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Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function.

Complex bidirectional interactions between the nervous and cardiovascular systems are integrated through the heart–brain axis, a physiological pathway that governs both neural regulation of cardiovascular function and cardiovascular influences on brain health. Emerging evidence indicates that even in the absence of overt disease, subclinical changes in the heart, aortic arch, and extracranial arteries contribute to brain injury and cognitive vulnerability. This review synthesizes current knowledge on how subclinical heart–brain axis dysfunction affects brain structure and function, highlighting the roles of central and autonomic neural pathways as well as hormonal signaling in driving neurological decline. Key biomarkers linked to silent brain injury, cognitive decline, and dementia are discussed, emphasizing their potential for early risk stratification and as targets for preventive interventions. We also outline mechanistic pathways connecting subclinical heart–brain axis dysfunction to adverse brain outcomes, identify major gaps in current evidence, and propose priorities for future research and clinical trials aimed at early detection and risk reduction to preserve brain health.

Background: The management of asymptomatic high-grade carotid stenosis remains challenging, particularly in identifying individuals at highest risk for hypoperfusion-related stroke. Impaired cerebrovascular reactivity (CVR) has emerged as a potential predictor of future cerebrovascular events. Objective: To perform a systematic review and meta-analysis to quantify the association between impaired CVR and the risk of ipsilateral ischemic stroke or TIA in patients with asymptomatic high-grade carotid stenosis/occlusion. Methods: A systematic literature search of PubMed, Embase and Scopus was conducted from inception till July 2025. Eligible studies included asymptomatic patients with ≥70% carotid stenosis or occlusion who underwent CVR assessment and reported ipsilateral ischemic stroke or TIA outcomes. Pooled relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Forest plots were generated, and heterogeneity was assessed using the chi-square test and the I 2 statistic. Results: Six prospective observational studies including a total of 361 patients with asymptomatic high-grade carotid stenosis/occlusion (mean age 70.4 years; 73.6% male; 71.2% with hypertension; 28.6% with diabetes; 29.6% current or former smokers) were included in the analysis. Of these, 120 patients had impaired CVR and 241 had preserved CVR. Transcranial Doppler (TCD) was the most frequently used modality to assess CVR, with acetazolamide or CO 2 as the vasodilatory stimulus. Following CVR assessment, patients were monitored for a weighted mean follow-up of 26.2 months (range: 21.5 to 42.5 months). The incidence of ipsilateral ischemic stroke or TIA was 14.2% in patients with impaired CVR versus 2.1% in those with preserved CVR (RR 3.98; 95% CI 1.62–9.76; P = 0.003; Figure 1). When limited to ipsilateral ischemic stroke alone, the incidence was 21.4% in the impaired CVR group compared to 4.3% in the preserved CVR group (RR 3.35; 95% CI 1.54–7.25; P = 0.002; Figure 2). Conclusions: Impaired CVR is associated with a 3- to 4-fold increased risk of ipsilateral ischemic stroke or TIA in patients with high-grade carotid stenosis/occlusion. CVR assessment may help stratify risk and guide individualized management in this population.

Background: Previous studies have reported the mean difference in homocysteine level in patients with and without silent brain infarction. However, evidence regarding the rate of silent brain infarcts in the presence versus absence of hyperhomocysteinemia remains limited. Objective: We aim to perform a systematic review and meta-analysis to compare the rate of silent brain infarcts in patients with hyperhomocysteinemia compared with patients with normal or low homocysteine levels. Methods: A systematic search of PubMed, Embase, Web of Science, Scopus were searched from inception to June 18, 2025. Eligible studies compared the rate of image-confirmed silent brain infarcts in patients with hyperhomocysteinemia versus those with normal homocysteine levels. The primary outcome was the rate of silent brain infarcts; the secondary outcome was cognition assessed by the Mini-Mental State Examination (MMSE). Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model, and heterogeneity was assessed using I 2 statistics. Subgroup analyses were performed according to increasing hyperhomocysteinemia cutoffs (>12 μmol/L and 9–12 μmol/L) as defined in the included the studies. Results: Four observational studies involving 2331 patients were included (mean age was 58.0±6.4 years, 45.8% women). Of these, 1087 had hyperhomocysteinemia and 1244 had normal levels. The rate of silent brain infarcts was 23.3% (253/1087) in patients with hyperhomocysteinemia versus 22.8% (284/1244) in controls (OR 1.82; 95% CI 1.11-3.00; P = 0.02, Figure 1A). The association was higher in studies using a > 12 µmol/L cutoff (OR 3.08; 95% CI 1.85-5.11; P < 0.0001, Figure 1B). Patients with hyperhomocystinemia had lower MMSE score compared with controls (mean difference of -1.55; 95% CI -3.60-0.50; P = 0.14, Figure 2). Conclusions: Hyperhomocysteinemia is associated with increased risk of silent brain infarcts and numerically lower cognitive performance. Findings suggest a possible dose-dependent relationship between homocysteine level and silent stroke risk. Prospective studies are needed to determine whether homocysteine is a modifable therapeutic tharget for reducing silent infarcts and cognitive decline.

