Citations

Abstract Background XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK. Objective The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients. Methods We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls. Results In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N ‐acyl phosphatidylethanolamine was increased in the DLPFC. N ‐Acyl serine was reduced in all three regions. Conclusions Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease. © 2026 International Parkinson and Movement Disorder Society.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Abstract A challenge in the implementation of rapid risk-stratification algorithms for patients with suspected acute coronary syndrome is the turnaround time for cardiac troponin (cTn) from blood sampling to reporting of results. Measurement of cTn in whole blood using point of care (POC) offers a solution. There is lack of consensus on how these instruments should be assessed and deployed when implemented into routine practice. A pragmatic strategy is needed to balance the requirement for appropriate evaluation, validation and local verification of POC high sensitivity (hs) cTn assays whilst avoiding unnecessary duplication of previously conducted work using central laboratory assays. The International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) has developed an educational document to provide practical suggestions as to how hs-cTn POC assays may be implemented in acute health care settings and networks. The objective of this document is to provide a pragmatic framework for implementation of such systems. The article describes the validation and verification procedures and outlines what should be the responsibility of the manufacturers and provides recommendations on how a local verification may be undertaken before instruments are implemented into routine clinical practice.

Abstract Background Ceftriaxone-resistant Escherichia coli infections are increasingly common, partially because of the emergence of E. coli sequence type 131 (ST131), including its subclade C2/H30Rx, which produce extended-spectrum β-lactamases. Methods A prospective cohort including 14 US sites, which enrolled monomicrobial ceftriaxone-resistant and susceptible E. coli bloodstream infection (BSI) cases in a 1:1 ratio, was used to compare ST131 versus non-ST131 E. coli BSI, with specific attention to E. coli ST131 C2/H30Rx. Desirability of outcome ranking was determined at 30 days after infection onset. Results This analysis included 282 patients with E. coli BSI; 43% (121/282) were E. coli ST131 and 23% (66/282) belonged to the C2/H30Rx subclade. Resistance to ceftriaxone was present in 79% (96/121) ST131, 86% (57/66) E. coli ST131 C2/H30Rx, and 27% (43/161) E. coli non-ST131. Compared to patients with non-ST131 E. coli BSI, patients with ST131 BSI were older (median 70 years, [Q1 62, Q3 76] years vs 65 years, [51, 74]; P = .005) and more often admitted from long-term care facilities (21/121 [17%] vs 7/161 [4%], P < .001). Overall and empiric carbapenem use was more frequent in the treatment of patients with ST131 BSI compared with non-ST131 BSI (overall 89/121 [74%] vs 50/161 [31%]; empiric: 58/121 [48%] vs 31/161 [19%], P < .001). Desirability of outcome ranking outcomes were similar between groups. Conclusions Most ceftriaxone-resistant E. coli from US patients with E. coli BSI belong to ST131, particularly E. coli ST131 C2/H30Rx, serving as an important driver of carbapenem use.

Abstract Background Automated phlebotomy has the potential to improve patient outcomes and address phlebotomist workforce challenges. The Autonomous Blood Drawing Optimization and Performance Testing trial (ADOPT, ClinicalTrials.gov NCT05878483) assesses performance, safety, and patient experience of an autonomous robotic phlebotomy device (ARPD) that utilizes multimodal imaging. Methods Patients were recruited from outpatient phlebotomy departments in the Netherlands. In cohort 1, analytical equivalence was assessed by comparing within-subject test results from ARPD-collected and manually collected samples using Passing–Bablok regression analysis. In cohort 2, the ARPD was assessed in routine use. The primary performance endpoint was first-stick success rate; the primary safety endpoint was the rate of adverse events. Exploratory endpoints assessed pain and patient preference. Results One hundred fifty-three patients were enrolled in cohort 1. No statistically significant differences were observed in activated partial thromboplastin time, prothrombin time, lactate dehydrogenase, aspartate transaminase, or platelet count, indicating analytical equivalence. A total of 1633 patients were enrolled in cohort 2. The overall first-stick success rate, in patients where the ARPD could identify a suitable vein, was 94.5% (95% CI, 93.3–95.5) and remained high in patients with difficult venous access (92.7%), obesity (97.4%), and age ≥65 years (93.4%). Adverse events, all mild, occurred at a rate of 0.6%. Ninety percent of patients reported far less (19%), less (32%), or similar pain (39%) compared with manual phlebotomy. Eighty-two percent indicated they would strongly prefer (16%) or prefer (31%) use of the ARPD in the future or had no preference (35%). Conclusions Automated phlebotomy using the ARPD shows a favorable performance and safety profile and may improve patient experience. ClinicalTrials.gov Registration Number: NCT05878483

