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Abstract Background Severe alcoholic hepatitis is a catastrophic disease with a mortality rate of up to 35–50% at 30 days. Bacterial infection is an important prognostic factor in patients with severe alcoholic hepatitis, but it is difficult to detect the presence of infection immediately. Procalcitonin (PCT) is a well-known inflammatory marker that can detect bacterial infections in various diseases early. Therefore, we aimed to evaluate the diagnostic accuracy of PCT for bacterial infection in severe alcoholic hepatitis. Methods We prospectively enrolled patients with severe alcoholic hepatitis, defined as modified Maddrey’s Discriminant Function ≥ 32, from 10 medical centers. At admission, we performed an initial evaluation including physical examination, laboratory test, radiology, blood and urine culture, PCT, and C-reactive protein (CRP). We compared the receiver operating characteristic (ROC) curves of PCT and CRP for bacterial infection, systemic inflammatory response syndrome (SIRS), and sepsis among total patients. Results A total of 108 patients with severe alcoholic hepatitis were enrolled. The number of bacterial infections, SIRS, and sepsis were 31 (28.7%), 41 (38.0%), and 19 (17.6%), respectively. The patients with bacterial infection had significantly higher MELD scores (24.0 vs. 15.0), PCT levels (1.5 vs. 0.4 ng/mL), and CRP levels (4.9 vs. 2.5 mg/dL) compared to those without bacterial infection. The area under the ROC curve (AUROC) of PCT vs. CRP for bacterial infection was 0.752 and 0.655, respectively (P = 0.113). The AUROC of PCT vs. CRP for SIRS was 0.699 and 0.662, respectively (P = 0.490). The AUROC of PCT vs. CRP for sepsis was 0.780 and 0.630, respectively (P = 0.027). Conclusions Among patients with severe alcoholic hepatitis, PCT showed a trend of superior diagnostic performance in the early detection of bacterial infection and sepsis compared to CRP. Although PCT might have better potential to diagnose sepsis in the setting of severe alcoholic hepatitis, it is necessary to find more reliable diagnostic markers.

ABSTRACT Control of hospital-associated Enterococcus faecium infection is a strenuous task due to the difficulty of identifying transmission routes and the persistence of this nosocomial pathogen despite the implementation of infection control measures that have been successful with other important nosocomial pathogens. This study provides a comprehensive analysis of over 100 E. faecium isolates collected from 66 cancer patients at the University of Arkansas for Medical Sciences (UAMS) between June 2018 and May 2019. In the top-down approach used in this study, we employed, in addition to the 106 E. faecium UAMS isolates, a filtered set of 2,167 E. faecium strains from the GenBank database to assess the current population structure of E. faecium species and, consequently, to identify the lineages associated with our clinical isolates. We then evaluated the antibiotic resistance and virulence profiles of hospital-associated strains from the species pool, focusing on antibiotics of last resort, to establish an updated classification of high-risk and multidrug-resistant nosocomial clones. Further investigation of the clinical isolates collected from UAMS patients using whole-genome sequencing analytical methodologies (core genome multilocus sequence typing [cgMLST], core single nucleotide polymorphism [coreSNP] analysis, and phylogenomics), with the addition of patient epidemiological data, revealed a polyclonal outbreak of three sequence types occurring simultaneously in different patient wards. The integration of genomic and epidemiological data collected from the patients increased our understanding of the relationships and transmission dynamics of the E. faecium isolates. Our study provides new insights into genomic surveillance of E. faecium to assist in monitoring and further limiting the spread of multidrug-resistant E. faecium. IMPORTANCE Enterococcus faecium is a member of the gastrointestinal microbiota. Although its virulence is low in healthy, immunocompetent individuals, E. faecium has become the third leading cause of health care-associated infections in the United States. This study provides a comprehensive analysis of over 100 E. faecium isolates collected from cancer patients at the University of Arkansas for Medical Sciences (UAMS). We employed a top-down analytical approach (from population genomics to molecular biology) to classify our clinical isolates into their genetic lineages and thoroughly evaluate their antibiotic resistance and virulence profiles. The addition of patient epidemiological data to the whole-genome sequencing analytical methodologies performed in the study allowed us to increase our understanding of the relationships and transmission dynamics of the E. faecium isolates. This study provides new insights into genomic surveillance of E. faecium to help monitor and further limit the spread of multidrug-resistant E. faecium.

