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ABSTRACT Background Over the years, prognostic indexes have been developed to help clinicians stratify patients with biliary tract cancers (BTC) into risk groups. This study aims to identify a new prognostic index for patients with BTC treated with cisplatin, gemcitabine and durvalumab (CGD) in the first‐line setting. Patients and Methods The study population consisted of patients with BTC from 11 Eastern and Western Countries. Using multivariate analysis for overall survival (OS), we identified 5 baseline statistically significant variables: stage, carcinoembryonic antigen (CEA) levels, albumin levels, gamma glutamyl transferase (GGT) levels, neutrophil‐to‐lymphocyte ratio (NLR). Metastatic disease is a prognostic factor with a superior weight considering the HR of 3.62, while all the others can be considered prognostic factors with equivalent weight as the HRs are quite similar (HRs between 1.55 and 1.92). Based on these reasons, we developed a prognostic model called the MAGIC‐D index by assigning a score of 2 for metastatic disease, and a score of 1 for CEA increased levels, albumin decreased levels, GGT increased levels, NLR ≥ 3. Patients were stratified into three risk groups as follows: low‐risk group (Score from 0 to 2), intermediate‐risk group (Score from 3 to 4) and high‐risk group (Score from 5 to 6). At the first data cutoff (April 2024), these data were available for 319 patients that composed the training cohort used for the analysis. At the second data cutoff (May 2025), 79 patients were further enrolled and composed the validation cohort. Results Median progression‐free survival was 11.7 months in low‐risk group (20.7%), 8.7 months in intermediate‐risk group (46.4%) and 5.4 months in high‐risk group (32.9%) [low‐risk hazard ratio (HR): 0.27, intermediate‐risk HR: 0.55, high‐risk HR: 1, p < 0.0001]. Median OS was 18.4 months in low‐risk group,15.9 months in intermediate‐risk group and 7.8 months in high‐risk group (low‐risk HR: 0.17, intermediate‐risk HR: 0.43, high‐risk HR: 1, p < 0.0001). There was no difference in overall response rate (low‐risk: 31.8%, intermediate‐risk: 36.5% and high‐risk: 25.7%; p = 0.0718), while disease control rate was significantly different across the three risk groups (low‐risk: 83.3%, intermediate‐risk: 70.9% and high‐risk: 60.9%; p < 0.0001) as well as the rate of patients receiving a second‐line therapy (low‐risk: 54.5%, intermediate‐risk: 48.6% and high‐risk: 25.7%; p = 0.0061). Finally, the prognostic role in terms of OS and PFS of the MAGIC‐D index was confirmed in a validation cohort of 79 patients. Conclusion The MAGIC‐D index is an easy‐to‐use tool able to stratify patients with BTC with different prognoses undergoing first‐line therapy with CGD.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Background: Despite mounting clinical evidence for the utility of orthobiologics in nonoperative management of orthopaedic pathology, the market for orthobiologic therapies remains largely unregulated by the Food and Drug Administration, giving rise to a wide range of pricing for these therapeutics by different provider types. Purpose: To determine the availability and pricing for platelet-rich plasma (PRP), amniotic or adipose “stem cell,” and bone marrow aspirate concentrate (BMC) injections for the treatment of knee osteoarthritis among orthopaedic sports medicine and alternative providers (eg, chiropractic clinics and stand-alone “regenerative medicine” clinics) in a major metropolitan city. Study Design: Cross-sectional study. Methods: Orthopaedic sports medicine providers in the Chicagoland area were identified through the American Orthopaedic Society for Sports Medicine (AOSSM) and Arthroscopy Association of North America (AANA) surgeon databases. Alternative clinics offering orthobiologic injections were systematically compiled using Yelp! and Google search listings and reviews. Clinics were contacted using a standardized telephone script. Data were collected for each site on the types of injections offered, whether price was disclosed over the telephone, the price of injections offered, and the source of stem cell injections if they were provided. Mann-Whitney U tests were used to compare the mean price between practices. F tests for equality of variances were used to compare the variability in prices between practice types. Results: A total of 25 unique orthopaedic sports medicine practices (comprising 80 AOSSM/AANA surgeons) and 40 alternative clinics offered PRP, stem cell, and/or BMC injections, as indicated over the telephone. There was no difference in likelihood of offering PRP ( P = .698) or BMC injections ( P = .340). However, alternative clinics were significantly more likely to offer stem cell injections ( P < .001). There was no difference in the willingness to disclose the price for PRP ( P = .269), stem cell injections ( P = .302), and BMC ( P = .528) or the source of what each clinic advertised as stem cell injections ( P = .630). The mean price for a single PRP injection was significantly higher ( P = .011) and significantly more variable ( F statistic = .139; P < .001) at alternative clinics. Similarly, the mean price for a single stem cell injection was significantly higher ( P < .001) and significantly more variable ( F statistic = 0.080; P = .025) at alternative clinics. Conclusion: This study demonstrates that orthobiologic knee injections are highly prevalent for in-clinic use within the Chicago metropolitan area, with PRP being the most commonly used therapeutic. When compared with orthopaedic sports medicine providers, alternative clinics were more likely to offer stem cell injections and charge a significantly greater and more variable amount per PRP and stem cell treatment.

