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OBJECTIVE Patient-reported outcomes (PROs) have become the standard means to measure surgical outcomes. Insurers and policy makers are also increasingly utilizing PROs to assess the value of care and measure different aspects of a patient’s condition. For cervical myelopathy, it is currently unclear which outcome measure best reflects patient satisfaction. In this investigation, the authors evaluated patients treated for cervical myelopathy to determine which outcome questionnaires best correlate with patient satisfaction. METHODS The Quality Outcomes Database (QOD), a prospectively collected multi-institutional database, was used to retrospectively analyze patients undergoing surgery for cervical myelopathy. The North American Spine Society (NASS) satisfaction index, Neck Disability Index (NDI), numeric rating scales for neck pain (NP-NRS) and arm pain (AP-NRS), EQ-5D, and modified Japanese Orthopaedic Association (mJOA) scale were evaluated. RESULTS The analysis included 1141 patients diagnosed with myelopathy, of whom 1099 had an NASS satisfaction index recorded at any of the follow-up time points. Concomitant radiculopathy was an indication for surgery in 368 (33.5%) patients, and severe neck pain (NP-NRS ≥ 7) was present in 471 (42.8%) patients. At the 3-month follow-up, NASS patient satisfaction index scores were positively correlated with scores for the NP-NRS (r = 0.30), AP-NRS (r = 0.32), and NDI (r = 0.36) and negatively correlated with EQ-5D (r = −0.38) and mJOA (r = −0.29) scores (all p < 0.001). At the 12-month follow-up, scores for the NASS index were positively correlated with scores for the NP-NRS (r = 0.44), AP-NRS (r = 0.38), and NDI (r = 0.46) and negatively correlated with scores for the EQ-5D (r = −0.40) and mJOA (r = −0.36) (all p < 0.001). At the 24-month follow-up, NASS index scores were positively correlated with NP-NRS (r = 0.49), AP-NRS (r = 0.36), and NDI (r = 0.49) scores and negatively correlated with EQ-5D (r = −0.44) and mJOA (r = −0.38) scores (all p < 0.001). CONCLUSIONS Neck pain was highly prevalent in patients with myelopathy. Notably, improvement in neck pain–associated disability rather than improvement in myelopathy was the most prominent PRO factor for patients. This finding may reflect greater patient concern for active pain symptoms than for neurological symptoms caused by myelopathy. As commercial payers begin to examine novel remuneration strategies for surgical interventions, thoughtful analysis of PRO measurements will have increasing relevance.

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS). The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 years), pubertal stage, and body mass index z -score of 0.1 ± 1.2 and then between testosterone-treated ( n = 16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from that in controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (area under the curve > 0.9, P < 0.0001). Multiple saturated free fatty acids were higher in KS, while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial β-oxidation of long-chain saturated fatty acids (enrichment ratio 16, P < 0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from that in males without KS independent of age, obesity, pubertal development, or testosterone treatment status and is suggestive of differences in mitochondrial β-oxidation.

Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. Methods: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Results: Sequencing analyses identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Conclusion: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

AbstractBackgroundTraditional management of olfactory neuroblastoma (ONB) includes margin‐negative resection with removal of cribriform plate, dura, and olfactory bulb, regardless of intracranial disease. This approach may be overtreating certain patients. Our investigation examines risk factors associated with occult intracranial disease to optimize therapeutic outcomes.MethodsThis retrospective, multi‐institutional cohort study examined clinical covariates associated with occult intracranial involvement. Patient demographics, staging, Hyam's grade, and pathologic involvement of dura, olfactory bulb/tract, and brain were collected. Diagnostic imaging was reviewed. Positive and negative predictive value (NPV) were estimated along with effect size estimates. Cox hazard regression examined associations with overall survival (OS) and disease‐free survival (DFS).ResultsA total of 224 subjects with new diagnoses of ONB (2005–2021) were identified. Skull base bone involvement on computed tomography (CT) had the highest NPV for pathologic dura (88.0%), olfactory bulb (88%), and brain involvement (97.3%). Hyam's grade category was significantly associated with dural involvement (φC = 0.26; 95% confidence interval [CI]: 0.16, 0.42). Subjects without radiologic skull base involvement (n = 66) had pathologic positivity of 12.1%. Within this subgroup, Hyam's grade was clinically significant for dural positivity (φ = 0.34; 95% CI: −0.12, 0.71) with 28.6% involvement in high grade tumors. Neither clinical nor pathologic positivity of intracranial structures were associated with significantly different OS or DFS.ConclusionsBoth CT and magnetic resonance imaging (MRI) had reasonably good NPV for involvement of dura and olfactory bulb. Higher Hyam's grade was associated with dural involvement. Patients with low‐grade tumors not involving the skull base may be suitable for avoiding skull base resection; however, further investigation is warranted.

Abstract Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research. Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities. Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants. Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries. Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement.

Abstract Background Myocardial injury after non-cardiac surgery (MINS), based on measurement of troponin T, is associated with perioperative major adverse cardiovascular events (MACE). We therefore determined the high-sensitivity troponin I (hsTnI) thresholds associated with 30 day MACE after non-cardiac surgery. Methods We performed a nested biobank cohort study of 4553 patients from the Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Study. We measured hsTnI (ADVIA Centaur® hsTnI assay) on postoperative days 1 to 3 in patients ≥45 years undergoing non-cardiac surgery. An iterative Cox proportional hazard model determined peak postoperative hsTnI thresholds independently associated with MACE (i.e., death, myocardial infarction occurring on postoperative day 4 or after, non-fatal cardiac arrest, or congestive heart failure) within 30 days after surgery. Results MACE occurred in 89/4545 (2.0%) patients. Peak hsTnI values of &lt;75 ng/L, 75 ng/L to &lt;1000 ng/L, and ≥1000 ng/L were associated with 1.2% (95% CI, 0.9–1.6), 7.1% (95% CI, 4.8–10.5), and 25.9% (95% CI, 16.3–38.4) MACE, respectively. Compared to peak hsTnI &lt;75 ng/L, values 75 ng/L to &lt;1000 ng/L and ≥1000 ng/L were associated with adjusted hazard ratios (aHR) of 4.53 (95% CI, 2.75–7.48) and 16.17 (95% CI, 8.70–30.07), respectively. MACE was observed in 9% of patients with peak hsTnI ≥75 ng/L vs 1% in patients with peak hsTnI &lt;75 ng/L (aHR 5.76; 95% CI, 3.64–9.11). A peak hsTnI ≥75 ng/L was associated with MACE in the presence (aHR 9.35; 95% CI, 5.28–16.55) or absence (aHR 3.99; 95% CI, 2.19–7.25) of ischemic features of myocardial injury. Conclusion A peak postoperative hsTnI ≥75 ng/L was associated with &gt;5-fold increase in the risk of 30 days MACE compared to levels &lt;75 ng/L. This threshold could be used for MINS diagnosis when the ADVIA Centaur hsTnI assay is used. Clinicaltrials.gov Registration Number: NCT00512109.

Abstract Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent “vulnerable spots” within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.