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Wei-Chen Tai,1 Chih-Ming Liang,1 Kuo-Wei Bi,2 Chung-Mou Kuo,1 Lung-Sheng Lu,1 Cheng-Kun Wu,1 Shih-Cheng Yang,1 Yuan-Hung Kuo,1 Chen-Hsiang Lee,3 Chih-Fang Huang,4 Chien-Ning Hsu,5 Pin-I Hsu,6 Deng-Chyang Wu,7 Tsung-Hui Hu,1,8 Keng-Liang Wu,1,8 Seng-Kee Chuah1,8 1Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Division of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Division of Family Physician, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 5Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 6Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang-Ming University, Kaohsiung, Taiwan; 7Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan; 8Chang Gung University College of Medicine, Taoyuan City, TaiwanCorrespondence: Seng-Kee Chuah; Chung-Mou KuoDivision of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung 833, TaiwanTel +886 7 731 7123 ext. 8301Fax +886 7 732 2402Email chuahsk@seed.net.tw; kuo51116@gmail.comPurpose: Steadily maintaining high intra-gastric PH is the major factor for successful Helicobacter pylori (H.pylori) eradication. It is important to search for a stronger PPI. Dexlansoprazole MR is a dual delayed release formulation PPI taken once daily which is capable of maintaining longer duration of high intra-gastric PH. It is very effective in treating gastroesophageal disease but reports on H, pylori eradication is very rare. This study sought to compare dexlansoprazole MR-based concomitant treatment and lansoprazole-based concomitant treatment in H. pylori infection and to investigate the factors that affect the eradication rates.Methods: Two hundred two participants with H. pylori infection were included and randomly assigned to seven days of dexlansoprazole MR-based concomitant therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily; DACM group) or a seven days of lansoprazole-based concomitant therapy (lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily, and metronidazole 500 mg twice daily; LACM group). The participants were asked to perform urea breath tests eight weeks later.Results: The eradication rates in the DACM group were 86.1% [95% confidence interval (CI): 77.8%–92.2%] in the ITT analysis and 90.6% (95% CI: 82.9%–95.6%) in the PP analysis, respectively, as compared with 90.1% (95% CI: 82.6%–95.2%) and 92.6% (95% CI: 85.5%–96.9%) (p=0.384 and p=0.572, respectively) in the LACM group for the same analyses. The adverse event rates were 11.5% in the DACM group and 10.2% in the LACM group (p=0.779).Conclusion: As a first-line H. pylori treatment regimen, dexlansoprazole MR-based concomitant therapy attained a successful eradication rate of 90%, which was non inferior to that of lansoprazole-based concomitant treatment.ClinicalTrials.gov identifier: NCT03829150.Keywords: Helicobacter pylori eradication, strong proton-pump inhibitor, dexlansoprazole MR-based concomitant therapy, lansoprazole-based concomitant therapy, antibiotic resistance

Chih-Chien Yao,1 Chung-Mou Kuo,1 Chien-Ning Hsu,2 Shih-Cheng Yang,1 Cheng-Kun Wu,1 Wei-Chen Tai,1 Chih-Ming Liang,1 Keng-Liang Wu,1 Chih-Fang Huang,3 Kuo-Wei Bi,4 Chen-Hsiang Lee,5 Seng-Kee Chuah11Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; 2Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung and School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Division of Family physician, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanPurpose: To assess the difference of the first-line therapy for Helicobacter pylori in patients with or without type 2 diabetes (DM) and to investigate the clinical factors influencing treatment outcomes.Patients and methods: In total, 719 patients with H. pylori infection were treated with 7-day standard first-line triple therapy, of whom 182 did and 537 did not have DM. Propensity score matched at a 1:2 ratio – for age, sex and body mass index was performed for the two groups, yielding a DM group with 147 patients and a non-DM group with 249 matched controls for analysis. Urea breath test was performed 6–8 weeks after treatment. Clinical and laboratory parameters were collected for identifying factors associated with failed eradication.Results: H. Pylori was eradicated in 74.1% (95% confidence interval [CI] =66.2–81.0) of the DM group and 85.3% (95% CI =80.8–89.4) of the non-DM group (p=0.005). Of 51 gastric biopsy samples cultured for H. pylori, 41 were positive. In the DM group, the rates of resistance to amoxicillin, clarithromycin, levofloxacin, and tetracycline were 0%, 50.0%, 50.0% and 0%, respectively. In the non-DM group, the comparable proportions were 2.9%, 17.1%, 22.9%, and 0%, respectively. Univariate analysis revealed that DM (Odds ratio [OR], 1.771, 95% CI, 1.167–2.668, p=0.006), clarithromycin resistance (OR, 15.273; 95% CI, 1.687–138.269; p=0.015), and amoxicillin resistance (OR, 4.672; 95% CI, 2.431–8.979; p90% eradication.Keywords: Helicobacter pylori infection, standard triple therapy

Chronic kidney disease (CKD) is a widespread condition often resulting from multiple factors, including maternal influences. These risk factors not only heighten the likelihood of developing CKD but increase the risk of a preterm birth. Adverse events during nephrogenesis can disrupt kidney development, leading to a reduced number of nephrons. As survival rates for preterm infants improve, more individuals are living into adulthood, thereby elevating their risk of CKD later in life. This review aims to explore the connections between preterm birth, kidney development, and the increased risk of CKD, while proposing practical solutions for the future through a multidisciplinary approach. We examine human studies linking preterm birth to negative kidney outcomes, summarize animal models demonstrating kidney programming and reduced nephron numbers, and consolidate knowledge on common mechanisms driving kidney programming. Additionally, we discuss factors in the postnatal care environment that may act as secondary insults contributing to CKD risk, such as acute kidney injury (AKI), the use of nephrotoxic drugs, preterm nutrition, and catch-up growth. Finally, we outline recommendations for action, emphasizing the importance of avoiding modifiable risk factors and implementing early CKD screening for children born preterm. Together, we can ensure that advancements in kidney health keep pace with improvements in preterm care.

