Citations

Abstract Provided herein are novel compounds as orexin 2 receptor agonists, pharmaceutical compositions, use of such compounds in treating narcolepsy, and processes for preparing such compounds.

Abstract Immune checkpoint inhibitors (ICIs) which target immune checkpoint proteins like programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have revolutionized cancer therapy. Skeletal toxicities are emerging immune-related adverse events for patients treated with ICIs, and PD-1 blockade in pre-clinical mouse models significantly reduces bone mass. However, the effect of PD-L1 inhibition on the bone throughout development is not well understood. We investigated the role of PD-L1 loss on bone microarchitecture with genetic PD-L1 knockout in myeloid cells using LysM-Cre;PD-L1Flox/Flox mice and pharmacologic inhibition with a PD-L1 neutralizing antibody in adult and aged mice. We report that neither PD-L1 deletion in myeloid cells nor inhibition with α-PD-L1 significantly impacts femoral trabecular bone microarchitecture; however, α-PD-L1 treatment increases vertebral trabecular bone volume. Additionally, PD-L1 blockade influences T cell expansion by decreasing naïve T cells and increasing effector memory T cells in the bone marrow, consistent with previous studies on the effects of PD-1 inhibition. The trabecular bone-sparing effect of PD-L1 inhibition is strikingly different from the bone loss observed with PD-1 blockade. Clinical studies are necessary and justified to determine if PD-L1 may be a less bone destructive alternative for cancer patients treated with ICIs who are at high risk of fracture.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Tackling hospital emergency department (ED) overcrowding is a paramount challenge for healthcare systems. To combat this issue, an innovative approach is to identify patients who can be served vertically (i.e., in a seated position) and route them to a dedicated area termed the vertical processing pathway (VPP). Successfully implementing this design requires understanding which patients should be routed to the VPP and when. Currently, the decision to leverage the VPP is made in an ad hoc fashion. To assist our partner hospital and other EDs in capturing the value of the VPP, we develop a machine learning model that provides personalized risk scores predicting whether each arriving patient needs an ED bed. We use these scores as input to a stochastic patient flow model and analytically characterize the optimal VPP policy that minimizes length of stay. We then combine our results to derive an interpretable VPP patient streaming protocol suitable for implementation in practice and conduct a before-and-after experiment in which we leverage empirical analyses to evaluate the impact of integrating it into practice. The implemented protocol led to an 11-minute (4.2%) reduction in ED length of stay in our partner hospital without any adverse effect on quality-of-care outcomes. This effect was statistically significant and remained robust after controlling for various confounding factors and potential sources of endogeneity. Our VPP protocol can also be utilized in other EDs, offering operational improvements without requiring additional resources. This paper was accepted by Stefan Scholtes, healthcare management. Funding: S. Saghafian received financial support from the NSF [Grant CMMI-15 62645], “Data-Driven Management of Post-Transplant Medications,” which partially enabled this work, as well as funding and support from the Harvard Data Science Initiative and the Harvard Mossavar-Rahmani Center for Business and Government. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2024.07517 .

ABSTRACT Purpose Standard spatial‐spectral excitation pulses apply a fly‐back gradient between sub‐pulses, limiting, for example, how thin the slices can be (> 4 mm). Without fly‐back gradients, slices can be as thin as 1.7 mm but require a phase calibration for the sub‐pulses with inverted gradients due to system imperfections. Here we propose and test a fast (< 1 s), localized pre‐scan enabling thin‐slice frequency‐selective excitation. Methods The calibration pre‐scan determines the correction phase between even and odd sub‐pulses by measuring the phase difference of two FIDs excited with either the last or second‐to‐last RF sub‐pulse of the spatial‐spectral pulse. Non‐localized and localized versions of the calibration pre‐scan are tested and validated for water‐only excitation in phantoms and the human heart. As an example, breath‐held coronary MR angiography is performed with a spiral multi‐slice sequence employing the proposed pulses with a slice thickness of 1.7 mm. Results The proposed calibration pre‐scan takes 11.1 ms per slice, whether it is localized or not. Localized calibration phases are validated with an image‐based calibration map. Slice profiles are visualized for pulses with different time‐bandwidth products. Fat is suppressed to below 20% and 25% of the surrounding water signal in both phantoms and the human heart, respectively. High‐quality coronary angiograms are demonstrated in all test subjects. Conclusion Spatial‐spectral pulses without fly‐back gradients can be calibrated quickly (up to 90 slices in 1 s), enabling thinner slices, higher excitation angles, or pulses with sharper slice profiles using waveforms with higher time‐bandwidth products.

