Preliminary Purification and Partial Characterization of a Functional Bacteriocin of Lacticaseibacillus paracasei Zhang and Mining for its Gene Cluster.

Bacteriocins produced by lactic acid bacteria (LAB) have good potential for use as food biopreservatives. Lacticaseibacillus paracasei Zhang (L. paracasei Zhang) is both a food use and a probiotic bacterium. This study aimed to purify and preliminary characterize the active antibacterial metabolite of L. paracasei Zhang. The cell-free supernatant of L. paracasei Zhang was collected and purified by ultrafiltration and gel filtration chromatography. The 1-3 kDa active fraction could inhibit the growth of Staphylococcus aureus but not Escherichia coli. Further antibacterial activity assays revealed its capacity to suppress various foodborne and human opportunistic pathogens (including Staphylococcus aureus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Listeria monocytogenes, and Bacillus cereus), but not fungi. The antibacterial activity showed good tolerance to heat (40 to 100 °C), acid-base (pH 2-3 and pH 6-10), and digestions by a number of industrial and animal/human enzymes (such as trypsin, pepsin, α-amylase, and protease K, except papain); these desired properties make it a suitable biopreservative to be used in harsh and complex industrial production processes. The high papain sensitivity suggested a proteinaceous/peptide nature of the bioactivity. Moreover, our genomic data mining for bacteriocin through BAGEL4 revealed an area of interest encoding a complete set of putative genes required for bacteriocin production. In conclusion, our study showed that L. paracasei Zhang can produce extracellular functional antibacterial metabolite, likely a class II bacteriocin. Our preliminary extraction and characterization of the active metabolite demonstrated that it has good potential to be used as a biopreservative or an agent for suppressing gastrointestinal infections.

Human Breast Milk: The Role of Its Microbiota and Metabolites in Infant Health.

This review explores the role of microorganisms and metabolites in human breast milk and their impact on neonatal health. Breast milk serves as both a primary source of nutrition for newborns and contributes to the development and maturation of the digestive, immunological, and neurological systems. It has the potential to reduce the risks of infections, allergies, and asthma. As our understanding of the properties of human milk advances, there is growing interest in incorporating its benefits into personalized infant nutrition strategies, particularly in situations in which breastfeeding is not an option. Future infant formula products are expected to emulate the composition and advantages of human milk, aligning with an evolving understanding of infant nutrition. The long-term health implications of human milk are still under investigation.

Administering Lactiplantibacillus fermentum F6 decreases intestinal Akkermansia muciniphila in a dextran sulfate sodium-induced rat colitis model.

Probiotics are increasingly used to manage gut dysbiosis-related conditions due to their robust ability to manipulate the gut microbial community. However, few studies have reported that probiotics can specifically modulate individual gut microbes. This study demonstrated that administering the probiotic, Lactiplantibacillus fermentum F6, could ameliorate dextran sulfate sodium-induced colitis in a rat model, evidenced by the decreases in the disease activity index score, histopathology grading, and serum pro-inflammatory cytokine levels, as well as the increase in the serum anti-inflammatory cytokine levels. Shotgun metagenomics revealed that the fecal metagenomic of colitis rats receiving the probiotic intervention contained substantially fewer Akkermansia muciniphila than the dextran sulfate sodium group. Thus, the probiotic mechanism might be exerted by reducing specific gut microbial species associated with disease pathogenesis. A new paradigm for designing probiotics that manage diseases through direct and precise manipulation of gut microbes has been provided through this study.

A nomogram to predict cognitive function impairment in patients with chronic kidney disease: A national cross-sectional survey.

