The clinical utility of streptokinase, a widely used and cost-effective thrombolytic agent, has gained importance post COVID-19 due to increase in cardiovascular diseases globally. But the strong humoral immunogenicity exhibited by it, restricts its usage. Building upon our prior work of developing truncated streptokinase variants and their plasminogen activation study, we report here the results of immunogenicity studies for identification of variants with reduced immunogenicity. A panel of ten rationally truncated and recombinantly expressed streptokinase fragments were screened for antibody recognition and immunogenicity potential. Out of the ten fragments, two N-terminal constructs (amino acid residues 1-300 and 1-173) exhibited approximately 40-45% lower ELISA immunoreactivity compared with full-length streptokinase during initial in vitro screening. These fragments were also already reported to retain >85% of native plasminogen activation activity. In vivo evaluation of the fragments in rabbits demonstrated significantly attenuated humoral responses over a 28-day immunization period, confirmed by longitudinal antibody titration and cumulative area-under-the-curve analysis when compared to the full-length streptokinase. Fragment 1-173 emerged as a promising lower-immunogenic thrombolytic candidate, and this work demonstrates that rational domain minimization can decouple functional competence from immunodominant regions in streptokinase establishing a broadly applicable framework for engineering improved therapeutic proteins.

Microplastics-derived dissolved organic matter (MPs-DOM) has emerged as a potential precursor of disinfection byproducts (DBPs), yet its behavior under realistic short-term chlorination remains poorly understood. Here, we investigated the formation patterns of both conventional and unknown DBPs from polystyrene (PS) and polyethylene terephthalate (PET) leachates under short contact times, combining bulk DBP analysis with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Abundant traditional DBPs were formed rapidly, with trihalomethanes (THMs) as the dominant species. In comparison, PS-DOM showed higher chlorine consumption but PET-DOM produced higher DBP yields and a broader spectrum of species, accounting for 14.63 µg/mg DOC of total 15 DBPs subtypes versus 8.56 µg/mg DOC of total 12 DBPs subtypes for 60 min. For unknown DBPs, molecular-level analysis revealed that PET-DOM generated a more diverse pool of DBPs enriched in oxidized compounds, whereas DBPs derived from PS-DOM were relatively more unsaturated and aromatic-like. Further analysis reflect distinct transformation for two DOM during chlorination. PS-DOM underwent decarbonization, and mono-halogenation dominated its DBP formation. In contrast, PET-DOM exhibited oxidation transformation, with mono- and multi-halogenation contributing comparably to DBP formation. These findings demonstrate that DBP formation from MPs-DOM is highly dependent on polymer structure and can occur rapidly under short-term chlorination. And the elevated DBP formation potential of PET-DOM highlights a greater risk of PET MPs in aquatic environments.

Lipoprotein(a) is an independent cardiovascular risk factor with limited therapeutic options. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce lipoprotein(a), but comparative real-world data across available agents are scarce. We aimed to evaluate lipoprotein(a) reduction with PCSK9i in a large prospective registry.

We analysed 1112 patients from a prospective single-centre PCSK9i registry with available baseline lipoprotein(a) measurements and follow-up data. Patients received alirocumab, evolocumab, or inclisiran according to clinical practice. Lipoprotein(a) changes were assessed at 3, 9, and 21 months using mixed-effects models and inverse probability of treatment weighting (IPTW).

Clinical atherosclerotic disease was present in 52.4% of patients; median baseline LDL-C and lipoprotein(a) concentrations were 3.8 mmol/L (IQR 2.4-4.9) and 67.3 mg/dL (IQR 13.9-130.8), respectively. PCSK9i therapy resulted in a significant and sustained reduction in lipoprotein(a), with mean changes of -15.3%, -16.7%, and -19.0% at 3, 9, and 21 months, respectively (all p < 0.001). In unadjusted analyses, reductions ranged from -14% to -21% with alirocumab and evolocumab and from -8% to -17% with inclisiran. After IPTW adjustment, similar patterns were observed (-13% to -19% vs -8% to -17%), with no statistically significant differences between treatment groups at any time point (all p > 0.05).

