Cardiovascular risk in metabolic disease persists long after the initiating metabolic abnormalities are corrected, a phenomenon termed metabolic memory. The DCCT/EDIC cohort is illustrative: early glycemic control produced cardiovascular protection that peaked within a decade and left a lasting legacy. The same strategy applied after prolonged hyperglycemia, however, has not reproduced this benefit. This conceptual Review proposes a framework in which such persistent risk arises from four distinct processes: encoded epigenetic memory, irreversible structural damage, chronic input from dysfunctional organs, and delayed tissue remodeling, each with a different therapeutic logic. Persistence of these encoded marks is established most directly in immune-lineage cells; its extension to cardiomyocytes remains a working hypothesis. Only encoded memory is accessible to chromatin-directed reversal, and only before metabolic stress exhausts the erasure machinery that keeps marks revisable, a time-dependence proposed to explain why early intervention succeeds where late intervention fails. Clinical efficacy therefore may depend on engaging the substrate maintaining pathology rather than normalizing a surrogate biomarker, a substrate-alignment principle consistent with the divergent outcomes of recent cardiometabolic trials. We apply the framework to atherosclerosis, heart failure, and diabetic cardiomyopathy, grade its claims by a three-tier evidence classification, and specify testable predictions that could refute it.

Tumors actively remodel the tumor microenvironment (TME) to foster therapy resistance. However, the underlying mechanisms remain poorly defined. This study aims to characterize how colorectal cancer (CRC) cells drive TME remodeling to promote radioresistance.

A radioresistant CRC cell line was established via serial in vivo irradiation. Single-cell RNA sequencing characterized TME alterations. The role of tumor-derived small extracellular vesicles (sEVs) in macrophage polarization was assessed. Proteomic analysis identified ANXA2 as a key sEVs cargo, and calcium-dependent sEV secretion was investigated through SLC8A1 modulation. Clinical relevance analyses were further assessed.

The radioresistant model exhibited enhanced treatment resistance to irradiation and increased infiltration of M2-like tumor-associated macrophages (TAMs), while TAM depletion restored radiosensitivity. Tumor-derived sEVs promoted M2 polarization by activating STAT6 phosphorylation, with ANXA2 as the key functional cargo. Further analysis revealed that SLC8A1 deficiency increased intracellular Ca^{2 +} levels, boosting secretion of ANXA2⁺ sEVs and subsequent TAM M2 polarization. Clinically, low SLC8A1 expression correlated with higher M2 TAM infiltration, poorer therapeutic response, and worse survival outcomes in CRC patients.

CRC cells with low SLC8A1 expression remodel the TME to foster radioresistance via calcium-dependent secretion of ANXA2⁺ sEVs and subsequent M2 polarization of TAMs.

Background/Objectives: Cerebral small vessel disease (CSVD) is an important contributor to motor impairment. Cortical cerebral microinfarct (CCMI) is an emerging imaging marker of CSVD. Although its association with cognitive impairment has been well established, its relationship with motor function remains unclear. We explored associations of CCMI with motor performance at baseline and 1-year follow-up in this secondary analysis of data from the China Imaging-based Biobank of Cerebral Small Vessel Diseases. Methods: CCMI was assessed on baseline brain magnetic resonance imaging. Motor function was assessed at baseline and at 1-year follow-up. Outcomes were gait speed, poor balance performance (Short Physical Performance Battery balance score ≤ 2), abnormal gait (Scale for the Assessment and Rating of Ataxia gait score ≥ 2), and repeated chair-stand time. Gait speed was the primary outcome and all other motor outcomes were secondary. Multivariable linear and logistic regression models were used, with Benjamini-Hochberg correction applied to secondary outcomes. Results: The analysis included 192 patients, of whom 74 had 1-year follow-up motor data. At baseline, 55 patients (28.65%) had CCMI. Compared with patients without CCMI, those with CCMI had lower gait speed [0.92 (0.75-1.12) vs. 1.05 (0.87-1.16) m/s]. They also had higher prevalences of poor balance performance (29.09% vs. 14.60%) and abnormal gait (63.64% vs. 36.50%). However, fully adjusted analyses provided no conclusive evidence of baseline associations. At 1-year follow-up, CCMI was associated with slower gait speed after adjustment for demographic factors, baseline gait speed, and total CSVD burden (adjusted β -0.16, 95% CI -0.24 to -0.08; p < 0.001). CCMI was also nominally associated with longer repeated chair-stand time (adjusted β 2.07, 95% CI 0.39-3.75; nominal p = 0.02; adjusted p = 0.06), but this association did not survive correction for multiple comparisons. Conclusions: CCMI was associated with slower gait speed at 1-year follow-up in patients with CSVD. This finding is hypothesis-generating and requires confirmation.

