Digital Commons Network^™

Improving Infant Health Equity: What Have We Learned, What Do We Do, Dewayne M Pursley, F Sessions Cole

2020-Current year OA Pubs

The United States neonatal and infant mortality rates have declined substantially over the last six decades. Despite these reductions, significant racial disparities in mortality and other important outcomes have persisted. While increased risk of preterm birth is a major contributor to these differences, racial inequities in risk-adjusted outcomes such as gestational age-specific and major congenital anomaly-associated mortality remain. Race-specific differences in inter- and intra-neonatal intensive care unit (NICU) practices associated with worse outcomes for infants of color suggest opportunities for reducing these disparate health outcomes during and after NICU hospitalization. Identifying NICU-based contributing factors and implementing factor-specific improvement strategies can …

Cardiorespiratory Signatures Of Necrotizing Enterocolitis: A 4-Nicu Study Of Very Low Birth Weight Infants, Sherry L Kausch, Zachary A Vesoulis, Colm P Travers, Carie Taveras, Rachel Benz, Amanda Duncan, Angela K S Gummadi, Katy N Krahn, Rakesh Sahni, Joseph Isler, Namasivayam Ambalavanan, J Randall Moorman, Douglas E Lake, Karen D Fairchild, Brynne A Sullivan

2020-Current year OA Pubs

BACKGROUND: Necrotizing enterocolitis (NEC) is a disorder in very low birth weight (VLBW, < 1500 g) infants, associated with significant morbidity and mortality. Earlier detection of NEC may improve outcomes. We hypothesized that NEC's physiological signature resembles that of sepsis and that our model developed for sepsis, the Pulse Oximetry Warning System (POWS), would also predict NEC.

OBJECTIVES: Assess relationships between continuous heart rate (HR) and oxygen saturation (SpO

METHODS: In a retrospective multicenter analysis, we studied VLBW infants at four level IV NICUs, identifying cases of late-onset sepsis (LOS) and NEC (Bell stages 2 or 3). Using HR and SpO

RESULTS: Among 3914 infants evaluated, 5% had NEC and 13% had LOS. Cardiorespiratory data analysis showed that HR/SpO

CONCLUSION: NEC shares a cardiorespiratory signature with LOS. POWS predicted NEC with a dynamic rise before clinical diagnosis.

IMPACT: A cardiorespiratory early warning score analyzing …

Diagnostic Stewardship Of Respiratory Cultures Using Clinical Decision Support In The Picu, Anna C Sick-Samuels, John C Lin, Rebecca G Same, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Endotracheal aspirate culture (EAC) practices for evaluation of ventilator-associated infections (VAI) vary widely across pediatric hospitals, and overuse can contribute to overdiagnosis and overtreatment for VAI. Diagnostic stewardship strategies to optimize EAC testing practices may reduce overtesting and unnecessary antibiotic treatment.

OBJECTIVE: To evaluate the association of diagnostic stewardship of EACs using clinical decision support with culture rates, antibiotic use, and patient outcomes across a multicenter collaborative of pediatric intensive care units (PICUs).

DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter cohort study with a pre-post study design among the BrighT STAR (Testing Stewardship for Antibiotic Reduction) Quality Improvement …

Prescribed Short-Acting Hormonal Contraceptive Use Among Premenopausal Females, Israel Bacha, Suleepon Uttamapinan, Hannah Harsanyi, Abigail Liberty, Lin Yang, Adetunji T Toriola

2020-Current year OA Pubs

IMPORTANCE: Hormonal contraceptive use has important implications for both reproductive and general health. However, the patterns and trends of short-acting hormonal contraceptive use among US premenopausal females remain insufficiently characterized.

OBJECTIVE: To evaluate trends in and factors associated with prescribed short-acting hormonal contraceptive use among US premenopausal females.

