Proton pump inhibitors use is associated with a higher prevalence of kidney stones: NHANES 2007-2018.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used throughout the world as an effective gastrointestinal drug. Nevertheless, according to the existing literature, PPIs can reduce the excretion of magnesium, calcium and other components in urine, which may promote the formation of kidney stones. We used the National Health and Nutrition Examination Survey (NHANES) database to further investigate the association between the use of PPIs and the prevalence of kidney stones. METHODS: We performed a cross-sectional analysis using data from 2007 to 2018 NHANES. PPIs use information of 29,910 participants was obtained by using prescription medications in the preceding month, and kidney stones were presented by a standard questionnaire. Multiple regression analysis and stratified analysis were used to estimate the association between PPIs use and kidney stones after an adjustment for potential confounders. RESULTS: The multiple logistic regression indicated that the PPIs exposure group (P1) had a significantly higher risk of nephrolithiasis than the PPIs non-exposure group (P0) in Model 3 (OR 1.24, 95% CI 1.10-1.39, P < 0.001). The stratified analyses indicated there were significant statistical differences between PPIs use and kidney stones among females (OR 1.36, 95% CI 1.15-1.62, P < 0.001), non-Hispanic whites (OR 1.27, 95% CI 1.09-1.48, P = 0.002), individuals with an education level than 11th grade (OR 1.41, 95% CI 1.13-1.76, P = 0.002) and individuals with an annual family income of $0 to $19,999 (OR 1.32, 95% CI 1.06-1.65, P = 0.014) and $20,000 to $44,999 (OR 1.25, 95% CI 1.02-1.54, P = 0.033) in Model 3. CONCLUSIONS: Our study revealed that PPIs use is associated with a higher prevalence of kidney stones for the US population, primarily among women, non-Hispanic whites, individuals with low education levels and individuals with low household income levels. Further studies are required to confirm our findings.

14-3-3ζ: A suppressor of inflammatory arthritis.

Inflammatory arthritis (IA) is a common disease that affects millions of individuals worldwide. Proinflammatory events during IA pathogenesis are well studied; however, loss of protective immunity remains underexplored. Earlier, we reported that 14-3-3zeta (ζ) has a role in T-cell polarization and interleukin (IL)-17A signal transduction. Here, we demonstrate that 14-3-3ζ knockout (KO) rats develop early-onset severe arthritis in two independent models of IA, pristane-induced arthritis and collagen-induced arthritis. Arthritic 14-3-3ζ KO animals showed an increase in bone loss and immune cell infiltration in synovial joints. Induction of arthritis coincided with the loss of anti-14-3-3ζ antibodies; however, rescue experiments to supplement the 14-3-3ζ antibody by passive immunization did not suppress arthritis. Instead, 14-3-3ζ immunization during the presymptomatic phase resulted in significant suppression of arthritis in both wild-type and 14-3-3ζ KO animals. Mechanistically, 14-3-3ζ KO rats exhibited elevated inflammatory gene signatures at the messenger RNA and protein levels, particularly for IL-1ß. Furthermore, the immunization with recombinant 14-3-3ζ protein suppressed IL-1ß levels, significantly increased anti-14-3-3ζ antibody levels and collagen production, and preserved bone quality. The 14-3-3ζ protein increased collagen expression in primary rat mesenchymal cells. Together, our findings indicate that 14-3-3ζ causes immune suppression and extracellular remodeling, which lead to a previously unrecognized IA-suppressive function.

OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall's plaque formation.