605 Background: Patients with stage I testicular cancer (TCa) have excellent survival, and surveillance after orchiectomy is often preferred. Limited data exist on survivorship outcomes of surveillance versus adjuvant therapy. We compared systemic health outcomes between patients managed with surveillance and those treated with upfront therapy. Methods: Claims data from the OptumLabs Data Warehouse (2007–2022) identified stage I TCa patients managed with surveillance, chemotherapy, or radiation. Adjuvant therapy was defined as chemotherapy or radiation within 4 months of diagnosis with no further therapy. Chemotherapy codes were required within 42 days to ensure multiple cycles were not given. Propensity score–matched cohorts were created using logistic regression. A 3-year analysis evaluated new diagnoses of cardiopulmonary complications, metabolic syndrome, men’s health, psychological, and miscellaneous systemic conditions. Outcomes were stratified by treatment group. Chi-square tests and Cox regression analyses compared survivorship outcomes between adjuvant therapy and surveillance. Results: Eight-hundred forty-two patients had 3 years of coverage: 531 surveillance, 159 chemotherapy, and 152 radiation. No significant differences were found in cardiopulmonary, metabolic, psychological, or other systemic outcomes between therapy and surveillance (Table 1). Men’s health diagnoses were more frequent with chemotherapy (35.2% vs 23.9%, p=0.027) compared to surveillance. However, Cox regression showed no significant time-to-event differences on time-to-event analysis between groups. Conclusions: Adjuvant chemotherapy may be associated with higher rates of men’s health complications (infertility, erectile dysfunction, hypogonadism), but over time the risk is not significantly different than surveillance. Propensity-score matched survivorship outcomes: A) surveillance vs chemotherapy; B) surveillance vs radiation. A) Surveillance (N=159) Chemotherapy (N=159) p value Cardiopulmonary Complications 0.157 Yes 14 (8.8%) 22 (13.8%) No 145 (91.2%) 137 (86.2%) Men’s Health Complications 0.027 Yes 38 (23.9%) 56 (35.2%) No 121 (76.1%) 103 (64.8%) Metabolic Syndrome Complications 0.631 Yes 53 (33.3%) 49 (30.8%) No 106 (66.7%) 110 (69.2%) Miscellaneous Systemic Disorders 0.879 Yes 25 (15.7%) 26 (16.4%) No 134 (84.3%) 133 (83.6%) Psychological Diagnoses 0.401 Yes 29 (18.2%) 35 (22.0%) No 130 (81.8%) 124 (78.0%) B) Surveillance (N=152) Radiation (N=152) p value Cardiopulmonary Complications 0.682 Yes 12 (7.9%) 14 (9.2%) No 140 (92.1%) 138 (90.8%) Men’s Health Complications 0.630 Yes 51 (33.6%) 55 (36.2%) No 101 (66.4%) 97 (63.8%) Metabolic Syndrome Complications 0.086 Yes 42 (27.6%) 56 (36.8%) No 110 (72.4%) 96 (63.2%) Miscellaneous Systemic Disorders 0.650 Yes 25 (16.4%) 28 (18.4%) No 127 (83.6%) 124 (81.6%) Psychological Diagnoses 0.650 Yes 28 (18.4%) 25 (16.4%) No 124 (81.6%) 127 (83.6%)

