1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma.

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.

The Los Angeles motor scale (LAMS) is independently associated with CT perfusion collateral status markers.

BACKGROUND AND AIM: The Los Angeles Motor Scale (LAMS) is an objective tool that has been used to rapidly assess and predict the presence of large vessel occlusion (LVO) in the pre-hospital setting successfully in several studies. However, studies assessing the relationship between LAMS score and CT perfusion collateral status (CS) markers such as cerebral blood volume (CBV) index, and hypoperfusion intensity ratio (HIR) are sparse. Our study therefore aims to assess the association of admission LAMS score with established CTP CS markers CBV Index and HIR in AIS-LVO cases. MATERIALS AND METHODS: In this prospectively collected, retrospectively reviewed analysis, inclusion criteria were as follows: a) CT angiography (CTA) confirmed anterior circulation LVO from 9/1/2017 to 10/01/2023, and b) diagnostic CT perfusion (CTP). Logistic regression analysis was performed to assess the relationship between admission LAMS with CTP CS markers HIR and CBV Index. p ≤ 0.05 was considered significant. RESULTS: In total, 285 consecutive patients (median age = 69 years; 56 % female) met our inclusion criteria. Multivariable logistic regression analysis adjusting for sex, age, ASPECTS, tPA, premorbid mRS, admission NIH stroke scale, prior history of TIA, stroke, atrial fibrillation, diabetes mellitus, hyperlipidemia, coronary artery disease and hypertension, admission LAMS was found to be independently associated with CBV Index (adjusted OR:0.82, p < 0.01), and HIR (adjusted OR:0.59, p < 0.05). CONCLUSION: LAMS is independently associated with CTP CS markers, CBV index and HIR. This finding suggests that LAMS may also provide an indirect estimate of CS.

Central Giant Cell Granuloma of the Mandible: A Case Report.

This article presents a clinical case of a central giant cell granuloma (CGCG) resembling a periapical lesion of endodontic origin. A 39-year-old, otherwise healthy male patient was referred to the department of oral and maxillofacial surgery for its diagnosis and subsequent management. The patient presented with an asymptomatic, progressively increasing intraoral swelling associated with the mandibular left para-symphysis region. On radiographic evaluation, a unilocular radiolucent lesion involving 33-34 teeth was noted. An incisional biopsy presented a giant cell lesion, following which surgical curettage was done. Histopathological examination was in accordance with the diagnosis of CGCG. Therefore, it is imperative for clinicians to accurately diagnose and rule out similarly presenting lesions.

Lower admission stroke severity is associated with good collateral status in distal medium vessel occlusion stroke.

BACKGROUND AND PURPOSE: Distal medium vessel occlusions (DMVOs) are a significant contributor to acute ischemic stroke (AIS), with collateral status (CS) playing a pivotal role in modulating ischemic damage progression. We aimed to explore baseline characteristics associated with CS in AIS-DMVO. METHODS: This retrospective analysis of a prospectively collected database enrolled 130 AIS-DMVO patients from two comprehensive stroke centers. Baseline characteristics, including patient demographics, admission National Institutes of Health Stroke Scale (NIHSS) score, admission Los Angeles Motor Scale (LAMS) score, and co-morbidities, including hypertension, hyperlipidemia, diabetes, coronary artery disease, atrial fibrillation, and history of transient ischemic attack or stroke, were collected. The analysis was dichotomized to good CS, reflected by hypoperfusion index ratio (HIR) <.3, versus poor CS, reflected by HIR ≥.3. RESULTS: Good CS was observed in 34% of the patients. As to the occluded location, 43.8% occurred in proximal M2, 16.9% in mid M2, 35.4% in more distal middle cerebral artery, and 3.8% in distal anterior cerebral artery. In multivariate logistic analysis, a lower NIHSS score and a lower LAMS score were both independently associated with a good CS (odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.82-0.95, p < .001 and OR: 0.77, 95% CI: 0.62-0.96, p = .018, respectively). Patients with poor CS were more likely to manifest as moderate to severe stroke (29.1% vs. 4.5%, p < .001), while patients with good CS had a significantly higher chance of having a minor stroke clinically (40.9% vs. 12.8%, p < .001). CONCLUSIONS: CS remains an important determinant in the severity of AIS-DMVO. Collateral enhancement strategies may be a worthwhile pursuit in AIS-DMVO patients with more severe initial stroke presentation, which can be swiftly identified by the concise LAMS and serves as a proxy for underlying poor CS.

