Medicine and Health Sciences Commons^™

Intersecting Challenges: Substance Use And Mental Health Disparities Across Self-Reported Disability Status, Jessica Williams, Xiao Li, Hannah S Szlyk, Erin Kasson, Nathaniel A Dell, Alex Ramsey, Patricia A Cavazos-Rehg

2020-Current year OA Pubs

PURPOSE: Substance use and substance use disorders (SUD) disproportionately affect people with disabilities (PWD), yet PWD remain under-represented in addiction treatment literature. While recent work has begun to address SUD prevalence and recovery service gaps, little is known about how disability status shapes substance use outcomes. The present study is the first to our knowledge to investigate how recovery, mental health comorbidities, and barriers to care differ across disability status using structured survey data from people who use substances.

METHODS: 333 participants who use substances and provided information about their disability status in the baseline survey for a digital intervention …

Ultrasound Applications In The Treatment Of Major Depressive Disorder: A Systematic Review Of Techniques And Therapeutic Potentials In Clinical Trials And Animal Model Studies, Gansheng Tan, Hong Chen, Eric C Leuthardt

2020-Current year OA Pubs

OBJECTIVE: Major depressive disorder (MDD) is a debilitating condition that inflicts significant personal and economic burdens and affects approximately 8% of the US population. Approximately 30% of patients with MDD do not respond to conventional antidepressant and psychotherapeutic treatments. Current treatment options for refractory MDD include transcranial magnetic stimulation (TMS) and invasive surgical procedures such as surgical ablation, vagus nerve stimulation, and deep brain stimulation. In this context, therapeutic ultrasound emerges as a promising alternative for treating refractory MDD, which has the unique advantage of combining noninvasiveness with selective targeting. Over the past ten years, there has been growth in …

Accelerated Diffusion Basis Spectrum Imaging With Tensor Computations, Kainen L Utt, Jacob S Blum, Donsub Rim, Sheng-Kwei Song

2020-Current year OA Pubs

This paper introduces an advanced framework for accelerated processing of diffusion-weighted imaging (DWI) data that utilizes an entire-image modeling approach to optimize the estimation of diffusion parameters from DWIs by mapping input diffusion data to predicted signals and estimating parameter values via a stochastic gradient descent optimizer (Adam). To validate this approach, we applied this framework to diffusion basis spectrum imaging (DBSI) and analyzed in vivo human brain and ex vivo mouse brain DWIs. Results demonstrate significant improvements to computational speed and signal-to-noise ratio (SNR) in estimated parameter maps compared to standard DBSI. Our approach is applicable to any diffusion …

Leveraging The Pedsnet Clinical Research Network And Electronic Health Record Data To Enhance Efficiency Of Trial Enrollment For A Rare Pediatric Rheumatic Disease, Pamela F Weiss, Levon Utidjian, Mitchell Maltenfort, Hanieh Razzaghi, Timothy G Brandon, Cassandra Muir, Cora Sears, Edward J Oberle, Jennifer Cooper, Kevin Baszis, Mary B Toth, Esi M Morgan, Christopher B Forrest

2020-Current year OA Pubs

BACKGROUND: We evaluated the PEDSnet clinical research network for study enrollment of juvenile spondyloarthritis, a rare rheumatic disease that includes enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). METHODS: An electronic health record (EHR)-based typology was developed by an interdisciplinary team to query EHR data for a spectrum of pediatric rheumatic diseases (2009–2023) from 8 PEDSnet centers. The prevalence, characteristics and drug exposures for juvenile spondyloarthritis was explored to gauge feasibility of leveraging the network for study enrollment. Next, the typology was adapted to identify subjects for a clinical trial; the efficiency of EHR typology query was compared to standard screening …

Human Chorionic Gonadotropin Decreases Cerebral Cystic Encephalomalacia And Parvalbumin Interneuron Degeneration In A Pro-Inflammatory Model Of Mouse Neonatal Hypoxia-Ischemia, Benjamin Miller, Alexander Crider, Bhooma Aravamuthan, Rafael Galindo