Background: Cognitive function impairment (CFI) is common in patients with chronic kidney disease (CKD) and significantly impacts treatment adherence and quality of life. This study aims to create a simplified nomogram for early CFI risk detection. Methods: Data were obtained from the National Health and Nutrition Examination Survey cycles spanning from 1999 to 2002 and again from 2011 to 2014. Stepwise logistic regression was used to select variables and construct a CFI risk prediction model. Furthermore, C-statistic and Brier Score (BS) assessed model performance. Additionally, Kaplan-Meier survival curves were utilised to assess risk group-death prognosis relationships. Results: Of the 545 participants in the CKD model development cohort, a total of 146 (26.8 %) had CFI. The final model included the variables of age, race, education, annual family income, body mass index, estimated glomerular filtration rate, serum albumin and uric acid. The model had a C-statistic of 0.808 (95 % confidence interval (CI): 0.769-0.847) and a BS of 0.149. Furthermore, the 5-fold cross-validation internal C-statistic was 0.764 (interquartile range: 0.763-0.807) and BS was 0.154. Upon external validation, the model's C-statistic decreased to 0.752 (95 % CI: 0.654-0.850) and its BS increased to 0.182. The Kaplan-Meier survival curves demonstrated that intermediate-to-high-risk participants had shorter overall survival time than low-risk participants (log-rank test: p = 0.00042). Conclusions: This study established an effective nomogram for predicting CFI in patients with CKD, which can be used for the early detection of CFI and guide the treatment of patients with CKD.

The effect of improved metabolic syndrome parameters on live birth.

OBJECTIVE: To determine whether improvements in metabolic syndrome before ovarian stimulation with intrauterine insemination affects live birth among women with obesity and unexplained infertility after fertility treatment. DESIGN: Secondary analysis of the randomized controlled clinical trial Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE). SUBJECTS: Three hundred seventy-nine women with obesity and unexplained infertility who underwent standard infertility treatment after a lifestyle intervention. INTERVENTION: The FIT-PLESE trial evaluated whether prepregnancy lifestyle interventions (diet with weight loss medication and exercise vs. exercise alone) before ovarian stimulation with intrauterine insemination improved the live birth rate among women with obesity and unexplained infertility. Utilizing FIT-PLESE data, we compared the association between improved Metabolic Syndrome (by diagnostic criteria parameters and Metabolic Syndrome Z-scores) and live birth in a subset of women who have Metabolic Syndrome. MAIN OUTCOME MEASURES: Live birth by groups were compared using chi-square and Fisher's exact tests, and continuous variables were compared using Student's t-tests. Logistic regression was used to assess Metabolic Syndrome Z-score difference and live birth. RESULTS: 191 study participants were diagnosed with Metabolic Syndrome at baseline. Thirty of these women exhibited a decline in the number of metabolic syndrome parameters and 33 had decline in their Metabolic Syndrome Z-scores during the preconception lifestyle intervention phase. There were no statistically significant differences in live birth among those who exhibited decline in the number of metabolic parameters compared to those who had no decline (33.3% versus 19.9%; p=0.102). Those who improved their Metabolic Syndrome Z-score had a live birth rate of 17.2% compared to 20.8% of those whose Metabolic Syndrome Z-scores were worsened or unchanged (p=0.055). CONCLUSION: Analysis of the FIT-PLESE data was unable to demonstrate that women with improvement in Metabolic Syndrome prior to fertility treatment, as shown by decreased number of metabolic parameters and/or improved Metabolic Syndrome Z-scores, benefit with improved fertility and live birth outcomes.

Dynamic Changes of the Gut Microbiota and Its Functional Metagenomic Potential during the Development of Non-Small Cell Lung Cancer.

The gut microbiota plays a significant role in tumor pathogenesis by regulating the host metabolism and immune response, and there are few studies focused on tracking changes in the gut microbiota from the onset of lung cancer. Therefore, the aim of our study is combining preclinical and clinical research to thoroughly analyze the signatures of fecal microbiota in lung cancer, which will be useful for early diagnosis and predicting the therapeutic efficacy of lung cancer. The first part of this study analyzed the fecal metagenomic differences between patients with non-small cell lung cancer and healthy subjects, and the second part of this work constructed a murine lung cancer model to monitor changes in mouse fecal metagenomics and T cell immunology during lung cancer progression. We found that the fecal microbiota was altered in both humans and mice with lung cancer, characterized by a significantly reduced microbial diversity and number of beneficial microbes, with increases in potential pathogens. The fecal level of Akkermansia muciniphila and the gut metabolic module of the secondary bile acid metabolism were diminished in both humans and mice with lung cancer compared with healthy subjects. Splenomegaly was observed in the lung cancer mice. Flow cytometer analysis of the splenocytes revealed substantial alterations in the proportions of T cell subsets in the lung cancer mice, characterized by significant increases in CD4+Foxp3+CD25+ T regulatory cells (p < 0.05) while significant decreases in CD3+ T cells (p < 0.001), CD4+ T cells (p < 0.001), and the CD4+/CD8+ ratio (p < 0.01). Vertical and longitudinal analyses of the fecal microbiota of the two mouse groups identified some lung cancer biomarkers (including Acutalibacter timonensis, Lachnospiraceae bacterium NSJ-38 sp014337195, etc.). The fecal microbiota of the lung cancer mice had a reduced metagenomic potential for neurotransmitters (melatonin, γ-aminobutyric acid, and histamine) compared with healthy mice. In summary, this study found that the diversity, structure, and composition of gut microbiota vary between cancer and healthy conditions, ultimately leading to changes in the potential for functional metagenomics.

