Citations

Cancer stem cells (CSCs) are increasingly recognized as central drivers of tumorigenesis, therapeutic resistance, and recurrence across diverse malignancies. This review synthesizes our current understanding of CSC biology across CNS tumors, with a focus on glioblastoma, where stem-like cells are sustained by specialized and overlapping tumor microenvironmental niches. Perivascular, hypoxic, invasive, immunosuppressive, and extracellular matrix-associated niches cooperatively enforce stemness, metabolic adaptability, immune evasion, and phenotypic plasticity, enabling CSC persistence despite maximal surgical resection and standard-of-care therapy. Notably, CSCs extend beyond radiographically defined tumor margins and populate peritumoral regions, providing a biological basis for near-universal recurrence. Advances in multiparametric imaging, stem cell-based ex vivo and in vivo models, and single-cell and spatial profiling have refined insight into CSC heterogeneity, niche dependence, and treatment resistance. Together, these findings reframe therapeutic strategies, highlighting the need for function-preserving maximal resection and multimodal therapies that target both CSC-intrinsic pathways and their supportive microenvironments.

Background Tricuspid regurgitation (TR) is a common valvular disorder that can affect patients’ quality of life and survival. The impact of TR etiology on overall survival and the associated risk factors in each subgroup are not well studied. Methods Multisite, retrospective study evaluating survival based on TR etiology using Kaplan–Meier and Cox regression models. Stepwise approach was used to define TR etiology (≥moderate): primary (PTR; presence of a primary valvular pathology), lead associated (LTR; lead interfering with closure), and secondary TR (STR) in the setting of left‐sided valvular disease, left ventricular disease, other causes of pulmonary hypertension, right ventricular disease, and atrial secondary TR. Results A total of 12 899 patients were included (3% PTR, 90% STR, 7% LTR). The mean age was 68±14, 73±13, and 71±13 years, respectively (44%–55% female patients). Adjusting for age, sex, and TR severity, patients with PTR had better overall survival (PTR: reference; STR hazard ratio [HR], 1.4 [1.2–1.6], LTR HR, 1.5 [1.1–1.7]). On multivariable Cox regression, the Tricuspid Regurgitation Impact on Outcomes score was associated with mortality across all groups ( P <0.05 for all). In addition, other risk factors associated with worse outcomes included pulmonary hypertension and ≥moderate right ventricular enlargement in PTR; left‐sided valvular disease, pulmonary hypertension, and ≥moderate right ventricular dysfunction in STR; and left ventricular disease and ≥moderate right ventricular dysfunction in LTR. Conclusions Patients with PTR have better survival than STR and LTR. Tricuspid Regurgitation Impact on Outcomes score was associated with mortality across etiologies, whereas other risk factors are etiology specific. Improved risk profiling may enhance patient selection, treatment decisions, and outcomes.

BACKGROUND: Cerebral microbleeds (CMBs) are associated with dementia, but the impact of specific microbleed patterns (with distinct pathophysiologies) is unclear. Lobar CMBs commonly result from cerebral amyloid angiopathy (sometimes with cortical superficial siderosis [cSS]), while subcortical microbleeds indicate a hypertensive cause. This study investigates the association of CMB presence, patterns, and frequency with dementia risk. METHODS: Participants from the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study), a community-based longitudinal cohort, with a 3T research magnetic resonance imaging scan at visit 5 (2011–2013) and without prior intracerebral hemorrhage or dementia were included. CMB and cSS presence and location were evaluated using a T2* gradient-recalled echo sequence. Each individual’s pattern of CMBs was classified as no CMBs, subcortical only, mixed (subcortical and lobar±cSS), lobar±cSS only, or cSS. Dementia adjudication was determined by blinded review of cognitive testing, informant interviews, and hospital discharge codes or death certificates (from follow-up visits and ongoing surveillance). Cox proportional hazards models assessed associations between CMBs and incident dementia through 2020, adjusted for demographics, vascular risk factors, and white matter hyperintensities. RESULTS: Among 1583 participants (mean age, 76 years; 24.7% cumulative dementia incidence over a median of 23.6 follow-up years), 361 had CMBs. Compared with individuals without CMBs, those with mixed (hazard ratio, 1.99 [95% CI, 1.40–2.83]) or lobar±cSS (hazard ratio, 1.96 [95% CI, 1.30–2.97]) CMB patterns had increased dementia risk, whereas individuals with a subcortical-only pattern did not (hazard ratio, 1.04 [95% CI, 0.78–1.39]). cSS presence (n=21; versus absence) showed an increased risk of dementia (hazard ratio, 2.57 [95% CI, 1.36–4.89]). Greater numbers of microbleeds across all CMB subtypes exhibited an increased risk of dementia. CONCLUSIONS: Lobar and mixed CMB patterns and increasing numbers of CMBs are associated with incident dementia. Certain CMB patterns have differential associations with dementia, but severe enough disease burden, regardless of CMB distribution, is associated with increased dementia risk.