498 Background: Radiotherapy-based metastasis-directed therapy (MDT) has emerged as a viable treatment paradigm for oligometastatic clear cell renal cell carcinoma (ccRCC). However, the optimal integration of MDT with frontline immune checkpoint inhibition (ICI) is unclear, especially in light of the M1 NED subgroup analysis of KEYNOTE-564 suggestive of a larger benefit from adjuvant pembrolizumab. Here, we sought to compare the effects of MDT with or without pembrolizumab on clinical and translational outcomes among patients with oligometastatic ccRCC enrolled on two prospective phase II trials. Methods: We undertook an exploratory cohort study of two prospective, single-arm, investigator-initiated phase II trials. The RAPPORT trial (NCT02855203) assigned 30 patients to radiotherapy-based MDT followed by pembrolizumab 200 mg Q3W for eight cycles (MDT+ICI cohort). The MD Anderson trial (NCT03575611) assigned 121 patients to serial MDT (which was almost exclusively radiotherapy-based) without systemic therapy (MDT cohort). For both trials, eligibility criteria consisted of 1 to 5 ccRCC metastatic lesions amenable to MDT. For the present analysis, the primary endpoint was progression-free survival (PFS), prospectively defined by RECIST v1.1 and analyzed using Cox regression. Peripheral blood flow cytometry obtained at baseline, end of MDT in both cohorts (after 1 cycle of ICI in the MDT+ICI cohort), and after completion of all treatment in both cohorts (3 months in the MDT alone cohort and 12 months in the MDT+ICI cohort) was compared using adjusted linear mixed effect models. Results: A total of 150 patients were included for analysis (MDT+ICI: 30; MDT: 120). Median follow-up time was 34 months (MDT+ICI: 28; MDT: 36). At enrollment, the MDT+ICI cohort had a larger number of metastases (median 3 vs 1). Adjusted for prognostic factors, median PFS was 28 months after MDT+ICI and 17 months after MDT (HR, 0.57; 95% CI: 0.31 to 0.998; P = 0.049). Induction of activated systemic CD8 + T cells (ICOS + ) was observed in both cohorts following MDT; however, this increase was greater in the MDT+ICI cohort. Moreover, there was evidence of decreased systemic CD8 + T cell immunosuppression (CD73 + ) following treatment cessation in the MDT+ICI group. Conclusions: To our knowledge, this is the largest prospective analysis of MDT for ccRCC in the ICI era. The addition of maintenance ICI to MDT may improve clinical outcomes in patients with oligometastatic ccRCC. Greater immunomodulatory signals were observed with MDT+ICI, providing a mechanistic link to the clinical benefits. The ASTROs trial (NCT06004336) randomizing patients with oligometastatic ccRCC to MDT with or without pembrolizumab has been initiated to test the hypotheses generated by the present study. Clinical trial information: NCT02855203 and NCT03575611 .

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

Background: To compare oncologic and postoperative outcomes in patients with scalp squamous cell carcinoma with periosteal, but not gross calvarial, involvement, treated with margin-clearing excision including either calvarial burring or periosteal excision alone. Study Design: Retrospective cohort study. Setting: Single tertiary academic referral center. Methods: We retrospectively reviewed surgical cases from January 2001 to January 2025. Inclusion criteria: patients ≥18 years with biopsy-proven scalp squamous cell carcinoma involving the periosteum without cortical invasion on imaging. Management of the deep margin included either burring of the outer table or periosteal excision alone. Demographic, surgical, and oncologic outcomes were collected and analyzed descriptively. Results: Twenty patients met inclusion criteria. Median age was 70 (range 56-92), and 18 (86%) were male. Thirteen (65%) patients underwent calvarial burring, 7 (35%) underwent periosteal excision. Local recurrence occurred in 31% and 29% of the burring group and non-burring group. Disease-free survival at 2 years was 46% and 57% in the burring and non-burring group, respectively. Overall survival at 2 years was 77% and 86% in the burring and non-burring group. Three patients in the burring group had local recurrences with intracranial extension, 1 died of disease, 1 died with disease and concurrent meningitis, 1 is alive with disease recurrence currently on palliative treatment. There were 7 disease-related deaths. Conclusion: Burring did not confer a significant oncologic advantage compared to periosteal excision alone when there was no gross cortical invasion. Local recurrence in patients undergoing calvarial burring was associated with intracranial extension of disease.