Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Aficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study. OBJECTIVES: The authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM. METHODS: Serial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF). RESULTS: Among 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal e' velocities, and lateral and septal E/e' (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (-4.8% [95% CI: -6.4 to -3.3]; P < 0.001) and absolute LV global circumferential strain (-3.7% [95% CI: 1.8-5.6]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/e' returned to baseline following washout. Among those treated with aficamten, improved pVO2 and reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral e' velocity and septal and lateral E/e' (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001). CONCLUSIONS: Compared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results from SEQUOIA-HCM.

BACKGROUND: A primary goal in treating obstructive hypertrophic cardiomyopathy (oHCM) is to improve patients' health status: their symptoms, function, and quality of life. The health status benefits of aficamten, a novel cardiac myosin inhibitor, have not been comprehensively described. OBJECTIVES: This study sought to determine the effect of aficamten on patient-reported health status, including symptoms of fatigue, shortness of breath, chest pain, physical and social limitations, and quality of life. METHODS: SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) randomized symptomatic adults with oHCM to 24 weeks of aficamten (n = 142) or placebo (n = 140), followed by a 4-week washout. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle Angina Questionnaire 7-item (SAQ7) were serially administered. Changes in mean KCCQ-Overall Summary Score (KCCQ-OSS) and SAQ7-Summary Score (SAQ7-SS) from baseline to 24 weeks and following treatment withdrawal were compared using linear regression adjusted for baseline scores and randomization strata. Proportions of patients with clinically important changes were compared. RESULTS: Among 282 participants, the mean age was 59 ± 13 years, 115 (41%) were female, and 223 (79%) were White. Baseline KCCQ-OSS (69.3 ± 20.1 vs 67.3 ± 18.8) and SAQ7-SS (72.0 ± 21.0 vs 72.4 ± 18.3) were similar between aficamten and placebo groups. Treatment with aficamten, compared with placebo, improved both the mean KCCQ-OSS (13.3 ± 16.3 vs 6.1 ± 12.6; mean difference: 7.9; 95% CI: 4.8-11.0; P < 0.001) and SAQ7-SS (11.6 ± 17.4 vs 3.8 ± 14.4; mean difference: 7.8; 95% CI: 4.7-11.0; P < 0.001) at 24 weeks, with benefits emerging within 4 weeks. No heterogeneity in treatment effect was found across subgroups. A much larger proportion of participants experienced a very large health status improvement (≥20 points) with aficamten vs placebo (KCCQ-OSS: 29.7% vs 12.4%, number needed to treat: 5.8; SAQ7-SS: 31.2% vs 13.9%, number needed to treat: 5.8). Participants' health status worsened significantly more after withdrawal from aficamten than placebo (KCCQ-OSS: -16.2 ± 19.0 vs -3.0 ± 9.6; P < 0.001; SAQ7-SS: -17.4 ± 21.4 vs -2.5 ± 13.3), further confirming a causal effect of aficamten. CONCLUSIONS: In patients with symptomatic oHCM, treatment with aficamten resulted in markedly improved health status, including significant improvement in chest pain-related health status, than placebo. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Tractography with T1-weighted MRI and associated anatomical constraints on clinical quality diffusion MRI.

Diffusion MRI (dMRI) streamline tractography, the gold-standard for in vivo estimation of white matter (WM) pathways in the brain, has long been considered as a product of WM microstructure. However, recent advances in tractography demonstrated that convolutional recurrent neural networks (CoRNN) trained with a teacher-student framework have the ability to learn to propagate streamlines directly from T1 and anatomical context. Training for this network has previously relied on high resolution dMRI. In this paper, we generalize the training mechanism to traditional clinical resolution data, which allows generalizability across sensitive and susceptible study populations. We train CoRNN on a small subset of the Baltimore Longitudinal Study of Aging (BLSA), which better resembles clinical scans. We define a metric, termed the epsilon ball seeding method, to compare T1 tractography and traditional diffusion tractography at the streamline level. We show that under this metric T1 tractography generated by CoRNN reproduces diffusion tractography with approximately three millimeters of error.

