Gestational diabetes mellitus, body mass index, and cardiometabolic multimorbidity: a prospective cohort study.

PURPOSE: Gestational diabetes mellitus (GDM) could increase the risks of type 2 diabetes mellitus (T2DM) and cardiovascular disease. However, evidence on its association with cardiometabolic multimorbidity (CMM) was limited. This study aimed to evaluate the association between GDM and the prevalence, incidence, patterns, and progression of CMM; and the role of body mass index (BMI) in such association. METHODS: This study included 203,372 women who have given birth in UK Biobank. The diagnoses of GDM and cardiometabolic diseases (including stroke, coronary heart disease [CHD], and T2DM) were reported by participants or obtained through linkage to inpatient hospital data until 31st December 2020. BMI was assessed at the baseline assessment. CMM was defined as having two or more of included cardiometabolic diseases. Logistic regression models and Cox proportional hazard models were used to assess the association between GDM and CMM, and the modifications on both additive and multiplicative scales were assessed to evaluate the effect of BMI on such association. RESULTS: A total of 1,217 women had a history of GDM, 2,351 participants had CMM at the end of follow-up and 1,601 was newly diagnosed during follow-up. GDM was associated with higher prevalence (odds ratio [OR]=4.64, 95% confidence interval [95% CI]=3.54-6.08) and incidence (hazard ratio [HR]=3.62, 95% CI=2.62-5.00) of CMM. In particular, GDM was associated with higher odds of T2DM, coexisting T2DM and vascular disease, and T2DM followed by vascular disease. Formal testing for effect modification suggested multiplicative modification by BMI for the association between GDM and incident CMM. CONCLUSIONS: GDM was associated with CMM in women's late life, with multiplicative modification effects of BMI. Our results suggest that maternal and lifestyle interventions (e.g., weight management) are warranted for the primary and secondary prevention of CMM, particularly in women with a history of GDM.

Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic.

Background: Cardiometabolic multimorbidity (CMM) and depression are often co-occurring in older adults and associated with neurodegenerative outcomes. The present study aimed to estimate the independent and joint associations of CMM and depression on cognitive function in multi-regional cohorts, and to validate the generalizability of the findings in additional settings, including clinical. Methods: Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed for generalization. Participants were eligible for inclusion if they had data for CMM and were free of dementia at baseline. Baseline CMM was defined as: 1) CMM 5, ≥2 among hypertension, hyperlipidemia, diabetes, stroke, and heart disease and 2) CMM 3 (aligned with previous studies), ≥2 among diabetes, stroke, and heart disease. Baseline depression was primarily characterized by binary classification of depressive symptom measurements, employing the Geriatric Depression Scale and the Center for Epidemiological Studies-Depression scale. Global cognition was standardized as z-scores through harmonizing multiple cognitive measures. Longitudinal cognition was calculated as changes in global cognitive z-scores. A pooled individual participant data (IPD) analysis was utilized to estimate the independent and joint associations of CMM and depression on cognitive outcomes in COSMIC studies, both cross-sectionally and longitudinally. Repeated analyses were performed in three external validation studies. Findings: Of the 32,931 older adults in the 14 COSMIC cohorts, we included 30,382 participants with complete data on baseline CMM, depression, and cognitive assessments for cross-sectional analyses. Among them, 22,599 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. The three external studies for validation had 1964 participants from 3 multi-ethnic Asian older adult cohorts in different settings (community-based, memory clinic, and post-stroke study). In COSMIC studies, each of CMM and depression was independently associated with cross-sectional and longitudinal cognitive function, without significant interactions between them (Ps > 0.05). Participants with both CMM and depression had lower cross-sectional cognitive performance (e.g. ß = -0.207, 95% CI = (-0.255, -0.159) for CMM5 (+)/depression (+)) and a faster rate of cognitive decline (e.g. ß = -0.040, 95% CI = (-0.047, -0.034) for CMM5 (+)/depression (+)), compared with those without either condition. These associations remained consistent after additional adjustment for APOE genotype and were robust in two-step random-effects IPD analyses. The findings regarding the joint association of CMM and depression on cognitive function were reproduced in the three external validation studies. Interpretation: Our findings highlighted the importance of investigating age-related co-morbidities in a multi-dimensional perspective. Targeting both cardiometabolic and psychological conditions to prevent cognitive decline could enhance effectiveness. Funding: Natural Science Foundation of China and National Institute on Aging/National Institutes of Health.

