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Meng-Ko Tsai,1– 3 Huey-Kang Sytwu,4,5 Tsai-Yuan Hsieh,6 Wu-Chien Chien,7,8 Chao-Hung Lai,9,&ast; Hsiang-Cheng Chen2,10,&ast; 1Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; 2Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 3Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan; 4National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan; 5Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan; 6Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 7School of Public Health, National Defense Medical Center, Taipei, Taiwan; 8Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 9Division of Cardiology, Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; 10Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hsiang-Cheng Chen, Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Tel +886-2-87927135, Fax +886-2-87927136, Email hccheng@mail.ndmctsgh.edu.twPurpose: Depression and anxiety have been reported to increase the risk of infectious diseases and reactivation of latent infection. We conducted a nationwide population-based retrospective cohort study to determine the relationship between hepatitis B flares and depression or anxiety, utilizing outpatient and inpatient data from the Taiwan National Health Insurance Research database collected from 2000 to 2015.Patients and Methods: A total of 12,992 patients with chronic hepatitis B and newly diagnosed anxiety/depression, without advanced liver disease, were propensity score-matched for age, sex, and comorbidities in a 1:4 ratio to 51,968 controls with chronic hepatitis B without depression/anxiety or advanced liver disease. Both groups were followed-up until December 31, 2015. Cox proportional hazards regression was used to determine the risk factors for hepatitis B flares. The Log rank test and Kaplan-Meier analysis were performed to assess differences in the cumulative incidence of hepatitis B flares according to anxiety/depression status.Results: The incidence of hepatitis B flares was higher in the depression/anxiety cohort than in the control cohort (log-rank; p < 0.001). Patients with depression/anxiety had a significantly higher incidence rate of hepatitis B flares than those without depression/anxiety (3017 per 105 person-years versus 2042 per 105 person-years, p = 0.003). After adjusting for age and comorbidities, anxiety/depression was independently associated with an increased risk of hepatitis B flares (hazard ratio, 1.173; 95% confidence interval, 1.033– 1.277; p = 0.003).Conclusion: This analysis suggests that in patients with chronic hepatitis B without advanced liver disease, those with concomitant depression or anxiety may be at higher risk of hepatitis B flares.Keywords: chronic hepatitis B, hepatitis B virus, hepatitis B virus reactivation, mental disorder, mood disorder

The authors describe their first 10 cases of minimally invasive renal transplantation experience in the retroperitoneum with the aid of the da Vinci surgical system through a gas-less extra-peritoneal approach with a muscle sparing Gibson incision. The authors claim that they have utilized robotic arms for both vascular anastomosis and abdominal wall lifting which can be limiting in the obese patients. In recent years there is an increasing tendency for minimally invasive renal transplantation such as transperitoneal laparoscopic or robotic assisted renal transplantation. Those techniques still need modifications and search for a better technique is still in progress. In this study, mimicking the well-established open procedure with a smaller incision can be a better alternative, which requires confirmation in the future

Background: Risk prediction models for hepatocellular carcinoma are available for individuals with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections who are at high risk but not for the general population with average or unknown risk. We developed five simple risk prediction models based on clinically available data from the general population.Methods: A prospective cohort of 428 584 subjects from a private health screening firm in Taiwan was divided into two subgroups-one with known HCV test results (n = 130 533 subjects) and the other without (n = 298 051 subjects). A total of 1668 incident hepatocellular carcinomas occurred during an average follow-up of 8.5 years. Model inputs included age, sex, health history-related variables; HBV or HCV infection-related variables; serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alfa-fetoprotein (AFP), as well as other variables of routine blood panels for liver function. Cox proportional hazards regression method was used to identify risk predictors of hepatocellular carcinoma. Receiver operating characteristic curves were used to assess discriminatory accuracy of the models. Models were internally validated. All statistical tests were two-sided.Results: Age, sex, health history, HBV and HCV status, and serum ALT, AST, AFP levels were statistically significant independent predictors of hepatocellular carcinoma risk (all P < .05). Use of serum transaminases only in a model showed a higher discrimination compared with HBV or HCV only (for transaminases, area under the curve [AUC] = 0.912, 95% confidence interval [CI] = 0.909 to 0.915; for HBV, AUC = 0.840, 95% CI = 0.833 to 0.848; and for HCV, AUC = 0.841, 95% CI = 0.834 to 0.847). Adding HBV and HCV data to the transaminase-only model improved the discrimination (AUC = 0.933, 95% CI = 0.929 to 0.949). Internal validation showed high discriminatory accuracy and calibration of these models.Conclusion: Models with transaminase data were best able to predict hepatocellular carcinoma risk even among subjects with unknown or HBV- or HCV-negative infection status. [ABSTRACT FROM AUTHOR]

