Efficacy of Silkworm Pupae Extract on Muscle Strength and Mass in Middle-Aged and Older Individuals: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: We investigated the efficacy and safety of silkworm pupae extract (SWP) consumption for 12 weeks on muscle mass and strength in middle-aged and older individuals with relatively low skeletal muscle mass who do regular low-intensity exercise. DESIGN: A randomized double-blinded placebo-controlled trial. PARTICIPANTS: The study was conducted with 54 participants with relatively low skeletal muscle mass (SMM) (64.4 ± 6.1 years; body mass index, 23.8 ± 2.4 kg/m2). INTERVENTION AND MEASUREMENTS: Participants were randomly assigned to one of two groups: 1000 mg of SWP/day plus regular exercise (SWP group, n=27) or placebo plus regular exercise (placebo group, n=27). All participants were required to engage in 30-60 minutes/day of walking for ≥3 days/week for 12 weeks. The primary outcome was knee extension/flexion strength (Nm), measured at the velocity of 60°/s. Secondary outcomes included body composition, biomarkers (creatine kinase and creatinine), handgrip strength, and quality of life questionnaire. RESULTS: Both the intention-to-treat (ITT) and per-protocol (PP) analyses revealed no significant impact of SWP on knee strength compared to the placebo group over 12 weeks. On the other hand, the SWP group had significantly greater increases in right-handgrip strength by 1.94 kg (95% CI: 0.08-3.79; p = 0.041) and left-handgrip strength by 1.83 kg (0.25-3.41; p = 0.024) compared to the placebo group in the ITT population, after 12 weeks. Moreover, in the PP population, the SWP group revealed an even greater increase in right-handgrip strength by 2.07 kg (0.15-3. 98; p = 0.035) and left-handgrip strength by 2.21 kg (0.60-3.83; p = 0.008) for the 12-week period. However, this study resulted in a failure to detect significant differences in the body composition, biomarkers, quality of life questionnaire, physical activity, and caloric intake between the groups. None of the participants in the SWP group experienced any significant adverse events. In the placebo group, two participants experienced urticaria and allergic side effects, leading to their withdrawal from the study and two exhibited elevated levels of liver enzyme and increased diastolic blood pressure, respectively at 12 weeks. CONCLUSION: SWP, in addition to low-intensity exercise, may enhance handgrip strengths in middle-aged and older adults with relatively lower SMM. Future studies need to use a large sample size over longer periods to validate our findings. This trial was registered at clinicaltrials.gov as NCT04994054.

Subjective Cognitive Complaints: Comparing the Relation between Self-Reported Versus Informant-Reported Subjective Cognitive Complaints and Cognitive Performances in Cognitively Unimpaired, Mild Cognitive Impairment and Populations with Dementia.

BACKGROUND: Subjective cognitive decline is proposed to be associated with future mild cognitive impairment and dementia. A better understanding of the roles of self-reported and informant-reported subjective cognitive complaints can provide a more delicate picture in dementia recognition and early diagnosis. OBJECTIVES: To evaluate the accuracy of self-reported and informant-reported subjective cognitive complaints and the relation of subjective cognitive complaints and neuropsychological function in cognitively unimpaired, mild cognitive impairment and populations with dementia. DESIGN: We conducted a cross-sectional survey and evaluate the relations between subjective cognitive complaint scores and cognitive function in the different diagnostic groups. SETTING: We recruited individuals diagnosed with cognitively unimpaired or mild cognitive impairment or dementia with Alzheimer's clinical syndrome from a memory clinic in a tertiary medical center in Taiwan. PARTICIPANTS: Participants, age greater than 50 years old, were enrolled in this study. Participants' informants were also enrolled for the cognitive questionnaire assessment. MEASUREMENTS: Participants' and informants' subjective cognitive complaint scores were collected based on a 12-item questionnaire. Neuropsychological assessments of global cognitive function, memory, language, executive function, visuospatial function and calculation were performed. The relations between subjective cognitive complaint scores and cognitive function in the different diagnostic groups were assessed by linear regression model. RESULTS: There were 1536 individuals and 1028 informants enrolled in this study. Self-reported subjective cognitive complaint scores from early and late mild cognitive impairment and dementia with Alzheimer's clinical syndrome participants showed no significant differences, but informants' subjective cognitive complaint scores showed a significant increase. Informant-reported subjective cognitive complaint scores related to neuropsychological tests in population with dementia. Neither self-reported nor informant-reported subjective cognitive complaint scores related to neuropsychological tests in cognitively unimpaired and mild cognitive impairment populations. CONCLUSIONS: Self-reported subjective cognitive complaints alone may not be sufficient to demonstrate clinical significance in different stages of cognitive impairment. Incorporating informant-reported subjective cognitive complaints, along with considering individual's anxiety and depressive status, are crucial in assessing cognitive statuses in clinical practice.