Introduction: Studies suggest that stroke and hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real-world populations. Hypothesis: We hypothesized that HF subtypes are differentially associated with cognitive impairment and that lower left ventricular ejection fraction (LVEF) correlates with poorer cognitive performance. Methods: We conducted a cross-sectional study of patients aged ≥18 years seen at a Heath System in 2022 who underwent both echocardiogram and cognitive assessment within one year. HF was classified into four groups based on 2022 American Heart Association HF guideline: No heart failure, HFpEF (HF with preserved LVEF), HFmrEF (HF with mid-range LVEF), and HFrEF (HF with reduced LVEF). Cognitive impairment was categorized using the Montreal Cognitive Assessment (MOCA) as normal (≥26), mild (18–25), moderate (10–17), and severe (<10). Multivariable linear regression assessed the correlation between EF and MoCA, and logistic regression evaluated the association between HF subtypes and severity of cognitive loss, adjusting for age, sex, race, hypertension, diabetes, dyslipidemia, chronic kidney disease, stroke. Results: A total of 1,695 patients were included in the study (mean age, 75.3±14 years; 48.3% female). 82.0% had HFpEF; 7.1%, HFmrEF; 7.9%, HFrEF, and 3.0% no HF. LVEF was positively associated with MoCA score (β=0.028, p=0.032). Patients with LVEF ≤40% had lower MoCA scores (17.7 ± 6.2 vs. 19.1 ± 5.9, p=0.008) and higher adjusted odds of moderate/severe cognitive impairment (aOR 2.49, 95%CI 1.20-5.15, p=0.014), compared to those with LVEF >40%. Adjusted odds of moderate to severe cognitive impairment were 1.14 for HFpEF, 0.99 for HFmrEF, and 2.81 for HFrEF compared to patients with no heart failure (trend-P=0.031, Table). Conclusions: Lower LVEF was independently associated with worse cognitive performance. Patients with HFrEF had a 2.5-fold higher risk of moderate to severe cognitive impairment. This association was not observed in patients with HFpEF or HFmrEF, suggesting differential cognitive effects across HF subtypes. Further studies are warranted to confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

Introduction: Cerebral amyloid angiopathy (CAA) is a progressive cerebrovascular disease caused by amyloid-beta (Aβ) deposition in cerebral vasculature. While CAA is a recognized cause of intracerebral hemorrhage (ICH) and cognitive decline, emerging evidence suggests that seizures are among a broader array of CAA clinical manifestations. However, the risk of seizures and status epilepticus in CAA remains poorly characterized. This study aimed to estimate incidence of seizures and status epilepticus in CAA using real-world data. Methods: A retrospective, longitudinal study was conducted using a nationally representative sample of administrative claims from US Medicare and commercial insurance beneficiaries (2017–2024). Patients with CAA (aged > 50 years with > 1 physician encounter with a validated ICD-10 code (I68.0)) were matched 1:4 to age- and sex-matched controls. The primary outcome was occurrence of seizure, ascertained using validated ICD-10 codes during acute care; the secondary outcome was hospitalization for status epilepticus. Follow-up continued until the end of enrollment or death. Descriptive statistics summarized patient characteristics and Poisson regression estimated incidence rates with 95% CIs. Cox proportional hazards regression assessed associations between CAA and outcomes of interest vs controls, adjusted for chronic kidney disease, liver disease, prior ICH, and seizure history. Results: We included 7294 patients with CAA and 29176 controls (median age: 77 years; 53.7% women; median follow-up: 29.4 months). Patients with CAA had higher rates of prior ICH (32.4% vs 0.5%) and prior seizure (18.7% vs 1.8%) than controls. The incidence rate of seizures was higher in patients with CAA than controls: 8.1 per 100 person-years (PY; 95% CI: 7.6–8.6) vs 0.4 per 100 PY (95% CI: 0.4–0.5). In the CAA cohort, seizure incidence rate was higher for those with prior ICH than those with no ICH history: 13.6 per 100 PY (95% CI: 12.5–14.8) vs 5.7 per 100 PY (95% CI: 5.2–6.3). Status epilepticus rates were higher in patients with CAA than controls: 0.7 per 100 PY (95% CI: 0.6–0.9) vs 0.03 per 100 PY (95% CI: 0.02–0.04). Adjusted models showed that CAA was associated with higher risk of seizures (HR: 6.7, 95% CI: 5.8–7.7) and status epilepticus (HR: 8.1, 95% CI: 4.8–13.7) than controls (Table 1). Conclusions: Patients with CAA have an increased risk of seizures and status epilepticus. These findings broaden the possible clinical spectrum of CAA.