Associations between socioeconomic inequalities and progression to psychological and cognitive multimorbidities after onset of a physical condition: a multicohort study.

Background: Chronic physical conditions (e.g., heart diseases, diabetes) increase with population ageing, contributing to psychological and cognitive multimorbidities. Yet, little is known about socioeconomic inequalities in this process. We examined the associations between socioeconomic status (SES) and progression to psychological and cognitive multimorbidities after onset of a physical condition. Methods: We used harmonized individual-level data from five prospective cohort studies across 24 countries in the US, Europe and Asia, with repeated morbidity measurements between 2002 and 2021. Participants with at least one new-onset physical conditions (hypertension, diabetes, heart diseases, stroke, chronic lung diseases, cancer, or arthritis) were followed up for progression to physical-psychological multimorbidity, physical-cognitive multimorbidity, and physical-psychological-cognitive multimorbidity. SES was determined based on educational level and total household wealth at the onset of a physical condition. Time to and incidence rates of progressing psychological and cognitive multimorbidities were estimated in analyses stratified by SES. Fine-Gray subdistribution hazard models and multi-state models were used to estimate the associations between SES and progression to psychological and cognitive multimorbidities. Findings: Among 20,250 participants aged ≥45 years (mean age at a physical condition onset 65.38 years, standard deviation 8.37) with at least one new-onset physical conditions in the analysis, 7928 (39.2%) progressed to psychological and cognitive multimorbidities during a median follow-up of 8.0 years (168,575 person-years). The mean survival time free from physical-psychological-cognitive multimorbidity was 11.96 years (95% confidence interval 11.57-12.34) in low SES individuals, compared to 15.52 years (15.40-15.63) in high SES individuals, with the corresponding incidence rate of 18.44 (16.32-20.82) and 3.15 (2.48-4.01) per 1000 person-years, respectively. The associations of education, household wealth and SES with multimorbidities followed a dose-dependent relation, with subdistribution hazard ratios per decreasing SES category being 1.24 (1.19-1.29) for physical-psychological multimorbidity, 1.47 (1.40-1.54) for physical-cognitive multimorbidity, and 1.84 (1.72-1.97) for physical-psychological-cognitive multimorbidity. The strongest SES-multimorbidities associations were observed in participants with arthritis, hypertension or diabetes. In multi-state models SES was linked to all five transitions from physical condition to physical-psychological multimorbidity, physical-cognitive multimorbidity and physical-psychological-cognitive multimorbidity. Interpretation: Socioeconomic inequalities are associated with the progression of a chronic physical condition, with the lower SES groups had both an earlier time to and a higher incidence of psychological and cognitive multimorbidities. These findings underscore the need for more effective equity-oriented policies and healthcare practices to address reduced psychological wellness and cognitive maintenance among individuals with low SES and physical conditions. Funding: Zhejiang University Hundred Talents Program Research Initiation Fund, Fundamental Research Funds for the Central Universities in China, Wellcome Trust, Medical Research Council, National Institute on Aging, Academy of Finland.

cGAS-STING pathway in systemic lupus erythematosus: biological implications and therapeutic opportunities.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been identified as a significant modulator of inflammation in various clinical contexts, including infection, cellular stress, and tissue injury. The extensive participation of the cGAS-STING pathway can be attributed to its ability to detect and control the cellular reaction to DNAs originating from both microorganisms and hosts. These DNAs are well recognized as molecules linked with potential risks. At physiological levels, the STING signaling system exhibits protective effects. However, prolonged stimulation of this pathway contributes to autoimmune disorder pathogenesis. The present paper provides an overview of the activation mechanism of the cGAS-STING signaling pathways and their associated significant functions, as well as therapeutic interventions in the context of systemic lupus erythematosus (SLE). The primary objective is to enhance our comprehension of SLE and facilitate more effective diagnosis and treatment strategies for this condition.

Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression.

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth-by 100 to 140 times-in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.

Integrated tea polyphenols and polydopamine functionalized graphene anode for improved bioelectricity generation and Cr(VI) reduction in microbial fuel cells.

Microbial fuel cells (MFCs) have the dual advantage of mitigating Cr(Ⅵ) wastewater ecological threats while generating electricity. However, the low electron transfer efficiency and the limited enrichment of active electrogens are barriers to MFCs advancement. This study describes the synthesis of the TP-PDA-RGO@CC negative electrode using tea polyphenol as a reducing agent and polydopamine-doped graphene, significantly enhances the roughness and hydrophilicity of the anode. The charge transfer resistance was reduced by 94%, and the peak MFC power was 1375.80 mW m-2. Under acidic conditions, the Cr(Ⅵ) reduction rate reached 92% within 24 h, with a 52% increase in coulombic efficiency. Biodiversity analysis shows that the TP-PDA-RGO@CC anode could enrich electrogens, thereby boosting the electron generation mechanism at the anode and enhancing the reduction efficiency of Cr(Ⅵ) in the cathode chamber. This work emphasizes high-performance anode materials for efficient pollutant removal, energy conversion, and biomass reuse.

Burden of multiple high-risk factors in pregnancy before and after the universal two-child policy in Chinese women: An observational study.

Background: The prevalence of high-risk pregnancy increased after the implementation of two-child policy in China, but the impact of this policy change on the burden and profile of multiple high-risk factors in pregnancy (MHFP) has been insufficiently explored. We hypothesised that the profile of MHFP might have changed after the two-child policy was implemented and aimed to estimate the prevalence, intercorrelation, and outcomes of MHFP before and after its introduction. Methods: We obtained data on the population of pregnant women before (2015) and after (2020/2021) the implementation of universal two-child policy in Huai'an. We then included 33 risk factors in our analysis based on the Five-Colour Management framework and defined MHFP as an individual having two or more of these factors. We also estimated the changes of the prevalence of each single factor and their coexistence. Lastly, we performed a network analysis to assess the intercorrelations across these factors and used logistic regression models to evaluate MHFP-related pregnancy outcomes. Results: We observed an increase in the prevalence of MHFP after the implementation of the universal two-child policy (25.8% in 2015 vs 38.4% in 2020/2021, P < 0.01). Chronic conditions (e.g. gestational diabetes mellitus, abnormal body mass index) had the largest increase among the included factors, while cardiovascular disease and hypertensive disorders were central factors of the network structures. The correlations of advanced maternal age with abnormal pregnancy histories and scarred uteri increased significantly from 2015 to 2020/2021. MHFP was associated with multiple pregnancy outcomes, including preterm birth (adjusted odds ratio (aOR) = 2.57; 95% confidence interval (CI) = 2.39-2.75), low birthweight (aOR = 2.77; 95% CI = 2.54-3.02), low Apgar score (aOR = 1.41; 95% CI = 1.19-1.67), perinatal death (aOR = 1.75; 95% CI = 1.44-2.12), and neonatal death (aOR = 1.76; 95% CI = 1.42-2.18). Moreover, an increasing number and certain combinations of MHFP were associated with higher odds of pregnancy outcomes. For example, the aOR of preterm birth increased from 1.67 (95% CI = 1.52-1.87) for one risk factor to 8.03 (95% CI = 6.99-9.22) for ≥4 risk factors. Conclusions: Chinese women experienced a higher burden of multiple high-risk factors after the introduction of the two-child policy, particularly those with advanced maternal age, obesity, and chronic conditions. Strategies targeting chronic conditions for women with MHFP should be prioritised and a shift to a multiple-factor-oriented framework is needed in the expanding Chinese maternal health care system.

Model-Informed individualized dosage regimen of sirolimus in pediatric patients with intractable lymphatic malformations.

Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5-15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0-18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.

Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study.