External assessment of preoperative scores for predicting outcome after microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Recently, two scoring systems have been developed for predicting pain-free outcomes after microvascular decompression (MVD). Evaluation of these scores on large external datasets has been limited. In this study, the authors aimed to evaluate the performance of published MVD scoring systems in predicting pain-free outcome. METHODS: A total of 458 patients who underwent MVD for trigeminal neuralgia (TN) between 2007 and 2020 and had at least 6 months of follow-up were included in this study. Hardaway and Panczykowski scores were retrospectively computed for each patient and compared with postoperative pain recurrence and pain-free duration. RESULTS: The mean ± SD area under the receiver operating characteristic curve for predicting any pain recurrence after MVD was 0.567 ± 0.081 using the Hardaway score and 0.546 ± 0.085 using the Panczykowski score. On log-rank tests and Kaplan-Meier analysis, the patients with Hardaway scores of 0-2 had significantly shorter pain-free survival times after MVD than did those with a score of 3. Patients with a Panczykowski score of 1 had a significantly shorter pain-free duration after surgery compared with both patients with scores of 2-3 and patients with scores of 4-5. Patients with Panczykowski scores of 2-3 also had significantly shorter pain-free duration compared with patients with scores of 4-5. CONCLUSIONS: Both the Hardaway and Panczykowski scores may be useful for predicting postoperative pain-free duration in TN patients, and their utility may be greatest when scores are clustered. Continued refinement of both scoring systems will help to improve our ability to predict patient outcomes after MVD.

Hemoglobin Drop is Associated with Early Post-operative Stroke Following Revascularization Surgery for Moyamoya Disease.

BACKGROUND: Postoperative stroke is a potentially devastating neurological complication following surgical revascularization for Moyamoya disease. We sought to evaluate whether peri-operative hemoglobin levels were associated with the risk of early post-operative stroke following revascularization surgery in adult Moyamoya patients. METHODS: Adult patients having revascularization surgeries for Moyamoya disease between 1999-2022 were identified through single institutional retrospective review. Logistic regression analysis was used to test for the association between hemoglobin drop and early postoperative stroke. RESULTS: In all, 106 revascularization surgeries were included in the study. A stroke occurred within 7 days after surgery in 9.4% of cases. There were no significant associations between the occurrence of an early postoperative stroke and patient age, gender, or race. Mean postoperative hemoglobin drop was greater in patients who suffered an early postoperative stroke compared with patients who did not (2.3±1.1 g/dL vs. 1.3±1.1 g/dL, respectively; P=0.034). Patients who experienced a hemoglobin drop post-operatively had 2.03 times greater odds (95% confidence interval, 1.06-4.23; P=0.040) of having a stroke than those whose hemoglobin levels were stable. Early postoperative stroke was also associated with an increase in length of hospital stay (P<0.001), discharge to a rehabilitation facility (P=0.014), and worse modified Rankin scale at 1 month (P=0.001). CONCLUSION: This study found a significant association between hemoglobin drop and early postoperative stroke following revascularization surgery in adult patients with Moyamoya disease. Based on our findings, it may be prudent to avoid hemoglobin drops in Moyamoya patients undergoing surgical revascularization.

Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

CT Perfusion Derived rCBV < 42% Lesion Volume Is Independently Associated with Followup FLAIR Infarct Volume in Anterior Circulation Large Vessel Occlusion.

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearman's rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = -0.214, p < 0.01), mTICI (beta = -0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.

Micro-RNAs With Prognostic Significance in Gallbladder Cancer: A Systematic Review and Meta-Analysis.

Gallbladder cancer (GBC) stands out as one of the most widespread malignancies impacting the biliary tract globally. Despite increasing interest, to the best of our knowledge, no meta-analysis has been undertaken to amalgamate the existing data concerning the prognostic significance of micro-RNAs (miRNAs) in GBC in comparison to studies on miRNAs in other cancers. Hence, this systematic review and meta-analysis aimed at determining the prognostic significance of miRNAs in GBC patients. Comprehensive literature searches were conducted across PubMed, Cochrane Library, Ovid, Scopus, and Science Direct databases. Studies that evaluated the association between miRNAs and overall survival in GBC patients were included. Random-effect meta-analysis was employed to pool hazard ratios (HRs) and their 95% confidence intervals (CIs) across studies. A total of 15 studies, encompassing 16 miRs, were included for our analysis. The pooled analysis revealed that a high expression of miR-204, miR-7-2-3p, miR-29c-3p, miR-125b, miR-20a, miR-139-5p, miR-141, miR-92b-3p, miR-335, and miR-372 was significantly associated with poor prognosis and increased risk (HR>1 and the upper bound of the 95% CI>1). Additionally, these miRNAs were associated with the overall survival (HR = 1.56, 95% CI = 0.91-2.20, I2 = 91.82%). Significant heterogeneity was observed and could be attributed to the limited number of studies available on the GBC and significant reliance on quantitative real-time PCR for the detection of miRNAs. In conclusion, specific miRNAs exhibit prognostic significance in GBC, with potential implications for patient stratification and targeted therapeutic interventions. However, due to the heterogeneity among studies, these findings should be interpreted cautiously and validated in larger cohorts.