Background: The convergence of cardiovascular, kidney, and metabolic disorders at the pathophysiological level has led to the recognition of cardiovascular-kidney-metabolic (CKM) syndrome, which represents a significant global health challenge. Polyphenols, a group of phytochemicals, have demonstrated potential health-promoting effects., Methods: This review highlights the impact of maternal polyphenol supplementation on the CKM health of offspring., Results: Initially, we summarize the interconnections between polyphenols and each aspect of CKM syndrome. We then discuss in vivo studies that have investigated the use of polyphenols during pregnancy and breastfeeding, focusing on their role in preventing CKM syndrome in offspring. Additionally, we explore the common mechanisms underlying the protective effects of maternal polyphenol supplementation., Conclusions: Overall, this review underscores the potential of early-life polyphenol interventions in safeguarding against CKM syndrome in offspring. It emphasizes the importance of continued research to advance our understanding and facilitate the clinical translation of these interventions.

Background: Offspring hypertension arising from adverse maternal conditions can be mitigated through dietary nutritional supplementation, including resveratrol. Previously, we identified derivatives of resveratrol butyrate ester (RBE), specifically 3,4'-di-O-butanoylresveratrol (ED2) and 3-O-butanoylresveratrol (ED4), demonstrating their superior antioxidant capabilities compared to RBE itself. This study sought to assess the protective impact of maternal supplementation with ED2 or ED4 on offspring hypertension in a rat model subjected to a high-fructose (HF) diet during pregnancy and lactation., Methods: Female Sprague-Dawley rats were distributed into distinct dietary groups throughout pregnancy and lactation: (1) standard chow; (2) HF diet (60%); (3) HF diet supplemented with ED2 (25 mg/L); and (4) HF diet supplemented with ED4 (25 mg/L). Male offspring were euthanized at the age of 12 weeks., Results: The maternal HF diet induced hypertension in the offspring, which was mitigated by perinatal supplementation with either ED2 or ED4. These protective effects were attributed to the antioxidant properties of ED2 and ED4, resulting in an increased availability of nitric oxide (NO). Additionally, supplementation with ED2 was connected to an increased abundance of Bifidobacterium and Clostridium genera, which was accompanied by a decrease in Angelakisella and Christensenella . On the other hand, ED4 supplementation shielded rat offspring from hypertension by elevating concentrations of short-chain fatty acids (SCFAs) and their receptors while reducing trimethylamine- N -oxide (TMAO) levels., Conclusions: These findings highlight the potential of purified RBE monomers, ED2 and ED4, as preventive measures against hypertension resulting from a maternal high-fructose diet. Further research is warranted to explore their clinical applications based on these promising results.

Background: Pediatric CKD is associated with a high risk of cardiovascular disease (CVD). Early detection of subclinical CVD in childhood CKD can be achieved through various cardiovascular (CV) assessments, including carotid intima-media thickness (cIMT), ambulatory blood pressure monitoring (ABPM), and arterial stiffness indices. Lactoferrin (LF), a key functional glycoprotein found in breast milk, has been linked to several diseases and has potential as a biomarker., Methods: In our study of 102 children with CKD stages G1-G4, we explored the relationship between LF and CV risk markers., Results: We found that LF concentration was not related to the severity or underlying causes of childhood CKD, but was positively correlated with overweight/obesity. Lower LF levels were correlated with increased cIMT and elevated arterial stiffness indices. Notably, abnormalities in ABPM profiles were observed in up to 60% of the children with CKD, with low LF levels linked to nighttime hypertension, nocturnal non-dipping, and ABPM abnormalities., Conclusions: In conclusion, LF shows promise as a biomarker for detecting subclinical CVD in children with CKD. Its potential utility in early detection could be instrumental in guiding timely interventions and improving long-term CV outcomes, although further research is needed to clarify the underlying mechanisms.

Dietary regulation has been recognized for its profound impact on human health. The convergence of cardiovascular, kidney, and metabolic disorders at the pathophysiological level has given rise to cardiovascular-kidney-metabolic (CKM) syndrome, which constitutes a significant global health burden. Maternal dietary nutrients play a crucial role in fetal development, influencing various programmed processes. This review emphasizes the effects of different types of dietary interventions on each component of CKM syndrome in both preclinical and clinical settings. We also provide an overview of potential maternal dietary strategies, including amino acid supplementation, lipid-associated diets, micronutrients, gut microbiota-targeted diets, and plant polyphenols, aimed at preventing CKM syndrome in offspring. Additionally, we discuss the mechanisms mediated by nutrient-sensing signals that contribute to CKM programming. Altogether, we underscore the interaction between maternal dietary interventions and the risk of CKM syndrome in offspring, emphasizing the need for continued research to facilitate their clinical translation.

Background: There have been concerns about the potential cardiovascular (CV) adverse effects associated with methylphenidate (MTH) use. However, only limited evidence exists on the long-term safety of MTH., Objective: To evaluate whether MTH use is associated with long-term CV risk., Methods: This was a retrospective cohort study using 2003-2017 data from the Health and Welfare Database in Taiwan. Patients newly diagnosed with attention deficit and hyperactivity disorder (ADHD) and between 3 and 18 years of age were included. Two treatment statuses were assessed: initial treatment ≥7 days and ≥180 days. Patients treated with MTH were compared with those receiving non-medication therapy. One-to-one propensity score matching was used to balance between-group differences. Study outcomes included major CV events, chronic CV disease, cardiogenic shock and all-cause mortality. Cox proportional hazard models were used to estimate HRs between the two groups., Results: We began with 307 459 patients with ADHD. After exclusion, 224 732 patients were included in the final cohort. The results showed that compared with non-ADHD medication users, patients who were treated with MTH for more than 7 days had a similar risk of major CV events (HR 0.85, 95% CI 0.72 to 0.99; p=0.040). Identical trends were found in groups who were treated for more than 180 days (HR 0.83, 95% CI 0.69 to 1.00; p=0.050). The results of the sensitivity analyses were consistent with the main analyses across all groups and individual outcomes., Conclusion: Short-term MTH use did not increase CV risk among patients with ADHD. More evidence on long-term MTH use and risk of cardiogenic shock and death is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Lactoferrin, a glycoprotein derived from breastmilk, is recognized for its health benefits in infants and children; however, its protective effects when administered during gestation and lactation against offspring hypertension remain unclear. This study aimed to investigate whether maternal lactoferrin supplementation could prevent hypertension in offspring born to mothers with chronic kidney disease (CKD), with a focus on nitric oxide (NO), renin-angiotensin system (RAS) regulation, and alterations in gut microbiota and short-chain fatty acids (SCFAs). Prior to pregnancy, female rats were subjected to a 0.5% adenine diet for 3 weeks to induce CKD. During pregnancy and lactation, pregnant rats received one of four diets: normal chow, 0.5% adenine diet, 10% lactoferrin diet, or adenine diet supplemented with lactoferrin. Male offspring were euthanized at 12 weeks of age (n = 8 per group). Supplementation with lactoferrin during gestation and lactation prevented hypertension in adult offspring induced by a maternal adenine diet. The maternal adenine diet caused a decrease in the index of NO availability, which was restored by 67% with maternal LF supplementation. Additionally, LF was related to the regulation of the RAS, as evidenced by a reduced renal expression of renin and the angiotensin II type 1 receptor. Combined maternal adenine and LF diets altered beta diversity, shifted the offspring's gut microbiota, decreased propionate levels, and reduced the renal expression of SCFA receptors. The beneficial effects of lactoferrin are likely mediated through enhanced NO availability, rebalancing the RAS, and alterations in gut microbiota composition and SCFAs. Our findings suggest that maternal lactoferrin supplementation improves hypertension in offspring in a model of adenine-induced CKD, bringing us closer to potentially translating lactoferrin supplementation clinically for children born to mothers with CKD.

