Medicine and Health Sciences Commons^™

Finding Significant Hits In Networks: A Network-Based Tool For Analyzing Gene-Level P-Values To Identify Significant Genes Missed By Standard Methods, Sandeep Acharya, Vaha Akbary Moghaddam, Wooseok J Jung, Yu S Kang, Shu Liao, Michael A Province, Michael R Brent

2020-Current year OA Pubs

Finding Significant Hits in Networks (FISHNET) uses prior biological knowledge, represented as gene interaction networks and gene function annotations, to identify genes that do not meet the genome-wide significance threshold but replicate, nonetheless. Its input is gene-level P-values from any source, including omicsWAS, aggregation of genome-wide association studies P-values, CRISPR screens, or differential expression analysis. It is based on the idea that genes whose P-values are low purely by chance are distributed randomly across networks and functions, so genes with suggestive P-values that cluster in densely connected subnetworks and share common functions are less likely to reflect chance and more …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Nathan O Stitziel, Et Al.

2020-Current year OA Pubs

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

Parkinson's Disease As A Somato-Cognitive Action Network Disorder, Jianxun Ren, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms

Intraocular Amyloidosis Presenting With Secondary Glaucoma: A Clinical-Pathologic Report And Literature Review, Joseph B Lin, James C Liu, Rajendra S Apte, George J Harocopos

2020-Current year OA Pubs

PURPOSE: We describe a case of intraocular amyloidosis presenting as secondary glaucoma, highlighting the clinical presentation and pathologic correlates. We also review the medical literature on all prior reported cases and discuss the diagnostic challenges pertinent to this particular case.

OBSERVATIONS: We report the case of a 72-year-old man presenting with medically intractable elevations of intraocular pressure. On clinical examination, the anterior segment was unremarkable, but there were significant vitreous opacities. The patient underwent tube shunt surgery, and a simultaneous aqueous humor biopsy was acellular and nondiagnostic. A subsequent pars plana vitrectomy demonstrated amyloid aggregates on histology. Mass spectrometric analysis …

Longitudinal Analysis Of Rotator Cuff Repair: Joint Kinematics And Clinical Outcomes, Sujata Khandare, Rebekah L Lawrence, Alena Jalics, Roger Zauel, Vasilios Moutzouros, Eric C Makhni, Stephanie Muh, Michael J Bey

2020-Current year OA Pubs

BACKGROUND: Rotator cuff repair is a common surgical procedure, but postoperative outcomes can be highly variable, and postoperative repair tissue healing remains a significant clinical challenge. Furthermore, the biomechanical effects of rotator cuff repair are not fully understood.

METHODS: Twenty-two participants scheduled for arthroscopic rotator cuff repair were evaluated preoperatively and at 3, 12, and 24 months postsurgery. The following data were recorded at each time point: glenohumeral and scapulothoracic kinematics, shoulder strength, and patient-reported measures of pain and function. Postoperative repair integrity was assessed via magnetic resonance imaging at 3 months and 24 months postsurgery.

RESULTS: At 3 months …

Piezo Mechanosensitivity In Chondrocytes Is Differentially Modulated By L-Type And T-Type Voltage-Sensitive Ion Channels, Alireza Savadipour, Gabrielle K Marushack, Robert J Nims, Jaquelin M Garcia-Castorena, Wolfgang Liedtke, Farshid Guilak

2020-Current year OA Pubs

OBJECTIVE: One of the primary factors contributing to OA development is altered or excessive mechanical stress on the joint, which chondrocytes sense in part through the PIEZO mechanosensitive ion channels. These channels activate signaling pathways that result in joint inflammation and cartilage degeneration. In addition to PIEZO channels, voltage-gated calcium (Ca

DESIGN: To better understand the relationship between PIEZO1 and VGCCs, we quantified porcine chondrocytes' intracellular Ca

RESULTS: In primary chondrocytes, nifedipine, an L-type VGCC blocker, reduced PIEZO1 sensitivity to both mechanical compression and pharmacological agonism, while NNC-55, a T-type VGCC blocker, increased PIEZO1 activation in response to both stimuli. …

Patient And Chondral Defect-Specific Characteristics And Associated Matrix-Induced Autologous Chondrocyte Implantation Conversion Rates Following Biopsy, Derrick M Knapik, Daniel C Touhey, S Ryan Pierson, Christopher K Bozorgmehr, Matthew V Smith, Matthew J Matava, Robert H Brophy

2020-Current year OA Pubs

BACKGROUND: Focal chondral defects in the knee lead to swelling, discomfort, and mechanical symptoms, resulting in disability and loss of function. Matrix-induced autologous chondrocyte implantation (MACI) has emerged as a viable treatment option, with satisfactory clinical outcomes reported compared with microfracture. Patient and lesion-specific variables associated with MACI after biopsy remain largely underreported.