Identification and characterisation of de novo germline structural variants in two commercial pig lines using trio-based whole genome sequencing.

BACKGROUND: De novo mutations arising in the germline are a source of genetic variation and their discovery broadens our understanding of genetic disorders and evolutionary patterns. Although the number of de novo single nucleotide variants (dnSNVs) has been studied in a number of species, relatively little is known about the occurrence of de novo structural variants (dnSVs). In this study, we investigated 37 deeply sequenced pig trios from two commercial lines to identify dnSVs present in the offspring. The identified dnSVs were characterised by identifying their parent of origin, their functional annotations and characterizing sequence homology at the breakpoints. RESULTS: We identified four swine germline dnSVs, all located in intronic regions of protein-coding genes. Our conservative, first estimate of the swine germline dnSV rate is 0.108 (95% CI 0.038-0.255) per generation (one dnSV per nine offspring), detected using short-read sequencing. Two detected dnSVs are clusters of mutations. Mutation cluster 1 contains a de novo duplication, a dnSNV and a de novo deletion. Mutation cluster 2 contains a de novo deletion and three de novo duplications, of which one is inverted. Mutation cluster 2 is 25 kb in size, whereas mutation cluster 1 (197 bp) and the other two individual dnSVs (64 and 573 bp) are smaller. Only mutation cluster 2 could be phased and is located on the paternal haplotype. Mutation cluster 2 originates from both micro-homology as well as non-homology mutation mechanisms, where mutation cluster 1 and the other two dnSVs are caused by mutation mechanisms lacking sequence homology. The 64 bp deletion and mutation cluster 1 were validated through PCR. Lastly, the 64 bp deletion and the 573 bp duplication were validated in sequenced offspring of probands with three generations of sequence data. CONCLUSIONS: Our estimate of 0.108 dnSVs per generation in the swine germline is conservative, due to our small sample size and restricted possibilities of dnSV detection from short-read sequencing. The current study highlights the complexity of dnSVs and shows the potential of breeding programs for pigs and livestock species in general, to provide a suitable population structure for identification and characterisation of dnSVs.

Ureaplasma urealyticum infection presenting as altered mental status in a post-chemotherapy patient: Case report and literature review.

Hyperammonemia due to Ureaplasma infection is rare but often fatal, largely due to the delayed recognition, diagnosis, and treatment of the condition. It has mostly been described in solid organ transplant patients in the literature. This case presents the diagnostic challenge of an immunocompromised patient with previous resected pancreatic head adenocarcinoma and chemotherapy, presenting with altered mental status due to hyperammonemia from Ureaplasma infection. It is imperative to consider this condition in unexplained hyperammonemia, especially in immunocompromised patients. Timely diagnosis of this condition can help to reduce complications from encephalopathy such as cerebral edema and seizures.

Evaluation of developmentally hypomineralised enamel after surface pretreatment with Papacarie Duo gel and different etching modes: an in vitro SEM and AFM study.