BACKGROUND: Both end-stage renal disease and chronic kidney disease are increasing worldwide; however, the full effect of chronic kidney disease is unknown because mortality risks for all five stages are unavailable. We assessed prevalence and mortality risks for all stages of chronic kidney disease and quantified its attributable mortality in Taiwan. METHODS: The cohort consisted of 462 293 individuals aged older than 20 years who participated in a standard medical screening programme since 1994. As of Dec 31, 2006, we identified 14 436 deaths. Chronic kidney disease was determined by glomerular filtration rate and urinary protein. We estimated national prevalence in Taiwan from the cohort by adjusting age and educational levels. Hazard ratios (HRs) were calculated with Cox proportionate hazards model. We calculated mortality attributable to chronic kidney disease for national population and for low socioeconomic status. FINDINGS: The national prevalence of chronic kidney disease was 11.93% (95% CI 11.66-12.28), but only 3.54% (3.37-3.68) of participants in the cohort were aware of their disorder. Prevalence was substantially higher in the group with low socioeconomic status than in the high status group (19.87% [19.84-19.91] vs 7.33% [7.31-7.35]). 56 977 (12%) of cohort participants had chronic kidney disease; those with disease had 83% higher mortality for all cause (HR 1.83 [1.73-1.93]) and 100% higher for cardiovascular diseases (2.00 [1.78-2.25]), in a cohort that was observed for 13 years with median follow-up of 7.5 years (IQR 4.0-10.1). 10.3% (95% CI 9.57-11.03) of deaths in the entire population were attributable to chronic kidney disease, but 17.5% (16.27-18.67) of deaths in the low socioeconomic status population. 2350 (39%) deaths occurred before 65 years of age in those with chronic kidney disease. Regular users of Chinese herbal medicines had a 20% (odds ratio 1.20 [1.16-1.24]) increased risk of developing chronic kidney disease. INTERPRETATION: The high prevalence of chronic kidney disease and its associated all-cause mortality, especially in people with low socioeconomic status, make reduction of this disorder a public-health priority. Promotion of its recognition through the general public knowing their glomerular filtration rate and testing their urine is crucial to reduce premature deaths from all causes and to attenuate this global epidemic. [ABSTRACT FROM AUTHOR]

Leisure-time physical activity (LTPA) has been closely related to health improvement. The under-appreciation for energy output by nutritionists stems in part from limited data expressed in caloric equivalent. We converted the frequency, duration, and intensity of LTPA, reported from 15,390 adults in the Taiwan National Health Interview Survey 2001, into kilocalories (kcal). Half of Taiwanese adults admit to no LTPA. Women, lower education or income, younger age, smokers and chewers of betel quid; exercised significantly less than their counterparts. Less than 1/5 (18.9%) of the population in Taiwan was physically active at >or=750 kcal/week, and only 1/7 (13.9%) reached a more desirable goal of >or=1,000 kcal/week, compared with 1/3 in the U.S. The most disconcerting finding was the Taiwan unique U-shaped prevalence for males, with the 25-44 age group being the least active, >or=65 age group being the most active; and S-shaped for females, lowest at age 18-24 years and highest at the two older groups (45-64 and >or=65 years). LTPA was under-appreciated, particularly among the most productive work force (25-44-year group), who exercised with a prevalence only 1/4 of their U.S. counterparts. Expressing LTPA in kcal makes direct comparison easier. Invoking a goal of >or=750 kcal/week for Asians, attainable by exercising 4 hours/week, can facilitate nutritionists in assessing LTPA adequacy. Currently, 4/5 of adults in Taiwan failed to reach this goal. Recognizing the concept of cumulative energy expenditure, in contrast to disciplined daily work for 5 or more days, will encourage the infrequent exercisers such as 'weekend warriors' to continue with their activities. [ABSTRACT FROM AUTHOR]

Background: Resting Heart Rate (RHR) is commonly viewed as a reflection of underlying co-morbidities and not an independent risk factor. Here we compared whether high RHR (80-99 beats/min) and hypertension (blood pressure, BP ≥140/90 mmHg) independently predict all-cause mortality in 692,217 adults from Asia and Europe., Methods: Taiwan MJ cohort constituted of 636,064 adults (1994-2017) and the HUNT cohort of 56,153 Norwegian adults (1995-1997). Both cohorts were followed for about 25 years. We report adjusted hazard ratios (HRs) for all-cause mortality, and life expectancy were calculated., Results: The prevalence of high RHR changed little between those aged 20-29 years (21.2 %) and ≥ 70 years (25.2 %, ns.), whereas hypertension prevalence increased from 4.5 % to 57.3 %, respectively. We observed similar all-cause mortality among those with a high RHR and a normal BP and those with hypertension and normal RHR of 60-69 beats/min. We observed higher all-cause mortality among those with normal BP (≤120/80 mmHg) but high RHR than among those with hypertension and normal RHR. All-cause mortality risk associated with hypertension was not significant for those <40 years of age, whereas risk associated with high RHR remained significant across all age groups. Reductions in life expectancy was larger among individuals with normal BP, but high RHR (10.29 years, 95 % CI 8.09-12.49) compared with those with hypertension but normal RHR (5.53 years, 95 % CI 3.57-7.59)., Conclusions: Our data clearly demonstrate that elevated RHR should be considered as an independent risk factor for all-cause mortality. The observation that elevated RHR in young adulthood to middle age (20-50 years of age) served as better predictor of all-cause mortality than hypertension calls for a paradigm shift particularly among these age groups, and we suggest it is time that RHR should be regarded as a vital clinical sign measured and evaluated at all clinical visits., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2025. Published by Elsevier Inc.)