BACKGROUND: Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated with an increased risk of developing such hallmark-related diseases. METHODS: In this multicohort study, we included people aged 38-72 years with data on weight, height, and waist circumference measured during a clinical examination at baseline between March 13, 2006, and Oct 1, 2010, from the UK Biobank with follow-up until Nov 12, 2021. To test reproducibility of the findings (replication analysis), we used data from people aged 40 years or older included in the Finnish Public Sector study and the Finnish Health and Social Support study who responded to the study surveys, had data on BMI, and were successfully linked to electronic health records from national registers up to Dec 31, 2016. Obesity and clinical characteristics were assessed at baseline. Via linkage to national health records, participants were followed up for 83 diseases related to nine ageing hallmarks (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication). Outcomes were the first instance of hallmark-related disease, in addition to co-occurrence of three or more hallmark-related diseases and mortality. FINDINGS: 496 530 adults (mean age 57·0 years [SD 8·1]) from the UK Biobank were included in the primary analysis, and 83 249 (mean age 48·2 years [6·4]) adults from the Finnish cohorts were included in the replication analysis. Median follow-up was 12·7 years (IQR 12·0-13·4) in the UK Biobank and 14·0 years (8·0-15·0) in the Finnish cohorts. After adjusting for demographic characteristics, lifestyle factors, and depression, UK Biobank participants with obesity (BMI ≥30·0 kg/m2) had a 1·40 (95% CI 1·38-1·41) times higher hazard ratio for the first hallmark-related disease than those with a healthy weight (BMI 18·5-24·9 kg/m2). The corresponding hazard ratios for three co-occurring diseases were 2·92 (95% CI 2·64-3·22) for deregulated nutrient sensing, 2·73 (2·46-3·02) for telomere attrition, 2·33 (2·10-2·60) for epigenetic alterations, 2·30 (2·14-2·48) for mitochondrial dysfunction, 2·23 (2·04-2·45) for stem cell exhaustion, 2·02 (1·89-2·16) for altered intercellular communication, 2·01 (1·89-2·15) for cellular senescence, 1·83 (1·67-2·00) for loss of proteostasis, and 1·39 (1·27-1·52) for genomic instability. These findings were replicated in the Finnish cohorts. In both studies, the associations between other risk factors (low education, unhealthy dietary factors [available only in the UK Biobank], smoking, high alcohol consumption, physical inactivity, and depression) and hallmark-related diseases were weaker than those with obesity. 45-60% of the excess mortality in people with obesity was attributable to hallmark-related diseases. INTERPRETATION: Obesity might have an important role in the development of diseases associated with cellular ageing. Tackling ageing mechanisms could potentially help to reduce the disease and mortality burden resulting from the obesity epidemic. FUNDING: Wellcome Trust, UK Medical Research Council, US National Institute on Aging, Academy of Finland, and Finnish Foundation for Cardiovascular Research. TRANSLATIONS: For the German and Finnish translations of the abstract see Supplementary Materials section.

Geometric Understanding of Discriminability and Transferability for Visual Domain Adaptation.

To overcome the restriction of identical distribution assumption, invariant representation learning for unsupervised domain adaptation (UDA) has made significant advances in computer vision and pattern recognition communities. In UDA scenario, the training and test data belong to different domains while the task model is learned to be invariant. Recently, empirical connections between transferability and discriminability have received increasing attention, which is the key to understand the invariant representations. However, theoretical study of these abilities and in-depth analysis of the learned feature structures are unexplored yet. In this work, we systematically analyze the essentials of transferability and discriminability from the geometric perspective. Our theoretical results provide insights into understanding the co-regularization relation and prove the possibility of learning these abilities. From methodology aspect, the abilities are formulated as geometric properties between domain/cluster subspaces (i.e., orthogonality and equivalence) and characterized as the relation between the norms/ranks of multiple matrices. Two optimization-friendly learning principles are derived, which also ensure some intuitive explanations. Moreover, a feasible range for the co-regularization parameters is deduced to balance the learning of geometric structures. Based on the theoretical results, a geometry-oriented model is proposed for enhancing the transferability and discriminability via nuclear norm optimization. Extensive experiment results validate the effectiveness of the proposed model in empirical applications, and verify that the geometric abilities can be sufficiently learned in the derived feasible range.

