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PURPOSE Patients with cancer take different types of medications with varying schedules and settings. They are also sometimes instructed to stop medications due to toxicity. To measure self-reported nonadherence in this heterogeneous population, we modified and evaluated a measure originally developed to assess nonadherence to daily oral antihypertensives, the Domains of Subjective Extent of Nonadherence (DOSE-Nonadherence). METHODS The measure was refined in an iterative process incorporating feedback from patient investigators and participant interviews in English and Spanish. Branching logic was added for participant selection of medication administration setting: (1) only home, (2) only clinic, or (3) partly home/partly clinic. Participants reported their adherence to medications taken over a setting-specific reference period (1 week for home, 1 month for clinic medications). Participants who missed medications then reported on reasons for nonadherence. Adherence was dichotomized for analysis (complete adherence v any nonadherence). For participants who received clinic-administered medications, concordance between chart-abstracted and self-reported adherence was evaluated. RESULTS Seventy-three participants completed the measure (68% English; 32% Spanish; 86% female; 44% age ≥60 years). The majority had breast cancer; 64% had metastatic disease. Twenty-six percent (15/58) of participants who received medication in clinic and 24% (11/46) of those who took medication at home reported nonadherence. Participants felt able to respond accurately to both reference periods and perceived all reasons for nonadherence to be relevant. Among participants who completed the final version of the measure for clinic-administered medication, 96% (26/27) accurately reported their adherence compared with chart-abstracted data. CONCLUSION Our results support the validity of the DOSE-Nonadherence-Cancer for assessing cancer treatment nonadherence. This measure can be used to assess nonadherence in patients with cancer receiving a broad array of systemic therapies.

ABSTRACT Background Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression‐free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints. Methods Two‐arm, superiority‐design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double‐blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety‐five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic regressions explored associations with trial‐level features. Results After screening, 237 trials were included, enrolling 127,518 patients. A double‐blind design was used in 105 trials (44%, 95% CrI 38%–51%). BICR was used in 111 trials (47%, 95% CrI 41%–53%), including 39 double‐blind trials (16%, 95% CrI 12%–22%). Trials with BICR had higher odds of meeting the primary endpoint (OR 1.84; 95% CI 1.06–3.18; p = 0.03). The PFS assessor identity (central vs. local) or blinding status was not reported in 50 trials (26%, 95% CrI 16%–27%). Trials that met prespecified significance criteria for PFS were more likely to report whether PFS assessors were blinded/unblinded and central/local (OR, 3.05; 95% Cl: 1.60–5.81; p = 0.0007). Conclusions Despite the importance of double blinding in combination with BICR for reducing bias, only a few trials blinded physicians, patients, and primary endpoint assessors. This meta‐epidemiological study illuminates the prevalence of potential assessment biases affecting PFS in Phase III oncology and secondarily emphasizes the need for improved methodology reporting.

Background: Obstructive Sleep Apnea (OSA) is a common occurrence in the perioperative patient population but is often undiagnosed. Point-of-Care Ultrasound (POCUS) has emerged as a promising tool for perioperative assessment; however, its effectiveness in detecting the presence or severity of OSA needs to be evaluated. Objective: We assessed the ability of airway POCUS as a screening and severity evaluation tool for OSA by examining its correlation with STOP-BANG scores and the Apnea–Hypopnea Index (AHI). Design: Cross-sectional observational study. Setting: A single-center study in a tertiary care hospital between June 2020 to May 2021. Patients: Adult patients aged 18–65 with prior Polysomnography (PSG) for OSA workup were screened. Interventions: The participants completed the STOP-BANG questionnaire and subsequently underwent POCUS examinations, either pre- or post-surgery. Ten different POCUS views previously used for evaluating OSA were acquired in a predefined sequence, with subsequent measurements of airway parameters. Outcome measures: Generalized linear modeling was used to explore and assess the relationships between the measured parameters, STOP-BANG, and AHI scores (modeled continuously and categorized into risk levels of STOP-BANG and AHI). Results: A total of 260 patients were screened, of which 142 were enrolled and 127 completed the scanning studies. The median AHI was 16.71, while the STOP-BANG scores were mostly between 5 and 6, indicating a moderate-to-high OSA risk in the study population. Notably, only neck circumference was significantly associated with AHI severity (p = 0.012), whereas none of the other POCUS measures were. Among the POCUS measures, significant associations with STOP-BANG scores were observed for the Tongue Cross-Sectional Area (T-CSA) (p = 0.002), Retro-Palatal Diameter (RPD) (p = 0.034), Distance Between Lingual Arteries (DLA) (p = 0.034), and Geniohyoid Muscle Thickness (GMT) (p = 0.040). Conclusions: Neck circumference is a more reliable predictor of OSA severity (AHI) compared to other POCUS measurements. Many of the POCUS measures had a good correlation with the STOP-BANG scores, highlighting the utility of POCUS as a screening tool for OSA rather than as a severity evaluation tool.

