BACKGROUND: The binary diagnosis of Metabolic Syndrome(MetS) fails to accurately evaluate its severity, and the association between MetS severity and frailty progression remains inadequately elucidated. This study aims to clarify the relationship between the severity of MetS and the progression of frailty among the middle-aged and elderly population in China.
METHODS: Participants from the 2011-2018 China Health and Retirement Longitudinal Study(CHARLS) were included for a longitudinal analysis. The study employs a frailty index(FI) based on 32 health deficits to diagnose frailty and to assess FI trajectories. An age-sex-ethnicity-specific MetS scoring model (MetS score) was used to assess metabolic syndrome severity in Chinese adults. The Cumulative MetS score from 2012 to 2015 was calculated using the formula: (MetS score in wave 1 + MetS score in wave 3) / 2 × time(2015 - 2012). The association between MetS score, Cumulative MetS score, and the risk and trajectory of frailty were evaluated using Cox regression/logistic regression, and linear mixed models. Restricted Cubic Splines(RCS) models were utilized to detect potential non-linear associations.
RESULTS: A higher MetS score was significantly associated with an increased risk of frailty(HR per 1 SD increase = 1.205; 95%CI: 1.14 to 1.273) and an accelerated FI trajectory(β per 1 SD increase = 0.113 per year; 95%CI: 0.075 to 0.15 per year). Evaluating changes in MetS score using a Cumulative MetS score indicated that each 1 SD increase in the Cumulative MetS score increased the risk of frailty by 22.2%(OR = 1.222; 95%CI: 1.133 to 1.319) and accelerated the rate of increase in FI(β = 0.098 per year; 95%CI: 0.058 to 0.138 per year). RCS model results demonstrated a dose-response curve relationship between MetS score and Cumulative MetS score with frailty risk. Stratified analysis showed consistency across subgroups. The interaction results indicate that in males and individuals under aged 60, MetS score may accelerate the increase in FI, a finding consistent across both models.
CONCLUSIONS: Our findings underscore the positive correlation between the severity of MetS and frailty progression in the middle-aged and elderly, highlighting the urgent need for early identification of MetS and targeted interventions to reduce the risk of frailty.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), and its pathogenesis has not been clarified. Current research suggests that DKD involves multiple cell types and extra-renal factors, and it is particularly important to clarify the pathogenesis and identify new therapeutic targets. Single-cell RNA sequencing (scRNA-seq) technology is high-throughput sequencing of the transcriptomes of individual cells at the single-cell level, which is an effective technology for exploring the development of diseases by comparing genetic information, reflecting the differences in genetic information between cells, and identifying different cell subpopulations. Accumulating evidence supports the role of scRNA-seq in revealing the pathogenesis of diabetes and strengthening our understanding of the molecular mechanisms of DKD. We reviewed the scRNA-seq data this time. Then, we analyzed and discussed the applications of scRNA-seq technology in DKD research, including annotation of cell types, identification of novel cell types (or subtypes), identification of intercellular communication, analysis of cell differentiation trajectories, gene expression detection, and analysis of gene regulatory networks, and lastly, we explored the future perspectives of scRNA-seq technology in DKD research.

Unsupervised feature selection is a critical step for efficient and accurate analysis of single-cell RNA-seq data. Previous benchmarks used two different criteria to compare feature selection methods: (i) proportion of ground-truth marker genes included in the selected features and (ii) accuracy of cell clustering using ground-truth cell types. Here, we systematically compare the performance of 11 feature selection methods for both criteria. We first demonstrate the discordance between these criteria and suggest using the latter. We then compare the distribution of selected genes in their means between feature selection methods. We show that lowly expressed genes exhibit seriously high coefficients of variation and are mostly excluded by high-performance methods. In particular, high-deviation- and high-expression-based methods outperform the widely used in Seurat package in clustering cells and data visualization. We further show they also enable a clear separation of the same cell type from different tissues as well as accurate estimation of cell trajectories.