PURPOSE: To examine patient- and defect-specific characteristics associated with conversion to MACI after biopsy from a single institution.

STUDY DESIGN: Cohort study; Level of evidence, 3.

METHODS: A retrospective chart review of prospectively collected data from June 2018 to March 2025 was performed. Inclusion criteria included patients …

Bach2 Regulates T Cell Lineage State To Enhance Car T Cell Function, Tien-Ching Chang, Amanda Heard, John Lattin, John M Warrington, Amanda Barrett, Jack H Landmann, Yangdon Tenzin, Vishaal Ganesh, Bryant Thompson, Sadia Afrin, Deepesh Kumar Gupta, Ju-Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, A J Federico, Avery Horn, Michael P Meers, John F Dipersio, Nathan Singh, Et Al.

2020-Current year OA Pubs

Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells …

Trajectories And Predictors Of Activity Participation Among People With Parkinson Disease: A 3-Year Longitudinal Study, Moon Young Kim, Yejin Lee, Carolyn M Baum, Lisa T Connor, Chih-Hung Chang, Linda Tickle-Degnen, Erin R Foster

2020-Current year OA Pubs

OBJECTIVE: To investigate how participation changes over time among individuals with Parkinsondisease (PD) and identify factors influencing these changes, focusing on impairment level and social factors.

DESIGN: Secondary analysis of a 3-year prospective cohort study of social self-management of PD. Data were collected during 4 in-person assessments conducted at baseline and then annually thereafter. Multilevel modeling was used to analyze data from the 4 time points.

SETTING: Department of Occupational Therapy Research Laboratory and Department of Neurology Movement Disorder Clinic.

PARTICIPANTS: A total of 86 individuals (N = 86) with idiopathic PD (Hoehn & Yahr stages I-IV; mean age ± …

Real-World Experience With Selexipag In Patients With Pulmonary Arterial Hypertension: Treatment Patterns And Outcomes Across Baseline Risk Strata (Sphere And Exposure Studies), Pilar Escribano Subias, Murali M Chakinala, Et Al.

2020-Current year OA Pubs

BACKGROUND: Treatment strategies for pulmonary arterial hypertension (PAH) depend on patients' 1-year mortality risk; however, real-world practices and outcomes remain inadequately described.

OBJECTIVE: We aimed to investigate real-world experience with selexipag, an oral selective prostacyclin I2 receptor agonist used to treat PAH.

METHODS: This analysis of two large, prospective, observational studies: SPHERE (NCT03278002; USA; completed) and EXPOSURE (EUPAS19085; Europe and Canada; ongoing, data cutoff November 2021) included adults newly initiating selexipag with follow-up available.

RESULTS: Of 1366 selexipag users, 894 met eligibility criteria. At selexipag initiation, the median (Q1-Q3) age was 61 (48-70) years and the time since diagnosis was …

Atypical Superotemporal Iris And Retinal Coloboma, Katina N Patterson, Margaret M Reynolds, Gregg T Lueder

2020-Current year OA Pubs

PURPOSE: To report our findings in a patient with an atypical case of supertemporal iris and retinal coloboma, and to assess its systemic associations and potential genetic causes.

OBSERVATIONS: A premature female infant born at 31 weeks gestation presented a left eye superotemporal coloboma affecting both the iris and retina. Systemic abnormalities included a left multicystic kidney, hypoplastic left kidney, atrial septal defect, ventricular septal defect, and mild pulmonary valve stenosis. Whole genome sequencing and mitochondrial deoxyribonucleic acid (DNA) sequencing were performed, and both returned negative results.

