Maladaptive daydreaming (MD) is increasingly recognized as a complex psychological phenomenon that extends beyond ordinary fantasy. While it has been predominantly conceptualized within a dissociative framework, the present study aimed to extend this perspective by proposing a complementary integrative model focusing on less extensively examined but interacting domains, including neurodevelopmental traits, behavioral addictions, and socio-psychological factors, in a sample of university students in Türkiye. A total of 848 participants (mean age = 21.50 ± 2.59 years; 73.2% female) completed validated self-report measures assessing MD (MDS-16), ADHD symptoms, autism spectrum traits, behavioral addictions (social media and gaming), and psychosocial variables including anxiety, depression, self-esteem, narcissism, and loneliness. Using a cut-off score of ≥50 on the MDS-16, the prevalence of MD among university students was 18.3%. MD severity was positively associated with ADHD symptoms (r = 0.335), autism spectrum traits (r = 0.218), social media use (r = 0.309), anxiety (r = 0.339), and narcissistic traits (r = 0.256), and positively associated with higher RSES scores (r = 0.315; indicating lower self-esteem) and negatively associated with age (r = -0.231) (all p < .001). In hierarchical linear regression analyses, low self-esteem, ADHD symptoms, and autism traits emerged as the strongest predictors of MD severity, while anxiety, social media addiction, and narcissistic traits also contributed significantly. Age and year of study showed consistent inverse associations with MD severity (adjusted R2 = 0.283). These findings indicate that MD reflects a multidimensional process in which neurodevelopmental vulnerabilities, emotional dysregulation, and behaviorally reinforced patterns converge, supporting an integrative account that complements dissociative conceptualizations.
The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.
Adults with diabetes mellitus are at an increased risk of poor oral health; however, how individual- and community-level factors jointly contribute to oral health disparities in this population remains unknown. This study aimed to examine multilevel determinants of self-rated oral health among adults with diabetes in South Korea. A cross-sectional analysis was conducted using data from 21,996 adults aged ≥19 years with physician-diagnosed diabetes who participated in the 2021 Korea Community Health Survey. Self-rated oral health was dichotomized as good or poor. Individual- and community-level variables representing health behaviors, clinical care, social and economic factors, and physical environment were selected, guided by the County Health Rankings model. Multilevel logistic regression models accounted for clustering within administrative districts. At the individual level, poorer self-rated oral health was significantly associated with sociodemographic disadvantages (older age, male sex, not married, lower education, and economic inactivity), poorer general health status, adverse health behaviors (lifetime smoking and inadequate toothbrushing), and unmet dental care needs (all p < 0.05). At the community level, greater accessibility to public transportation was associated with better self-rated oral health (OR = 0.997, 95% CI: 0.993-1.000), whereas a higher prevalence of moderate-intensity physical activity was associated with poorer oral health (OR = 1.006, 95% CI: 1.000-1.011). Self-rated oral health among adults with diabetes is influenced by individual-level socioeconomic and behavioral factors alongside selected community-level contextual conditions. Multilevel strategies integrating oral health into chronic disease management are required, while addressing structural barriers to dental care.