Background: Heart failure (HF) remains a significant public health challenge globally. This study aims to systematically analyze the global HF disease burden from 1990 to 2021 across temporal, spatial, and demographic dimensions to provide evidence for targeted prevention and control strategies. Methods: Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed the global HF burden through prevalent cases, years lived with disability (YLDs), and age-standardized rates per 100,000 population. Temporal trends were evaluated using estimated annual percentage change (EAPC) and joinpoint regression analysis. The relationship between the Socio-demographic Index (SDI) and disease burden was explored through Pearson correlation analysis, while attribution analysis identified the main causes of HF. When appropriate, analyses were stratified by 5 SDI regions, 21 GBD regions, 204 countries and territories, 20 age groups, and both sexes. Results: Global HF prevalence and YLDs burden showed substantial increases from 1990 to 2021, with age-standardized prevalence increasing from 641.14 to 676.68 per 100,000 population. Notably, high-SDI regions exhibited a declining burden since 2019, indicating a potential global turning point. High-income North America bears the heaviest burden while South Asia shows the fastest growth rate. The correlation between disease burden and SDI level was negligible. The disease burden in males consistently exceeded that in females, with prevalence and YLDs rates rising sharply after age 60. The main causes and their attributable proportions were: ischemic heart disease (34.53%), hypertensive heart disease (22.53%), other cardiomyopathies (7.61%), chronic obstructive pulmonary disease (6.51%), and congenital heart anomalies (5.69%), with their distribution patterns differing across age groups and regions. Conclusion: Global burden of HF increased significantly over recent decades, with a potential turning point in 2019 and marked regional disparities. It is essential to prioritize regions with heavy burdens or rapid growth rates, strengthen the management of major causes, and monitor HF burden trends in the post-COVID era. [ABSTRACT FROM AUTHOR]

Genome-wide chromosomal microarray is extensively used to detect copy number variations (CNVs), which can diagnose microdeletion and microduplication syndromes. These small unbalanced chromosomal structural rearrangements ranging from 1 kb to 10 Mb comprise up to 15% of human mutations leading to monogenic or contiguous genomic disorders. Albeit rare, CNVs at 1p13.3 cause a variety of neurodevelopmental disorders (NDDs) including development delay (DD), intellectual disability (ID), autism, epilepsy, and craniofacial anomalies (CFA). Most of the 1p13.3 CNV cases reported in the pre-microarray era encompassed a large number of genes and lacked the demarcating genomic coordinates, hampering the discovery of positional candidate genes within the boundaries. In this study, we present four subjects with 1p13.3 microdeletions displaying DD, ID, autism, epilepsy, and CFA. In silico comparative genomic mapping with three previously reported subjects with CNVs and 22 unreported DECIPHER CNV cases has resulted in the identification of four different sub-genomic loci harboring five positional candidate genes for DD, ID, and CFA at 1p13.3. Most of these genes have pathogenic variants reported, and their interacting genes are involved in NDDs. RT-qPCR in various human tissues revealed a high expression pattern in the brain and fetal brain, supporting their functional roles in NDDs. Interrogation of variant databases and interacting protein partners led to the identification of another set of 11 potential candidate genes, which might have been dysregulated by the position effect of these CNVs at 1p13.3. Our studies define 1p13.3 as a genomic region harboring 16 NDD candidate genes and underscore the critical roles of small CNVs in in silico comparative genomic mapping for disease gene discovery. Our candidate genes will help accelerate the isolation of pathogenic heterozygous variants from exome/genome sequencing (ES/GS) databases.

A circular capacitive rainfall sensor can operate from non-touch mode to touch mode; that is, under the action of enough rainwater, its movable electrode plate can form a circular contact area with its fixed electrode plate. Therefore, the weight of rainwater is borne by only its movable electrode plate in non-touch mode operation but by both its movable and fixed electrode plates in touch mode operation, and the total capacitance of its touch mode operation is much larger than that of its non-touch mode operation. Essential to its numerical design and calibration is the ability to predict the deflection shape of its moveable electrode plate to determine its total capacitance. This requires the analytical solution to the fluid–structure interaction problem of its movable electrode plate under rainwater. In our previous work, only the analytical solution for the fluid–structure interaction problem before its movable electrode plate touches its fixed electrode plate was obtained, and how to numerically design and calibrate a circular non-touch mode capacitive rainfall sensor was illustrated. In this paper, the analytical solution for the fluid–structure interaction problem after its movable electrode plate touches its fixed electrode plate is obtained, and how to numerically design and calibrate a circular touch mode capacitive rainfall sensor is illustrated for the first time. The numerical results show that the total capacitance and rainwater volume when the circular capacitive rainfall sensor operates in touch mode is indeed much larger than that when the same circular capacitive rainfall sensor operates in non-touch mode, and that the average increase in the maximum membrane stress per unit rainwater volume when the circular capacitive rainfall sensor operates in touch mode can be about 20 times smaller than that when the same circular capacitive rainfall sensor operates in non-touch mode. This is where the circular touch mode capacitive rainfall sensor excels. [ABSTRACT FROM AUTHOR]