CONCLUSIONS AND IMPORTANCE: The absence of genetic findings from the negative results of …

Single Zonular Fiber Extraction And Characterization: A Platform For Biomechanical, Biochemical And Structural Analyses, Riley Forinash, Sean Staggs, Steven Bassnett, Juan Rodriguez

2020-Current year OA Pubs

Zonular fibers are essential for suspending the lens within the eye and, in primates, for transmitting forces generated by the ciliary body to drive ocular accommodation. Despite their biomechanical importance, the response of these fibers to sudden strains, and the molecular basis of their exceptional durability remain poorly understood. This is due, in part, to the absence of tools for studying them in isolation. Here, we present a custom-built, cost-effective apparatus designed to isolate, manipulate, and characterize individual zonular fibers under controlled physical and chemical conditions. The apparatus enables quantification of elastic moduli, stress-relaxation behavior, Poisson's ratio, and response to …

Recent Trends In The Utilization Of Molecular Breast Imaging In The United States, Ria Dave, Lin Gu, Heather V Garrett, Debbie Bennett, Dustin Stwalley, Sydney Singer, Sherwin Chiu, Michelle V Lee

2020-Current year OA Pubs

OBJECTIVE: The objective of this study was to assess trends in Molecular Breast Imaging (MBI) utilization among privately insured women in the United States (U.S.) from 2017 to 2022.

METHODS: The utilization of MBI among women aged 25-64 years from January 1, 2017, to December 31, 2022, was obtained using the Merative MarketScan Commercial Database. MBI utilization was captured from the outpatient services file using Current Procedural Terminology (CPT) or Healthcare Common Procedure Coding System (HCPCS) codes for MBI.

RESULTS: During the 6-year retrospective claims analysis, 3024 study-eligible women underwent 3648 MBI exams. The overall trend in MBI utilization was …

Emerging Options And Future Strategies In Immunotherapy For Advanced Lung Squamous-Cell Carcinoma, Y Wang, R Rosell, F R Hirsch, S Lu, R Govindan, K Park, S Peters, J J Zhang

2020-Current year OA Pubs

Advanced-stage lung squamous-cell carcinoma (LUSC) remains a therapeutic challenge. Although immune checkpoint inhibitors (ICIs) have revolutionized LUSC treatment, only a small subset of LUSC patients can achieve durable clinical benefits, underscoring the need for novel strategies. Emerging immunotherapy strategies have demonstrated early evidence of promise for LUSC patients, particularly multi-specific antibodies and fusion proteins, antibody-drug conjugates, adoptive cell therapies, and cancer vaccines. Additionally, advances in multi-omics and artificial intelligence offer potential for precise immunotherapy by deciphering the complex tumor-immune microenvironment and predicting therapeutic responses. The future of LUSC treatment lies in rational multi-target and biological therapies to boost immune cytotoxicity, …

Astrocyte-Specific Deletion Of Lrrc8a Causes Neurological Dysfunction But Not Chronic White Matter Edema, Sven Kerst, Leoni Hoogterp, Marjolein Breur, Gemma M Van Rooijen-Van Leeuwen, Marianna Bugiani, Rajan Sah, Huibert D Mansvelder, Marjo S Van Der Knaap, Rogier Min

2020-Current year OA Pubs

Volume-regulated anion channels (VRACs) are central to cell volume homeostasis. They mediate swelling-induced efflux of chloride and organic osmolytes to drive regulatory volume decrease. In the brain, VRACs have been proposed to play a key role in astrocytic volume regulation. Genetic defects in astrocytic VRAC modulating proteins (MLC1, GlialCAM, Aquaporin-4, GPRC5B) cause the leukodystrophy Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by chronic white matter edema and myelin vacuolization. Disrupted VRAC activity in MLC-patient-derived lymphoblasts and primary astrocytes from MLC mice further supports a pathogenic link between defective VRAC activity and MLC. Here, we studied the physiological and pathological consequences …

The Win Ratio For Evaluating Edoxaban Vs Dalteparin For Cancer-Associated Venous Thromboembolism: An Analysis Of The Randomized Hokusai Venous Thromboembolism Cancer Trial, Nick Van Es, Luuk J J Scheres, Kristen M Sanfilippo, Harry Büller, Marc Carrier, Marcello Di Nisio, Michael Grosso, Renato D Lopes, William F Mcintyre, Bjorn Redfors, Annelise Segers, Peter Verhamme, Jeffrey I Weitz, Patrick M Bossuyt, Deborah M Siegal

2020-Current year OA Pubs

BACKGROUND: The Hokusai Venous Thromboembolism (VTE) Cancer trial demonstrated that edoxaban was noninferior to dalteparin for the treatment of cancer-associated venous VTE.