BACKGROUND: Randall's plaques (RP) are identified as anchored sites for kidney calcium oxalate stones, but the mechanism remains unclear. Given the importance of osteogenic-like cells in RP formation and OCT4 in reprogramming differentiated cells to osteoblasts, the current study explored the potential role of OCT4 in RP formation. METHODS: OCT4 and biomineralization were evaluated in RP, and immunofluorescence co-staining was performed to identify these cells with alteration of OCT4 and osteogenic markers. Based on the analysis of tissue, we further investigated the mechanism of OCT4 in regulating osteogenic-like differentiation of primary human renal interstitial fibroblasts (hRIFs) in vitro and vivo. RESULTS: We identified the upregulated OCT4 in RP, with a positive correlation to osteogenic markers. Interestingly, fibroblast marker Vimentin was partially co-localized with upregulated OCT4 and osteogenic markers in RP. Further investigations revealed that OCT4 significantly enhanced the osteogenic-like phenotype of hRIFs in vitro and in vivo. Mechanically, OCT4 directly bound to BMP2 promoter and facilitated its CpG island demethylation to transcriptionally promote BMP2 expression. Furthermore, combination of RIP and RNA profiling uncovered that lncRNA OLMALINC physically interacted with OCT4 to promote its stabilization via disrupting the ubiquitination. Additionally, OLMALINC was upregulated in fibroblasts in RP visualized by FISH, and a positive correlation was revealed between OLMALINC and OCT4 in RP. CONCLUSIONS: The upregulation of OCT4 in hRIFs was a pathological feature of RP formation, and OLMALINC/OCT4/BMP2 axis facilitated hRIFs to acquire osteogenic-like phenotype under osteogenic conditions, through which the pathway might participate in RP formation. Our findings opened up a new avenue to better understand RP formation in which osteogenic-like process was partially triggered by lncRNAs and pluripotency maintenance related genes.

Screen time and health issues in Chinese school-aged children and adolescents: a systematic review and meta-analysis.

BACKGROUNDS: Many literature reviews summarized relationships between screen time and child health, but they only included a few studies conducted in Chinese children and adolescents. The potential influence of screen time may vary by social context. The current systematic review and meta-analysis aimed to evaluate relationships between screen time and health issues among Chinese school-aged children and adolescents. METHODS: Peer-reviewed articles written in Chinese and English were retrieved from CNKI, Wanfang, PubMed, Embase, and Web of Science from inception to June 2020. The Downs & Black checklist was applied to assess study quality. Meta analyses used random effect models and mixed effects model to calculate pooled adjusted odds ratios and 95% confidence intervals. Heterogeneity, sensitivity, and publication bias were assessed using Q and I2 statistics, "one-study removed" analysis, the funnel plot, trim and fill analysis, and classical fail-safe N, respectively. RESULTS: In total, we identified 252 articles reporting 268 studies with unique samples. These studies investigated relationships between screen time and health issues of adiposity, myopia, psycho-behavioral problems, poor academic performance, cardiometabolic disease risks, sleep disorder, poor physical fitness, musculoskeletal injury, sub-health, and miscellaneous issues of height and pubertal growth, injury, sick leave, and respiratory symptoms. Proportions of studies reporting positive relationships with screen time were lowest in adiposity (50.6%) and higher in myopia (59.2%) and psycho-behavioral problems (81.8%). Other health issues were examined in 10 or less studies, all of which had more than half showing positive relationships. The pooled odds ratio from 19 studies comparing health risks with the screen time cutoff of 2 hours per day was 1.40 (95% CI: 1.31 to 1.50, I2 = 85.9%). The pooled effect size was 1.29 (95% CI: 1.20 to 1.39) after trimming 7 studies for publication bias adjustments. CONCLUSIONS: Findings exclusively generated from Chinese school-aged children and adolescents resonate those mainly from western countries. Evidence suggests that higher levels of screen time are related with greater risks of various health issues, although the relationships appear to be weak and intertwined with other confounding factors. Future studies need to investigate health-specific dose effects and mechanisms of screen time.

Influence of paternal general parenting on Latino early adolescents' energy balance-related behaviours and interactions with behaviour-specific parenting practices.

