This study aimed to investigate the associations of long-term exposure to PM2.5 constituents with microvascular complications among participants with T2DM. This prospective study involved 27,579 participants with T2D without microvascular complications at baseline from the UK Biobank. PM2.5 and its five main constituents, including elemental carbon (EC), organic matter (OM), ammonium (NH4+), nitrate (NO3-), and sulfate (SO42-) were estimated were estimated using EMEP4UK-WRF model meteorology. Quantile g-computation (QgC) approach was applied to estimate the joint effect of PM2.5 constituents and identify which constituents contribute most to it. In the multivariate-adjusted model, increased exposure levels for PM2.5 constituents were significantly associated with increased risk of diabetic microvascular complications among individuals with T2DM. In detail, per IQR increment in PM2.5 (HR = 1.09, 95% CI: 1.06-1.14), EC (HR = 1.06, 95% CI: 1.02-1.10), OM (HR = 1.05, 95% CI: 1.01-1.09), NH4+ (HR = 1.15, 95% CI: 1.10-1.21), NO3- (HR = 1.10, 95% CI: 1.07-1.13), and SO42- (HR = 1.13, 95% CI: 1.07-1.19) was significantly associated with a higher risk of diabetic microvascular complications. Similar associations were observed for diabetic neuropathy, nephropathy, and retinopathy. The QgC methods showed that the mixed constituents were positively associated with microvascular complications (HR = 1.59, 95% CI: 1.54-1.64, P < 0.001) and specific subtypes. The constituent with the largest estimated positive weight was SO42-, followed by NH4+ and EC. In summary, long-term exposure to PM2.5 constituents with an increased risk of diabetic microvascular complications among participants with T2DM. Importantly, SO42- might take primary responsibility for these relationships.
This study aimed to evaluate the clinical utility of novel inflammatory and metabolic composite indices in early risk prediction of microvascular complications in patients with type 2 diabetes mellitus (T2DM), and to provide reliable evidence for early precision risk stratification. A retrospective analysis was conducted on 964 hospitalized patients with T2DM admitted to the Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, from September 2023 to March 2025. Patients were randomly assigned to a training cohort and a validation cohort at a ratio of 7:3 using a random number table. In the training cohort, least absolute shrinkage and selection operator (LASSO) regression was applied for variable selection and to reduce multicollinearity, followed by univariate and multivariate logistic regression analyses to identify independent risk factors for T2DM related microvascular complications. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were employed to comprehensively assess the predictive performance and clinical utility of the model. Multifactorial logistic regression analysis showed that age, duration of diabetes, duration of hypertension, urine albumin-to-creatinine ratio (UACR) > 30 mg/g, as well as core indicators SIRI and TyG index, were significantly associated with the occurrence of microvascular complications in type 2 diabetes mellitus (T2DM) (P < 0.05). The predictive model constructed based on LASSO-logistic regression demonstrated an AUC of 0.869 (95% CI: 0.842-0.895) in the training set and an AUC of 0.864 (95% CI: 0.824-0.905) in the validation set, indicating stable and excellent discriminatory ability. This study confirms that SIRI and TyG index can serve as independent risk factors for microvascular complications in T2DM. The nomogram model constructed based on LASSO-logistic regression shows significantly better predictive performance than single indicators, with good model calibration, demonstrating excellent clinical net benefit. This model can accurately assess the risk of microvascular complications, providing reliable decision support for early clinical screening and risk stratification management.