Background: Survival after early breast cancer has improved to the point where reproductive health is no longer a peripheral concern in young survivors but a routine one. This review synthesizes current evidence on oncologic safety, obstetric and neonatal outcomes, fertility preservation, breastfeeding, and psychosocial survivorship to develop a counseling framework that clinicians can apply in practice. Methods: This narrative review was informed by a structured literature search of PubMed/MEDLINE, Embase, and the Cochrane Library covering studies published from January 2000 to July 2026, with greater analytic weight given to studies published from 2010 onward to ensure the synthesis reflects contemporary treatment standards. Relevant evidence was identified and narratively synthesized according to the clinical and reproductive aspects of pregnancy after breast cancer. No formal risk-of-bias assessment or quantitative synthesis was undertaken. Results: On the currently available evidence, pregnancy after breast cancer is not associated with an increased risk of recurrence. This holds in hormone receptor-positive disease and in BRCA1/2 carriers, and it is supported prospectively by the POSITIVE trial, whose preplanned update at a median follow-up of 71 months found a five-year incidence of breast cancer-free interval events of 12.3% against 13.2% in matched external controls. Obstetric and neonatal risks are higher than in the general obstetric population, although the pooled effect sizes are small to moderate: odds ratios are approximately 1.14 for cesarean delivery, 1.45 for preterm birth, 1.50 for low birth weight, and 1.16 for small-for-gestational-age birth. The excess concentrates in pregnancies conceived within the first one to two years after diagnosis and attenuates thereafter. Fertility preservation techniques appear both effective and oncologically safe. Fertility-related distress, by contrast, is common and does not reliably resolve once treatment ends. Conclusions: Oncologic risk alone is not a reason to advise against pregnancy after breast cancer. Early oncofertility referral, multidisciplinary planning, and risk-adapted obstetric surveillance remain the priorities. Because the evidence base is predominantly observational, these conclusions describe what the current data show rather than establishing safety definitively.

To explore the role of abdominal skeletal muscle mass in metabolic dysfunction-associated steatotic liver disease (MASLD) incidence and resolution, we established two independent cohorts in a Chinese population.

This study included 3139 participants without MASLD (incidence cohort) and 1130 MASLD patients (resolution cohort) at baseline, all of whom underwent abdominal computed tomography (CT) during routine health examinations from 2019 to 2024. Skeletal muscle mass was quantified from the third lumbar vertebra (L3) CT images using automated deep learning and analyzed in tertiles. MASLD was diagnosed by ultrasonographic hepatic steatosis and cardiometabolic risk factors. Cox models assessed the association of muscle mass with MASLD; logistic regression was used to assess the joint effects of skeletal muscle change rate and MASLD-related genetic risk on resolution.

Among the incidence cohort (median follow-up: 1.8 years), 516 developed MASLD. Lower body weight-adjusted total abdominal muscle area (TAMA/weight) was associated with higher MASLD incidence, regardless of sex. Compared with the highest tertile of TAMA/weight, the lowest tertile had hazard ratio (HR) of 2.39 (95% confidence interval [CI], 1.75 to 3.26) in men, and 2.11 (95% CI, 1.45 to 3.07) in women, respectively. Higher annual TAMA/weight promoted MASLD resolution, with the odds ratio (OR) of 1.81 (95% CI, 1.28-2.56) in men and 1.75 (95% CI, 1.04-2.96) in women. Increased muscle mass tended to be more associated with MASLD resolution in low genetic risk individuals.