Nonparametric two-sample tests of high dimensional mean vectors via random integration.

Testing the equality of the means in two samples is a fundamental statistical inferential problem. Most of the existing methods are based on the sum-of-squares or supremum statistics. They are possibly powerful in some situations, but not in others, and they do not work in a unified way. Using random integration of the difference, we develop a framework that includes and extends many existing methods, especially in high-dimensional settings, without restricting the same covariance matrices or sparsity. Under a general multivariate model, we can derive the asymptotic properties of the proposed test statistic without specifying a relationship between the data dimension and sample size explicitly. Specifically, the new framework allows us to better understand the test's properties and select a powerful procedure accordingly. For example, we prove that our proposed test can achieve the power of 1 when nonzero signals in the true mean differences are weakly dense with nearly the same sign. In addition, we delineate the conditions under which the asymptotic relative Pitman efficiency of our proposed test to its competitor is greater than or equal to 1. Extensive numerical studies and a real data example demonstrate the potential of our proposed test.

Both viable Bifidobacterium longum subsp. infantis B8762 and heat-killed cells alleviate the intestinal inflammation of DSS-induced IBD rats.

In view of the safety concerns of probiotics, more and more attention is paid to the beneficial effects of dead probiotics cells. Herein, we investigated and compared the alleviation effects of viable Bifidobacterium longum subsp. infantis B8762 (B. infantis B8762) and its heat-killed cells on dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) rats. Four groups of rats (n = 12 per group) were included: normal control, DSS-induced colitis rats without bacterial administration (DSS), DSS-induced colitis rats with viable B. infantis B8762 administration (VB8762), and DSS-induced colitis rats with dead B. infantis B8762 administration (DB8762). Our results showed that both VB8762 and DB8762 administration exerted significant protective effects on DSS-induced IBD rats, as evidenced by a reduction in mortality, disease activity index score, body weight loss, as well as decreased histology score, which were companied by a significant decrease in serum pro-inflammatory factors compared with DSS group, and a stronger effect on modulating the fecal microbiota alpha-diversity and beta-diversity compared with DSS group. Additionally, the fecal metabolome results showed that both VB8762 and DB8762 interventions indeed altered the fecal metabolome profile and related metabolic pathways of DSS-induced IBD rats. Therefore, given the alleviation effects on colitis, the DB8762 can be confirmed to be a postbiotic. Overall, our findings suggested that VB8762 and DB8762 had similar ability to alleviate IBD although with some differences. Due to the minimal safety concern of postbiotics, we propose that the postbiotic DB8762 could be a promising alternative to probiotics to be applied in the prevention and treatment of IBDs.IMPORTANCEInflammatory bowel disease (IBD) has emerged as a global disease because of the worldwide spread of western diets and lifestyles during industrialization. Up to now, many probiotic strains are used as a modulator of gut microbiota or an enhancer of gut barrier to alleviate or cure IBD. However, there are still many issues of using probiotics, which were needed to be concerned about, for instance, safety issues in certain groups like neonates and vulnerable populations, and the functional differences between viable and dead microorganisms. Therefore, it is of interest to investigate the beneficial effects of dead probiotics cells. The present study proved that both viable Bifidobacterium longum subsp. infantis B8762 and heat-killed cells could alleviate dextran sodium sulfate-induced colitis in rats. The findings help to support that some heat-killed probiotics cells can also exert relevant biological functions and can be used as a postbiotic.