DESIGN, SETTING, AND PARTICIPANTS: Serial, cross-sectional analyses were conducted using US nationally representative data from the National Health and Nutrition Examination Survey (NHANES), including 10 survey cycles between 1999 to 2000 and 2017 to 2020 (before the COVID-19 pandemic). Participants included noninstitutionalized premenopausal females aged 15 years to younger than 60 years …

Beyond Lactate: Real-Time Resuscitation Targets For Septic Shock During Critical Care Transport, James L Li, Aaron J Lacy, Michael J Defilippo

2020-Current year OA Pubs

No abstract provided.

Brain Volumes In Fetuses With Congenital Heart Disease And Placental Vascular Abnormalities, Erin A O'Brien, Kaylin Taylor, Joshua S Shimony, Cynthia M Ortinau, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Investigate the association between placental vascular abnormalities and regional brain volumes in congenital heart disease (CHD) fetuses with and without genetic abnormalities.

STUDY DESIGN: Secondary analysis of brain magnetic resonance imaging (MRI) and placental pathology data from 121 CHD fetuses enrolled in prospective neuroimaging studies at two centers.

RESULTS: Placental vascular abnormality was present in 46% of fetuses, and genetic abnormality was present in 19%, including 12% with both abnormalities. Fetuses with the combination of placental and genetic abnormalities had smaller brain volumes compared to fetuses without either abnormality for total brain, subcortical gray matter, brainstem, and cerebellum, with …

Cumulative Dose Of Chemotherapy And Survival Outcomes In Children With Average-Risk Medulloblastoma Treated On Children's Oncology Group Study Acns0331, Erin Wright, Catherine Billups, Sarah Rush, Yimei Li, Anna Janns, Jeff M Michalski, Ralph Salloum, Peter De Blank

2020-Current year OA Pubs

BACKGROUND: Although survival outcomes for average-risk (AR) medulloblastoma remain excellent, patients experience significant long-term toxicities. To evaluate the effect of therapy dose modifications among children with AR medulloblastoma, we examined the association of cumulative chemotherapy dose with overall survival (OS) and event-free survival (EFS) for patients treated on Children's Oncology Group (COG) study ACNS0331.

METHODS: A cohort of children enrolled on ACNS0331 (medulloblastoma confirmed by methylation, received standard dose craniospinal radiation, and completed all cycles of chemotherapy) were evaluated for cumulative chemotherapy dose intensity continuously and categorically (≥75% or < 75% of planned dose). Cox proportional hazards regression models were used to examine associations of proportion of planned chemotherapy received with outcome. A secondary analysis separately evaluated each of the 4 molecular subgroups: Wnt-activated (WNT), Sonic Hedgehog Activated (SHH), group 3 and group 4.

RESULTS: Two hundred thirty-five children were followed for a median of …

Characteristics Of Mortality In Hiv-Negative Cryptococcosis Patients: Analysis Of A Cohort Of 743 Patients, Kai Dai, Xinyao Jian, Chongliang Luo, Siguang Wang, Qiyu Pan, Xiaofeng Xu, Jia Liu, Fuhua Peng, Yong Chen, Ying Jiang

2020-Current year OA Pubs

BACKGROUND: Reports of cryptococcosis among patients without human immunodeficiency virus (HIV) infection are increasing. However, there is still a lack of data regarding the mortality characteristics in this population.

METHOD: The clinical, laboratory, imaging data from 743 HIV-negative patients with cryptococcosis were analyzed. Kaplan-Meier analysis was used to estimate all-cause mortality at 2-week, 10-week, and 1-year, with comparisons between groups using log-rank tests. Risk factor analysis was conducted using Cox models. Additionally, a meta-analysis was conducted on four recent large-scale cohort studies to investigate the differences in 2-week mortality of HIV-negative cryptococcosis across different regions. Statistical analyses were performed using …

Integration Of A Task Strengthening Strategy For Hypertension Management Into Hiv Care In Nigeria: Baseline Characteristics Of Participants In A Cluster Randomized Controlled Trial, Weixi Chen, Juliet Iwelunmor, Et Al.

