Citations

Color Doppler twinkling improves visibility and ultrasound-guided localization of biopsy markers made of polymethyl methacrylate (PMMA). This study examines the time- and frequency-domain features of twinkling. We performed beamforming on the raw radiofrequency (RF) data collected using a L7-4 transducer, followed by in-phase/quadrature (IQ) demodulation and wall filtering. Frequency content variations were evaluated both within individual Doppler ensembles (pulse-to-pulse) and across multiple frames. Normalized FFT magnitude spectra were computed for both twinkling and non-twinkling (metal) cases using beamformed RF and IQ data. The median of the normalized FFT magnitude (3–10 MHz) was consistently higher for the twinkling case compared to the metal case across RF (–13.75 dB vs –17.29 dB) and the IQ real component (–12.72 dB vs –16.15 dB), indicating broader and more energetic spectral content in twinkling. The frequency spread above the –20 dB threshold was approximately 2.5 times wider (5.38 MHz vs 1.95 MHz) in the twinkling case compared to the metal case. In time domain, the RMS of the standard deviation for the twinkling signal was approximately 28 times higher than that of the metal case across both RF and IQ data. These findings indicate that the ultrasound data from twinkling exhibits a more distributed frequency profile, consistent with observed aperiodic nature.

Color Doppler twinkling is associated with rough-surfaced objects like kidney stones, some clinical breast biopsy markers, and polymethyl methacrylate (PMMA) bone cement. Microbubbles are theorized as the predominant source of twinkling, supported by decreased twinkling under increased pressure. PMMA, metallic breast markers, a low-twinkling PMMA sample, and a non-twinkling metal rod were scanned in a pressure chamber up to 1000 psi using a General Electric Logiq E9 system and C1-6 probe (1.7–3.6 MHz Doppler transmit frequency). Clinical markers maintained distinct twinkling up to 250 psi. PMMA often twinkled at higher pressures, sometimes up to 1000 psi. The controls showed no twinkling. To understand physical structure associations with twinkling, the samples were scanned in a micro-CT system with a pixel resolution of 2 μm. Analysis of PMMA and Cork internal voids showed no correlation with twinkling. However, a correlation between Sa (average difference between the mean surface profile and actual surface profile) values and twinkling was found. This indicates that internal structure is not important for twinkling, and certain surface roughness is critical, possibly providing sites for surface microbubbles to oscillate from incident ultrasound waves.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Purpose To evaluate the correlation between occupational burnout and depression, frequency with which they coexist, how often 1 condition may be present in the absence of the other, and their association with suicidal ideation. Method The authors conducted a secondary analysis of cross-sectional national surveys of practicing U.S. physicians (conducted October 19, 2023, to March 3, 2024) and residents/fellows (“trainees”; conducted November 30, 2023, to January 2, 2024). They measured correlation between emotional exhaustion (EE) and depersonalization (DP) scores using the Maslach Burnout Inventory and depression T-scores using the National Institutes of Health Patient Reported Outcomes Measurement Information System Depression scale. Results A total of 5993 practicing physicians and 2676 trainees were included in the analysis. The pooled R2 value between EE and depression scores for physicians and trainees was 0.42 (P < .001) and between DP and depression scores was 0.28 (P < .001). Among the 4087 practicing physicians with normal depression scores, 1201 (29.4%) had high EE and/or high DP. Among the 1601 trainees with normal depression scores, 485 (30.3%) had high EE and/or high DP. On multivariable logistic regression adjusting for age, gender, relationship status, and work hours, each 1-point increase in depression T-score was associated with 15% higher odds of suicidal ideation among practicing physicians (OR 1.15; 95% CI, 1.13–1.17; P < .001) and trainees (OR 1.15, 95% CI, 1.13–1.17; P < .001). No statistically significant association between EE or DP scores and suicidal ideation was observed. Conclusions Occupational burnout and depression are correlated but distinct constructs with distinct outcomes. Less than half the variation in burnout is explained by depression (and vice versa). Population health approaches to improve physician well-being should address both conditions. Organizational efforts should go beyond providing support for individuals experiencing distress and also address the work environment factors that contribute to it.

Abstract Introduction Klinefelter syndrome (KS) is a chromosomal condition marked by hypogonadism and disturbances in hormonal regulation. The relationship between KS and co-occurring sleep disorders has not been extensively characterized, creating a need for more detailed investigation. Methods We identified individuals with Klinefelter syndrome (KS) evaluated at our institution between January 2000 and December 2025 using ICD-9 and ICD-10-CM codes. Electronic health records were then manually reviewed to confirm KS status and to exclude miscoded entries. For confirmed cases, we extracted data on sleep-related complaints, diagnoses, diagnostic testing (overnight oximetry, polysomnography, home sleep testing), and treatment. Sleep disorders were categorized operationally: obstructive sleep apnea (OSA), central sleep apnea (CSA), insomnia, hypersomnia/narcolepsy, or other according to documented clinician diagnosis or diagnostic test results. When structured Sleep Center data were available, these were included. We summarized cohort characteristics using means (± SD) or medians (interquartile range) as appropriate. For comparison between subgroups (e.g., those with vs without documented sleep-disordered breathing), we applied Welch’s t-test and binomial proportion tests. Analyses were conducted using Python scripts and spreadsheet software. Results Nearly one-third of patients with confirmed KS in this series had either diagnosed or suspected obstructive sleep apnea (OSA), substantially exceeding prevalence estimates in the general population. The frequency of central sleep apnea (CSA) was comparable to that seen in the general population, however its occurrence without usual predisposing factors suggests a predisposition toward idiopathic CSA in KS. Circadian rhythm disorders were rare, occurring in < 1% of the cohort. Notably, nearly 75% of KS patients with documented sleep-related symptoms had never undergone formal evaluation in a Sleep Center. Conclusion The observed rate of presumed idiopathic CSA among individuals with KS suggests the possibility of KS-specific mechanisms affecting ventilatory control stability. Additionally, there appeared to be a larger prevalence of OSA in this patient population. Notably, approximately three-quarters of KS patients who reported sleep-related symptoms had never undergone a formal Sleep Medicine assessment, highlighting a significant gap in structured evaluation that may relate to limited access to specialized care, referral patterns, or other systemic barriers, and warrants additional study. Support (if any) None

