Hospital water environment and antibiotic use: Key factors in a nosocomial outbreak of carbapenemase-producing Serratia marcescens.

BACKGROUND: The healthcare water environment is a potential reservoir of carbapenem-resistant organisms (CROs). Here, we report the role of the water environment as a reservoir and the infection control measures applied to suppress a prolonged outbreak of Klebsiella pneumoniae carbapenemase-producing Serratia marcescens (KPC-SM) in two intensive care units (ICUs). METHODS: The outbreak occurred in the ICUs of a tertiary hospital from October 2020 to July 2021. Comprehensive patient contact tracing and environmental assessments were conducted, and a case-control study was performed to identify factors associated with the acquisition of KPC-SM. Associations among isolates were assessed via pulsed-field gel electrophoresis (PFGE). Antibiotic usage was analyzed. . RESULTS: The outbreak consisted of two waves involving a total of 30 patients with KPC-SM. Multiple environmental cultures identified KPC-SM in a sink, a dirty utility room, and a communal bathroom shared by the ICUs, together with the waste bucket of a continuous renal replacement therapy (CRRT) system. The genetic similarity of the KPC-SM isolates from patients and the environment was confirmed by PFGE. A retrospective review of 30 cases identified that the use of CRRT and antibiotics were associated with acquisition of KPC-SM (p < 0.05). There was a continuous increase in the use of carbapenems; notably, the use of colistin has increased since 2019. CONCLUSION: Our study demonstrates that CRRT systems, along with other hospital water environments, are significant potential sources of resistant microorganisms, underscoring the necessity of enhancing infection control practices in these areas.

Korea Nurses' Health Study and the health of reproductive-aged women: a cohort profile.

The Korea Nurses' Health Study (KNHS) is an ongoing, large-scale, prospective cohort study of female nurses, focusing on the effects of occupational, environmental, and lifestyle factors on the health of women. The first KNHS survey was performed in 2013-2014 (n=20,613). As of December 2023, 11 follow-up surveys have been conducted. Participants who were pregnant were asked to participate in the early pregnancy survey (n=2,179) and postpartum survey after giving birth (n=2,790). The main variables included sociodemographic, work-related, lifestyle, physical, mental, and women's health factors. Blood, urine, and toenail samples were collected from a participant subgroup of the first survey (n=1,983). The subgroups of the second survey completed a food frequency questionnaire in 2019 (n=300) and 2021 (n=871). In 2020, a subgroup of the first survey answered a coronavirus disease 2019 (COVID-19)-related survey (n=975). To examine various health-related factors in young adults, new participants were added to the KNHS cohort in the 11th (n=1,000) and 12th (n=1,002) surveys. The KNHS cohort will help identify health and illness determinants in Korean women. Data can be accessed at https://coda.nih.go.kr/frt/index.do.

Evaluating cardiovascular disease risk stratification using multiple-polygenic risk scores and pooled cohort equations: insights from a 17-year longitudinal Korean cohort study.

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, caused by a complex interplay of genetic and environmental factors. This study aimed to evaluate the combined efficacy of multi-polygenic risk scores and pooled cohort equations (PCE) for predicting future CVD risks in the Korean population. In this longitudinal study, 7,612 individuals from the Ansan and Ansung cohorts were analyzed over a 17-year follow-up period. The participants were genotyped using the Korea Biobank Array, and quality-controlled genetic data were subjected to imputation analysis. The weighted sum of the PRSs (wPRSsum) was calculated using PRS-CS with summary statistics from myocardial infarction, ischemic stroke, coronary artery disease, and hypertension genome-wide association studies. The recalibrated PCE was used to assess clinical risk, and the participants were stratified into risk groups based on the wPRSsum and PCE. Associations between these risk scores and incident CVD were evaluated using Cox proportional hazards models and Kaplan-Meier analysis. The wPRSsum approach showed a significant association with incident CVD (HR = 1.15, p = 7.49 × 10-5), and the top 20% high-risk genetic group had an HR of 1.50 (p = 5.04 × 10-4). The recalibrated PCE effectively differentiated between the low and high 10-year CVD risk groups, with a marked difference in survival rates. The predictive models constructed using the wPRSsum and PCE demonstrated a slight improvement in prediction accuracy, particularly among males aged <55 years (C-index = 0.640). We demonstrated that while the integration of wPRSsum with PCE did not significantly outperform the PCE-only model (C-index: 0.703 for combined and 0.704 for PCE-only), it provided enhanced stratification of CVD risk. The highest risk group, identified through the combination of high wPRSsum and PCE scores, exhibited an HR of 4.99 for incident CVD (p = 1.45 × 10-15). These findings highlight the potential of integrating genetic risk assessments with traditional clinical tools for effective CVD risk stratification. Although the addition of wPRSsum to the PCE provided a marginal predictive improvement, it proved valuable in identifying high-risk individuals and supporting personalized treatment strategies. This study reinforces the utility of multi-PRS in conjunction with clinical risk assessment tools, paving the way for more tailored approaches for CVD prevention and management in diverse populations.