Cellular movement is essential for many vital biological functions where it plays a pivotal role both at the single cell level, such as during division or differentiation, and at the macroscopic level within tissues, where coordinated migration is crucial for proper morphogenesis. It also has an impact on various pathological processes, one for all, cancer spreading. Cell migration is a complex phenomenon and diverse experimental methods have been developed aimed at dissecting and analysing its distinct facets independently. In parallel, corresponding analytical procedures and tools have been devised to gain deep insight and interpret experimental results. Here we review established experimental techniques designed to investigate specific aspects of cell migration and present a broad collection of historical as well as cutting-edge computational tools used in quantitative analysis of cell motion.

BACKGROUND: No study has concentrated on the association of LE8 with cancer risk and death. We aim to examine the association of LE8 with death and cancer.
METHODS: A total of 94733 adults aged 51.42 ± 12.46 years and 77551 participants aged 54.09±12.06 years were enrolled in longitudinal and trajectory analysis respectively. Baseline LE8 was divided into three groups based on the American Heart Association criteria and three trajectory patterns by latent mixture models. We reviewed medical records and clinical examinations to confirm incident cancer during the period from 2006 to 2020. Death information was collected from provincial vital statistics offices. Cox models were used.
RESULTS: 12807 all-cause deaths and 5060 cancers were documented during a 14-year follow-up. Relative to participants with high LE8 at baseline, participants with lower levels of LE8 have a significantly increased risk of mortality and incident cancer. All these risks have an increasing trend with LE8 level decreasing. Meanwhile, the trajectory analysis recorded 7483 all-cause deaths and 3037 incident cancers after approximately 10 years. The associations of LE8 with death and cancer were identical to the longitudinal study. In the subtype cancer analysis, LE8 has a strong effect on colorectal cancer risk. Moreover, the cut point is 56.67 in the association between LE8 and death, while the cut point altered to 64.79 in the association between LE8 and incident cancers. These associations were enhanced among younger adults.
CONCLUSIONS: There was a significant association of LE8 with death and cancer risk, especially for the young population.

Drawing upon the framework of life course epidemiology, this study aligns with research on the mental health consequences of significant social transitions during early adulthood. The focus is on the variation in initial labour market attachment and the development of depressiveness, assuming that a firm attachment is associated with decreasing depressiveness.
The baseline investigation of the studied cohort (n = 1,001) took place during their final year of compulsory schooling at age 16. Follow-up surveys were conducted at ages 18, 21, 30, and 43. Depressiveness was measured with a five-item score. Multiple trajectory analysis, incorporating five labour market statuses observed over seven half-year periods from ages 18 to 21, was employed to categorize the cohort into six distinct groups. Among these, \'All-time education,\' \'From education to employment,\' \'Education and employment,\' and \'From employment to education\' were considered to demonstrate firm labour market attachment. Meanwhile, \'Active labour market policy\' and \'Unemployment\' represented less firm attachment.
The trajectory of depressive symptoms among the total cohort from age 16 to age 43 exhibited a \'broken stick\' pattern, reaching its lowest point at age 21. This pattern was evident in all groups classified as having a firm attachment. A substantial decrease in depressiveness was also observed in the relatively weakly attached \'Active labour market policy\' group, whereas no \'broken stick\' pattern emerged in the \'Unemployment\' group. The disparities in the levels of depressiveness observed at age 21 remained relatively stable across the measurements at ages 30 and 43.
The results were as expected, except for the observed improvement in mental health within the \'Active labour market policy\' group. Supported labour market attachment during emerging adulthood can enhance mental well-being similarly to regular mainstream attachment. In terms of policy recommendations, the consistently high levels of depressiveness within the \'Unemployment\' group underscore the importance of reducing long-term and repeated unemployment in young age. The findings regarding the \'Active labour market policy\' provide evidence of the intervention\'s benefits. While the primary goal of these measures is to create jobs for the unemployed, they also include elements that contribute to participants\' mental health.