Although the relationship between high-impact sports like football and basketball and the development of knee osteoarthritis is well established, the effect of martial arts on the knee joint remains unclear. To compare the imaging abnormalities of knee joints and T2 relaxation times of cartilage in professional martial arts athletes and healthy controls. Cross-sectional study. Hospital imaging center. Nine asymptomatic professional martial arts athletes and 18 healthy volunteers. We performed 3T magnetic resonance imaging of the knee on both legs of athletes and the dominant leg of controls. The magnetic resonance imaging protocol included conventional sequences used for morphological assessment (cartilage, meniscus, ligaments, joint effusion, and bone marrow edema) and T2 mapping used for quantitatively evaluating the cartilage. Knee cartilage was manually divided into 8 regions, and T2 relaxation times of the corresponding subregions were measured. Fisher exact test and t test were used to compare the frequency of lesions and cartilage T2 values both between groups and between the athletes' limbs. P <.05 was considered significant. Professional martial arts athletes exhibited significantly higher frequencies of cartilage (55.6% vs 11.1%, P =.023) and ligament lesions (66.7% vs 16.7%, P =.026) compared with the control group. Athletes showed higher T2 values in 3 distinct cartilage segments: the central weight-bearing segment of the medial femoral condyle (P =.006), the medial tibial plateau (P =.012), and the trochlea (P =.032), when compared with the controls. Additionally, the dominant leg of athletes showed significantly higher T2 values compared with the nondominant leg. The findings demonstrated the impact of martial arts on the knee joint, characterized by higher prevalence of lesions and elevated cartilage T2 values, particularly in the medial compartment. The dominant legs of martial arts athletes seem to have higher risk of cartilage degeneration due to the observed interlimb differences in T2 values. [ABSTRACT FROM AUTHOR]

To research the fuel-switching rules for gas turbine dual-fuel combustor, the effects of fuel change rate, fuel compensation rate, permissible fluctuation limit of outlet temperature, and fuel matching on the fuel-switching performance were studied experimentally by using a real dual-fuel gas turbine combustor. The experimental results show that increasing fuel change rate can reduce fuel-switching time, but the influence of fuel viscosity and evaporative atomization combustion hysteresis leads to the increase of outlet temperature amplitude fluctuation. The fuel compensation rate corresponds to the optimal solution for this combustion chamber; when the fuel change rate decreases, the optimal fuel compensation coefficient will be increase. Meanwhile, by increasing the allowable fluctuation range of outlet temperature and reducing the difference of calorific value of natural gas and diesel, the fuel-switching time can be effectively reduced, and the fuel-switching stability can be improved.

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens.Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC.Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC.Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Introduction. In spite of the established importance of detecting angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker- (ARB-) induced hyperkalemia, there have not been many studies on the time of its occurrence. Methods. We retrospectively analyzed electronic medical records to determine the onset time and incidence rate of hyperkalemia (serum potassium>5.5 mEq/L or 6.0 mEq/L) among hospitalized patients newly started on a 15-day ACEI or ARB therapy. Results. Among 3101 hospitalized patients, hyperkalemia incidence was 0.5%–0.9% and 0.8%–2.1% in the ACEI and ARB groups, respectively. However, it was not significantly different among different ARB types. Hyperkalemia’s onset was distributed throughout 15 days, without any trend. Hyperkalemia incidence was 7.3 and 35.1 times higher at 5.5 mEq/L (hazard ratio HR=7.31, 95%confidence interval CI=4.19–12.76, p