2020-Current year OA Pubs

Human chorionic gonadotropin (hCG) is an immunoregulatory and neurotrophic glycoprotein of potential clinical utility in the neonate at risk for cerebral injury. However, hCG has not been demonstrated to affect the pro-degenerative actions of inflammation in neonatal brain injury. Here we utilize a neonatal mouse model of mild hypoxia-ischemia (HI) combined with intraperitoneal administration of lipopolysaccharide (LPS) to evaluate the neuroprotective actions of hCG in the setting of systemic inflammation. Intraperitoneal treatment with hCG significantly decreased tissue loss and cystic degeneration in the hippocampus and cerebral cortex of term-equivalent neonatal mice exposed to LPS and HI. Noting that parvalbumin immunoreactive …

Sequential Platinum And Parp Inhibition Enhances Pd1 Immunotherapy Efficacy In Murine Brca2 Mutated Pancreatic Cancer, John C Mcvey, Max M Wattenberg, Heather Coho, Kayjana Infante, Kelly Markowitz, Devora Delman, Cynthia Clendenin, Emma E Furth, Rashmi Tondon, Ben Z Stanger, Robert H Vonderheide, Kim A Reiss, Gregory L Beatty

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA-mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA-mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, …

A Heterogeneous Population Code At The First Synapse Of Vision, Tessa Herzog, Takeshi Yoshimatsu, Jose Moya-Diaz, Ben James, Leon Lagnado, Tom Baden

2020-Current year OA Pubs

Vision begins when photoreceptors convert fluctuations in light intensity into temporal patterns of glutamate release that drive the retinal network. The input-output relation at this first stage has not been studied in vivo so it is not known how it operates across a photoreceptor population. Using glutamate imaging in zebrafish, we find that individual type 1 cones (PR1; ancestral red cones), which dominate daylight vision in non-avian vertebrates, encode visual stimuli with high reliability and time-precision but routinely vary in sensitivity to luminance, contrast and frequency across the population. Variations in input-output relations are generated by feedback from the horizontal …

Establishing T1 And Ecv Mapping Based Nomogram Differentiate Acute Ischemic And Nonischemic Myocardial Injury: A Proof-Of-Concept Study, Yanping Su, Kan Liu, Et Al.

2020-Current year OA Pubs

OBJECTIVES: To develop and validate a nomogram based on T1 and extracellular volume fraction (ECV) mapping derived from cardiovascular magnetic resonance (CMR) for differentiating ischemic from nonischemic cardiomyopathies during the acute phase.

METHODS: This retrospective study included patients who underwent CMR at the Fifth Affiliated Hospital of Wenzhou Medical University (internal dataset) and the Fifth Affiliated Hospital of Sun Yat-sen University (external dataset). Patients were assigned to a training set (n = 73), a test set (n = 30), an internal validation set (n = 28), and an external validation set (n = 16). Six multivariable logistic regression models were …

Olutasidenib In Recurrent/Relapsed Locally Advanced Or Metastatic Idh1-Mutated Chondrosarcoma: Phase 1b/2 Trial, Robin L Jones, Roman Groisberg, Jean-Yves Blay, Howard Colman, Macarena De La Fuente, Patricia Roxburgh, Mwe Mwe Chao, Hua Tian, Florence Duffaud, Rastislav Bahleda, Brian A Van Tine

2020-Current year OA Pubs

Chondrosarcomas are rare cartilaginous neoplasms with limited treatment options. Isocitrate dehydrogenase 1/2 (mIDH1/2) mutations occur in 65% of chondrosarcomas. Here we report safety and efficacy of olutasidenib, an mIDH1 inhibitor, evaluated in patients with locally advanced or metastatic mIDH1 chondrosarcoma (Clinicaltrials.gov identifier: NCT03684811). The primary endpoint was objective response rate by tumor evaluation; secondary endpoints included adverse events, progression-free and overall survival. Patients received olutasidenib 150 mg twice daily. Twenty-three patients were enrolled; 16 were diagnosed with conventional chondrosarcoma (cCS). Median age was 57 (range, 30-71) years. In 21 response-evaluable patients, 11 (52%) had stable disease, 8 (38%) had progressive …

