Background/Aims: The pathophysiology of refractory gastroesophageal reflux disease (RGERD), which differs from proton pump inhibitor dependent gastroesophageal reflux disease (DGERD), remains incompletely elucidated. This study aims to compare esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and reflux profiles between RGERD and DGERD patients, and to delineate dynamic pressure gradient-esophagogastric junction (EGJ) interactions in these patients. Methods: In this retrospective study, 274 patients who underwent 24-hour impedance-pH monitoring and high-resolution manometry, along with an assessment of proton pump inhibitor responsiveness, were classified as RGERD (32.5%), DGERD (54.4%), or non-GERD (13.1%). Clinical characteristics, TPG, esophageal motility, and reflux metrics were compared between RGERD and DGERD patients. Subgroup analysis excluding hiatal hernia (HH) was conducted to investigate the pathophysiology of RGERD. Results: The RGERD group exhibited a significantly higher proportion of chest pain compared to the DGERD group. Regarding reflux profiles, RGERD patients without HH (RGERDHH- group) experienced increased weakly acidic reflux (P < 0.001) and prolonged bolus exposure (P = 0.006) compared to their counterparts (DGERDHH- group). Mechanistically, the RGERDHH- group showed reduced lower esophageal sphincter basal pressure (P = 0.010) and EGJ contractile integral (P = 0.005). Notably, following a wet-swallow, the RGERDHH- group experienced the significant elevation in gastric pressure and TPG. Correlation analyses revealed weakly acidic reflux and bolus exposure were positively correlated with gastric pressure variation, and inversely correlated with lower esophageal sphincter basal pressure. Conclusions Transient gastric pressure elevation and compromised EGJ barrier function drive weakly acidic reflux and esophageal bolus exposure. This pressure gradient-barrier mismatch underpins the refractoriness of RGERD.

Cerebral small vessel disease （CSVD） is a heterogeneous condition affecting small vessels in the brain and is closely associated with cognitive dysfunction， gait abnormalities， and emotional disorder in the elderly. Based on the collateral disease theory of traditional Chinese medicine （TCM）， a "form-function" pathogenesis framework for elderly CSVD is proposed from the perspective of their relationship. In this framework， the "form" refers to the morphological basis of the brain collaterals and sweat pore， while the "function" refers to the activities of qi-blood circulation， nourishment and regulation， as well as the body fluid transportation and distribution； the two are interdependent and jointly maintain the mental activities of the brain. Under this framework， the dynamic pathogenesis evolution patterns of CSVD， namely collateral fragility， collateral rigidity， collateral stagnation， and collateral damage， are systematically explained， revealing the potential mechanisms underlying the transformation of age-related physiological decline of brain collaterals into pathological impairment. This provides a theoretical foundation for the diagnosis and treatment of elderly CSVD with TCM.

Cerebral small vessel disease （CSVD） is a heterogeneous condition affecting small vessels in the brain and is closely associated with cognitive dysfunction， gait abnormalities， and emotional disorder in the elderly. Based on the collateral disease theory of traditional Chinese medicine （TCM）， a "form-function" pathogenesis framework for elderly CSVD is proposed from the perspective of their relationship. In this framework， the "form" refers to the morphological basis of the brain collaterals and sweat pore， while the "function" refers to the activities of qi-blood circulation， nourishment and regulation， as well as the body fluid transportation and distribution； the two are interdependent and jointly maintain the mental activities of the brain. Under this framework， the dynamic pathogenesis evolution patterns of CSVD， namely collateral fragility， collateral rigidity， collateral stagnation， and collateral damage， are systematically explained， revealing the potential mechanisms underlying the transformation of age-related physiological decline of brain collaterals into pathological impairment. This provides a theoretical foundation for the diagnosis and treatment of elderly CSVD with TCM.

Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.
G-Quadruplexes ; Cellular Senescence ; Ribosomes/genetics* ; Humans ; Animals ; Mice ; DEAD-box RNA Helicases/genetics* ; Protein Biosynthesis ; RNA/chemistry* ; Neoplasm Proteins

