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Sharing research code in an open access version-controlled repository offers significant benefits for both science as a whole and for individual researchers. In this article, we focus on this practice, which is fully aligned with the NIH’s Gold Standard Science (GSS) program as well as FAIR (findable, accessible, interoperable, reusable) and TRUST (transparency, responsibility, user focus, sustainability, technology) principles. Gold Standard Science supports open science by emphasizing transparency, reproducibility, and the use of best practices that enable others to verify and extend research. Pairing a research article’s cited data snapshot with a versioned, environment-specific code release, deposited in a companion code repository, ensures that, upon submission to a medical journal, readers and reviewers can directly verify results. An executable and updatable companion code repository complements, rather than replaces, established research data repositories. When code underlying medical research results is made openly available, then other scientists can inspect, run, and validate analyses. These activities enhance reproducibility, which is a core aim of GSS. Shared code also facilitates collaborative innovation by allowing researchers to extend the utility of the code to new datasets and applications. For researchers, code sharing can increase visibility, credibility, and citation impact. Demonstrating transparency through shared executable and updatable code builds trust with journal readers, peer reviewers, funders, and peers. Shared code in an open access repository signals adherence to high standards of scientific integrity and attracts opportunities for collaboration. A researcher who shares code receives recognition as a leader in reproducible, trustworthy research consistent with NIH’s GSS principles.

Background Dual antiplatelet therapy (DAPT) is recommended around carotid artery stenting (CAS) to reduce periprocedural stroke risk. Clopidogrel is widely used, but response variability related to pharmacokinetics and CYP2C19 polymorphisms may limit its effectiveness. Ticagrelor is a more potent, direct acting P2Y12 inhibitor, but its comparative effectiveness in CAS remains uncertain. Methods We conducted a retrospective cohort study in the TriNetX database, identifying adults with carotid artery stenosis who underwent CAS between January 2016 and August 2025 and received either ticagrelor or clopidogrel. Primary outcomes at 180 days included ischemic stroke, major hemorrhage, intracranial hemorrhage, and all cause mortality. Secondary outcomes included inpatient readmission and emergency department (ED) visits. Propensity score matching (1:1), Kaplan–Meier survival, and Cox proportional hazards analysis were used. Results Among 6996 patients, 378 received ticagrelor and 6618 received clopidogrel; aspirin co-use was similar (89.7% vs 91.7%). After matching, 377 patients remained in each cohort. Ischemic stroke (2.7% vs 4.2%; HR 0.56, 95% CI 0.25 to 1.27; P=0.159) and major hemorrhage (2.9% vs 4.8%; HR 0.61, 95% CI 0.29 to 1.30; P=0.197) were numerically lower with ticagrelor. Rates of intracranial hemorrhage were similar (2.7% vs 2.7%; HR 0.61, 95% CI 0.14 to 2.53; P=0.488). Mortality was numerically higher with ticagrelor (3.4% vs 2.7%; HR 1.64, 95% CI 0.68 to 3.97; P=0.263). ED visits were similar (14.3% vs 14.6%; HR 0.97, 95% CI 0.67 to 1.42; P=0.895). Inpatient readmission was numerically lower with ticagrelor (15.9% vs 19.1%; HR 0.81, 95% CI 0.57 to 1.14; P=0.223). Conclusion Ticagrelor and clopidogrel showed comparable safety and effectiveness following CAS. Future prospective genotype informed trials are warranted to confirm these findings.

Abstract Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality worldwide, and there are limited molecular screening options. Following a prior discovery and validation studies in subjects from the United States, China, and Iran, we aimed to validate methylated DNA markers (MDM) for ESCC detection in Malawi, a country with one of the highest ESCC incidence. Fourteen MDMs were tested on 177 tissue samples. Ten MDMs showed excellent performance (AUCs ≥ 0.85); a random forest model achieved an AUC of 0.97. The consistent cross-population performance suggests potential for universal application of these MDMs and further justifies exploring nonendoscopic sampling methods, such as swallowed cell collection devices in combination with MDMs, for efficient and cost-effective screening in high-incidence populations. Prevention Relevance: This study validates MDMs for early detection of ESCC in Malawi, supporting their potential role in noninvasive, population-based screening strategies in Africa to enable early detection and timely intervention for cancer interception, potentially reducing cancer burden in high-incidence, resource-limited regions.