2020-Current year OA Pubs

BACKGROUND: Improved access to antiretroviral therapy (ART) has increased survival among people living with HIV (PLWH) but also the burden of cardiovascular risk factors like hypertension. While the task-strengthening strategy for hypertension control (TASSH) is a viable integrated care model, evidence of its clinical impact in Africa is limited. This report presents baseline findings from a trial evaluating 2 implementation strategies for integrating TASSH into HIV care across primary health centers (PHCs) in Lagos, Nigeria.

METHODS: A total of 3,504 PLWH on antiretroviral therapy in 30 PHCs were screened, and 830 were enrolled. Baseline data on patient sociodemographic, clinical, laboratory …

Association Between Thumb Hypoplasia, Radial Longitudinal Deficiency, And Radial Polydactyly, Emma Payne, Charles A Goldfarb, M Claire Manske, Apurva Shah, Andrea Bauer, Lindley B Wall, Could Study Group

2020-Current year OA Pubs

PURPOSE: The expression of the sonic hedgehog protein has been associated with induction of both radial longitudinal deficiency (RLD) and radial polydactyly in animal studies. We sought to investigate the co-occurrence of thumb hypoplasia/RLD and radial polydactyly in a large registry patient cohort and to investigate the clinical presentations of such patients.

METHODS: The Congenital Upper Limb Differences (CoULD) registry was queried for all patients with contralateral diagnoses of thumb hypoplasia/RLD and radial polydactyly, as defined by the Oberg-Manske-Tonkin classification system, between June 2014 and January 2026. The demographic information, medical and musculoskeletal comorbidities, radiographs, and clinical images were collected. …

U2af1s34f And U2af1q157r Myeloid Neoplasm-Associated Hotspot Mutations Induce Distinct Hematopoietic Phenotypes In Mice, Michael O Alberti, Sridhar Nonavinkere Srivatsan, Jin Shao, Dennis L Fei, Mengou Zhu, Claudia Cabrera Pastrana, Monique Chavez, Stefan P Tarnawsky, Sarah Grieb, Timothy A Graubert, Omar Abdel-Wahab, Matthew J Walter

2020-Current year OA Pubs

Recurrent somatic mutations in the spliceosome genes SF3B1, SRSF2, and U2AF1 are frequently identified in patients with myeloid neoplasms, such as myelodysplastic syndromes. We characterized the in vivo consequences of expressing two hotspot mutations in U2AF1 that code for the S34F and Q157R substitutions. Our results indicate that the two mutations induce distinct hematopoietic phenotypes in mice, suggesting that the U2AF1

Enhancing Validation Of Case-Control Omics Signatures Through "Minimalist" Single-Subject Analysis (N-Of-1 Trials): Proof Of Concept In Sepsis, Liam S Wilson, Nima Pouladi, Rachel F Nelson, Elizabeth A Middleton, Neal D Tolley, Mahdieh Shabanian, Colleen Kenost, Robert A Campbell, Matthew T Rondina, Yves A Lussier

2020-Current year OA Pubs

OBJECTIVE: To evaluate if a single-subject study (S3) design, utilizing paired transcriptome samples from the same patient (eg, "sepsis" vs "recovered"), can replicate transcriptomic signatures from small case-control studies, addressing challenges in patient accrual for rare or sub-stratified diseases.

METHODS: We generated a sepsis gene signature (SGS) comprising 300 differentially expressed genes (DEGs; FDR <  5%) from a human sepsis case-control cohort using general linear models (GLMs). Reproducibility of SGS was assessed through three approaches applied to sub-sampled independent datasets: single-subject analyses (N-of-1-MixEnrich), anticipated to perform better; conventional paired-sample GLM analyses; and a traditional case-control GLM analysis.

RESULTS: SGS reproducibility in GLM analyses was inconsistent at smaller cohort sizes (∼80% reproducibility; n = 5) but stabilized at cohort sizes >6. Remarkably, the single-subject-study approach consistently reproduced SGS in each of the 18 subjects individually (100% reproducibility; n = 1).

