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Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

ABSTRACT This study aims to develop MRI‐based 3D statistical shape models for patellar dislocation patients and investigate bone shape features that distinguish between single and recurrent dislocation populations, as well as control and patellar dislocation populations. MRIs from 16 single dislocation patients, 17 recurrent dislocation patients, and 20 control subjects were used to build statistical shape models for femur and patella bones. Bone shape features were extracted and tested for statistical significance ( p < 0.05) for distinguishing the single dislocation group from the recurrent dislocation groups, and the control group from the dislocation group. Statistically significant shape features distinguishing the three groups were identified for both bones. A shallower trochlear groove and smaller patellar ridge told the dislocation groups apart from the control group. A prolonged lateral condyle in femur and a laterally shifted ridge and hood shaped lateral facet in patella distinguished the recurrent dislocation group from the single dislocation group. The study's findings from 3D statistical shape modeling of the femur and patella reveal distinct anatomical differences across control, single dislocation, and recurrent patellar dislocation groups. This advanced understanding aids in identifying individuals at higher risk for initial or recurring patellar dislocations, enabling clinicians to tailor treatment and management strategies more effectively to prevent further dislocations and mitigate potential patellofemoral joint damage.

ABSTRACT Background Pulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. Methods We applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. Results WGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, β-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5α-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. Conclusions These findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

Background: There is growing support for high-efficacy disease-modifying therapy (DMT) in multiple sclerosis (MS), but escalation (ESC) approaches remain common. Objective: To describe decision-making in a pragmatic trial of early high-efficacy treatment (EHT) versus ESC. Methods: DELIVER-MS is a multi-center, pragmatic, randomized controlled trial (RCT) with a parallel observational study (OBS), which enrolled treatment-naïve people with RRMS in 31 UK/US sites. Primary outcome was as follows: 36-month brain volume loss according to initial treatment approach (EHT vs. ESC). Stepwise multivariable logistic regression was used to predict participation in RCT versus OBS and choice of EHT versus ESC within the OBS cohort. Results: In total, 816 people with MS were enrolled. Participants declined randomization due to preference for a particular DMT (85%), efficacy concerns (20%), and safety concerns (9%). RCT versus OBS participation was associated with lower relapse rate ( p = 0.043) and greater brain parenchymal fraction ( p = 0.002). Among 374 in the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT. People commencing EHT had higher education attainment ( p < 0.001) and relapse rate ( p = 0.025). Conclusion: Baseline DELIVER-MS data demonstrate that participants with milder disease are more likely to participate in RCT. The choice of EHT versus ESC was associated with demographic factors and disease activity. Clinical trial registration: NCT03535298

BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

ABSTRACT Accurate identification of dysplasia in Barrett's esophagus (BE) remains a challenge. Advanced optical imaging techniques may allow for better localization of dysplasia in BE. Here, we have assessed the potential clinical utility of a previously described multimodal imaging probe combining optical coherence tomography (OCT) with angle‐resolved low coherence interferometry (a/LCI) to prospectively identify dysplasia in BE. Imaging was conducted on 37 patients undergoing endoscopic surveillance of BE, yielding co‐registered biopsies of 50 esophageal sites. The a/LCI nuclear morphology data were compared to a previous decision line to prospectively predict dysplasia, demonstrating 100% sensitivity, 93% specificity, and 94% overall accuracy. The NPV was 100%, comparable to previous a/LCI studies. The addition of OCT imaging markedly improved PPV and specificity, compared to previous studies with a/LCI alone, illustrating the clinical utility of the combined platform. These findings suggest that combining OCT and a/LCI enables better detection of dysplasia by providing better guidance.