Carbon carrier-based rapid Joule heating technology: a review on the preparation and applications of functional nanomaterials.

Compared to conventional heating techniques, the carbon carrier-based rapid Joule heating (CJH) method is a new class of technologies that offer significantly higher heating rates and ultra-high temperatures. Over the past few decades, CJH technology has spawned several techniques with similar principles for different application scenarios, including ultra-fast high temperature sintering (UHS), carbon thermal shock (CTS), and flash Joule heating (FJH), which have been widely used in material preparation research studies. Functional nanomaterials are a popular direction of research today, mainly including nanometallic materials, nanosilica materials, nanoceramic materials and nanocarbon materials. These materials exhibit unique physical, chemical, and biological properties, including a high specific surface area, strength, thermal stability, and biocompatibility, making them ideal for diverse applications across various fields. The CJH method is a remarkable approach to producing functional nanomaterials that has attracted attention for its significant advantages. This paper aims to delve into the fundamental principles of CJH and elucidate the efficient preparation of functional nanomaterials with superior properties using this technique. The paper is organized into three sections, each dedicated to introducing the process and characteristics of CJH technology for the preparation of three distinct material types: carbon-based nanomaterials, inorganic non-metallic materials, and metallic materials. We discuss the distinctions and merits of the CJH method compared to alternative techniques in the preparation of these materials, along with a thorough examination of their properties. Furthermore, the potential applications of these materials are highlighted. In conclusion, this paper concludes with a discussion on the future research trends and development prospects of CJH technology.

The hidden dangers of short-term glucocorticoid use in children: A genomic analysis.

OBJECTIVE: Glucocorticoid (GC) administration has been associated with adverse drug reactions (ADRs) affecting multiple organ systems. While long-term use is widely recognized as a significant independent predictor of ADRs, it is important to note that even short-term use can lead to serious ADRs. The considerable inter-individual variability in ADRs occurrence may be influenced by genetic factors. This study, we present a case of a child who experienced significant weight gain and osteoporosis, following a brief administration of GC. METHODS: To comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype. RESULTS: The pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases. CONCLUSIONS: Consequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.

Social Environment, Lifestyle, and Genetic Predisposition With Dementia Risk: A Long-Term Longitudinal Study Among Older Adults.

BACKGROUND: The role of social environment, that is, the aggregate effect of social determinants of health (SDOHs), in determining dementia is unclear. METHODS: We developed a novel polysocial risk score for dementia based on 19 SDOH among 5 199 participants in the Health and Retirement Study, United States, to measure the social environmental risk. We used a survival analysis approach to assess the association between social environment and dementia risk in 2006-2020. We further studied the interaction between social environment and lifestyles, and explored racial disparities. RESULTS: The study participants (mean age = 73.4 years, SD = 8.3; 58.0% female; 11.6% African American) were followed up for an average of 6.2 years, and 1 089 participants developed dementia. Every 1-point increase in the polysocial risk score (ranging from 0 to 10) was associated with a 21.6% higher risk (adjusted hazard ratio [aHR] = 1.21, 95% confidence intervals [95% CI] = 1.15-1.26) of developing dementia, other things being equal. Among participants with high social environmental risk, regular exercise and moderate drinking were associated with a 43%-60% lower risk of developing dementia (p < .001). In addition, African Americans were 1.3 times (aHR = 2.28, 95% CI = 1.96-2.66) more likely to develop dementia than European Americans, other things being equal. CONCLUSION: An adverse social environment is linked to higher dementia risk, but healthy lifestyles can partially offset the increased social environmental risk. The polysocial risk score can complement the existing risk tools to identify high-risk older populations, and guide the design of targeted social environmental interventions, particularly focusing on improving the companionship of the older people, to prevent dementia.

Natural tea polyphenol functionalized graphene anode for simultaneous power production and degradation of methyl orange dye in microbial fuel cells.

