Citations

Background: Positioning the pharyngeal flap base high along the posterior pharyngeal wall is essential for optimizing speech outcomes. Objective data on where to place the flap base are lacking. Further, adenoid tissue can restrict cephalad positioning of the flap. This study aimed to improve the design of the pharyngeal flap by measuring the distance from the first cervical vertebrae (C1) to the palatal plane, and the adenoid depth in children undergoing evaluation for velopharyngeal insufficiency. Methods: This retrospective cross-sectional study analyzed magnetic resonance imaging (MRI) scans of the velopharynx and measured the distance between C1 and the palatal plane, and the adenoid depth at the level of the palatal plane in millimeters. Results: Thirty-four patients met the inclusion criteria. The mean age at the time of MRI was 7.4 years (range: 3.9–11.9 y). The anterior tubercle of C1 was below the palatal plane in 97% (n = 33) of patients. On average, this landmark was 10.5 mm (SD = 5.0) below the palatal plane. Adenoid tissue was present at the level of the palatal plane in 91% (n = 31) of patients. Conclusions: Positioning the pharyngeal flap base at C1 is too low to aid with velopharyngeal closure. Further, adenoid tissue is frequently present at the level of velopharyngeal closure, limiting superior positioning of the pharyngeal flap base. When this occurs, surgeons should consider adenoidectomy before pharyngeal flap surgery. Preoperative MRI may be beneficial for planning pharyngeal flap positioning relative to C1 and assessing adenoid tissue at the palatal plane.

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.

Type 2 diabetes (T2D) and obesity are chronic metabolic diseases with global morbidity and mortality. Decades of evidence from surgical and endoscopic procedures bypassing the duodenum underscore the duodenum’s critical role in regulating glycemia and body weight. Although metabolic surgeries and endoscopic procedures are effective, their invasiveness, cost, and scalability limit patient access. We developed an orally administered mucin complexing polymeric (MCP) drug, designed to replicate duodenal exclusion physiology. MCPs, intended to have electrostatic and covalent cross-linkages with mucin glycoproteins, form extended network structures with resulting alteration of mucus barrier properties. Selective targeting of the duodenum is achieved via pH-based activation chemistry. Following screening for physiochemical properties, pharmacokinetics, and efficacy, GLY-200 emerged as the lead drug candidate replicating duodenal exclusion physiology with improved glycemia, reduced body weight, and modulation of gut hormones in rodent models. This targeted oral therapy holds promise for treatment of T2D and obesity by mimicking duodenal exclusion without the invasiveness of surgery or endoscopic procedures.

Abstract Background Radiofrequency ablation (RFA) of neuromas has emerged as a potential treatment option for refractory neuroma‐associated postamputation pain (PAP). Objective To evaluate the feasibility of using internally cooled radiofrequency ablation (C‐RFA) for treating neuroma‐associated PAP. Design Prospective single‐arm pilot study. Setting Tertiary academic medical center. Participants Eight participants with neuroma‐associated PAP (mean age 56.5 [ interquartile range, 50.5–68.5] years; mean body mass index 30.2 [ interquartile range, 26.3–34.8] kg/m 2 ). Intervention Participants were recruited and treated with C‐RFA between 2019 and 2023. Main Outcome Measures Pain and functional outcomes were assessed at 1, 3, 6, and 12 months after C‐RFA using Numeric Rating Scale (NRS), Groningen Activity Restriction Scale (GARS), Patient Global Impression of Change (PGIC), and Medication Quantification Scale III (MQS‐III). Responder definitions for each outcome measure were ≥50% NRS reduction, ≥30% GARS improvement, ≥6 on PGIC, and ≥6.8‐point MQS‐III reduction. Results NRS responder rates at 1, 3, 6, and 12 months were 25.0% (95% CI, 7.0%–59.1%), 50.0% (95% CI, 21.5%–78.5%), 37.5% (95% CI, 13.7%–69.4%), and 50.0% (95% CI, 21.5%–78.5%), respectively. Responder rates for GARS were 25.0% (95% CI, 7.1%–59.1%) at 1 month and 12.5% (95% CI, 2.2%–47.1%) at 3, 6, and 12 months. The proportion of PGIC responders was 37.5% (95% CI, 13.7%–69.4%) at 1 and 3 months and 12.5% (95% CI, 2.2%–47.1%) at 6 and 12 months. MQS‐III responder rates were 25.0% (95% CI, 7.1%–59.1%) at 1 month, 12.5% (95% CI, 2.2%–47.1%) at 3 months, and 37.5% (95% CI, 13.7%–69.4%) at 6 and 12 months. There were no complications associated with the C‐RFA procedure. Conclusions These findings indicate the feasibility of neuroma C‐RFA as a treatment for refractory neuroma‐associated PAP but also suggest that further patient selection and C‐RFA technique optimization are warranted before investigating this treatment paradigm in a larger prospective study.