Background: Regular physical activity (PA) is important for reducing the risk of chronic diseases and improving overall health. Activity Quotient (AQ) is a novel metric that translates heart rate during PA into a weekly score, providing an objective measure of an individual's PA. We prospectively examined the association of AQ with cancer and cardiovascular (CVD) mortality outcomes, the two major causes of death, in a Taiwanese population., Methods: A cohort of 515,608 healthy adults (52 % women) enrolled in a standard medical screening program was followed for mortality outcomes. The weekly AQ score of each participant was estimated based on self-reported PA intensity and weekly duration, and placed into six categories (0, ≤50, 51-99,100-149, 150-199, or ≥ 200 AQ per week). We used multivariable Cox proportional hazard models adjusted for potential confounders to estimate the hazard ratios (HR) and 95 % confidence intervals (CI)., Results: Higher weekly AQ scores were associated with lower risks of CVD, cancer, and all-cause mortalities. Compared with inactive individuals, HRs (CI) for the association of AQ scores of ≤50, 50-99, 100-149, 150-199, and ≥ 200 were 0.93 (0.89-0.97), 0.91 (0.85-0.96), 0.84 (0.77-0.91), 0.84 (0.74-0.96), and 0.81 (0.73-0.90) with cancer mortality; and 0.88 (0.83-0.93), 0.86 (0.80-0.93), 0.81 (0.73-0.90), 0.71 (0.60-0.85), and 0.73 (0.64-0.84) with CVD mortality, respectively. Subgroup analyses showed that meeting 50 AQ a week was associated with lower risk of disease specific mortality risk across age groups and among individuals with known risk factors. Higher weekly AQ scores were also associated with longer life expectancy, with the highest gains observed among those achieving 150-199 weekly AQ., Conclusion: Our findings show that AQ may be an objective tool for assessing and tracking PA and predicting mortality risks. Encouraging individuals to achieve ≥50 AQ a week could have substantial public health benefits, including lower mortality from major chronic diseases as well as prolonged health- and life expectancy., Competing Interests: Declaration of competing interest None., (Copyright © 2025. Published by Elsevier Inc.)

Objective: The study aimed to assess the clinical effects of employing the Huangqi formula (Eefooton; EFT) for chronic kidney disease (CKD) treatment. A narrative literature review was undertaken to elucidate the specific ingredients of EFT and their potential impact on renal health., Methods: A retrospective observational study investigated EFT treatment in outpatients with stable CKD (stages 3B to 5) from March 2019 to March 2021. Patients received 20 mL of EFT thrice daily for 6 months, along with standard treatment. Control groups were matched to the EFT cohort. Regular assessments of renal, liver functions, and lipid profiles were conducted., Results: Serum creatinine (Cr) and eGFR levels consistently improved in stage 3B CKD patients at each follow-up visit. At 6 months, improvement in Cr and eGFR was observed for stage 4 and 5 CKD. Stage 3B CKD patients exhibited notable reductions in systolic blood pressure after 3 and 6 months of EFT treatment. Remarkably, a substantial decrease in HbA1C was noted in stage 4 CKD individuals after three months of therapy. Additionally, stage 4 CKD patients saw a significant reduction in LDL levels after both 3 and 6 months of EFT treatment. A literature review on EFT ingredients indicated that the positive effects of EFT might be associated with its anti-inflammatory, antioxidant, and anti-fibrotic properties., Conclusions: This research demonstrated that incorporating EFT alongside standard treatment enhanced renal function in individuals with CKD. EFT is proposed as a feasible complementary treatment for CKD patients, emphasizing the importance of early intervention.

We investigated the photoinduced relaxation of Kasha-type emitting ruthenium-(bidentate cyclometalated aromatic ligand), Ru-CM, chromophores of [Ru(pzpy) 2 (CM)] + ions (CM = 1-phenylisoquinoline, 2,3-diphenylpyrazine, and 1,4-diazatriphenylene and pzpy = 2-pyrazol-1-yl-pyridine). This is the first report of the phosphorescence behavior of pure Ru-(bidentate CM) chromophores. The 77 K photoinduced relaxation characteristics of phosphorescence chromophores showed emission quantum yields higher than those of reference Ru-bpy (bpy = 2,2'-bipyridine) chromophores in the emission region of 670-900 nm. This phenomenon of the Ru-CM chromophores could be attributed to their unusually low magnitudes for 77 K nonradiative rate constants ( k NRD ), although their radiative rate-constants ( k RAD ) are not remarkable. In order to examine the 77 K photoinduced behavioral relaxation difference between Ru-CM and Ru-bpy chromophores, we used computational simulation, applying the fundamental formalism of k RAD and temperature-independent k NRD equations, which included calculated spin-orbit coupling values.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding., (© 2024 Wiley Periodicals LLC.)

Objective: To investigate the specific role of inflammation in the connection between obesity and the overall incidence of cancer., Methods: A total of 356,554 participants in MJ cohort study were included. Systemic inflammation markers from blood samples and anthropometric measurements were determined using professional instruments. The Cox model was adopted to evaluate the association., Results: Over a median follow-up of 8.2 years, 9,048 cancer cases were identified. For individual systemic inflammation biomarkers, the overall cancer risk significantly escalated as blood C-reactive protein (CRP) (hazard ratio (HR)=1.036 (1.017-1.054)) and globulin (GLO) (HR=1.128 (1.105-1.152)) levels increased, and as hemoglobin (HEMO) (HR=0.863 (0.842-0.884)), albumin (ALB) (HR=0.846 (0.829-0.863)) and platelets (PLA) (HR=0.842 (0.827-0.858)) levels decreased. For composite indicators, most of them existed a significant relationship to the overall cancer risk. Most indicators were correlated with the overall cancer and obesity-related cancer risk, but there was a reduction of association with non-obesity related cancer risk. Most of indicators mediated the association between anthropometric measurements and overall cancer risk., Conclusions: Systemic inflammatory state was significantly associated with increased risks of cancer risk. Inflammation biomarkers were found to partly mediate the association between obesity and cancer risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bian, Xu, Wang, Tsai, Chu, Tu, Wen and Wu.)