Fetal growth restriction(FGR) is a common pregnancy complication leading to adverse perinatal outcomes and long-term developmental risks. Beyond placental insufficiency, increasing evidence suggests that maternal systemic and microvascular alterations may contribute to its pathophysiology. Optical coherence tomography angiography (OCTA) enables non-invasive evaluation of retinal microvasculature and may provide insights into maternal microvascular alterations in pregnancies complicated by FGR. To assess maternal retinal and choroidal microvascular changes in pregnancies with late-onset FGR and to examine their relationship with Doppler ultrasound parameters. A total of 25 pregnant women with isolated late-onset FGR and 30 healthy pregnant women with appropriate-for-gestational-age(AGA) fetuses were included.OCTA imaging was used to measure retinal and choroidal thickness, vessel density in the superficial and deep capillary plexuses, and foveal avascular zone (FAZ) area.Doppler ultrasound measurements of the umbilical artery(UA) and middle cerebral artery(MCA) pulsatility indices(PI) were also recorded and the cerebroplacental ratio (CPR) was calculated. The late-onset FGR group exhibited a significantly wider FAZ area and reduced vessel density in both the superficial and deep capillary plexuses compared to the AGA group (p=0.004,p=0.019,p=0.022 respectively). Choroidal thickness was significantly lower in the FGR group (p=0.022). A positive correlation was observed between the umbilical artery PI and deep capillary plexus vessel density (p: 0.030,r: 0.486). No significant difference was found in the choriocapillaris vessel density between the groups (p=0.928). Maternal retinal vascular changes detected by OCTA in late-onset FGR may reflect impaired maternal hemodynamic adaptation, providing insight into underlying pathophysiological mechanisms.
Pulmonary arterial hypertension (PAH) is a progressive disorder with systemic vasculopathy, and noninvasive assessment remains challenging. The retina, sharing anatomical similarities with the cerebral microcirculation, is an accessible site for visualizing systemic vascular compromise. This study quantitatively evaluated retinal microvascular and neuroretinal structural changes in PAH patients compared to healthy controls using optical coherence tomography angiography (OCTA). In this single-center, cross-sectional case-control study, 40 patients with group 1 PAH and 38 healthy controls were enrolled. For statistical independence, only the right eye of each participant was analyzed (total: 78 eyes). All participants underwent high-resolution OCTA imaging. Key metrics including vascular density (VD) in the superficial (SCP) and deep capillary plexus (DCP), foveal avascular zone (FAZ) flow density (FD), and neuroretinal thicknesses (ganglion cell complex [GCC] and retinal nerve fiber layer [RNFL]) were quantified and compared using nonparametric tests. Comparison of PAH patients and controls revealed significantly reduced VD in the PAH group. In the SCP, VD was significantly lower in the whole image (p = 0.004) and the ETDRS grid (p = 0.005). Similarly, the DCP showed reduced VD in the whole image (p = 0.006). Quadrant analysis indicated marked reduction in the superior quadrant for both plexuses (p < 0.01). While FAZ area was similar between the groups (p = 0.779), FAZ FD was significantly decreased in PAH patients (p = 0.001). Structurally, mean GCC thickness was significantly reduced (p = 0.006), but RNFL thickness remained preserved (p = 0.267). PAH is associated with significant retinal microvascular density reduction across all plexuses. These findings provide evidence corroborating the systemic nature of PAH vasculopathy. OCTA is a promising noninvasive tool for assessing systemic microvascular involvement in this population. However, further longitudinal studies are needed to validate its utility for disease monitoring.
Microvascular dysfunction is a central determinant of organ failure in sepsis, reflecting early endothelial activation, increased permeability, and impaired capillary perfusion. Experimental evidence suggests that the endocannabinoid system (ECS) modulates these immunovascular processes, yet mechanistic insights remain dispersed across heterogeneous models. We conducted a PRISMA-guided systematic review of experimental studies assessing pharmacological modulation of ECS components under sepsis or endotoxemia conditions. Eleven studies met inclusion criteria, encompassing in vivo microcirculatory preparations and in vitro endothelial or immune-cell systems. Across models, three mechanistic domains consistently emerged: leukocyte-endothelial adhesion, endothelial barrier integrity, and vascular reactivity. Among these, cannabinoid receptor 2 (CB2) activation produced the most reproducible effects, reducing adhesion molecule expression and attenuating leukocyte recruitment. Endocannabinoid-endovanilloid signaling contributed to the stabilization of endothelial junctions and limitation of inflammatory hyperpermeability, whereas cannabinoid receptor 1 (CB1) signaling showed context-dependent influences on vascular tone and microvascular flow. These findings outline a coherent framework in which ECS activity-particularly through CB2-shapes early microvascular responses to sepsis. Standardized and clinically relevant models will be essential to determine whether targeting ECS pathways can yield effective strategies to protect the microcirculation during sepsis.