Defining The Heterogeneous Molecular Landscape Of Lung Cancer Cell Responses To Epigenetic Inhibition, Chuwei Lin, Catherine M Sniezek, Christopher D Mcgann, Rashmi Karki, Ross M Giglio, Benjamin A Garcia, José L Mcfaline-Figueroa, Devin K Schweppe

2020-Current year OA Pubs

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative …

Mast Cells Promote Pathology And Susceptibility In Tuberculosis, Ananya Gupta, Vibha Taneja, Javier Rangel-Moreno, Nilofer Naqvi, Abhimanyu, Yun Tao, Mushtaq Ahmed, Kuldeep Singh Chauhan, Daniela Trejo-Ponce De Leon, Gustavo Ramírez-Martínez, Luis Jiménez-Alvarez, Cesar Luna-Rivero, Joaquin Zuniga, Deepak Kaushal, Shabaana A Khader

2020-Current year OA Pubs

Tuberculosis (TB), caused by the bacterium

The Effects Of Ovine-Derived Reinforced Tissue Matrix Surrounding Silicone-Based Implants In A Rat Prepectoral Reconstruction Model, Sai L Pinni, Cameron Martin, Nicholas Fadell, Xiaochao Xia, Evan Marsh, Lauren Schellhardt, Xiaowei Li, Matthew D Wood, Justin M Sacks

2020-Current year OA Pubs

Silicone-based implants have been widely used in breast reconstruction but have also been associated with poorly understood complications, including pathologic foreign body responses such as capsular contracture. In this study, we leveraged 3D-printing technology to generate silicone-based implants in a novel, anatomically relevant, prepectoral rat model. We used this model to evaluate the response to an extracellular matrix-based product: ovine-derived reinforced tissue matrix (RTM). Two-piece negative molds were developed through computer-aided design and 3D-printed. The molds were filled with various polydimethylsiloxane mixtures and dip-coated to fabricate implants. Implant material characterization revealed that the implants retained the original 3D-printed mold shape …

Biomarkers Of Response To Neoadjuvant Palbociclib Plus Anastrozole In Endocrine-Resistant Estrogen Receptor-Positive/Her2-Negative Breast Cancer: A Phase 2 Trial, Tim Kong, Alex Mabry, Maureen Highkin, Jeremy Hoog, Zhanfang Guo, Adrian Gonzales-Gonzales, Shana Thomas, Yingduo Song, Feng Gao, Mateusz Opyrchal, Lindsay Peterson, Foluso Ademuyiwa, Julie Margenthaler, Rebecca Aft, Katherine Glover-Collins, Leslie Nehring, Yu Tao, Souzan Sanati, Ian S Hagemann, Fouad Boulos, Li Ding, Stephen T Oh, Ron Bose, Jason D Weber, Jingqin Luo, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

CDK4/6 inhibitors (CDK4/6i) improve outcomes for estrogen receptor (ER) positive/HER2-negative breast cancers (BCs), yet intrinsic and acquired resistance exist. Here, we evaluated anastrozole in combination with palbociclib (ANA/PAL) in the NeoPalAna Endocrine-Resistant cohort (NCT01723774). Thirty-four patients with clinical stage II/III ER + /HER2- BCs resistant to standard neoadjuvant endocrine therapy (on-treatment Ki67 > 10%) received neoadjuvant ANA/PAL, with serial biopsies analyzed. The primary endpoint, complete cell cycle arrest (CCCA; Ki67

Expression Spectrum Of Te-Driven Transcripts In Human Adult Tissues, Benpeng Miao, Xinlong Luo, Amina Ademovic, Yushan Yang, Tao P Wu, Bo A Zhang

2020-Current year OA Pubs

BACKGROUND: Transposable elements (TEs) are vital components of eukaryotic genomes and have played a critical role in genome evolution. Although most TEs are silenced in the mammalian genome, increasing evidence suggests that certain TEs are actively involved in gene regulation during early developmental stages. However, the extent to which human TEs drive gene transcription in adult tissues remains largely unexplored. RESULTS: In this study, we systematically analyze 17,329 human transcriptomes to investigate how TEs influence gene transcription across 47 adult tissues. Our findings reveal that TE-driven transcripts are broadly expressed in human tissues, contributing to both housekeeping functions and tissue-specific …

