19043 research outputs found
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Advanced Wound, Ischemia, and Foot Infection Stage Is Associated With Poor Outcomes in the BEST-CLI Trial
No full textObjective: Wound, Ischemia, and foot Infection (WIfI) staging was established to provide objective classification in patients with chronic limb-threatening ischemia (CLTI) and to predict 1-year major amputation risk. Our goal was to validate WIfI staging using data from the Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. Methods: Data from the BEST-CLI Trial, a prospective randomized trial comparing surgical revascularization (OPEN) and endovascular revascularization (ENDO), were used to assess the association of WIfI stage on long-term outcomes in an intention-to-treat analysis. Patients were prospectively allocated to two cohorts, which included patients with and without adequate single-segment greater saphenous vein, respectively. The primary outcome of this analysis was major amputation. Results: There were 1568 patients analyzed, representing 86% of the entire trial population; of these 35.5%, 29.6%, and 34.9% were categorized as WIfI stage 4, WIfI stage 3, and WIfI stage 1/2, respectively. There were 1223 patients (606 OPEN, 617 ENDO) and 345 patients (OPEN 172, ENDO 173) in cohorts 1 and 2, respectively. On unadjusted Kaplan-Meier analysis, WIfI clinical stages 4 and 3, compared with WIfI stage 1/2, were associated with higher rates of major amputation (21.4%, 16.2% vs 10.7%), death (33.5%, 35.7% vs 24.6%), amputation/death (44.9%, 44.5% vs 31.3%), major adverse limb events (MALEs)/death (34.4%, 33.9% vs 29.5%), and reintervention/amputation/death (69.9% vs 69% vs 60.4%) (P \u3c .05 for all) at 3 years. On risk-adjusted analysis, compared with WIfI stage 1/2, major amputation was associated with WIfI stage 4 (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.44-2.96; P \u3c .001) and WIfI stage 3 (HR, 1.62; 95% CI, 1.1-2.37; P = .013) stages. Death was associated with WIfI stage 4 (HR, 1.3; 95% CI, 1.03-1.63; P = .027) and WIfI stage 3 (HR, 1.42; 95% CI, 1.13-1.79; P = .003). MALE/death was associated with WIfI stage 4 (HR, 1.29; 95% CI, 1.02-1.63; P = .036. Reintervention amputation/death was associated with WIfI stage 4 (HR, 1.28; 95% CI, 1.09-1.50; P = .03) and WIfI stage 3 (HR, 1.22, 99% CI 1.03-1.43); P = .018). When examining OPEN vs ENDO revascularization by each WIfI stage, OPEN intervention was favored in cohort 1 for MALE/death for each stage. Conclusions: In BEST-CLI, WIfI stage was strongly associated with major amputations, death, and MALEs/death after revascularization for CLTI. Cohort 1 patients, with an adequate preoperative single segment greater saphenous vein, had lower MALE/death with OPEN intervention across all WIfI stages. This validation of WIfI score in a prospective multicenter trial reinforces its importance in shared-decision making, informed consent, and prognostication
The P12 Subunit Choreographs the Regulation and Functions of Two Forms of DNA Polymerase Δ in Mammalian Cells
No full textThere are two forms of DNA polymerase δ in human cells, Pol δ4 and Pol δ3, which differ based on their possession of the p12 subunit. The degradation of p12 has emerged as an important regulatory mechanism that controls the generation of Pol δ3. The underlying importance of this system lies in the altered enzymatic properties of the two forms of Pol δ engendered by the influence of p12. We briefly review how the balance of these two forms is regulated through the degradation of p12. We focus on the roles of Pol δ4, whose cellular functions are less well known. This is significant because recent studies show that this is the form engaged in the homology-dependent repair of double-strand breaks. We consider new horizons for future research into this system and their potential involvement in tumorigenesis
Higher Incidence of Dermatological Immune-Related Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitors vs. Other Treatments: A Trinetx Research Network Study
No full textECM, Integrins, and Ddrs: A Nexus of Cancer Progression, Therapy, and Future Directions
No full textCollagen is the most abundant protein in mammals, significantly contributing to cancer progression. Cells express two primary well-conserved collagen receptors, integrins and discoidin domain receptors (DDRs), which bind collagen on distinct sites, suggesting that cancer cells must integrate both signals to decide their fate. The crosstalk between integrins and DDRs mediated by collagen binding produces dynamic, integrated signals that control tumor progression, therapeutic resistance, and cancer cell heterogeneity. This review will discuss the dynamic interplay among collagen, integrins, and DDRs in ECM remodeling during cancer progression and these receptors\u27 crosstalk. In addition, we explored current and future directions for ECM receptor-targeted therapies, including nanotechnologies and precision medicine, to improve therapeutic outcomes by establishing a proper balance between integrins and DDRs in cancer