Peritoneal dialysis (PD)-associated peritonitis is a major cause of peritoneal dysfunction and failure. The main issue regarding the treatment is whether to remove the catheter surgically or to treat with antibiotics alone. Notably, PD-associated peritonitis is commonly caused by gram-positive cocci, but rarely by Listeria monocytogenes and Burkholderia cepacia . Here, we report a patient diagnosed with PD-associated peritonitis caused by L. monocytogenes and B. cepacia who presented with a fever, abdominal pain, and turbid dialysate and had been receiving PD for over 20 years. After 2 weeks of antibiotic treatment, the catheter in the patient was surgically removed. Culture and pathology results revealed pathogen growth, foreign body granuloma with chronic inflammation, and inflammatory cells with fibroblast infiltration. The patient was switched to hemodialysis. She eventually recovered and was discharged. The patient presented fair health at the 3-month follow-up. In conclusion, sequential dialysate white blood cell count may help clinicians decide the course of treatment and guide the timing of surgical intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tsai, Tsai, Kung and Wang.)

The dynamic characterization of guest molecules in the metal-organic frameworks (MOFs) can always provide the insightful and inspiring information to facilitate the synthetic design of MOF materials from the bottom-up design of perspective. Herein, we present a series of atomistic molecular dynamics simulation for investigating the bipyridine dicarboxylate (bpydc) linker rotation effect on guest molecule adsorption with and without considering the transition metal (TM) chelation in MOF-253 materials. The simulated PXRD patterns of the various linker orientations present the challenge of distinguishing these structural varieties by the conventional crystalline spectroscopic measurements. The observed short inter-TM stable structure may subsequently lead to the formation of a binuclear TM catalytic site, and a proposed formic acid generation mechanism from CO 2 and H 2 is derived based upon the density functional theory calculations for the application of CO 2 reduction.

Background: While all-cause mortality is reportedly increased in preserved ratio impaired spirometry (PRISm), no remedial efforts have been suggested., Aim: To study the ability of physical activity (PA) on reducing the morality increased in PRISm patients., Design: We prospectively enrolled a cohort of Taiwanese adults from 1994 to 2018 in a health surveillance program., Methods: Mortality risks of those who were inactive were compared against those meeting the current recommendation of 150 min/week of PA. Cox proportional hazards models were used for hazard ratios and life table method was for estimating loss of life expectancy., Results: A total of 461 183 adults were enrolled. Among them, one-seventh of the cohort (65 832 or 14.3%) had PRISm, and 53.1% were inactive. Those who were inactive with PRISm had 28% increased mortality from all-cause, 45% from cardiovascular diseases (CVDs) and 67% from respiratory disease, with a 3-year reduction in life expectancy (males, 3.72 and females, 2.93). In PRISm patients who met the exercise recommendation, excess mortality was reduced by two-third, both all-cause (from 28% to 9%) and CVD (from 45% to 15%)., Conclusion: PRISm involves a large portion of general population (14.3%) and shortens life expectancy by 3 years. More than half of the subjects were physically inactive, and adherence to 150 min/week of PA was associated with a two-third reduction of excess mortality from all cause and from CVD. Recommending PA among those with PRISm might be highly beneficial, although exercise alone may not eliminate all risks associated with PRISm., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Most cancers are diagnosed in persons over the age of sixty, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation - widely understood to contribute to cancer risk - it is also associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many, but not all, tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K/AKT pathway, weakened to a disproportionate extent. Single-cell transcriptomic analysis revealed that neoplastic cells from tumors in old mice retain many age-related transcriptomic changes, showing that age has an enduring impact that persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings suggest that the relationship between age and lung cancer incidence may reflect an integration of the competing effects of driver mutation accumulation and tumor suppressive effects of aging.