In this large real-world cohort, PCSK9i therapies produced modest but significant reductions in lipoprotein(a). No statistically significant differences between agents were detected, although estimates for inclisiran were less precise because of the smaller sample size. Reductions were smaller than in randomised clinical trials, highlighting the need for targeted therapies.

Chronic cardiovascular diseases (CVD) care quality remains suboptimal, globally. We assessed the feasibility, acceptability, fidelity, and preliminary effect of a multicomponent, collaborative quality improvement (C-QIP) strategy among patients with CVD attending outpatient clinics in India.

In this pragmatic feasibility randomized controlled trial, 410 adults with ischemic heart disease, ischemic stroke, or heart failure attending four public and private hospitals were randomized to C-QIP (electronic decision support for providers, non-physician care coordination, patient education, text-message reminders, and audit-feedback) or usual care. Primary outcomes were feasibility, fidelity, adoption, and acceptability; secondary outcomes included guideline-directed medical therapy (GDMT), self-reported adherence, care processes, and risk factors. At end of study (median follow-up 15 months), retention was 192/206 (93.2%) in C-QIP and 187/204 (91.7%) in usual care. Fidelity was high: 187/198 (94.4%) C-QIP participants received lifestyle counseling at end of study. C-QIP increased GDMT use for ischemic heart disease (58.3% versus 32.4%; relative risk [RR] 1.45, 95% CI [1.18, 1.78]) and ischemic stroke (76.7% versus 31.8%; RR 2.41, 95% CI [1.52, 3.81]), but not heart failure. Self-reported adherence was higher for medications (90.9% versus 82.3%; RR 1.08, 95% CI [1.04, 1.12]), diet (91.9% versus 82.3%; RR 1.07, 95% CI [1.02, 1.13]), and physical activity (91.4% versus 70.4%; RR 1.23, 95% CI [1.16, 1.30]). Limitations include feasibility design, individual randomization within shared clinics, and limited power for clinical outcomes and subgroup analysis.

The C-QIP trial demonstrated that a multicomponent strategy is feasible, acceptable, and improved chronic CVD care processes in India. Future large, confirmatory hybrid trials are needed to establish whether such quality improvement strategies can reduce cardiovascular morbidity and mortality.

NCT05196659; CTRI/2022/04/041847.

BACKGROUND Image-guided pericardiocentesis is a diagnostic and potentially life-saving intervention, yet even under guidance, rare complications can occur. Among them, bowel perforation with subsequent fecal pericarditis is an exceptionally uncommon and often under-recognized occurrence. CASE REPORT We describe the case of a 72-year-old man with multiple comorbidities, including acute colonic pseudo-obstruction (Ogilvie syndrome), Parkinson disease, and chronic kidney disease, who underwent urgent fluoroscopy-guided pericardiocentesis for a large pericardial effusion. After the procedure, his drain ceased to release any fluid, and he experienced progressive tachycardia. Imaging revealed that the catheter inadvertently penetrated the transverse colon, resulting in pneumoperitoneum and pneumopericardium. He required combined thoracic and abdominal surgery, including a pericardial window, controlled drain removal, primary colonic repair, and diverting colostomy. His recovery was uneventful, and he was discharged in stable condition. CONCLUSIONS Only a handful of similar cases are reported in the literature. Our case presents additional evidence that image-guided pericardiocentesis may be associated with an increased risk of iatrogenic bowel injury in patients with abdominal distension or colonic dysmotility. The patient was treated surgically for pericardial drainage and repair of colonic perforation, further addressing the patient's dysmotility at the time of surgery with the creation of a diverting colostomy. Awareness of unusual drain behavior and early imaging can expedite recognition and management of this life-threatening complication.

