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Background: Homologous recombination deficiency (HRD) stands as a clinical indicator for discerning responsive outcomes to platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors. One of the conventional approaches to HRD prognostication has generally centered on identifying deleterious mutations within the BRCA1/2 genes, along with quantifying the genomic scars, such as Genomic Instability Score (GIS) estimation with scarHRD. However, the scarHRD method has limitations in scenarios involving tumors bereft of corresponding germline data. Although several RNA-seq-based HRD prediction algorithms have been developed, they mainly support cohort-wise classification, thereby yielding HRD status without furnishing an analogous quantitative metric akin to scarHRD. This study introduces the expHRD method, which operates as a novel transcriptome-based framework tailored to n-of-1-style HRD scoring., Results: The prediction model has been established using the elastic net regression method in the Cancer Genome Atlas (TCGA) pan-cancer training set. The bootstrap technique derived the HRD geneset for applying the expHRD calculation. The expHRD demonstrated a notable correlation with scarHRD and superior performance in predicting HRD-high samples. We also performed intra- and extra-cohort evaluations for clinical feasibility in the TCGA-OV and the Genomic Data Commons (GDC) ovarian cancer cohort, respectively. The innovative web service designed for ease of use is poised to extend the realms of HRD prediction across diverse malignancies, with ovarian cancer standing as an emblematic example., Conclusions: Our novel approach leverages the transcriptome data, enabling the prediction of HRD status with remarkable precision. This innovative method addresses the challenges associated with limited available data, opening new avenues for utilizing transcriptomics to inform clinical decisions., (© 2024. The Author(s).)

Background: Suicide rates in older adults are much higher than those in younger age groups. Given the rapid increase in the proportion of older adults in Korea and the high suicide rate of this age group, it is worth investigating the mechanism of suicidal ideation for older adults. Generally, adverse childhood experiences are positively associated with suicidal ideation; however, it is not fully understood what mediating relationships are linked to the association between these experiences and current suicidal ideation., Methods: The data from 685 older Korean adults were analyzed utilizing logistic regression, path analyses, and structural equation modeling. Based on our theoretical background and the empirical findings of previous research, we examined three separate models with mental health, physical health, and social relationship mediators. After that, we tested a combined model including all mediators. We also tested another combined model with mediation via mental health moderated by physical health and social relationships., Results: The univariate logistic regression results indicated that childhood adversity was positively associated with suicidal ideation in older adults. However, multivariate logistic regression results demonstrated that the direct effect of childhood adversity became nonsignificant after accounting all variables. Three path models presented significant mediation by depression and social support in the association between childhood adversity and suicidal ideation. However, combined structural equation models demonstrated that only mediation by a latent variable of mental health problems was statistically significant. Social relationships moderated the path from mental health problems to suicidal ideation., Conclusions: Despite several limitations, this study has clinical implications for the development of effective strategies to mitigate suicidal ideation. In particular, effectively screening the exposure to adverse childhood experiences, early identification and treatment of depressive symptoms can play a crucial role in weakening the association between childhood adversity and suicidal ideation in older adults., (© 2024. The Author(s).)

Background: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging., Methods: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations., Results: scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELL hi regulatory T cells (Tregs) and activated TIGIT hi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs., Conclusion: We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis., (© 2024. The Author(s).)

Background and Objectives: Few studies have reported which inhaled combination therapy, either bronchodilators and/or inhaled corticosteroids (ICSs), is beneficial in patients with bronchiectasis and airflow obstruction. Our study compared the efficacy and safety among different inhaled combination therapies in patients with bronchiectasis and airflow obstruction., Methods: Our retrospective study analyzed the patients with forced expiratory volume in 1 s (FEV 1 )/forced vital capacity < 0.7 and radiologically confirmed bronchiectasis in chest computed tomography between January 2005 and December 2021. The eligible patients underwent baseline and follow-up spirometric assessments. The primary endpoint was the development of a moderate-to-severe exacerbation. The secondary endpoints were the change in the annual FEV 1 and the adverse events. Subgroup analyses were performed according to the blood eosinophil count (BEC)., Results: Among 179 patients, the ICS/long-acting beta-agonist (LABA)/long-acting muscarinic antagonist (LAMA), ICS/LABA, and LABA/LAMA groups were comprised of 58 (32.4%), 52 (29.1%), and 69 (38.5%) patients, respectively. ICS/LABA/LAMA group had a higher severity of bronchiectasis and airflow obstruction, than other groups. In the subgroup with BEC ≥ 300/uL, the risk of moderate-to-severe exacerbation was lower in the ICS/LABA/LAMA group (adjusted HR = 0.137 [95% CI = 0.034-0.553]) and the ICS/LABA group (adjusted HR = 0.196 [95% CI = 0.045-0.861]) compared with the LABA/LAMA group. The annual FEV 1 decline rate was significantly worsened in the ICS/LABA group compared to the LABA/LAMA group (adjusted β-coefficient=-197 [95% CI=-307--87]) in the subgroup with BEC < 200/uL., Conclusion: In patients with bronchiectasis and airflow obstruction, the use of ICS/LABA/LAMA and ICS/LABA demonstrated a reduced risk of exacerbation compared to LABA/LAMA therapy in those with BEC ≥ 300/uL. Conversely, for those with BEC < 200/uL, the use of ICS/LABA was associated with an accelerated decline in FEV 1 in comparison to LABA/LAMA therapy. Further assessment of BEC is necessary as a potential biomarker for the use of ICS in patients with bronchiectasis and airflow obstruction., (© 2024. The Author(s).)

Background: Robots have the potential to assist older adults in their home-based daily living tasks. Previous studies indicated that older adults generally accept robot assistance. However, the preferences of older adults with different functional dependence levels are lacking. These older adults encounter varying levels of difficulty in daily living and may have distinct preferences for robot assistance. This study aimed to describe and compare the preferences for robot assistance on domestic tasks in older adults with different functional dependence levels., Methods: This cross-sectional descriptive study recruited a convenience sample of 385 older adults in Hong Kong. They were categorized as independent, partially dependent, and dependent using the Katz Index of Independence in Activities of Daily Living. Their preferences for robot assistance on a list of 48 domestic tasks under six categories were assessed through the Assistance Preference Checklist. Differences in preferences between the three groups were compared using one-way ANOVA test., Results: Findings revealed the differences and similarities in preferences between participants with different dependence levels. In most domestic tasks under the personal care category, dependent and partially dependent older adults reported a significantly lower preferences for human assistance or a higher preferences for robot assistance (p < 0.001), compared with the independent ones. The effect size varied from medium to large (eta squared = 0.07 to 0.52). However, participants, regardless of functional dependence levels, preferred human to assist in some domestic tasks under the health and leisure activities category and preferred robot to assist in most of the domestic tasks under the chores, information management, and manipulating objects category., Conclusions: Older adults with different levels of functional dependence exhibit different preferences for robotic assistance. To effectively use robots and assist older adults as they age, the specific preferences of older adults must be considered before designing and introducing robots in domestic care., (© 2024. The Author(s).)

Background: Prediabetes, an intermediate stage between normal blood sugar levels and a diabetes mellitus diagnosis, is increasing in prevalence. Severe prediabetes is associated with a similar risk of complications as diabetes, but its relationship with peripheral arterial disease remains underexplored., Methods: We conducted a retrospective cohort study involving 36,950 adult patients, utilizing electronic medical records from the National Taiwan University Hospital between 2014 and 2019. We employed multivariable Cox regression and Kaplan-Meier analysis with the log-rank test to analyze major adverse limb events (MALE) and major adverse cardiovascular events (MACE) in relation to normal glucose regulation (NGR) and prediabetes., Results: During the 131,783 person-years follow-up, 17,754 cases of prediabetes and 19,196 individuals with normal glucose regulation (NGR) were identified. Kaplan-Meier analysis revealed an increased incidence of both MALE and MACE in individuals with prediabetes. (log-rank p = 0.024 and < 0.001). Prediabetes exhibited a significant association with an elevated risk of MALE (adjusted hazard ratio (aHR) 1.26 [95% CI 1.10-1.46], p = 0.001) and MACE (aHR 1.46 [1.27-1.67], p < 0.001). Furthermore, in individuals with prediabetes, the elevation in the risk of MALE commenced before HbA1c levels surpassed 5.0% (for HbA1c 5.0-5.5%: aHR 1.78 (1.04-3.04), p = 0.036; HbA1c 5.5-6.0%: aHR 1.29 [1.06-1.58], p = 0.012; aHbA1c 6.0-6.5%: aHR 1.39 [1.14-1.70], p < 0.001). Similarly, the onset of increased MACE risk was observed when HbA1c levels exceeded 5.5% (for HbA1c 5.5-6.0%: aHR 1.67 [1.39-2.01], p < 0.001; HbA1c 6.0-6.5%: HR 2.10 [1.76-2.51], p < 0.001). Factors associated with both MALE and MACE in prediabetes include advanced age, male gender, higher body mass index, and a history of heart failure or atrial fibrillation., Conclusion: We demonstrated higher susceptibility to MALE and MACE in prediabetes compared to normoglycemic counterparts, notwithstanding lower HbA1c levels. Complications may manifest at an earlier prediabetes trajectory. Intensive lifestyle modification may improve the prognosis of severe prediabetes., (© 2023. The Author(s).)