Background: Outcomes after arthroscopic rotator cuff repair (RCR) are frequently measured through clinically significant outcomes (CSOs) such as the minimal clinically important difference, the substantial clinical benefit, and the Patient Acceptable Symptom State. Global achievement of CSOs is challenging to predict. Purpose: To determine if unsupervised machine learning can identify distinct patient subgroups based on CSO achievement after elective arthroscopic RCR. Study Design: Case-control study; Level of evidence, 3. Methods: A prospectively collected database was analyzed to identify patients who underwent elective arthroscopic RCR from 2015 to 2017. Tear dimensions were measured on magnetic resonance imaging utilizing a validated technique. CSO achievements on the American Shoulder and Elbow Surgeons, the Single Assessment Numeric Evaluation, and the Constant-Murley subjective score at 2-year follow-up were calculated. An unsupervised random forest algorithm was utilized to develop and internally validate patient subgroups with significantly different rates of CSO achievement. Patient subgroup membership, along with a total of 30 demographic and clinical variables, as well as preoperative patient-reported outcomes, were incorporated into a stepwise multivariable logistic regression to identify factors predictive of optimal CSO achievement. Results: A total of 346 patients (192 male; mean ± SD age, 57.2 ± 9.1 years; body mass index, 30.1 ± 5.4 kg/m 2 ) were eligible for inclusion and followed for a mean of 3.8 years (range, 2.0-6.2 years) Of these, a total of 333 patients were partitioned by the random forest algorithm into 2 subgroups (stability, 0.16; connectivity: 180.8; Dunn: 0.16; silhouette: 0.05), with 176 patients in the optimal achievement subgroup and 157 patients in the suboptimal achievement subgroup. The 2 subgroups differed significantly (all P ≤ .004) in the likelihood of achievement of all CSOs. Stepwise multivariable logistic regression identified an increase of 1 mm in tear size in the sagittal dimension beyond 1.9 cm to predict a 10% increase in the probability of suboptimal achievement. Additional risk factors for suboptimal CSO achievement included increasing number of tendons involved (odds ratio [OR], 14.07; 95% CI, 4.50-44.02; P < .001), subscapularis involvement (OR, 8.67; 95% CI, 2.45-30.71; P = .01), and increased preoperative CMS score (OR, 1.11; 95% CI, 1.04-1.18; P = .001). Protective factors included performance of a subpectoral biceps tenodesis compared with biceps tenotomy (OR, 0.22; 95% CI, 0.05-0.92; P = .03). Conclusion: Clinically meaningful subgroups were uncovered using an unsupervised machine learning algorithm in patients undergoing arthroscopic RCR. Tear size, number of tendons involved, and subscapularis involvement were significant and additive predictors of suboptimal CSO achievement at 2-year minimum follow-up. Treatment of concurrent biceps pathology with tenodesis conferred 78% increased likelihood of CSO achievement compared with tenotomy.

Multiple sclerosis is characterized by CNS infiltration of autoreactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8 + antineural T cells in the neurodegeneration that underlies irreversible clinical progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8 + T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8 + T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8 + T cell–mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer–based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8 + T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8 + T cell–mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8 + T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.

Background Given the low haemorrhagic risk of intracranial low-grade dural arteriovenous fistulas (dAVFs), the benefits of routine intervention remain controversial. This study compares patient outcomes treated with stereotactic radiosurgery (SRS) versus conservative management. Method Multicentre retrospective analysis of the Consortium for Dural Arteriovenous Fistula Outcomes Research and the International Radiosurgery Research Foundation data. Inclusion criteria were (1) intracranial low-grade dAVF diagnosed by catheter-based angiography, (2) no prior dAVF-related haemorrhage and (3) management with upfront SRS (intervention group) or conservative management (observation group). The primary outcome was symptomatic improvement. Secondary outcomes included dAVF obliteration, up-conversion, haemorrhage, improvement and favourable modified Rankin Scale (mRS) at follow-up. Results 304 patients with a mean age of 56 years (SD 13.5) and a follow-up of 46.7 months (SD 45.5) were included. 135 (44.4%) were managed conservatively and 169 (55.6%) had upfront SRS. Compared with the observation group, symptomatic and mRS Score improvement (≥1-point decrease in baseline score) was more likely in the intervention group (95.1% vs 58.5%; OR=13.75 (5.61–33.69) and 37.0% vs 24.0%; OR=1.85 (1.09–3.15), respectively). These findings remained significant after multiple imputation and propensity score matching. Remaining outcomes were similar between groups. The all-cause mortality rate was 5.4% (n=16), unrelated to the dAVF or treatment. Five (3.0%) SRS-related complications were reported and resolved during the follow-up period. Conclusions SRS was associated with increased symptomatic and mRS Score improvement for low-grade dAVFs compared with conservative management. SRS had a low complication risk and did not appear to alter dAVF obliteration or haemorrhage. Future prospective trials on SRS as a first-line intervention for symptomatic low-grade dAVFs should be considered.