800 Background: Primary squamous cell carcinoma (SCC) of the small intestine is exceedingly rare and associated with poor prognosis. Literature is currently limited to a few case reports, and, to our knowledge, this is the first population-based analysis of patients with small intestine SCC. This study aimed to identify patient demographics and predictors of survival outcomes. Methods: Patients with histologically confirmed primary SCC of the small intestine diagnosed between 2000 and 2022 were identified from the SEER database; autopsy-only cases were excluded. Patient demographics, tumor site, stage (SEER summary stage), and initial treatments were summarized. Overall survival (OS) was defined from diagnosis to death, with one-year OS estimated by Kaplan–Meier methods. Multivariate Cox proportional hazards models evaluated associations between patient variables (age, sex, race, residence, year of diagnosis, surgery, and chemotherapy) and mortality. All statistical analyses were performed using R version 4.4.2. Results: A total of 89 patients diagnosed with primary small intestine SCC were identified. The median age at diagnosis was 68 years; 43 % were female, and 67 % were non-Hispanic White. Most patients (82 %) resided in urban counties. Tumor site was mostly the duodenum (37 %), followed by ileum (16 %) and jejunum (10 %); 33 % were not otherwise specified. Among patients with a recorded stage, 45 % had localized disease, 38 % regional disease, and 17 % distant metastases. Initial treatment comprised surgery in 60 % of patients, chemotherapy in 25 %, and radiation in 10%. The median OS was approximately six months, and the one-year OS was 36.7 % (95 % CI 27.9–48.3). Women had a higher one-year OS (42 %) than men (33 %), although this difference was not statistically significant. In multivariable analysis, surgical resection was associated with a markedly lower hazard of death (HR = 0.43, 95 % CI 0.25–0.74). Chemotherapy was associated with an insignificantly improved survival (HR 0.54, 95 % CI 0.27–1.09). Additionally, rural residence (HR ≈ 2.9) and older age (HR ≈ 1.03) were independently associated with worse survival (p<0.05). Conclusions: This population-based study highlights the rarity and aggressiveness of primary small bowel SCC, with a median OS of six months. Surgical resection was strongly associated with improved survival (adjusted HR ≈ 0.43), reinforcing its role as the cornerstone of management. Chemotherapy showed a nonsignificant survival benefit, highlighting the need for prospective studies. The association of rural residence with higher mortality suggests disparities in access to care and underscores the need for strategies to improve early detection and referral. Overall, these findings support a multimodal approach centered on surgery and warrant further studies to elucidate pathogenesis and optimize systemic therapy.

158 Background: PIK3CA mutations are common in CRC and may be a negative prognostic factor. INAVO is a potent and selective PI3Kα inhibitor that also promotes mut p110α degradation. BEV and CETUX are standard treatment (tx) components for RAS mut and RAS -wildtype (wt) mCRC, respectively. The Phase I/Ib INTRINSIC open-label umbrella study (NCT04929223) evaluates targeted therapies in biomarker-selected mCRC subpopulations. We report INAVO + BEV and INAVO + CETUX results. Methods: Patients (pts) with PIK3CA mut, RAS mut mCRC received INAVO (9 mg oral once daily) + BEV (intravenous [IV] 15 mg/kg every 3 weeks). Pts with PIK3CA mut, RAS wt mCRC received INAVO + CETUX (IV 400 mg/m 2 then 250 mg/m 2 weekly thereafter). Primary endpoint: confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), and safety. Progression-free survival (PFS) and overall survival (OS) were exploratory. Results: At the clinical cut-off dates, 16 pts were enrolled in the BEV arm; 35, in the CETUX arm. Most had ≥2 metastatic sites at enrollment (n = 16 [100%] and 30 [85.8%], respectively) and ≥2 prior lines of metastatic therapy (16 [100%] and 28 [80.0%]). In the BEV arm, 3 pts (18.8%) had no prior BEV. In the CETUX arm, 25 pts (71.4%) had no prior CETUX; 17 (48.6%) had prior anti-EGFR therapy. All pts in the BEV arm and 34 in the CETUX arm were evaluated for efficacy and safety. Median follow-up was 9.4 months (mo; interquartile range: 5.5–14.4) and 12.6 mo (8.9–16.6), respectively. Efficacy is shown in the Table. All pts had adverse events (AEs); 15 (93.8%) and 34 (100%), respectively, had tx-related AEs (TRAEs); 5 (31.2%) and 12 (35.3%), grade 3–4 TRAEs; 2 (12.5%) and 11 (32.4%), serious AEs. One grade 5 AE (infusion-related reaction) occurred (CETUX arm). Dose reduction/interruption due to AEs occurred in 12 (75.0%) and 27 (79.4%) pts; tx withdrawal due to AEs, in 0 and 4 (11.8%) pts, respectively. Hyperglycemia was the most common AE, TRAE, and AE leading to dose reduction/interruption in both cohorts. Hypertension was observed more frequently with BEV; dermatitis acneiform and dry skin, with CETUX. Conclusions: INAVO + BEV and INAVO + CETUX showed encouraging efficacy in pts with PIK3CA mut mCRC, with no new or unexpected safety signals. Clinical trial information: NCT04929223 . INAVO + BEV(n = 16) INAVO + CETUX(n = 34) cORR, all PR, n (%) 1 (6.3) 7 (20.6)* SD, n (%) 10 (62.5) 17 (50.0) Progressive disease, n (%) 3 (18.8) 9 (26.5) Missing/NE, n (%) 2 (12.5) 1 (2.9) mDoR, mo (90% CI) 7.7 (NE) 4.4 (4.2–5.3) DCR, n (%) 11 (68.8) 15 (44.1) mPFS, mo (90% CI) 4.2 (2.8–6.8) 3.5 (2.8–4.4) mOS, mo (90% CI) 11.0 (8.5–14.5) 12.8 (10.7–13.8) CI, confidence interval; m, median; NE, not evaluable; PR, partial response; SD, stable disease. *3 pts with PRs received prior anti-EGFR therapy; 1 had a best prior response of SD (last dose 233 days before study tx) and 2 had best prior responses of PRs (last doses 134 and 171 days before study tx).