Ablation Of Cd38 In Multiple Myeloma Cells Leads To An Aggressive Phenotype In A Mouse Xenograft Model, Michael R Dyer, Alex Zheleznyak, Erin N Teubner, Julie L Prior, Brad Manion, Zhenghan Jing, Amit K Sharma, Junwei Du, Rui Tang, Mark A Fiala, John F Dipersio, Deborah Veis, Julie O'Neal, Mikhail Y Berezin, Monica Shokeen

2020-Current year OA Pubs

Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain and end-organ failure. A major challenge in treating MM is therapeutic resistance. CD38-targeted immunotherapies, such as daratumumab, have significantly improved outcomes; however, variable responses, resistance, and relapse remain vital challenges. We hypothesized that loss of CD38 drives a more aggressive phenotype and resistance to therapy. To test this, we developed a CD38 knockout (KO) clone of a human MM cell line and evaluated it in immunodeficient mice. Mice with CD38 KO tumors exhibited an increased tumor burden and reduced survival compared with those with CD38 wild-type (WT) tumors. …

Myd88 Signaling In Myeloid Cells Induces Gastrointestinal Tract Injury And Systemic Inflammation After West Nile Virus Infection, Shih-Ching Lin, Fang R Zhao, Matthias Mack, Gabriel Mbalaviele, Michael S Diamond

2020-Current year OA Pubs

Humans with autoantibodies to type I interferons (IFNs) are at higher risk for neurological disease after West Nile virus (WNV) infection. IFN signaling deficient WNV-infected mice develop greater inflammation in the brain, which correlates with loss of gut barrier integrity. Here, we investigate the immune pathways that mediate this virus-gut-brain axis of inflammation. Myd88

Dual Roles Of Trpv2 In The Innate Immune Response To Cytosolic Dna: Arresting Dormant And Boosting Activated Sting, Chen Cheng, Hsiang-Ting Lu, Shan Li, Zhongsheng You

2020-Current year OA Pubs

The cGAS/STING-dependent innate immune pathway is central in the cellular response to cytosolic DNA derived from viral infections, genotoxic stress, or mitochondrial defects. While efficient activation of the pathway is crucial for defending against pathogens and cancer, maintaining its dormancy without stimuli is equally important to avoid autoimmunity. However, the precise control of the cGAS/STING pathway remains poorly understood. Here, we report that the ion channel TRPV2 regulates both the dormancy and activation of STING. TRPV2 associates with STING and suppresses spontaneous STING activation in the absence of cytoDNA but dissociates from STING and promotes its activation by releasing Ca

Distinct Contributions Of Etv2+ And Flk1+ Progenitors To Endothelial, Hematopoietic, And Cardiac Lineages, Dereck Alleyne, Minseo Kim, Jun Wu, Yoojung Kwon, Ye-Ram Kim, Ashraf Ul Kabir, Matthew Ishahak, Jeffrey R Millman, Changxu Fan, Hyung Joo Lee, Karen Krchma, Xiaoyun Xing, Kory Lavine, Ting Wang, Kyunghee Choi

2020-Current year OA Pubs

The ETS family transcription factor ETV2, VEGFA, and its receptor FLK1 are essential for hematopoietic, vascular, and cardiac development. Here, we combine dual Etv2 and Flk1 lineage tracing with molecular profiling to define how mesoderm progenitors are allocated to hematopoietic, endothelial, cardiomyocyte, and smooth muscle lineages. We demonstrate that hematopoietic, endothelial, and cardiac valves arise from dual Etv2

Redefining The Role Of Chaperones For Dot/Icm T4bss-Mediated Substrate Translocation By Legionella Pneumophila, Sukhithasri Vijayrajratnam, Ahmet Hasanovic, Joseph P Vogel

