Extremely severe hypertriglyceridemia associated with diabetic ketoacidosis (DKA), shock, cerebral edema, acute kidney injury (AKI), and pneumonia represents a rare but life-threatening clinical emergency, particularly when occurring as the initial presentation of previously undiagnosed diabetes mellitus (DM). In such critically ill patients, prompt management is challenging because clear evidence-based guidelines regarding the role and timing of therapeutic plasma exchange (TPE) remain limited. To our knowledge, this is the first reported case from Bangladesh describing severe combined hyperlipidemia with DKA as the initial manifestation of DM requiring urgent TPE. A 15-year-old girl presented with altered consciousness and hemodynamic instability. She underwent immediate intubation upon admission due to severe metabolic decompensation. Further evaluation revealed DKA with extremely severe hypertriglyceridemia associated with combined hyperlipidemia. On the second day of hospitalization, her condition was further complicated by pneumonia and AKI. Despite standard intensive management, including insulin therapy, fluid resuscitation, and supportive care, no significant overall clinical improvement was observed. Considering the progressive deterioration and risk of fatal complications, TPE was initiated on day 3. Following a single session of TPE, her clinical status improved dramatically, with rapid hemodynamic stabilization and metabolic recovery, allowing successful weaning from ventilatory support within 24 hours. This case highlights that TPE may be a valuable adjunctive treatment in carefully selected patients with DKA complicated by extremely severe hypertriglyceridemia and multiorgan dysfunction when conventional therapy fails to produce adequate clinical improvement. We also review previously reported cases and discuss the potential role of TPE in managing this rare but life-threatening condition. As plasmapheresis remains costly and less accessible in resource-limited settings like Bangladesh, greater clinical awareness and further evidence are needed to guide future management recommendations for similar critically ill patients.

Hyperosmolar dextrose infused through peripheral venous access can extravasate into surrounding soft tissue and produce local injury. We present the case of a 44-year-old woman with a history of seizure disorder and hyperlipidemia who underwent anterior lumbar interbody fusion (ALIF). On the day of admission, she experienced a witnessed generalized seizure on the floor that terminated following administration of intravenous lorazepam. Point-of-care glucose obtained during the event was 39 mg/dL and corrected with intravenous dextrose. She was transferred to the intensive care unit (ICU), where hypoglycemia recurred despite continuous dextrose support. Computed tomography (CT) of the head showed no acute intracranial process, and electroencephalography (EEG) demonstrated diffuse slowing without epileptiform activity. Endocrinology was consulted, and the clinical picture was felt to be most consistent with endogenous hyperinsulinism from a suspected insulinoma. At a serum glucose of 55 mg/dL, insulin was 13 uIU/mL and C-peptide was 4.7 ng/mL, both inappropriately unsuppressed and consistent with endogenous hyperinsulinism. She was maintained on continuous 10% dextrose at 150-200 mL per hour with as-needed 50% dextrose boluses, glucagon, and subcutaneous octreotide 200 mcg every eight hours, with capillary glucose monitoring every two hours. On hospital day 4, the peripheral catheter site was found to be infiltrated, and the catheter was removed, with the infusion transferred to central access. On hospital day 6, nursing and physician staff identified multiple tense, fluid-filled bullae over the right anterior forearm with associated swelling and erythema at the site of a previously removed peripheral intravenous catheter. The patient reported that forearm tenderness had been present since admission and had progressively worsened. Examination demonstrated moderate asymmetric swelling of the right upper extremity with intact distal pulses and preserved sensation. Range of motion was limited by swelling and a sensation of heaviness rather than by pain. The findings were felt to be most consistent with hyperosmolar dextrose extravasation injury. This case demonstrates that sustained peripheral administration of concentrated dextrose can produce progressive bullous and soft tissue injury and that these changes may evolve insidiously over several days. Early changes may be subtle and difficult to distinguish from routine infusion site irritation. Patients with suspected endogenous hyperinsulinism often require a multiday dextrose bridge while localization and definitive treatment are arranged, which places them at particular risk. Early consideration of central venous access, structured infusion site surveillance, and prompt escalation when local changes are identified are important components of care in patients requiring prolonged high-concentration dextrose therapy.