TENSOR QUANTILE REGRESSION WITH LOW-RANK TENSOR TRAIN ESTIMATION.

Neuroimaging studies often involve predicting a scalar outcome from an array of images collectively called tensor. The use of magnetic resonance imaging (MRI) provides a unique opportunity to investigate the structures of the brain. To learn the association between MRI images and human intelligence, we formulate a scalar-on-image quantile regression framework. However, the high dimensionality of the tensor makes estimating the coefficients for all elements computationally challenging. To address this, we propose a low-rank coefficient array estimation algorithm based on tensor train (TT) decomposition which we demonstrate can effectively reduce the dimensionality of the coefficient tensor to a feasible level while ensuring adequacy to the data. Our method is more stable and efficient compared to the commonly used, Canonic Polyadic rank approximation-based method. We also propose a generalized Lasso penalty on the coefficient tensor to take advantage of the spatial structure of the tensor, further reduce the dimensionality of the coefficient tensor, and improve the interpretability of the model. The consistency and asymptotic normality of the TT estimator are established under some mild conditions on the covariates and random errors in quantile regression models. The rate of convergence is obtained with regularization under the total variation penalty. Extensive numerical studies, including both synthetic and real MRI imaging data, are conducted to examine the empirical performance of the proposed method and its competitors.

Association of cognitive impairment with the interaction between chronic kidney disease and depression: findings from NHANES 2011-2014.

BACKGROUND: Cognitive impairment (CoI), chronic kidney disease (CKD), and depression are prevalent among older adults and are interrelated, imposing a significant disease burden. This study evaluates the association of CKD and depression with CoI and explores their potential interactions. METHOD: Data for this study were sourced from the 2011-2014 National Health and Nutritional Examination Survey (NHANES). Multiple binary logistic regression models assessed the relationship between CKD, depression, and CoI while controlling for confounders. The interactions were measured using the relative excess risk of interaction (RERI), the attributable proportion of interaction (AP), and the synergy index (S). RESULTS: A total of 2,666 participants (weighted n = 49,251,515) were included in the study, of which 700 (16.00%) had CoI. After adjusting for confounding factors, the risk of CoI was higher in patients with CKD compared to non-CKD participants (odds ratio [OR] = 1.49, 95% confidence interval [CI]:1.12-1.99). The risk of CoI was significantly increased in patients with depression compared to those without (OR = 2.29, 95% CI: 1.73-3.03). Furthermore, there was a significant additive interaction between CKD and depression in terms of the increased risk of CoI (adjusted RERI = 2.01, [95% CI: 0.31-3.71], adjusted AP = 0.50 [95% CI: 0.25-0.75], adjusted S = 2.97 [95% CI: 1.27-6.92]). CONCLUSION: CKD and depression synergistically affect CoI, particularly when moderate-to-severe depression co-occurs with CKD. Clinicians should be mindful of the combined impact on patients with CoI. Further research is needed to elucidate the underlying mechanisms and assess the effects specific to different CKD stages.

Postbiotic Administration Ameliorates Colitis and Inflammation in Rats Possibly through Gut Microbiota Modulation.

Postbiotics are preparations of inanimate microorganisms and/or their components that are beneficial to host health. Compared with probiotics, the postbiotic dose required for exerting obvious protective effects is unknown. Thus, we conducted a dose-dependent postbiotic intervention study in dextran sulfate sodium (DSS)-induced colitis rats. The trial included five rat groups, including: control without DSS/postbiotic treatment, group C; 7-day DSS treatment, group D; 14-day low, medium, and high probiotic doses (0.1, 0.2, 0.4 g/kg; groups L, M, H, respectively) after DSS induction. We found that postbiotic intervention effectively mitigated the symptoms and inflammation in colitis rats, evidenced by the improved spleen index, less severe colon tissue damage, and changes in serum cytokine levels (decreases in tumor necrosis factor-α and interleukin-1ß; increase in interleukin-10) in postbiotic groups compared with group D. Moreover, the therapeutic effect was dose-dependent. Fecal metabolomics analysis revealed that the postbiotic recipients had more anti-inflammatory metabolites, namely, salicyloyl phytophingosine, podophylloxin, securinine, baicalein, and diosmetin. Fecal metagenomics analysis revealed that the postbiotic recipients had more beneficial microbes and less pro-inflammatory bacteria. This study confirmed that postbiotics are effective in alleviating colitis in a dose-dependent manner. Our findings are of interest to food scientists, clinicians, and the health food industry.