OBJECTIVES: We reanalyzed the trial using the win ratio, an approach that evaluates a composite of outcomes in a hierarchical order.

METHODS: Forty-nine thrombosis experts ranked 10 outcomes in order of clinical importance from all-cause death (most important) to clinically relevant nonmajor bleeding (least important). We performed unmatched pairwise comparisons between participants on edoxaban and those on dalteparin at 6- and 12-month follow-up. Within each pair, edoxaban was assigned a win, loss, or tie according to the hierarchy …

Aging Reduces Motivation Through Decreased Bdnf Expression In The Ventral Tegmental Area, Hanyue Cecilia Lei, Kyle E Parker, Chao-Cheng Kuo, Carla M Yuede, Jordan G Mccall, Shin-Ichiro Imai

2020-Current year OA Pubs

Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown. Here, we used multiple mouse models to evaluate motivation and related affective states in young and old mice. We also compared the effect of social isolation, a common stressor in aged populations, to those of aging. We found that both social isolation and aging decreased motivation in mice, but that Bdnf expression in the ventral tegmental area (VTA) was selectively …

Accuracy And Reliability Of Artery-Vein Differentiation In Small-Field Macular Oct Angiography, Haneen Alfauri, Tugce Ilayda Turer, Cyriac Manjaly, Aditya Santoki, Senyue Hao, Marin Woronets, Chao Zhou, Rithwick Rajagopal

2020-Current year OA Pubs

PURPOSE: Accurate artery-vein (AV) differentiation in small-field macular optical coherence tomography angiography (OCTA) remains challenging due to a lack of standardized guidelines. We propose and validate criteria for

APPROACH: Small field-of-view (FOV) OCTA scans were analyzed using established AV criteria for large-field (

RESULTS: A total of 465 vessels from 20 healthy eyes were evaluated across 3 pseudo-branching orders using the criteria for OCTA. Annotators achieved high accuracy (95.1%, 92.3%) and strong intra/inter-rater reliability (

CONCLUSIONS: Accurate and reproducible AV labeling is feasible in

Cdk4/6 Inhibition Mitigates Chemotherapy-Induced Expansion Of Tp53-Mutant Clonal Hematopoiesis, Irenaeus C C Chan, Giulia Petrone, J Scott Beeler, Duc Tran, Griffen Mustion, Catrina Fronick, Carlos Cruchaga, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of …

Cholecalciferol (Vitamin D3) Is An Agonist Of The Alzheimer's Disease-Associated Immune Receptor Trem2, Hunter B Dean, Ryan A Tuckey, Rory A Greer, Jessica A Greven, Shan-Zhong Yang, Daniel S Elston, Gunnar N Eastep, Yuwei Song, Thomas J Brett, Yuhua Song, Erik D Roberson

2020-Current year OA Pubs

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at …

Mapping Charge Interactions In Intrinsically Disordered Proteins, Michael Phillips, Andrea Holla, Magdalena Wojtas, Aritra Chowdhury, Andrea Sottini, Sebastian L B König, Natalie Mutter, Nick Lamb, Jonathan Huihui, Monika Lopko, Andrea Soranno, Daniel Nettels, Andrzej Ożyhar, Benjamin Schuler, Kingshuk Ghosh

2020-Current year OA Pubs

Intrinsically disordered proteins (IDPs) are often rich in charged residues, and electrostatic interactions have a pronounced effect on their conformational distributions, interactions and functions. However, attaining quantitative understanding of electrostatics is challenging because of the sequence-specific arrangement of charges in the chain, the long-range nature of electrostatic interactions, charge screening, and the condensation of counterions-effects that all need to be taken into account self-consistently. Here, analytically tractable quantitative models are developed to predict ensemble average distances between any pair of residues in IDPs as a function of sequence and salt concentration, explicitly considering charge patterning. These models are tested systematically …

Durability Of Efficacy, Safety, And Quality Of Life 5 Years After Valoctocogene Roxaparvovec Gene Transfer For Severe Hemophilia A: Final Phase 3 Gener8-1 Trial Results, Andrew D Leavitt, Elaine Majerus, Et Al.