Type 2 diabetes mellitus (T2DM) is a major risk factor for atherosclerotic cardiovascular disease (CVD), and hyperlipidemia (HLD) frequently coexists. Shear wave elastography (SWE) quantifies carotid stiffness and may improve CVD risk stratification. To evaluate the impact of HLD on carotid stiffness in T2DM using SWE. We conducted a cross-sectional study of 112 adults with T2DM: simple diabetes (Group B, n = 52) and T2DM with HLD (Group C, n = 60): and 55 healthy controls (Group A). Demographic, clinical, and biochemical data were collected. Conventional ultrasound measured carotid intima-media thickness, diastolic diameter, systolic diameter, and peak systolic velocity. Arterial distensibility and the stiffness coefficient were calculated. SWE provided maximum, mean, and minimum elastic moduli. Pearson correlation tested associations between SWE parameters and risk factors; multivariable linear regression identified independent determinants of SWE values. Compared with controls, Groups B and C had higher fasting glucose, glycated hemoglobin, total cholesterol (TC), triglycerides (TG), and LDL-C (all P < .05); TC, TG, and LDL-C were higher in Group C than Group B (all P < .05). high-density lipoprotein cholesterol (HDL-C) were lower in both Group B and Group C compared to Group A (both P < .05), and were also lower in Group C than in Group B (P < .05). Mean elastic modulus, maximum elastic modulus, and minimum elastic modulus were greater in Groups B and C than in controls and were highest in Group C (all P < .05). SWE parameters correlated positively with carotid intima-media thickness, TC, TG, and LDL-C, and negatively correlated with HDL-C (all P < .05). In multivariable models, hyperlipidemia: driven primarily by elevated TC, TG, and LDL-C and reduced HDL-C: was independently associated with increased SWE values in T2DM (all P < .05). HLD exacerbates carotid atherosclerosis in T2DM. SWE is a noninvasive, quantitative, and efficient method for assessing carotid stiffness and cardiovascular risk in T2DM, particularly among patients with concurrent HLD.

Background: Type 2 diabetes mellitus (T2DM) and hyperlipidemia are interrelated metabolic disorders that significantly increase cardiovascular risk. Thiazolidinediones are known insulin sensitizers, whereas quinoline derivatives possess diverse pharmacological activities. To explore their complementary activity, we designed a novel hybrid compound integrating a thiazolidinedione core with a quinoline moiety via a carbon spacer. Materials and Methods: The hybrid molecule was synthesized through a straightforward route and structurally confirmed by spectroscopic analyses. Zebrafish (Danio rerio) were employed as an in vivo model, with hyperglycemia induced by immersion in 100 mM glucose monohydrate for 12 days. Fish were divided into treatment groups receiving 20 or 80 mg/kg of the compound, alongside the controls. Biochemical parameters (glucose, triglycerides, insulin) and gene expression levels (NF-κB, ACOX1, ACCα) were assessed. In silico docking was conducted to predict molecular interactions. Results: Treatment with the hybrid compound significantly restored glucose, triglyceride, and insulin levels. High-dose administration suppressed NF-κB expression and normalized ACOX1 levels, while both low- and high-dose treatments downregulated ACCα compared with untreated hyperglycemic controls. Computational studies supported multitarget activity through predicted binding to PPAR-α and ACOX1. Conclusions: Quinoline-Thiazolidine-2,4-Dione demonstrated strong antihyperglycemic and antihypertriglyceridemic activities in zebrafish models, supported by in silico validation.