Identification of functional white matter networks in BOLD fMRI.

White matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimer's Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLD-FMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well-defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.

Characterizing Low-cost Registration for Photographic Images to Computed Tomography.

Mapping information from photographic images to volumetric medical imaging scans is essential for linking spaces with physical environments, such as in image-guided surgery. Current methods of accurate photographic image to computed tomography (CT) image mapping can be computationally intensive and/or require specialized hardware. For general purpose 3-D mapping of bulk specimens in histological processing, a cost-effective solution is necessary. Here, we compare the integration of a commercial 3-D camera and cell phone imaging with a surface registration pipeline. Using surgical implants and chuck-eye steak as phantom tests, we obtain 3-D CT reconstruction and sets of photographic images from two sources: Canfield Imaging's H1 camera and an iPhone 14 Pro. We perform surface reconstruction from the photographic images using commercial tools and open-source code for Neural Radiance Fields (NeRF) respectively. We complete surface registration of the reconstructed surfaces with the iterative closest point (ICP) method. Manually placed landmarks were identified at three locations on each of the surfaces. Registration of the Canfield surfaces for three objects yields landmark distance errors of 1.747, 3.932, and 1.692 mm, while registration of the respective iPhone camera surfaces yields errors of 1.222, 2.061, and 5.155 mm. Photographic imaging of an organ sample prior to tissue sectioning provides a low-cost alternative to establish correspondence between histological samples and 3-D anatomical samples.

Urinary and fecal potassium excretion prediction in dairy cattle: A meta-analytic approach.

Quantification of potassium (K) excretion in dairy cattle is important to understand the environmental impact of dairy farming. To improve and monitor the environmental impact of dairy cows, there is a need for a simple, inexpensive, and less laborious method to quantify K excretion on dairy farms. The adoption of empirical mathematical models has been shown to be a promising tool to address this issue. Thus, the current study aimed to develop empirical predictive models for K excretion in dairy cattle from urine and feces that can help evaluate efficiency and monitor the environmental impact of milk production. To develop urine K (KUr, g/d) and fecal K (KFa, g/d) excretion prediction models, published literature that involved 45 and 54 treatment means from 10 and 14 studies, respectively, were used. Some studies reported either urinary or fecal K excretion or both, but in total, treatment means used to develop the models were from 17 studies. The linear mixed models were fitted with the fixed effect of K intake, DMI, dietary K content, urine volume, milk yield, and water intake, and the random effect of study weighted according to the number of observations. Leave-one-study out cross-validation was used to evaluate the performance of the proposed models and the best model was based on the lowest root mean square prediction error as a percentage of the observed mean values (RMSPE%) and highest concordance correlation coefficient (CCC). As expected, most daily K excretion was through urine (202.5 ± 92.1 g/d) than through feces (43.5 ± 21.0 g/d), and among the proposed models, the model including dietary K concentration showed poor predictive ability for both KUr and KFa with the lowest CCC values (-0.15 and -0.02, respectively) and systematic bias. The model developed using DMI to predict KFa excretion showed reasonable accuracy, as indicated by RMSPE, CCC, and R2 marginal of 46.6%, 0.42, and 48%, respectively. Among the proposed models for KUr and KFa, the model with K intake demonstrated better predictive performance, showing minimal systematic bias and random errors due to data variability of >92%. While these proposed models suggested that reducing K intake can lead to a decrease in K excretion, it is important to ensure that dairy cows receive adequate amounts of this nutrient to maintain optimal health and productivity, especially during periods of heat stress.

An international study presenting a federated learning AI platform for pediatric brain tumors.

While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances.

Sclerotic prostate cancer bone metastasis: woven bone lesions with a twist.

