Body Mass Index and Risk of Female Reproductive System Tumors Subtypes: A Meta-Analysis Using Mendelian Randomization.

Introduction: A strong association was previously established between body mass index (BMI) and female reproductive system tumors; however, the causal relationship is unclear. We conducted a Mendelian randomization (MR) study to further explore this association. Methods: Genetic information for BMI was retrieved from a published genome-wide association study involving 339,224 participants. Genetic associations with five common female reproductive system tumors were obtained from the FinnGen, UK Biobank studies, and other large consortia. Results: Genetic predisposition towards BMI exhibits a significant association with multiple tumors of the female reproductive system. Specifically, for every 1-unit increase in BMI log-transformed odds ratio (OR). The OR fluctuations overall for patients with breast cancer ranged from 0.661 to 0.996 (95% confidence interval [CI],0.544-1.000, P < 0.05). When stratified by estrogen receptor (ER) status, the OR for patients with ER (+) breast cancer ranged from 0.782 to 0.844 (95% CI, 0.616-0.994, P < 0.05) and that for those with ER (-) breast cancer ranged from 0.663 to 0.789 (95% CI, 0.498-0.991, P < 0.05). Additionally, ORs were as follows for cancer types: 1.577-1.908 (95% CI, 1.049-2.371, P < 0.05) for endometrial carcinoma; 1.216-1.303 (95% CI, 1.021-1.591, P < 0.05) for high-grade serous ovarian cancer; 1.217 (95% CI, 1.034-1.432, P < 0.05) for low-grade malignant serous ovarian cancer; and 1.502 (95% CI, 1.112-2.029, P < 0.05) for endometrioid ovarian carcinoma. Furthermore, our findings indicated that genetic predisposition towards BMI did not exhibit a causal association with uterine fibroids, cervical precancerous lesions, or cervical cancer itself. Conclusion: A genetic association was established between a high BMI and high risk of developing multiple tumors of the female reproductive system and their associated subtypes. This underscores the significance of taking measures to prevent reproductive system tumors in women who have a high BMI.

Forecasting Informal care needs of the urban-rural older adults in China based on microsimulation model.

BACKGROUND: Forecasting the intensity, source, and cost of informal care for older adults in China is essential to establish and enhance policy support systems for informal care within the context of East Asian traditional culture that emphasizes filial piety. This study aims to analyze the current situation and influencing factors for the informal care needs and predict the trends of informal care needs for older adults in China from 2020 to 2040. METHODS: Using the CHARLS database from 2015 to 2018, this study first combined a two-part model and a multinomial logit to analyze the influencing factors for the informal care needs of urban-rural older adults in China. Secondly, a multi-state Markov model was constructed to forecast the number of urban-rural older populations in each health state from 2020 to 2040. Finally, based on a microsimulation model, this study predicted the trends of informal care intensity, source, and cost for older adults in urban and rural areas from 2020 to 2040. RESULTS: In 2040, the size of the disabled older population in China will expand further. In rural areas, the total number of disabled people in 2040 (39.77 million) is 1.50 times higher than that in 2020; In urban areas, the total number of disabled people in 2040 (56.01 million) is 2.51 times higher than that in 2020. Compared with 2020, older adults population with mild, moderate and severe disability in 2040 would increase by 87.60%, 101.70%, and 115.08%, respectively. In 2040, the number of older adults receiving low-, medium-, and high-intensity care in China will be 38.60 million, 22.89 million, and 41.69 million, respectively, and older people will still rely on informal care provided by spouses and children (from spouses only: 39.26 million, from children only: 36.74 million, from spouses and children only: 16.79 million, other: 10.39 million). The total cost of informal care in 2040 will be 1,086.65 billion yuan, 2.22 times that of 2020 (490.31 billion yuan), which grows faster than the economic growth rate. CONCLUSION: From 2020 to 2040, the informal care needs of older people in rural areas will increase first and then decrease due to the demographic structure and rapid urbanization. In contrast, the informal care needs of older people in urban areas will continuously increase from 2020 to 2040, with the growth rate gradually slowing down. This study provides an evidence-based rationale for scientifically measuring the economic value of informal care and reasonably allocating care resources.