Background: This study aimed to identify and select age-related diseases (ARDs) in Korea, which is about to have a super-aged society, and to elucidate patterns in their incidence rates., Methods: The National Health Insurance Service-National Sample Cohort, comprising 1 million health insurance and medical benefit beneficiaries in Korea from 2002 to 2019, was utilized. We selected 14 diseases with high disease burden and prevalence among Koreans from the 92 diseases defined in the Global Burden of Diseases, Injuries, and Risk Factors Study as ARDs. The annual incidence rate represented the number of patients newly diagnosed with an ARD each year from 2006 to 2019, excluding those with a history of ARD diagnosis from 2002 to 2005. The incidence rate by age was categorized into 10-year units based on age as of 2019. The number of patients with ARDs in each age group was used as the numerator, and the incidence rate for each age group was calculated with the age group as the denominator., Results: Regarding the annual incidence rates of ARDs from 2006 to 2019, chronic obstructive pulmonary disease, congestive heart failure, and ischemic heart disease decreased annually, whereas dyslipidemia, chronic kidney disease, cataracts, hearing loss, and Parkinson's disease showed a significant increase. Hypertension, diabetes, cerebrovascular disease, osteoporosis, osteoarthritis, and age-related macular degeneration initially displayed a gradual decrease in incidence but exhibited a tendency to increase after 2015. Concerning age-specific incidence rates of ARDs, two types of curves emerged. The first type, characterized by an exponential increase with age, was exemplified by congestive heart failure. The second type, marked by an exponential increase peaking between ages 60 and 80, followed by stability or decrease, was observed in 13 ARDs, excluding congestive heart failure. However, hypertension, ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and hearing loss in men belonged to the first type., Conclusions: From an epidemiological perspective, there are similar characteristics in age-specific ARDs that increase with age, reaching a peak followed by a plateau or decrease in Koreans., (© 2023. The Author(s).)

Background: The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer's disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown., Methods: Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age., Results: In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-β accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib -/- mice., Conclusion: Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications., (© 2023. The Author(s).)

Background: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC., Methods: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and Kras G12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status., Results: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log 2 OR = 1.65, P = 3.08 × 10 -3 ). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67 + cells increased significantly in pancreatic organoids derived from Galc knockout Kras G12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant., Conclusions: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Methanotrophs have emerged as promising hosts for the biological conversion of methane into value-added chemicals, including various organic acids. Understanding the mechanisms of acid tolerance is essential for improving organic acid production. WatR, a LysR-type transcriptional regulator, was initially identified as involved in lactate tolerance in a methanotrophic bacterium Methylomonas sp. DH-1. In this study, we investigated the role of WatR as a regulator of cellular defense against weak organic acids and identified novel target genes of WatR., Results: By conducting an investigation into the genome-wide binding targets of WatR and its role in transcriptional regulation, we identified genes encoding an RND-type efflux pump (WatABO pump) and previously unannotated small open reading frames (smORFs), watS1 to watS5, as WatR target genes activated in response to acetate. The watS1 to watS5 genes encode polypeptides of approximately 50 amino acids, and WatS1 to WatS4 are highly homologous with one predicted transmembrane domain. Deletion of the WatABO pump genes resulted in decreased tolerance against formate, acetate, lactate, and propionate, suggesting its role as an efflux pump for a wide range of weak organic acids. WatR repressed the basal expression of watS genes but activated watS and WatABO pump genes in response to acetate stress. Overexpression of watS1 increased tolerance to acetate but not to other acids, only in the presence of the WatABO pump. Therefore, WatS1 may increase WatABO pump specificity toward acetate, switching the general weak acid efflux pump to an acetate-specific efflux pump for efficient cellular defense against acetate stress., Conclusions: Our study has elucidated the role of WatR as a key transcription factor in the cellular defense against weak organic acids, particularly acetate, in Methylomonas sp. DH-1. We identified the genes encoding WatABO efflux pump and small polypeptides (WatS1 to WatS5), as the target genes regulated by WatR for this specific function. These findings offer valuable insights into the mechanisms underlying weak acid tolerance in methanotrophic bacteria, thereby contributing to the development of bioprocesses aimed at converting methane into value-added chemicals., (© 2023. The Author(s).)

Background: The therapeutic effect of selenium has been demonstrated in mild Graves' ophthalmopathy (GO) in a European region where selenium status is suboptimal. However, there is a lack of evidence to support selenium use in selenium-sufficient areas. The aim of this study is to evaluate the therapeutic effect of selenium in mild-to-moderate GO in selenium-sufficient South Korea., Methods: The SeGOSS trial is a multicenter, prospective, randomized, open-label trial in South Korea. Eighty-four patients aged 19 years or older with mild-to-moderate GO will be randomized to receive either vitamin B complex alone or vitamin B complex with selenium for 6 months with three monthly follow-up visits. The primary outcome is comparison of the improvement in quality of life at 6 months from baseline between the control and selenium groups. The secondary outcomes are intergroup differences in changes in quality of life at 3 months, clinical activity of GO at 3 and 6 months, thyroid autoantibody titers at 3 and 6 months, and the response rate at 3 and 6 months from baseline. Quality of life will be measured by questionnaire for patients with GO, and the clinical activity of GO will be evaluated by the clinical activity score (CAS). A positive response is defined as either changes in the CAS < 0 or the changes in the GO-QOL score ≥ 6., Discussion: The SeGOSS study will evaluate the therapeutic potential of selenium for mild-to-moderate GO in a selenium-sufficient area and provide support in tailoring better treatment for GO., Trial Registration: KCT0004040. Retrospectively registered on 5 June 2019. https://cris.nih.go.kr/cris/search/detailSearch.do/14160 ., (© 2023. The Author(s).)

Background: Skin metastasis from papillary thyroid cancer (PTC) is a rare entity that can occur up to decades after treatment of the primary tumor. Here, we present a patient who developed skin metastasis 10 years after treatment of her primary tumor and describe the molecular findings of the metastatic lesion., Case Presentation: A 44-year-old female with a history of PTC who underwent a total thyroidectomy and radioactive iodine (RAI) treatment 10 years ago presented with a 1.3-cm skin lesion along the prior thyroidectomy scar. A biopsy revealed metastatic PTC, and the patient underwent surgical excision of the lesion. ThyroSeq molecular testing showed the copresence of BRAF V600E mutation and TERT promoter C228T mutation. The patient subsequently received one round of adjuvant RAI therapy., Conclusions: A high index of suspicion is warranted in patients with a history of PTC who develop a skin lesion, even several years after remission of the primary disease. In patients with high-risk mutations, such as BRAF V600E and TERT promoter C228T mutations, long-term surveillance of disease recurrence is particularly important., (© 2023. The Author(s).)

Background: Coronary artery disease is a cardiovascular disease with a high mortality and mortality rate in modern society. Vascular stent insertion to restore blood flow is essential to treat this disease. A fully biodegradable vascular scaffold (BVS) is a vascular poly (L-lactic acid) (PLLA) stent that is receiving growing interest as this is biodegradable in the body and does not require secondary removal surgery. However, acidic byproducts composed of PLLA produced during the biodegradation of the BVS can induce an inflammatory response. Magnesium hydroxide, a basic inorganic particle, neutralizes the acidic byproducts of PLLA.  METHODS: In this study, we investigated using a BVS coated with everolimus and surface-modified magnesium hydroxide that suppresses smooth muscle cell proliferation and protects endothelial cells, respectively. The various characteristics of the functional stent were evaluated using in vitro and in vivo analyses.  RESULTS: The BVS was successfully prepared with evenly coated everolimus and surface-modified magnesium hydroxide. A neutral pH value was maintained by magnesium hydroxide during degradation, and everolimus was released for one month. The coated BVS effectively inhibited protein adsorption and platelet adhesion, demonstrating excellent blood compatibility. In vitro analysis showed that BVS protects endothelial cells with magnesium hydroxide and selectively inhibits smooth muscle cell proliferation via everolimus treatment. The functional BVS was inserted into porcine coronary arteries for 28 days, and the results demonstrated that the restenosis and inflammation greatly decreased and re-endothelialization was enhanced as compared to others., Conclusions: This study provides new insights into the design of drug-incorporated BVS stent for coronary artery disease., (© 2022. The Author(s).)