An inherent genetic enzyme disorder in humans, known as glucose-6-phosphate dehydrogenase (G6PD) deficiency, arises due to specific mutations. While the prevailing approach for investigating G6PD variants involves biochemical analysis, the intricate structural details remain limited, impeding a comprehensive understanding of how different G6PD variants of varying classes impact their functionality. This study 22 examined the dynamic properties of G6PD wild types and six G6PD variants from 23 different classes using molecular dynamic simulation (MDS). The wild-type and variant 24 G6PD structures unveil high fluctuations within the amino acid range of 274-515, the structural NADP+ binding site, pivotal for enzyme dimerization. Specifically, two variants, G6PDZacatecas (R257L) and G6PDDurham (K238R), demonstrate compromised structural stability at the dimer interface, attributable to the disruption of a salt bridge involving Glu 206 and Lys 407, along with the disturbance of hydrogen bonds formed by Asp 421 at the βN-βN sheets. Consequently, this impairment cascades to affect the binding affinity of crucial interactions, such as Lys 171-Glucose-6-Phosphate (G6P) and Lys 171-catalytic NADP+, leading to diminished enzyme activity. This study underscores the utility of computational in silico techniques in predicting the structural alterations and flexibility of G6PD variants. This insight holds promise for guiding future endeavors in drug development targeted at mitigating the impacts of G6PD deficiency.

BACKGROUND: Functional decline associated with dementia, including in Alzheimer\'s disease (AD), is not uniform across individuals, and respective heterogeneity is not yet fully explained. Such heterogeneity may in part be related to genetic variability among individuals. In this study, we investigated whether the SNP rs6859 in nectin cell adhesion molecule 2 (NECTIN2) gene (a major risk factor for AD) influences trajectories of cognitive decline in older participants from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI).
METHODS: We retrospectively analyzed records on 1310 participants from the ADNI database for the multivariate analysis. We used longitudinal measures of Mini-Mental State Examination (MMSE) scores in participants, who were cognitively normal, or having AD, or other cognitive deficits to investigate the trajectories of cognitive changes. Multiple linear regression, linear mixed models and latent class analyses were conducted to investigate the association of the SNP rs6859 with MMSE.
RESULTS: The regression coefficient per one allele dose of the SNP rs6859 was independently associated with MMSE in both cross-sectional (-2.23, p < 0.01) and linear mixed models (-2.26, p < 0.01) analyses. The latent class model with three distinct subgroups (class 1: stable and gradual decline, class 2: intermediate and late decline, and class 3: lowest and irregular) performed best in the posterior classification, 42.67% (n = 559), 21.45% (n = 281), 35.88% (n = 470) were classified as class 1, class 2, and class 3. In the heterogeneous linear mixed model, the regression coefficient per one allele dose of rs6859 - A risk allele was significantly associated with MMSE class 1 and class 2 memberships and related decline; Class 1 (-2.28, 95% CI: -4.05, -0.50, p < 0.05), Class 2 (-5.56, 95% CI: -9.61, -1.51, p < 0.01) and Class 3 (-0.37, 95% CI: -1.62, 0.87, p = 0.55).
CONCLUSIONS: This study found statistical evidence supporting the classification of three latent subclass groups representing complex MMSE trajectories in the ADNI cohort. The SNP rs6859 can be suggested as a candidate genetic predictor of variation in modeling MMSE trajectory, as well as for identifying latent classes with higher baseline MMSE. Functional studies may help further elucidate this relationship.