Frailty detection with routine blood tests using data from the english longitudinal study of ageing (ELSA).

PURPOSE: Frailty is a rising global health issue in ageing society. Easily accessible and sensitive tools are needed for frailty monitoring while routine blood factors can be potential candidates. METHODS: Data from 1907 participants (aged 60 years or above) were collected from the 4th to 9th wave of the English longitudinal study of ageing. 14 blood factors obtained from blood tests were included in the analysis. A 52-item frailty index (FI) was calculated for frailty evaluation. Logistic regression and Cox proportional hazards analysis were used to explore the relationships between baseline blood factors and the incidence of frailty over time respectively. All analyses were controlled for age and sex. RESULTS: The mean age of participants was 67.3 years and 47.2% of them were male. Our study identified that 8 blood factors (mean corpuscular haemoglobin, HDL, triglyceride, ferritin, hsCRP, dehydroepiandrosterone, haemoglobin, and WBC) involved in inflammatory, nutritional and metabolic processes were associated with frailty. The combined model with these 8 blood factors had an AUC of 0.758 at cross-sectional level. In the Cox proportional hazards analysis, higher triglyceride (HR: 1.30, 95%CI: 1.07 ~ 1.59), WBC (HR: 1.16, 95%CI: 1.05 ~ 1.28), and lower HDL (HR: 0.58, 95%CI: 0.38 ~ 0.90) at baseline were linked to greater risk of developing frailty within 10 years. Compared to adults without abnormal blood factors at baseline, the hazard ratios of participants with two or more abnormal blood factors were almost twofold higher in developing frailty over time. CONCLUSIONS: Routine blood factors, particularly triglyceride, HDL and WBC, could be used for frailty screening in clinical practice and estimate the development of frailty over time.

Survival prediction in second primary breast cancer patients with machine learning: An analysis of SEER database.

BACKGROUND: Studies have found that first primary cancer (FPC) survivors are at high risk of developing second primary breast cancer (SPBC). However, there is a lack of prognostic studies specifically focusing on patients with SPBC. METHODS: This retrospective study used data from Surveillance, Epidemiology and End Results Program. We selected female FPC survivors diagnosed with SPBC from 12 registries (from January 1998 to December 2018) to construct prognostic models. Meanwhile, SPBC patients selected from another five registries (from January 2010 to December 2018) were used as the validation set to test the model's generalization ability. Four machine learning models and a Cox proportional hazards regression (CoxPH) were constructed to predict the overall survival of SPBC patients. Univariate and multivariate Cox regression analyses were used for feature selection. Model performance was assessed using time-dependent area under the ROC curve (t-AUC) and integrated Brier score (iBrier). RESULTS: A total of 10,321 female FPC survivors with SPBC (mean age [SD]: 66.03 [11.17]) were included for model construction. These patients were randomly split into a training set (mean age [SD]: 65.98 [11.15]) and a test set (mean age [SD]: 66.15 [11.23]) with a ratio of 7:3. In validation set, a total of 3,638 SPBC patients (mean age [SD]: 66.28 [10.68]) were finally enrolled. Sixteen features were selected for model construction through univariate and multivariable Cox regression analyses. Among five models, random survival forest model showed excellent performance with a t-AUC of 0.805 (95 %CI: 0.803 - 0.807) and an iBrier of 0.123 (95 %CI: 0.122 - 0.124) on testing set, as well as a t-AUC of 0.803 (95 %CI: 0.801 - 0.807) and an iBrier of 0.098 (95 %CI: 0.096 - 0.103) on validation set. Through feature importance ranking, the top one and other top five key predictive features of the random survival forest model were identified, namely age, stage, regional nodes positive, latency, radiotherapy, and surgery. CONCLUSIONS: The random survival forest model outperformed CoxPH and other machine learning models in predicting the overall survival of patients with SPBC, which was helpful for the monitoring of high-risk populations.

LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3.

BACKGROUND: Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored. AIMS: To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3. METHODS: Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated ß-galactosidase (SA-ß-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification. RESULTS: The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process. CONCLUSIONS: Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.

What determines informal care need among community-dwelling older adults in China? Results from a longitudinal study.

BACKGROUND: With an intensified aging population and an associated upsurge of informal care need in China, there is an ongoing discussion around what factors influence this need among older adults. Most existing studies are cross-sectional and do not focus on older people living in the community. Conversely, this study empirically explores the factors that affect informal care need of Chinese community-dwelling older individuals based on longitudinal data. METHODS: This study constructed panel data using the China Health and Retirement Longitudinal Research Study (CHARLS) from 2011 to 2018 for analysis. Generalized linear mixed models were used to analyze the factors affecting reception of informal care, and linear mixed models were used to analyze the factors affecting informal care sources and intensity. RESULTS: During the follow-up period, 7542, 6386, 5087, and 4052 older adults were included in 2011-2018, respectively. The proportion receiving informal care increased from 19.92 to 30.78%, and the proportion receiving high-intensity care increased from 6.42 to 8.42% during this period. Disability (estimate = 4.27, P < 0.001) and living arrangement (estimate = 0.42, P < 0.001) were the critical determinants of informal care need. The rural older adults reported a greater tendency to receive informal care (estimate = 0.14, P < 0.001). However, financial support from children did not affect informal care need (P > 0.05). CONCLUSIONS: At present, there is a great demand for the manpower and intensity of informal care, and the cost of informal care is on the rise. There are differences in informal care needs of special older groups, such as the oldest-old, living alone and severely disabled. In the future, the region should promote the balance of urban and rural care service resources, rationally tilt economic support resources to rural areas, reduce the inequality of long-term care resources, improve the informal care support system, and provide a strong community guarantee for the local aging of the older adults.

Longitudinal analysis on inflammatory markers and frailty progression: based on the English longitudinal study of aging.

PURPOSE: Frailty is a common health state that is closely linked to adverse health outcomes in aging society. Although many inflammatory biomarkers have been cross-sectionally associated with frailty, knowledge on the longitudinal association is still limited. This study investigated the associations between inflammatory factors in clinical practice and frailty progression over time. METHODS: To investigate the associations of three common inflammatory markers (hypersensitive C-reactive protein [hsCRP], white blood cell [WBC] and fibrinogen) with the progression of frailty. METHODS: Data of 2316 participants (age 67.9 ± 6.1 years) were obtained from the English longitudinal study of aging (wave 4, 6 and 8) over an 8-year follow-up. The frailty index (FI) was calculated from 52 items. Mixed-effects models and Cox proportional hazards (Cox-PH) models were used to analyze the associations of hsCRP, WBC and fibrinogen with frailty progression. Values of inflammatory biomarkers were log-transformed. Age, sex and gross wealth were controlled. RESULTS: Mixed-effects models showed that at a cross-sectional level, higher levels of hsCRP (ß: 0.007, 95% CI 0.004-0.010), WBC (ß: 0.021, 95% CI 0.010-0.032) and fibrinogen (ß: 0.022, 95% CI 0.005-0.038) were associated with greater FI values while no significant time interaction was found. Cox-PH models showed that higher baseline levels of hsCRP (HR: 1.10, 95% CI 1.03-1.17) and WBC (HR: 1.23, 95% CI 1.10-1.37) were linked to a greater risk of developing frailty within 8 years. CONCLUSIONS: We concluded that hsCRP, WBC and fibrinogen can reflect frailty status at a cross-sectional level while only hsCRP and WBC are associated with frailty progression over an 8-year period.