Background: Knowing the lowest acceptable radiation dose of multiphase hepatic CT may allow us to reduce the radiation dose for detecting HCC., Purpose: To prospectively assess the image quality and diagnostic performance of low-dose and ultra-low-dose multiphase hepatic computed tomography using a dual-source CT scanner., Methods: Three reconstructed different dose scan images (standard-dose, low-dose, and ultra-low-dose) of hepatic multiphase CT were obtained from 67 patients with a dual-source CT scanner. The image quality and the diagnostic performance of the three radiation dose CT scans of the hepatic focal lesion (≥ 0.5 cm) were analyzed by two independent readers using the Liver Imaging Reporting and Data System., Results: Qualitative image quality and signal-to-noise ratio were significantly different among the radiation doses (p < 0.001). In total, 154 lesions comprising 32 hepatocellular carcinomas (HCC) and 122 non-HCC were included. The sensitivities of SDCT, LDCT, and ULDCT were 90.6%(29/32), 81.3%(26/32), and 56.2%(18/32), respectively. The accuracies of SDCT, LDCT, and ULDCT were 98.1%(151/154), 96.1%(148/154), and 89.6%(138/154), respectively. On per-lesion analysis, SDCT and LDCT did not show significantly different sensitivity and accuracy in diagnosing HCC (p = 0.250 and 0.250)., Conclusions: The diagnostic performance of dynamic hepatic LDCT with 33% reduced radiation dose in comparison to SDCT would be acceptable even though its image quality was qualitatively and quantitatively inferior. However, few HCCs could be overlooked. Therefore, with caution, radiation dose reduction by one-third could be implemented for follow-up CT scans for patients suspected of having HCC with caution and further studies are needed in the future., (© 2022. The Author(s).)

Background: Rotavirus is one of important pathogens which require infection control in nurseries and neonatal intensive care unit (NICU)., Method: We retrospectively reviewed 1,135 out-born newborns who were transferred to a regional tertiary NICU of Chungbuk National University Hospital between January 2012 and December 2016. We assessed the clinical characteristics of newborns based on the results of rotavirus surveillance tests. The prevalence of rotavirus was evaluated according to the year, month, and season., Results: Among the 1,135 infants, 213 (18.8%) had positive results in the rotavirus surveillance test. The rotavirus positive group had a significantly higher gestational age, birth weight, and Apgar score. They also had a significantly higher rate of postpartum care centers when compared to the rotavirus negative group (45.5% vs. 12.6%, P < 0.001). Notably, the prevalence of rotavirus was significantly increased from 3.2 to 33.8% when infants were hospitalized 48 h after birth (P < 0.001). During the study period, there were no significant differences in the annual, monthly, or seasonal prevalence of rotavirus infection. CONCLUSION AND DISCUSSION: These findings suggest that more active screening for rotavirus infection is necessary, especially for out-born newborns admitted to NICUs 48 h after birth or hospitalized after using postpartum care centers in Korea., (© 2022. The Author(s).)

Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of treatment, but can be challenging due to the high bleeding risk in some cancers and the high risk of recurrent venous thromboembolism (VTE) in patients with malignancies. Direct oral anticoagulants (DOACs) are well established as first-choice treatments for VTE in non-cancer patients, offering a more convenient and less invasive treatment option than low-molecular-weight heparin (LMWH). Asian patients have exhibited comparable efficacy and safety outcomes with other races in trials of DOACs for VTE in the general population. Although no specific data are available in Asian patients with CAT, results from randomized controlled trials of apixaban, edoxaban, or rivaroxaban versus the LMWH, dalteparin, indicate that DOACs are a reasonable alternative to LMWH for anticoagulation in Asian patients with CAT. This is further supported by analyses of real-world data in Asian populations demonstrating the efficacy and safety of DOACs in Asian patients with CAT. Apixaban, edoxaban, or rivaroxaban are recommended in the most recently updated international guidelines as first-line therapy for CAT in patients without gastrointestinal or genitourinary cancers and at low risk of bleeding. An increased risk of major gastrointestinal bleeding was evident with edoxaban or rivaroxaban, but not apixaban, versus dalteparin in the clinical trials, suggesting that apixaban could be a safe alternative to LMWH in patients with gastrointestinal malignancies. Determining the optimal anticoagulant therapy for patients with CAT requires careful consideration of bleeding risk, tumor type, renal function, drug-drug interactions, financial costs, and patients' needs and preferences., (© 2022. The Author(s).)

Objective: Ethnic disparity persists despite equal access to health care in Singapore, with Malay-Muslim women having the lowest mammogram uptake rate and highest breast cancer mortality rate. We sought to understand barriers to and facilitators for mammogram uptake in this community., Methods: We used a sequential mixed-methods design to first explore reasons for screening and not screening for breast cancer, then determine factors associated with screening and regular screening in a survey. We used maximum variation sampling for semi-structured in-depth interviews to select screeners and non-screeners of diverse ages and educational levels. Twenty-three Malay-Muslim women aged 40-69 years old were interviewed. Themes were categorized using thematic analysis. For the survey, we applied the Health Belief Model, Social Ecological Model, as well as themes from the interviews and findings from previous studies on factors influencing screening in Muslim women to guide questionnaire design. We surveyed 271 Malay-Muslim women aged 50-69 years old in a nationally representative sample. Multivariable logistic regression was used to determine factors associated with ever gone for mammogram and regular mammogram uptake., Results: Through in-depth-interviews, we found perceived benefits of saving lives and breasts from early detection, reminders from doctors and husbands, symptoms, perceived test from God, and personal responsibility to care for one's health facilitated screening. Barriers were perceived low susceptibility, inconvenience, cost, negative psychological effects, misinformation on mammogram triggering cancer cells, religious beliefs, perceived negative outcomes from mammography and distrust of doctor. From the survey, we found cues from health care professionals and needing symptoms before deciding to go for mammogram to be significantly associated with ever gone for mammogram and regular mammogram. Factors associated with ever gone for mammogram only included age, perceived benefits of saving lives from early detection, perceived importance of mammogram, Punishing Allah Reappraisal, and modesty. Factors associated with regular mammogram only included household income, perceived structural barriers to screening and perceived susceptibility to breast cancer., Conclusions: Mammogram uptake is affected by multiple levels of influence. Interventions to promote screening should be designed with multiple stakeholders including doctors, religious leaders and women who had attended screening., (© 2022. The Author(s).)

Background: Intellectual disability affects approximately one third of individuals with autism spectrum disorder (autism). Yet, a major unresolved neurobiological question is what differentiates autistic individuals with and without intellectual disability. Intelligence quotients (IQs) are highly variable during childhood. We previously identified three subgroups of autistic children with different trajectories of intellectual development from early (2-3½ years) to middle childhood (9-12 years): (a) persistently high: individuals whose IQs remained in the normal range; (b) persistently low: individuals whose IQs remained in the range of intellectual disability (IQ < 70); and (c) changers: individuals whose IQs began in the range of intellectual disability but increased to the normal IQ range. The frontoparietal (FPN) and default mode (DMN) networks have established links to intellectual functioning. Here, we tested whether brain regions within the FPN and DMN differed volumetrically between these IQ trajectory groups in early childhood., Methods: We conducted multivariate distance matrix regression to examine the brain regions within the FPN (11 regions x 2 hemispheres) and the DMN (12 regions x 2 hemispheres) in 48 persistently high (18 female), 108 persistently low (32 female), and 109 changers (39 female) using structural MRI acquired at baseline. FPN and DMN regions were defined using networks identified in Smith et al. (Proc Natl Acad Sci U S A 106:13040-5, 2009). IQ trajectory groups were defined by IQ measurements from up to three time points spanning early to middle childhood (mean age time 1: 3.2 years; time 2: 5.4 years; time 3: 11.3 years)., Results: The changers group exhibited volumetric differences in the DMN compared to both the persistently low and persistently high groups at time 1. However, the persistently high group did not differ from the persistently low group, suggesting that DMN structure may be an early predictor for change in IQ trajectory. In contrast, the persistently high group exhibited differences in the FPN compared to both the persistently low and changers groups, suggesting differences related more to concurrent IQ and the absence of intellectual disability., Conclusions: Within autism, volumetric differences of brain regions within the DMN in early childhood may differentiate individuals with persistently low IQ from those with low IQ that improves through childhood. Structural differences in brain networks between these three IQ-based subgroups highlight distinct neural underpinnings of these autism sub-phenotypes., (© 2022. The Author(s).)

Background: The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted., Methods: This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited., Discussion: This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB., Trial Registration: ClinicalTrials.gov NCT04485156 . Registered on July 24, 2020., (© 2022. The Author(s).)