2020-Current year OA Pubs

BACKGROUND: Valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and confers bleed control.

OBJECTIVES: To present the final 5-year efficacy and safety results from the phase 3 GENEr8-1 trial.

METHODS: Adult men (

RESULTS: Median follow-up was 261.1 weeks; 128 of 134 participants completed the study. For the 112 participants who enrolled from a previous noninterventional study (rollover population), mean ABR for treated bleeds declined by 83.3% (

CONCLUSION: Valoctocogene roxaparvovec provides durable hemostatic efficacy, FVIII activity, and improved health-related quality of life for ≥5 years, with no new safety signals.

Comparing Ckd Populations With T1d And T2d: A Perspective Based On The Fine-One And Fidelity Populations, Hiddo J L Heerspink, Janet B Mcgill, Et Al.

2020-Current year OA Pubs

Chronic kidney disease (CKD) is a common comorbidity of both type 1 diabetes (T1D) and type 2 diabetes (T2D) and is associated with increased mortality, end-stage kidney disease and cardiovascular disease risk. Despite standard-of-care treatment with renin-angiotensin system inhibitors added to blood pressure and glycaemic control, people with CKD and T1D have a residual risk of CKD progression. Advances in therapeutic management have been limited over the past 3 decades, especially compared with CKD in T2D, for which new treatment options have emerged in the last 5 years. In this review article we discuss the similarities and differences between T1D …

What Constitutes Risk In Implementation Research? Perspectives From A Qualitative Key-Informant Study, Emmanuel K Tetteh, Gifty Aboagye-Mensah, Nwaliweaku Anidi, Elvin H Geng, Byron J Powell, Enola K Proctor, Mark D Huffman, Alison L Antes

2020-Current year OA Pubs

BACKGROUND: As implementation research increasingly occurs within routine care settings, determining what constitutes minimal risk is critical to ensuring that ethical oversight is appropriate and proportional. Current regulatory definitions often do not reflect the unique features of implementation studies, including implementation strategy-related risks and system-level effects. Yet, little empirical evidence exists on how researchers themselves interpret minimal risk in this context.

METHODS: We conducted semi-structured qualitative interviews with 11 key informants, including investigators with experience in domestic and global implementation research. Participants were recruited through purposive sampling. Interviews explored how participants interpret the concept of minimal risk, identify risk-related concerns, …

Recognizing Structural And Social Determinants Of Health In The Diagnosis And Care Of Dementia, Shana D Stites, Sharnita Midgett, Nisha Patel, Kimberly Halberstadter, Rosalie Schumann, Marissa L Streitz, Yidan Shi, John C Morris, Jason Flatt, Crystal M Glover, Dawn Mechanic-Hamilton

2020-Current year OA Pubs

Structural and social determinants of health are environmental conditions that affect individuals' health and functioning across the life course. These determinants are salient factors at the apex of individual psychology, community variables, and larger sociological factors, exerting prominent effects on individuals' wellbeing. The National Institute on Aging seeks to understand their influence on aging and Alzheimer's disease. We propose that the benefits of doing so may reach beyond knowledge of disease mechanisms - it may also improve clinical outcomes. We describe efforts introducing structural and social determinants of health data into the national network of Alzheimer's disease research centers. We …

Laser Interstitial Thermal Therapy And Adjuvant Pembrolizumab In Recurrent High-Grade Astrocytoma: A Phase 1/Randomized Phase 2b Trial, Jian L Campian, Omar H Butt, Yifei Xu, Jingxia Liu, William A Leidig, Tanner Johanns, George Ansstas, Alice Y Zhou, Sangami Pugazenthi, Jiayi Huang, Milan G Chheda, Albert H Kim, Eric C Leuthardt, Et Al.