Examining individual and contextual predictors of disability in Chinese older adults: A machine learning approach.

BACKGROUND: There is a large gap of understanding the determinants of disability, especially the contextual characteristics. Therefore, this study aimed to examine the important predictors of disability in Chinese older adults based on the social ecological framework. METHODS: We used the China Health and Retirement Longitudinal Study to examine predictors of disability, defined as self-report of any difficulty for six activity of daily living items. We restricted analytical sample to older adults aged 65 or above (N=1816). We considered 44 predictors, including personal-, behavioral-, interpersonal-, community-, and policy-level characteristics. The built-in variable importance measure (VIM) of random forest and SHapley Additive exPlanations (SHAP) were applied to assess key predictors of disability. A multilevel logit regression was further used to examine the associations of individual and contextual characteristics with disability. RESULTS: The mean age of study sample was 72.62 years old (standard deviation: 5.77). During a 2-year of follow-up, 518 (28.52 %) of them developed into disability. Walking speed, age, and peak expiratory flow were the top important predictors in both VIM and SHAP. Contextual characteristics such as humidity, PM2.5, temperature, normalized difference vegetation index, and landscape also showed promise in predicting disability. Multilevel logit regression showed that people with male gender, arthritis, vision impairment, unable to finish semi tandem, no social activity, lower grip strength, and higher waist circumference, had much higher risk of disability. CONCLUSION: Disability prevention strategies should specifically focus on multilevel factors such as individual and contextual characteristics, although the latter is warranted to be verified in future studies.

Long-term PM2.5 exposure and peak expiratory flow in middle-aged and older people in China: A quasi-experimental study.

China's Clean Air Act (CCAA) has been demonstrated to reduce the public health burden of ambient air pollution. Few studies have assessed the health effects of CCAA on lung function. We aimed to investigate the effects of CCAA and PM2.5 exposures on peak expiratory flow (PEF) in middle-aged and older people in China. Three waves (2011, 2013, and 2015) of the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. We performed a difference-in-difference (DID) model and mixed effect method to assess the association between CCAA, PM2.5, and PEF. To increase the reliability, multiple environmental factors were considered, and spline function was utilized to fit the spatial autocorrelations. We found that the risk of decreased PEF in the policy intervention group was reduced by 46% (95% CI: 23%~62%). The estimate showed a 10µg/m3 increase in PM2.5 would increase the risk of decreased PEF by 10% (95% CI: 3%~18%). The results of the mixed effect model showed a 10 µg/m3 increase in PM2.5 concentration was associated with a 2.23% (95% CI: 1.35%~3.06%) decrease in the PEF. These results contributed to the limited epidemiology evidence on demonstrating the effect of PM2.5 on lung function.

FKBP51 is involved in LPS-induced microglial activation via NF-κB signaling to mediate neuroinflammation.

AIMS: FKBP5 encodes FKBP51, which has been implicated in stress-related psychiatric disorders, and its expression is often increased under chronic stress, contributing to mental dysfunctions. However, the precise role of FKBP51 in brain inflammation remains unclear. This study aimed to investigate the role of FKBP51 in microglia-mediated inflammatory responses in the central nervous system. MAIN METHODS: We employed a peripheral lipopolysaccharide (LPS) administration model to compare microglial activation and cytokine gene expression between Fkbp5 knockout (Fkbp5-KO) and wild-type (WT) male mice. Additionally, we used both BV2 and primary microglia in vitro to examine how Fkbp5 deletion influenced inflammation-related pathways and microglial functions. KEY FINDINGS: This study revealed that systemic LPS-induced microglial activation was significantly attenuated in Fkbp5-KO mice compared with WT mice. In Fkbp5-KO mice following the LPS challenge, there was a notable decrease in the expression of pro-inflammatory genes, coupled with an increase in the anti-inflammatory gene Arg1. Furthermore, Fkbp5 knockdown in BV2 microglial cells led to reduced expression of LPS-induced inflammatory markers, and targeted inhibition of NF-κB activation, while Akt signaling remained unaffected. Similar results were observed in Fkbp5-KO primary microglia, which exhibited not only decreased microglial activation but also a significant reduction in phagocytic activity in response to LPS stimulation. SIGNIFICANCE: This study highlights the critical role of FKBP51 in LPS-induced microglial activation and neuroinflammation. It shows that reducing FKBP51 levels attenuates inflammation through NF-κB signaling in microglia. This suggests that FKBP51 is a potential target for alleviating neuroinflammation-induced stress responses.