Bone metastases are the most severe and prevalent consequences of prostate cancer (PC), affecting more than 80% of patients with advanced PC. PCBMs generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences. Radiographically, PCBMs are predominantly osteosclerotic, but the mechanisms of abnormal bone formation and how this pathological increase in bone density is related to fractures are unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM specimens and 12 cancer-free specimens as controls. We used micro-computed tomography to determine 3D organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nanoindentation to determine mechanical properties, and histological and immunohistochemical analysis of bone structure and composition. We define 4 PCBM phenotypes: osteolytic, mixed lytic-sclerotic, and 2 subgroups of osteosclerotic lesions-those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone accumulated on trabeculae surfaces and within intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology, and irregular lacunae orientation. However, mineral content, hardness, and elastic modulus at micron-scale were indistinguishable between this irregular bone and residual trabeculae. The collagen matrix of this abnormal bone presents with irregular organization and a prominent collagen III composition. These characteristics suggest that osteosclerotic PCBMs initiate new bone deposition as woven bone; however, the lack of subsequent bone remodeling, absence of lamellar bone deposition on its surface, and presence of collagen III distinguish this pathologic matrix from conventional woven bone. Although the mineralized matrix retains normal bone hardness and stiffness properties, the lack of fibril anisotropy presents a compromised trabecular structure, which may have clinical implications.

Metabolic dysfunction and incidence of heart failure subtypes among Black individuals: The Jackson Heart Study.

AIMS: The extent to which metabolic syndrome (MetS) severity influences subclinical myocardial remodelling, heart failure (HF) incidence and subtypes, remains unclear. We assessed the association of MetS with incident HF (including ejection fraction subtypes) among Black individuals. METHODS AND RESULTS: We included 4069 Jackson Heart Study participants (mean age 54.4 years, 63.8% women, 37.2% with MetS) without HF. We categorized participants based on MetS status and MetS severity scores (based on waist circumference [MetS-Z-WC] and body mass index [MetS-Z-BMI]). We assessed the associations of MetS indices with echocardiographic parameters, biomarkers of myocardial damage (high-sensitivity cardiac troponin I [hs-cTnI] and B-type natriuretic peptide [BNP]) and incident HF hospitalizations including HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). MetS severity was associated with subclinical cardiac remodelling (assessed by echocardiographic measures and biomarkers of myocardial damage). Over a median of 12 years, 319 participants developed HF (157 HFpEF, 149 HFrEF and 13 HF of unknown type). MetS was associated with a twofold greater risk of HF (hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.64-2.61). Compared to the lowest quartile (Q1) of MetS-Z-WC, the highest quartile (Q4) conferred a higher risk of HF (HR 2.35, 95% CI 1.67-3.30), with a stronger association for HFpEF (Q4 vs. Q1: HR 4.94, 95% CI 2.67-9.14) vs. HFrEF (HR 1.69, 95% CI 1.06-2.70). CONCLUSIONS: Metabolic syndrome severity was associated with both HF subtypes among Black individuals, highlighting the importance of optimal metabolic health for preventing HF.

Molecular detection of Coxiella burnetii in ticks infesting wild and domestic animals in the Eastern region of Punjab, Pakistan.

Tick-borne pathogens are significant for human, veterinary, and wildlife health. Coxiella burnetii is an example that is widely distributed across various hosts and can cross species boundaries. In Pakistan, there is a scarcity of data regarding C. burnetii at the intersection of wildlife and livestock. Ticks were collected from ruminants and wildlife from the districts of Kasur, Pakpattan, and Okara in Pakistan. Five tick species totaling 571 ticks were collected, with the following distribution: 56.4% Hyalomma anatolicum, 22.4% Rhipicephalus microplus, 10.5% Hyalomma marginatum, 7.9% Rhipicephalus sanguineus, and 2.8% Rhipicephalus turanicus. Fifty tick pools were screened for C. burnetii to amplify a segment of the IS1111 using real-time PCR assays. Ticks collected from sheep and goats had a greater rate of positivity for C. burnetii (40% and 38%, respectively) compared to Indian long-eared hedgehogs with a prevalence of 2%. Coxiella burnetii was prominent in Rhipicephalus microplus (92.3%) and Hyalomma anatolicum (88.9%), followed by Rhipicephalus turanicus (66.6%), Rhipicephalus sanguineus (33.3%), and Hyalomma marginatum (25.0%). Ticks from Pakpattan district displayed the highest prevalence of C. burnetii (88.9%), whereas the lowest was observed in ticks from Kasur district (77.3%). There was no significant association between tick gender and C. burnetii infection. Female host animals were more likely to harbor ticks containing C. burnetii, with a prevalence rate of 81.8%. The research underscores the urgent need for comprehensive studies on C. burnetii in Pakistan, especially at the interface of wildlife and livestock. The high prevalence rates observed in certain tick species and geographic regions emphasize the importance of targeted public health interventions. Future research should focus on elucidating the transmission dynamics and implementing effective control measures to mitigate the impact of these pathogens on human, veterinary, and wildlife health in the region.

