Ethylene signals modulate the survival of Arabidopsis leaf explants.

BACKGROUND: Leaf explants are major materials in plant tissue cultures. Incubation of detached leaves on phytohormone-containing media, which is an important process for producing calli and regenerating plants, change their cell fate. Although hormone signaling pathways related to cell fate transition have been widely studied, other molecular and physiological events occurring in leaf explants during this process remain largely unexplored. RESULTS: Here, we identified that ethylene signals modulate expression of pathogen resistance genes and anthocyanin accumulation in leaf explants, affecting their survival during culture. Anthocyanins accumulated in leaf explants, but were not observed near the wound site. Ethylene signaling mutant analysis revealed that ethylene signals are active and block anthocyanin accumulation in the wound site. Moreover, expression of defense-related genes increased, particularly near the wound site, implying that ethylene induces defense responses possibly by blocking pathogenesis via wounding. We also found that anthocyanin accumulation in non-wounded regions is required for drought resistance in leaf explants. CONCLUSIONS: Our study revealed the key roles of ethylene in the regulation of defense gene expression and anthocyanin biosynthesis in leaf explants. Our results suggest a survival strategy of detached leaves, which can be applied to improve the longevity of explants during tissue culture.

Acquired susceptibility to autoimmune diseases in pediatric patients with Escherichia coli infection: A population-matched retrospective cohort study.

BACKGROUND: Escherichia coli (E.coli) infection has been proposed to play an important role as an initial trigger in the development of autoimmunity via molecular mimicry. However, there has been no preliminary cohort study to establish the association of E.coli infection with autoimmune diseases. Therefore, we conducted a large scale, population-matched cohort study to determine the risk of autoimmune disease among patients with exposure to E.coli. METHODS: Utilizing the National Health Insurance Service database, we retrospectively analyzed a total of 259,875 Korean children that consisted of 23,625 exposed and 236,250 unexposed persons from January 1, 2002 to December 31, 2017. The exposed cohort was defined as patients diagnosed with E.coli infection. Unexposed controls were matched by birth year and sex at a 1:10 ratio for each exposed patient, using incidence density sampling. The primary outcome was autoimmune disease development. We used the Cox model to estimate the risks of autoimmune diseases among patients diagnosed with E.coli infection. RESULTS: Over a mean follow-up of 10 years, there were 1455 autoimmune disease cases among exposed patients (incidence rate, 63.6 per 10,000 person-years) and 11,646 autoimmune disease cases among unexposed persons (incidence rate, 50.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.254 (95% CI 1.187-1.325). E.coli infection was associated with increased risks of autoimmune diseases; Reactive arthritis, HR 1.487, 95% CI 1.131-1.956; Henoch Schönlein purpura, HR 1.265, 95% CI 1.050-1.524; Systemic lupus erythematosus, HR 1.838, 95% CI 1.165-2.898; Sjögren's syndrome, HR 2.002, 95% CI 1.342-2.987; IgA nephropathy, HR 1.613, 95% CI 1.388-1.874. Kaplan-Meier cumulative incidence curves also showed a significant association between E.coli infection and incident autoimmune disease (p < 0.0001). This relationship was not only independent of demographic variables, but also remained consistent across various sensitivity analyses. On the other hand, patients with longer hospital stay for E.coli infection were at a higher risk of autoimmune disease (p = 0.0003), and the risk of autoimmune disease also tended to increase, as the frequency of E.coli infection was higher. Moreover, the relative risk of autoimmune disease seemed to be attenuated by use of antibiotics and a history of intestinal infectious disease, but elevated by coexistence of other autoimmune diseases. CONCLUSIONS: Our cohort study indicates that E.coli infection was significantly associated with increased susceptibility to autoimmune diseases, even after adjusting for different factors. Thus, among environmental factors, a previous history of E.coli infection could be a predisposing risk factor in the development of autoimmune diseases.

Wound-induced signals regulate root organogenesis in Arabidopsis explants.