PURPOSE: This study aimed at investigating the surface morphology and nanotopography of normal enamel (NE) and developmentally hypomineralised enamel (HE) when subjected to various pretreatment protocols under scanning electron microscopy (SEM) and atomic force microscopy (AFM). METHODS: Sixteen NE, 16 creamy/white (CW) HE and 16 yellow/brown (YB) HE specimens sectioned from extracted hypomineralised first permanent molars (FPMs) were included in this study. They were randomly distributed into 12 experimental groups (n = 4). Each group involved the following: (1) deproteinisation with Papacarie Duo® gel or no deproteinisation, and (2) the use of Scotchbond™ Universal Adhesive (Scotchbond) in self-etch (SE) mode or 37% phosphoric acid etchant. Subsequently, the surface morphology and nanotopography of pretreated enamel specimens were evaluated under SEM and AFM, respectively. RESULTS: SEM observation showed that deproteinisation with Papacarie Duo® gel before phosphoric acid etching led to favourable etching patterns. This was consistent across all groups irrespective of the type of enamel specimen and the severity of hypomineralisation. In contrast, AFM results identified three factors that influenced surface parameters: (1) type of enamel specimen, (2) severity of hypomineralisation and (3) etching mode. YB HE recorded higher surface roughness values than CW HE and NE when subjected to the same pretreatment protocol. Deproteinisation and the application of Scotchbond in SE mode led to minimal topographic changes; however, acid etching was associated with an increase in surface roughness. CONCLUSION: Deproteinisation with Papacarie Duo® gel followed by acid etching contributed to improved etching patterns on HE.

SOX9+ enthesis cells are associated with spinal ankylosis in ankylosing spondylitis.

OBJECTIVE: Although cartilage degeneration and invasion of the subchondral bone plate in entheseal lesion has been considered to consequently lead bony ankylosis in ankylosing spondylitis (AS), no evident mechanisms are known. DESIGN: To identify histopathological and physiological changes in enthesitis-related ankylosis in AS, we performed molecular characterization of transcription factors and surface markers, and transcriptome analysis with human tissues. Entheseal tissue containing subchondral bone was obtained from the facet joints of 9 patients with AS and 10 disease controls, and assessed by using differential staining techniques. Enthesis cells were isolated, characterized, stimulated with TNF and/or IL-17A, and analysed by cell-based experimental tools. RESULTS: We found diffusely distributed granular tissue and cartilage in the subchondral bone in AS. Co-expression of SOX9, a specific transcription factor in cartilage, and matrix metalloproteinase 13 (MMP13) was found in the granular tissues within the subchondral bone from AS patients. Intriguingly, SOX9 expression was significantly higher in AS enthesis cells than controls and correlated with TNFR1 and IL-17RA expressions, which is important for high reactivity to TNF and IL-17A cytokines. Co-stimulation by TNF and IL-17A resulted in accelerated mineralization/calcification features, and increased OCN expression in AS enthesis cells. Furthermore, SOX9 overexpression in enthesis leads to promoting mineralization feature by TNF and IL-17A stimuli. Finally, OCN expression is elevated in the destructive enthesis of advanced AS. CONCLUSION: These findings provide insight into the links between inflammation and the mineralization of entheseal tissue as the initiation of spinal ankylosis, emphasizing the importance of SOX9+ enthesis cells.

Effect of the use of earplugs and eye masks on the quality of sleep after major abdominal surgery: a randomised controlled trial.

Significant sleep disturbance can occur following major abdominal surgery. We aimed to evaluate the effectiveness of earplugs and eye masks in improving sleep quality and patient satisfaction, reducing nursing demands and in the incidence of delirium in patients after major abdominal surgery. We conducted a randomised controlled trial in 100 patients undergoing major abdominal surgery. We randomly allocated participants to sleep with or without earplugs and eye masks on postoperative days 1-3. The primary outcome measure was sleep quality as measured by the Richards-Campbell Sleep Questionnaire. Secondary outcomes were patient satisfaction, frequency of nursing demand and incidence of delirium measured by the Neelon and Champagne Confusion Scale. Median (IQR [range]) sleep scores were 64 (38-74 [0-100] and 60 (44-82 [18-100]) for the control and intervention groups, respectively (p = 0.310). Age and Pittsburgh Sleep Quality Index scores were found to be significant factors affecting sleep quality. There were no differences in patient satisfaction, reduction in frequency of nursing demands or incidence of delirium on postoperative days 1-3 after major abdominal surgery. The compliance rate in the intervention group was 60-65%. This study has demonstrated that the use of earplugs and eye masks did not contribute to improvements in sleep quality. Of note, sleep quality was moderate, with higher age and worse baseline sleep quality contributing to worse sleep scores. More studies are needed to investigate interventions to improve sleep quality after major abdominal surgery.