Abstract Background and aims Systemic inflammation has been implicated in cognitive decline and dementia pathogenesis. Interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cardiovascular disease, may play a role in cerebrovascular and neurodegenerative processes. We examined the relationship between IL-6 levels and incident dementia risk using the Atherosclerosis Risk In Communities (ARIC) study. Methods ARIC study participants at Visit 4 (1996-1998) had IL-6 measurements and were followed for incident dementia over 25 years. IL-6 levels were dichotomized at the median value of 1.5 pg/mL. Incident dementia cases were identified through standardized surveillance. Cox proportional hazards regression calculated hazard ratios (HR) with 95% confidence intervals (CI), adjusting for age, race, gender, hypertension, diabetes, obesity, physical activity, smoking, alcohol use, education, income, insurance status, and ApoE-ε4 allele status. Results Participants (n=5,662; mean age 62.4±5.6 years, 55% female, 83% White, 17% Black) were followed for a median of 25 years. Those with IL-6 >1.5 pg/mL demonstrated significantly increased dementia risk versus IL-6 ≤1.5 pg/mL. The crude HR was 1.23 (95% CI 1.11-1.37). After adjustment, the association remained significant with HR 1.13 (95% CI 1.01-1.27). Kaplan-Meier survival curves showed progressive divergence between groups, with lower dementia-free survival in the higher IL-6 group, log-rank p<0.001. Conclusions Elevated mid-life IL-6 levels (>1.5 pg/mL) independently predict increased long-term dementia risk over 25 years, even after adjusting for cardiovascular and sociodemographic confounders. These findings support systemic inflammation's role in dementia pathogenesis and highlight IL-6 as a potential biomarker for dementia risk. Conflict of interest Karly Pikel, Natasha Carmichael, Alana E. Barton, Kevin Moss, Christine Downey, Ryan T. Demmer, Pamela L. Lutsey, Souvik Sen: Nothing to disclose Figure 1 - belongs to Conclusions

PURPOSE Most oncology trials define superiority according to dichotomized P value thresholds, which are frequently misinterpreted. Posterior probability, however, directly estimates the probability of the hypothesis at hand. Here, we reanalyze a large collection of modern phase III trials and benchmark posterior probability versus the standard trial interpretation based on statistical significance. METHODS Outcomes from 194,129 patients were manually reconstructed from the primary end points of 230 phase III, superiority-design oncology trials. Posterior probabilities of treatment effect were then calculated across multiple priors and several effect sizes of clinical relevance, including minimum clinically important difference (MCID) defined as hazard ratio (HR) < 0.8 per ASCO criteria or HR < 0.64 per European Society of Medical Oncology (ESMO) criteria. RESULTS All trials interpreted as superior using P value thresholds had probabilities >90% for achieving at least marginal benefits (HR < 1). However, only 62% of positive trials (74/120) had >90% probabilities of achieving the ASCO MCID (HR < 0.8), even under an enthusiastic prior, including 70% of trials (57/82) leading to regulatory approval. Only 30% of positive trials (36/120) had >90% probability of achieving the ESMO MCID (HR < 0.64). Conversely, 24% of trials (26/110) interpreted as not superior had >90% probability of achieving marginal benefits (HR < 1), even under a skeptical prior. CONCLUSION Bayesian models, although often in agreement with statistical significance thresholds, add considerable unique interpretative value for a subset of phase III oncology trials. Posterior probability may provide a solution for overcoming the discrepancies between refuting the null hypothesis and detecting clinically relevant effects.

Abstract Cerebellopontine angle (CPA) tumors, including vestibular schwannomas (VS), often require microsurgical resection. These are typically surgical procedures performed by co-surgeons, and some controversy and confusion exist regarding use of common procedural terminology (CPT) codes for billing, given the American Medical Association (AMA) describes two distinct coding sets for such cases. This investigation endeavored to: (1) Comprehensively review all surgical coding options; (2) instruct on application; and (3) explore contemporary coding trends among surgeons. A multi-disciplinary task force (otologist/neurotologists and neurosurgeons) performed direct correspondence with various surgical societies, private consultancies, and the AMA. Survey instruments were distributed to active surgeons. Investigational period: 2022 to 2025. Survey instruments distributed at the 2023 American Neurotology Society (ANS) Fall Meeting. ANS, American Academy of Otolaryngology (AAO-HNSF), and the North American Skull Base Society (NASBS) representatives. Usage rate for CPT code sets (percentage of responders). Two CPT coding systems are currently accepted for surgical management of CPA tumors. The traditional/legacy codes (Indicator-2) allow use of co-surgery modifiers (-62). The newer approach/resection codes (skull base codes; Indicator-1) restrict modifier use. The history, application, and controversies surrounding the codes are detailed herein. About 40% of surgeons reported use of the traditional codes, while 45 to 49% use the skull base codes. Response rate was 31% of the active ANS membership in 2023. The AMA recognizes two CPT code sets for surgical management of CPA tumors. Both are appropriate, if properly applied. Contemporary surgeons likely utilize the sets in equal proportions.