Climate change-related severe weather events are heavily impacting regions with the highest prevalence of HIV, creating additional vulnerabilities for already vulnerable populations. Little is understood about how people perceive or experience the mechanisms by which extreme weather events affect the health of people living with HIV (PLHIV). We conducted a qualitative study using in-depth, semi-structured interviews with 40 PLHIV enrolled in a cluster randomized clinical trial that included 8 pairs of health facilities in rural Western Kenya, who were 18 years or older, receiving ART for > 6 months; had moderate to severe food insecurity; and practiced smallholder farming with access to surface water or aquifers. Intervention participants received a loan to purchase an irrigation pump and farming inputs and were provided climate-responsive, sustainable agriculture and financial literacy training. This study did not evaluate the impacts of the clinical trial. We aimed to understand participant perceptions of how climate change impacted their HIV health, and associated pathways for these impacts. Interviews were transcribed, translated, and double coded using an inductive-deductive-abductive thematic content approach. Almost all participants noted that droughts, flooding, and elevated temperatures had serious negative impacts on their health and wellbeing. Extreme weather negatively impacted their health via five key pathways, with the first being most prominent: (1) decreases in agricultural yields and income; (2) increased food insecurity and undernutrition; (3) medication non-adherence, missed clinic visits, and infrastructure erosion; (4) increased infections, and (5) displacement and forced migration. Several pathways were interrelated, with decreased agricultural yields and income being proximal to most other pathways. Participants perceived pathways by which severe weather negatively impacted their HIV health, and these pathways were bi-directional and reinforcing. Food and livelihood sources were devastated, and housing and infrastructure were negatively affected, causing a cascade of nutrition and health vulnerabilities. Understanding the contexts in which PLHIV are vulnerable to impacts of climate change will be essential to establish climate-responsive policies that can interrupt the pathways identified here. Cross-sector collaboration between the Kenyan Ministries of Agriculture and Health to develop climate-responsive policies to support PLHIV should be prioritized. The clinical trial start date was June 23, 2016. Trial Registration: Registered with ClinicalTrials.gov Identifier: NCT02815579.
Despite progress in elucidating the molecular landscape and actionable vulnerabilities of cholangiocarcinoma, clinical outcomes for patients with advanced disease remain dismal. In this issue of Cancer Cell, Entrialgo-Cadierno et al. raise the bar for the ∼20%-25% of patients with oncogenic KRAS mutations by unlocking the therapeutic potential of direct RAS-GTP inhibition.
A novel photoreceptor structure, called the accessory inner segment (aIS), was recently identified in human rod photoreceptors. It is described as a microtubule-based, mitochondria-rich extension of the conventional inner segment attached externally to the outer segment. Human retinal organoids recapitulate many developmental and mature cellular features of the human retina. Thus, we sought to determine if retinal organoids exhibit an aIS-like structure, to support future in vitro studies of its role in photoreceptor structure and disease. Mature retinal organoids were derived from human induced pluripotent stem cells and displayed stratified photoreceptor layers with inner- and outer segment-like processes. Immunohistochemistry and confocal imaging were used to identify aIS-like projections extending from inner segments. Electron microscopy (EM) was used to evaluate these structures in both transverse and longitudinal orientations. Co-staining of β-tubulin with ATP synthase revealed examples of discrete microtubule- and mitochondria-rich projections, respectively, emerging apically from the inner segments of mature organoids, consistent with previously-described aIS morphology observed in cadaveric human retina. β-tubulin and GPR98 co-staining further supported the presence of aIS-associated projections, spatially distinct from the outer segment axonemes, extending from the inner segment. Transmission EM confirmed examples of aIS-like structures enriched with microtubules and mitochondria, positioned apposed to the presumptive outer segment. Here, we provide the first evidence that aIS-like structures, previously observed only in cadaveric human retina, can be recapitulated in human retinal organoids. These findings may enable future in vitro investigations of photoreceptor structure to uncover new vulnerabilities relevant to retinal degenerations.
This study aimed to co-design a tailored model of care for older people with long COVID. Using a human-centred design approach, semistructured interviews were conducted with patients and health professionals from a long COVID service to explore their experiences. Insights were further developed during a co-design workshop involving patients, health professionals and community members who identified as older people and who had experience with chronic illness. Key themes were identified and used to map an ideal patient journey and inform the final model of care. Long COVID outpatient service in a tertiary hospital in Adelaide, South Australia. Four patients and four health professionals participated in the interviews. The workshop included four patients, five health professionals and seven community members. The co-design process identified challenges experienced by people with long COVID, including lack of validation, delayed multidisciplinary care, mental health deterioration and difficulties navigating the healthcare system. These challenges were described as having particular relevance for older adults. In response, a model of care was developed focused on comprehensive assessment, coordinated multidisciplinary care, education for self-management, mental health support and opportunities for research participation. A comprehensive and adaptable model of care is needed to address the complex and multifaceted nature of long COVID. This human-centred design approach ensured the model was grounded in lived experience, clinically informed and aligned with patient priorities. While not unique to older adults, the findings highlight areas that may require particular attention in this population, including care coordination, validation and support for comorbidities and social vulnerabilities. While developed in a single tertiary service, these principles may inform the design of services for similar populations in other healthcare settings.