Objective To develop a diagnostic model combining the CT angiography(CCTA)-derived myocardial radiomics signatures with the CT-derived fractional flow reserve(CT-FFR)based on coronary CCTA and investigate the diagnostic accuracy of the hybrid model for hemodynamically significant coronary artery disease(CAD).Methods The patients presenting stable angina pectoris,diagnosed with CAD,and clinically referred for CCTA examination and invasive coronary angiography were prospectively recruited.Radiomics features of the left ventricular myocardium were extracted from the three main perfusion territories demarcated according to the coronary blood supply.The extracted features were first selected by the minimum redundancy maximum relevance feature ranking method.A least absolute shrinkage and selection operator Logistic regression algorithm with leave-one-out cross-validation was then employed to construct a radiomics model.The CT-FFR value was generated for each blood vessel.The area under the receiver operating characteristics curve(AUC_ROC),sensitivity,and specificity were adopted to evaluate the performance of each model against the reference standard invasive coronary angiography/FFR.Results A total of 70 patients[42 men and 28 women;(61±10) years old] were included in this study and complemented CCTA examination,with 175 vessels and the corresponding myocardial territories undergoing invasive coronary angiography/FFR.A total of 1 656 specific radiomics parameters were extracted,from which 14 features were selected to establish the radiomics model.The AUC_ROC,sensitivity,and specificity were 0.797(95%CI=0.732-0.861),77.1%,and 73.7%for the radiomics model,0.892(95%CI=0.841-0.943),81.4%,and 88.8%for the CT-FFR model,and 0.928(95%CI=0.890-0.965),83.3%,and 88.4%for the hybrid model,respectively.The hybrid model outperformed the radiomics model and CT-FFR alone(P=0.040).Conclusions The radiomics signatures of the vessel-related myocardium from CCTA could provide incremental value to the diagnostic performance of CT-FFR and improve vessel-specific ischemia detection.The hybrid model combining CT-FFR with radiomics signatures is potentially feasible for improving the diagnostic accuracy for hemodynamically significant CAD.
Coronary Angiography/methods* ; Tomography, X-Ray Computed ; Humans ; Hemodynamics ; Coronary Artery Disease/diagnostic imaging* ; Male ; Female ; Middle Aged ; Aged ; Radiomics ; Angina Pectoris/diagnostic imaging* ; China ; Image Processing, Computer-Assisted ; Coronary Vessels/diagnostic imaging*

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

AIM:To investigate the protective ef-fect of sinomenine hydrochloride(SIN)on adjuvant arthritis(AA)rats by regulating the NLRP3/Gasder-min D/Caspase-1/Interleukin-1β pyroptosis path-way.METHODS:Sixty rats were randomly divided into 6 groups,10 rats in each group:Con group(normal rats),AA group(AA rat model),L-SIN group(AA rats were intragastrically administered with 100 mg/kg SIN),M-SIN group(AA rats were intra-gastrically administered with 200 mg/kg SIN),H-SIN group(AA rats were intragastrically administered with 400 mg/kg SIN),ACG group(positive drug group:AA rats were intragastrically administered with 150 mg/kg Wantong Jingu Tablets).Observe the degree of joint swelling and arthritis index.HE was used to observe the pathological changes of the right ankle joint tissue of rats.The levels of in-flammatory factors and oxidative stress-related in-dicators in synovial tissue were detected.Western Blot was used to detect the expression levels of NL-RP3/Gasdermin D/Caspase-1/Interleukin-1β pyrop-tosis pathway-related proteins.RESULTS:Com-pared with Con group,the degree of joint swelling,arthritis index,inflammatory factors and oxidative stress levels,NLRP3,GSDMD,Caspase-1 and IL-1β protein expression levels in AA group were signifi-cantly increased(P<0.05).Compared with AA group,the degree of joint swelling,arthritis index,inflammatory factors and oxidative stress levels,NL-RP3,GSDMD,Caspase-1 and IL-1β protein expres-sion levels were significantly decreased in SIN treat-ment group with the increase of treatment dose(P<0.05).Compared with AA group and L-SIN group,the degree of joint swelling,arthritis index,inflam-matory factors and oxidative stress levels,NLRP3,GSDMD,Caspase-1 and IL-1β protein expression levels in ACG group were significantly decreased(P<0.05).Compared with H-SIN group,the degree of joint swelling,arthritis index,inflammatory factors and oxidative stress levels,NLRP3,GSDMD,Cas-pase-1 and IL-1β protein expression levels in ACG group were significantly increased(P<0.05).CON-CLUSION:SIN can alleviate the inflammatory injury of AA rats and reduce the levels of inflammatory factors and oxidative stress,thus exerting a protec-tive effect on AA rats.The mechanism may be based on the NLRP3/Gasdermin D/Caspase-1/Inter-leukin-1β pyroptosis pathway.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

This article systematically analyzes the scientific connotations of the four core elements of traditional Chinese medicine-natural view,holistic view,epistemology,and methodology-from a modern scientific perspective.By integrating literature analysis with modern scientific research,this study explores the compatibility between the concept of"harmony between heaven and man"in traditional Chinese medicine and the interactive relationship between"human-environment-microorganisms"in modern biology.It analyzes the theoretical value of holistic views such as consistency of form and spirit,and consistency of time and space in systems medicine,clarifies the understanding of the essence of dynamic balance of life by the concept of constant movement and the monism of Qi,as well as the model of the Yin Yang Five Elements system in the human body.Finally,modern interpretations of traditional Chinese medicine methodologies such as taking signs and fortune,syndrome differentiation and treatment,and preventing diseases are provided.This cross temporal theoretical resonance not only verifies the scientific connotation of traditional Chinese medicine theory,but also provides integrated and innovative ideas for modern medicine to understand the human body and diseases.It has important theoretical significance and practical value for promoting the modernization and development of traditional Chinese medicine theory.