Genomic DNA is the best “unique identifier” for organisms. Alignment-free phylogenomic analysis, simple, fast, and efficient method to compare genome sequences, relies on looking at the distribution of small DNA sequence of a particular length, referred to as k-mer. The k-mer approach has been explored as a basis for sequence analysis applications, including assembly, phylogenetic tree inference, and classification. Although this approach is not novel, selecting the appropriate k-mer length to obtain the optimal resolution is rather arbitrary. However, it is a very important parameter for achieving the appropriate resolution for genome/sequence distances to infer biologically meaningful phylogenetic relationships. Thus, there is a need for a systematic approach to identify the appropriate k-mer from whole-genome sequences. We present K-mer–length Iterative Selection for UNbiased Ecophylogenomics (KITSUNE), a tool for assessing the empirically optimal k-mer length of any given set of genomes of interest for phylogenomic analysis via a three-step approach based on (1) cumulative relative entropy (CRE), (2) average number of common features (ACF), and (3) observed common features (OCF). Using KITSUNE, we demonstrated the feasibility and reliability of these measurements to obtain empirically optimal k-mer lengths of 11, 17, and ∼34 from large genome datasets of viruses, bacteria, and fungi, respectively. Moreover, we demonstrated a feature of KITSUNE for accurate species identification for the two de novo assembled bacterial genomes derived from error-prone long-reads sequences, and for a published yeast genome. In addition, KITSUNE was used to identify the shortest species-specific k-mer accurately identifying viruses. KITSUNE is freely available at https://github.com/natapol/kitsune.

Due to animal welfare issues, European Union has banned the use of conventional cages (CC) and non-EU countries including the US are also under constant public pressure to restrict their use in egg production. Very limited information is available on the composition of the microbial community of hens raised in different housing environments. This study was conducted to determine the effects of CC and enriched colony cages (EC) on cecal microbiota of two commercial laying hen strains, Hy-Line W36 (W36) and Hy-Line Brown (HB) during the late production stage (53, 58, 67, and 72 weeks of age). Cecal microbiota was studied by analyzing 16S rRNA gene sequences with Quantitative Insights Into Microbial Ecology (QIIME) 2 ver. 2018.8. Differentially abundant taxa were identified by Linear discriminant analysis Effect Size (LEfSe) analysis (P < 0.05, LDA score > 2.0). At phylum level, Actinobacteria was significantly enriched in W36 at all time points while Synergistetes (53 weeks), Spirochaetes (58 weeks), and Synergistetes and Spirochaetes (67 weeks) were significantly higher in HB. At genus level, Bifidobacterium (at all time points) and butyric acid producing genera such as Butyricicoccus and Subdoligranulum (58 and 72 weeks) were significantly higher in W36 as compared to HB. Moreover, Proteobacteria (72 weeks) and its associated genus Campylobacter (67 and 72 weeks) were significantly enriched in EC as compared to CC. Alpha diversity was significantly higher in HB (at all time points) and in EC (67 weeks) as compared to W36 and CC, respectively. Similarly, there was a significant difference in community structure (beta diversity) between W36 and HB (all time points) as well as between EC and CC (67 weeks). The effect of housing and strains was not only seen at the bacterial composition and structure but also reflected at their functional level. Notably, KEGG metabolic pathways predicted to be involved in carbohydrates degradation and amino acids biosynthesis by PICRUSt analysis were significantly different between W36 and HB housed at CC and EC. In sum, cecal microbiota composition, diversities, and their functional pathways were affected by housing type which further varied between two commercial laying hen strains, HB and W36. This suggests that both housing and genetic strains of laying hens should be considered for selection of the alternative housing systems such as enriched colony cage.

Abstract Background Here we investigated the influence of different stabilization and storage strategies on the quality and composition of the fecal microbial community. Namely, same-day isolated murine DNA was compared to samples stored for 1 month in air at ambient temperature, with or without preservative buffers (i.e. EDTA and lysis buffer), different temperatures (i.e. 4 °C, − 20 °C, and − 80 °C), and hypoxic conditions. Results Only storage in lysis buffer significantly reduced DNA content, yet without integrity loss. Storage in EDTA affected alpha diversity the most, which was also reflected in cluster separation. Distinct changes were also seen in the phyla and bacterial species abundance per storage strategy. Metabolic function analysis showed 22 pathways not significantly affected by storage conditions, whereas the tyrosine metabolism pathway was significantly changed in all strategies except by EDTA. Conclusion Each long-term storage strategy introduced a unique post-collection bias, which is important to take into account when interpreting data.

We sequenced the virus genomes from 3 pregnant women in Thailand with Zika virus diagnoses. All had infections with the Asian lineage. The woman infected at gestational week 9, and not those infected at weeks 20 and 24, had a fetus with microcephaly. Asian lineage Zika viruses can cause microcephaly.