Background: Adipose-derived stem cell (ASC) has been considered as a desirable source for cell therapy. In contrast to combining scaffold materials with cells, ASCs can be fabricated into scaffold-free three-dimensional (3D) constructs to promote regeneration at tissue level. However, previous reports have found decreased expression of vascular endothelial growth factor (VEGF) in ASC sheets. In this study, we aimed to integrate ASC spheroids into ASC sheets to enhance the angiogenic capability of cell sheets., Methods: ASCs were seeded in agarose microwells to generate uniform cell spheroids with adjustable size, while extracellular matrix deposition could be stimulated by ascorbic acid 2-phosphate to form ASC sheets. RNA sequencing was performed to identify the transcriptomic profiles of ASC spheroids and sheets relative to monolayer ASCs. By transferring ASC spheroids onto ASC sheets, the spheroid sheet composites could be successfully fabricated after a short-term co-culture, and their angiogenic potential was evaluated in vitro and in ovo., Results: RNA sequencing analysis revealed that upregulation of angiogenesis-related genes was found only in ASC spheroids. The stimulating effect of spheroid formation on ASCs toward endothelial lineage was demonstrated by enhanced CD31 expression, which maintained after ASC spheroids were seeded on cell sheets. Relative to ASC sheets, enhanced expression of VEGF and hepatocyte growth factor was also noted in ASC spheroid sheets, and conditioned medium of ASC spheroid sheets significantly enhanced tube formation of endothelial cells in vitro. Moreover, chick embryo chorioallantoic membrane assay showed a significantly higher capillary density with more branch points after applying ASC spheroid sheets, and immunohistochemistry also revealed a significantly higher ratio of CD31-positive area., Conclusion: In the spheroid sheet construct, ASC spheroids can augment the pro-angiogenesis capability of ASC sheets without the use of exogenous biomaterial or genetic manipulation. The strategy of this composite system holds promise as an advance in 3D culture technique of ASCs for future application in angiogenesis and regeneration therapies., (© 2022. The Author(s).)

Objectives: This study aimed to develop a new chewing problem directory (CPD) and validate it with oral health indicators such as total occlusion force, number of natural and rehabilitated teeth (NRT), NRT posterior, natural teeth, natural teeth posterior, and dental status among Korean elders., Background: Chewing problem is the main oral health problem in elders. However, there has been no validated tool using both subjective and objective assessment of chewing problem., Subjects and Methods: A total of 537 participants aged 65 years or more were randomly assigned into 2 subsamples: developing sample (n = 260) for developing and internally validating the new CPD as the 1st stage and confirmation sample (n = 277) for confirming validation of CPD as the 2nd stage. CPD was developed using three subjective questionnaires (general eating, chewing nuts, and chewing meat problem) and objective NRT. Periodontitis, age, sex, education, smoking, alcohol drinking, metabolic syndrome, and frailty were considered as confounders. Following the development of CPD, CPD was validated using multiple multivariable logistic regression after controlling for confounders in confirmation sample and total sample., Results: The Cronbach's alpha value for three subjective questionnaires of CPD was 0.87. Among oral health indicators, NRT (0-28) showed the highest impact association with subjective chewing problem score (partial r = - 0.276). The chewing problem from the new CPD was associated with all items of oral health indicators. The prevalence of chewing problems by CPD was 57.7% in developing sample. Elders with NRT ≤ 24, compared with those with NRT ≥ 25, showed the highest impact on chewing problems by new CPD (Odds Ratio = 7.3 in the confirmation sample and 5.04 in the total sample, p < 0.05) among oral health indicators., Conclusion: This new CPD was developed as a valid tool to evaluate the chewing problem for Korean elders in dental clinics and community-based settings., (© 2022. The Author(s).)

Background: NADPH is used as a reductant in various biosynthetic reactions. Cell-free bio-systems have gained considerable attention owing to their high energy utilization and time efficiency. Efforts have been made to continuously supply reducing power to the reaction mixture in a cyclical manner. The thylakoid membrane (TM) is a promising molecular energy generator, producing NADPH under light. Thus, TM sustainability is of major relevance for its in vitro utilization., Results: Over 70% of TMs prepared from Synechocystis sp. PCC6803 existed in a sealed vesicular structure, with the F 1 complex of ATP synthase facing outward (right-side-out), producing NADPH and ATP under light. The NADPH generation activity of TM increased approximately two-fold with the addition of carbonyl cyanide-p-(trifluoromethoxy) phenylhydrazone (FCCP) or removal of the F 1 complex using EDTA. Thus, the uncoupling of proton translocation from the electron transport chain or proton leakage through the F o complex resulted in greater NADPH generation. Biosilicified TM retained more than 80% of its NADPH generation activity after a week at 30°C in the dark. However, activity declined sharply to below 30% after two days in light. The introduction of engineered water-forming NADPH oxidase (Nox m ) to keep the electron transport chain of TM working resulted in the improved sustainability of NADPH generation activity in a ratio (Nox m to TM)-dependent manner, which correlated with the decrease of singlet oxygen generation. Removal of reactive oxygen species (ROS) by catalase further highlighted the sustainable NADPH generation activity of up to 80% in two days under light., Conclusion: Reducing power generated by light energy has to be consumed for TM sustainability. Otherwise, TM can generate singlet oxygen, causing oxidative damage. Thus, TMs should be kept in the dark when not in use. Although NADPH generation activity by TM can be extended via silica encapsulation, further removal of hydrogen peroxide results in an improvement of TM sustainability. Therefore, as long as ROS formation by TM in light is properly handled, it can be used as a promising source of reducing power for in vitro biochemical reactions., (© 2022. The Author(s).)

Background: Women have been underrepresented in the literature; the effects of female sex on outcomes in patients with acute myocardial infarction (AMI) remain unclear., Objectives: This study compares the real-world outcomes of women and men with AMI who have undergone revascularization via percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG)., Methods: This is a retrospective cohort study utilizing data from the Taiwan National Health Insurance database. We identified patients who were admitted for AMI and who underwent coronary revascularization during the index admission period between January 1, 2001, and December 31, 2013. Patients were then categorized based on the treatment received into PCI and CABG groups. In-hospital and long-term outcomes were compared between women and men in each group. Interaction tests were then performed to determine whether the differences between sexes were modified by the mode of revascularization. Analyses were repeated after propensity score matching between women and men in each group to minimize possible confounders. We also conducted subgroup analyses, stratifying by the presence of diabetes mellitus, congestive heart failure, and chronic kidney disease., Results: We enrolled 67,534 patients who met the inclusion criteria in the analysis; 60,207 patients had undergone PCI (13,514 female and 46,693 male), while 7327 patients had received CABG (1762 female and 5565 male). Prior to matching, enrolled female patients were older on average, with more comorbidities. In-hospital and long-term outcomes were worse in women, particularly in the PCI group. After matching, the incidence of hospitalization for heart failure (HHF) was higher in women (10.4% vs 8.0%, OR 1.32, 95% CI 1.22-1.43), with fewer repeat revascularizations (28.1% vs 32.4%, OR 0.84, 95% CI 0.81-0.88). Both observations were more pronounced in the PCI group (HHF: P for interaction = 0.0496; repeat revascularization: P for interaction = 0.021)., Conclusions: Women presenting with AMI exhibited worse in-hospital and long-term outcomes than men, especially among women who received PCI as the initial mode of revascularization. Women who underwent PCI were more likely to be admitted for heart failure during follow-up. Possible socioeconomic inequalities or a distinct pathobiology of cardiac ischemia between sexes may underlie these results; thus, further investigation is needed., (© 2022. The Author(s).)

Background: The effect of menopausal hormone therapy (MHT) on gastrointestinal (GI) cancers is controversial, and no research has been conducted in the East. This study investigates the association between MHT and GI cancer risks in South Korea., Methods: A prescription-based cohort study was conducted using the NHIS Sample Cohort (2002-2013) of Korea. We used 1:5 propensity score matching, and 22,577 MHT users and 111,113 non-users were selected. Kaplan-Meier survival curves with log-rank tests were used. Cox proportional hazard models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Landmark analysis was used to determine dose-response relationship., Results: The median follow-up was 79.6 of months. Kaplan-Meier survival curve showed less frequent GI cancer diagnoses in MHT users compared to non-users (0.13 vs. 0.16 per 100,000 person-years). Menopausal hormone therapy was associated with decreased incidence of GI cancer (HR = 0.809, 95%CI = 0.691-0.946) and colorectal cancer (CRC) (HR = 0.757, 95%CI = 0.577-0.995). Gastric cancer (GC) incidence showed marginal significance (HR = 0.787, 95%CI = 0.605-1.023). The mortality from GI cancer was lower in MHT users than in non-users (HR = 0.737, 95%CI = 0.547-0.993). The relationship between MHT and GI cancer was stronger with increasing MHT dose in terms of both incidence (P trend  = 0.0002) and mortality (P trend  = 0.0064)., Conclusions: The association between MHT use and reduced risks of GI cancers was attributed to CRC and GC and showed a dose-response relationship in a population-based cohort study., (© 2021. The Author(s).)