Maintaining a stable cerebral blood flow (CBF) despite variations in blood pressure is crucial for normal brain function. This process, called cerebral autoregulation, is often impaired in pathologies such as ischemic stroke, underlining its clinical importance. However, how local vascular responses interact across complex cerebrovascular networks to stabilize perfusion remains poorly understood. Here, we present an in silico model of static autoregulation that can be applied to realistic microvascular networks, providing vessel-specific insights into vasoreactivity and perfusion dynamics. Our simulations revealed a hierarchical organization of autoregulatory responses, in which pial surface arteries act as key regulators that buffer pressure changes across large vascular territories. Arterial density emerged as a decisive determinant of network-specific autoregulatory capacity, highlighting the importance of vascular topology for maintaining stable perfusion. During poststroke reperfusion, alterations in vasoreactivity, rather than collateral extent alone, emerged as the main contributor to pathogenic hyperperfusion. Simulations of chronic autoregulatory dysfunction showed that progressive loss of vascular reactivity can produce substantial downstream disturbances in capillary perfusion and alter the autoregulation curve. Overall, our framework reveals how interactions between vascular topology and vessel-specific regulatory mechanisms shape CBF regulation across scales, from individual arteries to whole-network perfusion. These findings highlight myogenic tone as a potential therapeutic target to reduce reperfusion-related complications in stroke.

Atherosclerosis is a chronic inflammatory disease in which oxidative stress serves as a final common mechanism linking endothelial injury, lipoprotein oxidation, immune activation, and plaque progression. Since the original description of reactive oxygen species (ROS) generating and antioxidant systems in atherogenesis, substantial advances have reshaped the mechanistic and therapeutic landscape. This review provides a comprehensive update on oxidative stress in atherosclerosis, with particular emphasis on the LOX-1-NLRP3 inflammasome axis as a central driver of residual inflammatory risk.

The lectin-like oxidized LDL receptor-1 (LOX-1) has been established as a regulated, druggable node through the identification of TRIM31-mediated ubiquitination. The first-in-human LOX-1 antibody trial (GOLDILOX-TIMI 69) demonstrated near-complete soluble LOX-1 suppression and IL-6 reduction, though plaque regression was not achieved. The mechanistic cascade linking LOX-1 activation to mitochondrial DNA damage, impaired autophagy, and NLRP3 inflammasome-driven IL-1β release now provides a molecular explanation for persistent vascular inflammation even when LDL-C targets are met with high-intensity statins and PCSK9 inhibitors. Clinical validation of the inflammation hypothesis through CANTOS, COLCOT, and LoDoCo2 has led to FDA approval of colchicine for secondary cardiovascular prevention. Emerging evidence implicates clonal hematopoiesis, vascular senescence, and the senescence-associated secretory phenotype as amplifiers of oxidative-inflammatory signaling in the vessel wall. The LOX-1-NLRP3 axis represents an important mechanistic advance since the original characterization of oxidative stress in atherosclerosis. Future strategies, including direct NLRP3 inhibitors, longer-duration LOX-1 antibody trials, biomarker-guided combination therapy, and mitochondria-targeted antioxidants, aim to close the residual inflammatory risk gap that persists despite optimal lipid-lowering therapy.

To investigate the prevalence of sleep problems and their risk factors among older adults with type 1 diabetes.

Participants with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study completed validated questionnaires to assess sleep-related problems, including risk of obstructive sleep apnea (OSA) (intermediate/high risk: STOP-Bang ≥3), poor sleep quality (Pittsburgh Sleep Quality Index >5), and mild or greater levels of excessive daytime sleepiness (Epworth Sleepiness Scale >10). Logistic regression models assessed the odds of each sleep problem by demographic and clinical variables, glycemia, and diabetes complications.

In 963 participants (52% male, mean [SD] age 64 [7] years) with type 1 diabetes (mean [SD] duration 43 [5] years), diagnosed OSA and current positive airway pressure device use were reported by 29% and 19% of participants, respectively. Increased OSA risk was present in 64%, poor sleep quality in 43%, and daytime sleepiness in 10% of participants. Each 1% absolute increase (11 mmol/mol) in current or mean HbA1c was associated with 15% to 20% higher odds of any sleep problem. In models adjusted for age, sex, BMI, and mean HbA1c, cardiovascular autonomic neuropathy was associated with higher odds of intermediate/high OSA risk, and albuminuria and severe hypoglycemia were associated with higher odds of poor sleep quality.