BACKGROUND: Reactive oxygen species (ROS) and calcium ions (Ca2+) are representative signals of plant wound responses. Wounding triggers cell fate transition in detached plant tissues and induces de novo root organogenesis. While the hormonal regulation of root organogenesis has been widely studied, the role of early wound signals including ROS and Ca2+ remains largely unknown. RESULTS: We identified that ROS and Ca2+ are required for de novo root organogenesis, but have different functions in Arabidopsis explants. The inhibition of the ROS and Ca2+ signals delayed root development in detached leaves. Examination of the auxin signaling pathways indicated that ROS and Ca2+ did not affect auxin biosynthesis and transport in explants. Additionally, the expression of key genes related to auxin signals during root organogenesis was not significantly affected by the inhibition of ROS and Ca2+ signals. The addition of auxin partially restored the suppression of root development by the ROS inhibitor; however, auxin supplementation did not affect root organogenesis in Ca2+-depleted explants. CONCLUSIONS: Our results indicate that, while both ROS and Ca2+ are key molecules, at least in part of the auxin signals acts downstream of ROS signaling, and Ca2+ acts downstream of auxin during de novo root organogenesis in leaf explants.

Surgically Metabolic Resection of Pericardial Fat to Ameliorate Myocardial Mitochondrial Dysfunction in Acute Myocardial Infarction Obese Rats.

BACKGROUND: Pericardial fat (PF) is highly associated with cardiovascular disease but the effectiveness of surgical resection of PF is still unknown for myocardial mitochondrial structure and function in acute myocardial infarction (AMI) with obesity. The aim of this study was to demonstrate the difference in myocardial mitochondrial structure and function between obese AMI with additionally resected PF and those without resected PF. METHODS: Obese rats with 12-week high fat diet (45 kcal% fat, n = 21) were randomly assigned into 3 groups: obese control, obese AMI and obese AMI with additionally resected PF. One week after developing AMI and additional resection of PF, echocardiogram, myocardial mitochondrial histomorphology, oxidative phosphorylation system (OXPHOS), anti-oxidative enzyme and sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) in the non-infarcted area were assessed between these groups. RESULTS: There was significant improvement of systolic function in AMI with PF resection compared with the AMI group in the echocardiogram. Even though the electron microscopic morphology for the mitochondria seems to be similar between the AMI with PF resection and AMI groups, there was an improved expression of PGC-1α and responsive OXPHOS including NDUFB3, NDUFB5 and SDHB are associated with the ATP levels in the AMI with PF resection compared with those in the AMI group. In addition, the expression levels of antioxidant enzymes (MnSOD) and SERCA2 were improved in the AMI with PF resection compared with those in the AMI group. CONCLUSION: Surgical resection of PF might ameliorate myocardial mitochondria dysfunction in obese AMI.

Prevalence and factors associated with pre-frailty and frailty among Korean older adults with heart failure.

AIM: To describe the prevalence and associated factors of pre-frailty and frailty in older patients with heart failure. DESIGN: Secondary analysis of data collected across two cross-sectional surveys on self-care behaviours of patients with heart failure. METHODS: We analysed the data of patients with heart failure who were 60 years or older (n = 407) in cardiovascular outpatient clinics at two tertiary medical centres in South Korea between 2018 and 2019. Frailty was evaluated using the Korean version of the 5-item fatigue, resistance, ambulation, illnesses and loss of weight (FRAIL) scale. Frailty status was categorized as robust, pre-frail and frail. Multivariate multinomial logistic regression was used to examine the associations between sociodemographic, clinical characteristics and frailty status. RESULTS: In our sample, the prevalence of pre-frailty and frailty was 45.6% and 28.3% respectively. Patients aged 80 years or older had a higher prevalence of pre-frailty and frailty than those younger than 80 years. Advanced age and the worst category in the New York Heart Association (NYHA) functional classification were significantly associated with the risk of pre-frailty and frailty. Additionally, having more comorbid conditions was associated with an increased risk of frailty. CONCLUSION: Our study identified advanced age, the NYHA functional classification, and the number of comorbidities as the major characteristics associated with the risk of frailty in older patients with heart failure. IMPACT: The findings of this study highlight the prevalence and associated characteristics of pre-frailty and frailty in older adults with heart failure in South Korea. Most older adults with heart failure were either pre-frail or frail. Advanced age, the NYHA functional classification, and the number of comorbidities were the major characteristics associated with frailty risk. Our findings highlight the importance of incorporating frailty screening into routine assessments in older patients with heart failure.

