Citations

Background: AF in the setting of cardiac amyloidosis is associated with a high risk of TEs, irrespective of CHA2DS2-VASc score. While warfarin has been the traditional anticoagulant, DOACs offer a promising alternative, but their safety in this population remains underexplored. This study aimed to evaluate the prevalence of thromboembolic events (TEs), including stroke and transient ischemic attack (TIA), and major bleeding events in patients with cardiac amyloidosis (CA) and atrial fibrillation (AF) treated with either warfarin or direct oral anticoagulants (DOACs). Additionally, we aimed to explore whether DOACs are at least as effective as warfarin in protecting against TEs in this population. Methods: This retrospective cohort study analyzed 422 patients with confirmed CA and AF from Mayo Clinic, with a median follow-up of 4.3 years. Data on anticoagulation therapy, baseline characteristics, and outcomes (TEs and bleeding) were collected. Statistical analyses included chi-square tests, t-tests, and Cox regression to assess the relationship between anticoagulation and TE. Results: Among 422 patients, 21 experienced a TE. The annual event rate was 0.83% for warfarin and 0.67% for DOACs, with no significant difference (HR 0.66, CI 0.22–2.01, p = 0.5). Patients with anticoagulation interruptions > 5 days had increased TE risk (HR 3.19, CI 0.97–10.5, p = 0.056). The bleeding rate was 9.9% over 4.3 years (2.33% per year), with no significant differences between anticoagulants. Conclusions: Both warfarin and DOACs have similar, low risks of TEs in CA and AF patients. However, anticoagulation interruptions were associated with increased TE risk, emphasizing the challenges in managing anticoagulation in this population.

Background: The rapid adoption of digital pathology and artificial intelligence (AI) in oncology creates multiple opportunities for precision diagnostics but also creates an urgent need for evidence-based standards to ensure safe and effective implementation. Goal: This article, developed by the Digital Pathology Association, presents recommendations for digital pathology as well as the validation and clinical utility of AI-enabled digital pathology tools in clinical practice. This guidance addresses analytical and clinical validation, algorithm reliability, and criteria for establishing clinical utility attributed to test use. Key recommendations emphasize separate validation of scanning processes and AI algorithms, concordance studies to support interscanner generalizability, rigorous assessment of accuracy and reliability in real-world settings, and clear description of algorithmic use limitations. These recommendations further provide frameworks for when AI may replace or augment existing diagnostic approaches, such as biomarker scoring, cancer diagnosis, and prognostic risk assessment. Conclusions: By considering payer, regulatory, and clinical perspectives, the recommendations promote transparency, trust, and reproducibility in digital pathology while encouraging value-based care delivery. We support responsible innovation in computational pathology, ensuring that AI applications achieve not only technical performance goals but also deliver measurable clinical benefit to patients.

Background: Facial nerve injury can result in a spectrum of clinical presentations from complete facial paralysis (CFP) to facial synkinesis. Willingness to pay (WTP) and quality-adjusted life years are established metrics used to assess the societal value of treatments. Objective: To quantify the perceived value of surgery for CFP and synkinesis amongst casual observers, as measured by WTP and quality of life indices. Methods: Casual observers were shown standardized videos of faces with complete paralysis, synkinesis, and nonparalyzed controls (eight videos each). Observers were asked to imagine having each condition and to rate their quality of life and WTP for surgical repair. Results: A total of 557 observers were included (mean age 36.5 years, 59% female). Both complete paralysis and synkinesis were associated with reduced quality-adjusted life year indices (0.9 [95% confidence interval [CI] 0.87–0.93]) for synkinesis; 0.86 (95% CI: 0.83–0.89) for complete paralysis, p = 0.0011). The mean WTP was $22,791 for complete flaccid paralysis and $15,718 for synkinesis repair and increased with income. WTP per quality-adjusted-life year gained was $6,844 for complete paralysis and $6,604 for synkinesis ( p > 0.05). Conclusion: Observers perceived surgical repair of CFP and synkinesis as highly valuable and within common cost-effectiveness thresholds.

Summary Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26/28) of patients ( P = 3.2x10 -5 ) and accurately identified 83% (10/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Abstract Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype–hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype–hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non–Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio ≥0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment. Clinical Perspective What Is New? In the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease Resting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept. A staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification. What Are the Clinical Implications? Pre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold. Intermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield. Exercise pulmonary capillary wedge pressure/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.

The primary aim of this study was to examine pitching performance metrics before and after ulnar collateral ligament reconstruction (UCLR) among Major League Baseball (MLB) starting and relief pitchers. The following information was extracted from the “Tommy John Surgery List” database regarding UCLR surgeries among MLB pitchers: UCLR date, pitcher type (starting pitcher, relief pitcher), and age at time of UCLR. Pitching performance metrics were extracted from the Baseball Savant online platform for the two seasons immediately prior to UCLR (pre) and the two seasons immediately following returning to pitching after UCLR (post). Fifty-nine pitchers were included in this study (29 starting pitchers, 30 relief pitchers). The outcome measures included the number of pitches thrown, earned run average (ERA), walks plus hits per inning pitched (WHIP), strikeout percentage, whiff percentage, walk percentage, batting average against, ground ball percentage, and fastball velocity. There was a pitcher type-by-time interaction effect for ERA (p = 0.01; η2 = 0.12) and WHIP (p = 0.01; η2 = 0.12). Starting pitcher ERA increased from 3.68 to 4.40 from pre- to post-surgery, while relief pitcher ERA decreased from 4.47 to 3.90. In addition, starting pitcher WHIP increased from 1.22 to 1.29 from pre- to post-surgery, while relief pitcher WHIP decreased from 1.38 to 1.28. There was a main effect of time for pitches thrown (p = 0.04; η2 = 0.07). Significant differences between starting and relief pitchers were observed for changes in ERA and WHIP following UCLR, whereas no pitcher type-by-time interactions were observed for the remaining performance metrics. Both starting and relief pitchers threw fewer pitches following UCLR, while fastball velocity and other key pitching performance metrics remained largely unchanged.