Lower muscle mass correlates with higher MASLD risk. Increasing skeletal muscle mass may help prevent and manage the disease.

Background/Objectives: Obesity and its metabolic comorbidities, including dyslipidemia and non-alcoholic fatty liver disease (NAFLD), are a growing global health burden, and current pharmacotherapies have limited efficacy and notable adverse effects. The gut microbiome has emerged as a key regulator of host metabolism, and its dysregulation is implicated in obesity. This study investigated the therapeutic potential of Piper sarmentosum Roxb. aqueous extract (PSRW) on metabolic dysfunction and gut microbiota composition in a high-fat diet (HFD)-induced obese rat model. Methods: HFD-induced obese male Wistar rats received PSRW, simvastatin, or their combination for 12 weeks. Serum lipids (TC, TG, HDL, LDL), liver enzymes (AST, ALT), and renal markers were measured, and gut microbiota were profiled by 16S rRNA (V4) sequencing with PICRUSt2/KEGG functional prediction. The phenolic composition of the same extract was characterized by HPLC in a companion study. Results: PSRW did not cause weight loss but significantly lowered serum TC, AST, and ALT, with efficacy comparable to simvastatin and significantly lower TG than control, though not significantly different from HFD. Co-administration of PSRW and simvastatin produced a greater reduction in TC and liver enzymes than either agent alone. HFD shifted microbial community structure and enriched pro-inflammatory phyla such as Desulfobacterota; PSRW partially reversed these changes, suppressing obesogenic Lachnospiraceae genera while enriching beneficial microbes including Dwaynesavagella, and functionally reprogrammed taxa such as Kineothrix and Muribaculum from detrimental to protective associations. HFD enriched microbial glycosphingolipid biosynthesis, whereas the PSRW simvastatin combination uniquely enhanced glycine, serine, and threonine metabolism. Conclusions:P. sarmentosum extract ameliorates HFD-induced dyslipidemia and hepatotoxicity, and these effects are accompanied by remodeling of the composition and predicted functional capacity of the gut microbiome. Its ability to act in combination with statins highlights its potential as a candidate complementary therapy for hyperlipidemia and NAFLD.

Sugar sweetened beverages (SSBs) are an important source of added sugars and a key target for fiscal policies aimed at preventing obesity, type 2 diabetes and other non-communicable diseases. This study assessed the association of SSB taxes, tax structure and tax-design elements and changes in per capita soft drink sales volume across geographies from 2010 to 2024. Annual Euromonitor International Passport sales data were combined with national SSB tax-policy data from the World Bank and macroeconomic indicators. The final sample includes 74 geographies and 1096 geography-year observations. We use a multi-period difference-in-difference technique with staggered implementation of the policy and event-study estimation. SSB taxes were associated with a reduction of 7.286 L per person (p < 0.01), about 10.4% of the sample mean. Taxes with an explicit health objective were associated with larger reductions than taxes without a health objective. Ad valorem, mixed, and specific taxes were related with lower sales volume, although differences across structures were not significant. Importantly, the results imply policy design matters. This indicates that governments should evaluate not only whether to impose SSB taxes but also how to design, position, and communicate them as health-oriented fiscal policies.