Nutrition survey methods and food composition database update of the Korean Genome and Epidemiology Study.

This study presents the nutrition survey methods and the updated food composition database for the Korean Genome and Epidemiology Study (KoGES). The KoGES, which is the largest and longest cohort study in Korea, aims to identify genetic and environmental factors associated with chronic diseases. This study has collected dietary data using a validated semi-quantitative food frequency questionnaire and/or the 24-hour recall method. However, these dietary survey methods use different food composition databases, and their nutritional values are out of date. Therefore, it became necessary to update the food composition database by correcting errors in nutrient analysis values to reflect improvements in the performance of food ingredient analysis equipment, revising international values ​​to analysis values ​​of Korean agricultural products, adjusting nutrient units, and adding newly reported nutrients related to chronic diseases. For this purpose, we integrated the different food composition databases used in each nutrition survey, updated 23 nutrients, and expanded 48 new nutrients for 3,648 food items using the latest reliable food composition databases published by national and international institutions. This revised food composition database may help to clarify the relationship between various nutrients and chronic diseases. It could serve as a valuable resource for nutritional, epidemiological, and genomic research and provide a basis for determining public health policies.

Associations of resistance training levels with low muscle mass: a nationwide cross-sectional study in Korea.

BACKGROUND: Low muscle mass is associated with adverse health outcomes such as functional decline and all-cause mortality. This study investigated the relationship between the risk of low muscle mass and the training period and/or frequency of resistance training (RT). METHODS: We included 126,339 participants (81,263 women) from nationwide cohorts in Korea. Low muscle mass was defined based on the fat-free mass index. To investigate the presence of an inverse dose-response relationship between RT levels and the risk of low muscle mass, the training period (months) and frequency (per week) of RT were used. Multiple logistic regression models were used to assess the risk of low muscle mass according to the RT levels. RESULTS: Prevalence rates for low muscle mass in our study population were 21.27% and 6.92% in men and women, respectively. When compared with not performing RT, performing RT for 3-4 days/week and ≥5 days/week decreased the risk of low muscle mass by 22% and 27%, respectively, and performing RT for 12-23 months and ≥24 months decreased the risk by 19% and 41%, respectively. When simultaneously considering both training period and frequency, performing RT for either 3-4 days/week or ≥5 days/week was significantly related to risk reduction, provided that the training period was at least 1 year. Importantly, performing RT for more than 2 years resulted in an additional risk reduction. However, there was no additional effect of performing RT for ≥5 days/week compared to 3-4 days/week, regardless of whether the RT duration was 1-2 years or more than 2 years. CONCLUSIONS: Since performing RT for 5 days/week or more did not yield any additional effects on the risk of low muscle mass, performing RT for 3-4 days/week was sufficient to prevent low muscle mass. The effectiveness of this preventive measure can be further enhanced by engaging in long-term RT, specifically for more than 2 years.

Early-onset vasomotor symptoms and development of depressive symptoms among premenopausal women.