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Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.
Acrodysostosis type 1 (ACRDYS1) is a rare multisystem developmental disorder affecting skeletal growth, endocrine function, neurodevelopment, metabolism, and tooth formation. It is caused by heterozygous mutations in PRKAR1A, which encodes the type Iα regulatory subunit (RIα) of protein kinase A (PKA), a central mediator of cyclic AMP (cAMP)-dependent signalling. Although ACRDYS1 belongs to the broader family of Gsα-cAMP-PKA-related disorders, its underlying mechanism is distinct. Disease-associated PRKAR1A mutations cluster within regions of RIα that bind cAMP and undergo conformational rearrangements required for PKA activation. These variants impair cAMP binding and disrupt the structural transitions needed to disinhibit catalytic subunits. Importantly, mutant RIα is expressed at near-normal levels and assembles efficiently into PKA holoenzymes, but these complexes respond weakly and sluggishly to physiological cAMP signals. Drawing on structural, biochemical, cellular, and in vivo studies, we define a dual pathogenic mechanism underlying ACRDYS1. First, defective cAMP-driven conformational changes reduce the sensitivity and amplitude of type I PKA activation, producing a hypomorphic signalling state despite intact upstream receptor coupling and cAMP production. Second, activation-resistant RIα holoenzymes impose a dominant-negative constraint by retaining catalytic subunits, further limiting the pool available for productive signalling in heterozygous cells. We relate this core defect in signal responsiveness to tissue-specific vulnerability. Impaired RIα-dependent decoding of cAMP signals disrupts the Ihh-PTHrP feedback loop in the growth plate, blunts hormone-responsive transcriptional programmes in endocrine epithelia, and alters spatially restricted PKA signalling domains in neurons and metabolically active tissues. Despite the diversity of affected organs, the unifying defect is an inability to generate appropriately timed and scaled PKA responses. This framework establishes ACRDYS1 as a disorder of signal decoding rather than signal generation, clarifies its mechanistic distinction from PRKAR1A-related Carney Complex, and highlights therapeutic strategies aimed at restoring local cAMP-PKA signalling dynamics rather than globally amplifying pathway activity.
Climate-related hazards such as floods and droughts disrupt household access to safe water, sanitation, and hygiene (WASH), undermining progress toward the Sustainable Development Goals (SDGs). Evidence on how household characteristics such as housing type, altitude, subjective social status, and disability status shape vulnerability to floods and drought and related risk mitigation in informal settlements remains limited. This study, therefore, assessed the vulnerability to climate impacts on WASH, risk mitigation, and its determinants among households in informal settlements in Eastern Uganda. This cross-sectional study applied nexus thinking and used an adapted questionnaire, informed by the World Health Organisation's climate vulnerability checklist, to collect data from 589 households in Eastern Uganda. Quantitative data on household characteristics, documented flood and drought impacts, as well as risk mitigation measures, were collected. Robust least squares regression was used to show predictors of climate impact scores as well as risk mitigation scores at 95% confidence level. Results show that 21.4% reported increased susceptibility to waterborne diseases due to contamination from animal faeces and sewage. Vulnerability to flood impacts was higher among households living in temporary housing or with disabled members, but lower among those in higher-altitude areas or with higher subjective socioeconomic status. Higher subjective social status was also linked to reduced drought impacts, whereas temporary housing reduced the capacity to mitigate drought risk. Overall, climate-related hazards compromise WASH in informal settlements, with cascading effects on health, education, food security, gender equality, and poverty reduction. These findings highlight the need to strengthen water governance, promote integrated (nexus) approaches, and build resilient WASH systems through multi-sectoral partnerships to mitigate climate risks in vulnerable communities.