Abstract Background Zika virus (ZIKV) is an emerging human pathogen. Since its arrival in the Western hemisphere, from Africa via Asia, it has become a serious threat to pregnant women, causing microcephaly and other neuropathies in developing fetuses. The mechanisms behind these teratogenic effects are unknown, although epidemiological evidence suggests that microcephaly is not associated with the original, African lineage of ZIKV. The sequences of 196 published ZIKV genomes were used to assess whether recently proposed mechanistic explanations for microcephaly are supported by molecular level changes that may have increased its virulence since the virus left Africa. For this we performed phylogenetic, recombination, adaptive evolution and tetramer frequency analyses, and compared protein sequences for the presence of protease cleavage sites, Pfam domains, glycosylation sites, signal peptides, trans-membrane protein domains, and phosphorylation sites. Results Recombination events within or between Asian and Brazilian lineages were not observed, and likewise there were no differences in protease cleavage, glycosylation sites, signal peptides or trans-membrane domains between African and Brazilian strains. The frequency of Retinoic Acid Response Element (RARE) sequences was increased in Brazilian strains. Genetic adaptation was also apparent by tetramer signatures that had undergone major changes in the past but has stabilized in the Brazilian lineage despite subsequent geographic spread, suggesting the viral population presently propagates in the same host species in various regions. Evidence for selection pressure was recognized for several amino acid sites in the Brazilian lineage compared to the African lineage, mainly in nonstructural proteins, especially protein NS4B. A number of these positively selected mutations resulted in an increased potential to be phosphorylated in the Brazilian lineage compared to the African linage, which may have increased their potential to interfere with neural fetal development. Conclusions ZIKV seems to have adapted to a limited number of hosts, including humans, during which its virulence increased. Its protein NS4B, together with NS4A, has recently been shown to inhibit Akt-mTOR signaling in human fetal neural stem cells, a key pathway for brain development. We hypothesize that positive selection of novel phosphorylation sites in the protein NS4B of the Brazilian lineage could interfere with phosphorylation of Akt and mTOR, impairing Akt-mTOR signaling and this may result in an increased risk for developmental neuropathies.

Abstract Background Functional annotation of bacterial genomes is an obligatory and crucially important step of information processing from the genome sequences into cellular mechanisms. However, there is a lack of computational methods to evaluate the quality of functional assignments. Results We developed a genome-scale model that assigns Bayesian probability to each gene utilizing a known property of functional similarity between neighboring genes in bacteria. Conclusions Our model clearly distinguished true annotation from random annotation with Bayesian annotation probability >0.95. Our model will provide a useful guide to quantitatively evaluate functional annotation methods and to detect gene sets with reliable annotations.

Abstract The intraspecies genomic diversity of the single‐strand RNA (+) virus species hepatitis A virus (Hepatovirus), hepatitis C virus (Hepacivirus), and hepatitis E virus (Orthohepevirus) was compared. These viral species all can cause liver inflammation (hepatitis), but share no gene similarity. The codon usage of human hepatitis A virus (HAV) is suboptimal for replication in its host, a characteristic it shares with taxonomically related rodent, simian, and bat hepatitis A virus species. We found this codon usage to be strikingly similar to that of Triatoma virus that infects blood‐sucking kissing bugs. The codon usage of that virus is well adapted to its insect host. The codon usage of HAV is also similar to other invertebrate viruses of various taxonomic families. An evolutionary ancestor of HAV and related virus species is hypothesized to be an insect virus that underwent a host jump to infect mammals. The similarity between HAV and invertebrate viruses goes beyond codon usage, as they also share amino acid composition characteristics, while not sharing direct sequence homology. In contrast, hepatitis C virus and hepatitis E virus are highly similar in codon usage preference, nucleotide composition, and amino acid composition, and share these characteristics with Human pegivirus A, West Nile virus, and Zika virus. We present evidence that these observations are only partly explained by differences in nucleotide composition of the complete viral codon regions. We consider the combination of nucleotide composition, amino acid composition, and codon usage preference suitable to provide information on possible evolutionary similarities between distant virus species that cannot be investigated by phylogeny.