Abstract Introduction The monoclonal gammopathies of renal significance (MGRS) are defined by the presence of a nephrotoxic monoclonal protein in the absence of a well-defined malignant entity. Mechanistically it has been postulated that, across the varied subtypes of MGRS, abnormal plasma cell or B-cell clones in the marrow produce nephrotoxic proteins; however, in many cases, no paraprotein is detected by conventional laboratory methods and the bone marrow can be morphologically normal. The genomic underpinnings of MGRS are unexplored and, due to the rarity of this disease, clinicians are often left to unable to determine the exact nature of the clonal cell populations. We carried out a pilot study to characterize ctDNA in MGRS patients (pts). The first phase of the protocol sought to collect peripheral blood samples and, when possible, matched bone marrow aspirates, from MGRS pts to evaluate the feasibility of ultra-low pass whole genome sequencing (ULP-WGS) from peripheral blood to identify and characterize ctDNA. Methods We report ULP-WGS results from peripheral blood samples in the initial phase of the study. Peripheral blood samples were collected from renal biopsy proven non-amyloidosis MGRS pts prior to the initiation of treatment. Cell free DNA (cfDNA) was extracted and quantified. A total of 5-20 ng of cfDNA input was used for ULP-WGS. Libraries were pooled and sequenced using 100-bp paired-end runs to an average genome-wide coverage of 0.5x. After deconvolution and alignment, fragments with size 90-150bp were extracted using samtools. IchorCNA was utilized to calculate tumor fraction based on a panel of normals derived from three plasma samples from healthy controls. Model parameters were optimized for low tumor fraction and a threshold of 3% ctDNA was used to identify positive samples. Renal responses were assessed based on International Kidney and Monoclonal Gammopathy (IKMG) group criteria. Results Nine pts and were consented and gave samples for the study along with 3 healthy controls. Seven pts were sequenced, 4 of which were females and 3 were males. Median age was 58 years. Among sequenced pts, 5 presented with proliferative glomerulonephritis with monoclonal immune deposition (PGNMID) and 2 with light chain deposition disease (LCDD). Both patients with LCDD were kappa predominant and showed detectable plasma clones (8% and 3%). One of these pts displayed t(11:14) on bone marrow FISH testing. Among the 5 pts with PGNMID, 3 had IgG kappa deposition and only one had a detectable plasma clone (5%), which harbored trisomy 9 by FISH. Bone marrow flow cytometry was positive in 2 pts. Median 24-hour urine protein content was 7.11g (0.92 – 10.58), median serum albumin 3.20 g/dL (2.90 – 4.90) and median serum creatinine at the time of diagnosis was 2.15 mg/dL (1.30-6.40). CKD was present in 6 of 7 pts at the time of diagnosis. Four pts had known hypertension. One exhibited a history of malignancy and one had a history of autoimmune disease. ctDNA was detectable at a threshold of &gt; 3.0% of cfDNA in 5 of 7 pts. Median ctDNA content was 4.0% (3.18% - 14.97%) of cfDNA. Four of the 5 samples containing ctDNA were hyperdiploid. Chromosome 19 was the most common site of copy number increase whereas chromosomes 6, 10, and 18 exhibited the most frequent decreases in copy number. Two pts with PGNMID had detectable ctDNA without evidence of a serological or marrow-based clone. All pts received daratumumab, cyclophosphamide, bortezomib and dexamethasone as initial treatment. Five pts responded to therapy. Two patients ultimately underwent autologous stem cell transplant and a single patient received venetoclax as second line therapy. Of the patients exhibiting detectable ctDNA, three did not exhibit renal response to initial treatment. Both pts without ctDNA had PGNMID and responded to frontline treatment. Mass spectrometry analysis and deep targeted sequencing of bone marrow aspirates and peripheral blood will be presented. Conclusions To our knowledge, this is the first study to detect ctDNA in MGRS. ULP-WGS, when combined with targeted sequencing and diagnostic modalities such as mass spectrometry, has the potential to not only to aid in diagnosis and treatment selection on a practical basis, but also to begin to unravel the underlying genomics of this rare disease. This approach has potential to serve as a platform for further genomic exploration and biomarker development in MGRS.

Abstract BACKGROUND The phase III ECOG-ACRIN E3F05 trial tested whether combined therapy with radiation and concomitant followed by adjuvant temozolomide is more effective than radiation alone in patients with grade II gliomas. The study incorporated 1p/19q analysis but predated assessment of IDH mutational status. We previously reported that the addition of temozolomide to radiotherapy significantly improved overall survival in grade II gliomas, with similar hazard ratios in co-deleted (0.56) and non-codeleted (0.53) tumors. Herein we incorporate the results of DNA methylation profiling to examine outcomes in IDHmt, non-codeleted subjects as well as co-deleted ones. METHODS All 172 subjects underwent 1p/19q co-deletion analysis as a stratification factor, 1p and 19q deletion analysis was performed on formalin-fixed paraffin-embedded (FFPE) gliomas by Fluorescent In Situ Hybridization (FISH) following standard methods, 97/172 (56.3%) had tissue with 60% or more tumor content available for DNA methylation profiling using Heidelberg classifier v12 and Bethesda Classifier 2.0 to ascertain classification as IDH mutant glioma and alternative evaluation of 1p/19q co-deletion status. RESULTS Of the 172 subjects, 74 (43.0%) had 1p/19q codeletion by FISH, 38 (22.1%) were IDHmt without codeletion, 14 (8.1%) were IDHwt, and 46 (26.7%) were non-codeleted with unknown IDH status (these include n=4 pts originally classified as 1p/19q undetermined). With a median follow-up of 130 months, the addition of TMZ to RT improved OS in patients with IDHmt, non-codeleted tumors (HR 0.15 (0.03-0.74)) and 10-year OS from 39% to 80%. In codeleted tumors, the addition of TMZ improved OS (HR 0.51 (0.19-1.42)) and 10-year OS from 68% to 90%. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and IDHmt, non-co-deleted grade II gliomas.