2020-Current year OA Pubs

Legionella pneumophila, the etiological agent of legionnaires' disease, establishes its intracellular niche through the Dot/Icm type IVB secretion system, which translocates ∼300 effector proteins into host cells. Efficient secretion of many effectors requires the IcmS and IcmW chaperones, which interact with both substrates and the type IV coupling protein DotL. A prior model proposed that IcmSW are released from substrates during translocation by transfer to the C terminus of DotL and then recycled to the cytoplasm. This model predicts an excess cytoplasmic pool of IcmSW and their dissociation from DotL. We tested these predictions using quantitative stoichiometric analysis of Dot/Icm …

Inducible Deletion Of Dgat1 And 2 From Microglia Exacerbates Neurodegeneration And Endolysosomal Lipid Accumulation In Male Ps19 Mice, G Travis Tabor, Alexandra Litvinchuk, Yun Chen, Austin Allison, Carisa Zeng, Hao Hu, Peter B Lin, Prabal Sharma, Samira Parhizkar, Sihui Song, Xin Bao, Abhirami K Iyer, Shih Feng You, Javier Remolina Serrano, Melissa Manis, Emily Franke, Anil G Cashikar, Carla M Yuede, Celeste M Karch, Eric J Huang, Maxim Artyomov, Jason D Ulrich, David M Holtzman, Et Al.

2020-Current year OA Pubs

Brain myeloid cells accumulate neutral lipids in multiple human neurodegenerative disorders and relevant mouse models. These lipids are often assumed to be contained in lipid droplets (LDs). While studies have been performed in cell culture and Drosophila models to characterize glial LDs, the roles of microglial LD biogenesis in mammalian tauopathy are unclear. To address this issue, we induced the deletion of diacylglycerol acyltransferases (DGATs) 1 and 2, enzymes critical for LD formation, from microglia in the PS19 mouse model of tauopathy. Microglial DGAT double knockout (KO) exacerbated neurodegeneration and increased the abundance of brain cholesteryl esters in male PS19 …

Collaborative Compliance: A Consortium-Based Framework For Achieving 21 Cfr Part 11 Readiness In Redcap Across Ctsa Institutions, Theresa Baker, Katie Keenoy, Et Al.

2020-Current year OA Pubs

Academic research institutions using REDCap often face challenges aligning with U.S. FDA requirements for electronic records and signatures under 21 CFR Part 11 (Part 11). A National Center for Advancing Translational Sciences(NCATS) working group developed an implementation guide for Part 11 compliance in REDCap. Within six months after release, 259 individuals representing 164 institutions accessed the guide. Individuals who downloaded the guide reported reduced vendor reliance, improved documentation, and establishment Part 11-ready REDCap instances. This working group demonstrated how collaboration between technical and regulatory experts at many peer institutions is effective in improving regulatory compliance across the research enterprise.

Routine Admission Urinalysis Has Low Clinical Utility In Psychiatric Hospitalizations, Tri Pham, Devanshi Patel, Ana Berce, Alice Bewley, Sena Sayood

2020-Current year OA Pubs

We examined the diagnostic utility of urinalyses (UAs) in psychiatric admissions. Admission UAs led to diagnosis of clinical urinary tract infections in 1.7% of cases. Among those treated with antibiotics, inappropriate prescriptions occurred in 71.3% of cases, with increased odds in older age, female sex, positive cultures, and certain psychiatric diagnoses.

Nutrition Assistance Programs And Pediatric Weight Outcomes: A Systematic Review, Dan Ferris, Genevieve Davison, Tyler Frank, Amanda Gilbert, Fanice Thomas, Sydney Rothman, Kim Lipsey, Sarah Moreland-Russell

2020-Current year OA Pubs

BACKGROUND/OBJECTIVES: Food insecurity and pediatric obesity have increased concurrently in the U.S., raising questions about the role of Federal Nutrition Assistance Programs (FNAPs) in shaping weight outcomes. This systematic review examined evidence on relationships between FNAP participation and pediatric weight outcomes.

METHODS: Six databases were searched for U.S.-based, peer-reviewed studies published through July 2024 that assessed FNAP participation and pediatric weight outcomes.