Non-communicable diseases (NCDs), including cardiovascular disease, cancer, and chronic respiratory disease, are major causes of death worldwide; addressing NCDs is thus essential. NCDs may contribute to health disparities between rural and urban areas. The COVID-19 pandemic has altered medical and social environments, and NCD management approaches may have changed accordingly. This scoping review aimed to examine themes of reported rural healthcare challenges related to NCD management before and after the COVID-19 pandemic. A literature search of original articles was conducted via PubMed. A thematic analysis was applied to compare the content of studies classified as pre-pandemic and post-pandemic. A total of 23 articles were identified, including 12 studies classified as pre-pandemic and 11 studies classified as post-pandemic. Before the pandemic, commonly reported challenges included low management rates of hypertension and diabetes, instability in pharmaceutical supply, and insufficient training of healthcare personnel. We integrated these into a theme related to "healthcare". After the pandemic, in addition to the low management rates, studies increasingly addressed mental and nutritional health, multimorbidity, and socioeconomic disparities. We integrated there into a theme related to "society". Namely, studies classified as pre-pandemic primarily reported healthcare-related aspects, whereas studies classified as post-pandemic more frequently reported broader societal aspects in addition to healthcare-related aspects. These findings may reflect changes in how rural healthcare challenges related to NCDs have been recognized and discussed following the COVID-19 pandemic. Further research is needed to clarify the significance and implications of these reported themes.

Diabetes mellitus is a leading global non-communicable disease associated with significant morbidity, mortality and healthcare burden. Diabetic foot complications represent a leading cause of hospitalization and lower-limb amputation in this population.

To systematically evaluate the effects of educational programmes on nurses' knowledge and practice regarding diabetic foot care.

A systematic search of quasi-experimental studies from 2015 to 2024 was performed. Web of Science, Cochrane Library, CINAHL, MEDLINE and Scopus databases were searched using a comprehensive search strategy. The Joanna Briggs Institute Critical Appraisal Checklist for Quasi-Experimental Studies was used to evaluate methodological quality. The results were summarized narratively due to variations in study designs, interventions and outcome measures. The GRADE approach was used for assessment of the evidence certainty.

A total of nine studies met the inclusion criteria. Educational interventions were found to be consistently linked to enhanced knowledge and/or clinical practice concerning diabetic foot care among nurses in the included studies. Interactive and practical educational approaches appeared particularly promising; however, considerable heterogeneity existed in intervention content, duration, measurement instruments and follow-up periods. The overall certainty of evidence for both knowledge and practice outcomes was rated as very low.

Educational programmes were consistently associated with improvements in nurses' knowledge and practice regarding diabetic foot care. The findings suggest that healthcare training could be integrated with ongoing professional development programmes, emphasizing experiential learning. However, the very low certainty of evidence and predominance of non-randomized quasi-experimental designs limit causal inference. More rigorous randomized or cluster-randomized studies with standardized outcome measures, longer follow-up and patient-level outcomes are needed.

PROSPERO: CRD420261404535.

Women with polycystic ovary syndrome (PCOS) are more susceptible to metabolic dysfunction, especially glucose impairment. Previous studies have considered prediabetes (pre-DM) and diabetes mellitus (DM) as single-point outcomes without accounting for the transition states. This study aimed to explore the transition between different blood glucose states using a multistate Markov model among women with and without PCOS.

This study employed a dataset from the population-based study of the Tehran Lipid and Glucose Study. Women, aged over 20 years, without pre-DM and DM at baseline (1999-2000) and with documented PCOS status, were included; subsequent follow-ups were conducted every 3 years, totaling six follow-up assessments. Three states of 'Normoglycemia', 'Pre-DM', and 'DM' and three possible transitions of (I) normoglycemia to pre-DM, (II) normoglycemia to DM, and (III) pre-DM to DM were defined. The multi-state Markov models were applied to examine the predictive effect of PCOS on the transition rates throughout the progression of DM.

Out of 1587 participated women, 782 (49.3%) remained free of pre-DM and DM at the end of the study. Transition from normoglycemia to pre-DM was the most frequent progression observed, affecting 46.6% of the study participants. Women with PCOS significantly had 23% higher hazard of transition I [HR (95% CI): 1.23 (1.01-1.49); p = 0.034] compared to those without PCOS. While being PCOS did not significantly affect the risk of other transitions.

This study underscores the significant impact of PCOS on the dynamic progression from normoglycemia to pre-DM. Future longitudinal studies are essential to support our findings.