OBJECTIVE: To investigate the influence of general parenting dimensions on adolescents' energy balance-related behaviours (EBRB) and its interactions with behaviour-specific parenting practices based on Darling and Steinberg's contextual model of parenting style. DESIGN: Multiple linear regression analyses and the Hayes PROCESS procedure to analyse self-reported cross-sectional survey data. SETTING: In-person survey. PARTICIPANTS: Latino early adolescents and their fathers (n 225 dyads) recruited using convenience sampling from metropolitan areas of north-central USA. RESULTS: Both paternal parenting dimensions of warmth and autonomy granting were positively associated with adolescents' fruit intake, vegetable intake and physical activity. Coercive control was positively associated with adolescents' sugary drink intake and sweets/salty snack intake. These associations were predominantly mediated by the parenting practices of setting expectations/allowances, role modelling, and managing availability and accessibility for corresponding EBRB. After adjusting for parenting practices, paternal warmth was inversely associated with adolescents' screen time, paternal autonomy was positively associated with sugary drink intake, and both paternal warmth and autonomy granting were positively associated with adolescents' fast food intake. In addition, positive associations between fathers' parenting practices and adolescents' sugary drink intake were significantly stronger among those who perceived high v. low levels of paternal warmth and autonomy granting. CONCLUSIONS: Paternal warmth and autonomy granting showed mixed effects on adolescents' EBRB, and coercive control showed undesirable relationships with adolescents' dietary intake via interactions with behaviour-specific parenting practices. Lifestyle intervention programmes for Latino adolescents need to consider incorporating paternal parenting education components.

Differences in reporting food insecurity and factors associated with differences among Latino fathers and mothers.

BACKGROUND: Food security status has been assessed as a representative score for households; however, different members in the same household may perceive and report food insecurity differently. A high prevalence of food insecurity has been reported among Latino households, therefore understanding differences in reporting food insecurity by Latino father-mother dyads may improve accuracy of assessment and plans to address food insecurity. This study aimed to 1) determine demographic characteristics and/or food-related factors associated with perceptions of food security status among Latino father-mother dyads, and 2) identify factors associated with discordance in perceptions of food insecurity between dyads. METHODS: Baseline data were used from a community-based, youth obesity prevention program among Latino families (n = 106 father-mother dyads). Food security was assessed with a 2-item food insecurity screen. Logistic regression models were used to evaluate associations between reporting food security status and predictor variables for fathers, mothers, and dyad-discordant responses. RESULTS: Food insecurity was reported by 39% of fathers and 55% of mothers. Adjusted odds of reporting food insecurity were significantly higher for fathers perceiving their neighborhood was unsafe vs. safe (OR: 3.7, p < 0.05) and reporting lower vs. higher household income (OR: 3.2, p < 0.05). Adjusted odds of reporting food insecurity were significantly higher for mothers perceiving their neighborhood was unsafe vs. safe (OR: 4.1, p < 0.01) and reporting lower vs. higher home availability of fruit and vegetable (OR: 5.5, p < 0.01). Dyad discordance in reporting food security status occurred in 24% of the dyads. Adjusted odds of dyad discordant reports of food insecurity status were significantly higher for dyads reporting discordant responses regarding previous nutrition education (OR: 3.4, p < 0.05) and higher home fruit and vegetable accessibility (OR: 3.1, p < 0.05) compared to dyads reporting concordant responses. Among the 28 dyads who reported discordant nutrition education participation, 21 reported that fathers had never participated but mothers had participated more than once. CONCLUSIONS: Differential factors were associated with reporting food security among Latino father-mother dyads. Nutrition education for fathers that improves awareness of home food supplies and a better understanding of how food accessibility influences maternal perceptions may improve dyad discordance in reporting household food security.

Eating green for health or social benefits? Interactions of attitudes with self-identity on the consumption of vegetarian meals among U.S. and Chinese college students.

Encouraging greater consumption of vegetarian foods could be a strategy to improve plant-based food intake among non-vegetarians. Prior research on vegetarianism has focused mostly on people's motivations to be a vegetarian. However, the factors that motivate non-vegetarians to consume vegetarian meals remain largely unknown. The current research tested associations between attitudes, self-identity, and vegetarian meal consumption among 746 U.S. college students and 484 Chinese college students. Two types of attitudes were assessed: attitudes towards vegetarian food (ATF), which represents the personal benefits (including healthiness, tastiness, and enjoyableness) and attitudes towards people who are vegetarians (ATP), which represents the social benefits (perceived as being environmentally friendly, nice, and good-looking). Results showed that U.S. college students were more likely to be either vegetarians or non-vegetarians, while more Chinese college students tended to report being semi-vegetarians. In both samples, ATF and ATP were positively associated with self-identity and vegetarian meal consumption. Moderation analyses suggested that associations between attitudes and consumption were significant only among people who do not hold a definite self-identity as a vegetarian. In addition, ATP was significantly associated with vegetarian meal consumption among U.S. non- and semi-vegetarians alike, but among Chinese non-vegetarians only. These findings suggest that self-identity and cross-cultural differences are important to consider in promoting consumption of vegetarian meals through improving the public's attitudes towards vegetarian food and vegetarians.