Abstract Congenital disorders of glycosylation (CDG) are a group of neurogenetic conditions resulting from disruptions in the cellular glycosylation machinery. The majority of CDG patients have compound heterozygous pathogenic variants in the phosphomannomutase 2 ( PMM2) gene. Individuals with PMM2-CDG exhibit multi-systemic symptoms, prominently featuring neurological deficits with nearly all patients exhibiting cerebellar hypoplasia and ataxia. To overcome embryonic lethality caused by whole body knock-out of Pmm2 and mimic patient-related compound heterozygous pathogenic variants, we paired a Pmm2 flox allele ( Pmm2 fl ) with a catalytically inactive knock-in allele ( Pmm2 R137H ), commonly present in PMM2-CDG patients. Mice with post-mitotic loss of PMM2 from neurons or astrocytes are indistinguishable from unaffected littermates, including in a broad battery of neurological assessments. In contrast, removal of PMM2 from embryonic neural precursor cells leads to cerebellar hypoplasia, ataxia, seizures, and early lethality. Comprehensive multi-omics profiling, including metabolomics, glycomics, single-cell transcriptomics, proteomics, and glycoproteomics, reveal widespread molecular disturbances throughout the brain, with the cerebellum showing the most pronounced disruption. These findings highlight the heightened dependency of the developing cerebellum on intact N-glycosylation, aligning with clinical observations in PMM2-CDG patients. Importantly, glycoproteomic alterations identified in our mouse model are corroborated in PMM2-CDG patient post-mortem cerebellar tissue, underscoring the translational relevance of our findings and implicating impaired synaptic transmission as a key pathogenic mechanism.

11106 Background: Patients with cancer take different types of medication (e.g., enteral, parenteral), with varying treatment schedules, in various settings. They are also sometimes instructed to stop medication in response to toxicity. To measure medication nonadherence in this heterogenous population, we modified and pilot-tested a self-report measure originally developed to assess nonadherence to daily oral medication, the Domains of Subjective Extent of Nonadherence (DOSE-Nonadherence), in adults with cancer. Methods: Participants were ≥21 years, on active cancer treatment at Memorial Sloan Kettering, and spoke English and/or Spanish. A branching logic was added to allow participants to select the setting where they take cancer medication: 1) only at home, 2) only in clinic, or 3) partly at home/partly in clinic. Based on administration setting, participants reported nonadherence to medications their clinician expected them to take over a given reference period (1 week for home and 1 month for clinic medications). Participants then reported on setting-relevant reasons for nonadherence. Survey instructions/items were refined in an iterative process using feedback from a patient investigator committee and participant cognitive interviews. During interviews, we asked participants about the interpretation of instructions/items, recall period, and comprehensiveness of reasons for nonadherence, regardless of their own adherence. After initial testing in English, a Spanish version was developed through transcreation. Adherence was dichotomized for analysis (complete adherence vs. any nonadherence). For all participants who received clinic medications, concordance between chart abstracted and self-reported adherence was evaluated. Results: Of 55 participants who completed the surveys and interviews (67% in English; 33% in Spanish), 87% were female and 44% identified as Latino. The majority (73%) had breast cancer; 60% had metastatic disease. 12 of 45 who received medication in clinic reported nonadherence as did 8 of 35 who took medication at home. Participants felt able to respond accurately to both recall periods. All reasons for nonadherence were perceived as relevant to themselves or other patients. There was 89% concordance between self-reported and chart abstracted adherence for clinic-administered medication. To improve concordance, changes were made to the formatting and instructions. Of 12 participants who completed the final version of the survey for clinic-administered medication, there was 100% concordance between self-reported and chart abstracted nonadherence. Conclusions: Our results support the reliability and validity of modified DOSE-Nonadherence for cancer patients. This instrument can be used to better identify nonadherence to cancer medications in a population of adult patients with cancer receiving various treatment regimens.