Machine learning modeling for ultrasonic quality attribute assessment of pharmaceutical tablets for continuous manufacturing and real-time release testing.

In in-process quality monitoring for Continuous Manufacturing (CM) and Critical Quality Attributes (CQA) assessment for Real-time Release (RTR) testing, ultrasonic characterization is a critical technology for its direct, non-invasive, rapid, and cost-effective nature. In quality evaluation with ultrasound, relating a pharmaceutical tablet's ultrasonic response to its defect state and quality parameters is essential. However, ultrasonic CQA characterization requires a robust mathematical model, which cannot be obtained with traditional first principles-based modeling approaches. Machine Learning (ML) using experimental data is emerging as a critical analytical tool for overcoming such modeling challenges. In this work, a novel Deep Neural Network-based ML-driven Non-Destructive Evaluation (ML-NDE) modeling framework is developed, and its effectiveness for extracting and predicting three CQAs, namely defect states, compression force levels, and amounts of disintegrant, is demonstrated. Using a robotic tablet handling experimental rig, each attribute's distinct waveform dataset was acquired and utilized for training, validating, and testing the respective ML models. This study details an advanced algorithmic quality assessment framework for pharmaceutical CM in which automated RTR testing is expected to be critical in developing cost-effective in-process real-time monitoring systems. The presented ML-NDE approach has demonstrated its effectiveness through evaluations with separate (unused) test datasets.

Cemento-Ossifying Fibroma of the Mandible: A Case Report.

Benign osseous tumors of mesodermal origin that are included within the group of fibro-osseous lesions include cemento-ossifying fibromas (COFs). The fibrocellular component of these diseases originates from the periodontal ligament, which deposits bone and cementum encased in fibrous tissue. It typically appears in the mandible and presents as a solitary, nonaggressive, slowly developing, asymptomatic, expansile lesion, rarely occurring in the maxilla. The only intervention that proved to be successful in producing excellent outcomes and that may be regarded as a final therapeutic option is the complete surgical removal of COFs. Presenting herein is a case report describing a painless and expansile mass in the left mandibular region, histopathologically diagnosed as COF.

Pharmacokinetic Profile of Brepocitinib with Topical Administration in Atopic Dermatitis and Psoriasis Populations: Strategy to Inform Clinical Trial Design in Adult and Pediatric Populations.

INTRODUCTION: Topical brepocitinib, a tyrosine kinase (TYK)2/Janus kinase (JAK)1 inhibitor, is in development for psoriasis (PsO) and atopic dermatitis (AD). Quantitative analyses of prior clinical trial data were used to inform future clinical trial designs. METHODS: Two phase 2b studies in patients with AD and PsO were used to characterize the amount of topical brepocitinib and the resultant systemic trough concentration (CTrough) using a linear mixed-effects regression (LMER). This model was used to predict brepocitinib systemic CTrough for higher treated body surface areas (BSAs) in adults and children. Information from non-clinical and clinical trials with oral brepocitinib was leveraged to set safety thresholds. This combined approach was used to inform future dose-strength selection and treated BSA limits. RESULTS: Data from 256 patients were analyzed. Patient type, dose strength, and frequency had significant impacts on the dose-exposure relationship. Systemic concentration in patients with PsO was predicted to be 45% lower than in patients with AD from the same dose. When topically applied to the same percentage BSA, brepocitinib systemic exposures are expected to be comparable between adults and children. The systemic steady-state exposure after 3% once daily and twice daily (2 mg/cm2) cream applied to less than 50% BSA in patients with AD and PsO, respectively, maintains at least a threefold margin to non-clinical safety findings and clinical hematologic markers. CONCLUSION: The relationship between the amount of active drug applied and brepocitinib systemic CTrough, described by LMER, may inform the development strategy for dose optimization in the brepocitinib topical program.