OSA risk and poor sleep quality were common among DCCT/EDIC participants. Sleep assessments for older individuals with long-standing type 1 diabetes and research to identify mechanisms to explain the observed associations are warranted.

Heart failure (HF) is the end stage of various cardiovascular diseases, and persistent myocardial injury and adverse remodeling are major causes of its high hospitalization and mortality rates worldwide. Therefore, it is important to identify key molecules and effective agents that can slow or reverse HF progression. Cycloastragenol (CAG) is an active compound derived from Astragalus and has anti-inflammatory, antioxidant, and tissue-protective effects. The present study aimed to clarify the protective role of CAG in HF and to determine whether this effect is related to the regulation of ferroptosis through the PI3K/AKT/mTOR signaling pathway. The results showed that PI3K/AKT/mTOR signaling activity was markedly decreased in myocardial tissue from HF rats, accompanied by impaired cardiac function, aggravated myocardial injury, enhanced inflammatory response, and increased myocardial fibrosis and hypertrophic remodeling. At the same time, GSH levels were decreased, whereas ROS, MDA, and Fe²⁺ levels were increased. In addition, GPX4 and FTH1 expression was downregulated, ACSL4 expression was upregulated, and the Prussian blue-positive area was increased, indicating marked ferroptosis-related abnormalities. After CAG treatment, these changes were improved to different degrees. CAG restored cardiac function, reduced serum NT-proBNP, CK-MB, and cTnI levels, decreased inflammatory factor expression, and alleviated myocardial fibrosis and hypertrophy. Meanwhile, PI3K/AKT/mTOR signaling activity was restored, and iron deposition, lipid peroxidation, and ferroptosis-related molecular abnormalities were alleviated. In vitro experiments further showed that, in an OGD-induced H9c2 cell injury model, CAG increased cell viability, reduced LDH release, attenuated the inflammatory response, and alleviated mitochondrial membrane potential loss, ROS accumulation, and ferroptosis-related protein abnormalities. C11-BODIPY 581/591 flow cytometry further demonstrated that CAG reduced OGD-induced lipid ROS accumulation and lipid peroxidation. In addition, the ferroptosis inhibitor ferrostatin-1 partially rescued OGD-induced cell injury, restored cell viability, reduced LDH release, and suppressed lipid ROS accumulation, further supporting the involvement of ferroptosis-related processes. Further intervention with the AKT inhibitor MK-2206 partially weakened the protective effects of CAG, supporting the involvement of AKT signaling in its protective action. In conclusion, the present study showed that CAG improved HF-related myocardial injury and myocardial remodeling by restoring PI3K/AKT/mTOR signaling activity and inhibiting ferroptosis-related processes, suggesting that CAG may be a potential therapeutic agent for HF.

β2-microglobulin (B₂M), a structural component of major histocompatibility complex class I (MHC-I), is widely expressed on the surface of all nucleated cells, and exists in free form in blood, urine, and cerebrospinal fluid. Under normal physiological conditions, B₂M associates noncovalently with the MHC-I heavy chain, thereby supporting proper folding, peptide loading, complex stability, and cell surface expression; the assembled peptide-MHC-I complex is then recognized by CD8⁺ cytotoxic T cells during immune surveillance. B₂M is primarily eliminated through glomerular filtration, proximal tubular reabsorption, and metabolic clearance. In recent years, B₂M metabolic and expression abnormalities have been observed in various diseases, where it contributes to pathological processes such as inflammatory signaling, regulation of apoptosis, iron metabolism, and tumor immune evasion. B₂M has demonstrated potential value as a biomarker in multisystem diseases. This comprehensive review synthesizes current evidence on B₂M's multifaceted roles as a biomarker and functional regulator across cardiovascular, respiratory, renal and urinary, central nervous system, immune, neoplastic, and locomotor system disorders. We focus on the molecular mechanisms underlying these abnormalities and evaluate the evidence supporting B₂M as a candidate biomarker for diagnosis, assessment of disease activity or progression, and prognosis across different diseases. This review underscores B₂M's emerging significance beyond renal function, linking it to multisystem disease pathogenesis and translational medicine.