DISCUSSION: Conventional GLMs are …

Maternal Health And Sociodemographic Characteristics Influence Infant Growth To 24 Months In The Tunza Mwana Cohort: A Prospective Cohort Study, David Taylor Hendrixson, Mark J Manary, Et Al.

2020-Current year OA Pubs

Upstream pathways influencing child growth are complex. Weight-for-age z-score (WAZ) reflects both ponderal and linear growth and can identify children at high mortality risk. Using data from a prospective cohort of 326 mother-child pairs in Kenya, we evaluated whether associations between maternal exposures and child growth outcomes in early and later childhood. Growth trajectories were examined using locally weighted scatterplot smoothing and piecewise linear mixed-effect models with a knot at age 3 months. Poisson regression models examined associations between maternal characteristics and child underweight (WAZ <  -2) and stunting (LAZ <  -2) before and after 3 months. Mean WAZ increased to a peak at 3 months before declining steadily through 24 months. Lower maternal education (adjusted β [aβ] -0.18; 95% CI: -0.24, -0.13), household crowding (aβ -0.2; 95% CI: -0.28, -0.11), lower wealth quintile (aβ -0.04; 95% CI: -0.06, -0.02) and multiparity (aβ -0.16; 95% CI: -0.23, -0.1) were associated with lower monthly rate of change in WAZ prior to age 3 months. Younger maternal age was associated with an increased monthly rate of change in WAZ (aβ = 0.13; 95% CI: 0.08, 0.18) before 3 months and decreased monthly WAZ (aβ -0.02; 95% CI: -0.03, -0.01) after 3 months. Preterm birth was associated with increased risk of underweight in both periods (aRR 2.77; 95% CI: 1.39-5.50). Maternal mental health, intimate partner violence and adverse childhood experiences were not significantly associated with child growth. Maternal nutritional, socio-economic and household-level factors shape early growth, emphasising the need for cross-sectoral programs to support growth.

Patient-Centered Approach To Surgical Prevention Of Ovarian Cancer: A Nonrandomized Clinical Trial, Karen H Lu, Andrea R Hagemann, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Risk-reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk individuals, but adverse effects from premature menopause are a barrier to uptake. Interval salpingectomy with delayed oophorectomy (ISDO) may be an effective alternative.

OBJECTIVE: To evaluate the association of ISDO vs RRSO and sexual function and menopausal symptoms.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter, nonrandomized (patient preference) clinical trial was performed among Women Choosing Surgical Prevention participants with a pathogenic or likely pathogenic germline variant conferring an increased risk for ovarian cancer. Patients from 9 US centers were enrolled from June 2, 2016, to October …

Elevated Phagocytic Capacity Directs Innate Spinal Cord Repair, Dana Klatt Shaw, Vishnu Muraleedharan Saraswathy, Anthony R Mcadow, Lili Zhou, Dongkook Park, Ridim Mote, Amulya Saini, Ashley J Douthitt, Katerina Stepankova, Brittney Unverzagt, Cédric G Geoffroy, Aaron N Johnson, Mayssa H Mokalled

2020-Current year OA Pubs

Immune cells elicit a continuum of transcriptional states after spinal cord injury (SCI). In mammals, inefficient debris clearance and chronic inflammation impede recovery and overshadow pro-regenerative immune functions. We found that zebrafish SCI elicits transient immune activation and efficient debris clearance. Transcriptomics and genetic ablation showed zebrafish macrophages are highly phagocytic and required for regeneration. Comparisons between zebrafish and mammalian macrophages identified transcription and immune response regulator (tcim) as an immune-enriched regenerative gene. Deletion of zebrafish tcim impairs phagocytosis and regeneration and activates a pro-inflammatory signature in leukocytes. Tcim expression in zebrafish and mouse macrophages establishes its conserved roles by …

Bottlebrush Polymer Conjugates For Enhanced Antisense Oligonucleotide Therapy In Myotonic Dystrophy Type 1, Yao Li, Gyu Seong Heo, Yongjian Liu, Et Al.