A dominant strain of Elizabethkingia anophelis emerged from a hospital water system to cause a three-year outbreak in a respiratory care center.

BACKGROUND: Elizabethkingia species are ubiquitous bacteria but uncommonly cause human infection. An outbreak of Elizabethkingia anophelis bacteraemia was observed in a respiratory care center of a tertiary hospital in Taiwan from 2015 to 2018. METHODS: Clinical and environmental isolates were collected for the outbreak investigation. Pulsed-field gel electrophoresis (PFGE) and complete-genome sequencing were conducted to elucidate the mechanism of transmission. FINDINGS: The three-year outbreak involved 26 patients with E. anophelis bacteraemia and the incidence significantly increased during the outbreak period compared with that observed from 2010 to 2014 (P<0.05). All 26 clinical isolates during the outbreak period belonged to a cluster by PFGE analysis. In contrast, the PFGE pattern was heterogeneous among comparative historical strains. Hospital tap water was highly contaminated by Elizabethkingia species (18/34, 52.9%); among that, five E. anophelis belonged to the outbreak cluster (5/18, 27.8%). As for the inanimate surface survey, 3.4% sites (4/117) revealed positive growth of E. anophelis including two from feeding tubes/bags and two from sputum suction regulators. All four isolates belonged to the outbreak clone. The outbreak strain had no apparent relationship to currently known E. anophelis strains worldwide through complete-genome sequencing analysis. Specific infection control strategies aimed at water source control and environmental disinfection were implemented subsequently and the outbreak ended in mid-2018. CONCLUSIONS: A specific E. anophelis strain was identified from a three-year outbreak. The elucidation of the mechanism of dominance and intra-hospital transmission is crucial for development of corresponsive infection control policies and outbreak control.

Let-7 derived from endometrial extracellular vesicles is an important inducer of embryonic diapause in mice.

Embryonic diapause is a maternally controlled phenomenon. The molecule controlling the onset of the phenomenon is unknown. We demonstrated that overexpression of microRNA let-7a or incubation with let-7g-enriched extracellular vesicles from endometrial epithelial cells prolonged the in vitro survival of mouse blastocysts, which developed into live pups after having been transferred to foster mothers. Similar to in vivo dormant blastocysts, let-7-induced dormant blastocysts exhibited low level of proliferation, apoptosis, and nutrient metabolism. Let-7 suppressed c-myc/mTORC1 and mTORC2 signaling to induce embryonic diapause. It also inhibited ODC1 expression reducing biosynthesis of polyamines, which are known to reactivate dormant embryos. Furthermore, the overexpression of let-7 blocked trophoblast differentiation and implantation potential of human embryo surrogates, and prolonged survival of human blastocysts in vitro, supporting the idea that embryonic diapause was an evolutionary conserved phenomenon. In conclusion, let-7 is the main factor inducing embryonic diapause.

Association of antimicrobial resistance and gut microbiota composition in human and non-human primates at an urban ecotourism site.