Background: With an increase in deep vein thrombosis (DVT) following total knee arthroplasty (TKA) in the Asian population, most surgeons today use a form of prophylactic anticoagulant agents in patients after TKA. Nevertheless, DVT occasionally develops even in these patients with prophylaxis. The purpose of this study was to identify the risk factors for DVT after TKA in cases of postoperative low-molecular-weight heparin (LMWH) use., Methods: We designed a retrospective study with 103 patients who underwent primary TKA. From the second postoperative day, 60 mg of LMWH was subcutaneously injected into the patients daily. On the seventh postoperative day, patients had computed tomography angiography to check whether they had DVT. Regarding risk factors, we investigated patients' gender, age, surgical site (unilateral/bilateral), body mass index, method of anesthesia, preoperative hypertension, diabetes, hypercholesterolemia status, and prothrombin time/international normalized ratio from electronic medical records. We analyzed the statistical significance of these risk factors., Results: Statistically significant factors in the single-variable analysis were surgical site (unilateral/bilateral), body mass index, preoperative hypertension status, and anesthesia method. Multiple logistic regression analysis with these factors revealed that the surgical site (unilateral/bilateral, p = 0.024) and anesthesia method (p = 0.039) were significant factors for the occurrence of postoperative DVT after TKA., Conclusions: Patients undergoing simultaneous bilateral TKAs and patients undergoing TKA with general anesthesia need more attention regarding DVT even with chemoprophylaxis using LMWH after TKA., (© 2021. The Author(s).)

Background: The 2013 Malaysian Clinical Practice Guidelines on the Management of Osteoarthritis (OA) recommend a linear step-up approach to manage knee OA. However, patients with knee OA often require a multimodal approach to address OA-related pain symptoms and functional limitations. This consensus aimed to provide doctors with an updated set of evidence-based, clinical experience-guided recommendations to manage knee OA., Methods: A multi-speciality expert panel consisting of nine Malaysian physicians from different healthcare settings who manage a diverse OA patient population was convened. Using a combination of the ADAPTE process and modified Delphi method, the panel reviewed current evidence on the management of knee OA and synthesised a set of nine recommendations on the management of knee OA, supported by an algorithm that summarises the consensus' core messages., Results: A multimodal intervention strategy is the mainstay of OA management and the choice of any single or multimodal intervention may vary over the course of the disease. Overall, a non-pharmacological core treatment set of patient education, weight loss and exercise is recommended for all patients. When pharmacotherapy is indicated, symptomatic slow-acting drugs for osteoarthritis are recommended at the early stage of disease, and they can be paired with physical therapy as background treatment. Concurrent advanced pharmacotherapy that includes non-steroidal anti-inflammatory drugs, intraarticular injections and short-term weak opioids can be considered if patients do not respond sufficiently to background treatment. Patients with severe symptomatic knee OA should be considered for knee replacement surgery. Management should begin with specific treatments with the least systemic exposure or toxicity, and the choice of treatment should be determined as a shared decision between patients and their team of healthcare providers., Conclusions: This consensus presents nine recommendations that advocate an algorithmic approach in the management of patients living with knee OA. They are applicable to patients receiving treatment from primary to tertiary care providers in Malaysia as well as other countries.

Background: Salivary function has been suggested to be associated with cognitive impairment. However, the effect of salivary flow rate (SFR) on cognitive impairment remains unclear. This study aimed to investigate whether SFR is associated with cognitive impairment among Korean elders., Methods: This cross-sectional study included 649 elders aged 65 and older in the Korean community-dwelling population. Cognitive impairment was assessed using the Mini-Mental Status Examination. Unstimulated SFR was measured and dichotomized. Denture status, age, sex, education level, smoking, drinking, diabetes, hypertension, and obesity were considered confounders. Multivariable logistic regression analysis was applied to assess the adjusted association. Stratified analysis by sex and denture status was performed to clarify the effect modification., Results: Participants without cognitive impairment showed a higher SFR level than those with cognitive impairment (0.81 mL/min for non-cognitive impairment versus 0.52 mL/min for cognitive impairment, p < 0.001). After controlling for confounders, participants with low SFR (< 0.3 mL/min) were more likely to have cognitive impairment by 1.5 times than participants with normal SFR (odds ratio [OR] = 1.5, confidence interval [CI] = 1.05-2.10). The association of low SFR with cognitive impairment was higher in women and dentate participants: about 10% higher in women (OR = 1.63, CI = 1.07-2.50) and about 22% higher in dentate participants (OR = 1.82, CI = 1.41-2.90)., Conclusions: Salivary flow rate is independently associated with cognitive impairment among Korean elders. The association was modified in females and dentate elders. Physicians and dentists should consider low SFR and cognitive impairment as a risk factor between them in clinics.

Background: Complementary and alternative medicine use among Americans is prevalent. Originating in India, Ayurvedic medicine use in the United States has grown 57% since 2002. CAM accounts for a significant proportion of drug induced liver injury in India and China, but there have been only three reports of drug induced liver injury from Ayurvedic medications in the U.S. We report three cases of suspected Ayurvedic medication associated liver injury seen at a Southern California community hospital and review literature of Ayurvedic medication induced liver injury., Case Presentations: Three patients presented with acute hepatocellular injury and jaundice after taking Ayurvedic supplements for 90-120 days. First patient took Giloy Kwath consisting solely of Tinospora cordifolia. Second patient took Manjishthadi Kwatham and Aragwadhi Kwatham, which contained 52 and 10 individual plant extracts, respectively. Third patient took Kanchnar Guggulu, containing 10 individual plant extracts. Aminotransferase activities decreased 50% in < 30 days and all 3 patients made a full recovery. Roussel Uclaf Causality Assessment Method (RUCAM) scores were 7-8, indicating probable causality. These products all contained ingredients in other Ayurvedic and traditional Chinese medicines with previously reported associations with drug induced liver injury., Conclusions: These patients highlight the risk of drug induced liver injury from Ayurvedic medications and the complexity of determining causality. There is a need for a platform like LiverTox.gov to catalog Ayurvedic ingredients causing liver damage.

Background: Obesity is well known as a risk factor for cardiovascular disease. We aimed to determine the performance of and the optimal cutoff values for obesity indices to discriminate the presence of metabolic abnormalities as a primary risk factor for cardiovascular diseases in a Health Examinees study (HEXA)., Methods: The current study analyzed 134,195 participants with complete anthropometric and laboratory information in a Health Examinees study, consisting of the Korean population aged 40 to 69 years. The presence of metabolic abnormality was defined as having at least one of the following: hypertension, hyperglycemia, or dyslipidemia. The area under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs) were calculated for body mass index, waist to hip ratio, waist to height ratio, waist circumference, and conicity index., Results: The AUC of metabolic abnormalities was the highest for waist-to-height ratio (AUC [95% CIs], 0.677 [0.672-0.683] among men; 0.691 [0.687-0.694] among women), and the lowest for the C index (0.616 [0.611-0.622] among men; 0.645 [0.641-0.649] among women) among both men and women. The optimal cutoff values were 24.3 kg/m 2 for the body mass index, 0.887 for the waist-to-hip ratio, 0.499 for the waist-to-height ratio, 84.4 cm for waist circumference and 1.20 m 3/2 /kg 1/2 for the conicity index among men, and 23.4 kg/m 2 for the body mass index, 0.832 for the waist-to-hip ratio, 0.496 for the waist-to-height ratio, 77.0 cm for the waist circumference and 1.18 m 3/2 /kg 1/2 for the conicity index among women., Conclusion: The waist-to-height ratio is the best index to discriminate metabolic abnormalities among middle-aged Koreans. The optimal cutoff of obesity indices is lower than the international guidelines for obesity. It would be appropriate to use the indices for abdominal obesity rather than general obesity and to consider a lower level of body mass index and waist circumference than the current guidelines to determine obesity-related health problems in Koreans.

Background: Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood., Results: Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson's disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis., Conclusions: This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson's disease, where immune dysfunction is implicated in their etiology.

Background: Although social capital has been shown to be one of the important social determinants of health, the association between social trust and the risk of cardiovascular disease (CVD) is not clear yet. We aimed to investigate the association of social trust with CVD risk using a large Korean population based data., Methods: The data of this study was derived from the Korean National Health Insurance Service database. Community-level social trust was determined from the Korean Community Health Survey. The study population consisted of 2,156,829 participants. According to social trust index measured in the area of residence during 2011, participants were followed-up from 1 January 2012 to 31 December 2016. Multivariate Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD risk according to quintiles of social trust., Results: Compared to participants with the lowest quintile of social trust, those within the highest quintile had lower risk for CVD (aHR 0.91, 95% CI = 0.89 to 0.93), CHD (aHR 0.92, 95% CI = 0.89 to 0.95), and stroke (aHR 0.90, 95% CI = 0.87 to 0.93). The risk-reducing association of high social trust on CVD risk was preserved after additional adjustments for lifestyle behaviors including smoking, alcohol consumption, and physical activity., Conclusion: Higher social trust was associated with reduced risk of CVD even after considering lifestyle behaviors. Social trust in a community level is an important determinant of CVD and enhancing social trust may lead to reduced risk of CVD.