ImportanceHip fractures present a substantial public health challenge, with projections of more than 500 000 per year by 2040. As such, frailty indices such as the Revised Risk Analysis Index (RAI) and the Modified Five-Item Frailty Index (mFI-5) have been recently investigated as metrics for preoperative risk stratification for these patients.ObjectiveTo understand the accuracy of frailty, as measured by the RAI and the mFI-5, for estimating 30-day mortality following surgically managed hip fractures.Design, Setting, and ParticipantsThis retrospective cross-sectional analysis used the American College of Surgeons’ National Surgical Quality Improvement database. Patients aged 65 years old with surgically managed traumatic hip fracture from 2015 to 2019 were included. Frailty was evaluated using the RAI, a 5-domain scale with 14 weighted variables graded from 0 to 81, and the mFI-5, a 2-domain scale with 5 unweighted variables graded from 0 to 5; for both, a higher score denotes worse frailty. Data collection occurred from May to June 2024.ExposureDiagnosis of hip fracture and undergoing surgical fixation, hemiarthroplasty, or total hip arthroplasty.Main Outcomes and MeasuresThe primary outcome was 30-day mortality. Multivariable regression was conducted to assess the estimating value of frailty scales. Discriminatory accuracy was assessed using a receiver operating characteristic curve and quantified using a C-statistic.ResultsThe cohort consisted of 114 359 patients (70 038 female [69.9%]; median [IQR] age, 84 [77-89] years) with 51 071 prefrail patients (44.7%) according to the mFI-5 and 31 883 very frail patients (27.9%) according to the RAI comprising the largest frailty groups. Increasing frailty status was associated with greater odds ratio (OR) for 30-day mortality for both the mFI-5 (prefrail OR, 1.35 [95% CI, 1.24-1.47]; frail OR, 2.11 [95% CI, 1.94-2.30]; severely frail OR, 3.53 [95% CI, 3.20-3.90]; P < .001 for all) and RAI (normal OR, 1.55 [95% CI, 1.35-1.79]; frail OR, 2.97 [95% CI, 2.59-3.42]; very frail OR, 6.17 [95% CI, 5.38-7.08]; P < .001 for all). The RAI demonstrated superior discriminatory accuracy for 30-day mortality compared with the mFI-5 (area under the receiver operating characteristic curve, 0.73 [95% CI, 0.72-0.73] vs 0.61 [95% CI, 0.60-0.62]; P < .001).Conclusions and RelevanceIn this cross-sectional study of 114 359 patients, the RAI demonstrated superior odds and discriminatory accuracy for estimating 30-day mortality following surgical management of hip fractures. The RAI may be considered as a risk stratification tool for orthopedic surgeons to adjunct surgical planning, thereby reducing postoperative mortality.