BACKGROUND: The rise of nature-based ecotourism in the past decade has introduced unprecedented challenges in managing the increasing interaction between humans and animals. The potential transmission of antibiotic resistant microbes between humans and non-human primate populations is a concern due to their genetic similarity. Malaysia is well known for hotspots of wildlife diversity where non-human primates like monkeys and orangutans have become popular tourist attractions. In this study, we assessed the prevalence of antimicrobial resistant Staphylococcus aureus, Enterococcus species, and other Enterobacteriaceae in the faeces of human (HS) and two non-human primates (NHP) in Malaysia, the Long-tailed macaque (Macaca fascicularis, MF) and Silvered leaf monkey (Trachypithecus cristatus, TC). In addition, the faecal bacterial composition was profiled to evaluate the potential association between antibiotic resistant profiles and composition of gut microbiota. RESULTS: We tested the isolated bacteria using a selection of antibiotics. The results showed that both the number of antibiotic resistant strains and resistance level were higher in humans than NHPs. Overall, the composition of gut microbiome and pattern of antibiotic resistance showed that there was higher similarity between MF and TC, the two NHPs, than with HS. In addition, samples with higher levels of antibiotic resistance showed lower bacterial richness. Homo sapiens had the lowest bacterial diversity and yet it had higher abundance of Bacteroides. In contrast, NHPs displayed higher bacterial richness and greater prevalence of Firmicutes such as Ruminococceae and Oscillospira. CONCLUSION: Higher antibiotic susceptibility in NHPs is likely related to low direct exposure to antibiotics. The lack of resistance may also suggest limited antimicrobial resistance transmission between humans and NHP. Nonetheless, continued monitoring over a long period will help mitigate the risk of anthropozoonosis and zooanthroponosis.

Rapid tool for identification of bacterial strains using Fourier transform infrared spectroscopy on genomic DNA.

AIMS: We developed a new rapid and reliable method for identifying bacteria using a combination of Fourier transform infrared (FT-IR) spectroscopy of bacterial genomic DNA and multivariate analysis. METHODS AND RESULTS: FT-IR spectra of genomic DNA from four type strains of Pseudomonas spp., three type strains of Escherichia spp. and two type strains of Bacillus spp. were analysed in the 4000-400 cm-1 region. Spectral differences were found in the frequency regions of N-H stretching (amide I), C=O stretching vibrations (amide II) and PO2 - ionized asymmetric and symmetric stretching. Partial least squares discriminant analysis of the FT-IR spectra showed that the microbial strains could be discriminated by hierarchical clustering analysis. CONCLUSIONS: FT-IR spectral analysis of bacterial genomic DNA has potential for the rapid identification of bacteria at the genus and species levels. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports a new bacterial identification method using multivariate analysis of FT-IR spectra of bacterial genomic DNA.

Genetic profiles of transcriptomic clusters of childhood asthma determine specific severe subtype.

BACKGROUND: Previous studies have defined transcriptomic subtypes of adult asthma using samples of induced sputum and bronchial epithelium; however, those procedures are not readily applicable in the clinic, especially for childhood asthma. OBJECTIVE: We aim to dissect the transcriptomic clusters of childhood asthma using highly variably expressed genes of peripheral blood mononuclear cells (PBMC) among patients. METHODS: Gene expression of PBMC from 133 asthmatic children and 11 healthy controls was measured with Illumina microarrays. We applied the k-means clustering algorithm of 2048 genes to assign asthmatic children into clusters. Genes with differential expression between asthma clusters and healthy controls were used to investigate whether they could identify severe asthma of children and adults. RESULTS: We identified 3 asthma clusters with distinct inflammatory profiles in peripheral blood. Cluster 1 had the highest eosinophil count. Cluster 2 showed lower counts of both eosinophils and neutrophils. Cluster 3 had the highest neutrophil count and the poorest treatment control. Compared with other patients, Cluster 3 exhibited a unique gene expression pattern which was associated with changes in the glucocorticoid signalling and activation of the T helper 1/T helper 17 (TH 1/TH 17) immune pathways. In the validation studies, an 84-gene signature could identify severe asthma in children on leucocytes, as well as severe asthma in adults on CD8+ T cells. CONCLUSIONS AND CLINICAL RELEVANCE: Gene expression profiling of PBMC is useful for the identification of TH 1/TH 17-mediated asthma with poor treatment control. PBMC and CD8+ T cells could be important targets for the investigation and identification of severe asthma.

Childhood asthma clusters reveal neutrophil-predominant phenotype with distinct gene expression.