Background: Whether community level social capital is associated with mortality within an Asian population is yet unclear., Methods: The study population was derived from the Korean National Health Insurance Service-National Sample Cohort. A total of 636,055 participants were followed-up during 2012-2013 for deaths from all causes, cardiovascular disease (CVD), cancer, and other causes. Community level social trust and reciprocity at the administrative district level were derived from the Korean Community Health Survey. Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for mortality according to levels of community level social trust and reciprocity., Results: Compared to participants who reside in areas within the lower half of community level social trust, those who reside in areas within the upper half had lower risk of death from all causes (aHR 0.84, 95% CI 0.78-0.89), CVD (aHR 0.82, 95% CI 0.67-0.99), and cancer (aHR 0.85, 95% CI 0.73-0.98). Similarly, residing in areas in the upper half of community level social reciprocity was associated with reduced risk for all-cause mortality (aHR 0.80, 95% CI 0.75-0.86). The protective association of high community level social trust and reciprocity on mortality remained after additional adjustments for smoking, alcohol intake, and physical activity., Conclusions: Residing in areas with high community level social trust and reciprocity may be associated with better population health status.

Background: Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3-4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors., Results: Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits., Conclusion: Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

Background: We aimed to explore the efficacy of orbital radiotherapy (RT) in patients with moderate-to-severe active Graves' orbitopathy (GO), including long-lasting disease, and to determine the predictive factors associated with treatment response., Methods: This was a retrospective study of 62 moderate-to-severe active GO patients treated with RT. Demographic data and ophthalmic findings prior to RT and at 3 and 6 months afterward were analyzed. Computed tomography was performed before and after RT to compare orbital volume change. We used logistic regression to determine the predictive factors for treatment response. Subjects were divided into early- and late-active phase groups based on GO duration of 24 months and treatment outcomes were compared with each other to observe the effects of RT timing on treatment response., Results: Forty (64.5%) and forty-six (74.1%) patients experienced improvements in GO at 3 and 6 months after radiotherapy, respectively. Ocular parameters such as clinical activity score (CAS), proptosis, extraocular muscle (EOM) limitation, and compressive optic neuropathy (CON) were improved by RT. Volumes of EOM significantly decreased after RT. The enlargement of EOMs and EOM limitation were predictive factors for a good response to RT. At 6 months after RT, 22 (68.8%) patients of late-active phase group exhibited improvement in GO, which is comparable to the number of 24 (80.0%) patients of early-active phase group. In the late-active phase group, CAS, diplopia, and visual acuity were improved significantly, but there was no change in EOM limitation., Conclusions: In moderate-to-severe active GO patients, orbital RT may help improve high CAS, proptosis, EOM limitation, and CON. The orbital RT in long-lasting active GO patients may be considered as treatments for the relief of symptoms including high CAS and poor visual acuity.

Background: The decision of transarterial chemoembolization (TACE) initiation and/or repetition remains challenging in patients with unresectable hepatocellular carcinoma (HCC). The aim was to develop a prognostic scoring system to guide TACE initiation/repetition., Methods: A total of 597 consecutive patients who underwent TACE as their initial treatment for unresectable HCC were included. We derived a prediction model using independent risk factors for overall survival (OS), which was externally validated in an independent cohort (n = 739)., Results: Independent risk factors of OS included Albumin-bilirubin (ALBI) grade, maximal tumor size, alpha-fetoprotein, and tumor response to initial TACE, which were used to develop a scoring system ("ASAR"). C-index values for OS were 0.733 (95% confidence interval [CI] = 0.570-0.871) in the derivation, 0.700 (95% CI = 0.445-0.905) in the internal validation, and 0.680 (95% CI = 0.652-0.707) in the external validation, respectively. Patients with ASAR< 4 showed significantly longer OS than patients with ASAR≥4 in all three datasets (all P < 0.001). Among Child-Pugh class B patients, a modified model without TACE response, i.e., "ASA(R)", discriminated OS with a c-index of 0.788 (95% CI, 0.703-0.876) in the derivation, and 0.745 (95% CI, 0.646-0.862) in the internal validation, and 0.670 (95% CI, 0.605-0.725) in the external validation, respectively. Child-Pugh B patients with ASA(R) < 4 showed significantly longer OS than patients with ASA(R) ≥ 4 in all three datasets (all P < 0.001)., Conclusions: ASAR provides refined prognostication for repetition of TACE in patients with unresectable HCC. For Child-Pugh class B patients, a modified model with baseline factors might guide TACE initiation.

Background: The C:G > T:A substitution at the CpG dinucleotide contexts is the most frequent substitution type in genome evolution. The mutational process is obviously ongoing in the human germline; however, its impact on common and rare genomic polymorphisms has not been comprehensively investigated yet. Here we observed the landscape and dynamics of C:G > T:A substitutions from population-scale human genome sequencing datasets including ~ 4300 whole-genomes from the 1000 Genomes and the pan-cancer analysis of whole genomes (PCAWG) Project and ~ 60,000 whole-exomes from the Exome Aggregation Consortium (ExAC) database., Results: Of the 28,084,558 CpG sites in the human reference genome, 26.0% show C:G > T:A substitution in the dataset. Remarkably, CpGs in CpG islands (CGIs) have a much lower frequency of such mutations (5.6%). Interestingly, the mutation frequency of CGIs is not uniform with a significantly higher C:G > T:A substitution rate for intragenic CGIs compared to other types. For non-CGI CpGs, the mutation rate was positively correlated with the distance from the nearest CGI up to 2 kb. Finally, we found the impact of negative selection for coding CpG mutations resulting in amino acid change., Conclusions: This study provides the first unbiased rate of C:G > T:A substitution at the CpG dinucleotide contexts, using population-scale human genome sequencing data. Our findings provide insights into the dynamics of the mutation acquisition in the human genome.

Background: Social capital is a collective attribute of communities that determines health and well-being of populations. The collective resources in a high social capital community have been reported to result in better health outcomes. While evidence supports the links between social capital and various health outcomes, it is not clear about underlying mechanisms connecting multiple dimensions of social capital to health., Methods: Using the two-wave data from a nationally representative cohort study of Australian adults (N = 16,637), this study examined the effects of two dimensions of social capital (i.e., structural and cognitive social capital) on physical and mental health in the Australian adult population. Based on prior literature and theoretical reasoning, it was anticipated that the structural and cognitive social capital would influence self-assessed health status (physical and mental health). Additionally, these two dimensions of social capital were hypothesized to moderate the relationships between chronic health conditions and these two aspects of health status., Results: Analyses showed that the effects of chronic health conditions on mental health status were moderated by the structural social capital (β = .652, SE = .249, p = .009). Additionally, it was found that perceived community cohesion was predictive of mental health (β = .295, SE = .103, p = .004). Our analysis also indicated that perceptions of disadvantaged neighbourhood environment contributed to poorer mental health status (β = -.461, SE = .144, p = .001). However, none of the social capital variables significantly predicted physical health status., Conclusions: Findings suggest that the structural dimension of social capital would function as a buffer against the malicious effects of chronic health conditions, impairments and disabilities. Specifically, community participation (structural social capital) is indispensable to develop an effective community-based program to improve health and well-being of those with chronic health conditions or disabilities, as increasing active participation may generate beneficial effects in this vulnerable population. Subjective perceptions about communities can also play an important role in improving better health outcomes. Further research is needed to examine underlying mechanisms linking the multiple dimensions of social capital to health outcomes among individuals who are vulnerable to external stressors.

Background: We investigated the incidence and location of heterotopic ossification (HO) following hip arthroscopy., Methods: This retrospective study enrolled 327 patients who underwent hip arthroscopy from January 2010 to December 2015. From this cohort, we extracted an HO group with simple radiographs or three-dimensional computed tomography (3D CT). Findings consistent with HO were classified according to the Brooker classification aided with 3D CT for the location of HO. The indication for revision arthroscopic excision of HO was painful, functional impairment of the hip. Patient clinical outcomes were assessed pre- and postoperatively, with modified Harris Hip Scores (mHHS), a visual analogue scale (VAS) for pain, and the Hip Outcome Score-Activity of Daily Living (HOS-ADL) and Sport Specific Subscales (HOS-SSS)., Results: In all, 14 (4.28%) of the 327 patients had confirmed HO radiographically. The mean follow-up was 39 months. In 13 patients, HO formed in the central area of the arthroscopic portals or capsulotomy. Ten patients had Brooker Grade 1 and four had Grade 2. At the last follow-up, 12 asymptomatic patients had significant (P < 0.001) improvements in all clinical outcome scores (mHHS, pain VAS, HOS-ADL, and HOS-SSS). Two patients developed symptoms sufficient to require revision hip arthroscopy for HO excision. After revision hip arthroscopy, both symptomatic patients had improved significantly in all clinical outcomes at the final follow-up., Conclusions: HO is a minor complication of hip arthroscopy, but sometimes induces severe pain and functional impairment. Usually, HO forms in the arthroscopic portal or capsulotomy area.