BACKGROUND: We investigated the association between vasomotor symptoms (VMSs) and the onset of depressive symptoms among premenopausal women. METHODS: This cross-sectional study included 4376 premenopausal women aged 42-52 years, and the cohort study included 2832 women without clinically relevant depressive symptoms at baseline. VMSs included the symptoms of hot flashes and night sweats. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale; a score of ≥16 was considered to define clinically relevant depressive symptoms. RESULTS: Premenopausal Women with VMSs at baseline exhibited a higher prevalence of depressive symptoms compared with women without VMSs at baseline (multivariable-adjusted prevalence ratio 1.76, 95 % confidence interval [CI] 1.47-2.11). Among the 2832 women followed up (median, 6.1 years), 406 developed clinically relevant depressive symptoms. Women with versus without VMSs had a significantly higher risk of developing clinically relevant depressive symptoms (multivariable-adjusted hazard ratio, 1.72; 95 % CI 1.39-2.14). VMS severity exhibited a dose-response relationship with depressive symptoms (P for trend <0.05). LIMITATIONS: Self-reported questionnaires were only used to obtain VMSs and depressive symptoms, which could have led to misclassification. We also could not directly measure sex hormone levels. CONCLUSIONS: Even in the premenopausal stage, women who experience hot flashes or night sweats have an increased risk of present and developed clinically relevant depressive symptoms. It is important to conduct mental health screenings and provide appropriate support to middle-aged women who experience early-onset VMSs.

Temporal Changes in Resting Heart Rate and Risk of Diabetes Mellitus.

Background: To investigate the association between the time-varying resting heart rate (RHR) and change in RHR (∆RHR) over time and the risk of diabetes mellitus (DM) by sex. Methods: We assessed 8,392 participants without DM or atrial fibrillation/flutter from the Korean Genome and Epidemiology Study, a community-based prospective cohort study that was initiated in 2001 to 2002. The participants were followed up until December 31, 2018. Updating RHR with biennial in-study re-examinations, the time-varying ∆RHR was calculated by assessing the ∆RHR at the next follow-up visit. Results: Over a median follow-up of 12.3 years, 1,345 participants (16.2%) had DM. As compared with RHR of 60 to 69 bpm, for RHR of ≥80 bpm, the incidence of DM was significantly increased for both male and female. A drop of ≥5 bpm in ∆RHR when compared with the stable ∆RHR group (-5< ∆RHR <5 bpm) was associated significantly with lower risk of DM in both male and female. However, an increase of ≥5 bpm in ∆RHR was significantly associated with higher risk of DM only in female, not in male (hazard ratio for male, 1.057 [95% confidence interval, 0.869 to 1.285]; and for female, 1.218 [95% confidence interval, 1.008 to 1.471]). Conclusion: In this community-based longitudinal cohort study, a reduction in ∆RHR was associated with a decreased risk of DM, while an increase in ∆RHR was associated with an increased risk of DM only in female.

Folate, vitamin B12, and homocysteine status in the Korean population: data from the 2013-2015 Korea National Health and Nutrition Examination Survey.

OBJECTIVES: We aimed to assess the serum folate, vitamin B12, and homocysteine status in Korean adolescents and adults using national data. METHODS: Blood samples were collected from participants aged ≥10 years in the Korea National Health and Nutrition Examination Survey 2013-2015. The stored serum samples were used to measure folate, vitamin B12, and homocysteine concentrations. A total of 8,016 participants were included in this analysis. Unweighted descriptive statistics and adjusted geometric means of the B vitamins and homocysteine concentrations were estimated. RESULTS: Females had higher serum folate and vitamin B12 concentrations and lower serum homocysteine concentrations than males. Folate deficiency (<6.8 nmol/L) and hyperhomocysteinemia (>15 µmol/L) were found in 8.6% and 11.8% of males, respectively. Approximately 3% of males had low or marginally low vitamin B12 status (≤221 pmol/L). Folate and vitamin B12 deficiencies and hyperhomocysteinemia were found in <2% of females. Suboptimal folate status was prevalent among adolescents and young adults, while suboptimal vitamin B12 status and hyperhomocysteinemia were relatively higher in older adults. Adjusted mean homocysteine concentrations were sharply decreased from the first to second decile of serum folate in males. CONCLUSIONS: In the Korean population, the proportion of males who achieved desirable folate and homocysteine concentrations were lower than those of females. Although most Koreans have adequate vitamin B12, a suboptimal folate status is common, particularly among adolescents and young adults. These findings could establish a foundation for public health initiatives aimed at improving folate levels in the Korean population.

Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study.

Exome and genome sequencing (ES/GS) in genetic medicine and research leads to discovering genomic secondary findings (SFs) unrelated to the purpose of the primary test. There is a lack of agreement to return the SF results for individuals undergoing the test. The aim of this study is to investigate the frequency of actionable secondary findings using GS data obtained from the rare disease study and the Korean Genome and Epidemiology Study (KoGES) in the National Project of Bio Big Data pilot study. Pathogenic (P) or likely pathogenic (LP) variants of 78 SF genes recommended by the American College of Medical Genetics and Genomics (ACMG) were screened in the rare disease study and KoGES. The pathogenicity of SF gene variants was determined according to the ACMG interpretation. The overall SF rate was 3.75% for 280 individuals with 298 P/LP variants of 41 ACMG SF genes which were identified among 7472 study participants. The frequencies of genes associated with cardiovascular, cancer, and miscellaneous phenotypes were 2.17%, 1.22%, and 0.58%, respectively. The most frequent SF gene was TTN followed by BRCA2. The frequency of actionable SFs among participants with rare disease and general population participants in the Korean population presented here will assist in reporting results of medically actionable SFs in genomic medicine.

Substantial Lipid Increases During Menopausal Transition in Korean Middle-Aged Women.

BACKGROUND: Adverse lipid profiles are observed in postmenopausal women. However, there is insufficient evidence of the association between lipids and reproductive aging in Korean women. We aimed to characterize lipid changes with respect to timing relative to menopause in Korean middle-aged women. METHODS: This study included 1,436 premenopausal women who had a natural menopause during the follow-up period (median = 15.76 years) from the Korean Genome and Epidemiology Study (KoGES) Ansan and Anseong cohort. Lipid levels were measured every 2 years, and the magnitudes of annual lipid changes and differences in the changes by premenopausal body mass index were estimated using piecewise linear mixed-effects models. RESULTS: All lipid levels increased greatly from 3 or 5 years before menopause to 1 year after menopause in all women, regardless of their premenopausal body mass index. During the period, high-density lipoprotein cholesterol (HDL-C) levels increased at 0.42 mg/dL per year (95% confidence interval [CI], 0.29 to 0.55 mg/dL). Nevertheless, non-HDL-C levels simultaneously increased at 3.42 mg/dL per year (95% CI, 3.11 to 3.72 mg/dL), and an annual change in the non-HDL-C to HDL-C ratio was 0.05 (95% CI, 0.04 to 0.06). One year after menopause, changes in all lipid parameters significantly slowed down, except for the non-HDL-C to HDL-C ratio (P < 0.001 for all). The ratio continued to increase until 3 years after menopause, but thereafter, the change leveled off. CONCLUSION: Women experienced remarkable increases in lipid levels during menopausal transition, highlighting the need for early intervention strategies for cardiovascular disease prevention in women.

Sex-based differences in the association of leisure-time physical activity with the risk of depression: the Ansan and Ansung study of the Korean Genome and Epidemiology Study (KoGES).

Objective: Depression is a serious mental disorder which is the leading cause of suicide. This study investigated the association between incident depression and 4-year leisure-time physical activity (PA) levels and/or resistance training (RT). Methods: This community-based Korean cohort included 3,967 participants without depression at baseline. The average PA-time (the total duration of moderate-intensity leisure-time PA) up to 4 years prior to baseline enrollment was calculated to evaluate the cumulative levels of PA. Participants were divided into four groups based on their average PA-time: "Non-PA," " <150 min/week," "150-299 min/week," and "≥300 min/week." Furthermore, based on compliance to PA guidelines (≥150 min/week of PA-time) and participation in RT, the participants were categorized into four subgroups: "Low-PA," "Low-PA+RT," "High-PA," and "High-PA+RT." A multivariate Cox proportional hazards regression model was used to assess the 4-year incidence of depression according to leisure-time PA levels and/or regularity of RT. Results: During the mean 3.72 ± 0.69 years of follow-up, 432 participants (10.89%) developed depression. In women, performing 150-299 min/week of moderate-intensity leisure-time PA was associated with a 38% risk reduction for incident depression (HR, 0.62; CI, 0.43-0.89; p < 0.05), whereas more than 300 min/week of that was related to a 44% risk reduction for incident depression (HR, 0.56; CI, 0.35-0.89; p < 0.05) as compared to that in the Non-PA group. However, in men, there was no significant relationship between the amount of leisure-time PA per week and the risk of incident depression. Moreover, in both sexes, RT had no significant effect on depression in either the Low-PA or High-PA group. Conclusions: There was an inverse dose-response association between leisure-time PA levels and incident depression only in women, whereas adding RT to high levels of PA had no significant effect on depression in either sex.