Background: It has been known that smoking and various lung diseases including lung cancer can cause lung function impairment. However, the impact of different types of lung function impairments, such as preserved ratio impaired spirometry (PRISm) and airflow obstruction (AO), on the incidence and mortality of lung cancer in both general and never-smoker populations remains unclear. We wished to examine the effect of lung function impairments on lung cancer risks., Methods: This was a retrospective cohort study (1 January 1994 to 31 December 2017) of individuals from a health surveillance programme in Taiwan who underwent baseline spirometry tests at the entry point. PRISm was defined as an FEV 1 /FVC (forced expiratory volume in 1 s/forced vital capacity) ratio >0.7 and FEV 1 <0.8, while AO was defined as an FEV 1 /FVC ratio <0.7. Cox proportional hazards models and cubic spline curves were used to examine the associations between lung function impairments and lung cancer risks., Results: The study included 461,183 individuals, of whom 14.3% had PRISm and 7.9% had AO. A total of 4038 cases of lung cancer and 3314 lung cancer-related deaths were identified during the 23 years of follow-up. Individuals with PRISm and AO exhibited a higher risk of lung cancer incidence and mortality compared with those with normal lung function. The adjusted HRs and 95% CIs were 1.14 (1.03 to 1.26) and 1.23 (1.10 to 1.37) in the overall cohort, and 1.08 (0.93 to 1.24), and 1.23 (1.05 to 1.45) in the never-smoker cohort. The risks of both developing and dying of lung cancer increased with the severity levels of lung function impairments and lower FEV 1 values., Conclusion: Impaired lung function is associated with increased risks of developing lung cancer and subsequent mortality. The study highlights the importance of considering lung function in lung cancer screening for better candidate selection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Background: Fecal immunochemical test (FIT) is for colorectal cancer (CRC) screening. Its association with non-CRC mortality has been overlooked. Given the quantitative FIT values, its dose-response relationships with different causes of deaths and years of life shortened were assessed., Methods: This retrospective study included 546,214 adults aged ≥ 20 who attended a health surveillance program from 1994 to 2017 and were followed up until the end of 2020. FIT ≥ 20 μg Hb/g was defined as positive. The Cox model was used to assess adjusted hazard ratios (aHR)., Results: Positive FIT was associated with increased all-cause mortality (aHR: 1.34, 95 % CI: 1.25-1.44) and all-cancer mortality (aHR: 1.71, 95 % CI: 1.55-1.89), with a reduction of life expectancy by 4 years. The association remained even with CRC excluded. With each 10 μg Hb/g increase in FIT above 20 μg Hb/g, life expectancy was reduced by one year, and mortality increased by 4 %. About 18.6 % of deaths with positive FIT were attributed to cardiovascular disease (CVD), followed by CRC (13.5 %) and upper gastrointestinal (GI) cancers (4.5 %). The all-cause mortality rate after excluding CRC for positive FIT was 3.56/1,000 person-year, comparable to the all-cause mortality rate of 3.69/1,000 person-year for hypertension., Conclusion: Positive FIT was associated with increased mortality in a dose-response manner and shortened life expectancy by 4 years, an overlooked risk comparable to hypertension, even with CRC excluded. After a negative colonoscopy, subjects with positive FIT should undergo a workup on CVD risk factors and look for other upper GI cancers., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Importance: For the first time, the 2020 World Health Organization guidelines on physical activity recommended reducing sedentary behaviors owing to their health consequences. Less is known on the specific association of prolonged occupational sitting with health, especially in the context of low physical activity engagement., Objective: To quantify health risks associated with prolonged occupational sitting and to determine whether there is a certain threshold of physical activity that may attenuate it., Design, Setting, and Participants: This prospective cohort study included participants in a health surveillance program in Taiwan who were followed-up between 1996 and 2017. Data on occupational sitting, leisure-time physical activity (LTPA) habits, lifestyle, and metabolic parameters were collected. Data analysis was performed in December 2020., Main Outcomes and Measures: The all-cause and cardiovascular disease (CVD) mortality associated with 3 occupational sitting volumes (mostly sitting, alternating sitting and nonsitting, and mostly nonsitting) were analyzed applying multivariable Cox regression models to calculate the hazard ratios (HRs) for all participants and by subgroups, including 5 LTPA levels and a personal activity intelligence (PAI)-oriented metric. Deaths occurring within the initial 2 years of follow-up were excluded to prevent reverse causality., Results: The total cohort included 481 688 participants (mean [SD] age, 39.3 [12.8] years; 256 077 women [53.2%]). The study recorded 26 257 deaths during a mean (SD) follow-up period of 12.85 (5.67) years. After adjusting for sex, age, education, smoking, drinking, and body mass index, individuals who mostly sat at work had a 16% higher all-cause mortality risk (HR, 1.16; 95% CI, 1.11-1.20) and a 34% increased mortality risk from CVD (HR, 1.34; 95% CI, 1.22-1.46) compared with those who were mostly nonsitting at work. Individuals alternating sitting and nonsitting at work did not experience increased risk of all-cause mortality compared with individuals mostly nonsitting at work (HR, 1.01; 95% CI, 0.97-1.05). For individuals mostly sitting at work and engaging in low (15-29 minutes per day) or no (<15 minutes per day) LTPA, an increase in LTPA by 15 and 30 minutes per day, respectively, was associated with a reduction in mortality to a level similar to that of inactive individuals who mostly do not sit at work. In addition, individuals with a PAI score exceeding 100 experienced a notable reduction in the elevated mortality risk associated with prolonged occupational sitting., Conclusions and Relevance: As part of modern lifestyles, prolonged occupational sitting is considered normal and has not received due attention, even though its deleterious effect on health outcomes has been demonstrated. In this study, alternating between sitting and nonsitting at work, as well as an extra 15 to 30 minutes per day of LTPA or achieving a PAI score greater than 100, attenuated the harms of prolonged occupational sitting. Emphasizing the associated harms and suggesting workplace system changes may help society to denormalize this common behavior, similar to the process of denormalizing smoking.

Background: The relationship between resting heart rate (RHR) and the risk of end-stage renal disease (ESRD) among those without cardiovascular disease remains unclear. We aim to establish temporal consistency and elucidate the independent relationship between RHR and the risk of ESRD., Methods and Results: This cohort enrolled participants from 476 347 individuals who had taken part in a screening program from 1996 to 2017. We identified 2504 participants who had ESRD, and the median follow-up was 13 years. RHR was extracted from electrocardiography results, and the study assessed the relationship between RHR and the risk of ESRD using the Cox proportional hazards model. Of the participants, 32.6% had an RHR of 60 to 69 beats per minute (bpm), and 22.2% had an RHR of ≥80 bpm. Participants with an RHR of ≥80 bpm had a higher stage of chronic kidney disease, lower estimated glomerular filtration rate, and more proteinuria than those with an RHR of 60 to 69 bpm. Participants with an RHR of 80 to 89 and ≥90 bpm had a 24% (hazard ratio [HR], 1.24 [95% CI, 1.09-1.42]) and 64% (HR, 1.64 [95% CI, 1.42-1.90]) higher risk of ESRD, respectively. The risk of ESRD remained significantly elevated (HR, 1.32 [95% CI, 1.10-1.58] per 10-beat increase from 60 bpm) after excluding participants who smoked; had hypertension, diabetes, or hyperlipidemia; or were overweight., Conclusions: An RHR of ≥80 bpm is significantly associated with an increased risk of ESRD. These results suggest that RHR may serve as a risk factor for kidney disease in individuals without established cardiovascular disease risk factors.