PURPOSE Many trials ask patients to complete patient-reported outcome measures (PROMs) via the web, excluding patients unable to use/access the Internet. The PRO-TECT trial (AFT-39, ClinicalTrials.gov identifier: NCT03249090 ) also offered a telephone interface option (interactive voice response [IVR]). We compared patients choosing IVR versus web on alert rates to nurses and clinical outcomes to determine if a telephone option can close disparities in symptom management. METHODS PRO-TECT randomized 26 community oncology practices to the PROM intervention arm where concerning symptoms generated automated alerts to nurses. IVR and web patients were compared for social determinants of health (SDOH) using analysis of variance and chi-square tests. After accounting for clustering and confounders, we used generalized estimating equations to compare alert rates, mixed models for quality of life (QOL) at 3 months, and Cox regression for emergency visits and survival at 12 months. RESULTS Among 593 patients, 215 (36%) chose IVR and 378 (64%) chose web. IVR patients were older (65.2 v 60.8 years) and were more often rural residents (32% v 23%), Black (27% v 11%), and with less education (54% v 27% ≤high school; all P < .01). Patients choosing IVR had more surveys with concerning symptoms (49% v 37%) and nurses felt clinical attention was warranted more often (4.8 surveys v 3.4 surveys; all P < .001) but ultimately experienced similar benefits as web in QOL, emergency visits, and survival. CONCLUSION One third of community patients choose a telephone option over the web for reporting PROMs during cancer care. These patients are disproportionately from SDOH backgrounds at risk of poor clinical outcomes and have higher symptom management needs but ultimately experience similar clinical benefits as patients choosing the web. PROM programs should offer web alternatives to close disparities in symptom management.

Abstract RATIONALE: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality worldwide. We previously published the polygenic transcriptome risk score (PTRS) which uses the cumulative effect of predicted gene expression to construct genetic predictors for complex diseases, and we demonstrated the value of PTRS for COPD built on Genotype-Tissue Expression (GTEx) Lung tissue with significantly improved cross-ancestry portability. However, the postmortem collection and lack of lung disease status on GTEx samples likely affect results. We hypothesized that the performance of PTRS will be improved by using disease-relevant expression quantitative trait loci (eQTLs) to construct the score. Here, we aimed to improve performance of PTRS by leveraging disease-relevant eQTLs. METHODS: We constructed two transcriptome prediction models, Elastic Net (EN) and Prediction Using Models Informed by Chromatin conformation and Epigenomics (PUMICE), using TOPMed lung RNA-seq data from the Lung Tissue Research Consortium (LTRC), which included COPD patients undergoing lung surgery. We compared their performance with two published models built on RNA-seq from GTEx Lung tissue, GTEx-EN and GTEx-PUMICE. We first integrated each of four transcriptome models with multi-ancestry GWAS of FEV1/FVC ratio (Shrine et al. 2023) to generate transcriptome-wide association study (TWAS) results, which produced trait-associated genes. Pathway analysis was then conducted on significant TWAS genes. Finally, the PTRS was computed on TWAS genes that were included in the top 20 significantly enriched pathways. We tested performance of PTRS in race-stratified analysis for moderate-to-severe and severe COPD in COPDGene. RESULTS: Our models produced more significant TWAS genes (FDR&lt;0.05) and had more overlaps with genes identified for FEV1/FVC ratio from Shrine et al. 2023 compared to two GTEx models (Fig. A). Additionally, our models had significantly higher AUC for predicting both moderate-to-severe and severe COPD in race-stratified analysis. The mean AUC from LTRC-EN for predicting severe COPD was 0.57 and 0.55 respectively for EUR and AFA, which was significantly higher than mean AUC of 0.54 and 0.51 from GTEx-EN (Delong p-value=8.15x10-10 for EUR and 1.42x10-3 for AFA) (Fig. B). Similarly, the PTRS derived from our models produced higher Odds Ratios (OR) per standard deviation. The mean OR from LTRC-PUMICE for moderate-to-severe COPD was 1.25 and 1.18 respectively for EUR and AFA, while it was 1.17 and 1.12 from GTEx-PUMICE (Fig. C). CONCLUSIONS: Our study demonstrates the value of leveraging disease-relevant RNA-seq to construct transcriptome prediction models and their improvement on identifying lung function genes and predicting COPD across ancestries.