6057 Background: The incidence rate of human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) has persistently increased over the past decade and is anticipated to rise further over the next decade. Cost effective, accurate, and less invasive screening options for HPV(+)OPSCC have remained stagnant leading to the interrogation of circulating tumor DNA in liquid biopsies such as plasma. We hypothesized that candidate methylated DNA markers (MDMs), previously described by our group, would be present in the plasma of patients with HPV(+)OPSCC and absent in controls. Methods: HPV(+)OPSCC cases were enrolled from a high-volume referral practice. Cancer-free control patients were identified from the surrounding 7-county catchment area and frequency matched to cases by age and alcohol use. cfDNA was extracted from 4 mL of plasma and bisulfite converted prior to Target Enrichment Long-probe Quantitative Amplified Signal assays for 15 MDMs. Strand counts for individual MDMs were normalized to a methylated genomic reference marker. An MDM score was derived via random forest modeling of the 15 MDMs. Area under the receiver operator characteristic curve (AUC) for discriminating cases from controls was evaluated for individual markers and for the MDM score. The sensitivity of the MDM score at 95% specificity was also evaluated. Results: The study consisted of 96 HPV(+)OPSCC and 100 cancer-free controls. The study population was predominately white (95%) with a median age of 61 yrs (IQR: 52-69 yrs). Eighty-nine percent of the cases were male with cancers affecting either the tonsil in 50 (52%) or base of the tongue in 46 (48%) patients; by design 50% of controls were male. Stage I:II:III:IV disease was present in 66%:22%:9%:3% of the cases. The median (IQR) AUC across the 15 MDMs was 0.83 (0.82-0.85) overall: 0.78 (0.77-0.83) for stage I disease and 0.92 (0.91-0.93) for stage II-IV disease. The MDM score for the combined panel of 15 MDMs achieved a cross-validated AUC of 0.93 (CI: 0.89-0.97) overall: 0.90 (CI: 0.84-0.96) for stage I disease and 0.98 (CI: 0.97-1.00) for stage II-IV disease. At 95% specificity, the cross-validated sensitivity of the MDM score for HPV(+)OPSCC was 80% (CI: 71-87%) overall: 73% (CI: 60-83%) for stage I disease and 94% (CI: 78-99%) for stage II-IV disease. Conclusions: We validated a set of previously discovered MDM markers in HPV(+)OPSCC in a robust case control cohort using plasma. The MDMs were detected in both early and late-stage disease. Additional prospective studies in larger intended use cohorts are needed to validate our results for clinical use.

e17159 Background: Socioeconomic inequality (SI) is a recognized risk factor for negative outcomes in prostate cancer (PCa), influenced by biology, healthcare access, and lifestyle. This study aims to explore the molecular impact of SI on PCa, focusing on targetable and prognostic biomarkers. Methods: We conducted a retrospective analysis of 100 metastatic hormone-sensitive PCa patients (2016-2023), with 97 undergoing next-generation sequencing (NGS). We examined only pathogenic variants alongside clinical variables. The Area Deprivation Index (ADI) assessed neighborhood SI, with higher scores indicating greater disadvantage. Patients were divided into tertiles. Chi-square and Fisher’s exact tests evaluated the relationships between tertiles and genomic alterations, while ordinal logistic regression analyzed outcomes by various stratifications. Results: Of the 97 patients, 29 were in tertile 1, 34 in tertile 2, and 35 in tertile 3. Tertile 1 had a significantly higher percentage of non-Hispanic patients (90%) compared to tertile 2 (62%) and tertile 3 (37%), p=0.0001. Other demographic factors, such as age, comorbidities, and cancer history, showed no significant differences by tertile. Median PSA levels increased from tertile 1 (22 ng/mL) to tertile 3 (95 ng/mL), although this was not statistically significant (p=0.14). Tumor volume and visceral metastasis were notably higher in tertile 3 (p=0.029 and p=0.02). BRCA1/2 mutations were more prevalent in tertile 3 (11%, p=0.03) via liquid biopsy compared to tertiles 1 and 2 (0%). TMPRSS2-ERG fusion mutations were significantly more common in tertile 3 (66.6%) compared to tertile 2 (19.1%) and tertile 1 (14.2%), p=0.009. The association between ADI tertile and TMPRSS2 approached significance when controlled for ethnicity (p=0.061), with Hispanic ethnicity having 3.5 times the odds of the fusion compared to non-Hispanics (p=0.02). Tertile 1 patients were more associated with receiving progressive therapy lines (2L p=0.01, 3L p=0.03, 4L p=0.04), but median time to subsequent treatment at 5 years was similar across tertiles (p=0.84). Conclusions: Higher SI was linked to increased PSA, tumor volume, visceral metastasis risk, and higher prevalence of BRCA1/2 and TMPRSS2-ERG mutations. This study highlights the need for further research on the molecular impacts of SI on adverse PCa outcomes, particularly among Hispanic populations.