Association between epicardial adipose tissue and embolic stroke after catheter ablation of atrial fibrillation.

INTRODUCTION: Risk factors of embolic stroke (ES) after atrial fibrillation (AF) ablation have not been fully elucidated especially among the Asian subjects, particularly regarding epicardial adipose tissue (EAT) in cardiac imaging. We aimed to assess the incidence of ES during a long-term follow-up period after AF ablation and to identify the risk factors associated with postablation ES, specifically focusing on EAT. METHODS AND RESULTS: We enrolled patients who experienced postablation ES and control subjects from a consortium of AF ablation registries from three institutes in Korea. EAT was assessed using multislice computed tomography before AF ablation. A total of 3464 patients who underwent AF ablation were recruited and followed-up. During a follow-up of 47.2 ± 36.4 months, ES occurred in 47 patients (1.36%) with a CHA2 DS2 -VASc score of 1.48 ± 1.39 and the overall annual incidence of ES was 0.34%. Compared with the control group (n = 190), the ES group showed significantly higher prior thromboembolism (TE) and AF recurrence rates, larger left atrium size, lower creatinine clearance rate (CCr), and greater total and peri-atrial EAT volume. Multivariate regression analysis demonstrated larger peri-atrial EAT volume (hazards ratio, 1.065; 95% confidence interval, 1.005-1.128), in addition to a prior history of TE and lower CCr, was independently associated with postablation ES. When a cut-off value of peri-atrial EAT volume of ≥20.15 mL was applied, patients with smaller peri-atrial EAT volume showed significantly higher ES-free survival. CONCLUSION: Larger peri-atrial EAT volume, in addition to prior TE and lower CCr, was independently associated with postablation ES regardless of AF recurrence and CHA2 DS2 -VASc score. (ClinicalTrials.gov number, NCT03479073).

Morphological characteristics of optical coherence tomography defined plaque fissure in patients with acute coronary syndrome.

We assessed the plaque disruption in 245 consecutive patients with acute coronary syndrome undergoing percutaneous coronary intervention. The plaque fissure was diagnosed with optical coherence tomography, and intravascular ultrasound was used to determine arterial remodeling. Of them, 26 fissures were found in this study. The definite fissure was seen in 17 (65.4%) and probable fissure was seen in 9 (34.6%) patients. In 18 (69.2%), plaque fissure component was lipidic or thin-capped fibroatheroma. Eighteen (69.2%) of fissured plaque were seen within 30 mm of coronary ostium. Combined plaque fissure with plaque rupture/erosion was seen in 21 (80.8%) cases. The isolated fissure was seen in 5 (19.2%). Compared to the maximal necrotic core site of the ruptured plaque, the fissure site showed a smaller %necrotic core (p = 0.012), however, greater in fissure site than minimal lumen area site (24.93 ± 11.50% vs 15.34 ± 10.40%, p < 0.0001). The remodeling index was higher at fissure site as compared to minimal lumen area site (1.02 ± 0.22 vs 0.94 ± 0.27; p = 0.047), but similar to the rupture plaque (p = 0.31). The frequency of positive remodeling was 34.6% (9/26) at the plaque fissure. Although the plaque fissure can be interchangeable with the rupture in acute coronary syndrome, the limited extension to the small lipid core might and less positive remodeling provoke a fissuring of the plaque. Further study is necessary to assess the plaque fissure.

Usefulness of Doppler waveform analysis before performing a complex procedure using femoral venous access.

Ultrasonography is a well-defined and widely accepted technique in the settings of interventional procedures requiring peripheral venous access, either for the confirmation of the vein patency (with the compression test) or for guiding needle insertion. This report describes a case of unsuccessful guidewire passage through the right iliac vein in spite of successful ultrasonography-guided puncture of the femoral vein. On repeat duplex ultrasonography, the Doppler waveform showed a continuous pattern without respiratory phasicity, which was consistent with proximal venous occlusion. Venous Doppler signal waveform analysis can be helpful for ensuring downstream patency when planning long-distance catheterization via femoral venous access.

Changes in Left Atrial Transport Function in Patients Who Maintained Sinus Rhythm After Successful Radiofrequency Catheter Ablation for Atrial Fibrillation: A 1-Year Follow-Up Multislice Computed Tomography Study.