Pregnant women with chronic kidney disease (CKD) face increased risks of adverse outcomes in their adult offspring. Offspring rats born to dams fed an adenine diet develop hypertension, coinciding with dysregulated hydrogen sulfide (H 2 S) and nitric oxide (NO) pathways, as well as alterations in gut microbiota. Chondroitin sulfate (CS) is a multifunctional food known for its diverse bioactivities. As a sulfate prebiotic, CS has shown therapeutic potential in various diseases. Here, we investigated the protective effects of maternal CS supplementation against hypertension in offspring induced by an adenine diet. Mother rats were administered regular chow, 0.5% adenine, 3% CS, or a combination throughout gestation and lactation. Maternal CS supplementation effectively protected offspring from hypertension induced by the adenine diet. These beneficial effects of CS were connected with increased renal mRNA and protein levels of 3-mercaptopyruvate sulfurtransferase, an enzyme involved in H 2 S production. Furthermore, maternal CS treatment significantly enhanced alpha diversity and altered beta diversity of gut microbiota in adult offspring. Specifically, perinatal CS treatment promoted the abundance of beneficial microbes such as Roseburia hominis and Ruminococcus gauvreauii . In conclusion, perinatal CS treatment mitigates offspring hypertension associated with maternal adenine diet, suggesting that early administration of sulfate prebiotics may hold preventive potential. These findings warrant further translational research to explore their clinical implications.

Background: A fixed 10-year lead-time in composite time-trade-off (C-TTO) tasks might compromise the precision of utility values below - 1. This study explored how alternative lead-times (ALTs) influence EQ-5D-5L value sets and their implications in economic evaluations., Methods: Leveraging data from Taiwan's EQ-5D-5L valuation and capitalizing on its exploratory willingness-to-accept question, we explored participants' quantification of "worse-than-dead (WTD)" health states with ALTs up to 50 years. We then derived alternative value sets incorporating these ALTs through interval regression and compared them against those from conventional models. To evaluate their impact on health change valuation, we simulated utility differences for all possible EQ-5D-5L health-state-pairs using each value set., Results: With a salient floor effect observed in the C-TTO values, the model with ALT led to a wider range of predicted utilities ( - 2.3897 ~ 1), compared with those of conventional models (generalized least squares (GLS):  - 0.7773 ~ 1; Tobit-GLS:  - 0.9583 ~ 1). Compared to the Tobit-GLS model, the model with ALT increased the numerical distance in 80% of health-state-pairs, with 11% decreasing and 9% altering direction (e.g., positive to negative) in utility differences., Conclusions: While ALTs offer insights into patient preferences, their integration into economic evaluations might require rescaling. Future research should prioritize advanced rescaling methods or enhanced elicitation strategies for populations with substantial censoring. This is pivotal for improving the elicitation of extreme WTD states and accurately discerning the relative distances between health states. Countries developing EQ-5D-5L value sets should consider pilot studies and incorporating region-specific questions on social determinants, especially where pronounced floor effects are suspected., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale & Objective: The potential effects of antenatal glucocorticoid exposure on the health of children are unclear. We examined the association of gestational exposure to maternal systemic glucocorticoids and the risk of developing chronic kidney disease (CKD) in childhood., Study Design: Retrospective cohort study., Setting & Participants: Newborns cared for at the largest health care delivery system in Taiwan between 2004 and 2018., Exposure: Maternal prescriptions for systemic glucocorticoids between the last menstrual period and birth as a proxy for gestational exposure., Outcome: Incidence of childhood CKD, including congenital anomalies of the kidney and urinary tract (CAKUT) and other kidney diseases (non-CAKUT), over 10 years., Analytical Approach: Cox proportional hazards models with stabilized inverse probability of treatment weighting and robust sandwich estimator were used to estimate the average association between systemic glucocorticoids and incident CKD after adjustment for offspring characteristics (adjusted HR: AHR)., Results: Among 23,363 singleton-born children, gestational systemic glucocorticoid exposure was significantly associated with a higher risk of childhood CKD (AHR, 1.69 [95% CI, 1.01-2.84]). Stratified analyses showed stronger associations between systemic glucocorticoids and childhood CKD within the strata of birth<37 weeks' gestational age (AHR, 2.38 [95% CI, 1.19-4.78]), male sex (AHR, 1.89 [95% CI, 1.00-3.55]), gestational exposure in the second trimester (AHR, 6.70 [95% CI, 2.17-20.64]), and total dose of>24mg hydrocortisone equivalent (AHR, 1.91 [95% CI, 1.05-3.47])., Limitations: Study was limited to the Taiwan health care delivery system and childhood CKD events through the age of 10 years., Conclusions: The findings of this study suggest that gestational exposure to systemic glucocorticoids is associated with the occurrence of kidney disease in childhood. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy., Plain-Language Summary: In a singleton-born cohort of neonates, maternal exposure to antenatal systemic glucocorticoids was significantly associated with a 1.7-fold increased risk of the children developing chronic kidney disease over the first 10 years of life. Children of mothers who received>24mg of hydrocortisone equivalent, systemic glucocorticoid treatment in second trimester of gestation, and children born at<37 weeks of gestational age had a higher risk of childhood kidney disease after gestational systemic glucocorticoid exposure. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy., (Copyright © 2024. Published by Elsevier Inc.)