Blap-6, a Novel Antifungal Peptide from the Chinese Medicinal Beetle Blaps rhynchopetera against Cryptococcus neoformans.

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus that can cause life-threatening meningitis, particularly in individuals with compromised immune systems. The current standard treatment involves the combination of amphotericin B and azole drugs, but this regimen often leads to inevitable toxicity in patients. Therefore, there is an urgent need to develop new antifungal drugs with improved safety profiles. We screened antimicrobial peptides from the hemolymph transcriptome of Blaps rhynchopetera (B. rhynchopetera), a folk Chinese medicine. We found an antimicrobial peptide named blap-6 that exhibited potent activity against bacteria and fungi. Blap-6 is composed of 17 amino acids (KRCRFRIYRWGFPRRRF), and it has excellent antifungal activity against C. neoformans, with a minimum inhibitory concentration (MIC) of 0.81 µM. Blap-6 exhibits strong antifungal kinetic characteristics. Mechanistic studies revealed that blap-6 exerts its antifungal activity by penetrating and disrupting the integrity of the fungal cell membrane. In addition to its direct antifungal effect, blap-6 showed strong biofilm inhibition and scavenging activity. Notably, the peptide exhibited low hemolytic and cytotoxicity to human cells and may be a potential candidate antimicrobial drug for fungal infection caused by C. neoformans.

Neurosyphilis complicated by anti-γ-aminobutyric acid-B receptor encephalitis: A case report.

BACKGROUND: Syphilis is an infectious disease caused by Treponema pallidum that can invade the central nervous system, causing encephalitis. Few cases of anti-N-methyl-D-aspartate receptor autoimmune encephalitis (AE) secondary to neurosyphilis have been reported. We report a neurosyphilis patient with anti-γ-aminobutyric acid-B receptor (GABABR) AE. CASE SUMMARY: A young man in his 30s who presented with acute epileptic status was admitted to a local hospital. He was diagnosed with neurosyphilis, according to serum and cerebrospinal fluid (CSF) tests for syphilis. After 14 d of antiepileptic treatment and anti-Treponema pallidum therapy with penicillin, epilepsy was controlled but serious cognitive impairment, behavioral, and serious psychiatric symptoms were observed. He was then transferred to our hospital. The Mini-Mental State Examination (MMSE) crude test results showed only 2 points. Cranial magnetic resonance imaging revealed significant cerebral atrophy and multiple fluid-attenuated inversion recovery high signals in the white matter surrounding both lateral ventricles, left amygdala and bilateral thalami. Anti-GABABR antibodies were discovered in CSF (1:3.2) and serum (1:100). The patient was diagnosed with neurosyphilis complicated by anti-GABABR AE, and received methylprednisolone and penicillin. Following treatment, his mental symptoms were alleviated. Cognitive impairment was significantly improved, with a MMSE of 8 points. Serum anti-GABABR antibody titer decreased to 1:32. The patient received methylprednisolone and penicillin after discharge. Three months later, the patient's condition was stable, but the serum anti-GABABR antibody titer was 1:100. CONCLUSION: This patient with neurosyphilis combined with anti-GABABR encephalitis benefited from immunotherapy.

Association of Performance on Multiple Cognitive Domains with Sarcopenia among Middle-Aged and Older Adults.