Vertical selection for nuclear and mitochondrial genomes shapes gut microbiota and modifies risks for complex diseases.

Here we postulate that the heritability of complex disease traits previously ascribed solely to the inheritance of the nuclear and mitochondrial genomes is broadened to encompass a third component of the holobiome, the microbiome. To test this, we expanded on the selectively bred low capacity runner/high capacity runner (LCR/HCR) rat exercise model system into four distinct rat holobiont model frameworks including matched and mismatched host nuclear and mitochondrial genomes. Vertical selection of varying nuclear and mitochondrial genomes resulted in differential acquisition of the microbiome within each of these holobiont models. Polygenic disease risk of these novel models were assessed and subsequently correlated with patterns of acquisition and contributions of their microbiomes in controlled laboratory settings. Nuclear-mitochondrial-microbiotal interactions were not for exercise as a reporter of health, but significantly noted for increased adiposity, increased blood pressure, compromised cardiac function, and loss of long-term memory as reporters of disease susceptibility. These findings provide evidence for coselection of the microbiome with nuclear and mitochondrial genomes as an important feature impacting the heritability of complex diseases.

Associations of outdoor activity and screen time with adiposity: findings from rural Chinese adolescents with relatively low adiposity risks.

BACKGROUND: Whether and to what extent outdoor activity and screen time are relevant to adiposity among rural adolescents remain largely unknown as most of relevant evidence was generated from high-income countries and urban areas. This study aimed to investigate associations of outdoor activity and screen time with adiposity among early adolescents living in rural southwest China. METHODS: In this cross-sectional study, seventh graders (n = 2264) were recruited from 10 middle schools of a rural county. Overweight and obesity was assessed using adolescents' body mass index and waist circumference. Adolescents' outdoor activity and screen time were measured using self-reported daily time spending on outdoor activity, watching TV, playing video games, and computers on weekdays and weekends, respectively. RESULTS: The prevalence of overweight/obesity and high waist circumferences were 8.0 and 4.9% and were higher among those from one-child families and with parents having high school or higher education and whose fathers were not farmers. Adolescents who did not have ≥1 h outdoor activity on weekdays were more likely to be overweight/obese (OR: 1.86, 95% CI: 1.30, 2.66) and have high waist circumferences (OR: 2.22, 95%CI: 1.39, 3.57). Adolescents who had > 2 h screen time on weekends were more likely to have high waist circumferences (OR: 2.08, 95% CI: 1.14, 3.80). Lack of outdoor activity and excessive screen time also showed synergistic effects on overweight/obesity (OR: 1.93. 95% CI: 1.15, 3.24) and high waist circumferences (OR: 3.02, 95% CI: 1.54, 5.94). CONCLUSIONS: Lack of outdoor activity and excessive screen time were relevant to adiposity among rural Chinese adolescents even when the obesity prevalence was low. Efforts to promote active lifestyles may help prevent rural adolescents from losing their advantage in the era of the global obesity epidemic.

Latino adolescent-father discrepancies in reporting activity parenting practices and associations with adolescents' physical activity and screen time.