Background: The gut microbiota is believed to influence neurodevelopment through the gut-brain axis, but prior studies have shown inconsistent results regarding early childhood antibiotic exposure and subsequent risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The purpose of this study was to evaluate the hypothesis that exposure to antibacterial agents in the first 2 years of life increases the risk of ASD and/or ADHD., Methods: This was a retrospective cohort study using 2003-2019 data from the National Health Insurance Research Database in Taiwan. Livebirths born between 2004 and 2016 were identified and separated into singleton, full sibling, and exposure-discordant sibling pair cohorts. The exposure group included children who filled at least one prescription for antibacterial agents between 0 and 2 years old in outpatient settings. The outcome, ASD and/or ADHD, was defined by at least one inpatient or outpatient diagnosis. The maximum follow-up age was 15 years in this study. Potential neonatal, maternal and paternal confounders were adjusted for. Cox proportional hazards models were used to estimate the relative event risk., Results: The final sample contained 946,581 children in the singleton cohort, 1,142,693 children in the full sibling cohort, and 352,612 children in the exposure-discordant sibling pair cohort. Antibiotic exposure marginally increased the risk of ASD and/or ADHD in the singleton cohort (adjusted hazard ratio [aHR]: 1.06, 95% confidence interval [CI]: 1.04-1.07) and in the full sibling cohort (aHR: 1.03, 95% CI: 1.01-1.04). A slight decrease in the risk of ASD and/or ADHD was observed in the exposure-discordant sibling pair cohort (aHR: 0.92, 95% CI: 0.90-0.94)., Conclusions: The results suggest that early life antibiotic exposure has minimal impact on the risk of ASD and/or ADHD. Given that the estimated effects are marginal and close to null, concerns about ASD and/or ADHD risk increase should not postpone or deter timely and reasonable antibiotic use., (© 2024. The Author(s).)

Resveratrol, acting as a prebiotic, and propionate, functioning as a postbiotic, hold promise for preventing hypertension in chronic kidney disease (CKD). Previously, we employed propionate to enhance the bioavailability of resveratrol through esterification, resulting in the production of a resveratrol propionate ester (RPE) mixture. In this study, we purified 3-O-propanoylresveratrol (RPE2) and 3,4'-di-O-propanoylresveratrol (RPE4) and investigated their protective effects in a juvenile rat adenine-induced CKD model. To this end, male Sprague Dawley rats aged three weeks ( n = 40) were divided into five groups: control; CKD (rats fed adenine); CKRSV (CKD rats treated with 50 mg/L resveratrol); CDRPE2 (CKD rats treated with 25 mg/L RPE2); and CKRPE4 (CKD rats treated with 25 mg/L RPE 4). RPE2 and PRE4 similarly exhibited blood pressure-lowering effects comparable to those of resveratrol, along with increased nitric oxide (NO) availability. Furthermore, RPE2 and RPE4 positively influenced plasma short-chain fatty acid (SCFA) levels and induced distinct alterations in the gut microbial composition of adenine-fed juvenile rats. The supplementation of RPE2 and RPE4, by restoring NO, elevating SCFAs, and modulating the gut microbiota, holds potential for ameliorating CKD-induced hypertension.

The movement of liquid droplets on the energy gradient surface has attracted extensive attention inspired by biological features in nature, such as the periodic spindle-shaped nodes in spider silks and conical-like barbs of cacti, and the structure-property-function relationship of multifunctional gradient surfaces. In this study, a series of specific patterns are fabricated with 3D printing technology, followed by modification via the atmospheric pressure plasma treatment and liquid phase chemical deposition, resulting in enhancing the ability of water droplets of 5 μL to travel 18.47 mm on a horizontal plane and 22.75 mm against gravity at up to a 20° tilting angle. Additionally, analysis techniques have been employed, including a contact angle analyzer, ESCA, and a laser confocal microscope to evaluate the sample performance. This work could further be applied to many applications related to microfluidic devices, drug delivery and water/fog collection.

Introduction: There is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes., Methods: SGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases., Results: After matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87-1.20)/1.09 (0.92-1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions., Conclusion: Using metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes., 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 Chong, Chang, Lin, Hsu, Wang, Wang, Huang, Lin and Ou.)

Recent human and animal studies have delineated hypertension can develop in the earliest stage of life. A lack or excess of particular nutrients in the maternal diet may impact the expression of genes associated with BP, leading to an increased risk of hypertension in adulthood. Modulations in gene expression could be caused by epigenetic mechanisms through aberrant DNA methylation, histone modification, and microRNAs (miRNAs). Several molecular mechanisms for the developmental programming of hypertension, including oxidative stress, dysregulated nutrient-sensing signal, aberrant renin-angiotensin system, and dysbiotic gut microbiota have been associated with epigenetic programming. Conversely, maternal nutritional interventions such as amino acids, melatonin, polyphenols, resveratrol or short chain fatty acids may work as epigenetic modifiers to trigger protective epigenetic modifications and prevent offspring hypertension. We present a current perspective of maternal malnutrition that can cause fetal programming and the potential of epigenetic mechanisms lead to offspring hypertension. We also discuss the opportunities of dietary nutrients or nutraceuticals as epigenetic modifiers to counteract those adverse programming actions for hypertension prevention. The extent to which aberrant epigenetic changes can be reprogrammed or reversed by maternal dietary interventions in order to prevent human hypertension remains to be established. Continued research is necessary to evaluate the interaction between maternal malnutrition and epigenetic programming, as well as a greater focus on nutritional interventions for hypertension prevention towards their use in clinical translation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The effects of gut microbiota on the association between carbohydrate intake during pregnancy and neonatal low birth weight (LBW) were investigated. A prospective cohort study was conducted with 257 singleton-born mother-child pairs in Taiwan, and maternal dietary intake was estimated using a questionnaire, with each macronutrient being classified as low, medium, or high. Maternal fecal samples were collected between 24 and 28 weeks of gestation, and gut microbiota composition and diversity were profiled using 16S rRNA amplicon gene sequencing. Carbohydrates were the major source of total energy (56.61%), followed by fat (27.92%) and protein (15.46%). The rate of infant LBW was 7.8%, which was positively correlated with maternal carbohydrate intake. In the pregnancy gut microbiota, Bacteroides ovatus and Dorea spp. were indirectly and directly negatively associated with fetal growth, respectively; Rosenburia faecis was directly positively associated with neonatal birth weight. Maternal hypertension during pregnancy altered the microbiota features and was associated with poor fetal growth. Microbiota-accessible carbohydrates can modify the composition and function of the pregnancy gut microbiota, thus providing a potential marker to modulate deviations from dietary patterns, particularly in women at risk of hypertension during pregnancy, to prevent neonatal LBW.