INTRODUCTION: The relationship between cognitive function and subsequent sarcopenia remains unclear. Therefore, this study aimed to examine the associations of performance on multiple cognitive domains with sarcopenia in the middle-aged and older adults. METHODS: This longitudinal analysis (wave 2011-2013) included 2,934 participants from the CHARLS study. Sarcopenia was defined by the Asian Sarcopenia Working Group 2019 criteria. Cognitive function was measured by the Chinese version of the Mini-Mental State Examination (MMSE). Three interpretable techniques, namely SHapley Additive exPlanations (SHAP) and two built-in methods (coefficients of logistic regression and Gini importance of random forest), were used to assess the relationship between MMSE, its components (orientation, attention, episodic memory, and visuospatial ability) and sarcopenia. In addition, the association of MMSE score and its components with sarcopenia was further validated using stepwise regression. RESULTS: All interpretable methods showed that MMSE score was important predictors of sarcopenia, especially the SHAP (MMSE score ranked top one). For its components, episodic memory, visuospatial ability, and attention showed high predictive value compared with orientation. Stepwise regression analyses showed that MMSE score and its components of episodic memory and visuospatial ability were correlated with sarcopenia, with their odds ratios of 0.93 (95% CI: 0.91-0.96, p < 0.001), 0.87 (95% CI: 0.82-0.93, p < 0.001), and 1.32 (95% CI: 1.05-1.65, p = 0.016), respectively. CONCLUSIONS: Better cognitive function especially episodic memory and visuospatial ability was negatively associated with incident sarcopenia among community middle-aged and older adults.

Blood Profiles of Community-Dwelling People with Sarcopenia: Analysis Based on the China Health and Retirement Longitudinal Study.

INTRODUCTION: Routine blood factors can be economical and easily accessible candidates for sarcopenia screening and monitoring. The associations between sarcopenia and routine blood factors remain unclear. This study aimed to examine sarcopenia and blood factor associations based on a nation-wide cohort in China. METHODS: A total of 1,307 participants and 17 routine blood indices were selected from two waves (year 2011 and year 2015) of the China Health and Retirement Longitudinal Study (CHARLS). The diagnosis of sarcopenia was based on the criteria proposed by the Asian Working Group for Sarcopenia (AWGS 2019). Generalized mixed-effects models were performed for association analyses. A logistic regression (LR) model was conducted to examine the predictive power of identifying significant blood factors for sarcopenia. RESULTS: A higher sarcopenia risk was cross-sectionally associated with elevated blood concentrations of high-sensitivity C-reactive protein (hsCRP) (OR = 1.030, 95% CI [1.007, 1.053]), glycated hemoglobin (HbA1c) (OR = 1.407, 95% CI [1.126, 1.758]) and blood urea nitrogen (BUN) (OR = 1.044, 95% CI [1.002, 1.089]), and a decreased level of glucose (OR = 0.988, 95% CI [0.979, 0.997]). A higher baseline hsCRP value (OR = 1.034, 95% CI [1.029, 1.039]) and a greater over time change in hsCRP within 4 years (OR = 1.034, 95% CI [1.029, 1.039]) were associated with a higher sarcopenia risk. A higher BUN baseline value was related to a decreased sarcopenia risk over time (OR = 0.981, 95% CI [0.976, 0.986]), while a greater over time changes in BUN (OR = 1.034, 95% CI [1.029, 1.040]) and a smaller over time change in glucose (OR = 0.992, 95% CI [0.984, 0.999]) within 4 years were also related to a higher sarcopenia risk. LR based on significant blood factors (i.e., hsCRP, HbA1c, BUN, and glucose), and sarcopenia status in year 2015 yielded an area under the curve of 0.859 (95% CI: 0.836-0.882). CONCLUSION: Routine blood factors involved in inflammation, protein metabolism, and glucose metabolism are significantly associated with sarcopenia. In clinical practice, plasma hsCRP, BUN, blood sugar levels, sex, age, marital status, height, and weight might be helpful for sarcopenia evaluation and monitoring.