Impacts of the COVID-19 Pandemic on the HIV Care Continuum and Associated Factors in High-Income Nations: A Mixed-Methods Systematic Review
No full textThe COVID-19 pandemic has significantly impacted the HIV care continuum (HCC), presenting challenges while also driving positive transformations globally. This study examines the impact of the COVID-19 pandemic on HCC in high-income countries, aiming to identify barriers and facilitators to care delivery amidst global health challenges. This study employs JBI mixed-methods systematic review methodology. The search strategy included CINAHL, OVID-Medline, CAB Direct, and OVID-Embase databases and manual citation review. After systematic screening and data extraction, quality assessment was performed, and integrated findings were presented. A systematic search of online databases retrieved 20,305 records, with 14,600 unique records screened after removing duplicates; 607 full-text articles were reviewed, and 88 studies meeting eligibility criteria were included in the final analysis. The COVID-19 pandemic has disrupted various aspects of the HIV care continuum, posing challenges in testing, prevention, appointments, adherence, linkage to care, viral suppression, and treatment engagement. However, the pandemic has also spurred positive changes, notably through the widespread adoption of telemedicine, enhancing access to care and support services. Efforts to mitigate structural barriers, enhance access to care, and promote ART adherence are essential to ensure continuity of care and mitigate long-term consequences. Tailored interventions for vulnerable populations and addressing disparities in care access are crucial for fostering equitable HIV care delivery
Pan-Cancer Analysis of Oncogenic MET Fusions Reveals Distinct Pathogenomic Subsets With Differential Sensitivity to MET-Targeted Therapy
No full textMET fusions (MET-F) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F–positive tumors from an institutional cohort of 91,119 patients (79,864 DNA sequencing plus 11,255 RNA sequencing) uncovered two forms of MET-F pathobiology. The first group featured 5′ partners with homodimerization domains fused in-frame with the MET tyrosine kinase domain, primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in preclinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET trans-membrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with receptor tyrosine kinase co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET TKI sensitivity are determined by structural topology and pathogenomic context
Response To: Other Factors That Can Affect Wound Healing With Elective Lumbar Spine Surgery and Perioperative Nutritional Supplementation in Patients
No full text
Validation of a Novel Low-Cost Glaucoma Risk Calculator for Community-Based Screening in High-Risk Populations
No full textPurpose: To assess the validity of a novel, low-cost glaucoma screening calculator in determining glaucoma risk in high-risk New York communities. Patients and Methods: This prognostic community-based study was conducted in New York City neighborhoods from 2022 to 2024 among participants aged 40 years and older. Glaucoma screenings were held at community gatherings including local fairs, senior citizen homes, places of worship, and in the lobby of medical offices. The screenings were conducted by trained non-physician medical personnel comprised medical students and medical assistants working under physician supervision. Participants’ intraocular pressure (IOP) and central corneal thickness (CCT) were measured in both eyes with a handheld tonometer and pachymeter, respectively. Participants then completed a comprehensive eye exam by an ophthalmologist to confirm glaucoma status. Statistical analysis was completed using MedCalc version 22.023 (MedCalc Software Ltd. Ostend, Belgium) with 95% confidence intervals. Results: Of the 823 study participants, 716 (mean age 62.9 ± 11.9 years) were eligible to participate and completed the comprehensive follow-up exam. 68% identified as Black, 6.7% identified as Hispanic/Latino, and 52.5% identified as female. The Laroche glaucoma calculator had a sensitivity of 93.5% (CI 89.1–96.5%), specificity of 91.3% (CI 88.5–93.6%), positive predictive value of 80.5% (CI 75.7–84.6%), negative predictive value of 97.3% (CI 95.5–98.4%) and accuracy of 91.9% (CI 89.6–93.8%). Conclusion: The Laroche glaucoma calculator shows high sensitivity, specificity, positive predictive value, negative predictive value, and accuracy using affordable screening methods to determine glaucoma risk