Utilizing imaging parameters for functional outcome prediction in acute ischemic stroke: A machine learning study.

BACKGROUND AND PURPOSE: We aimed to predict the functional outcome of acute ischemic stroke patients with anterior circulation large vessel occlusions (LVOs), irrespective of how they were treated or the severity of the stroke at admission, by only using imaging parameters in machine learning models. METHODS: Consecutive adult patients with anterior circulation LVOs who were scanned with CT angiography (CTA) and CT perfusion were queried in this single-center, retrospective study. The favorable outcome was defined as a modified Rankin score (mRS) of 0-2 at 90 days. Predictor variables included only imaging parameters. CatBoost, XGBoost, and Random Forest were employed. Algorithms were evaluated using the area under the receiver operating characteristic curve (AUROC), the area under the precision-recall curve (AUPRC), accuracy, Brier score, recall, and precision. SHapley Additive exPlanations were implemented. RESULTS: A total of 180 patients (102 female) were included, with a median age of 69.5. Ninety-two patients had an mRS between 0 and 2. The best algorithm in terms of AUROC was XGBoost (0.91). Furthermore, the XGBoost model exhibited a precision of 0.72, a recall of 0.81, an AUPRC of 0.83, an accuracy of 0.78, and a Brier score of 0.17. Multiphase CTA collateral score was the most significant feature in predicting the outcome. CONCLUSIONS: Using only imaging parameters, our model had an AUROC of 0.91 which was superior to most previous studies, indicating that imaging parameters may be as accurate as conventional predictors. The multiphase CTA collateral score was the most predictive variable, highlighting the importance of collaterals.

CT perfusion based rCBF <38% volume is independently and negatively associated with digital subtraction angiography collateral score in anterior circulation large vessel occlusions.

BACKGROUND: Collateral status (CS) is an important biomarker of functional outcomes in patients with acute ischemic stroke secondary to large vessel occlusion (AIS-LVO). Pretreatment CT perfusion (CTP) parameters serve as reliable surrogates of collateral status (CS). In this study, we aim to assess the relationship between the relative cerebral blood flow less than 38% (rCBF <38%), with the reference standard American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score (CS) on DSA. METHODS: In this prospectively collected, retrospectively reviewed analysis, inclusion criteria were as follows: (a) CT angiography (CTA) confirmed anterior circulation large vessel occlusion from 9/1/2017 to 10/01/2023; (b) diagnostic CT perfusion; and (c) underwent mechanical thrombectomy with documented ASITN CS. The ratios of the CTP-derived CBF values were calculated by dividing the values of the ischemic lesion by the corresponding values of the contralateral normal region (which were defined as rCBF). Spearman's rank correlation and logistic regression analysis were performed to determine the relationship of rCBF <38% lesion volume with DSA ASITN CS. p ≤ .05 was considered significant. RESULTS: In total, 223 patients [mean age: 67.77 ± 15.76 years, 56.1% (n = 125) female] met our inclusion criteria. Significant negative correlation was noted between rCBF <38% volume and DSA CS (ρ = -0.37, p < .001). On multivariate logistic regression analysis, rCBF <38% volume was found to be independently associated with worse ASITN CS (unadjusted OR: 3.03, 95% CI: 1.60-5.69, p < .001, and adjusted OR: 2.73, 95% CI: 1.34-5.50, p < .01). CONCLUSION: Greater volume of tissue with rCBF <38% is independently associated with better DSA CS. rCBF <38% is a useful adjunct tool in collateralization-based prognostication. Future studies are needed to expand our understanding of the role of rCBF <38% within the decision-making in patients with AIS-LVO.

The Relative Cerebral Blood Volume (rCBV) < 42% Is Independently Associated with Collateral Status in Anterior Circulation Large Vessel Occlusion.

Background: The pretreatment CT perfusion (CTP) marker the relative cerebral blood volume (rCBV) < 42% lesion volume has recently been shown to predict 90-day functional outcomes; however, studies assessing correlations of the rCBV < 42% lesion volume with other outcomes remain sparse. Here, we aim to assess the relationship between the rCBV < 42% lesion volume and the reference standard digital subtraction angiography (DSA)-derived American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) collateral score, hereby referred as the DSA CS. Methods: In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 1 September 2017 and 1 October 2023. Group differences were assessed using the Student's t test, Mann-Whitney U test and Chi-Square test. Spearman's rank correlation and logistic regression analyses were used to assess associations between rCBV < 42% and DSA CS. Results: In total, 222 patients (median age: 69 years, 56.3% female) met our inclusion criteria. In the multivariable logistic regression analysis, taking into account age, sex, race, hypertension, hyperlipidemia, diabetes, atrial fibrillation, prior stroke or transient ischemic attack, the admission National Institute of Health stroke scale, the premorbid modified Rankin score, the Alberta stroke program early CT score (ASPECTS), and segment occlusion, the rCBV < 42% lesion volume (adjusted OR: 0.98, p < 0.05) was independently associated with the DSA CS. Conclusion: The rCBV < 42% lesion volume is independently associated with the DSA CS.