BACKGROUND: Functional remodeling of left atrium (LA) after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) has not been fully elucidated. This study aimed to determine the impact of RFCA on LA transport function in patients who maintained sinus rhythm (SR) after AF ablation. METHODS AND RESULTS: A total of 96 patients (paroxysmal AF [PAF] = 52) who maintained SR during 1 year after AF ablation were enrolled. Multislice computed tomography was performed to determine LA volume (LAV) and LA emptying fraction (LAEF) at pre-RFCA and 1-year post-RFCA. Creatine kinase-MB (CK-MB) and troponin-T levels were analyzed 1-day post-RFCA. At 1-year post-RFCA, mean LAV and LAEF decreased in overall patients. Based on LAEF change (ΔLAEF) cutoff of 5.0%, LAEF reduced in 41 patients (worsened group) and improved or showed no change in 55 patients (preserved group). Compared with preserved group, worsened group had a higher proportion of PAF, higher levels of CK-MB and troponin-T, and additional LA ablation. ΔLAEF was inversely correlated with CK-MB and troponin-T levels. Subgroup analysis showed that LAEF significantly decreased in PAF patients who underwent additional LA ablation. Multivariate analysis revealed that high baseline LAEF and additional LA ablation were independent predictors for worsened LAEF. CONCLUSIONS: Although SR was maintained for 1 year after AF ablation, LAEF as well as LAV decreased. The extent of LAEF deterioration was significantly associated with the amount of iatrogenic myocardial damage. Our data indicate that extensive atrial ablation may lead to LA functional deterioration, especially in patients with PAF.

Percutaneous Retrieval of Dislodged Left Atrial Appendage Occlusion Devices through the Transseptal Approach.

Percutaneous left atrial appendage (LAA) occlusion is a promising treatment option in patients with atrial fibrillation who have a high risk of embolic stroke and are not eligible for chronic oral anticoagulation therapy. This procedure, however, can induce several complications. Device embolization can result in a serious situation, requiring immediate and safe device removal. We report two cases in which dislodged LAA occlusion devices were flitting in the left atrium or entrapped in the mitral valve leaflets and were successfully retrieved through a transseptal approach without complications.

Gap junction remodelling by chronic pressure overload is related to the increased susceptibility to atrial fibrillation in rat heart.

AIMS: Left atrial (LA) fibrosis caused by various pathological stimuli is a common finding. However, the difference of atrial remodelling via haemodynamic change in diverse cardiomyopathy has not been elucidated. METHODS AND RESULTS: Male Sprague-Dawley rats (6-8 weeks, n = 180) were randomly assigned to three groups and corresponding sham control groups: (i) ischaemic cardiomyopathy, (ii) left ventricular hypertrophy (LVH), and (iii) dilated cardiomyopathy. At 12 weeks after operation, atrial fibrillation (AF) inducibility and duration were assessed by in vivo burst transoesophageal pacing. Using the Langendorff apparatus, left ventricular (LV) function and pressure were measured. The expression of connexin-43 (Cx43) and alpha-smooth muscle actin (α-SMA) in atrial tissues was assessed by quantitative real-time polymerase chain reaction and immunohistochemical staining. Fibrosis was analysed by Masson's trichrome staining. Compared with controls, the LA weight/heart weight ratio was increased in the LVH group alone, and was significantly correlated with AF duration (P < 0.001, R = 0.388). Atrial fibrillation inducibility and duration were higher and longer only in the LVH group (P = 0.002, 0.079, respectively), and isolated LV diastolic dysfunction and elevated LV pressure were observed. Although α-SMA expression and fibrosis were increased in all three cardiomyopathy models, down-regulation of Cx43 expression in the LA was observed in the LVH group alone. CONCLUSION: Chronic pressure overload in the absence of LV systolic dysfunction resulted in LA hypertrophy and increased susceptibility to AF, which might be related to conduction abnormality via decreased expression and lateral distribution of Cx43 as well as interstitial fibrosis.

The protective effect of heat shock protein 70 (Hsp70) in atrial fibrillation in various cardiomyopathy conditions.