RESULTS: Seventy-five studies met the inclusion criteria, and no consistent pattern indicated that any single FNAP or program type (educational setting-based or direct financial support) reliably reduced or increased childhood overweight or obesity risk. Twenty studies found statistically …

Impact Of Social Vulnerability On Glycemic Control And Diabetes Technology Use In Youth With Type 1 Diabetes, Nicholas R Banull, Melanie Bryan, Stephen I Stone, Hope Shimony, Amanda Ingram, Ana María Arbeláez

2020-Current year OA Pubs

BACKGROUND: Diabetes technology has been shown to improve glycemic control in people with type 1 diabetes (T1DM). Despite their benefits, these technologies are used less frequently by youth from lower socioeconomic backgrounds and racial minorities worldwide. This study aimed to examine the relationship between social vulnerability, disparities in diabetes technology use, and glycemic control in youth with T1DM. METHODS: This retrospective billing code analysis included 1,460 patients with T1DM, aged ≤ 23 years old, who were seen at a large academic diabetes center in the Midwest between January 2020 and April 2022, before the expansion of insurance coverage for diabetes …

Two Axes Of White Matter Development, Audrey C Luo, Deanna M Barch, Et Al.

2020-Current year OA Pubs

Despite decades of neuroimaging research, how white matter develops along the length of major tracts in humans remains unknown. Here, we identify fundamental patterns of white matter maturation by examining developmental variation along major, long-range cortico-cortical tracts in youth ages 5-23 years using diffusion MRI from three large-scale, cross-sectional datasets (total N = 2716). Across datasets, we delineate two replicable axes of human white matter development. First, we find a deep-to-superficial axis, in which superficial tract regions near the cortical surface exhibit greater age-related change than deep tract regions. Second, we demonstrate that the development of superficial tract regions aligns …

Creative Arts To Enhance Cervical Cancer Awareness Using Art-Based Messages From A Nigerian Crowdsourcing Open Call: Qualitative Thematic Analysis, Abdulhammed O Babatunde, Olufunto A Olusanya, Peter Kalulu, Temitope Ojo, Onyekachukwu Anikamadu, Juliet Iwelunmor, Et Al.

2020-Current year OA Pubs

BACKGROUND: Cervical cancer is a leading cause of cancer deaths among women in Nigeria, yet awareness is low. Historically, art has served as a medium for processing emotions and sharing experiences, which can be effective in promoting health and behavior change.

OBJECTIVE: This study aimed to examine art submissions and social media engagement from a Nigerian crowdsourcing open call to inform co-designed strategies for cervical cancer prevention among women.

METHODS: This study reported following the SRQR (Standard Reporting for Qualitative Research) guideline. From October to November 2023, we launched an open call for art on social media, inviting adult women …

Evaluation Of Adalimumab Tapering Regimens In Children And Adolescents With Juvenile Idiopathic Arthritis In Remission: A Simulation Study, Dominic S Bräm, Verena Gotta, Gilbert Koch, Klervi Golhen, Andreas Woerner, Andrew Atkinson, Johannes N Van Den Anker, Marc Pfister, Tatjana Welzel