Dissecting the molecular basis of spike traits by integrating gene regulatory networks and genetic variation in wheat.

Spike architecture influences both grain weight and grain number per spike, which are the two major components of grain yield in bread wheat (Triticum aestivum L.). However, the complex wheat genome and the influence of various environmental factors pose challenges in mapping the causal genes that affect spike traits. Here, we systematically identified genes involved in spike trait formation by integrating information on genomic variation and gene regulatory networks controlling young spike development in wheat. We identified 170 loci that are responsible for variations in spike length, spikelet number per spike, and grain number per spike through genome-wide association study and meta-QTL analyses. We constructed gene regulatory networks for young inflorescences at the double ridge stage and the floret primordium stage, in which the spikelet meristem and the floret meristem are predominant, respectively, by integrating transcriptome, histone modification, chromatin accessibility, eQTL, and protein-protein interactome data. From these networks, we identified 169 hub genes located in 76 of the 170 QTL regions whose polymorphisms are significantly associated with variation in spike traits. The functions of TaZF-B1, VRT-B2, and TaSPL15-A/D in establishment of wheat spike architecture were verified. This study provides valuable molecular resources for understanding spike traits and demonstrates that combining genetic analysis and developmental regulatory networks is a robust approach for dissection of complex traits.

Cost-effectiveness analysis of expectant vs active management for treatment of persistent pregnancies of unknown location.

BACKGROUND: Persistent pregnancies of unknown location are defined by abnormally trending serum human chorionic gonadotropin with nondiagnostic ultrasound. There is no consensus on optimal management. OBJECTIVE: This study aimed to assess the cost-effectiveness of 3 primary management strategies for persistent pregnancies of unknown location: (1) expectant management, (2) empirical 2-dose methotrexate, and (3) uterine evacuation followed by methotrexate, if indicated. STUDY DESIGN: This was a prospective economic evaluation performed concurrently with the Expectant versus Active Management for Treatment of Persistent Pregnancies of Unknown Location multicenter randomized trial that was conducted from July 2014 to June 2019. Participants were randomized 1:1:1 to expectant management, 2-dose methotrexate, or uterine evacuation. The analysis was from the healthcare sector perspective with a 6-week time horizon after randomization. Costs were expressed in 2018 US dollars. Effectiveness was measured in quality-adjusted life years and the rate of salpingectomy. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were generated. Sensitivity analyses were performed to assess the robustness of the analysis. RESULTS: Methotrexate had the lowest mean cost ($875), followed by expectant management ($1085) and uterine evacuation ($1902) (P=.001). Expectant management had the highest mean quality-adjusted life years (0.1043), followed by methotrexate (0.1031) and uterine evacuation (0.0992) (P=.0001). The salpingectomy rate was higher for expectant management than for methotrexate (9.4% vs 1.2%, respectively; P=.02) and for expectant management than for uterine evacuation (9.4% vs 8.1%, respectively; P=.04). Uterine evacuation, with the highest costs and the lowest quality-adjusted life years, was dominated by both expectant management and methotrexate. In the base case analysis, expectant management was not cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year given an incremental cost-effectiveness ratio of $175,083 per quality-adjusted life year gained (95% confidence interval, -$1,666,825 to $2,676,375). Threshold analysis demonstrated that methotrexate administration would have to cost $214 (an increase of $16 or 8%) to favor expectant management. Moreover, expectant management would be favorable in lower-risk patient populations with rates of laparoscopic surgical management for ectopic pregnancy not exceeding 4% of pregnancies of unknown location. Based on the cost-effectiveness acceptability curves, the probability of expectant management being cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year gained was 50%. The results were dependent on the cost of surgical intervention and the expected rate of methotrexate failure. CONCLUSION: The management of pregnancies of unknown location with a 2-dose methotrexate protocol may be cost-effective compared with expectant management and uterine evacuation. Although uterine evacuation was dominated, expectant management vs methotrexate results were sensitive to modest changes in treatment costs of both methotrexate and surgical management.