Chronological age is widely used to estimate surgical risk but may inadequately reflect early postoperative recovery. Markers of physiological reserve, including frailty and muscle strength, may better capture vulnerability to surgical stress. We conducted a prospective multicenter cohort study of 223 adults undergoing elective abdominal surgery. Frailty was assessed using a phenotype-based model, and handgrip strength (HGS) was measured at admission and discharge, with 90-day follow-up in a subset. Length of stay (LOS) and postoperative complications were analyzed using multivariable regression. Frailty independently predicted prolonged LOS and postoperative morbidity, whereas age did not. Oncologic surgery showed the strongest association with extended hospitalization. Higher preoperative HGS was independently associated with shorter LOS. Acute perioperative changes in HGS were not associated with outcomes. Early postoperative recovery appears more closely related to physiological reserve than to age.
Microplastics (MPs) are increasingly recognized as widespread contaminants in aquatic environments, including remote freshwater systems, where their presence is linked to waste generation and transport pathways. This study examined the occurrence, spatial-temporal distribution, polymer composition, and ecological risks of MPs in surface sediments from Black Lake and Devil Lake, two high-altitude glacial lakes in Durmitor National Park, Montenegro. Sediment samples were collected across three seasons and analyzed using standardized methods, including density separation, visual identification, and polymer characterization. MPs abundance averaged 5.1 ± 1.4 items per 100 g of dry sediment in Black Lake and 3.8 ± 0.5 items per 100 g in Devil Lake. Fibers and fragments were dominant morphotypes, with particles sized 1-3 mm prevailing. Blue particles were most frequent. Five polymer types were identified, with polyethylene as the dominant polymer. Pollution load index values indicated moderate contamination, while polymer hazard and ecological risk indices suggested high to very high environmental risk. The presence of MPs in protected, high-altitude glacial lakes highlights their vulnerability to diffuse pollution sources, including tourism and long-range transport. The findings provide baseline data for alpine freshwater environments and underline the importance of integrating MPs pollution into waste management and environmental protection strategies.
Early life adversity (ELA) is associated with cardiometabolic risk over the lifespan. While cumulative risk models of ELA have provided insights into those most vulnerable, emerging evidence suggests that ELA dimensions of threat and deprivation have distinct consequences for neurodevelopment. However, these dimensions remain understudied in relation to cardiometabolic risk. We assessed associations between ELA-comparing cumulative risk and dimensional approaches-with a cardiometabolic risk composite in youth aged 9-19 (n=117). Using a multi-method approach, youth and caregivers reported on youths' ELA experiences at baseline and 2-year follow-up visits; reports were aggregated to reflect lifetime experiences of threat and deprivation at follow-up. In addition to threat and deprivation composites, a cumulative ELA composite was calculated by summing the number of threat- and deprivation-related experiences. At follow-up, youth provided measures of blood pressure, body mass index, and waist circumference; indicators were standardized and summed. Regression models revealed that the cumulative ELA composite was not significantly associated with cardiometabolic risk. However, threat-related ELA, but not deprivation-related ELA, was associated with greater cardiometabolic risk, adjusting for age and sex. Furthermore, age moderated the deprivation-cardiometabolic risk association, such that greater deprivation was linked to lower cardiometabolic risk in late childhood/early adolescence, but not in middle or late adolescence. Results indicate that dimensional models of ELA may offer more nuanced understanding of biological embedding of adversity and its relevance for cardiometabolic risk, with stronger risk associations observed for threat-related experiences in youth.
Cancer stem cells (CSCs) shape immunosuppressive tumor microenvironments through diverse mechanisms. In this issue of Cancer Cell, Fan et al. demonstrate that CSC-derived extracellular vesicles promote regulatory T cell expansion and facilitate immune evasion. The mechanistic details reveal a therapeutic vulnerability that enhances responses to checkpoint blockade.