Background/Objective: Traditionally derived from the dried leaves of Microcos paniculata L., Microctis folium (M. folium) has been employed to manage various inflammatory and metabolic conditions. Despite its reported hypolipidemic potential, the active constituents contributing to this effect and their molecular mechanisms of action remain to be determined. Therefore, this study aimed to systematically identify the active hypolipidemic constituents of M. folium and elucidate their mechanisms of action through an integrated strategy combining chemical profiling, pharmacokinetic screening, network pharmacology, and experimental validation. Methods: UPLC fingerprint and UPLC-QQQ-MS/MS were employed to characterize and quantify the chemical constituents of M. folium. Pharmacokinetic analysis was conducted to identify systemically absorbed compounds. Network pharmacology was applied to predict potential targets and signaling pathways. The lipid-lowering effects were subsequently validated in vitro using an oleic acid/palmitic acid (OA/PA)-induced lipid accumulation model in HepG2 cells and in vivo in a Triton WR-1339-induced hyperlipidemia mouse model. Results: UPLC fingerprint analysis identified 15 common peaks among 21 batches of M. folium, with similarity values ranging from 0.885 to 0.990, indicating good chemical consistency. Eighteen representative compounds were quantified, among which flavone C-glycosides and phenolic acids were predominant. Pharmacokinetic results demonstrated that multiple M. folium's constituents were absorbed into systemic circulation. Network pharmacology analysis identified 73 potential targets related to hyperlipidemia and highlighted the PI3K-Akt signaling pathway as a key regulatory pathway. In vitro experiments showed that M. folium's compounds significantly reduced intracellular lipid accumulation and oxidative stress in OA/PA-induced HepG2 cells. Furthermore, in vivo studies demonstrated that vitexin, ferulic acid, isoferulic acid, and N-trans-feruloyltyramine significantly reduced serum and hepatic lipid levels, including TC, TG, and LDL-c, alleviated hepatic steatosis, and improved liver injury and oxidative stress markers in Triton WR-1339-induced hyperlipidemic mice. Conclusions: M. folium exerts significant lipid-lowering effects through multi-component and multi-target mechanisms involving regulation of lipid metabolism and oxidative stress, partly mediated by activation of the PI3K-Akt signaling pathway. These findings provide a scientific basis for the development of M. folium's natural agents for the treatment of hyperlipidemia.

Background: High-density lipoprotein (HDL) exerts atheroprotective properties, partially by maintaining endothelial function. Protocatechuic acid (PCA) has been shown to improve endothelial function in mice. However, whether PCA improves endothelial function in humans is currently unknown. Our studies aimed to evaluate the effects of PCA on endothelial function and HDL concentration, subclass distribution, and functionality in humans. Methods: A double-blind, randomized, placebo-controlled trial was conducted in 150 hypercholesterolemic participants (aged 35-65 y) daily receiving 20 mg PCA or placebo capsules for 12 weeks. Endothelial function [brachial artery flow-mediated dilation (FMD)], serum cyclic guanosine monophosphate (cGMP), HDL concentration, subclass distribution (pre-β-HDL, HDL3, HDL2), and functionality [endothelial nitric oxide synthase (eNOS) activity] were tested at baseline, 6 weeks, and 12 weeks. Results: PCA consumption for 12 weeks significantly improved brachial artery FMD [1.77% (95% CI: 1.46 to 2.08)] and increased cGMP [11.72 pmol/L (95% CI: 6.16 to 17.28)] as compared to the placebo treatment, along with increased HDL3, decreased HDL2, and non-significantly changed in HDL and pre-β-HDL. PCA consumption also increased eNOS activity of HDL [0.39 (95% CI: 0.29 to 0.49)]. In the PCA group, the changes in HDL functionality on eNOS activity were positively correlated with the changes in brachial artery FMD, cGMP, and HDL3, whereas negatively correlated with HDL2. Conclusions: PCA consumption improves endothelial function and HDL functionality in humans with hypercholesterolemia, with accompanying shifts in HDL subclass distributions. These findings are hypothesis-generating and require confirmation in larger, long-term trials.

The spectrum of diseases in individuals with human immunodeficiency virus (HIV) receiving successful antiretroviral therapy has evolved over time. In the past, they developed opportunistic infections and malignancies, whereas today, cardiovascular disease is among the most common causes of illness and premature death. Traditional risk factors for atherosclerosis (hypertension, hyperlipidemia, smoking, diabetes, family history of heart disease) are more prevalent in people with HIV than in the general population. However, it is well established that HIV itself causes increased immune activation, chronic inflammation, vascular dysfunction, and a cluster of metabolic abnormalities that contribute to a faster-than-usual rate of biological aging and a higher risk of developing atherosclerosis, a risk not fully captured by current risk models. In the REPRIEVE study, treatment with pitavastatin was shown to reduce the rate of first cardiovascular events among individuals with HIV receiving antiretroviral therapy. Importantly, the beneficial effects of statins on atherosclerosis likely extend beyond lowering cholesterol to include effects on vascular function and on immune and metabolic systems altered by HIV. Even among individuals on statins, a considerable risk of cardiovascular disease remains. Here, We provide a narrative review of current evidence and an expert perspective on emerging approaches to residual cardiovascular risk after REPRIEVE. We review the current understanding of atherosclerosis pathogenesis in individuals with HIV, focusing on recent findings from the REPRIEVE trial. We outline current approaches to improving cardiovascular risk assessment across clinical, biological, and computational levels. We also examine a growing number of therapeutic options that address residual inflammation and atherogenic metabolic disturbance in individuals with HIV on long-term, effective antiretroviral therapy. Significantly, after REPRIEVE, we must move from prescribing statins to all individuals with HIV toward more individualized cardiovascular disease prevention strategies, integrating clinical information, a variety of biomarkers, imaging studies, and even molecular information to generate optimal individualized cardiovascular disease prevention regimens that reflect the complexity of this outcome in naturally diverse individuals.