Long-Term Tracking of the Effects of Colostrum-Derived Lacticaseibacillus rhamnosus Probio-M9 on Gut Microbiota in Mice with Colitis-Associated Tumorigenesis.

Intestinal bacteria play important roles in the progression of colitis-associated carcinogenesis. Colostrum-derived Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9) has shown a protective effect in a colitis-associated cancer (CAC) model, but detailed metagenomic analysis had not been performed. Here, we investigated the preventive effects of the probiotic Probio-M9 on CAC-model mice, tracking the microbiota. Feces were obtained at four time points for evaluation of gut microbiota. The effect of Probio-M9 on tight junction protein expression was evaluated in co-cultured Caco-2 cells. Probio-M9 treatment decreased the number of tumors as well as stool consistency score, spleen weight, inflammatory score, and macrophage expression in the CAC model. Probio-M9 accelerated the recovery of the structure, composition, and function of the intestinal microbiota destroyed by azoxymethane (AOM)/dextran sulfate sodium (DSS) by regulating key bacteria (including Lactobacillus murinus, Muribaculaceae bacterium DSM 103720, Muribaculum intestinale, and Lachnospiraceae bacterium A4) and pathways from immediately after administration until the end of the experiment. Probio-M9 co-culture protected against lipopolysaccharide-induced impairment of tight junctions in Caco-2 cells. This study provides valuable insight into the role of Probio-M9 in correcting gut microbiota defects associated with inflammatory bowel disease carcinogenesis and may have clinical application in the treatment of inflammatory carcinogenesis.

The FTO-CMPK2 Pathway in Fibroblast-like Synoviocytes Modulates Rheumatoid Arthritis Synovial Inflammation and Cartilage Homeostasis via mtDNA Regulation.

In rheumatoid arthritis (RA), a debilitating autoimmune disorder marked by chronic synovial inflammation and progressive cartilage degradation, fibroblast-like synoviocytes (FLS) are key pathogenic players. Current treatments targeting these cells are limited. Our study focused on the Fat Mass and Obesity-associated protein (FTO), known for its roles in cell proliferation and inflammatory response modulation, and its involvement in RA. We specifically examined the inflammatory regulatory roles of FTO and CMPK2, a mitochondrial DNA synthesis protein, in FLS. Utilizing a combination of in vitro and in vivo methods, including FTO inhibition and gene knockdown, we aimed to understand FTO's influence on RA progression and chondrocyte functionality. Our findings showed that increased FTO expression in RA synovial cells enhanced their proliferation and migration and decreased senescence and apoptosis. Inhibiting FTO significantly slowed the disease progression in our models. Our research also highlighted that the FTO-CMPK2 pathway plays a crucial role in regulating synovial inflammation through the mtDNA-mediated cGAS/STING pathway, affecting chondrocyte homeostasis. This study indicates that targeting the FTO-CMPK2 axis could be a promising new therapeutic strategy for managing RA.

How to minimize the dropout and crossover in an infertility trial?

Randomized controlled trials and intent-to-treat analyses are important for infertility clinical studies. Dropouts or crossovers during the study process will disrupt the randomization design and affect the intent-to-treat analysis. In this review, we have briefly introduced the occurrence of dropout and crossover from our previous Reproductive Medicine Network and other related studies and provided some experience obtained from these studies on how to minimize and reduce the occurrence of dropout and crossover for infertility randomized clinical studies.

Association between estimated glomerular filtration rate and reversion to normoglycemia in people with impaired fasting glucose: a 5-year retrospective cohort study.