BACKGROUND: Latino fathers may play important roles in adolescents' physical activity and screen time. However, informant discrepancies regarding paternal activity parenting practices may challenge studies supporting evidence-based applications. This study examined Latino adolescent-father discrepancies in reporting paternal activity parenting practices, types of discrepancies by participant characteristics, and associations between discrepancy types and adolescents' physical activity and screen time. METHODS: The sample for this cross-sectional study included Latino early adolescents and their fathers (n = 138 dyads) from baseline data collected for a family-centered, healthy lifestyle intervention in a metropolitan area. In parallel measures, Latino adolescents and fathers reported paternal activity parenting practices related to expectation or allowance, behavioral modeling, and providing opportunities for physical activity or screen time. Level of agreement and discrepancies were examined using the percentage of agreement, weighted kappa statistics, Pearson correlation coefficients, and paired-sample t-tests. Undesirable discrepancy types included adolescents reporting lower scores for paternal physical activity parenting practices or higher scores for paternal screen time parenting practices than fathers. Participants' sociodemographic characteristics and weight status were compared by discrepancy type using between-group t-tests or Chi-square tests. Associations between discrepancy type and adolescents' physical activity and screen time were examined using multivariate regression analyses. RESULTS: The study sample was low-income with a high prevalence of overweight and obesity. Adolescent and paternal reports of activity parenting practices had poor agreement (percentages of agreement: 22.2-34.3%, weighted kappa statistics: < 0.2, and correlation coefficients: 0.06-0.25). An undesirable discrepancy type for certain parenting practices was more likely to be observed among fathers without full-time employment, girls, older adolescents, and adolescents and fathers within overweight or obese BMI categories. Discrepancies in paternal expectation regarding physical activity and allowance of screen time had adverse associations with adolescents' physical activity (ß = - 0.18, p = 0.008) and screen time (ß = 0.51, p <  0.001). CONCLUSION AND IMPLICATIONS: Discrepancies in reporting activity parenting practices were evident between Latino adolescents and their fathers, especially among certain sociodemographic and weight status groups. Adolescents' perceptions on paternal parenting practices tended to be better indicators of their activity levels than fathers' reports.

Influence of parenting styles in the context of adolescents' energy balance-related behaviors: Findings from the FLASHE study.

Lack of compliance with dietary and activity guidelines contributes to the high prevalence of overweight and obesity among adolescents. Intervention programs need enhanced strategies to promote healthy lifestyle behaviors. Although adolescents have more autonomy than younger children, parents still play an important role in influencing adolescents' energy balance-related behaviors (EBRBs). Parenting style may have an overarching effect on adolescents' EBRBs. The purpose of this study was to inform improvements to the design of intervention programs for the parents of adolescents by examining influences of parenting styles on adolescents' EBRBs. The current study used data from the Family Life, Activity, Sun, Health, and Eating (FLASHE) Study, which was an online survey on factors affecting adolescents' EBRBs among a national sample of adolescent-parent dyads (n = 1521; aged 12-17). Adolescents reported parenting dimensions of responsiveness and demandingness as well as parenting practices related to fruit and vegetable intake, junk food and sugary drink intake, physical activity, and screen time. They also reported food intake frequencies and time spent in physical activity and sedentary behaviors. Moderation and mediation analyses found that the potential protective effect of junk food/sugary drink- and physical activity-related parenting practices were significant among non-authoritarian parents. In addition, parenting styles had significant associations with adolescents' EBRBs after adjusting for the mediation effects of corresponding parenting practices. These findings suggest that further research and intervention programs need to consider the potential influence of parenting styles on adolescents' EBRBs. Parenting skill education to improve the connection between parents and adolescents may enhance the effectiveness of healthy lifestyle interventions.

Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B.

UNLABELLED: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71) ≤ Pmeta ≤ 9.92 × 10(-7) ). CONCLUSION: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.

Evidence for a link between gut microbiota and hypertension in the Dahl rat.