DESIGNER fraction concept unmasks minor bioactive constituents in red clover (Trifolium pratense L.).

In botanical extracts, highly abundant constituents can mask or dilute the effects of other, and often, more relevant biologically active compounds. To facilitate the rational chemical and biological assessment of these natural products with wide usage in human health, we introduced the DESIGNER approach of Depleting and Enriching Selective Ingredients to Generate Normalized Extract Resources. The present study applied this concept to clinical Red Clover Extract (RCE) and combined phytochemical and biological methodology to help rationalize the utility of RCE supplements for symptom management in postmenopausal women. Previous work has demonstrated that RCE reduces estrogen detoxification pathways in breast cancer cells (MCF-7) and, thus, may serve to negatively affect estrogen metabolism-induced chemical carcinogenesis. Clinical RCE contains ca. 30% of biochanin A and formononetin, which potentially mask activities of less abundant compounds. These two isoflavonoids are aryl hydrocarbon receptor (AhR) agonists that activate P450 1A1, responsible for estrogen detoxification, and P450 1B1, producing genotoxic estrogen metabolites in female breast cells. Clinical RCE also contains the potent phytoestrogen, genistein, that downregulates P450 1A1, thereby reducing estrogen detoxification. To identify less abundant bioactive constituents, countercurrent separation (CCS) of a clinical RCE yielded selective lipophilic to hydrophilic metabolites in six enriched DESIGNER fractions (DFs 01-06). Unlike solid-phase chromatography, CCS prevented any potential loss of minor constituents or residual complexity (RC) and enabled the polarity-based enrichment of certain constituents. Systematic analysis of estrogen detoxification pathways (ERα-degradation, AhR activation, CYP1A1/CYP1B1 induction and activity) of the DFs uncovered masked bioactivity of minor/less abundant constituents including irilone. These data will allow the optimization of RCE with respect to estrogen detoxification properties. The DFs revealed distinct biological activities between less abundant bioactives. The present results can inspire future carefully designed extracts with phytochemical profiles that are optimized to increase in estrogen detoxification pathways and, thereby, promote resilience in women with high-risk for breast cancer. The DESIGNER approach helps to establish links between complex chemical makeup, botanical safety and possible efficacy parameters, yields candidate DFs for (pre)clinical studies, and reveals the contribution of minor phytoconstituents to the overall safety and bioactivity of botanicals, such as resilience promoting activities relevant to women's health.

Vasomotor and other menopause symptoms and the prevalence of ideal cardiovascular health metrics among premenopausal stage women.