Mood disorders are hypothesized to increase susceptibility to intensive care unit (ICU) delirium, but the evidence remains limited. This study evaluated the overall association and investigated risk heterogeneity across clinical subgroups and diagnostic subtypes. Using the Medical Information Mart for Intensive Care (MIMIC)-IV database, we identified incident delirium via the Confusion Assessment Method for the ICU (CAM-ICU). Primary analysis employed 1:3 propensity score matching to estimate the overall association and explore risk variation across clinical subgroups. Secondary analysis used multivariable Cox regression on the full cohort to investigate risk heterogeneity across diagnostic subtypes. In 36,944 matched patients, mood disorders were independently associated with an increased risk of delirium (HR, 1.24; 95% CI, 1.19-1.30). Subgroup analyses within this cohort showed higher relative risk in patients typically considered low-risk: those younger than 65 years, without sepsis, and not receiving advanced critical care interventions. Notably, subtype analysis in the full cohort revealed a distinct risk gradient: bipolar disorder conferred the highest risk (HR, 1.54; 95% CI, 1.40-1.69), followed by major depressive disorder (HR, 1.39; 95% CI, 1.32-1.47), while other mood disorders showed no significant association (HR, 1.04; 95% CI, 0.97-1.11). Mood disorders are independent risk factors for ICU delirium, particularly robust in younger or lower-acuity populations. This risk is primarily driven by bipolar disorder and major depressive disorder. Consequently, incorporating mood disorder history may serve as an additional marker of vulnerability to inform future delirium risk stratification for patients with major affective disorders, even without traditional high-risk characteristics.
Late-onset mood disorders frequently emerge in the context of aging-related brain changes, medical comorbidity, and cognitive vulnerability, complicating diagnosis and treatment. Symptom-based criteria alone lack biological specificity in older adults, contributing to diagnostic heterogeneity and variable outcomes. Converging neuropathological, neuroimaging, and circulating biomarker evidence suggests that vascular injury, chronic neuroinflammation, and early neurodegeneration may contribute to a meaningful subset of late-onset depressive and bipolar syndromes. This perspective synthesizes current evidence and proposes a neuropathology-informed framework integrating accessible biomarkers (including white matter hyperintensities, C-reactive protein, and neurofilament light chain) into staged clinical and research pathways. We emphasize that current evidence is largely observational and that randomized trials testing biomarker-guided care are needed before routine implementation. A phased research and infrastructure-building agenda is outlined, alongside ethical considerations including equity, diagnostic uncertainty, and the potential harms of premature adoption. This framework offers a hypothesis-generating path toward precision geriatric psychiatry while underscoring the need for rigorous validation.
Climate change is increasingly recognized as a psychological stressor, with older adults representing a particularly vulnerable yet understudied group. This study evaluated the psychometric performance of three climate anxiety measures-the Hogge Climate Anxiety Scale (HCAS), Clayton Climate Change Anxiety Scale (CCCA), and Simon Climate Anxiety Scale (SCAS)-among 279 Persian-speaking older adults in Iran. Using a cross-sectional design, we examined structural validity, diagnostic accuracy, measurement invariance, and reliability, employing the GAI-SF as the criterion measure. All three instruments demonstrated acceptable construct validity based on exploratory and confirmatory factor analyses. SCAS showed a stable three-factor structure and excellent internal consistency (ω = 0.97). In classification analyses, SCAS achieved the highest sensitivity (0.89) and overall diagnostic accuracy (DOR = 3.09), whereas CCCA demonstrated slightly higher specificity (0.36). Bland-Altman analysis indicated that HCAS had the lowest measurement bias relative to GAI-SF scores. Measurement invariance testing supported full scalar invariance for SCAS across gender and anxiety subgroups, while HCAS and CCCA achieved only partial invariance. Mokken scale analysis further confirmed strong scalability (H > 0.40) and satisfactory reliability (α > 0.85) across all measures, with CCCA showing the highest Loevinger's H (0.52). Age significantly predicted climate anxiety scores across all three scales (p < 0.001). Overall, SCAS emerged as the most robust and reliable instrument for assessing climate anxiety in Persian-speaking older adults, while HCAS showed the closest agreement with the criterion measure. These findings highlight the importance of culturally adapted, psychometrically sound tools for capturing climate anxiety in aging populations.