OBJECTIVE: This study compared opioid utilization trajectories of persons initiating tramadol, short-acting hydrocodone, or short-acting oxycodone, and it characterized opioid dose trajectories and type of opioid in persistent opioid therapy subsamples.
METHODS: A retrospective cohort study of adults with chronic non-cancer pain who were initiating opioid therapy was conducted with the IQVIA PharMetrics® Plus for Academics data (2008-2018). Continuous enrollment was required for 6 months before (\"baseline\") and 12 months after (\"follow-up\") the first opioid prescription (\"index date\"). Opioid therapy measures were assessed every 7 days over follow-up. Group-based trajectory modeling (GBTM) was used to identify trajectories for any opioid and total morphine milligram equivalent measures, and longitudinal latent class analysis was used for opioid therapy type.
RESULTS: A total of 40 276 tramadol, 141 023 hydrocodone, and 45 221 oxycodone initiators were included. GBTM on any opioid therapy identified 3 latent trajectories: early discontinuers (tramadol 39.0%, hydrocodone 54.1%, oxycodone 61.4%), late discontinuers (tramadol 37.9%, hydrocodone 39.4%, oxycodone 33.3%), and persistent therapy (tramadol 6.7%, hydrocodone 6.5%, oxycodone 5.3%). An additional fourth trajectory, intermittent therapy (tramadol 16.4%), was identified for tramadol initiators. Of those on persistent therapy, 2687 individuals were on persistent therapy with tramadol, 9169 with hydrocodone, and 2377 with oxycodone. GBTM on opioid dose resulted in 6 similar trajectory groups in each persistent therapy group. Longitudinal latent class analysis on opioid therapy type identified 6 latent classes for tramadol and oxycodone and 7 classes for hydrocodone.
CONCLUSIONS: Opioid therapy patterns meaningfully differed by the initial opioid prescribed, notably the presence of intermittent therapy among tramadol initiators and higher morphine milligram equivalents and prescribing of long-acting opioids among oxycodone initiators.

This study aimed to assess the association of baseline insulin resistance (IR) surrogates and their longitudinal trajectories with cardiovascular diseases (CVD) to provide a useful reference for preventing CVD.
This study was a prospective cohort study conducted in the 51st Regiment of the Third Division of Xinjiang Corps. A total of 6362 participants were recruited in 2016 to conduct the baseline survey, and the follow-up surveys in 2019, 2020, 2021, and 2022. The Kaplan-Meier method was used to estimate the cumulative incidence of CVD according to the baseline IR surrogates of metabolic insulin resistance score (METS-IR) and triglyceride-glucose (TyG) index. Cox regression models were used to assess the association between the baseline IR surrogates and CVD. The impact of the longitudinal trajectories of the IR surrogates on CVD was analyzed after excluding those with IR surrogate data measured ≤2 times. Based on the group-based trajectory model (GBTM), the trajectory patterns of IR surrogates were determined. The Kaplan-Meier method was used to estimate the cumulative incidence of CVD in each trajectory group of METS-IR and TyG index. Cox regression models were used to analyze the association between different trajectory groups of each index and CVD. In addition, the Framingham model was utilized to evaluate whether the addition of the baseline IR surrogates increased the predictive potential of the model.
Baseline data analysis included 4712 participants. During a median follow-up of 5.66 years, 572 CVD events were recorded (mean age, 39.42 ± 13.67 years; males, 42.9%). The cumulative CVD incidence increased with the ascending baseline METS-IR and TyG index quartiles (Q1-Q4). The hazard ratio and 95% confidence interval for CVD risk in Q4 of the METS-IR and TyG index were 1.79 (1.25, 2.58) and 1.66 (1.28, 2.17), respectively, when compared with Q1. 4343 participants were included in the trajectory analysis, based on the longitudinal change patterns of the METS-IR and TyG index, the following three trajectory groups were identified: low-increasing, moderate-stable, and elevated-increasing groups. Multivariate Cox regression revealed that the hazard ratio (95% confidence interval) for CVD risk in the elevated-increasing trajectory group of the METS-IR and TyG index was 2.13 (1.48, 3.06) and 2.63 (1.68, 4.13), respectively, when compared with the low-rising group. The C-index, integrated discrimination improvement value, and net reclassification improvement value were enhanced after adding the baseline METS-IR and TyG index values to the Framingham model (P<0.05).
Elevated baseline IR surrogates and their higher long-term trajectories were strongly associated with a high risk of CVD incidence in Xinjiang\'s rural areas. Regular METS-IR and TyG index monitoring can aid in the early detection of CVD-risk groups.