Ceramides and chronic kidney disease (CKD) independently associate with coronary microvascular dysfunction (CMD), but their combined association remains unestablished, warranting investigation. This cross-sectional analysis included coronary artery disease (CAD) patients from the CRUISE-MET trial (NCT06383208) who underwent coronary angiography and ceramide profiling measurement. The microvascular resistance was assessed in all patients using the angiography-derived microcirculatory resistance (AMR). CKD was classified based on both estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The combined associations and statistical mediation of ceramides and renal dysfunction on CMD was examined, with sensitivity analyses to ensure the robustness. In this analysis of 794 CAD patients, CKD patients demonstrated significantly higher AMR values [2.56 ± 0.51 vs 2.46 ± 0.48, p = 0.003] and CMD prevalence (57.1% vs 41.7%, p<0.001). Three ceramide species - Cer(18:1/16:0), Cer(18:1/18:0), and Cer(18:1/24:1) - showed strong positive correlations with AMR (all p < 0.05). LASSO regression identified 14 factors associated with CMD, with E/e', CKD, and Cer(18:1/16:0) emerging as top correlates. Cer(18:1/16:0) demonstrated superior predictive performance (AUC=0.609, 95%CI: 0.570-0.648, p<0.001), with its addition to baseline models significantly improving reclassification (δAUC=0.03, p=0.010; cNRI＞0=0.23, p<0.001; IDI=0.03, p<0.001). Notably, patients with concurrent CKD and elevated Cer(18:1/16:0) exhibited significantly higher odds of CMD (OR=3.74, 95%CI: 2.39-5.84). Statistical mediation analysis suggested that Cer(18:1/16:0) mediated 13.8% of the association between CKD and CMD. Ceramides, particularly Cer(18:1/16:0), partially mediated the statistical association between CKD and CMD. These findings highlight the potential role of sphingolipid metabolism in cardiorenal pathophysiology.
To evaluate long-term pain outcomes and safety after microvascular decompression (MVD) for primary trigeminal neuralgia (TN) in a single-center cohort and to explore whether age and intraoperative neurovascular compression severity were associated with favorable long-term pain relief. We retrospectively reviewed 134 consecutive patients with primary TN who underwent first-time MVD between January 2016 and December 2018 at a single institution, with at least 36 months of follow-up. Pain outcomes were assessed using the Barrow Neurological Institute (BNI) pain intensity scale. Postoperative complications, medication use, Kaplan-Meier analysis, and uni- and multivariable logistic regression were used to evaluate outcomes and associated factors. At 1 month after surgery, 95% of patients achieved favorable pain relief (BNI grades I-III). At the final follow-up, 77% maintained favorable pain relief, and 69 patients achieved complete pain relief (BNI grade I). Ninety-four patients reduced antiepileptic medication use by at least 50%, and 69 discontinued medication completely. The most common complications were dizziness (4.4%), facial numbness (2.9%), and hearing impairment (2.9%). Age ≥70 years and significant intraoperative neurovascular compression were independently associated with favorable long-term pain relief. In this retrospective single-center series, MVD was associated with durable pain relief, substantial medication reduction, and an acceptable complication profile. Age ≥70 years and significant intraoperative neurovascular compression were associated with favorable long-term pain relief in our cohort. These findings reflect institutional experience and may assist patient selection and counseling.