In the UK, a range of services provide same day, urgent and emergency care (UEC). Urgent medical needs can be addressed through pharmacy services, same day general practice (GP) appointments, phone or online triage services, out-of-hours GP appointments and urgent treatment centres (or equivalents). For emergency medical needs, patients can access emergency departments (EDs) and ambulance services. These services are highly vulnerable to excessive strain due to rising, unpredictable demand and limitations in patient flow across the system. The workforce operates in time-critical situations, often with limited resources, which can lead to staff burnout, low job satisfaction and retention and poor health. The organisation of services and their workforce continues to evolve in response to local and national pressures and varies considerably across the UK, where there are four distinct, publicly funded healthcare systems managed separately in each country. This makes it difficult to describe and compare services within and across regions and understand the impact of workforce organisation on service delivery, staff well-being and patient care. This study aims to develop a comprehensive understanding of the range and types of UK UEC services, the relative experiences of the workforce and the available workforce data. This mixed-methods study includes two components, integrated through an explanatory sequential design. Study 1 will use data on NHS service availability and direct enquiry to map UEC services and populate a structured database, which will facilitate the generation of a UEC typology of the range and types of services and regional variation across the UK. Multiple case studies will be conducted in a subset of services using qualitative interviews (n=136-220) with service leaders (n=3-5), workforce (n=10-12), and patients or carers (n=4-5), as well as document analysis where relevant, in each service of interest (n=8-10). Study 2 will create a metadata catalogue of workforce data and produce descriptive summaries of key metrics (eg, staffing levels and skill mix). The study will be supported by our Community Inclusion and Engagement (CIE) panel and Patient and Public Advisory Group (PPAG) to ensure relevance, inclusivity and impact. This study received ethical approval from Yorkshire and The Humber - Sheffield Research Ethics Committee (04/08/2025, IRAS ID: 357276, REC Reference: 25/YH/0125) and HRA and Health and Care Research Wales approval (12/08/2025). Data collection poses minimal risk, informed consent will be obtained, and participants may withdraw at any time. Dissemination will follow knowledge mobilisation principles to maximise impact. We will build on our existing networks and work with our CIE panel and PPAG to tailor study outputs to different audiences. The outputs will improve understanding of the variation in how UEC services and workforces are organised across the UK, as well as the type and format of available workforce data, and provide benchmarks for future research. Research Registry (REF: researchregistry11555; https://www.researchregistry.com/register-now/%23home/registrationdetails/68d402672341e502cd0ce888/).
Carotid blowout syndrome (CBS) is a rare but devastating complication following radiotherapy for nasopharyngeal carcinoma (NPC). This study aimed to identify clinically actionable risk factors for CBS and to explore heterogeneity among anatomically high-risk patients METHODS AND MATERIALS: Patients with NPC treated with a single course of definitive radiotherapy were retrospectively analyzed. Propensity score matching was applied to balance baseline characteristics between patients with and without CBS. Clinical, anatomical, and dosimetric variables were evaluated using logistic regression, with variable selection by least absolute shrinkage and selection operator (LASSO). Model discrimination was assessed using the area under the receiver operating characteristic curve (AUC). Heterogeneity analyses were performed among patients with macroscopic internal carotid artery (ICA) encasement. After matching, 31 patients with CBS and 62 matched controls were analyzed. Macroscopic ICA encasement and hypertension were strongly associated with CBS occurrence. In multivariable analysis, ICA encasement, hypertension, and ICA D0.5cc remained independent predictors of CBS, yielding good discrimination (AUC = 0.83). Among patients with macroscopic ICA encasement, those who developed CBS more frequently had hypertension and tended to receive higher irradiation to the pericarotid soft tissues, although dose differences were not statistically significant. Notably, progression to nasopharyngeal soft tissue necrosis with ICA exposure was observed exclusively in patients who developed CBS, whereas no patient who remained CBS-free demonstrated overt soft tissue necrosis during follow-up. CBS risk after definitive radiotherapy for NPC is primarily driven by anatomical vulnerability and systemic vascular factors. Pericarotid soft tissue injury and impaired post-radiotherapy healing appear to modulate progression from anatomical risk to clinical events. These findings support a risk-adapted surveillance and management strategy for patients with ICA encasement.