Background: Data on clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in patients with chronic kidney disease (CKD) are scarce. We investigated the clinical features and risk factors of NAFLD using noninvasive serum markers in CKD patients and attempted the temporal validation of a predictive model for CKD based on NAFLD., Methods: This retrospective cross-sectional study was conducted in a single tertiary center. We enrolled 819 CKD patients and evaluated the predictive performance of relevant clinical and laboratory markers for the presence of NAFLD in both derivation (data from 2011 to 2014, n = 567) and validation (data from 2015 to 2016, n = 252) groups., Results: In the derivation group, NAFLD was observed in 89 patients (15.7%; mean body mass index (BMI), 24.6 kg/m 2 ; median estimated glomerular filtration rate (eGFR), 28.0 ml/min). BMI, hemoglobin, serum alanine aminotransferase, eGFR, and triglyceride-glucose index were used to derive a prediction model for the presence of NAFLD. Using the cutoff value of 0.146, the area under the receiver operating characteristic curve (AUROC) for the prediction of NAFLD was 0.850. In the validation group, NAFLD was observed in 51 patients (20.2%; mean BMI, 25.4 kg/m 2 ; median eGFR, 36.0 ml/min). Using the same prediction model and cutoff value, the AUROC was 0.842. NAFLD prevalence in CKD patients was comparable to that in the general population, increasing over time., Conclusions: Our model using BMI, renal function, triglyceride-glucose index, serum alanine aminotransferase, and hemoglobin accurately predicted the presence of NAFLD in CKD patients.

Background: Vietnam has been successful in increasing access to maternal, neonatal, and child health (MNCH) services during last decades; however, little is known about whether the primary MNCH service utilization has been properly utilized under the recent rapid urbanization. We aimed to examine current MNCH service utilization patterns at a district level., Methods: The study was conducted qualitatively in a rural district named Quốc Oai. Women who gave a birth within a year and medical staff at various levels participated through 43 individual in-depth interviews and 3 focus group interviews., Results: Primary MNCH services were underutilized due to a failure to meet increased quality needs. Most of the mothers preferred private clinics for antenatal care and the district hospital for delivery due to the better service quality of these facilities compared to that of the commune health stations (CHSs). Mothers had few sociocultural barriers to acquiring service information or utilizing services based on their improved standard of living. A financial burden for some services, including caesarian section, still existed for uninsured mothers, while their insured counterparts had relatively few difficulties., Conclusions: For the improved macro-efficiency of MNCH systems, the government needs to rearrange human resources and/or merge some CHSs to achieve economies of scale and align with service volume distribution across the different levels.

Background: To report a case of type III dens invaginatus associated with peri-invagination periodontitis in an immature permanent mandibular central incisor with open apex, in which only the invagination area was treated and vitality was preserved., Case Presentation: A 9-year-old boy was referred complaining of pain in the mandibular left central incisor. After radiographic examination, an invagination into the pulp chamber of the tooth associated with periapical radiolucency was detected. Endodontic access was performed and the orifice was identified under a dental operating microscope. The invagination area was chemo-mechanically cleaned. After 1 week, the invagination was obturated with mineral trioxide aggregate. During the 2-year follow up period, the tooth was asymptomatic. Radiographic examination revealed significant progression of periapical healing and root development in the main root canal of the tooth., Conclusion: Non-surgical root canal treatment of the invagination may preserve pulp vitality, and continuous root development of the tooth.

Background: It has been suggested that the anterolateral ligament (ALL) is an important anterolateral stabilizer of the knee joint which functions to prevent anterolateral subluxation and anterior subluxation at certain flexion angles in the knee., Purpose: To analyze and systematically interpret the biomechanical function of the ALL., Methods: An online search was conducted for human cadaveric biomechanical studies that tested function of the ALL in resisting anterolateral subluxation and anterior subluxation of the knee. Two reviewers independently searched Medline, Embase, and the Cochrane Database of Systematic Reviews for studies up to 25 September 2018. Biomechanical studies not reporting the magnitude of anterior tibial translation or tibial internal rotation in relation to the function of the ALL were excluded., Results: Twelve biomechanical studies using human cadavers evaluating parameters including anterior tibial translation and/or internal tibial rotation in anterior cruciate ligament (ACL)-sectioned and ALL-sectioned knees were included in the review. Five studies reported a minor increase or no significant increase in anterior tibial translation and internal tibial rotation with further sectioning of the ALL in ACL-deficient knees. Five studies reported a significant increase in knee laxity in tibial internal rotation or pivot shift with addition of sectioning the ALL in ACL-deficient knees. Two studies reported a significant increase in both anterior tibial translation and internal tibial rotation during application of the anterior-drawer and pivot-shift tests after ALL sectioning., Conclusion: There was inconsistency in the biomechanical characteristics of the ALL of the knee in resisting anterolateral and anterior subluxation of the tibia.

Background: The core symptoms of autism spectrum disorder (ASD) are widely theorized to result from altered brain connectivity. Diffusion-weighted magnetic resonance imaging (DWI) has been a versatile method for investigating underlying microstructural properties of white matter (WM) in ASD. Despite phenotypic and etiological heterogeneity, DWI studies in majority male samples of older children, adolescents, and adults with ASD have largely reported findings of decreased fractional anisotropy (FA) across several commissural, projection, and association fiber tracts. However, studies in preschool-aged children (i.e., < 30-40 months) suggest individuals with ASD have increased measures of WM FA earlier in development., Methods: We analyzed 127 individuals with ASD (85♂, 42♀) and 54 typically developing (TD) controls (42♂, 26♀), aged 25.1-49.6 months. Voxel-wise effects of ASD diagnosis, sex, age, and their interaction on DWI measures of FA, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were investigated using tract-based spatial statistics (TBSS) while controlling mean absolute and relative motion., Results: Compared to TD controls, males and females with ASD had significantly increased measures of FA in eight clusters (threshold-free cluster enhancement p < 0.05) that incorporated several WM tracts including regions of the genu, body, and splenium of the corpus callosum, inferior frontal-occipital fasciculi, inferior and superior longitudinal fasciculi, middle and superior cerebellar peduncles, and corticospinal tract. A diagnosis by sex interaction was observed in measures of AD across six significant clusters incorporating areas of the body, genu, and splenium of the corpus collosum. In these tracts, females with ASD showed increased AD compared to TD females, while males with ASD showed decreased AD compared to TD males., Conclusions: The current findings support growing evidence that preschool-aged children with ASD have atypical measures of WM microstructure that appear to differ in directionality from alterations observed in older individuals with the condition. To our knowledge, this study represents the largest sample of preschool-aged females with ASD to be evaluated using DWI. Microstructural differences associated with ASD largely overlapped between sexes. However, differential relationships of AD measures indicate that sex likely modulates ASD neuroanatomical phenotypes. Further longitudinal study is needed to confirm and quantify the developmental relationship of WM structure in ASD.

Background: The global burden of seasonal influenza on medical care has been one of the greatest in the pediatric population. The attention drawn to influenza B was relatively low compared to influenza A, probably because the influenza B virus was thought to be less virulent and have a lower pandemic potential. This study aimed to compare the clinical features of influenza A and B in children., Methods: This retrospective study included children diagnosed and treated for influenza as inpatients or outpatients during the 2017/18 influenza season at a tertiary referral hospital. Data regarding clinical characteristics, diagnoses, laboratory results, and vaccination histories were collected and reviewed., Results: Over the study period, 128 patients with influenza A and 109 patients with influenza B were identified. The mean age of patients with influenza B was significantly higher than that of patients with influenza A (5.6 ± 4.4 vs 4.1 ± 4.4 years, p = 0.010). Fever was the most common manifestation of influenza followed by respiratory symptoms. No single symptom was specifically associated with either type of influenza. The total duration of fever (4.3 ± 2.3 vs 3.7 ± 2.6 days), 'time from fever onset to initiation of antivirals', and 'time from initiation of antivirals to defervescence' were similar between the two influenza types, even though all three time periods tended to be longer for influenza B. The platelet counts and proportions of neutrophils were higher for influenza A than for influenza B infections, although the values were within normal limits for both influenza types., Conclusions: We found overall clinical similarities between influenza A and B with no less clinical significance or severity of influenza B compared to those of influenza A. Equal levels of awareness and attention should be paid to both influenza types.

Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (α-syn) inclusions, the major component of Lewy bodies. Extracellular α-syn aggregates act as a damage-associated molecular pattern (DAMP) and the presence of autoantibodies against α-syn species in the cerebrospinal fluid and the serum of PD patients implicate the involvement of innate and adaptive immune responses. In non-transgenic (Tg) mice, intrastriatal injection of preformed fibril (PFF) α-syn results in widespread pathologic α-syn inclusions in the CNS. While the PFF model has been broadly utilized to study the mechanistic relationship between α-syn transmission and other neuropathological phenotypes, the immune phenotypes in this model are not clearly demonstrated. This study aimed to characterize the immune phenotypes during pathologic α-syn propagation by utilizing PFF α-syn-injected non-tg mice. Here, we showed that pathologic α-syn inclusions are prevalent in various brain regions and the gut at 5 months post injection (p.i.), preceding the degeneration of dopaminergic neurons in substantia nigra (SN). We discovered a distinct inflammatory response involving both activation of microglia and astrocytes and infiltration of B, CD4+ T, CD8+ T, and natural killer cells in the brain at 5 months p.i. Moreover, PFF α-syn-injected mice display significant alterations in the frequency and number of leukocyte subsets in the spleen and lymph nodes with minimum alterations in the blood. Our data provide primary evidence that intracerebral-initiated synucleinopathies in non-tg mice alter immune cell profiles both in the CNS and peripheral lymphoid organs. Furthermore, our data provides support for utilizing this mouse model to assess the mechanistic connection between immune responses and synuclein pathology.

Background: Mycoplasma pneumoniae is a common cause of respiratory tract infections in children and adults. This study applied high-throughput whole genome sequencing (WGS) technologies to analyze the genomes of 30 M. pneumoniae strains isolated from children with pneumonia in South Korea during the two epidemics from 2010 to 2016 in comparison with a global collection of 48 M. pneumoniae strains which includes seven countries ranging from 1944 to 2017., Results: The 30 Korean strains had approximately 40% GC content and ranged from 815,686 to 818,669 base pairs, coding for a total of 809 to 828 genes. Overall, BRIG revealed 99% to > 99% similarity among strains. The genomic similarity dropped to approximately 95% in the P1 type 2 strains when aligned to the reference M129 genome, which corresponded to the region of the p1 gene. MAUVE detected four subtype-specific insertions (three in P1 type 1 and one in P1 type 2), of which were all hypothetical proteins except one tRNA insertion in all P1 type 1 strains. The phylogenetic associations of 30 strains were generally consistent with the multilocus sequence typing results. The phylogenetic tree constructed with 78 genomes including 30 genomes from Korea formed two clusters and further divided into two sub-clusters. eBURST analysis revealed two clonal complexes according to P1 typing results showing higher diversity among P1 type 2 strains., Conclusions: The comparative whole genome approach was able to define high genetic identity, unique structural diversity, and phylogenetic associations among the 78 M. pneumoniae strains isolated worldwide.

Background: Older surgical patients are at high risk of developing postoperative delirium. Non-pharmacological strategies are recommended for delirium prevention, but no pharmacological agents have compelling evidence to decrease the incidence of delirium. The purpose of this study was to assess whether perioperative melatonin decreases the incidence of delirium in older adults undergoing surgical procedures., Methods: A systematic search using PubMed/Medline, Embase, PsycINFO, CINAHL, and references of identified articles published in English between January 1990 and October 2017 was performed. Two independent reviewers screened titles and abstracts, and then extracted data following a full-text review of included articles with consensus generation and bias assessment. Studies reporting outcomes for melatonin or ramelteon use to prevent delirium in postoperative hospitalized patients (mean age ≥ 50 years) were eligible for inclusion. Data were pooled using a fixed-effects model to generate a forest plot and obtain a summary odds ratio for the outcome of interest (delirium incidence). Cochran's Q and I 2 values were used to investigate heterogeneity., Results: Of 335 records screened, 6 studies were selected for the qualitative analysis and 6 were included in the meta-analysis (n = 1155). The mean age of patients in included studies ranged from 59 to 84 years. Patients in intervention groups typically received melatonin or ramelteon at daily doses of two to eight milligrams around cardiothoracic, orthopedic, or hepatic surgeries for one to nine days, starting on the evening before or the day of surgery. The incidence of delirium ranged from 0 to 30% in the intervention groups versus 4-33% in the comparator groups, and was significantly reduced in the melatonin group, with a summary effect of the meta-analysis yielding an odds ratio of 0.63 (95% CI 0.46 to 0.87; 0.006; I 2  = 72.1%). A one study removed analysis reduced overall odds ratio to 0.310 (95% CI 0.19 to 0.50), while reducing heterogeneity (Cochran's Q = 0.798, I 2  = 0.000)., Conclusion: Perioperative melatonin reduced the incidence of delirium in older adults in the included studies. While optimal dosing remains an unanswered question, the potential benefit of melatonin and melatonin receptor agonists may make them a reasonable option to use for delirium prevention in older adults undergoing surgical procedures.

Background: Lymph-node (LN) metastasis is an important prognostic factor in resected pancreatic cancer. In this study, the prognostic value of American Joint Committee on Cancer (AJCC) 8th edition N stage, lymph-node ratio (LNR), and log odds of positive lymph nodes (LODDS) in resected pancreatic cancer was investigated., Methods: Between January 2005 and December 2017, there were 351 patients with pancreatic cancer treated with R0 resection and adjuvant therapy at Seoul National University Hospital. Relationships between the three LN parameters and overall survival (OS) and recurrence-free survival (RFS) were evaluated using a log-rank test and Cox proportional hazard regression model. Each multivariate-adjusted LN parameter was internally validated by bootstrap-corrected Harrell's C-index., Results: The mean duration from surgery to adjuvant therapy was 47.6 ± 17.4 days. In total, the median OS and RFS was 31.7 (95% CI, 27.2-37.2) and 15.4 (95% CI, 13.5-17.7) months. The three LN classification systems were significantly correlated with OS and RFS in log-rank tests and multivariate-adjusted models (all p < 0.05). When internally validated, LNR showed the highest discrimination ability in predicting OS and RFS (each C-index = 0.65). LNR also showed the highest C-index in subgroup analysis, classified by adjuvant therapy modality. LNR and the AJCC 8th edition LN classification system were significantly associated with loco-regional recurrence (p = 0.026 and p = 0.027, respectively)., Conclusions: LNR, which showed the best prognostic performance and significant relationship with loco-regional recurrence, can help further stratify the patients and establish an active treatment plan.

Background: Methane, a main component of natural gas and biogas, has gained much attention as an abundant and low-cost carbon source. Methanotrophs, which can use methane as a sole carbon and energy source, are promising hosts to produce value-added chemicals from methane, but their metabolic engineering is still challenging. In previous attempts to produce lactic acid (LA) from methane, LA production levels were limited in part due to LA toxicity. We solved this problem by generating an LA-tolerant strain, which also contributes to understanding novel LA tolerance mechanisms., Results: In this study, we engineered a methanotroph strain Methylomonas sp. DH-1 to produce d-lactic acid (d-LA) from methane. LA toxicity is one of the limiting factors for high-level production of LA. Therefore, we first performed adaptive laboratory evolution of Methylomonas sp. DH-1, generating an LA-tolerant strain JHM80. Genome sequencing of JHM80 revealed the causal gene watR , encoding a LysR-type transcription factor, whose overexpression due to a 2-bp (TT) deletion in the promoter region is partly responsible for the LA tolerance of JHM80. Overexpression of the watR gene in wild-type strain also led to an increase in LA tolerance. When d form-specific lactate dehydrogenase gene from Leuconostoc mesenteroides subsp. mesenteroides ATCC 8293 was introduced into the genome while deleting the glgA gene encoding glycogen synthase, JHM80 produced about 7.5-fold higher level of d-LA from methane than wild type, suggesting that LA tolerance is a critical limiting factor for LA production in this host. d-LA production was further enhanced by optimization of the medium, resulting in a titer of 1.19 g/L and a yield of 0.245 g/g CH 4 ., Conclusions: JHM80, an LA-tolerant strain of Methylomonas sp. DH-1, generated by adaptive laboratory evolution was effective in LA production from methane. Characterization of the mutated genes in JHM80 revealed that overexpression of the watR gene, encoding a LysR-type transcription factor, is responsible for LA tolerance. By introducing a heterologous lactate dehydrogenase gene into the genome of JHM80 strain while deleting the glgA gene, high d-LA production titer and yield were achieved from methane., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)