Background The role of dose escalation of radiotherapy (RT) in unresectable stage III NSCLC followed by immunotherapy is unclear. The objective of the current study is to investigate if intermediate dose escalation (IDE) is beneficial in stage III NSCLC patients who receive definitive concurrent chemoradiation (dcCRT) followed by immunotherapy. Materials and methods The study used data from the National Cancer database. Multivariable Cox regression analysis was used to assess the all-cause mortality of patients who received standard RT dose (SD) (60 Gy ± 10%) and IDE (64–74 Gy). Results 47,315 patients were diagnosed in the era before immunotherapy and received dcCRT only, while 4,947 patients were treated with dcCRT and immunotherapy. In the cohort with dcCRT only, patients who received SD had statistically significant worse mortality but clinically minimal difference compared to patients with IDE (HR: 1.09, 95% CI: 1.07-1.12; p&lt;0.0001). In the era of immunotherapy, SD was still associated with worse mortality compared to IDE (HR: 1.17, 95% CI: 1.03-1.33; p=0.02). However, the survival benefit associated with IDE was only restricted to patients who started immunotherapy within six weeks after RT completion (HR: 1.26, 95% CI: 1.05-1.6; p=0.01). There was no difference in mortality between SD and IDE among patients who started immunotherapy between 7–10 weeks (HR: 1.13, 95% CI: 0.88-1.45; p=0.35) or &gt;10 weeks after RT completion (HR: 0.74, 95% CI: 0.51-1.07; p=0.11). Conclusion IDE of RT is not needed for patients diagnosed with stage III unresectable NSCLC who receive immunotherapy &gt; six weeks after dcCRT.

Abstract Objective Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

Importance The Surgery as Needed for Oesophageal Cancer (SANO) trial introduced active surveillance as a noninferior alternative to esophagectomy for patients with esophageal cancer who achieve a clinical complete response (cCR) after neoadjuvant chemoradiation (nCRT). However, concerns remain about recurrence risk, long-term survival, and quality-of-life trade-offs with organ-preserving strategies. Objective To evaluate the long-term comparative effectiveness of active surveillance vs standard esophagectomy in patients with cCR following nCRT for locally advanced esophageal cancer, using updated data from the SANO trial. Design, Setting, and Participants This decision analytical model used Markov modeling and probabilities and utility inputs derived from the SANO trial and existing literature. The base case was a 60-year-old male with good functional status and cT3N1M0 esophageal cancer achieving cCR after nCRT. Exposures Standard routine esophagectomy vs active surveillance after neoadjuvant chemoradiation. Main Outcomes and Measures The primary outcome was quality-adjusted life-years (QALYs); the secondary outcome was life-years. Additional model scenarios explored (1) quality-of-life impacts of esophagectomy modeled as a time-varying covariate and (2) 2-year outcomes to align with the SANO trial time horizon. Sensitivity analyses evaluated recurrence probabilities and surgery-related quality-of-life trade-offs. Results At 5 years, standard surgery yielded greater QALYs (1.74 vs 1.34; incremental gain of 0.40 QALYs or ~4.8 months in perfect health) and life-years (3.11 vs 2.41; incremental gain of 0.70 life-years or ~8.4 months) compared with active surveillance. However, at a 2-year horizon, active surveillance was preferred for QALYs (incremental gain of ~15 days), consistent with the SANO trial. Sensitivity analyses revealed the model favored active surveillance when the recurrence probability was less than 43%, the likelihood of local/resectable recurrence was greater than 94%, or the negative quality-of-life impact of esophagectomy was substantial. Modeling esophagectomy’s quality-of-life impact as time limited further strengthened surgery’s long-term QALY benefit. Conclusions and Relevance This study found that while active surveillance offers short-term quality-of-life benefits and may be appropriate in select patients, particularly those at low recurrence risk or with high surgical risk, esophagectomy remains the preferred strategy for maximizing long-term survival and QALYs. These findings support a nuanced, individualized approach to post-nCRT management, balancing organ preservation with long-term oncologic outcomes.