Microvascular obstruction (MVO) frequently occurs after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) and can be classified as transient or persistent based on its resolution on follow-up cardiac magnetic resonance (CMR) imaging. This meta-analysis aims to compare the prognostic significance of persistent MVO versus transient MVO and no MVO in patients with STEMI undergoing primary PCI. we conducted a systematic search for cohort studies comparing persistent MVO to transient MVO or no MVO in patients with STEMI who underwent primary PCI and CMR imaging. For the meta-analysis, we used R software (version 4.5.0) with RStudio. We included seven cohort studies with a total of 2180 patients. Compared to transient MVO, persistent MVO was associated with significantly higher risks of MACE and death. Persistent MVO also demonstrated significantly lower LVEF and larger infarct size, but no significant association with recurrent MI or heart failure readmission. Compared to no-MVO, persistent MVO showed even stronger associations with adverse outcomes: MACE, death, heart failure readmission, lower LVEF, and larger infarct size. Persistent MVO may be associated with worse clinical outcomes, adverse left ventricular remodeling, and larger infarct size compared to both transient MVO and no MVO. These findings support the role of follow-up CMR for risk stratification to identify high-risk population. However, the definition and timing of persistent MVO varied considerably across studies (1 week to 12 months), which introduce clinical heterogeneity highlighting the need for future studies with standardized definitions.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy characterized by recurrent inflammatory attacks within the central nervous system. Beyond optic neuritis, diffuse retinal and cerebral alterations may occur. Optical coherence tomography angiography (OCTA) enables the non-invasive assessment of retinal microvasculature and may provide insight into longitudinal retinal changes and their association with cerebral white matter hyperintensities (WMHs). In this longitudinal observational study, 45 aquaporin-4 antibody-positive NMOSD patients and 45 age- and sex-matched healthy controls underwent OCTA imaging. Radial peripapillary capillary (RPC) density was measured in the peripapillary region, while superficial vascular complex (SVC), deep vascular complex (DVC), and foveal avascular zone (FAZ) area were assessed in the macular region. Brain MRI was performed at baseline and at a 1-year follow-up, and WMH burden was rated using the Fazekas scale. Associations between OCTA metrics and WMHs were evaluated using regression models adjusted for age and disease duration, and longitudinal changes were analyzed using mixed-effects models. At baseline, NMOSD eyes, including those without prior optic neuritis, showed significantly reduced RPC, SVC, and DVC densities and an enlarged FAZ area compared with controls (all p < 0.0001). Lower RPC density was associated with higher periventricular and total WMH burden (standardized β range: -0.45 to -0.52, all p < 0.01). Over 1 year, RPC and SVC densities declined further (both p < 0.0001), whereas DVC density and FAZ area remained stable. RPC density demonstrated the highest discriminatory performance in ROC analyses (AUC = 0.78). OCTA reveals dynamic retinal microvascular alterations in NMOSD and a consistent association between reduced peripapillary capillary density and WMH burden. These findings are observational and do not imply causality, but they support the use of OCTA as a sensitive tool for monitoring retinal involvement in NMOSD.
Behçet's disease (BD) is a systemic vasculitis that can present with cardiac involvement. The aim of this study is to evaluate subclinical cardiac involvement in BD patients using left ventricular global longitudinal strain (GLS), right ventricular strain (RVGLS), and coronary sinus flow (CSF) measurements, and to investigate the relationship between echocardiographic findings and disease activity (BDCAF) and cumulative damage (BODI) scores. This cross-sectional study included 48 BD patients and 35 healthy controls. All participants underwent transthoracic echocardiography (TTE); biventricular strain was measured to evaluate function, and coronary sinus parameters were measured to evaluate coronary flow. In the BD group, disease activity was evaluated using the BDCAF, and cumulative organ damage was evaluated using the BODI score. Compared to the control group, GLS (absolute; 18.51 ± 2.02 vs. 19.53 ± 1.71, p = 0.018), right ventricular free wall strain (RVFWS; absolute) (25.35 ± 3.32 vs. 26.87 ± 3.01, p = 0.047), and CSF index (2.62 ± 0.99 vs. 3.58 ± 1.17 mL/min/g, p < 0.001) were found to be significantly lower in the BD group. The CSF index showed a positive correlation with both GLS (r = 0.31, p = 0.004) and RVFWS (r = 0.26, p = 0.021). In multivariable linear regression analysis, the CSF index and gender were identified as independent predictors of GLS. While the BODI score, indicating cumulative organ damage, showed a significant negative correlation with biventricular strain parameters (GLS long axis; GLS-L, RVGLS, RVFWS) (p < 0.05); no significant relationship was observed between the BDCAF score, which reflects acute disease activity, and echocardiographic parameters. Furthermore, the combined model using GLS and the CSF index exhibited a higher diagnostic performance in distinguishing BD patients compared to their individual use (AUC: 0.759, 80.9% sensitivity, 65.7% specificity). In BD patients, the decrease in CSF, reflecting coronary microangiopathy, is independently associated with the deterioration in myocardial deformation. Our findings suggest that subclinical cardiac involvement may be linked to the chronic disease burden accumulated over the years, rather than transient acute inflammatory flares. The integrated assessment of CSF and GLS with TTE provides a valuable and non-invasive strategy for the early detection of high-risk patients.