Prolonged venous transit on perfusion imaging is associated with higher odds of mortality in successfully reperfused patients with large vessel occlusion stroke.

BACKGROUND: Poor venous outflow (VO) profiles are associated with unfavorable outcomes in patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO), despite achieving successful reperfusion. The objective of this study is to assess the association between mortality and prolonged venous transit (PVT), a novel visual qualitative VO marker on CT perfusion (CTP) time to maximum (Tmax) maps. METHODS: We performed a retrospective analysis of prospectively collected data from consecutive adult patients with AIS-LVO with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b/2c/3). PVT+ was defined as Tmax ≥10 s timing on CTP Tmax maps in at least one of the following: superior sagittal sinus (proximal venous drainage) and/or torcula (deep venous drainage). PVT- was defined as lacking this in both regions. The primary outcome was mortality at 90 days. In a 1:1 propensity score-matched cohort, regressions were performed to determine the effect of PVT on 90-day mortality. RESULTS: In 127 patients of median (IQR) age 71 (64-81) years, mortality occurred in a significantly greater proportion of PVT+ patients than PVT- patients (32.5% vs 12.6%, P=0.01). This significant difference persisted after matching (P=0.03). PVT+ was associated with a significantly increased likelihood of 90-day mortality (OR 1.22 (95% CI 1.02 to 1.46), P=0.03) in the matched cohort. CONCLUSIONS: PVT+ was significantly associated with 90-day mortality despite successful reperfusion therapy in patients with AIS-LVO. PVT is a simple VO profile marker with potential as an adjunctive metric during acute evaluation of AIS-LVO patients. Future studies will expand our understanding of using PVT in the evaluation of patients with AIS-LVO.

Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.

BACKGROUND AND OBJECTIVES: As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor). METHODS: Longitudinal exposure-response (ER) modeling was conducted to describe ritlecitinib efficacy in alopecia areata patients. The Severity of Alopecia Tool (SALT) score (a continuous bounded outcome [CBO] score [0-100]) was used as the efficacy response. The average concentration during the time interval between two adjacent SALT scores was used as the exposure metric driving efficacy. RESULTS: The developed model well described the longitudinal SALT profile of ritlecitinib as well as the frequency of boundary data. The CBO model indicated tested doses in the phase 2b/3 clinical trial are in the ascending region of ER and contextualized a loading dose effect that impacted onset of efficacy without long-term benefit. It also identified disease severity as the only covariate impacting efficacy. The model-based simulation further informed impact of treatment interruption on the loss of efficacy in the absence of a dedicated treatment withdrawal study. Results indicated temporary treatment interruption ≤ 6 weeks is not expected to result in significant loss of efficacy. CONCLUSION: The CBO modeling approach and simulation supported the single pivotal trial strategy and guided dose selection in the accelerated drug development program of ritlecitinib, which can be applied to many indications where efficacy is measured on a bounded scale.

Microvascular insulin resistance associates with enhanced muscle glucose disposal in CD36 deficiency.

Dysfunction of endothelial insulin delivery to muscle associates with insulin resistance. CD36, a fatty acid transporter and modulator of insulin signaling is abundant in endothelial cells, especially in capillaries. Humans with inherited 50% reduction in CD36 expression have endothelial dysfunction but whether it is associated with insulin resistance is unclear. Using hyperinsulinemic/euglycemic clamps in Cd36-/- and wildtype mice, and in 50% CD36 deficient humans and matched controls we found that Cd36-/- mice have enhanced systemic glucose disposal despite unaltered transendothelial insulin transfer and reductions in microvascular perfusion and blood vessel compliance. Partially CD36 deficient humans also have better glucose disposal than controls with no capillary recruitment by insulin. CD36 knockdown in primary human-derived microvascular cells impairs insulin action on AKT, endothelial nitric oxide synthase, and nitric oxide release. Thus, insulin resistance of microvascular function in CD36 deficiency paradoxically associates with increased glucose utilization, likely through a remodeling of muscle gene expression.