Heat shock proteins (Hsp) protect myocardial cells from acute stress such as atrial fibrillation (AF) and also from the chronic stress. It is not understood that Hsp70 can prevent AF under cardiomyopathy (CM) conditions. Therefore, we hypothesized that Hsp70 might beneficially influence on the occurrence of AF in CM conditions. We purposed to investigate the correlation between Hsp70 and the AF inducibility in various CM conditions that are unclear. We constructed four different animal models using Sprague-Dawley rats: an ischemic CM group (n = 12), a non-ischemic dilated CM group (n = 12), a pressure-overload hypertrophic CM group (n = 12), and a sham group (CON, n = 12). After 4-6 weeks of intervention animals, AF was induced acutely prior to hemodynamic studies. Hemodynamic data using the Langendorff technique and histologic evaluation were conducted sequentially in all animal groups. Afterwards, levels of Hsp70 were measured from atrial tissues by real-time polymerase chain reaction study. The hemodynamic data and histologic studies proved that each animal model was suitable to this study protocol. All CM groups showed that Hsp70 was elevated significantly compared to the control groups (P < 0.005). Among these CM groups, the TAC group revealed lower Hsp70 levels and higher induction rates of atrial fibrillation than the other groups (P < 0.005). The level of Hsp70 was elevated in all the CM models and it was negatively correlated with AF induction rate in sham group. However, we could not find correlation between Hsp70 and AF among the CM models.

Self-care Behavior Based on Integrated Behavioral Model in Patients With Atrial Fibrillation: A Structural Equation Modeling Approach.

BACKGROUND: There is limited research exploring the behavioral intentions, beliefs, and application of theoretical models in relation to self-care in patients with atrial fibrillation (AF). OBJECTIVE: This study aimed to identify the factors that influence self-care behavior in patients with AF. METHODS: The study used an integrated behavioral model and collected data from 216 patients diagnosed with AF. Data were analyzed using SPSS 24.0 and AMOS/WIN 24.0 to verify the fit of the hypothesis model, confirm factor analysis, and the validity of the hypothesis itself. RESULTS: Self-care behavioral intention (ß = 0.433, p < .001) and habit (ß = 0.395, p = .005) had a significant direct effect, while instrumental attitude (ß = 0.077, p = .045), injunctive norm (ß = 0.084, p = .037), and self-efficacy (ß = 0.249, p = .011) had a significant indirect effect on self-care behavior, explaining 64.4% of the variance. CONCLUSION: The final model validated the factors that impact self-care behavior in patients with AF, highlighting the importance of fostering positive recognition of instrumental attitude, bolstering social influence and self-efficacy through significant individuals to improve self-care behavior. It is recommended to create an intervention program that encourages intentions and motivations for self-care behavior and incorporates tactics to make self-care behavior a habit. The study's path diagram can serve as a conceptual framework for designing strategies to enhance self-care behavior in patients with AF.

MicroRNA396 negatively regulates shoot regeneration in tomato.

Numerous studies have been dedicated to genetically engineering crops to enhance their yield and quality. One of the key requirements for generating genetically modified plants is the reprogramming of cell fate. However, the efficiency of shoot regeneration during this process is highly dependent on genotypes, and the underlying molecular mechanisms remain poorly understood. Here, we identified microRNA396 (miR396) as a negative regulator of shoot regeneration in tomato. By selecting two genotypes with contrasting shoot regeneration efficiencies and analyzing their transcriptome profiles, we found that miR396 and its target transcripts, which encode GROWTH-REGULATING FACTORs (GRFs), exhibit differential abundance between high- and low-efficiency genotypes. Suppression of miR396 functions significantly improved shoot regeneration rates along with increased expression of GRFs in transformed T0 explants, suggesting that miR396 is a key molecule involved in the determination of regeneration efficiency. Notably, we also showed that co-expression of a miR396 suppressor with the gene-editing tool can be employed to generate gene-edited plants in the genotype with a low capacity for shoot regeneration. Our findings show the critical role of miR396 as a molecular barrier to shoot regeneration in tomato and suggest that regeneration efficiency can be improved by blocking this single microRNA.

Risk of avascular necrosis in patients with inflammatory bowel disease: Insights from a nationwide cohort study and the impact of corticosteroid use.