126 Background: NNT/NNH analyses can estimate the magnitude of benefit vs harm of therapeutic agents and can inform clinical decision making. We quantified the benefit/risk profile of fruquintinib (F; a highly selective, oral inhibitor of all 3 VEGFRs) vs other later-line mCRC monotherapies. Methods: Six phase 3 randomized (2:1), placebo (P)-controlled trials (F: FRESCO, FRESCO-2; regorafenib [rego]: CONCUR, CORRECT; TAS-102: TERRA, RECOURSE) were identified. NNT (average number of pts needing treatment to prevent 1 additional death/progression event) for overall survival (OS) and progression-free survival (PFS) was calculated as the inverse of difference in survival function between treatment and P. NNH (average number of pts needing treatment for 1 additional pt to have an adverse event; AE) for treatment-emergent AEs (TEAEs) was calculated as the inverse of absolute risk increase relative to P. Low NNTs and high NNHs suggest a more favorable treatment profile. Results: F had the lowest NNT (most favorable) for 6-month OS (FRESCO-2) and PFS (FRESCO) vs rego and TAS-102 (Table). F had the highest NNH (most favorable) for grade ≥3 TEAEs, palmar-plantar erythrodysesthesia (PPE; FRESCO-2), and fatigue (FRESCO). TAS-102 (TERRA) had the highest NNH for diarrhea, followed by F (FRESCO-2). Consistent with mechanism of action of anti-VEGFRs, F and rego had lower NNHs for hypertension (HTN) vs TAS-102 (TERRA). F (FRESCO) had the lowest NNH for discontinuation due to TEAEs. Conclusions: In this cross-trial comparison, F had the lowest NNT for OS (FRESCO-2) and PFS (FRESCO/FRESCO-2), indicating survival benefit. F had the highest NNHs for grade ≥3 TEAEs, PPE (FRESCO-2), and fatigue (FRESCO), indicating a low risk profile. The analysis highlights fruquintinib as a favorable treatment for pts with mCRC. Clinical trial information: NCT02314819 , NCT04322539 , NCT01584830 , NCT01103323 , NCT01955837 , NCT01607957 . NNT/NNH (95% CI) for mCRC treatments.* F Rego TAS-102 FRESCO NCT02314819 N=416 FRESCO-2 NCT04322539 N=691 CONCUR NCT01584830 N=204 CORRECT NCT01103323 N=760 TERRA NCT01955837 N=406 RECOURSE NCT01607957 N=800 6-month OS 6.5(5.5–8.1) 5.3(4.8–5.9) 5.9(NA) 9.8(NA) 14.1(NA) 7.2(NA) 6-month PFS 4.2(3.7–4.8) 4.4(3.9–5.1) 5.0(NA) 9.1(NA) 7.1(NA) 7.2(NA) Grade ≥3 TEAEs 2.4 (2.0–3.1) 8.1 (5.0–22.5) 2.6 (2.0–3.7) 2.5 (2.2–3.0) 2.8 (2.3–3.6) 5.9 (4.1–10.2) TEAE leading to discontinuation 10.8 (6.7–28.5) NA † (18.0–NA) 12.5 (6.2–NA) 17.5(11.3–39.2) 250.0 (15.3–NA) 50.0 (22.9–NA) PPE 2.2 (1.9–2.5) 6.0 (4.8–8.0) 1.4 (1.3–1.7) 2.6 (2.2–3.0) NA (NA) NA (46.0–NA) HTN 2.4 (2.0–3.0) 3.6 (3.0–4.5) 5.3 (3.6–9.5) 4.5 (3.7–5.8) 14.3 (10.0–25.2) NA (NA) Diarrhea 5.1 (3.8–7.4) 7.3 (5.2–12.3) 6.2 (4.3–11.4) 3.8 (3.2–4.8) 7.9 (5.7–13.0) 5.0 (3.9–6.9) Fatigue 32.5 (10.3–NA) 25.8 (10.1–NA) 10 (5.3–80.3) 5.3 (3.8–8.4) 7.4 (5.0–13.9) 8.3 (5.4–18.1) *All trials except TERRA included best supportive care in both arms. † Lower rate of pts discontinued F vs P due to TEAEs, thus NNH was not applicable (NA).

ABSTRACT Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267