch.The sequences of P.chinensis in the large and small hilly areas clustered into two geographical clades.In the small hilly areas,the sequences of P.chinensis aggregates showed small genetic differences,the pathogen infection was consistent,and the cases showed an epidemic spread trend.Large genetic differences at the molecular level were observed among sandflies in dif-ferent ecological regions,thus indicating key effects on leishmaniasis transmission.On the basis of these findings,prevention and con-trol strategies should be adapted to local conditions,and precise and effective prevention and control measures should be formulated according to the genetic evolution characteristics of sandflies in different regions,to better control the transmission of Kala-azar.