2020-Current year OA Pubs

Oligonucleotides are a promising class of genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs following systemic administration has hindered drug development, and no curative treatment currently exists. DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is sequestered, posing additional challenges after cellular internalization regarding endosomal escape and nuclear uptake. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUG repeat RNA tracts, conjugated to a bottlebrush polymer, exhibits improved muscle distribution and potent correction of DM1-associated splicing dysregulation in a …

Chiari Malformation Type 1 Is Associated With A Smaller Fourth Ventricle Volume - A Multi-Cohort Replication Study, Jarod L Roland, Thanda Meehan, Alexandra Gabliani, Scott Marek, Nico Dosenbach, Joshua S Shimony, Nilay Jakati, Yi Li, Leo Sugrue, Jennifer M Strahle, Chenyang Lu, David D Limbrick, Gabe Haller

2020-Current year OA Pubs

Chiari Malformation Type 1 (CM1) is canonically defined by ectopic position of the cerebellar tonsils with additional anatomic variations described inconsistently. Effect on fourth ventricle volume is controversial with prior studies reporting disparate results and methodologically limited to single institution series that hinder generalizability. This limitation was addressed utilizing multiple data sources, longitudinal replication, and reproducible methods using both FreeSurfer and the deep learning-based DL+DiReCT tools for automated volumetrics. First, we analyzed a local retrospective clinical cohort of individuals with CM1 and controls. Using data from the Adolescent Brain Cognitive Development (ABCD) Study, we analyzed volumes at baseline then replicated …

Broadly Reactive Human Monoclonal Antibodies Targeting Influenza A Nucleoprotein Lack Protective Activity In Vivo, Walter N Harrington, David C Brice, Aaron J Schmitz, Jackson S Turner, Rafael Brent, Philip A Mudd, Ali H Ellebedy, Richard J Webby

2020-Current year OA Pubs

The antibody response to influenza virus infection targets numerous viral proteins, with those specific for the hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins being the most extensively studied. Antibodies to HA and NA function as independent immune correlates of protection and form the basis of most vaccine approaches. In contrast, the contribution of antibodies to other viral proteins such as the nucleoprotein (NP) remains unclear, and existing studies have reached conflicting conclusions. In this work, we examined three human monoclonal NP antibodies isolated from plasmablasts of two individuals naturally infected with influenza A virus (IAV) during the 2018-2019 influenza season. …

Patterns Of Brain-Wide Associations Reflect Socioeconomics, Scott Marek, Meghan Rose Donohue, Nicole R Karcher, Caroline P Hoyniak, Roselyne J Chauvin, Ashley C Meyer, John Miller, Andrew N Van, Anxu Wang, Noah J Baden, Vahdeta Suljic, Kristen M Scheidter, Julia Monk, Forrest I Whiting, Nadeshka J Ramirez-Perez, Samuel R Krimmel, Athanasia Metoki, Rebecca F Schwarzlose, Steven E Petersen, Joan Luby, Benjamin P Kay, Evan M Gordon, Timothy O Laumann, Deanna M Barch, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Previous brain-wide association studies (BWAS) have linked specific environmental and behavioral variables to brain variability. In this work, we mapped 649 variables to children's brains and compared the resultant BWAS maps with each other and with neurobiological reference patterns. Socioeconomic status (SES) showed the strongest brain-wide associations. The SES associations were strongest in motor and sensory but not cognitive regions, a pattern shared across many BWAS maps, including intelligence quotient (IQ). A single, common BWAS brain pattern existed across variables that was most reflective of a child's socioeconomics. Adjusting for SES weakened brain-IQ associations, eliminating the BWAS motor and sensory …

Opposing Regulation By Rev1 Of Dna Polymerase Zeta Activity On Damaged Versus Undamaged Dna, Rachel Bezalel-Buch, Carrie Stith, Alena V Makarova, Sara K Binz, Peter M Burgers