BACKGROUND AND AIM: Corticosteroid use is a risk factor for avascular necrosis (AVN) and inflammatory bowel disease (IBD) patients are often exposed to higher corticosteroid usage. We investigated the epidemiology and risk factors of AVN in a nationwide population-based cohort of IBD patients. METHODS: Patients newly diagnosed with IBD were identified, and sex- and age-matched participants from the general population were selected in a 1:3 IBD:non-IBD ratio. We investigated newly diagnosed AVN and assessed the incidence rates and risk of AVN with multivariate Cox regression models. RESULTS: During the median follow-up period of 7.22±3.85 years, 357 (0.62 %) were newly diagnosed with AVN. The risk of AVN was higher in IBD (aHR = 1.42, 95 % CI: 1.25-1.62). Ulcerative colitis (UC) patients showed a particularly elevated risk of developing AVN. IBD patients with higher cumulative corticosteroid intake and exposed to a mean prednisolone-equivalent daily dose>20 mg for >1 month were at higher risk of AVN. In Crohn's disease (CD), longer exposure time to >20 mg prednisolone-equivalent presented a trend in increased risk. CONCLUSION: AVN risk was higher in IBD than in those without, particularly in UC and corticosteroid use in IBD could pose a crucial role. These underscore the importance of considering the AVN etiological factors, particularly corticosteroid use.

Histologic features and predicting prognosis in ulcerative colitis patients with mild endoscopic activity.

BACKGROUND/AIMS: We aimed to evaluate the histologic features predictive of prognosis and correlate them with endoscopic findings in patients with ulcerative colitis (UC) having complete or partial mucosal healing (MH). METHODS: We prospectively collected and reviewed data from patients with UC who underwent colonoscopy or sigmoidoscopy with biopsy. Complete and partial MH were defined as Mayo endoscopic subscores (MESs) of 0 and 1, respectively. Histologic variables, including the Nancy index (NI), predicting disease progression (defined as the need for medication upgrade or hospitalization/surgery), were evaluated and correlated with endoscopic findings. RESULTS: Overall, 441 biopsy specimens were collected from 194 patients. The average follow-up duration was 14.7 ± 7.4 months. There were 49 (25.3%) and 68 (35.1%) patients with MESs of 0 and 1, respectively. Disease progression occurred only in patients with an MES of 1. NI ≥ 3 was significantly correlated with disease progression during follow-up. Mucosal friability on endoscopy was significantly correlated with NI ≥ 3 (61.1% in NI < 3 vs. 88.0% in NI ≥ 3; p = 0.013). CONCLUSION: Histological activity can help predict the prognosis of patients with UC with mild endoscopic activity. Mucosal friability observed on endoscopy may reflect a more severe histological status, which can be a risk factor for disease progression.

Clinicians' Knowledge, Attitudes, and Practices Regarding the Management of Functional Gastrointestinal Disorders With Neuromodulators and Psychological Treatment.

Background/Aims: Little is known about the practical clinical application of neuromodulators and psychiatric treatments in patients with functional gastrointestinal disorders (FGIDs). We investigate the knowledge, attitudes, and practices of Korean clinicians regarding the use of neuromodulators and psychiatric treatments for FGIDs. Methods: This prospective, online, cross-sectional study was conducted between May and August 2022. A questionnaire regarding the knowledge, attitude, and practice of neuromodulators and psychiatric treatments for FGIDs was developed and administered to primary care clinicians and gastroenterologists in university hospitals in Korea. Results: Overall, 451 clinicians from primary (n = 179, 39.7%), secondary (n = 113, 25.1%), and tertiary (n = 159, 35.3%) hospitals participated in the survey. Most of them considered that neuromodulators (98.7%) and psychiatric treatment (86.5%) were required for patients with FGIDs. However, approximately one-third of them did not prescribe neuromodulators, mainly due to unfamiliarity with the drugs, and only one-quarter considered psychiatric referral. Compared to gastroenterologists at university hospitals, primary care clinicians' prescriptions had a lower rate (87.2% vs 64.2%, P < 0.001) and shorter duration of neuromodulator. The psychiatric referral rate was lower for primary care clinicians than for gastroenterologists at university hospitals (19.0% vs 34.2%, P < 0.001). Conclusions: Knowledge, attitude, and practice levels regarding neuromodulators and psychiatric treatment among clinicians are inhomogeneous, and a knowledge gap exists between primary care clinicians and gastroenterologists at university hospitals. Encouraging ongoing education for Korean clinicians regarding the appropriate use of neuromodulators and psychiatric treatments in patients with FGIDs is suggested.