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To evaluate retinal microcirculation in biologic-treated ankylosing spondylitis (AS) using optical coherence tomography angiography (OCTA) and its association with disease activity. Fifty-seven AS patients (31 active, 26 inactive) under biologic therapy and 57 age- and sex-matched healthy controls were included. Right eyes underwent 10°×10° macular OCTA imaging (Heidelberg Spectralis). Vessel area density (VAD), foveal avascular zone (FAZ) metrics, and vessel density within a 300-µm-wide ring surrounding the FAZ (FD-300) were quantified for the superficial and deep vascular complexes (SVC and DVC). Structural OCT provided foveal and parafoveal retinal thickness, peripapillary retinal nerve fiber layer (RNFL), and subfoveal choroidal thickness. Biologic therapy details and disease activity indices (Ankylosing Spondylitis Disease Activity Score-C-reactive protein [ASDAS-CRP], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Bath Ankylosing Spondylitis Functional Index [BASFI]) were obtained from records. OCTA and structural parameters were compared among active AS, inactive AS, and control groups. Parafoveal SVC VAD was reduced only in the active AS group (p = 0.007), whereas DVC total/parafoveal VAD and FD-300 values were lower in both AS groups compared with controls (all p < 0.01). Retinal thickness, RNFL, and choroidal thickness were similar across groups (all p > 0.05). For distinguishing AS patients from controls, DVC metrics showed the highest performance (AUC ≈ 0.70-0.73; 0.63 for SVC), while the combined model including age, sex, and OCTA parameters achieved an AUC of 0.77. For differentiating disease activity, DVC-FAZ alone showed limited performance (AUC = 0.67). A parsimonious multivariable model including age, sex, BASFI, and DVC FAZ area yielded an AUC of 0.88 (95% CI: 0.80-0.97). In AS patients receiving biologic therapy, retinal microcirculatory alterations were detected-particularly within the DVC-while retinal and choroidal structural measurements appeared to remain largely preserved. Further studies are warranted to confirm these findings.
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The SGLT2 inhibitor empagliflozin (EMPA) has been found to reduce the combined risk of cardiovascular death or hospitalization for heart failure in patients with or without reduced left ventricular ejection fraction, irrespective of diabetes status. The underlying mechanisms remain to be elucidated. Endothelial-to-mesenchymal transition (EndoMT) has been reported to play a pivotal role in the microvascular rarefaction. This study aimed to evaluate the effect of EMPA on angiotensin II (Ang II)-induced left ventricular dysfunction and to explore the underlying mechanism. In vivo, C57BL/6J mice were infused with saline or Ang II (1.5 mg/kg/day) and subsequently treated with or without EMPA (10 mg/kg) for 2 weeks. mRNA sequencing and gene set enrichment analysis (GSEA) indicated that the PI3K/AKT/eNOS signalling pathway may mediate the protective effects of empagliflozin in heart failure with preserved ejection fraction (HFpEF). Finally, in vitro, PI-103 was used to treat cells, and immunofluorescence, western blotting, qPCR, and other methods were used to verify whether empagliflozin exerts its effects through the PI3K/AKT/eNOS pathway. In vivo, the mice treated with Ang II exhibited left ventricular dysfunction, increased microvascular rarefaction, and EndoMT, all of which were attenuated by EMPA treatment. In vitro, primary cardiac microvascular endothelial cells (CMECs) exposed to Ang II showed increased EndoMT, which was significantly inhibited by EMPA. EMPA also reversed the downregulation of PI3K/AKT/eNOS signalling and nitric oxide (NO) levels. PI-103 abrogated the anti-EndoMT effects of EMPA in CMECs. Our study suggested that EMPA can protect against Ang II-induced left ventricular dysfunction and microvascular rarefaction by suppressing EndoMT via PI3K/AKT/eNOS signalling.