The microbial fuel cell (MFCs) has dual functions, capable of achieving dye decolorization and synchronous power generation. Despite these advantages, the MFCs have faced challenges related to low electron transfer efficiencies and limited dye treatment capacity in wastewater applications. This work introduces an innovative approach by employing reduced graphene oxide-modified carbon cloth (TP-RGO@CC) anodes, utilizing tea polyphenols as the reducing agent. This modification significantly enhances the hydrophilicity and biocompatibility of the anodes. The MFC equipped with the TP-RGO@CC anode demonstrated a remarkable increase in the maximum power density, reaching 773.9 mW m-2, representing a 22% improvement over the plain carbon cloth electrode. The decolorization rate of methyl orange (50 mg L-1, pH 7) reached 99% within 48 h. Biodiversity analysis revealed that the TP-RGO@CC anode selectively enriched electrogens producing and organic matter-degrading bacteria, promoting a dual mechanism of dye decolorization, degradation, and simultaneous electro-production at the anode. This work highlights advanced anode materials that excel in effective pollutant removal, energy conversion, and biomass reuse.

Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery.

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of -31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.

Associations between factors in childhood and young adulthood and childlessness among women in their 40s: A national prospective cohort study.

BACKGROUND: While the risk factors for infertility are well-established, research on factors associated with voluntary childlessness is limited and mainly focused on adulthood factors. Thus, we examined the associations between factors in childhood and young adulthood and different types of childlessness. METHODS: The analysis included 4653 women from the Australian Longitudinal Study on Women's Health from 1996 to 2021. Childlessness was categorised as: voluntary, due to infertility issues, or due to other reasons. The associations between factors in childhood and young adulthood and childlessness were assessed using multinomial logistic regression models. RESULTS: In their 40s, 4.8 % of women were voluntarily childless, 6.7 % were childless due to infertility issues, and 7.8 % were childless due to other reasons. Regardless of types of childlessness, being childless was associated with poorer self-rated health during childhood and having been unpartnered and obese in young adulthood. Ex-smokers in young adulthood had lower odds of childlessness. Childhood physical abuse was associated with childlessness due to infertility issues and other reasons. Voluntary childlessness and childlessness due to infertility issues were associated with having identified as non-exclusively heterosexual in early adulthood. Lower social support in early adulthood was associated with voluntary childlessness and childlessness due to other reasons. LIMITATIONS: The direction of the associations could not be determined and using self-reported data may introduce recall bias. CONCLUSIONS: Factors in childhood and young adulthood were associated with different types of childlessness, highlighting the importance of adopting a life course perspective when studying childlessness.

A multimodal approach using fundus images and text meta-data in a machine learning classifier with embeddings to predict years with self-reported diabetes - An exploratory analysis.

AIMS: Machine learning models can use image and text data to predict the number of years since diabetes diagnosis; such model can be applied to new patients to predict, approximately, how long the new patient may have lived with diabetes unknowingly. We aimed to develop a model to predict self-reported diabetes duration. METHODS: We used the Brazilian Multilabel Ophthalmological Dataset. Unit of analysis was the fundus image and its meta-data, regardless of the patient. We included people 40 + years and fundus images without diabetic retinopathy. Fundus images and meta-data (sex, age, comorbidities and taking insulin) were passed to the MedCLIP model to extract the embedding representation. The embedding representation was passed to an Extra Tree Classifier to predict: 0-4, 5-9, 10-14 and 15 + years with self-reported diabetes. RESULTS: There were 988 images from 563 people (mean age = 67 years; 64 % were women). Overall, the F1 score was 57 %. The group 15 + years of self-reported diabetes had the highest precision (64 %) and F1 score (63 %), while the highest recall (69 %) was observed in the group 0-4 years. The proportion of correctly classified observations was 55 % for the group 0-4 years, 51 % for 5-9 years, 58 % for 10-14 years, and 64 % for 15 + years with self-reported diabetes. CONCLUSIONS: The machine learning model had acceptable accuracy and F1 score, and correctly classified more than half of the patients according to diabetes duration. Using large foundational models to extract image and text embeddings seems a feasible and efficient approach to predict years living with self-reported diabetes.