Amino acids are essential for normal pregnancy and fetal development. Disruptions in maternal amino acid metabolism have been associated with various adult diseases later in life, a phenomenon referred to as the developmental origins of health and disease (DOHaD). In this review, we examine the recent evidence highlighting the significant impact of amino acids on fetal programming, their influence on the modulation of gut microbiota, and their repercussions on offspring outcomes, particularly in the context of cardiovascular-kidney-metabolic (CKM) syndrome. Furthermore, we delve into experimental studies that have unveiled the protective effects of therapies targeting amino acids. These interventions have demonstrated the potential to reprogram traits associated with CKM in offspring. The discussion encompasses the challenges of translating the findings from animal studies to clinical applications, emphasizing the complexity of this process. Additionally, we propose potential solutions to overcome these challenges. Ultimately, as we move forward, future research endeavors should aim to pinpoint the most effective amino-acid-targeted therapies, determining the optimal dosage and mode of administration. This exploration is essential for maximizing the reprogramming effects, ultimately contributing to the enhancement of cardiovascular-kidney-metabolic health in offspring.

Early life exposure lays the groundwork for the risk of developing cardiovascular-kidney-metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future.

Background: Statins may reduce the risk of recurrent gallstone disease by decreasing bile cholesterol saturation and pathogenicity. However, limited studies have investigated this issue. This study aimed to assess whether statin doses and serum cholesterol levels were associated with a decreased risk of recurrent biliary stone diseases after the first event index, with a follow-up time of 15 years., Methods: Based on the Chang Gung Research Database (CGRD) between January 1, 2001, and December 31, 2020, we enrolled 68,384 patients with the International Classification of Diseases, Ninth and Tenth Revision codes of choledocholithiasis. After exclusions, 32,696 patients were divided into non-statin (<28 cDDD, cumulative defined daily doses) (n = 27,929) and statin (≥28 cDDD) (n = 4767) user groups for analysis. Serum cholesterol trajectories were estimated using group-based trajectory modeling (n = 8410)., Results: The statin users had higher Charlson Comorbidity Index (CCI) scores than the non-statin users. Time-dependent Cox regression analysis showed that statin use >365 cDDD was associated with a significantly lower risk of recurrent biliary stones (adjusted hazard ratio [aHR] = 0.28, 95% CI, 0.24-0.34; p < 00.0001), acute pancreatitis (aHR = 0.24, 95% CI, 0.17-0.32, p < 00.0001), and cholangitis (aHR = 0.28, 95% CI, 0.25-0.32, p < 00.0001). Cholecystectomy was also a protective factor for recurrent biliary stones (aHR = 0.41, 95% CI, 0.37-0.46; p < 00.0001). The higher trajectory serum cholesterol group (Group 3) had a lower risk trend for recurrent biliary stones (aHR = 0.79, p = 0.0700) and a lower risk of cholangitis (aHR = 0.79, p = 0.0071)., Conclusion: This study supports the potential benefits of statin use and the role of cholecystectomy in reducing the risk of recurrent biliary stone diseases., Competing Interests: Declaration of Competing Interest The authors declared that they have no conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The identification of pathological links among metabolic disorders, kidney ailments, and cardiovascular conditions has given rise to the concept of cardiovascular-kidney-metabolic (CKM) syndrome. Emerging prenatal risk factors seem to increase the likelihood of CKM syndrome across an individual's lifespan. The renin-angiotensin system (RAS) plays a crucial role in maternal-fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review consolidates current preclinical evidence detailing how dysregulation of the RAS during pregnancy and lactation leads to CKM characteristics in offspring, elucidating the underlying mechanisms. The multi-organ effects of RAS, influencing fetal programming and triggering CKM traits in offspring, suggest it as a promising reprogramming strategy. Additionally, we present an overview of interventions targeting the RAS to prevent CKM traits. This comprehensive review of the potential role of the RAS in the early-life programming of CKM syndrome aims to expedite the clinical translation process, ultimately enhancing outcomes in cardiovascular-kidney-metabolic health.

Metabolic syndrome (MetS) denotes a constellation of risk factors associated with the development of cardiovascular disease, with its roots potentially traced back to early life. Given the pivotal role of oxidative stress and dysbiotic gut microbiota in MetS pathogenesis, comprehending their influence on MetS programming is crucial. Targeting these mechanisms during the early stages of life presents a promising avenue for preventing MetS later in life. This article begins by examining detrimental insults during early life that impact fetal programming, ultimately contributing to MetS in adulthood. Following that, we explore the role of oxidative stress and the dysregulation of gut microbiota in the initiation of MetS programming. The review also consolidates existing evidence on how gut-microbiota-targeted interventions can thwart oxidative-stress-associated MetS programming, encompassing approaches such as probiotics, prebiotics, postbiotics, and the modulation of bacterial metabolites. While animal studies demonstrate the favorable effects of gut-microbiota-targeted therapy in mitigating MetS programming, further clinical investigations are imperative to enhance our understanding of manipulating gut microbiota and oxidative stress for the prevention of MetS.