The gut microbiota plays a critical role in maintaining physiological homeostasis. This study was designed to evaluate whether gut microbial composition affects hypertension. 16S rRNA genes obtained from cecal samples of Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats were sequenced. Bacteria of the phylum Bacteroidetes were higher in the S rats compared with the R rats. Furthermore, the family S24-7 of the phylum Bacteroidetes and the family Veillonellaceae of the phylum Firmicutes were higher in the S rats compared with the R rats. Analyses of the various phylogenetic groups of cecal microbiota revealed significant differences between S and R rats. Both strains were maintained on a high-salt diet, administered antibiotics for ablation of microbiota, transplanted with S or R rat cecal contents, and monitored for blood pressure (BP). Systolic BP of the R rats remained unaltered irrespective of S or R rat cecal transplantation. Surprisingly, compared with the S rats given S rat cecal content, systolic BP of the S rats given a single bolus of cecal content from R rats was consistently and significantly elevated during the rest of their life, and they had a shorter lifespan. A lower level of fecal bacteria of the family Veillonellaceae and increased plasma acetate and heptanoate were features associated with the increased BP observed in the S rats given R rat microbiota compared with the S rats given S rat microbiota. These data demonstrate a link between microbial content and BP regulation and, because the S and R rats differ in their genomic composition, provide the necessary basis to further examine the relationship between the host genome and microbiome in the context of BP regulation in the Dahl rats.

Serum quantitative proteomic analysis reveals potential zinc-associated biomarkers for nonbacterial prostatitis.

BACKGROUND: Prostatitis is one of the most common urological problems afflicting adult men. The etiology and pathogenesis of nonbacterial prostatitis, which accounts for 90-95% of cases, is largely unknown. As serum proteins often indicate the overall pathologic status of patients, we hypothesized that protein biomarkers of prostatitis might be identified by comparing the serum proteomes of patients with and without nonbacterial prostatitis. METHODS: All untreated samples were collected from subjects attending the Fangchenggang Area Male Health and Examination Survey (FAMHES). We profiled pooled serum samples from four carefully selected groups of patients (n = 10/group) representing the various categories of nonbacterial prostatitis (IIIa, IIIb, and IV) and matched healthy controls using a mass spectrometry-based 4-plex iTRAQ proteomic approach. More than 160 samples were validated by ELISA. RESULTS: Overall, 69 proteins were identified. Among them, 42, 52, and 37 proteins were identified with differential expression in Category IIIa, IIIb, and IV prostatitis, respectively. The 19 common proteins were related to immunity and defense, ion binding, transport, and proteolysis. Two zinc-binding proteins, superoxide dismutase 3 (SOD3), and carbonic anhydrase I (CA1), were significantly higher in all types of prostatitis than in the control. A receiver operating characteristic curve estimated sensitivities of 50.4 and 68.1% and specificities of 92.1 and 83.8% for CA1 and SOD3, respectively, in detecting nonbacterial prostatitis. The serum CA1 concentration was inversely correlated to the zinc concentration in expressed-prostatic secretions. CONCLUSIONS: Our findings suggest that SOD3 and CA1 are potential diagnostic markers of nonbacterial prostatitis, although further large-scale studies are required. The molecular profiles of nonbacterial prostatitis pathogenesis may lay a foundation for discovery of new therapies.

The impact of anxiety on the risk of kidney stone disease: Insights into eGFR-mediated effects.

BACKGROUND: Previous studies have linked kidney stone disease (KSD) with depression, but there are no reports on the relationship between anxiety and KSD, and the mechanism underlying the potential relationship remains unclear. METHODS: Associations of anxiety and incident KSD were assessed in the National Health and Nutrition Examination Survey (NHENES) using multivariate logistic regression. Two-sample bidirectional Mendelian randomization studies and a two-step two-sample MR was used to estimate the mediating factors that influence KSD risk. RESULTS: Examinations of NHANES data revealed that a rise in the frequency and intensity of anxiety were independently associated with incident KSD. In MR analysis, anxiety (uk-a-51 and uk-b-6519) were from the UK Biobank, with sample sizes of 328,717 and 450,765 respectively. KSD data were from the FinnGen, including 8597 cases and 333,128 controls. In the IVW analysis, genetically predicted anxieties (ukb-a-51 and ukb-b-6519) were found to be causally associated with a higher risk of KSD, with odds ratios of 6.18 (95 % CI 2.54-15.04) and 3.44 (95 % CI 1.67-7.08), respectively. There were no reverse causal effects. Further mediation analysis indicated that anxiety increases the risk of KSD by raising eGFR, through which 11.8 % of the effect of anxiety on KSD risk was mediated. LIMITATIONS: The research was confined to individuals of European heritage, and there could be specific genetic variances among diverse ethnicities. CONCLUSION: The current study suggests anxiety as an independent causal risk factor for KSD and unveils a new pathogenic mechanism, showing that anxiety raises eGFR, thereby increasing the risk of KSD.

siRNA-mediated reduction of a circulating protein in swine using lipid nanoparticles.