Identification of Eukaryotic Translation Initiation Factor 4B as a Novel Candidate Gene for Congenital Hypothyroidism.

CONTEXT: Congenital hypothyroidism (CH) is the most common endocrine disorder in neonates, but its etiology is still poorly understood. OBJECTIVE: We performed whole exome sequencing to identify novel causative gene for CH and functional studies to validate its role in the occurrence of CH. METHODS: Whole exome sequencing in 98 CH patients not harboring known CH candidate genes and bioinformatic analysis were performed. Functional analysis was performed using morpholino, a synthetic short antisense oligonucleotide that contains 25 DNA bases on a methylene morpholine backbone, in zebrafish and CRISPR‒Cas9-mediated gene knockout in mice. RESULTS: Eukaryotic translation initiation factor 4B (EIF4B) was identified as the most promising candidate gene. The EIF4B gene was inherited in an autosomal recessive model, and one patient with thyroid dysgenesis carried EIF4B biallelic variants (p.S430F/p.P328L). In zebrafish, the knockdown of eif4ba/b expression caused thyroid dysgenesis and growth retardation. Thyroid hormone levels were significantly decreased in morphants compared with controls. Thyroxine treatment in morphants partially rescued growth retardation. In mice, the homozygous conceptuses of Eif4b+/- parents did not survive. Eif4b knockout embryos showed severe growth retardation, including thyroid dysgenesis and embryonic lethality before E18.5. CONCLUSION: These experimental data supported a role for EIF4B function in the pathogenesis of the hypothyroid phenotype seen in CH patients. Our work indicated that EIF4B was identified as a novel candidate gene in CH. EIF4B is essential for animal survival, but further studies are needed to validate its role in the pathogenesis of CH.

Associations of polycyclic aromatic hydrocarbons mixtures with cardiovascular diseases mortality and all-cause mortality and the mediation role of phenotypic ageing: A time-to-event analysis.

The associations of polycyclic aromatic hydrocarbons (PAHs) with cardiovascular diseases (CVDs) and all-cause mortality are unclear, especially the joint effects of PAHs exposure. Meanwhile, no studies have examined the effect of phenotypic ageing on the relationship between PAHs and mortality. Therefore, this study aimed to investigate the independent and joint associations between PAHs and CVDs, all-cause mortality, and assess whether phenotypic age acceleration (PhenoAgeAccel) mediate this relationship. We retrospectively collected data of 11,983 adults from the National Health and Nutrition Examination Survey database. Firstly, Cox proportional hazards regression and restricted cubic splines were applied to evaluate the independent association of single PAH on mortality. Further, time-dependent Probit extension of Bayesian Kernel Machine Regression and quantile-based g-computation models were conducted to test the joint effect of PAHs on mortality. Then, difference method was used to calculate the mediation proportion of PhenoAgeAccel in the association between PAHs and mortality. Our results revealed that joint exposure to PAHs showed positive association with CVDs and all-cause mortality. By controlling potential confounders, 1-Hydroxynapthalene (1-NAP) (HR = 1.24, P = 0.035) and 2-Hydroxyfluorene (2-FLU) (HR = 1.25, P < 0.001) showed positive association with CVDs mortality, and they were the top 2 predictors (weight: 0.82 for 1-NAP, 0.14 for 2-FLU) of CVDs mortality. 1-NAP (HR = 1.15, P < 0.001) and 2-FLU (HR = 1.13, P < 0.001) also showed positive association with all-cause mortality, and they were also the top 2 predictors of all-cause mortality (weight: 0.66 for 1-NAP, 0.34 for 2-FLU). PhenoAgeAccel mediated the relationship between 1-NAP, 2-FLU and CVDs, all-cause mortality, with a mediation proportion of 10.00 % to 24.90 % (P < 0.05). Specifically, the components of PhenoAgeAccel including C-reactive protein, lymphocyte percent, white blood cell count, red cell distribution width, and mean cell volume were the main contributors of mediation effects. Our study highlights the hazards of joint exposure of PAHs and the importance of phenotypic ageing on the relationship between PAHs and mortality.

Deficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion.

The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

Trajectories of cognitive decline in different domains prior to AD onset in persons with mild cognitive impairment.

OBJECTIVES: To explore the trajectories and the change-points of global and five domain-specific cognitive functions before the onset of Alzheimer's disease (AD). METHODS: Data was retrieved from the Alzheimer's Disease Neuroimaging Initiative with follow-up from 2005 to 2022. Participants with mild cognitive impairment (MCI) at baseline and those who progressed to AD during follow-up were included. The time of AD onset was defined as the visit time when participant was first diagnosed as AD during follow-up. Global and five domain-specific cognitive functions (immediate memory, visuospatial ability, language, processing speed and executive function) were assessed by Mini-Mental State Examination, Immediate recalling trials of Rey Auditory Verbal Learning Test, Clock Drawing Test, Animal Fluency Test, Part A and B of Trail Making Test, respectively. Their trajectories and change-points before AD onset were explored by generalized additive mixed models and piecewise linear regression models, respectively. RESULTS: 349 participants were diagnosed as MCI at baseline and converted to AD during follow-up, who were included in this study. They had been visited on an average of 4.6 times (SD = 2.1, range = 2.0-13.0), with a total of 1593 visits. Their mean baseline age and AD onset age were 74.4 (SD = 6.4, range = 60.0-88.4) and 77.0 (SD = 6.8, range = 60.5-94.7) years, respectively. Baseline age and educational year were significantly associated with global cognitive, immediate memory, language and executive function. Men presented better global cognitive function (ß = 0.54, p < 0.05) but poorer immediate memory (ß = -1.72, p < 0.05) than women. Immediate memory and visuospatial ability showed the earliest change-points at 4 years before the onset of AD (Note as T-4years), followed by language (T-3.5years), executive function (T-2.5 years), processing speed (T-2.0 years), and finally the global cognitive function (T-1.5years). CONCLUSIONS: The trajectories of the six neuropsychological scores were non-linear and showed deterioration in functions over time. Immediate memory and visuospatial ability showed the earliest change-points prior to AD onset.

Interpretable prediction models for disability in older adults with hypertension: the Chinese Longitudinal Healthy Longevity and Happy Family Study.

BACKGROUND: Older adults with hypertension have a high risk of disability, while an accurate risk prediction model is still lacking. This study aimed to construct interpretable disability prediction models for older Chinese with hypertension based on multiple time intervals. METHODS: Data were collected from the Chinese Longitudinal Healthy Longevity and Happy Family Study for 2008-2018. A total of 1602, 1108, and 537 older adults were included for the periods of 2008-2012, 2008-2014, and 2008-2018, respectively. Disability was measured by basic activities of daily living. Least absolute shrinkage and selection operator (LASSO) was applied for feature selection. Five machine learning algorithms combined with LASSO set and full-variable set were used to predict 4-, 6-, and 10-year disability risk, respectively. Area under the receiver operating characteristic curve was used as the main metric for selection of the optimal model. SHapley Additive exPlanations (SHAP) was used to explore important predictors of the optimal model. RESULTS: Random forest in full-variable set and XGBoost in LASSO set were the optimal models for 4-year prediction. Support vector machine was the optimal model for 6-year prediction on both sets. For 10-year prediction, deep neural network in full variable set and logistic regression in LASSO set were optimal models. Age ranked the most important predictor. Marital status, body mass index, score of Mini-Mental State Examination, and psychological well-being score were also important predictors. CONCLUSIONS: Machine learning shows promise in screening out older adults at high risk of disability. Disability prevention strategies should specifically focus on older patients with unfortunate marriage, high BMI, and poor cognitive and psychological conditions.