2020-Current year OA Pubs

Immune checkpoint inhibitors (ICIs) show minimal efficacy in recurrent high-grade astrocytoma (rHGA). Laser interstitial thermal therapy (LITT), a minimally invasive cytoreductive approach, may prime rHGA for ICI response. A phase 1/randomized phase 2b trial (ClinicalTrials.gov: NCT02311582 ) was designed to test pembrolizumab in combination with LITT in patients with rHGA. Nine patients were enrolled in the phase I dose-escalation lead-in study. No dose-limiting toxicities were observed and 200 mg of pembrolizumab every three weeks was determined as the recommended phase 2 dose. The phase 2b study was initially designed to randomize (up to 45) patients 1:1 to either LITT followed …

Regional Brain Age Is Decreased In Children With Sickle Cell Anemia, Amy E Mirro, Landon C Power, Jinli Wang, Paula Germino-Watnick, Heather Roberts, Yonca Cam, Kristin P Guilliams, Slim Fellah, Yasheng Chen, Hongyu An, Jin-Moo Lee, Andria L Ford, Melanie E Fields

2020-Current year OA Pubs

DeepBrainNet, a machine learning tool, uses magnetic resonance imaging (MRI) to predict an individual's brain age, allowing calculation of the brain age gap (predicted chronological age) for use as a biomarker of brain health. We tested the DeepBrainNet tool in sickle cell anemia (SCA) on 210 brain MRIs from 130 children (90 with SCA; 40 healthy controls) to investigate the hypothesis that children with SCA would have a younger predicted brain age than healthy controls as an index of aberrant brain development. DeepBrainNet estimates brain age from 80 axial slices of each brain, with the median used as global brain …

Ketogenic Diet Dampens Excitatory Neurotransmission By Shrinking Synaptic Vesicle Pools, Marion I Stunault, Pan-Yue Deng, Anjali Yadav, Erica M Periandri, Francisca N De Luna Vitorino, Michael B Thomsen, Jasmin Sponagel, Amelia J Barfield, Renzelle J Ponce, Layla Foroughi, Benjamin A Garcia, Gabor Egervari, Vitaly A Klyachko, Ghazaleh Ashrafi

2020-Current year OA Pubs

Ketogenic diet (KD) is used for the treatment of drug-resistant childhood epilepsy and has been proposed to improve outcomes in neurodegenerative diseases. However, the mechanisms by which KD alters brain circuitry remain unclear. Here, we investigated the impact of KD on hippocampal function through integrative analysis of gene expression and neurotransmission. We found that KD induces extensive transcriptional reprogramming, including altered expression of numerous synaptic genes. Proteomic and genomic profiling revealed significant changes in histone modifications, particularly at promoters of KD-regulated genes. Electrophysiological recordings showed that KD reduces excitatory synaptic gain and short-term plasticity at CA3-CA1 synapses, dampening the summation …

Applying Frame-Is To Characterize Provider-Led Adaptations To A Cervical Cancer Prevention Intervention In Kenya, Harriet Fridah Adhiambo, Katherine Thomas, Megan M Coe, Lynda Oluoch, Valary Ihaji, Mary Bernadette Kerubo, Alex Kinyua, Sarah Njoroge, Kenneth Ngure, Michelle Shin, Thomas A Odeny, Bryan Weiner, Nelly Mugo, Sarah Gimbel

2020-Current year OA Pubs

BACKGROUND: Implementation strategies that are contextually refined are essential for optimizing the delivery of evidence-based interventions (EBI) to prevent cervical cancer in low-resource settings. This paper reports the application of the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS) to capture and disseminate strategy adaptations made to a single-visit, screen-and-treat approach with thermal ablation (SV-SAT + TA) strategy aimed at establishing sustainable cervical cancer prevention services in Kenya.

METHODS: A FRAME-IS-based tracking spreadsheet was developed to document bundled site-specific implementation strategy adaptations and across 10 facilities. Data was collected during technical assistants' (TAs) site visits, phone calls, …

Estimating The Baseline Age When Longitudinal Changes In Biomarkers Accelerate: Application To An Imaging Study Of Preclinical Alzheimer Disease, Chengjie Xiong, Folasade Agboola, Jingqin Luo

2020-Current year OA Pubs

BACKGROUND: Biomarkers are routinely measured from human biospecimens and imaging scans in Alzheimer disease (AD) research. Age is a well-known risk factor for AD. Detecting the baseline age at which the longitudinal change in biomarkers starts to accelerate is important to design preventive interventions. METHODS: We analyzed longitudinal biomarker data by a random intercept and random slope model where the slope (longitudinal rate of change) was modeled as a piecewise linear and continuous function of baseline age. We proposed to estimate the baseline age at the intersection of the two linear functions by multiple methods: maximum (profile) likelihood, minimum squared …