Our research endeavored to formulate a patient-specific prognostic algorithm and elucidate the interconnection between critical genetic polymorphisms at PTPN1 loci and the predisposition to small vessel pathologies in Han Chinese subjects presenting with T2DM. From January 1, 2019, to June 30, 2024, a total of 3,847 patients with T2DM were enrolled in this cross-sectional case-control study. They were grouped into four groups by means of fundus examination and renal function assessment: the T2DM alone group (T2DM group), the T2DM combined with diabetic retinopathy (DR) group (T2DM + DR group), the T2DM combined with diabetic nephropathy (DN) group (T2DM + DN group), and the T2DM combined with DR + DN group (T2DM + DR +DN group). The genotypes of four SNP loci (rs968289, rs6067484, rs2206521, rs754118) of the PTPN1 gene were detected by PCR-RFLP. To evaluate the association between SNP loci and microvascular complications, multivariate logistic regression analysis was employed, followed by LASSO regression for variable selection to develop a nomogram prediction model. The rs968289-GG genotype demonstrated a statistically significant link to the risk of DR (adjusted OR = 1.47, 95%CI: 1.15-1.88, P = 0.002); the rs6067484-CC genotype exhibited a significant relationship with the risk of DN (adjusted OR = 1.58, 95%CI: 1.21-2.06, P < 0.001); The rs2206521-AA genotype significantly correlated with the risk of DR + DN co-morbidity (adjusted OR = 1.69, 95%CI: 1.28-2.24, P < 0.001). The column-line graphical model constructed based on nine independent predictors had AUCs of 0.823 and 0.808 in the training and validation sets, with sensitivity and specificity of 76.4%/78.9% and 74.2%/80.1%, respectively. Significant associations were observed between specific genotypic variants at the PTPN1 gene's rs968289, rs6067484 and rs2206521 loci and microvascular complication risk in Chinese Han T2DM patients. The column-line graph prediction model integrating genetic markers and clinical indicators has good discriminative ability and clinical utility, providing an important tool for individualized risk assessment and precise prevention of diabetic microvascular complications.
Myocardial ischemia-reperfusion (I/R) injury remains a major determinant of outcome after acute myocardial infarction (AMI) despite timely primary percutaneous coronary intervention (PPCI). Although epicardial patency is routinely restored, incomplete tissue reperfusion, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and maladaptive inflammation often limit myocardial salvage and promote adverse remodeling. In this narrative review, I/R injury is synthesized as a spatiotemporal, multicompartment network in which dominant mechanisms and actionable nodes shift from seconds to weeks and across cardiomyocytes, the coronary microvasculature, and systemic immune-metabolic programs. This framework helps explain why many single-target, single-window cardioprotective strategies have shown robust preclinical benefit yet failed to improve outcomes in contemporary ST-segment elevation myocardial infarction (STEMI) trials, where heterogeneity in ischemic time, comorbidities, microvascular injury patterns, and background pharmacotherapy reshapes injury topology and dilutes target-dominant subgroups. We propose an endpoint-anchored approach that distinguishes cardiomyocyte-vulnerability, microvascular-bottleneck, and resolution-deficient endotypes and matches interventions to phase-specific objectives using compartment-aligned endpoint stacks and target-engagement biomarkers. Within this rationale, defined bioactive compounds derived from traditional Chinese medicine (TCM) and selected standardized preparations are evaluated as potential network modulators with plausible actions on mitochondrial vulnerability, immunothrombosis, endothelial integrity, and inflammatory resolution. Translational priorities include stringent standardization, pharmacokinetic/pharmacodynamic (PK/PD)-informed dosing, PCI-compatible safety and drug-drug interaction assessment, and biomarker-guided trial designs enriched for mechanistically matched endotypes.