Genetic manipulation of animal models is a fundamental research tool in biology and medicine but is challenging in large animals. In rodents, models can be readily developed by knocking out genes in embryonic stem cells or by knocking down genes through in vivo delivery of nucleic acids. Swine are a preferred animal model for studying the cardiovascular and immune systems, but there are limited strategies for genetic manipulation. Lipid nanoparticles (LNPs) efficiently deliver small interfering RNA (siRNA) to knock down circulating proteins, but swine are sensitive to LNP-induced complement activation-related pseudoallergy (CARPA). We hypothesized that appropriately administering optimized siRNA-LNPs could knock down circulating levels of plasminogen, a blood protein synthesized in the liver. siRNA-LNPs against plasminogen (siPLG) reduced plasma plasminogen protein and hepatic plasminogen mRNA levels to below 5% of baseline values. Functional assays showed that reducing plasminogen levels modulated systemic blood coagulation. Clinical signs of CARPA were not observed, and occasional mild and transient hepatotoxicity was present in siPLG-treated animals at 5 h post-infusion, which returned to baseline by 7 days. These findings advance siRNA-LNPs in swine models, enabling genetic engineering of blood and hepatic proteins, which can likely expand to proteins in other tissues in the future.

Osteogenic-Like Microenvironment of Renal Interstitium Induced by Osteomodulin Contributes to Randall's Plaque Formation.

Calcium oxalate (CaOx) kidney stones are common and recurrent, lacking pharmacological prevention. Randall's plaques (RPs), calcium deposits in renal papillae, serve as niduses for some CaOx stones. This study explores the role of osteogenic-like cells in RP formation resembling ossification. CaP crystals deposit around renal tubules, interstitium, and blood vessels in RP tissues. Human renal interstitial fibroblasts (hRIFs) exhibit the highest osteogenic-like differentiation potential compared to chloride voltage-gated channel Ka positive tubular epithelial cells, aquaporin 2 positive collecting duct cells, and vascular endothelial cells, echoing the upregulated osteogenic markers primarily in hRIFs within RP tissues. Utilizing RNA-seq, osteomodulin (OMD) is found to be upregulated in hRIFs within RP tissues and hRIFs following osteogenic induction. Furthermore, OMD colocalizes with CaP crystals and calcium vesicles within RP tissues. OMD can enhance osteogenic-like differentiation of hRIFs in vitro and in vivo. Additionally, crystal deposits are attenuated in mice with Omd deletion in renal interstitial fibroblasts following CaOx nephrocalcinosis induction. Mechanically, a positive feedback loop of OMD/BMP2/BMPR1A/RUNX2/OMD drives hRIFs to adopt osteogenic-like fates, by which OMD induces osteogenic-like microenvironment of renal interstitium to participate in RP formation. We identify OMD upregulation as a pathological feature of RP, paving the way for preventing CaOx stones.

Protein is expressed in all major organs after intravenous infusion of mRNA-lipid nanoparticles in swine.

In vivo delivery of mRNA is promising for the study of gene expression and the treatment of diseases. Lipid nanoparticles (LNPs) enable efficient delivery of mRNA constructs, but protein expression has been assumed to be limited to the liver. With specialized LNPs, delivery to extrahepatic tissue occurs in small animal models; however, it is unclear if global delivery of mRNA to all major organs is possible in humans because delivery may be affected by differences in innate immune response and relative organ size. Furthermore, limited studies with LNPs have been performed in large animal models, such as swine, due to their sensitivity to complement activation-related pseudoallergy (CARPA). In this study, we found that exogenous protein expression occurred in all major organs when swine were injected intravenously with a relatively low dose of mRNA encapsulated in a clinically relevant LNP formulation. Exogenous protein was detected in the liver, spleen, lung, heart, uterus, colon, stomach, kidney, small intestine, and brain of the swine without inducing CARPA. Furthermore, protein expression was detected in the bone marrow, including megakaryocytes, hematopoietic stem cells, and granulocytes, and in circulating white blood cells and platelets. These results show that nearly all major organs contain exogenous protein expression and are viable targets for mRNA therapies.