Cardiovascular-kidney-metabolic (CKM) syndrome has emerged as a major global public health concern, posing a substantial threat to human health. Early-life exposure to oxidative stress may heighten vulnerability to the developmental programming of adult diseases, encompassing various aspects of CKM syndrome. Conversely, the initiation of adverse programming processes can potentially be thwarted through early-life antioxidant interventions. Melatonin, originally recognized for its antioxidant properties, is an endogenous hormone with diverse biological functions. While melatonin has demonstrated benefits in addressing disorders linked to oxidative stress, there has been comparatively less focus on investigating its reprogramming effects on CKM syndrome. This review consolidates the current knowledge on the role of oxidative stress during pregnancy and lactation in inducing CKM traits in offspring, emphasizing the underlying mechanisms. The multifaceted role of melatonin in regulating oxidative stress, mediating fetal programming, and preventing adverse outcomes in offspring positions it as a promising reprogramming strategy. Currently, there is a lack of sufficient information in humans, and the available evidence primarily originates from animal studies. This opens up new avenues for novel preventive intervention in CKM syndrome.

Background: This study aimed to explore the impact of diabetes on overactive bladder (OAB) presentations and related predictors of healthcare-seeking behavior among adults aged ≥ 40 years in China, Taiwan, and South Korea., Methods: An internet-based survey was conducted to assess the prevalence of diabetes, OAB presentations, and self-perceived urinary symptoms by a multi-national sample of 8284 individuals who completed the survey between June 2, 2015 and July 31, 2015. Independent associations with health-seeking behavior for urinary symptoms were estimated with odds ratio (OR) with 95% confidence interval (95% CI) using multivariate logistic regression., Results: Diabetes was reported in 13.6% of participants and OAB was 20.8%. Diabetic participants were older than non-diabetic participants in both sexes. Participants with diabetes reported a higher rate of OAB (43.1%) and increased bothersome symptoms associated with OAB than those without diabetes. Participants with diabetes (OR, 3.07 [2.39-3.96]], urgent incontinence (OR, 2.38 [1.86-3.03]), frequency (OR, 1.86 [1.45-2.38]), and nocturia (OR, 1.14 [1.05-1.24]) were associated with healthcare-seeking behavior., Conclusion: The proportion of diabetic participants with OAB was 2.5-fold higher than those without diabetes. Diabetes, urinary frequency, nocturia, and urgent incontinence are predictors of medical treatment-seeking behavior, but the key symptom of OAB-urgency is not a predictor of treatment-seeking behavior. It is important for clinicians to recognize the interplay between diabetes and OAB and to early identify various bothersome urinary symptoms for better health outcomes in daily practice., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin-angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens . Citrulline's ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats.

Children suffering from chronic kidney disease (CKD) have a high risk of cardiovascular disease (CVD). The early detection and diagnosis of subclinical CVD in pediatric CKD can reduce mortality later in life. Plasma factor 4 (PF4) is a chemokine released by activated platelets. We examined whether or not PF4 in the plasma and urine, its kidney function normalized ratio, and fractional excretion have differential associations with CVD risk markers in 139 youths aged 3 to 18 years old with CKD stages G1-G4. Significant negative correlations were observed between plasma PF4 and cardiovascular surrogate markers, such as the left ventricular mass index (LVMI), carotid intima-media thickness (cIMT), and pulse wave velocity (PWV). The plasma PF4/creatinine (Cr) ratio was lower in CKD children with a high daytime BP and 24 h BP, high BP load, and nocturnal non-dipping status. After adjusting for confounders, the plasma PF4 and plasma PF4/Cr ratio still independently predicted an abnormal ABPM profile. In addition, both the plasma PF4 and plasma PF4/Cr ratio presented a negative correlation with the L-arginine and asymmetric dimethylarginine ratio. These findings provide convincing evidence supporting the link between PF4 and CVD markers in pediatric CKD. Our study highlights the importance of further research to assess the performance of PF4-related biomarkers in predicting CVD events and CKD progression in children with CKD.

Taurine is a natural antioxidant with antihypertensive properties. Maternal chronic kidney disease (CKD) has an impact on renal programming and increases the risk of offspring hypertension in later life. The underlying mechanisms cover oxidative stress, a dysregulated hydrogen sulfide (H 2 S) system, dysbiotic gut microbiota, and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether perinatal taurine administration enables us to prevent high blood pressure (BP) in offspring complicated by maternal CKD. Before mating, CKD was induced through feeding chow containing 0.5% adenine for 3 weeks. Taurine was administered (3% in drinking water) during gestation and lactation. Four groups of male offspring were used ( n = 8/group): controls, CKD, taurine-treated control rats, and taurine-treated rats with CKD. Taurine treatment significantly reduced BP in male offspring born to mothers with CKD. The beneficial effects of perinatal taurine treatment were attributed to an augmented H 2 S pathway, rebalance of aberrant RAAS activation, and gut microbiota alterations. In summary, our results not only deepen our knowledge of the mechanisms underlying maternal CKD-induced offspring hypertension but also afford us the impetus to consider taurine-based intervention as a promising preventive approach for future clinical translation.