Smoking Cessation and Incident Cardiovascular Disease.

Importance: The association between smoking cessation and cardiovascular disease (CVD) risk in relation to cumulative smoking exposure remains poorly understood. Objective: To evaluate the associations among smoking cessation, lifetime smoking burden, and CVD risk according to the number of years elapsed after smoking cessation. Design, Setting, and Participants: This retrospective cohort study of the Korean National Health Insurance Service database investigated smoking duration and intensity between January 2006 and December 2008. Participants were categorized by self-reported smoking habits as current, ex-, or never-smokers. Smoking records were updated every 2 years until December 2019, with participants whose smoking status changed or whose smoking status was unclear excluded. Data analysis was performed between June and December 2022. Exposures: Time-updated self-reported smoking status, years since quitting, and cumulative smoking amount (pack-years [PY]). Main Outcomes and Measures: The primary outcome was incidence and hazard ratio of CVD (composite of cardiovascular death, myocardial infarction, stroke, and heart failure). Results: Overall, 5 391 231 participants (39.9% male; mean [SD] age, 45.8 [14.7] years; 853 756 [15.8%] current smokers, 104 604 [1.9%] ex-smokers, and 4 432 871 [82.2%] never smokers) were followed up for a mean (SD) of 4.2 (4.4) years. The median (IQR) baseline cumulative smoking amounts were 14.0 (7.5-20.0) PY in current smokers and 10.5 (5.3-20.0) PY in ex-smokers. The median (IQR) duration of smoking cessation was 4 (2-8) years for ex-smokers. Regardless of continued smoking, a dose-dependent association was evident between smoking and incident CVD. Compared with current smokers, ex-smokers with a lifetime smoking burden of less than 8 PY (light ex-smokers) experienced a significant reduction in CVD risk within 10 years of cessation, with a CVD risk similar to that of never-smokers. Conversely, ex-smokers with at least 8 PY (heavy ex-smokers) exhibited a slower decline in CVD risk than light ex-smokers, requiring more than 25 years for the residual CVD risk to disappear. Conclusions and Relevance: In this cohort study, smoking and CVD risk exhibited a dose-dependent association, with light ex-smokers having a CVD risk similar to that of never-smokers relatively soon after smoking cessation. For heavy ex-smokers, greater than 25 years might be required for the residual CVD risk to align with that of never-smokers.

Dynamic changes in the gut microbiota composition during adalimumab therapy in patients with ulcerative colitis: implications for treatment response prediction and therapeutic targets.

BACKGROUND: While significant research exists on gut microbiota changes after anti-tumor necrosis factor-alpha (anti TNF-α) therapy for ulcerative colitis, little is known about the longitudinal changes related to the effects of anti TNF-α. This study aimed to investigate the dynamics of gut microbiome changes during anti TNF-α (adalimumab) therapy in patients with ulcerative colitis (UC). RESULTS: The microbiota composition was affected by the disease severity and extent in patients with UC. Regardless of clinical remission status at each time point, patients with UC exhibited microbial community distinctions from healthy controls. Distinct amplicon sequence variants (ASVs) differences were identified throughout the course of Adalimumab (ADA) treatment at each time point. A notable reduction in gut microbiome dissimilarity was observed only in remitters. Remitters demonstrated a decrease in the relative abundances of Burkholderia-Caballeronia-Paraburkholderia and Staphylococcus as the treatment progressed. Additionally, there was an observed increase in the relative abundances of Bifidobacterium and Dorea. Given the distribution of the 48 ASVs with high or low relative abundances in the pre-treatment samples according to clinical remission at week 8, a clinical remission at week 8 with a sensitivity and specificity of 72.4% and 84.3%, respectively, was predicted on the receiver operating characteristic curve (area under the curve, 0.851). CONCLUSIONS: The gut microbiota undergoes diverse changes according to the treatment response during ADA treatment. These changes provide insights into predicting treatment responses to ADA and offer new therapeutic targets for UC.