2020-Current year OA Pubs

The Rev1 deoxycytidyl transferase functions as a scaffold protein for DNA polymerase ζ (Pol ζ)-mediated translesion synthesis (TLS). Biochemical studies with yeast enzymes indicate that Rev1 plays a dual regulatory role in TLS, stimulating Pol ζ activity at sites of damage but inhibiting its activity on undamaged DNA. An evolutionary conserved N-terminal alpha-helical motif (M1), located 10-20 amino acids upstream of Rev1's single BRCT domain, is required for the inhibitory activity of Rev1 on undamaged DNA. Mutations in the M1 motif result in a stimulation of Pol ζ replication activity on both undamaged and damaged DNA. Yeast cells carrying a …

Growth In Early Infancy Drives Optimal Brain Functional Connectivity Which Predicts Cognitive Flexibility In Later Childhood, Chiara Bulgarelli, Anna Blasi, Samantha Mccann, Bosiljka Milosavljevic, Giulia Ghillia, Ebrima Mbye, Ebou Touray, Tijan Fadera, Lena Acolatse, Sophie E Moore, Sarah Lloyd-Fox, Clare E Elwell, Adam T Eggebrecht, Bright Study Team

2020-Current year OA Pubs

Functional brain network organisation, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, for example undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onwards. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5-24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3-5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive …

Autoregulation Of Three Yeast Ribosomal Protein Genes By Splicing Inhibition, David Granas, Anirudh Kesanapally, Michael A White, Gary D Stormo

2020-Current year OA Pubs

Yeast ribosomal protein genes RPL18B, RPL28, and RPS22B are autoregulated by inhibition of splicing. This is demonstrated by inserting their introns into a chromosomal copy of GFP and observing repression upon induction of the cognate protein. In RPL18B and RPS22B, a predicted conserved secondary structure within the intron is required for regulation, while in RPL28, it is not.

Body Mass Index, Clinical Outcomes, And Mortality In Heart Failure: A Mendelian Randomization Study, Nicholas Sunderland, Douglas L Mann, Et Al.

2020-Current year OA Pubs

BACKGROUND: Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear.

OBJECTIVES: The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup.

METHODS: Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data …

Garlic-Derived Metabolite Activates Lkb1, Promotes Adipose Enampt Secretion, And Improves Age-Related Muscle Function Via Hypothalamic Signaling, Jun-Ichiro Suzuki, Kiyoshi Yoshioka, Masahiro Kurita, Takumi Sugimoto, Takahiro Eguchi, Naoki Ito, Aoi Kodama, Yasutomi Kamei, Masahiro Ohtani, Toshiaki Matsutomo, Shin-Ichiro Imai

2020-Current year OA Pubs

Garlic (Allium sativum L.) and its aged extract contain many bioactive compounds that can bring health benefits to humans. Among them, S-1-propenyl-L-cysteine (S1PC) has recently drawn significant attention in the field of nutriceutical research. However, the mechanism of its molecular action has remained poorly understood. Here, we show that S1PC significantly activates liver kinase B1 (LKB1) through enhancing its tertiary complex formation with STRAD and MO25, leading to stimulating the phosphorylation of a mammalian NAD

Wayfindr: Investigating Feedback In Biological Pathways, Polina Bombina, Reginald L Mcgee Ii, Jake Reed, Zachary B Abrams, Lynne V Abruzzo, Kevin R Coombes

2020-Current year OA Pubs

Understanding biological pathways requires more than static diagrams. We present WayFindR, an R package that converts pathway data from WikiPathways and KEGG into graph structures using igraph, enabling computational analysis of regulatory features such as negative feedback loops. Rooted in control theory, negative feedback is essential for system stability, yet it is often underrepresented in curated pathway data. In this study, we systematically analyzed pathway information from both databases across multiple species and found that feedback loops-particularly negative ones-are rarely captured. This gap likely reflects both biological and technical challenges. Biologically, feedback mechanisms are inherently complex and often remain uncharted …