Background: A substantially elevated Body Mass Index (BMI) is one of the largest global modifiable risk factors for stroke and heart diseases. Most studies classify BMI according to the WHO BMI cut-off point in stroke and heart disease studies. However, there is a limited understanding of the association between the BMI cut-off point in the Asian population category and stroke and heart disease. This study aimed to investigate the incidence rate ratio of stroke and heart disease by BMI categories for the Asian population., Methods: A 7-year prospective longitudinal study (2007-2014) was conducted on 6,688 adult Indonesian individuals (≥ 35 years) residing across 13 different provinces in Indonesia during the survey periods. Data on BMI were collected in 2007. Information on stroke and heart disease was obtained in both 2007 and in 2014. A multivariate-adjusted Poisson regression model was used to estimate the incidence rate ratio (IRR) and 95% confidence intervals (CIs) of either stroke or heart disease or both stroke and heart disease by BMI., Results: Among the 6,688 eligible participants, 334 (5%) were judged as stroke and heart disease in 2014. The IRR (95% CI) of stroke and heart disease for participants with obesity was 2.57 (1.64-4.04) compared with those within normal weight. This incidence rate ratio was more pronounced among middle-aged adults (< 55 years) rather than the older adults (≥55 years).The IRR of stroke and heart disease among obese middle-aged adults was 4.18 (95% CI 2.10-8.31)., Conclusions: An association was observed between obesity and the risk of stroke and heart disease, especially in middle-aged adults. These findings suggest that lowering BMI through the adoption of healthy dietary habits and increasing physical activity, particularly among middle-aged adults with high education, occupational employment, and residence in either urban or rural areas, may be beneficial for preventing stroke and heart disease., (© 2023. The Author(s).)

Background: Aging is a dynamic and heterogeneous process that may better be captured by trajectories of aging biomarkers. Biological age has been advocated as a better biomarker of aging than chronological age, and plant-based dietary patterns have been found to be linked to aging. However, the associations of biological age trajectories with mortality and plant-based dietary patterns remained unclear., Methods: Using group-based trajectory modeling approach, we identified distinctive aging trajectory groups among 12,784 participants based on a recently developed biological aging measure acquired at four-time points within an 8-year period. We then examined associations between aging trajectories and quintiles of plant-based dietary patterns assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) among 10,191 participants who had complete data on dietary intake, using multivariable multinomial logistics regression adjusting for sociodemographic and lifestyles factors. Cox proportional hazards regression models were applied to investigate the association between aging trajectories and all-cause mortality., Results: We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (OR = 0.75, 95% CI: 0.65, 0.86 for PDI; OR = 0.73, 95% CI: 0.62, 0.85 for hPDI) or high-degree (OR = 0.63, 95% CI: 0.46, 0.86 for PDI; OR = 0.62, 95% CI: 0.44, 0.88 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (OR = 1.72, 95% CI: 1.48, 1.99) or high-degree (OR = 1.70, 95% CI: 1.21, 2.38) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (HR = 1.56, 95% CI: 1.29, 1.89) or high-degree (HR = 3.72, 95% CI: 2.73, 5.08) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory., Conclusions: We identified three distinctive aging trajectories in a large Asian cohort and found that adopting a plant-based dietary pattern, especially when rich in healthful plant foods, was associated with substantially lowered pace of aging., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Data are limited regarding the long-term durability of sustained virologic response (SVR) in solid organ transplant recipients who achieve SVR 12 with direct-acting antivirals (DAAs) for hepatitis C virus (HCV). We reported the virologic outcomes in 42 recipients who received DAAs for acute or chronic HCV infection after heart, liver, and kidney transplantation. After achieving SVR 12 , all recipients received HCV RNA surveys at SVR 24 , and biannually until the last visit. If HCV viremia was detected during the follow-up period, direct sequencing and phylogenetic analysis were performed to confirm late relapse or reinfection. Sixteen (38.1%), 11 (26.2%), and 15 (35.7%) patients underwent heart, liver and, kidney transplantation. Thirty-eight (90.5%) received sofosbuvir (SOF)-based DAAs. No recipients had late relapse or reinfection after a median (range) of post-SVR 12 follow-up 4.0 (1.0-6.0) years. We demonstrate that the durability of SVR in solid organ transplant recipients is excellent once SVR 12 is achieved with DAAs., Competing Interests: Declaration of competing interest Chen-Hua Liu: advisory board for Abbvie, Gilead Sciences, Merck Sharp & Dohme; speaker's bureau for Abbott, Abbvie, Gilead Sciences, Merck Sharp & Dohme; research grant from Abbvie, Gilead Science, Merck Sharp & Dohme. Jia-Horng Kao: advisory board for Abbott, Abbvie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche; speaker's bureau for Abbott, Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche. All other authors declare no competing interests., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

An assessment of modifying the SchNET model for the predictions of experimental molecular photophysical properties, including absorption energy (Δ E abs ), emission energy (Δ E emi ), and photoluminescence quantum yield (PLQY), was reported. The solution environment was properly introduced outside the interaction layers of SchNET for not overly amplifying the solute-solvent interactions, particularly being supported by the changes of prediction errors between the presence and absence of the solvent effect. Two featurization schemes under the framework of the Schnet-bondstep approach, with featuring the concepts of reduced-atomic-number and reduced-atomic-neighbor, were demonstrated. These featurized models can consequently provide fine predictions for Δ E abs and Δ E emi with errors less than 0.1 eV. The corresponding predictions of PLQY were shown to be comparable to the previous graph convolution network model.

