Applications of Cell-Based Protein Array Technology to Preclinical Safety Assessment of Biological Products.

Off-target evaluation is essential in preclinical safety assessments of novel biotherapeutics, supporting lead molecule selection, endpoint selection in toxicology studies, and regulatory requirements for first-in-human trials. Off-target interaction of a therapeutic antibody and antibody derivatives has been historically assessed via the Tissue Cross-Reactivity (TCR) study, in which the candidate molecule is used as a reagent in immunohistochemistry (IHC) to assess binding of the candidate molecule to a panel of human tissue sections. The TCR approach is limited by the performance of the therapeutic as an IHC reagent, which is often suboptimal to outright infeasible.

Inpp5e Is Critical for Photoreceptor Outer Segment Maintenance.

In humans, inositol polyphosphate-5-phosphatase e (INPP5E) mutations cause retinal degeneration as part of Joubert and MORM syndromes and can also cause non-syndromic blindness. In mice, mutations cause a spectrum of brain, kidney, and other anomalies and prevent the formation of photoreceptor outer segments. To further explore the function of Inpp5e in photoreceptors, we generated conditional and inducible knockouts of mouse Inpp5e where the gene was deleted either during outer segment formation or after outer segments were fully formed.

Regio-Selective Mechanical Enhancement of Polymer-Grafted Nanoparticle Composites via Light-Mediated Crosslinking.

Polymer-brush-grafted nanoparticles (PGNPs) that can be covalently crosslinked post-processing enable the fabrication of mechanically robust and chemically stable polymer nanocomposites with high inorganic filler content. Modifying PGNP brushes to append UV-activated crosslinkers along the polymer chains would permit a modular crosslinking strategy applicable to a diverse range of nanocomposite compositions. Further, light-activated crosslinking reactions enable spatial control of crosslink density to program intentionally inhomogeneous mechanical responses.

A prospective study of diagnostic testing and hospital charges after brief resolved unexplained event.

Objectives: To evaluate diagnostic testing frequency/yield and determine drivers of hospital charges in a prospective cohort of infants with brief resolved unexplained event (BRUE) to test the hypothesis that length of stay (LOS), low-yield diagnostic testing, and repeat hospital visits increase costs.

Methods: We conducted a prospective cohort study of infants admitted after BRUE to determine how clinical practice impacts the cost of care. Charge data from our institution's billing records database included room and board, diagnostics, medications, and professional fees for index hospitalizations and 6-month follow-ups.

Durable suppression of seizures in a preclinical model of KCNT1 genetic epilepsy with divalent small interfering RNA.

Objective: Gain-of-function variants in the KCNT1 gene, which encodes a sodium-activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression of seizures in a genetic mouse model of KCNT1 epilepsy by reducing Kcnt1 transcript with divalent small interfering RNA (siRNA), an emerging variant of oligonucleotide technology developed for the central nervous system.

Parental Style, Grandchild Problematic Behaviors, and Parental Role Demands Among Grandparent Caregivers.

The present study evaluates the impact of grandchild distress on parental competence as mediated by Baumrind's parental styles in a sample of 238 custodial grandparents ( age = 58.06). AMOS structural equation findings yielded a model which indicated that both the Laissez-Faire and Authoritarian styles each predicted role stress and/or parental efficacy.

Extracting Housing and Food Insecurity Information From Clinical Notes Using cTAKES.

Objective: To assess the utility and challenges of using natural language processing (NLP) in electronic health records (EHRs) to ascertain health-related social needs (HRSNs) among older adults.

Study Setting And Design: We extracted HRSN information using the NLP system Clinical Text Analysis and Knowledge Extraction System (cTAKES), combined with Concept Unique Identifiers and Systematized Nomenclature for Medicine codes. We validated cTAKES performance, via manual chart review, on two HRSNs: food insecurity, which was included in the healthcare system's HRSN screening tool, and housing insecurity, which was not.

Couple-Based Intervention to Improve HIV Care Engagement for Women and their Partners in KwaZulu-Natal, South Africa: Outcomes of a Pilot Randomized Controlled Trial.

We evaluated a couple-based intervention targeting human immunodeficiency virus (HIV) care needs of women, with the option to support HIV-related needs of male partners. Adult women with HIV adherence difficulties in a monogamous relationship with a male partner for ≥6 months were recruited in KwaZulu-Natal, South Africa. Twenty couples were randomized (1:1) to either START Together, a five-session manualized behavioral intervention, or treatment as usual, adherence counseling referral.

Curvature Memory in Electrically Stimulated Lipid Membranes.

We demonstrate, using non-equilibrium molecular dynamics simulations, that lipid membrane capacitance varies with surface charge accumulation linked to membrane shape and curvature changes. Specifically, we show that lipid membranes exhibit a hysteretic response when exposed to oscillatory electric fields. The electromechanical coupling in these membranes leads to hysteretic buckling, in which the membrane can spontaneously buckle in one of two distinct directions along the electric field, even for the same ionic charge accumulation at the water-membrane interface.