BACKGROUND AND OBJECTIVES: Access to the orbit, cavernous sinus, Meckel cave (MC), and infratemporal fossa (ITF) remains challenging due to the complex 3-dimensional anatomy and proximity to critical neurovascular structures. An extradural endoscopic orbitozygomatic (OZ) approach has the potential to provide a direct surgical corridor across these compartments while minimizing the limitations of compartment-specific corridors. METHODS: Five formalin-fixed, silicone-injected cadaveric heads (10 sides) were dissected using an extradural OZ approach under operative microscopy supplemented with 0° and 30° rigid endoscopes. After a two-piece OZ craniotomy, extradural dissection was performed toward the superior orbital fissure and foramen rotundum/ovale, combined with anterior petrosectomy and opening of MC. Anatomic exposure, corridor continuity, and visualization of key neurovascular structures were qualitatively assessed. RESULTS: The extradural endoscopic OZ approach created a direct working corridor from the lateral orbit to the ITF and petroclival region. Endoscopic augmentation enhanced visualization of the lateral cavernous sinus wall, trigeminal divisions (V 1 -V 3 ), cavernous internal carotid artery, medial orbital apex, deep infratemporal recesses, and the petroclival region. Anterior petrosectomy extended exposure toward the upper clivus and ventrolateral brainstem. Limitations included restricted microscopic visualization of the medial orbit and inferior ITF, which were partially mitigated by angled endoscopy. CONCLUSION: This cadaveric study demonstrates that the extradural OZ–anterior petrosectomy approach establishes a continuous anatomic corridor integrating the orbit, cavernous sinus/MC, ITF, and petroclival region, while defining its boundaries, areas of optimal exposure, and inherent limitations. As a qualitative study, the findings are descriptive in nature and do not include quantitative morphometric analysis.

Abstract Burke, AA, Saine, ND, King, EL, Fields, JB, Jagim, AR, Miller, AD, Green, BC, and Jones, MT. Longitudinal modeling of pitching workload and countermovement jump performance as determinants of fastball velocity and consistency in collegiate baseball pitchers. J Strength Cond Res XX(X): 000–000, 2026—Maintenance of four-seam fastball (FSFB) velocity across the baseball season is critical, yet the extent to which workload and neuromuscular status relate to velocity is unclear. Thus, aims of the current study were to assess the relationship between external pitching workload metrics and FSFB velocity; quantify within-season FSFB velocity; and examine how countermovement jump (CMJ) performance predicts FSFB velocity. Collegiate pitchers ( n = 8) completed weekly CMJ testing during a 15-week, 53-game season. Countermovement jump metrics included jump height (JH), reactive strength index–modified (RSImod), peak braking force, and peak propulsive force normalized to body mass. Workload variables (innings, total pitches, FSFB pitches) and FSFB velocity were evaluated via repeated measures correlation (RMCORR). A longitudinal heat map visualized velocity trends, and a hierarchical location–scale model assessed predictors of mean velocity and variance. Repeated measures correlation showed weak negative associations between FSFB velocity and innings ( r = −0.15, p = 0.11), total pitches ( r = −0.18, p = 0.05), and FSFB pitches ( r = −0.18, p = 0.05). Heat map analysis identified 3 distinct velocity clusters. Location model results indicated no predictors of mean velocity. The scale model showed JH ( γ = −0.060, p = 0.001) predicted reduced velocity variance, and RSImod ( γ = 3.800, p < 0.001) predicted increased variance. Findings suggest that velocity patterns varied across athletes, where greater workloads were negatively associated with FSFB pitch velocity. Further, CMJ performance related to velocity stability rather than mean velocity. Routine longitudinal monitoring and continued strength-power training are recommended to support FSFB velocity.

Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

ABSTRACT Glioblastoma (GBM) is a highly aggressive brain tumor with a five-year survival rate of less than 5%. The current standard of care established 20 years ago includes maximal surgical resection and administration of alkylating agent temozolomide (TMZ). GBM is highly invasive, and GBM cells that evade surgical resection can become resistant to TMZ and develop new aggressive secondary tumors. Post-relapse there are few treatment options available to patients. Tissue engineering approaches suggest the opportunity to develop in vitro models of the GBM tumor microenvironment that may accelerate the discovery of novel therapies for GBM. Here, we report the adaptation of hydrogel microdroplets (microgels) to encapsulate GBM cells in a tailorable 3D matrix to assess patters of growth and to screen TMZ drug response using patient-derived xenograft (PDX) specimens. We exploit a unique aspect of the microgel system to account for the cellular heterogeneity within the tumor microenvironment (TME). We combine cell-laden microgels generated from TMZ-resistant and TMZ responsive variants of the same PDX specimens to create heterogeneous populations with varying levels of drug sensitivity. We demonstrate a range of drug resistance phenotypes as a function of the ratio of TMZ-responsive to resistance cells and identify the population required for TMZ-resistance to overtake take the response. We then investigate the influence of tumor mimetic shifts in hyaluronic acid bioavailability and hypoxia on patterns of TMZ resistance. We show exposure to matrix-bound hyaluronan increases TMZ resistance and the glioma stem cell population in both cell variants. Lastly, we report an increase in TMZ sensitivity but divergent changes in the GSC subfraction for TMZ resistant vs responsive GBM in the presence of hypoxia. Together, we demonstrate the versatility of cell-laden microgel approach to replicate heterogenous tumor populations, model shifts in the tumor microenvironment, and rapidly screen therapeutic response.

A vendor-neutral Agatston score enabled consistent aortic valve calcium quantification across CT systems and improved identification of severe aortic stenosis in patients with discordant echocardiographic findings.