BACKGROUND: Childhood asthma comprises different phenotypes with complex pathophysiology. Different asthma phenotypes evoke various clinical symptoms and vary in their responses to treatments. METHODS: We applied k-means clustering algorithm of twelve objective laboratory tests among 351 asthmatic children enrolled in the Taiwanese Consortium of Childhood Asthma Study (TCCAS). We constructed gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with different asthma phenotypes. RESULTS: Five distinct phenotypes of childhood asthma were identified and can be characterized by either eosinophil-predominant or neutrophil-predominant inflammatory characteristics. In the gene expression profile analysis, significant differences were noted for neutrophil-predominant asthma, compared with samples from all the other asthma phenotypes. The vast majority of the differentially expressed genes in neutrophil-predominant asthma was associated with corticosteroid response. From an independent inhaled corticosteroid (ICS) response cohort, we also found neutrophils could be activated in this severe asthma phenotype and neutrophil-predominant asthma may be associated with corticosteroid nonresponsiveness. CONCLUSION: Phenotype clustering of childhood asthma can be helpful to identify clinically relevant patients and reveal different inflammatory characteristics in asthmatic children. Neutrophil-predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Gene expression profile of different asthma phenotypes not only improve our knowledge of childhood asthma, but also can guide asthma precision medicine.

Sirtuin 6 attenuates periapical lesion propagation by modulating hypoxia-induced chemokine (C-C motif) ligand 2 production in osteoblasts.

AIM: To investigate the attenuating effect of sirtuin 6 (SIRT6) on hypoxia-induced production of chemokine (C-C motif) ligand 2 (CCL2) by osteoblasts and the relevance of this action on the pathogenesis of periapical lesions. METHODOLOGY: Sirtuin 6 was overexpressed in MC3T3-E1 murine osteoblasts by lentivirus-mediated gene transfer. The relationship between the antiglycolytic/antioxidative activities of SIRT6 and its effect on hypoxia-induced CCL2 production were examined. Pathogenetic relevance of the actions of SIRT6 was assessed in a rat model of induced apical periodontitis. The data were analysed statistically using Student's t-test or one-way analysis of variance (anova) and then a Tukey's multiple comparison test. RESULTS: In cultured murine osteoblasts, 24-h hypoxic treatment significantly enhanced the generation of reactive oxygen species (P = 0.003), expression of lactate dehydrogenase A (LDHA) and production of lactate (P = 0.007). A reciprocal effect between hypoxia-induced redox imbalance and hypoxia-enhanced glycolysis was noted which in turn augmented the secretion of CCL2. Through its antiglycolytic and antioxidative effects, SIRT6 blocked the vicious cycle to suppress CCL2 production. In normal periapical tissues of rats, strong expression of SIRT6 and low levels of LDHA and 8-OHdG (a marker of oxidative DNA damage) were found in osteoblasts. In induced apical periodontitis, osteoblastic expression of SIRT6 was significantly suppressed (P = 0.001) which was associated with significantly elevated levels of LDHA (P = 0.003) and 8-OHdG (P = 0.004) and significantly enhanced recruitment of macrophages (P = 0.004). CONCLUSIONS: Sirtuin 6 has a therapeutic effect on periapical lesions through suppression of CCL2 synthesis. The anti-inflammatory action of SIRT6 is closely related to its regulatory activities in cellular metabolism and redox homoeostasis.

Molecular detection of human adenovirus among hospitalized patients with lower respiratory tract infection in Hospital Sungai Buloh, Malaysia.

Human adenovirus (HAdV) is one of the common pathogens that are responsible for a wide variety of infectious diseases. There are about 54 different adenovirus serotypes that are responsible for respiratory infections in humans. The prevalence of lower respiratory tract infection (LRTI) - associated with HAdV varies throughout different regions. The prevalence of HAdV in Malaysia is rarely investigated and reported despite severity of infection worldwide. This study was undertaken to identify the HAdV types associated with lower respiratory tract infection (LRTI) in Hospital Sungai Buloh, Malaysia between April 2013 until January 2014, a total of 210 specimens were collected from patients hospitalized with LRTI. Human adenovirus was detected using polymerase chain reaction (PCR). The positive products were sequenced and phylogenetic analysis of the virus was performed. Eighteen of 210 specimens (8.57%) were positive with HAdV infection. Based on the phylogenetic analysis study, HAdV-7 strains were the most common serotype with 11 cases, followed by HAdV-1, HAdV-2 and HAdV-4 with 2 cases each and one case of HAdV-5. The HAdV strains in this study were closely related to strains in Singapore and India. In this study, HAdV infection from LRTI patients in Hospital Sungai Buloh Malaysia were caused by different types of adenovirus mainly HAdV-7. This study will become a reference for further epidemiological study in this country.