Introduction: Foot and ankle fractures are the most common military health problem. Automated diagnosis can save time and personnel. It is crucial to distinguish fractures not only from normal healthy cases, but also robust against the presence of other orthopedic pathologies. Artificial intelligence (AI) deep learning has been shown to be promising. Previously, we have developed HAMIL-Net to automatically detect orthopedic injuries for upper extremity injuries. In this research, we investigated the performance of HAMIL-Net for detecting foot and ankle fractures in the presence of other abnormalities., Materials and Methods: HAMIL-Net is a novel deep neural network consisting of a hierarchical attention layer followed by a multiple-instance learning layer. The design allowed it to deal with imaging studies with multiple views. We used 148K musculoskeletal imaging studies for 51K Veterans at VA San Diego in the past 20 years to create datasets for this research. We annotated each study by a semi-automated pipeline leveraging radiology reports written by board-certified radiologists and extracting findings with a natural language processing tool and manually validated the annotations., Results: HAMIL-Net can be trained with study-level, multiple-view examples, and detect foot and ankle fractures with a 0.87 area under the receiver operational curve, but the performance dropped when tested by cases including other abnormalities. By integrating a fracture specialized model with one that detecting a broad range of abnormalities, HAMIL-Net's accuracy of detecting any abnormality improved from 0.53 to 0.77 and F-score from 0.46 to 0.86. We also reported HAMIL-Net's performance under different study types including for young (age 18-35) patients., Conclusions: Automated fracture detection is promising but to be deployed in clinical use, presence of other abnormalities must be considered to deliver its full benefit. Our results with HAMIL-Net showed that considering other abnormalities improved fracture detection and allowed for incidental findings of other musculoskeletal abnormalities pertinent or superimposed on fractures., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cardiac rehabilitation is a comprehensive intervention recommended in international and Taiwanese guidelines for patients with acute myocardial infarction. Evidence supports that cardiac rehabilitation improves the health-related quality of life, enhances exercise capacity, reduces readmission rates, and promotes survival in patients with cardiovascular disease. The cardiac rehabilitation team is comprehensive and multidisciplinary. The inpatient, outpatient, and maintenance phases are included in cardiac rehabilitation. All patients admitted with acute myocardial infarction should be referred to the rehabilitation department as soon as clinically feasible. Pre-exercise evaluation, including exercise testing, helps physicians identify the risks of cardiac rehabilitation and organize appropriate exercise prescriptions. Therefore, the Taiwan Myocardial Infarction Society (TAMIS), Taiwan Society of Cardiology (TSOC), and Taiwan Academy of Cardiovascular and Pulmonary Rehabilitation (TACVPR) address this consensus statement to assist healthcare practitioners in performing cardiac rehabilitation in patients with acute myocardial infarction., Competing Interests: All the authors declare no conflict of interest.

Antrodia cinnamomea (AC), a medicinal mushroom, has multiple beneficial actions, such as acting as a prebiotic. The incidence of chronic kidney disease (CKD) in children has steadily increased year by year, and CKD is related to gut microbiota dysbiosis. Herein, we investigated the renoprotection of solid-state cultivated AC in adenine-induced CKD juvenile rats. CKD was induced in 3-week-old male rats by feeding with adenine (0.5%) for three weeks. Treated groups received oral administration of AC extracts at either a low (10 mg/kg/day) or high dose (100 mg/kg/day) for six weeks. At nine weeks of age, the rats were sacrificed. Renal outcomes, blood pressure, and gut microbiome composition were examined. Our results revealed that AC treatment, either low- or high-dose, improved kidney function, proteinuria, and hypertension in CKD rats. Low-dose AC treatment increased plasma concentrations of short-chain fatty acids (SCFAs). Additionally, we observed that AC acts like a prebiotic by enriching beneficial bacteria in the gut, such as Akkermansia and Turicibacter . Moreover, the beneficial action of AC against CKD-related hypertension might also be linked to the inhibition of the renin-angiotensin system. This study brings new insights into the potential application of AC as a prebiotic dietary supplement in the prevention and treatment of pediatric CKD.

Objective: To characterize longitudinal changes and correlations between the measures of EQ-5D-Y and generic PedsQL and their associations with clinical changes in children and adolescents with mild-to-moderate chronic kidney disease (CKD)., Methods: Participants were recruited from January 2017 to September 2021 in a medical center in Taiwan. Both instruments were administered in their initial visits and every 6-month subsequent visits. Spearman's Rho (ρ) was used to assess correlations between the scores of EQ-5D-Y and PedsQL measures in longitudinal changes. Cohen's effect size (ES) was used to evaluate the changes of scores/subscales over time. In addition, factors associated with longitudinal changes in the score/subscales were explored., Results: A total of 121 participants were enrolled, and 83 with ≥ 3 HRQOL measures during the 3.5 years follow-up were assessed their changes of HRQOL measures. The correlations (ρ > 0.3) appeared between the changes in the visual analog scale (VAS) of EQ-5D-Y and emotional and social subscales of PedsQL. ES was small (< 0.5) in the VAS and level-sum-score (LSS) of EQ-5D-Y scores for the clinical changes in comorbidities, while some PedsQL subscales were medium to high (0.5-0.8 or > 0.8). Hypertension, mineral bone disorder/anemia, and hyperuricemia associated with the changes in both HRQOL scores were varied by their various domains., Conclusion: Both EQ-5D-Y and PedsQL of HRQOL measures were responsive to worsened childhood CKD-related comorbidities during the follow-up; however, convergent validity between them was limited in some domains. The LSS of EQ-5D-Y showed greater changes than the VAS by comorbidity status; further comparison with utility weight is needed to determine the better performance of EQ-5D-Y., (© 2023. The Author(s).)

Background: The superior effects of gastric bypass surgery in preventing cardiovascular diseases compared with sleeve gastrectomy are well-established. However, whether these effects are independent of weight loss is not known., Methods: In this retrospective cohort study, we compared the change in cardiometabolic risks of 1073 diabetic patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 265), one-anastomosis gastric bypass (OAGB) (n = 619), and sleeve gastrectomy (SG) (n = 189) with equivalent weight loss from the Min-Shen General Hospital. Propensity score-weighting, multivariate regression, and matching were performed to adjust for baseline differences., Results: After 12 months, OAGB and, to a lesser extent, RYGB exhibited superior effects on glycemic control compared with SG in patients with equivalent weight loss. The effect was significant in patients with mild-to-modest BMI reduction but diminished in patients with severe BMI reduction. RYGB and OAGB had significantly greater effects in lowering total and low-density lipoprotein cholesterol than SG, regardless of weight loss. The results of matching patients with equivalent weight loss yielded similar results. The longer length of bypassed biliopancreatic (BP) limbs was correlated with a greater decrease in glycemic levels, insulin resistance index, lipids, C-reactive protein (CRP) levels, and creatinine levels in patients receiving RYBG. It was correlated with greater decreases in BMI, fasting insulin, insulin resistance index, and C-reactive protein levels in patients receiving OAGB., Conclusion: Diabetic patients receiving OAGB and RYGB had lower glucose and cholesterol levels compared with SG independent of weight loss. Our results suggest diabetic patients with cardiovascular risk factors such as hypercholesterolemia to receive bypass surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cardiovascular disease (CVD) is a significant cause of mortality and morbidity among children with chronic kidney disease (CKD). The causes of pediatric CKD differ from those in adults, as congenital anomalies in the kidney and urinary tract (CAKUT) are the leading causes in childhood. Identifying ideal markers of CVD risk early is crucial for CKD children to improve their care. Previously, we screened differentially expressed proteins in CKD children with or without blood pressure (BP) abnormalities and identified pregnancy zone protein (PZP). In 106 children and adolescents with CKD stages G1-G4, we analyzed plasma PZP concentration. The associations between PZP and ambulatory BP monitoring (ABPM) profile, parameters of cardiac and carotid ultrasounds, indices of arterial stiffness, and nitric oxide (NO) parameters were determined. We observed that PZP positively correlated with arterial stiffness indices, beta index, and pulse wave velocity in CAKUT. CKD children with abnormalities in ABPM and night dipping displayed a higher PZP concentration than those without. Additionally, the PZP level was positively correlated with NO bioavailability. In conclusion, our results suggest PZP has differential influences on cardiovascular risk in CAKUT and non-CAKUT children. Identification of this relationship is novel in the pediatric CKD literature.