OBJECTIVE: We examined the association between menopause symptoms and the prevalence of ideal cardiovascular health (CVH) metrics among premenopausal women. METHODS: This cross-sectional study comprised 4,611 premenopausal women aged 42 to 52 years. Data for CVH metrics were collected during health screening examinations. Menopause symptoms were measured using the Korean version of the Menopause-Specific Quality of Life questionnaire. For vasomotor, psychosocial, physical, and sexual symptoms, participants were divided into absent or symptomatic groups, further divided into tertiles (range, 0-7; 7 being the most bothersome). Ideal CVH metrics were defined according to the American Heart Association Life Simple 7 metrics, except dietary component. Cardiovascular health metrics were scored from 0 (unhealthy) to 6 (healthy) and classified as poor (0-2), intermediate (3-4), and ideal (5-6). Multinomial logistic regression models were used to estimate the prevalence ratios for intermediate and poor CVH metrics using ideal CVH as the reference. RESULTS: The overall and 4 menopause-specific quality of life domain scores were significantly associated with poorer CVH metrics scores in a dose-response manner ( P < 0.05). After adjusting for age, parity, education level, anti-Mullerian hormone levels, and alcohol intake, women with the most bothersome degree for vasomotor, psychosocial, physical, and sexual symptoms had significantly higher prevalence of poor CVH metrics, with corresponding prevalence ratios (95% confidence interval) of 2.90 (1.95-4.31), 2.07 (1.36-3.15), 3.01 (1.19-7.65), and 1.66 (1.15-2.39), respectively, compared with those without each vasomotor, psychosocial, physical, and sexual symptom. CONCLUSIONS: Premenopausal stage women with either vasomotor or nonvasomotor menopausal symptoms have significantly higher prevalence of poor CVH metrics, compared with those without any menopausal symptoms.

Risk of uterine leiomyomata with menstrual and reproductive factors in premenopausal women: Korea nurses' health study.

BACKGROUND: Uterine leiomyomata (UL) are benign smooth muscle tumors that may cause significant morbidity in women of reproductive age. This study aimed to investigate the relationship of menstrual and reproductive factors with the risk of UL in premenopausal women. METHODS: This prospective study included 7,360 premenopausal women aged 22-48 years who were part of the Korea Nurses' Health Study. Information on the menstrual cycle and reproductive history was assessed between 2014 and 2016, and self-reported cases of UL were obtained through 2021. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During 32,072 person-years of follow-up, 447 incident cases of UL were reported. After adjusting for other risk factors, women with late age at menarche had a lower incidence of UL (≥ 16 vs. 12-13 years: HR 0.68; 95% CI 0.47-0.99; p for trend = 0.026). The risk of UL was inversely associated with current menstrual cycle length (≥ 40 or too irregular to estimate vs. 26-31 days: HR 0.40; 95% CI 0.24-0.66) and cycle length at ages 18-22 years (HR 0.45; 95% CI 0.31-0.67; p for trend < 0.001, each). Parous women had lower risk of UL than nulliparous women (HR 0.40; 95% CI 0.30-0.53) and women who were aged 29-30 years at first birth had a lower risk of UL than those who were aged ≤ 28 years at first birth (HR 0.58; 95% CI 0.34-0.98). There was no significant association of the number of births or breastfeeding with the risk of UL among parous women. Neither a history of infertility nor oral contraceptive use was associated with the risk of UL. CONCLUSIONS: Our results suggest that age at menarche, menstrual cycle length, parity, and age at first birth are inversely associated with the risk of UL in premenopausal Korean women. Future studies are warranted to confirm the long-term effects of menstrual and reproductive factors on women's health.

Weight Changes and Unhealthy Weight Control Behaviors Are Associated With Dysmenorrhea in Young Women.

BACKGROUND: This study aimed to evaluate the prevalence of dysmenorrhea and to investigate the effect of weight changes or unhealthy weight control behaviors on dysmenorrhea in young Korean women. METHODS: We used large-scale data of women, aged 14 to 44 years, who participated in the Korean Study of Women's Health-Related Issues. Dysmenorrhea was measured using a visual analog scale and was categorized as none, mild, moderate, and severe according to the severity. Weight changes and unhealthy weight control behaviors (any of the behaviors, fasting/meal skipping, drugs, the use of unapproved dietary supplements, and one-food diets) over the past year were self-reported. We used multinomial logistic regression to investigate the association between weight changes or unhealthy weight control behaviors and dysmenorrhea. RESULTS: Of the 5,829 young women participating in the study, 5,245 (90.0%) participants experienced dysmenorrhea [2,184 (37.5%) had moderate and 1,358 (23.3%) had severe]. After adjusting for confounders, the odds ratios for moderate and severe dysmenorrhea in participants with weight changes ≥ 3 kg (vs. < 3 kg) were 1.19 (95% confidence interval: 1.05-1.35) and 1.25 (95% confidence interval: 1.08-1.45), respectively. The odds ratios in participants with any unhealthy weight control behaviors were 1.22 (95% confidence interval: 1.04-1.42) and 1.41 (95% confidence interval: 1.19-1.67) for those with moderate and severe dysmenorrhea, respectively. CONCLUSION: Weight changes (≥ 3 kg) or unhealthy weight control behaviors are common among young women, which may adversely affect dysmenorrhea. Therefore, attention needs to be paid to excessive weight changes and unhealthy weight control behaviors to improve dysmenorrhea in young women.