Association between obesity and risk of chronic kidney disease: A nationwide Cohort study in Taiwan.

BACKGROUND AND AIMS: Increased body fat relates to enhanced inflammatory cytokine production, which, in turn, activates the renin-angiotensin-aldosterone system and increases the risk of chronic kidney disease (CKD). Herein, we aimed to examine the association between obesity and the risk of CKD in a population-representative cohort in Taiwan. METHODS AND RESULTS: A multistage systematic sampling process was applied in the National Health Interview Survey (NHIS) 2000, 2005, and 2009. Participants were interviewed by a standardized face-to-face questionnaire to obtain information on their demographics, socioeconomic status, lifestyle factors, and body mass index (BMI). The BMI values were classified as follows: underweight (<18.5 kg/m2), normal (18.5-23.9 kg/m2), overweight (24-26.9 kg/m2), and obesity (≥27 kg/m2). The NHIS dataset was linked to National Health Insurance claims data to identify the incidence of CKD. Univariate and multivariate Cox proportional hazard models with competing risks were used to investigate the association between BMI and CKD incidence. We analyzed 45,012 subjects (mean age, 42.03 years; 50.09% males). During 374,254 person-years of follow-up, a total of 1913 new-onset CKD cases were identified. Kaplan-Meier curves comparing the four BMI groups revealed a significant difference (p < 0.01, log-rank test). After controlling for confounding factors, the relative risk of incident CKD was significantly higher in the obese group compared to the normal-weight group (adjusted hazard ratio = 1.32; 95% confidence interval: 1.17-1.49), with a significant linear trend (p < 0.01). CONCLUSION: Obesity was suggested as an independent risk factor for CKD. Further studies focusing on the effect of losing weight on CKD prevention are warranted.

Rapid adiposity growth increases risks of new-onset asthma and airway inflammation in children.

BACKGROUND/OBJECTIVES: We aim to (1) examine the influence of long-term adiposity status/short-term adiposity changes on asthma with high or low fractional exhaled nitric oxide (FeNO), and (2) to determine the differences in long-term adiposity status/short-term adiposity changes on atopy, airway inflammation and pulmonary function. SUBJECTS/METHODS: We recruited 2450 fourth- to sixth-grade children from the nationwide Taiwan Children Health Study. Data regarding various adiposity indicators, atopic status, pulmonary function tests and asthma outcomes were collected annually. New-onset asthma was stratified by airway inflammation status using FeNO. The generalized estimating equation was used for analyzing longitudinal relationships between long-term adiposity status/short-term adiposity changes and new-onset asthma. Individual adiposity growth slopes were obtained using a hierarchical linear model to establish the relationships between short-term adiposity changes and asthma among children with high airway inflammation. RESULTS: We found long-term adiposity status predicted childhood asthma with low FeNO, whereas short-term adiposity changes may increase risks of childhood asthma with high FeNO. Long-term adiposity status reduced pulmonary function, whereas short-term adiposity increase were associated with atopic diseases and airway inflammation. CONCLUSIONS: Obesity-induced asthma could be mediated by high or low airway inflammation, depending on the velocity of increase in adiposity. Rapid adiposity growth may increase risks of childhood asthma and airway inflammation.

Hyperglycemia impedes definitive endoderm differentiation of human embryonic stem cells by modulating histone methylation patterns.