The acute radiation syndrome is defined in large part by radiation injury in the hematopoietic and gastrointestinal (GI) systems. To identify new pathways involved in radiation-induced GI injury, this study assessed dose- and time-dependent changes in plasma metabolites in a nonhuman primate model of whole abdominal irradiation. Male and female adult Rhesus monkeys were exposed to 6 MV photons to the abdomen at doses ranging between 8 and 14 Gy. At time points from 1 to 60 days after irradiation, plasma samples were collected and subjected to untargeted metabolomics. With the limited sample size of females, different discovery times after irradiation between males and females were observed in metabolomics pattern. Detailed analyses are restricted to only males for the discovery power. Radiation caused an increase in fatty acid oxidation and circulating levels of corticosteroids which may be an indication of physiological stress, and amino acids, indicative of a cellular repair response. The largest changes were observed at days 9 and 10 post-irradiation, with most returning to baseline at day 30. In addition, dysregulated metabolites involved in amino acid pathways, which might indicate changes in the microbiome, were detected. In conclusion, abdominal irradiation in a nonhuman primate model caused a plasma metabolome profile indicative of GI injury. These results point to pathways that may be targeted for intervention or used as early indicators of GI radiation injury. Moreover, our results suggest that effects are sex-specific and that interventions may need to be tailored accordingly.

This study aimed to investigate the causal risk factors for intervertebral disc disorders (IVDD) to help establish prevention strategies for IVDD‐related diseases. We performed two‐sample Mendelian randomization analyses to investigate the causal effects of body mass index (BMI), education, and lifestyle behaviors (sedentary behavior, smoking, and sleeping) on thoracic/thoracolumbar/lumbosacral IVDD (TTL‐IVDD) and cervical IVDD. The inverse‐variance weighted (IVW) method was conducted as the primary model to pool effect sizes using odds ratio and 95% confidence interval. The strength of causal evidence was evaluated from the effect size and different Mendelian randomization methods (MR‐Egger/weighted median/weighted mode method, Cochran's Q test, leave‐one‐out analysis, MR Steiger, MR‐PRESSO and radial IVW analyses). We found strong evidence for the causal associations between IVDD and BMI (TTL‐IVDD, 1.27 [1.18, 1.37], p = 2.40 × 10−10; cervical IVDD, 1.24 [1.12, 1.37, p = 6.58 × 10−5), educational attainment (TTL‐IVDD, 0.57 [0.51, 0.64], p = 9.64 × 10−21; cervical IVDD, 0.58 [0.49, 0.68], p = 1.78 × 10−10), leisure television watching (TTL‐IVDD, 1.54 [1.29, 1.84], p = 7.80 × 10−6; cervical IVDD, 1.65 [1.29, 2.11], p = 0.0001), smoking initiation (TTL‐IVDD, 1.37 [1.25, 1.50], p = 1.78 × 10−10; cervical IVDD, 1.32 [1.16, 1.51], p = 6.49 × 10−5), short sleep (TTL‐IVDD, 1.28 [1.09, 1.49], p = 0.0027; cervical IVDD, 1.53 [1.21, 1.94], p = 0.0008), or frequent insomnia (TTL‐IVDD, 1.20 [1.11, 1.30], p = 1.54 × 10−5; cervical IVDD, 1.37 [1.20, 1.57], p = 7.80 × 10−6). This study provided genetic evidence that increased BMI, low educational attainment, sedentary behavior by leisure television watching, smoking initiation, short sleep, and frequent insomnia were causal risk factors for IVDD. More efforts should be directed toward increasing public awareness of these modifiable risk factors and mobilizing individuals to adopt healthy lifestyles. [ABSTRACT FROM AUTHOR]

Dietary factors modulate interactions between the microbiome, metabolome, and immune system. Sulforaphane (SFN) exerts effects on aging, cancer prevention and reducing insulin resistance. This study investigated effects of SFN on the gut microbiome and metabolome in old mouse model compared with young mice. Young (6–8 weeks) and old (21–22 months) male C57BL/6J mice were provided regular rodent chow ± SFN for 2 months. We collected fecal samples before and after SFN administration and profiled the microbiome and metabolome. Multi-omics datasets were analyzed individually and integrated to investigate the relationship between SFN diet, the gut microbiome, and metabolome. The SFN diet restored the gut microbiome in old mice to mimic that in young mice, enriching bacteria known to be associated with an improved intestinal barrier function and the production of anti-inflammatory compounds. The tricarboxylic acid cycle decreased and amino acid metabolism-related pathways increased. Integration of multi-omic datasets revealed SFN diet-induced metabolite biomarkers in old mice associated principally with the genera, Oscillospira, Ruminococcus, and Allobaculum. Collectively, our results support a hypothesis that SFN diet exerts anti-aging effects in part by influencing the gut microbiome and metabolome. Modulating the gut microbiome by SFN may have the potential to promote healthier aging.