Background: Eight Global Ophthalmology (GO) fellowship programs are available in the United States, and more than 30 U.S. GO fellows are now alumni. There are no standardized learning objectives for these programs, and fellows’ experiences vary widely between institutions. Purpose: To survey GO fellowship program directors in the United States to elucidate differences in learning objectives, duration of time abroad, funding sources, and other differences between GO fellowships. Methods: All program directors at all institutions with current GO fellowship programs in the United States were sent a 25-question questionnaire via email from October through December 2022. The questionnaire included distinct domains regarding the GO fellowship experience, care delivery, didactics, and best practices. Most questionnaire items were quantitative; 3 were qualitative. Responses to the quantitative and qualitative questions items were summarized descriptively. Results: All 10 program directors from the 8 GO fellowship programs that were current at the time of the survey participated. GO fellowship positions at most (88%) institutions were funded, in part, by the billing of care services provided by the fellows, with 50% of programs receiving supplemental funding from donations and 25% from nongovernmental organizations. Non-GO duties at the program home institutions constituted 29.5% of the time spent during the fellowships, on average. Policy advocacy occupies 2.3% of fellowship time, on average. Specific didactic topics covered in the GO programs and director perspectives on the pragmatic best practices for GO outreach varied considerably; however, inclusion of at least some public health topics and ethics appeared to be consistent among all of the programs. Conclusions: These findings provide insights into the landscape of GO fellowship programs in the United States, highlighting variations in funding, formal educational opportunities, and the allocation of time fellows spent working at the program home institution. Establishing standardized core competencies for fellows is recommended.

Introduction To examine within-class sulfonylurea safety, we compared risks of major adverse cardiovascular events (MACE) and severe hypoglycemia among adults with type 2 diabetes (T2D) and moderate cardiovascular risk following sulfonylurea initiation. Research design and methods We conducted a target trial emulation including adults ≥21 years old with T2D and moderate cardiovascular risk who initiated glimepiride, glipizide or glyburide between 2014 and 2021, using claims data from Optum Labs Data Warehouse and the Medicare fee-for-service 100% sample. Study outcomes were MACE (primary), expanded MACE and its components and emergency department or hospital encounters for hypoglycemia, ascertained during follow-up through 2022. Inverse probability of treatment weighting (IPTW) was applied using propensity scores estimated using the super learner ensemble, and outcomes were examined using IPTW Cox proportional hazards models. Results The weighted study cohort comprised 314 699 patients (mean age 66.9 years, 52.0% men, 76.6% non-Hispanic white). At 1 year, MACE was experienced by 2.5%, 2.7% and 2.8% of patients starting glimepiride, glipizide and glyburide, respectively. Compared with glimepiride, glyburide and glipizide were associated with higher risk of MACE (HR 1.10, 95% CI 1.05 to 1.16 for glyburide; HR 1.05, 95% CI 1.03 to 1.07 for glipizide). At 1 year, severe hypoglycemia was experienced by 0.3%, 0.3% and 0.4% of patients starting glimepiride, glipizide and glyburide, respectively. Glyburide was associated with a greater risk of severe hypoglycemia compared with glipizide (HR 1.43, 95% CI 1.23 to 1.65), while glipizide was associated with a lower risk compared with glimepiride (HR 0.82, 95% CI 0.77 to 0.87). Conclusions Among adults with T2D and moderate cardiovascular risk, glimepiride was associated with lowest risk of MACE and glipizide with lowest risk of severe hypoglycemia. These results can help inform treatment selection if sulfonylureas are used for glucose-lowering.

Objective This longitudinal study evaluated the long-term efficacy and safety of hematopoietic stem cell transplantation (HSCT) in slowing the progression of CSF1R-related disorder (CSF1R-RD).Methods Six symptomatic patients (mean follow-up, 6.6 years) were compared with six matched, untreated controls. The CSF1R Clinical Severity Score (CCSS), Montreal Cognitive Assessment, and Sundal radiological score were used for evaluation.Results Post-HSCT clinical progression slowed significantly from 14.1 to 3.7 CCSS/year, compared with 15.2 CCSS/year in the control group (p<0.01). Cognitive decline was substantially reduced (-1.5 points/year vs. -7.6 points/year), and radiological deterioration slowed (0.4 per year vs. 3.9 per year). Notably, during the observation period, all HSCT patients survived, whereas 50% of the patients in the control group died. No serious transplant-related complications were observed.Conclusion HSCT is a potent disease-modifying therapy for CSF1R-RD that drastically improves survival and slows deterioration. These findings underscore the necessity of early intervention during the symptomatic phase to maximize the preservation of quality of life for affected individuals.

Background: Use of pyrocarbon metacarpophalangeal (MCP) implants in rheumatoid arthritis (RA) patients has been associated with high rates of complications and reoperations. To date, few patient-specific prognostic factors have been identified. This study investigated body mass index (BMI) as a risk factor for RA patients undergoing pyrocarbon MCP arthroplasty. Methods: We included 148 joints (51 patients) that underwent pyrocarbon MCP implantation at our institution from 2000 to 2022. We analyzed survival free from revision, reoperation, and development of postoperative complications using cluster-robust Cox proportional hazard models with restricted cubic splines to plot non linear relationships. Secondarily, we compared survival above and below the World Health Organization cutoff for obesity of ≥ 30 kg/m 2 , adjusting for patient age and sex. Results: The relationship between BMI and risk for complications and revisions was J-shaped, with an increase in risk beyond 29 kg/m 2 . The relationship between BMI and late reoperations was U-shaped, with patients above 27.3 kg/m 2 and below 23.2 kg/m 2 at elevated risk. A BMI ≥ 30 kg/m 2 was associated with a 7.9-times increased risk for revision, 8.3-times increased risk for late reoperations, and 3.7-times increased risk for postoperative complications. Body mass index did not significantly influence risk for early reoperation. Conclusions: Body mass index was associated with pyrocarbon MCP implant failure in a non linear fashion, with overweight patients at risk for complications leading to revisions and late reoperations. Underweight patients may be at increased risk for late reoperations. These findings should inform patient and implant selection and help guide counseling for postoperative expectations.