Nitric oxide (NO) is a gaseous signaling molecule with renoprotective properties. NO can be produced in NO synthase (NOS)-dependent or -independent manners. NO deficiency plays a decisive role in chronic kidney disease (CKD). Kidney development can be affected in response to adverse intrauterine conditions that induce renal programming, thereby raising the risk of developing CKD in adulthood. Conversely, detrimental programming processes could be postponed or halted prior to the onset of CKD by early treatments, namely reprogramming. The current review provides an overview of the NOS/NO research performed in the context of renal programming and reprogramming. NO deficiency has been increasingly found to interact with the different mechanisms behind renal programming, such as oxidative stress, aberrant function of the renin-angiotensin system, disturbed nutrient-sensing mechanisms, dysregulated hydrogen sulfide signaling, and gut microbiota dysbiosis. The supplementation of NOS substrates, the inhibition of asymmetric dimethylarginine (ADMA), the administration of NO donors, and the enhancement of NOS during gestation and lactation have shown beneficial effects against renal programming in preclinical studies. Although human data on maternal NO deficiency and offspring kidney disease are scarce, experimental data indicate that targeting NO could be a promising reprogramming strategy in the setting of renal programming.

Impaired kidney function is associated with increased morbidity and mortality in patients undergoing liver transplantation. Although immunosuppressants are essential in these patients, they impair kidney function. This study aimed to compare adverse kidney outcomes between patients treated with a reduced dose of tacrolimus (calcineurin inhibitor) plus sirolimus or mycophenolate mofetil (MMF) in the liver transplant center at Kaohsiung Chang Gung Memorial Hospital between April 2011 and December 2017. Propensity score matching was used to identify 232 patients. The risk of adverse kidney outcomes was estimated using Cox proportional hazards regression, and changes in kidney function over time were analyzed using linear mixed modeling. Acute kidney disease risks in this study cohort were not significantly different for the two immunosuppressants (aHR 1.04; 95% CI: 0.70-1.55, p = 0.8328). However, sirolimus use was significantly associated with a higher risk of estimated glomerular filtration rate decline > 30% than MMF (aHR, 2.09; 95% CI: 1.33-3.28; p = 0.0014). Our results demonstrate that sirolimus use may have worsened long-term kidney outcomes compared to MMF. Close monitoring of kidney function, dose adjustment, and timely transition to MMF is necessary for LT patients receiving sirolimus.

Background/aims: Childhood-onset hypertension is associated with cardiovascular morbidity and adult mortality. This study aimed to assess guideline-adherent hypertension among Taiwanese youth and the agreement on hypertension between the 2017 American Academy of Pediatrics guidelines and the 2004 Fourth Report., Methods: In this cross-sectional study, we collected outpatient blood pressure (OBP) measurements obtained during routine care visits from a large healthcare delivery system between 2009 and 2018 to evaluate the rate of guideline-adherent hypertension and assess patient-related factors of pediatric hypertension., Results: In total, 12,469 children and adolescents who underwent three separate ≥3 OBP measurements over 33,369 person-years with a total of 95,608 BP measurements in an outpatient setting were analyzed. According to the 2017 American Academy of Pediatrics (AAP) guidelines, the rate of pediatric hypertension in the study setting, which included participants aged 1 to 17 years, ranged from 0.78 to 5.95 per 1000 persons. Although there was perfect agreement between the thresholds of the two guidelines for defining hypertension in the age groups of 1-7, 8-12, and 13-17 years (all κ statistic ≥ 0.85), the use of the AAP threshold classified more adolescents as having hypertension. Children and adolescents with hypertension often had complex chronic diseases and required substantial healthcare services in outpatient, emergency, and inpatient settings., Conclusions: The present study provides evidence of guideline-adherent pediatric hypertension and highlights the importance of regularly monitoring blood pressure to identify and manage hypertension in children and adolescents. Further research is required to determine the impact of new thresholds on the detection of target organ damage at a pediatric age., Competing Interests: The authors declare no conflicts of interest.

Hydrogen sulfide (H 2 S) and related reactive sulfur species are implicated in chronic kidney disease (CKD) and hypertension. Offspring born to CKD-afflicted mothers could develop hypertension coinciding with disrupted H 2 S and nitric oxide (NO) signaling pathways as well as gut microbiota. Thiosulfate, a precursor of H 2 S and an antioxidant, has shown anti-hypertensive effects. This study aimed to investigate the protective effects of sodium thiosulfate (STS) in a rat model of maternal CKD-induced hypertension. Before mating, CKD was induced through feeding 0.5% adenine chow for 3 weeks. Mother rats were given a vehicle or STS at a dosage of 2 g/kg/day in drinking water throughout gestation and lactation. Perinatal STS treatment protected 12-week-old offspring from maternal CKD-primed hypertension. The beneficial effects of STS could partially be explained by the enhancement of both H 2 S and NO signaling pathways and alterations in gut microbiota. Not only increasing beneficial microbes but maternal STS treatment also mediates several hypertension-associated intestinal bacteria. In conclusion, perinatal treatment with STS improves maternal CKD-primed offspring hypertension, suggesting that early-life RSS-targeting interventions have potential preventive and therapeutic benefits, awaiting future translational research.