Being obese in mid-life is an increased risk of dementia and cognitive decline in late-life, while being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies, which the above phenomenon is known as the "obesity paradox", however, the mechanisms underlying the phenomenon "obesity paradox" in Alzheimer's disease (AD) have not been clarified. Alterations in lipoprotein lipase (LPL) levels in adipose tissue and skeletal muscle are significant for individuals predisposed to obesity or those undergoing weight loss. LPL promotes the entry of low-density lipoprotein (LDL) into cells, which leads to the release of free cholesterol, influencing low-density lipoprotein receptor-related protein 1 (LRP1) levels. LRP1 located in brain microvascular endothelial cells plays a vital role in mediating intracerebral beta-amyloid protein (Aβ) trans-blood-brain barrier (BBB) transport. However, it is unknown whether LPL in peripheral tissues inhibits intracerebral Aβ trans-BBB transport via LRP1, and explains the observed "obesity paradox" in AD. This study aims to investigate whether LPL in peripheral tissues contributes to the "obesity paradox" by regulating LRP1 expressed on brain microvascular endothelial cells in AD. A population-based epidemiological case-control study, coupled with in vivo and in vitro experiments were adopted to elucidate the role of LPL in AD. A population-based epidemiological case-control study was adopted to elucidate the interaction between LPL alleles (rs285 and rs328) and apolipoprotein E4 (APOE4, the main risk gene for sporadic AD) promotes the occurrence and development of AD. We have adopted in vivo and in vitro experiments to elucidate LPL in adipose tissue influences the occurrence and development of AD by regulating LRP1 located in brain microvascular endothelial cells. These findings provide evidence that LPL plays a pivotal role in the pathogenesis of AD, and its variations in adipose tissue may explain the observed "obesity paradox" in AD.
Polygenic risk scores (PRSs) improve prediction of the development of type 2 diabetes over the use of clinical risk factors alone; however, they perform poorly in populations of non-European ancestry, limiting their global clinical utility. We aimed to deliver comprehensive and rigorously tested multi-ancestry PRSs for prediction in type 2 diabetes. We conducted meta-analyses using data from type 2 diabetes genome-wide association studies (GWAS) across cohorts from five major global ancestries: European, African or African American, Admixed American, South Asian, and East Asian. We used summary statistics from the GWAS to construct single-ancestry PRSs (using the continuous-shrinkage PRS-CS method) and multi-ancestry PRSs (using the PRS-CSx method), and constructed ancestry-specific linkage disequilibrium panels to model pairwise correlations between single-nucleotide polymorphisms in GWAS during PRS construction. Models were validated for association with type 2 diabetes in at least four independent cohorts per ancestry. The effect sizes of PRSs were estimated as the odds ratio (OR) per SD of the PRS, and ORs for individuals at the 90th, 95th, and 97·5th PRS percentiles were compared with the IQR as a reference. We also tested our PRS models for prediction of diabetes incidence with or without additional clinical factors, as well as microvascular complications and comorbidities. Our analysis used data from 409 959 individuals with type 2 diabetes and 1 983 345 controls: respectively, 359 819 and 1 825 729 indivduals were included in the GWAS dataset, with 10 992 and 31 792 individuals in the training dataset and 39 148 and 125 824 individuals in the validation dataset. The best predictive performance for the single-ancestry PRSs was in European (incremental AUC 0·07-0·14) and East Asian (0·02-0·16) ancestries, whereas prediction was poorer for African or African American (0·02-0·03), Admixed American (0·02-0·04), and South Asian (0·02-0·04) ancestries, correlating with sample sizes in the GWAS. Compared with single-ancestry PRSs, our multi-ancestry PRSs showed higher effect sizes and smaller 95% CIs across all ancestries: OR per SD 1·73 (95% CI 1·67-1·80) in African or African American, 2·82 (2·67-2·97) in Admixed American, 2·45 (2·36-2·54) in East Asian, 2·36 (2·32-2·41) in European, and 2·23 (2·05-2·42) in