Background: Variants of uncertain significance (VUS) in the LDLR gene remain a major barrier to the molecular diagnosis of familial hypercholesterolemia. Although computational approaches offer scalable prioritization, their clinical utility is limited by predictor discordance, incomplete annotations, and inflated performance arising from variant-type imbalance. We aimed to develop a calibrated, uncertainty-aware machine learning framework for LDLR VUS triage. Methods: We developed an end-to-end pipeline integrating multi-source variant annotations and 45 engineered features (expanded to 68 encoded features) to train RandomForest, XGBoost, and support vector machine models. The framework incorporates predictor concordance analysis, splice-aware annotation, and explicit uncertainty modeling. Models were trained using nested cross-validation and evaluated on an independent ClinGen FH-VCEP expert-panel dataset. Results: The XGBoost model achieved high discriminative performance (ROC-AUC up to 0.99 for all variants and ~0.97 for missense variants). Among 1092 LDLR VUS, 69% were assigned a directional classification, including 485 (44.4%) pathogenic-leaning and 268 (24.5%) benign-leaning variants. The remaining 31% were explicitly categorized as predictor-discordant (n = 170, 15.6%) or unresolved (n = 169, 15.5%), preserving uncertainty. Predictor discordance was particularly enriched among missense variants, indicating that naive aggregation of in silico predictors may lead to overclassification. Conclusions: This framework provides a scalable, transparent, and clinically aligned approach for LDLR VUS prioritization, generating ACMG/AMP-compatible computational evidence to support expert curation and downstream functional validation.

Hypercholesterolemia and hyperlipidemia are major contributors to the pathogenesis and progression of atherosclerosis and cardiovascular diseases (CVDs). Nuclear factor erythroid-derived 2-like 2 (NRF2) exerts antioxidant and anti-inflammatory effects while regulating glucose and lipid metabolism. However, the precise role and molecular mechanisms of NRF2 in hepatic cholesterol metabolism remain incompletely understood. Approach and Results: ApoE-knockout (ApoE-KO) mice were crossed with hepatocyte-specific Nrf2-knockout (Nrf2(H)-KO) mice to explore how NRF2 modulated cholesterol metabolism and the progression of atherosclerosis in vivo. Atherosclerotic lesion areas in Nrf2(H)-KO;ApoE-KO mice were significantly reduced compared with control counterparts (Nrf2-LoxP;ApoE-KO). Total cholesterol and LDL-cholesterol levels in plasma of Nrf2(H)-KO;ApoE-KO mice were significantly decreased, consistent with atherosclerotic phenotypes. Furthermore, hepatic triglyceride levels and cholesterol contents were increased in Nrf2(H)-KO;ApoE-KO mice. The hepatic transcriptomic analysis highlighted lipid metabolism pathway alterations in Nrf2(H)-KO;ApoE-KO mice, and carboxylesterase 1 (Ces1s) and lipocalin gene family member major urinary proteins (Mups) clusters markedly reduced expression in Nrf2(H)-KO;ApoE-KO livers. Liver proteomics analysis corroborated the transcriptomic findings. The current findings suggest that NRF2-modulated CES1s and MUPs may regulate cholesterol metabolism in the ApoE-KO model. Conclusions: Hepatocyte-specific Nrf2 deficiency significantly reduced plasma cholesterol levels, thereby attenuating atherosclerotic plaque formation and progression in the ApoE-KO background. This study established NRF2 in hepatocytes as a potential therapeutic target for controlling hypercholesterolemia and preventing atherosclerosis development.