Introduction: Bacillus Calmette-Guérin (BCG) vaccination has been reported to be protective against latent tuberculosis infection (LTBI) in the general population. The aim of this study was to investigate the protective effect of BCG vaccination against LTBI in adult patients with end-stage renal disease (ESRD) and renal transplants., Methods: Patients aged ≥ 20 years with ESRD who received hemodialysis (HD), peritoneal dialysis (PD) or kidney transplant were enrolled from January 2012 to December 2019 at a medical center and a regional hemodialysis center. Patients with active tuberculosis (TB), previously treated TB, active immunosuppressant therapy or human immunodeficiency virus infection were excluded. LTBI status was determined by QuantiFERON-TB Gold In-tube (QFT-GIT)., Results: After the exclusion of indeterminate results of QFT-GIT, 517 participants were enrolled and 97 (18.8%) were identified as having LTBI. Participants with LTBI were older (55.1 ± 11.4 vs. 48.5 ± 14.6 years, p < 0.001) and had a significantly higher proportion receiving HD than those without LTBI (70.1% vs. 56.7%, p = 0.001). The percentage with BCG scars was higher in the non-LTBI group than in the LTBI group (94.8% vs. 81.4%, p < 0.001), whereas the neutrophil-to-lymphocyte ratio (NLR) (≥ 2.68) was significantly higher in the LTBI group (62.8% vs. 45.5%, p = 0.02). By multivariate logistic regression analysis, presence of BCG scar and high NLR were independent protective factors against LTBI [adjusted OR: 0.19 (0.063-0.58, p = 0.001) and 0.50 (0.28-0.89, p = 0.02)]., Conclusion: The prevalence of LTBI was as high as 18.8% in patients with end-stage kidney disease or kidney transplant. BCG vaccination and high NLR might have protective effects against LTBI in patients with renal failure or transplant., (© 2023. The Author(s).)

Patients undergoing kidney transplantation have a poor response to vaccination and a higher risk of disease progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effectiveness of vaccine doses and antibody titer tests against the mutant variant in these patients remains unclear. We retrospectively analyzed the risk of SARS-CoV-2 infection in a single medical center according to vaccine doses and immune responses before the outbreak. Among 622 kidney transplant patients, there were 77 patients without vaccination, 26 with one dose, 74 with two doses, 357 with three, and 88 with four doses. The vaccination status and infection rate proportion were similar to the general population. Patients undergoing more than three vaccinations had a lower risk of infection (odds ratio = 0.6527, 95% CI = 0.4324-0.9937) and hospitalization (odds ratio = 0.3161, 95% CI = 0.1311-0.7464). Antibody and cellular responses were measured in 181 patients after vaccination. Anti-spike protein antibody titer of more than 1,689.3 BAU/mL is protective against SARS-CoV-2 infection (odds ratio = 0.4136, 95% CI = 0.1800-0.9043). A cellular response by interferon-γ release assay was not correlated with the disease (odds ratio = 1.001, 95% CI = 0.9995-1.002). In conclusion, despite mutant strain, more than three doses of the first-generation vaccine and high antibody titers provided better protection against the omicron variant for a kidney transplant recipient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Hsu, Huang, Lai, Wu, Lin, Hung, Lin, Huang, Lee, Tsai and Lee.)

Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes., (© 2023 Gonzalez et al.)

Objectives: To compare mortality risk and life expectancy among individuals with different sleep durations and sleeping pill use., Methods: A cohort of 484,916 community-dwelling adults in Taiwan was recruited into a health screening program from 1994 to 2011. Subjects were categorized by daily sleep duration into 4 groups: extremely short (<4 hours), short (4-6 hours), medium (6-8 hours), and long (>8 hours). Cox proportional hazards models were used to investigate the associations of mortality risk with sleep duration and sleeping pill use. Models were adjusted for sociodemographic characteristics, lifestyle, and comorbidities. Life expectancy tables were calculated among sleeping pill users and nonusers with different sleep durations., Results: With 6- 8 hours of daily sleep, sleeping pill nonusers had the lowest mortality risk. Sleeping pill users, even with this optimal amount of sleep, had a 55% (p < .001, 95% CI, 1.38-1.73) higher mortality risk than nonusers. The life expectancy of 30-year-old male sleeping pill users with extremely short or long sleep durations was 12-13 years shorter than sleeping pill nonusers who had 6-8 hours of sleep. On average, life expectancy in individuals using sleeping pills (vs. nonusers) was shorter by 5.3 (95% CI, 4.10-6.32) years in men and 5.7 (95% CI, 5.28-7.98) years in women., Conclusions: This study suggests that the use of sleeping pills is associated with an increased risk of mortality and shortened life expectancy, especially in extreme sleepers. Regular users should be aware of potential harms from sleeping pills., (Copyright © 2023 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Healthcare-associated COVID-19 infections caused by SARS-CoV-2 have increased morbidity and mortality. Hospitals and skilled nursing facilities (SNFs) have been challenged by infection control and management., Methods: This case study presents an outbreak investigation in a COVID-19-designated hospital and a hospital-based SNF. Real-time polymerase chain reaction (PCR) and other studies were performed on samples obtained from SNF residents, hospital patients, and healthcare workers (HCWs). The results of the laboratory tests and field epidemiological data were analyzed. Genome sequencing and phylogenetic analysis of SARS-CoV-2 were performed to identify the associations between cases. The tracer gas was released and recorded by a thermal imaging camera to investigate the spatial relations within clusters., Results: During the outbreak, 29 COVID-19 infections in 3 clusters were identified through hospital-wide, risk-guided, and symptom-driven PCR tests. This included 12 HCWs, 5 patients, and 12 SNF residents who had been hospitalized for at least 14 days. Serology tests did not identify any cases among the PCR-negative individuals. The phylogenetic analysis revealed that viral strains from the 3 clusters shared a common mutation of G3994T and were phylogenetically related, which suggested that this outbreak had a common source rather than multiple introductions from the community. Linked cases exhibited vertical spatial distribution, and the sulfur hexafluoride release test confirmed a potential airborne transmission., Conclusions: This report addressed the advantage of a multi-disciplinary team in outbreak investigation. Identifying an airborne transmission within an outbreak highlighted the importance of regular maintenance of ventilation systems., Competing Interests: Declaration of competing interest All authors denied any financial and personal conflict of interest that could inappropriately influence this article., (Copyright © 2023. Published by Elsevier B.V.)