Lingo4 Coordinates Ilc3-Intrinsic Il-22 Production And Microbiota-Mediated Ilc3 Homeostasis, José L Fachi, Tihana Trsan, Cristiane Sécca, Sarah De Oliveira, Vinícius R Rodovalho, Patrick Fernandes Rodrigues, Wandy L Beatty, Raki Sudan, Shitong Wu, Bishan Bhattarai, Santosh K Panda, Marina Cella, Susan Gilfillan, Marco Colonna

2020-Current year OA Pubs

LINGO4 is a leucine-rich repeat and immunoglobulin-like domain-containing transmembrane protein encoded immediately adjacent to Rorc, the gene for RORγt, raising the possibility that it contributes to the biology of RORγt+ lymphocytes. However, its impact on these cells and resistance to enteric infections has remained unknown. Here, we identify LINGO4 as a critical regulator of group 3 innate lymphoid cells (ILC3s). Lingo4-/- ILC3s exhibit a profound, cell-intrinsic defect in IL-22 production linked to impaired STAT3 activation, mitochondrial dysfunction, elevated ROS, and increased apoptosis. In vivo, Lingo4 deficiency also drives a dysbiotic gut microbiota, resulting in an additional, microbiota-dependent loss of ILC3s. …

Activation Of The Human Β3 Gabaa Receptor By Combinations Of Receptor Protonation With Chemical Agonists And Gain-Of-Function Mutations, Allison L Germann, Spencer R Pierce, Joe Henry Steinbach, Gustav Akk

2020-Current year OA Pubs

Native GABA

Human Stem Cell-Based Embryo Models: Innovation, Ethics, And Policy, Alfonso Martinez Arias, Thorold Theunissen, Et Al.

2020-Current year OA Pubs

The aim of this White Paper is to establish a foundational framework for research, technological development, and regulation in the emerging field of stem cell-based embryo models (SCBEMs). These models, generated from Pluripotent Stem Cells, are designed to recapitulate essential events in early stages of human development. They have the potential to illuminate the early stages of embryo development and implantation and hold promise as an avenue to address global health challenges, including infertility and pregnancy loss, congenital, neonatal and adult conditions, and the need for organ transplants. While SCBEMs are not a substitute for human embryos, their tractability for …

Noninvasive Enrichment Of Circulating Tumor Biomarkers In A Mouse Model Of Diffuse Midline Glioma Using Focused Ultrasound, Dingyue Zhang, Yimei Yue, Yan Gong, Leqi Yang, Kevin Xu, Jinyun Yuan, Hong Chen

2020-Current year OA Pubs

BACKGROUND: Diagnosing diffuse midline glioma (DMG) through invasive tissue biopsies is challenging due to the tumor's eloquent location at the pons. Liquid biopsies offer a promising noninvasive alternative; however, their limited detection sensitivity and lack of information on the source of biomarkers pose great challenges. This study aimed to evaluate the feasibility and safety of using focused ultrasound (FUS) with microbubbles to enrich circulating DMG tumor biomarkers in blood and cerebrospinal fluid (CSF) using a mouse model.

METHODS: Murine DMG cells, transfected with enhanced green fluorescent protein (EGFP) and firefly luciferase (Fluc) genes, were orthotopically injected into the mouse brain. …

Trastuzumab Deruxtecan In Hormone Receptor-Positive, Her2-Low/-Ultralow Metastatic Breast Cancer (Destiny-Breast06): Outcome Analyses By Time To Progression On Prior First-Line Endocrine Therapy With Cdk4/6 Inhibitor And Baseline Burden Of Disease, G Curigliano, N A Bagegni, Et Al.

2020-Current year OA Pubs

BACKGROUND: In DESTINY-Breast06, trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) versus physician's choice of chemotherapy (TPC) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low/-ultralow metastatic breast cancer (mBC), without new safety signals. We report additional analyses exploring outcomes for patients with characteristics that affect prognosis.

PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd (5.4 mg/kg) once every 3 weeks or TPC. Subgroups were specified post hoc from the intent-to-treat population (N = 866). Outcomes were PFS, objective response rate (ORR), and duration of response (DOR) by blinded independent central review …