Neuronal enhancers fine-tune adaptive circuit plasticity.

Neuronal activity-regulated gene expression plays a crucial role in sculpting neural circuits that underpin adaptive brain function. Transcriptional enhancers are now recognized as key components of gene regulation that orchestrate spatiotemporally precise patterns of gene transcription. We propose that the dynamics of enhancer activation uniquely position these genomic elements to finely tune activity-dependent cellular plasticity. Enhancer specificity and modularity can be exploited to gain selective genetic access to specific cell states, and the precise modulation of target gene expression within restricted cellular contexts enabled by targeted enhancer manipulation allows for fine-grained evaluation of gene function. Mounting evidence also suggests that enduring stimulus-induced changes in enhancer states can modify target gene activation upon restimulation, thereby contributing to a form of cell-wide metaplasticity. We advocate for focused exploration of activity-dependent enhancer function to gain new insight into the mechanisms underlying brain plasticity and cognitive dysfunction.

Developing Proficiency in Robotic Cardiac Surgery.

The purpose of this manuscript is to provide recommendations for cardiac surgeons interested in adopting a robotic platform into their programs. The recommendations are based on the experience of the authors and cover a diverse array of cardiac surgical procedures that are currently being performed with robotic assistance. The focus, as with any innovative surgical approach, is to ensure patient safety, maximize quality and efficacy, and to set realistic expectations about what is required to achieve proficiency in robotic cardiac surgery.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

Predictive Signatures for Responses to Checkpoint Blockade in Small-Cell Lung Cancer in Second-Line Therapy Do Not Predict Responses in First-Line Patients.

Although immune checkpoint blockade (ICB) is currently approved for the treatment of extensive-stage small-cell lung cancer (SCLC) in combination with chemotherapy, relatively few patients have demonstrated durable clinical benefit (DCB) to these therapies. Biomarkers predicting responses are needed. Biopsies from 35 SCLC patients treated with ICB were subjected to transcriptomic analysis; gene signatures were assessed for associations with responses. Twenty-one patients were treated with ICB in the first-line setting in combination with platinum-based chemotherapy; fourteen patients were treated in the second-line setting with ICB alone. DCB after ICB in SCLC in the second-line setting (3 of 14 patients) was associated with statistically higher transcriptomic levels of genes associated with inflammation (p = 0.003), antigen presentation machinery (p = 0.03), interferon responses (p < 0.05), and increased CD8 T cells (p = 0.02). In contrast, these gene signatures were not significantly different in the first-line setting. Our data suggest that responses to ICB in SCLC in the second-line setting can be predicted by the baseline inflammatory state of the tumor; however, this strong association with inflammation was not seen in the first-line setting. We postulate that chemotherapy alters the immune milieu allowing a response to ICB. Other biomarkers will be needed to predict responses in first-line therapy patients.

Hospital-Skilled Nursing Facility Integration and Participation in a Bundled Payment Initiative.