Purpose To perform a prospective, double‐blind, randomized controlled trial to assess differences in integration and patient‐reported outcomes metrics (PROMs) of osteochondral allograft transplantation with and without bone marrow aspirate concentrate (BMAC) augmentation. Methods Patients (n = 36) undergoing osteochondral allograft transplantation of the knee were consented and enrolled in this prospective study. They were randomized to either iliac crest BMAC or sham incision groups and blinded to their allocation. Computerized tomography (CT) scans of the knee were obtained at 6 months postoperatively after the index transplantation and graded by the semiquantitative assessment CT osteochondral allograft system. PROMs, including the International Knee Documentation Committee and Knee injury and Osteoarthritis Outcome Score–Joint Replacement, were obtained at 6 months, 1 year, and 2 years postoperatively. Results On 6‐month postoperative CT scans, patients receiving BMAC‐treated grafts were more likely to have small cystic changes ( P = .01), with an associated trend toward reduction in large cyst formation ( P = .06), but equal osseous integration, graft signal density, and presence of discernible clefts and intra‐articular fragments. The BMAC group was less likely to undergo subsequent surgery for graft debridement or revision (5.3% vs 35.3%; P = .02). There were no significant differences in PROMs between the 2 groups preoperatively or postoperatively at 6 months, 1 year, or 2 years. Patients receiving BMAC trended toward a higher rate of achievement of Knee Documentation Committee and Knee injury and Osteoarthritis Outcome Score–Joint Replacement minimal clinically important difference (88% vs 55%; P = .076). Conclusions Patients receiving BMAC‐treated grafts were more likely to have small cystic changes and were less likely to undergo subsequent surgery for persistent or new symptoms after the index procedure. No difference in postoperative PROMs was shown at the 6‐month, 1‐year, and 2‐year follow‐ups between the 2 groups. Level of Evidence Level I, prospective, randomized controlled trial.

Objective: We aimed to estimate the prevalence of cardiovascular diseases (CVDs) and cardiometabolic diseases (CMB) in Brazil, and their relationship with a healthy lifestyle score based on the six pillars of lifestyle medicine proposed by the American College of Lifestyle Medicine. Methods: Data were derived from the 2019 Brazilian National Health Survey, a nationwide cross-sectional study. The prevalence of CVDs/CMB was based on medical-endorsed, self-reported diagnoses and weighted for sample strata. A healthy lifestyle score (0-14 points; the higher the score, the better) incorporates physical activity, diet, sleep, mental health, risky substance use, and social connections. Results: Among 88,531 adults included in the analysis (mean age: 47.1 years; 52.9% female), the weighted prevalence of CVDs/CMB ranged from 1.9% (stroke) to 25.9% (hypertension). Weighted Poisson regression models, adjusted for age, sex, socioeconomic status, and geographic disparities, showed an inverse linear relationship between lifestyle score and CVDs/CMB prevalence. Participants in the highest lifestyle score quartile exhibited lower prevalence for heart diseases [0.48 (95% CI: 0.43, 0.53)], stroke [0.35 (95% CI: 0.29, 0.43)], hypertension [0.85 (95% CI: 0.80, 0.90)], diabetes [0.80 (95% CI: 0.70, 0.91)], dyslipidemia [0.73 (95% CI: 0.66, 0.80)], and obesity [0.81 (95% CI: 0.74, 0.88)], compared to the lowest quartile ( P < 0.001 for all). Conclusions: Higher scores on the six pillars of lifestyle medicine are associated with a lower prevalence of major CVDs/CMB in Brazil.

ABSTRACTBarriers to pediatric palliative care (PPC) integration in pediatric oncology encompass resource availability, provider attitudes, patient/family hesitancy, and timing. We report on a unique multistep approach for the creation of a pediatric palliative oncology program that (1) optimizes PPC delivery for all resource‐typed settings, (2) offers continuity of care by spanning inpatient and outpatient clinical settings, (3) improves PPC equity through standardized referral practices, and (4) promotes collaborator buy‐in and partnership through the utilization of tools to introduce PPC to patients/families. Our model demonstrates success through objective increases in PPC consultation and reported satisfaction from patients, families, and oncologists.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

SUMMARY Tuberculosis induces diverse lesions, such as necrotic pneumonia, contributing to disease progression and transmission. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in developing severe forms of tuberculosis, the regulation of this important signaling pathway remains unclear. Herein, we show that the ectonucleotidase CD39 plays an essential regulatory role in TB progression by preventing lung tissue damage, bacterial dissemination, and excessive inflammatory responses. Mechanistically, through its enzymatic activity on the cellular surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. We proposed that by protecting macrophages from P2RX7-mediated cell death and bacterial dissemination, CD39 prevents the development of necrotic lesions. Altogether, these findings uncover a significant role for CD39 as an essential component of the molecular regulation underlying the development of severe tuberculosis. GRAPHICAL ABSTRACT Brief In tuberculosis, necrotic granuloma-like structures release extracellular ATP (eATP), which triggers P2RX7-mediated immune cell death. CD39 degrades eATP, preventing P2RX7 activation and promoting macrophage survival, thereby limiting inflammation, tissue damage, and bacterial dissemination.