South Asian ancestries. Individuals in the 97·5th PRS percentile had a 3-7 times increased risk of type 2 diabetes compared with those in the IQR (OR 3·43 [95% CI 2·80-4·21] in African or African American, 7·47 [5·64-9·89] in Admixed American, 6·62 [5·58-7·85] in East Asian, 6·25 [5·72-6·82] in European, and 4·50 [2·70-7·53] in South Asian ancestries). These PRSs were also associated with earlier onset of type 2 diabetes, higher risk of developing microvascular complications, and provide additional predictive value beyond clinical factors. In individuals with type 2 diabetes, the association between multi-ancestry PRSs and risk of microvascular complications and comorbidity was studied in populations of African, Admixed American, and European ancestries and was significant in all three ancestry groups for diabetic retinopathy (ORs per SD 1·28-1·57), diabetic nephropathy (1·25-1·58), proliferative diabetic retinopathy (1·39-2·08), and end-stage diabetic nephropathy (1·44-1·87); PRS was associated with coronary artery disease in the Admixed American ancestry group only (1·16 [95% CI 1·08-1·25]). These validated, publicly available PRSs can improve risk stratification for type 2 diabetes onset and complications across diverse ancestries, supporting their further evaluation in clinical settings. The National Human Genome Research Institute of the US National Institutes of Health.
Pulmonary metastasis remains the leading cause of death in osteosarcoma; however, the pronounced and long-recognized subpleural predominance of metastatic nodules remains mechanistically unexplained. Contemporary "seed-and-soil" and pre-metastatic niche frameworks emphasize microenvironmental conditioning and spatial heterogeneity, but they do not explain why metastatic seeding consistently localizes to the peripheral 1-2 cm of the lung. Likewise, modern mechanical perspectives acknowledge that circulating tumor cells can be retained at multiple sites within the pulmonary microvasculature (including capillaries and pre-capillary arterioles), yet they do not account for a reproducible intra-organ, subpleural spatial bias. A testable model that links pulmonary microvascular geometry and hemodynamics to the consistent subpleural localization of early osteosarcoma metastatic seeding has yet to be established. We propose the Hemodynamic Mechanical-Filtration Hypothesis: a clinically relevant subset of osteosarcoma circulating material may travel as larger, relatively stiff embolic units, including circulating tumor cell clusters (CTC clusters) and/or complex aggregates involving platelets and fibrin (CTC-platelet aggregates). Because these units have less instantaneous deformability than single cells, they may undergo size-selective mechanical arrest in terminal pre-alveolar arterioles (20-40 μm), which constitute a functional bottleneck immediately proximal to the capillary bed. We further hypothesize that filtration-prone distal arteriolar segments are preferentially distributed within a defined subpleural distance, an explicitly testable quantitative anatomical premise. This initial mechanical arrest establishes a spatial template for seeding, upon which post-arrest metastatic niche maturation and outgrowth can proceed, potentially modulated by upstream pre-metastatic niche (PMN) priming. The hypothesis integrates pulmonary microvascular anatomy, tumor biomechanics, cluster/aggregate rheology, and hemodynamic gradients. We outline falsifiable predictions and multi-level validation strategies, including intravital imaging, compliant/endothelialized microfluidic models, computational flow simulations, and clinical spatial mapping of metastatic nodules as a function of distance from the pleura. By explicitly coupling embolic physical properties with hierarchical vascular geometry and regional hemodynamics, this framework provides a spatially resolved extension of mechanical arrest models and generates testable explanations for subpleural predominance as well as for the conditions under which the site of arrest may shift. If validated, this hypothesis would reframe early osteosarcoma lung seeding as a process constrained by microvascular biomechanics and could guide future mechanistic studies aimed at developing preventive strategies targeting embolic integrity and pulmonary microcirculatory conditions.