Importance: Reduced institutional postacute care has been associated with savings in alternative payment models. However, organizations may avoid voluntary participation if participation could threaten their own revenues. Objective: To characterize the association between hospital-skilled nursing facility (SNF) integration and participation in Medicare's Bundled Payments for Care Improvement Advanced (BPCI-A) program. Design, Setting, and Participants: This is a cross-sectional analysis of hospital participation in BPCI-A beginning with its launch in 2018. Each SNF-integrated hospital was matched with 2 nonintegrated hospitals for each of 4 episode-specific analyses. Fifteen hospital-level variables were used for matching: beds, case mix index, days, area SNF beds, metropolitan location, ownership, region, system membership, and teaching status. Hospitals were also matched on episode-specific volume, target price, and the interaction of target price and case mix. Episode-specific logistic models were estimated regressing hospital participation on integration and the previously listed variables. The marginal effect of integration on participation was then calculated. Analysis took place from August 2022 to May 2024. Exposure: Hospital-SNF integration, as defined by common ownership and referral patterns and identified using cost reports, Medicare claims, and Provider Enrollment, Chain, and Ownership System records. Additional sources included records of target prices and participation, the Area Health Resources File, and the Compendium of US Health Systems. Main Outcomes and Measures: Participation in BPCI-A. Results: In total, 1524 hospitals met criteria for inclusion in the hip and femur (HFP) analysis, 1825 were included in the major joint replacement of the lower extremity (MJRLE) analysis, 2018 were included in the sepsis analysis, and 1564, were included in the stroke-specific analysis. Across episodes, 191 HFP-eligible hospitals (12.5% of HFP-eligible hospitals), 302 MJRLE-eligible hospitals (16.5%), 327 sepsis-eligible hospitals (16.2%), and 185 sepsis-eligible hospitals (11.8%) were SNF integrated. In total, 79 hospitals (5.2%) participated in the HFP episode, 128 (7.0%) participated in the MJRLE episode, 204 (10.1%) participated in the sepsis episode, and 141 (9.0%) participated in the stroke episode. Integration was associated with a 4.7-percentage point decrease (95% CI, 2.4 to 6.9 percentage points) in participation in the MJRLE episode. There was no association between integration and participation for HFP (0.5-percentage point increase in participation moving from nonintegrated to integrated; 95% CI, -2.9 to 3.8 percentage points), sepsis (1.0-percentage point increase; 95% CI, -2.2 to 4.2 percentage points), and stroke (0.3-percentage point decrease; 95% CI, -3.1 to 3.8 percentage points). Conclusions and Relevance: In this cross-sectional study, there was an uneven association between hospital-SNF integration and participation in Medicare's BPCI-A program. Other factors may be more consistent determinants of selection into voluntary payment reform.

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

Expert classification of hypospadias: an external validation and evaluation of agreement for Glans-Urethral Meatus-Shaft (GMS) and Hypospadias Objective Penile Evaluation (HOPE) scores.

PURPOSE: This study evaluates the inter-rater agreements of both the Glans-Urethral Meatus-Shaft (GMS) hypospadias score and Hypospadias Objective Penile Evaluation (HOPE) score, aiming to standardize disease classification for consistent agreement in clinically relevant characteristics of hypospadias. METHODS: Photos of hypospadias in children were collected from two separate institutions. Three raters scored the photos using GMS and HOPE, excluding penile torsion and curvature assessment in HOPE due to photo limitations. RESULTS: A total of 528 photos were included. With GMS, Fleiss' multi-rater kappa showed an agreement of 0.745 for glans-urethral plate, 0.869 for meatus, and 0.745 for shaft. For HOPE scores, the agreements were 0.888 for position of meatus, 0.669 for shape of meatus, 0.730 for shape of glans, and 0.708 for the shape of the skin. The lower agreement in the shape of the meatus evaluation may be attributed to the lack of a quantitative classification method in HOPE. Experts rely on their subjective judgment based on the provided example photos and their index patient. CONCLUSIONS: While there is high agreement among experts when evaluating hypospadias using the GMS and HOPE scoring criteria, only the position of the meatus achieved nearly perfect agreement highlighting that the current scoring systems entail a subjective element in disease classification.