Endogenous sex hormones and C-reactive protein in healthy Chinese men.

OBJECTIVE: To examine the association of endogenous sex hormones and sex hormone-binding globulin (SHBG) with C-reactive protein (CRP) in Chinese men. DESIGN AND PARTICIPANTS: The study population comprised 1989 men at baseline recruitment of a population-based cohort in China. Participant information on risk factors was collected by a face-to-face interview and clinical examination. All subjects in the study were without taking any kind of medication for anti-inflammation purpose or treatment of hypogonadism and with CRP value less than 10 mg/l. Data were analysed using linear regression analyses. RESULTS: Higher levels of total testosterone (TT, ß = -0.114, 95%CI, -0.162 to -0.065), free testosterone (ß = -0.059, 95%CI, -0.106 to -0.012) and SHBG (ß = -0.116, 95%CI, -0.169 to -0.063) were statistically significantly related to lower levels of CRP, after adjustment for age, waist circumference (WC), triglycerides, high-density lipoprotein cholesterol, fasting glucose, insulin, smoking status, hypertension, diabetes and family history of hypertension or diabetes. In the subgroup of men with body mass index ≥ 27.5 kg/m(2) or with metabolic syndrome, findings for TT and SHBG were more pronounced, whereas the associations of TT with CRP were attenuated and nonstatistically significant among subjects with WC ≥ 90 cm or with insulin resistance. No associations were observed between estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and CRP. CONCLUSIONS: We have confirmed the association of androgens with reduced inflammation as measured by CRP in Chinese men. This is independent of conventional cardiovascular risk factors and is explained in part by markers of central obesity and insulin resistance, rather than metabolic syndrome.

Both total testosterone and sex hormone-binding globulin are independent risk factors for metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China.

BACKGROUND: Metabolic syndrome is often beneficial from testosterone replacement therapy. Although testosterone and sex hormone-binding globulin (SHBG) are inversely associated with the risk of metabolic syndrome, it is controversial whether the association between testosterone and metabolic syndrome is independent of SHBG. METHODS: Testosterone, SHBG and metabolic syndrome were evaluated in 2361 men aged 20-73 years, who participated in the population-based Fangchenggang Area Male Health and Examination Survey. Total testosterone, SHBG and other biochemical profiles were measured. Free testosterone and bioavailable testosterone were calculated on the basis of Vermeulen's formula. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria for Asian population. The independent associations with metabolic syndrome were determined by multivariate logistic regression analysis. RESULTS: Men with metabolic syndrome had a lower level of total testosterone, bioavailable testosterone, free testosterone, or SHBG than those without metabolic syndrome (all p < 0.001). Both total testosterone and SHBG were inversely correlated with body mass index or homeostasis model assessment of insulin resistance (all age-adjusted p < 0.001). Men within the lowest quartile of total testosterone [odds ratio (OR) = 4.86, 95% confidence interval (CI) = 2.72-8.68], bioavailable testosterone (OR = 3.04, 95% CI = 1.81-5.10), free testosterone (OR = 3.08, 95% CI = 1.81-5.27) or SHBG (OR = 4.28, 95% CI = 2.52-7.27) had a risk of metabolic syndrome after adjusting for age, smoking, homeostasis model assessment of insulin resistance and body mass index. Total testosterone remained inversely associated with metabolic syndrome after further adjusting for SHBG (OR = 0.95, 95% CI = 0.92-0.99), while SHBG remained inversely associated with metabolic syndrome after further adjusting for total testosterone (OR = 0.99, 95% CI = 0.97-1.00). CONCLUSION: Total testosterone and SHBG are independent risk factors of metabolic syndrome. Prospective studies are needed to explore whether the association between sex hormones and metabolic syndrome was mediated by insulin resistance or obesity.