Establishing Co-Culture Blood-Brain Barrier Models for Different Neurodegeneration Conditions to Understand Its Effect on BBB Integrity.

The blood-brain barrier (BBB) is a functional interface that provides selective permeability, protection from toxic substances, transport of nutrients, and clearance of brain metabolites. Additionally, BBB disruption has been shown to play a role in many neurodegenerative conditions and diseases. Therefore, the aim of this study was to establish a functional, convenient, and efficient in vitro co-cultured BBB model that can be used for several physiological conditions related to BBB disruption. Mouse brain-derived endothelial (bEnd.3) and astrocyte (C8-D1A) cells were co-cultured on transwell membranes to establish an intact and functional in vitro model. The co-cultured model and its effects on different neurological diseases and stress conditions, including Alzheimer's disease (AD), neuroinflammation, and obesity, have been examined by transendothelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran, and tight junction protein analyses. Scanning electron microscope images showed evidence of astrocyte end-feet processes passing through the membrane of the transwell. Moreover, the co-cultured model showed effective barrier properties in the TEER, FITC, and solvent persistence and leakage tests when compared to the mono-cultured model. Additionally, the immunoblot results showed that the expression of tight junction proteins such as zonula occludens-1 (ZO-1), claudin-5, and occludin-1 was enhanced in the co-culture. Lastly, under disease conditions, the BBB structural and functional integrity was decreased. The present study demonstrated that the co-cultured in vitro model mimicked the BBB's structural and functional integrity and, under disease conditions, the co-cultured model showed similar BBB damages. Therefore, the present in vitro BBB model can be used as a convenient and efficient experimental tool to investigate a wide range of BBB-related pathological and physiological studies.

Corrigendum: Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

[This corrects the article DOI: 10.3389/fimmu.2023.1101808.].

Time Dependent Changes in the Ovine Neurovascular Unit; A Potential Neuroprotective Role of Annexin A1 in Neonatal Hypoxic-Ischemic Encephalopathy.

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRß for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury.

Association of leisure-time physical activity and resistance training with risk of incident hypertension: The Ansan and Ansung study of the Korean Genome and Epidemiology Study (KoGES).

Hypertension is the most common preventable risk factor for the onset of cardiovascular disease and mortality. We aimed to investigate the association between incident hypertension and 4-year leisure-time physical activity (PA) levels and resistance training (RT). In this community-based Korean cohort, 5,075 participants without hypertension were included. To evaluate cumulative PA, the average PA time (the total time of moderate-intensity leisure-time PA) at baseline, 2-year follow-up, and 4-year follow-up were calculated. Based on participation in RT and compliance to PA guidelines (≥150 min/week of PA time), the participants were divided into the following four groups: Low-PA, Low-PA+RT, High-PA, and High-PA+RT. A multivariate Cox proportional hazards regression model was used to evaluate the 12-year incidence of hypertension in relation to leisure-time PA levels and RT regularity. During a mean 7.86 ± 4.20-year follow-up, 2,544 participants (1,366 women) were diagnosed with hypertension. Compared with Low-PA, High-PA, and High-PA+RT decreased the risk for hypertension by 30 and 39%, respectively. Participation in RT without compliance to PA guidelines did not affect the incidence of hypertension. The additive effect of RT on hypertension in the High-PA group was further examined. Although sex-based comparisons indicated that men had a significantly longer training period for RT than women, an additional reduction in the risk for hypertension in relation to the addition of RT was observed only in women (35%). PA may confer protective effects against hypertension, whereas the addition of RT to high levels of PA can further reduce the risk for hypertension in women.

Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

Introduction: Despite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. Methods: Here, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. Results: Differential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. Discussion: Aberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.