OBJECTIVES: The present body of evidence regarding the correlation between the estimated glomerular filtration rate (eGFR) and the reversal of impaired fasting glucose (IFG) to normoglycemia remains constrained. Consequently, the objective of our study is to examine the relationship between eGFR and the restoration of normoglycemia in individuals with IFG. METHODS: This retrospective cohort study consecutively collected data from 24,541 non-selective participants with IFG at Rich Healthcare Group in China from January 2010 to 2016. We aimed to investigate the association between baseline eGFR and reversion to normoglycemia using the Cox proportional-hazards regression model. Through the utilization of a Cox proportional hazards regression model featuring cubical spline smoothing, we were able to ascertain the non-linear correlation between eGFR and the return to normoglycemia. Furthermore, various sensitivity and subgroup analyses were carried out, and a competing risk multivariate Cox regression was employed to examine the progression to diabetes as a competing risk for the reversal of normoglycemic events. RESULTS: In our study, comprising 24,541 participants, the average age was 49.25 ± 13.77 years, with 66.28% being male. The baseline eGFR mean was 104.16 ± 15.78 ml/min per 1.73 m2. During a median follow-up period of 2.89 years, we observed a reversion rate to normoglycemia of 45.50%. Upon controlling for covariates, our findings indicated a positive correlation between eGFR and the probability of returning to normoglycemia (HR = 1.008, 95% CI 1.006-1.009). In addition, a non-linear association was observed between eGFR and the likelihood of transitioning from IFG to normoglycemia. The inflection point of eGFR was found to be 111.962 ml/min per 1.73 m2, with HRs of 1.003 (95% CI 1.001, 1.005) on the left side of the point and 1.019 (95% CI 1.015, 1.022) on the right side. Our robust results were supported by competing risks multivariate Cox's regression and sensitivity analysis. CONCLUSIONS: The findings of our investigation indicate a favorable and non-linear correlation between eGFR and the restoration of normoglycemia in Chinese individuals with IFG. Specifically, a reduction in renal function at an early stage in these patients may considerably diminish the likelihood of attaining normoglycemia.

Identification and validation of supervariants reveal novel loci associated with human white matter microstructure.

As an essential part of the central nervous system, white matter coordinates communications between different brain regions and is related to a wide range of neurodegenerative and neuropsychiatric disorders. Previous genome-wide association studies (GWASs) have uncovered loci associated with white matter microstructure. However, GWASs suffer from limited reproducibility and difficulties in detecting multi-single-nucleotide polymorphism (multi-SNP) and epistatic effects. In this study, we adopt the concept of supervariants, a combination of alleles in multiple loci, to account for potential multi-SNP effects. We perform supervariant identification and validation to identify loci associated with 22 white matter fractional anisotropy phenotypes derived from diffusion tensor imaging. To increase reproducibility, we use United Kingdom (UK) Biobank White British (n = 30,842) data for discovery and internal validation, and UK Biobank White but non-British (n = 1927) data, Europeans from the Adolescent Brain Cognitive Development study (n = 4399) data, and Europeans from the Human Connectome Project (n = 319) data for external validation. We identify 23 novel loci on the discovery set that have not been reported in the previous GWASs on white matter microstructure. Among them, three supervariants on genomic regions 5q35.1, 8p21.2, and 19q13.32 have P-values lower than 0.05 in the meta-analysis of the three independent validation data sets. These supervariants contain genetic variants located in genes that have been related to brain structures, cognitive functions, and neuropsychiatric diseases. Our findings provide a better understanding of the genetic architecture underlying white matter microstructure.

Towards precision oncology discovery: four less known genes and their unknown interactions as highest-performed biomarkers for colorectal cancer.

The goal of this study was to use a new interpretable machine-learning framework based on max-logistic competing risk factor models to identify a parsimonious set of differentially expressed genes (DEGs) that play a pivotal role in the development of colorectal cancer (CRC). Transcriptome data from nine public datasets were analyzed, and a new Chinese cohort was collected to validate the findings. The study discovered a set of four critical DEGs - CXCL8, PSMC2, APP, and SLC20A1 - that exhibit the highest accuracy in detecting CRC in diverse populations and ethnicities. Notably, PSMC2 and CXCL8 appear to play a central role in CRC, and CXCL8 alone could potentially serve as an early-stage marker for CRC. This work represents a pioneering effort in applying the max-logistic competing risk factor model to identify critical genes for human malignancies, and the interpretability and reproducibility of the results across diverse populations suggests that the four DEGs identified can provide a comprehensive description of the transcriptomic features of CRC. The practical implications of this research include the potential for personalized risk assessment and precision diagnosis and tailored treatment plans for patients.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.