Background: Although biological aging has been proposed as a more accurate measure of aging, few biological aging measures have been developed for Asians, especially for young adults., Methods: A total of 521 656 participants were enrolled in the MJ cohort (1996-2011) and were followed until death, loss-to-follow-up, or December 31, 2011, whichever came first. We selected 14 clinical biomarkers, including chronological age, using a random forest algorithm, and developed a multidimensional aging measure (MDAge). Model performance was assessed by area under the curve (AUC) and internal calibration. We evaluated the associations of MDAge and residuals from regressing MDAge on chronological age (MDAgeAccel) with mortality and morbidity, and assessed the robustness of our findings., Results: MDAge achieved an excellent AUC of 0.892 in predicting all-cause mortality (95% confidence interval [CI]: 0.889-0.894). Participants with higher MDAge at baseline were at a higher risk of death (per 5 years, hazard ration [HR] = 1.671, 95% CI: 1.662-1.680), and the association remained after controlling for other variables and in different subgroups. Furthermore, participants with higher MDAgeAccel were associated with shortened life expectancy. For instance, compared to men who were biologically younger (MDAgeAccel ≤ 0) at baseline, men in the highest tertiles of MDAgeAccel had shortened life expectancy by 17.23 years. In addition, higher MDAgeAccel was associated with having chronic disease either cross-sectionally (per 1-standard deviation [SD], odds ratio [OR] = 1.564, 95% CI: 1.552-1.575) or longitudinally (per 1-SD, OR = 1.218, 95% CI: 1.199-1.238)., Conclusion: MDAge accurately predicted mortality and morbidity, which has great potential in the early identification of individuals at higher risk and therefore promoting early intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The synthesis, electrochemistry, and photophysical characterization of five 2,2':6',2″-terpyridine ruthenium complexes (Ru-tpy complexes) is reported. The electrochemical and photophysical behavior varied depending on the ligands, i.e., amine (NH 3 ), acetonitrile (AN), and bis(pyrazolyl)methane (bpm), for this series of Ru-tpy complexes. The target [Ru(tpy)(AN) 3 ] 2+ and [Ru(tpy)(bpm)(AN)] 2+ complexes were found to have low-emission quantum yields in low-temperature observations. To better understand this phenomenon, density functional theory (DFT) calculations were performed to simulate the singlet ground state (S 0 ), T e , and metal-centered excited states ( 3 MC) of these complexes. The calculated energy barriers between T e and the low-lying 3 MC state for [Ru(tpy)(AN) 3 ] 2+ and [Ru(tpy)(bpm)(AN)] 2+ provided clear evidence in support of their emitting state decay behavior. Developing a knowledge of the underlying photophysics of these Ru-tpy complexes will allow new complexes to be designed for use in photophysical and photochemical applications in the future., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The epithelium-derived cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important mediators that initiate innate type 2 immune responses in asthma. Leukotriene receptor antagonists (LTRAs) are commonly used to prevent asthma exacerbations. However, the effects of LTRAs on epithelium-derived cytokines expression in airway epithelial cells are unclear. This study aimed to investigate the effects of LTRAs on the expression of epithelium-derived cytokines in human airway epithelial cells and to explore possible underlying intracellular processes, including epigenetic regulation. A549 or HBE cells in air-liquid interface conditions were pretreated with different concentrations of LTRAs. The expression of epithelium-derived cytokines and intracellular signaling were investigated by real-time PCR, enzyme-linked immunosorbent assay, and Western blot. In addition, epigenetic regulation was investigated using chromatin immunoprecipitation analysis. The expression of IL-25, IL-33, and TSLP was increased under LTRAs treatment and suppressed by inhaled corticosteroid cotreatment. Montelukast-induced IL-25, IL-33, and TSLP expression were mediated by the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways and regulated by histone H3 acetylation and H3K36 and H3K79 trimethylation. LTRAs alone might increase inflammation and exacerbate asthma by inducing the production of IL-25, IL-33, and TSLP; therefore, LTRA monotherapy may not be an appropriate therapeutic option for asthma.

Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRAS G12D -driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)