Exposure to maternal diabetes during fetal growth is a risk factor for the development of type II diabetes (T2D) in later life. Discovery of the mechanisms involved in this association should provide valuable background for therapeutic treatments. Early embryogenesis involves epigenetic changes including histone modifications. The bivalent histone methylation marks H3K4me3 and H3K27me3 are important for regulating key developmental genes during early fetal pancreas specification. We hypothesized that maternal hyperglycemia disrupted early pancreas development through changes in histone bivalency. A human embryonic stem cell line (VAL3) was used as the cell model for studying the effects of hyperglycemia upon differentiation into definitive endoderm (DE), an early stage of the pancreatic lineage. Hyperglycemic conditions significantly down-regulated the expression levels of DE markers SOX17, FOXA2, CXCR4 and EOMES during differentiation. This was associated with retention of the repressive histone methylation mark H3K27me3 on their promoters under hyperglycemic conditions. The disruption of histone methylation patterns was observed as early as the mesendoderm stage, with Wnt/ß-catenin signaling being suppressed during hyperglycemia. Treatment with Wnt/ß-catenin signaling activator CHIR-99021 restored the expression levels and chromatin methylation status of DE markers, even in a hyperglycemic environment. The disruption of DE development was also found in mouse embryos at day 7.5 post coitum from diabetic mothers. Furthermore, disruption of DE differentiation in VAL3 cells led to subsequent impairment in pancreatic progenitor formation. Thus, early exposure to hyperglycemic conditions hinders DE development with a possible relationship to the later impairment of pancreas specification.

Obesity/overweight reduces the risk of active tuberculosis: a nationwide population-based cohort study in Taiwan.

BACKGROUND: Obesity affects immune function by increasing the number of T helper lymphocytes, which may reduce the risk of tuberculosis (TB) infection. However, the effect of obesity on TB development has not been extensively studied. This nationwide population-based cohort study investigated the effect of obesity on TB development in Taiwanese adults. METHODS: We included 46 028 adult participants (age ⩾18 years) from three rounds (2001, 2005 and 2009) of the Taiwan National Health Interview Survey. Obesity and overweight were defined as a body mass index (BMI) ⩾27 and 24-26.9 (kg/m2), respectively. Data on BMI and other covariates at baseline were collected by in-person interviews. Incident cases of active TB were identified from the National Health Insurance database. Multivariable logistic regression was used to estimate the associations of obesity and overweight with active TB, with adjustment for age, sex, smoking, alcohol consumption, socioeconomic status and other covariates. RESULTS: In total, 241 new cases of active TB occurred during the study period. Obesity (adjusted odds ratio [AOR], 0.43; 95% confident interval [CI], 0.28-0.67) and overweight (AOR, 0.67; 95% CI, 0.49-0.91) were associated with lower risk of incident TB, after adjusting for demographic characteristics and comorbidities. There was a linear dose-response relation of BMI with active TB incidence (AOR per unit change in BMI, 0.92; 95% CI, 0.88-0.95; P <0.001). CONCLUSION: Obesity and overweight are associated with lower risk of active TB. Future studies should investigate the underlying mechanisms and clinical and epidemiological consequences of these findings.

The Forkhead box transcription factor FOXM1 is required for the maintenance of cell proliferation and protection against oxidative stress in human embryonic stem cells.

Human embryonic stem cells (hESCs) exhibit unique cell cycle structure, self-renewal and pluripotency. The Forkhead box transcription factor M1 (FOXM1) is critically required for the maintenance of pluripotency in mouse embryonic stem cells and mouse embryonal carcinoma cells, but its role in hESCs remains unclear. Here, we show that FOXM1 expression was enriched in undifferentiated hESCs and was regulated in a cell cycle-dependent manner with peak levels detected at the G2/M phase. Expression of FOXM1 did not correlate with OCT4 and NANOG during in vitro differentiation of hESCs. Importantly, knockdown of FOXM1 expression led to aberrant cell cycle distribution with impairment in mitotic progression but showed no profound effect on the undifferentiated state. Interestingly, FOXM1 depletion sensitized hESCs to oxidative stress. Moreover, genome-wide analysis of FOXM1 targets by ChIP-seq identified genes important for M phase including CCNB1 and CDK1, which were subsequently confirmed by ChIP and RNA interference analyses. Further peak set comparison against a differentiating hESC line and a cancer cell line revealed a substantial difference in the genomic binding profile of FOXM1 in hESCs. Taken together, our findings provide the first evidence to support FOXM1 as an important regulator of cell cycle progression and defense against oxidative stress in hESCs.