2020-Current year OA Pubs

BACKGROUND: Adalimumab (ADM) in children with juvenile idiopathic arthritis (JIA) is usually dosed using fixed weight-based bands (label dosing: 20 mg for <  30 kg, 40 mg for ≥ 30 kg) every other week (EOW). This has been shown to result in higher exposure after remission than targeted in adult patients with rheumatic diseases (trough concentrations of 2–8 mg/L) suggesting possibility of treatment adjustments and tapering, particularly in children weighing 30 to 50 kg. A pharmacometric simulation study was performed to evaluate different ADM dosing regimens supported by therapeutic drug monitoring (TDM) to provide insights for JIA management in remission. METHODS: This simulation study used a previously established pharmacokinetic ADM model. Simulation scenarios included dose reduction to 30 mg in children 30 to 50 kg and interval extension from 14 to 21 or 28 days. To further personalize ADM dosing and avoid exposure above predefined target range, TDM-guided tapering within mentioned simulation scenarios was investigated, i.e., adjusting dosing interval in children and adolescents whose ADM trough concentrations were above the upper limit of the predefined ADM target range of 9 mg/L. Proportions of virtual patients within the extrapolated target exposure range from adults including a safety-margin, i.e., 4–9 mg/L, were assessed and compared to label dosing, stratified by body weight. RESULTS: In children and adolescents with JIA weighing 30 to 50 kg both, dose interval extension to 21 days and dose reduction to 30 mg EOW increased proportion of patients within predefined target range from 17 - 29% (label dose regimen) to 34–43% or 28–43%, respectively. TDM-guided tapering for patients with trough concentrations > 9 mg/L further increased proportion with target exposure to 56–63% while keeping the proportion of patients with trough concentrations <  2 mg/L similar to label dosing (≤ 2%). CONCLUSION: This simulation study suggests that ADM tapering, in children with JIA who reached remission, may be applicable. Appropriate ADM dose reduction or dose interval extension, especially when supported by TDM, could help to reduce treatment-related and socioeconomic burden, while minimize risk of underexposure. Provided simulation framework can be validated and further fine-tuned once paediatric exposure-response data and target ranges have been established.

Phase 1b/2 Study Of Bms-813160, A Ccr2/5 Dual Antagonist, In Combination With Chemotherapy Or Nivolumab In Patients With Advanced Pancreatic Or Colorectal Cancer, Dung T Le, Nikolaos A Trikalinos, Et Al.

2020-Current year OA Pubs

BACKGROUND: Cysteine-cysteine chemokine receptors 2 (CCR2) and 5 (CCR5) contribute to immune suppression in tumor microenvironments. CCR2 and CCR5 antagonists have demonstrated antitumor activity in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), respectively. This phase 1b/2, open-label study evaluated BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy±nivolumab in advanced PDAC or metastatic CRC.

METHODS: Part 1 included patients with metastatic untreated (first-line (1L)) PDAC, 1L CRC, or previously treated (second or third line (2/3L)) microsatellite stable (MSS) CRC. Patients received 2 weeks of BMS-813160 monotherapy (300 mg two times a day, 600 mg once daily, 300 mg once …

A Retrospective Analysis Of Post-Stroke Rehabilitation With Real World Use Of Brain-Computer Interface, Neha K Prasad, Nikhita J Perry, Allison L Goldring, Lee A Fleisher, Leo Petrossian, Eric C Leuthardt, Lauren Souders, Seth J Wilk

2020-Current year OA Pubs

The IpsiHand™ System is an FDA-authorized, non-invasive therapy for chronic stroke-induced upper limb motor impairment that uses a brain-computer interface (BCI) to translate intent-to-move signals into hand movement. This retrospective study evaluated real-world outcomes in stroke survivors ≥ 6 months post-stroke who were prescribed IpsiHand™ and completed regular Upper Extremity Fugl-Meyer (UEFM) assessments as part of routine care. Patients were categorized as early responders (achieving the minimal clinically important difference [MCID] of 5.25 points in UEFM score by 6 weeks), intermediate responders (achieving MCID by 12 weeks but not at 6), or early non-responders (not reaching MCID by 12 weeks). …

Integrin Activation By Two Independently Regulated Calcium-Mediated Pathways Is Required For Neutrophil Recruitment, Marina Oguama, Pia Lindental, Regina A Clemens, Clifford A Lowell, Oliver Soehnlein, Johannes Roth, Tamam Bakchoul, Anika Cappenberg, Alexander Zarbock

2020-Current year OA Pubs

BACKGROUND: Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency syndrome in humans, characterized by reduced leukocyte recruitment. The regulation of intracellular calcium levels in neutrophils is important for cellular processes; however, the exact role of store-operated calcium entry (SOCE) and the involvement of stromal interaction molecule (STIM) calcium sensors, and ORAI1-3 calcium channels in neutrophil activation and recruitment is unknown.

METHODS: Using an acute kidney injury (AKI) model, intravital microscopy, and biochemical studies, we examined the molecular mechanisms of Ca

RESULTS: We demonstrate that STIM1 and ORAI1 in neutrophils are selectively required for E-selectin- and CXCL-1-, …