Targeting CRM1 for Progeria Syndrome Therapy.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by progerin, a mutant variant of lamin A. Progerin anchors aberrantly to the nuclear envelope disrupting a plethora of cellular processes, which in turn elicits senescence. We previously showed that the chromosomal region maintenance 1 (CRM1)-driven nuclear export pathway is abnormally enhanced in patient-derived fibroblasts, due to overexpression of CRM1.

Insights into Chemical and Structural Order at Planar Defects in PbMgWO Using Multislice Electron Ptychography.

Switchable order parameters in ferroic materials are essential for functional electronic devices, yet disruptions of the ordering can take the form of planar boundaries or defects that exhibit distinct properties from the bulk, such as electrical (polar) or magnetic (spin) response. Characterizing the structure of these boundaries is challenging due to their confined size and three-dimensional (3D) nature. Here, a chemical antiphase boundary in the highly ordered double perovskite PbMgWO is investigated using multislice electron ptychography.

Design and Validation of a High-Fidelity Left Atrial Cardiac Simulator for the Study and Advancement of Left Atrial Appendage Occlusion.

Purpose: Atrial fibrillation (AF) is the most common chronic cardiac arrhythmia that increases the risk of stroke, primarily due to thrombus formation in the left atrial appendage (LAA). Left atrial appendage occlusion (LAAO) devices offer an alternative to oral anticoagulation for stroke prevention. However, the complex and variable anatomy of the LAA presents significant challenges to device design and deployment.

Rethinking the residual approach: leveraging statistical learning to operationalize cognitive resilience in Alzheimer's disease.

Cognitive resilience (CR) describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals.

Selective use of ferumoxytol-enhanced magnetic resonance angiography in patients with renal insufficiency: insights from a pilot study.

The use of conventional contrast agents in computed tomography (CT) and magnetic resonance (MR) imaging is often limited in patients with chronic kidney disease (CKD) due to potential nephrotoxicity. Ferumoxytol, originally developed for iron supplementation, has emerged as a promising alternative MR contrast agent that is safer for patients with CKD. This study aims to present our center's experience with ferumoxytol as a contrast agent in CKD patients.

A genome-wide atlas of human cell morphology.

A key challenge of the modern genomics era is developing empirical data-driven representations of gene function. Here we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-wide genotype-phenotype maps comprising CRISPR-Cas9-based knockouts of >20,000 genes in >30 million cells. Our optical pooled cell profiling platform (PERISCOPE) combines a destainable high-dimensional phenotyping panel (based on Cell Painting) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries.

Black-vs-white racial disparities in 30-day outcomes following primary and revisional metabolic and bariatric surgery: a MBSAQIP database analysis.

Background: Previous studies have demonstrated Black-vs-White disparities in postoperative outcomes following primary metabolic and bariatric surgery (MBS). With the rising prevalence of MBS, it is important to examine racial disparities using quality indicators in primary and revisional procedures. This study explores Black-vs-White disparities in postoperative outcomes following primary and revisional MBS.

International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma.

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies.

Integrating representation learning, permutation, and optimization to detect lineage-related gene expression patterns.

Recent barcoding technologies allow reconstructing lineage trees while capturing paired single-cell RNA-sequencing (scRNA-seq) data. Such datasets provide opportunities to compare gene expression memory maintenance through lineage branching and pinpoint critical genes in these processes. Here we develop Permutation, Optimization, and Representation learning based single Cell gene Expression and Lineage ANalysis (PORCELAN) to identify lineage-informative genes or subtrees where lineage and expression are tightly coupled.

Not Like They Used To: The Decline of Procedural Competency in Medical Training.

As a primary care pediatrician trained before work hour restrictions were enacted, I spent hours mastering procedures that trainees today rarely perform. The changing landscape of health care clinician roles, technology, and work hour restrictions have all contributed to a remarkable decline in trainees' procedural competence which has significant negative effects for patients, health care systems, and physicians themselves. I suggest simulation, live training, mentoring, and scheduled opportunities as ways to reemphasize the importance of learning these technical skills.

Intervention Stage Completion and Behavioral Health Outcomes: An Integrated Behavioral Health and Primary Care Randomized Pragmatic Trial.

Purpose: We performed a pragmatic, cluster randomized controlled trial of a comprehensive practice-level, multistage practice transformation intervention aiming to increase behavioral health integration in primary care practices and improve patient outcomes. We examined associations between completion of intervention stages and patient outcomes across a heterogeneous national sample of primary care practices.

Methods: Forty-two primary care practices across the United States with colocated behavioral health and 2,945 patients with multiple chronic medical and behavioral health conditions completed surveys at baseline, midpoint, and 2-year follow-up.

Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma.

Background: Programmed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired resistance to ICI. Poly ADP ribosyl polymerase 14 (PARP14), an IFNγ-responsive gene product, partially mediates IFNγ-driven resistance.

The influence of exposure to early-life adversity on agency-modulated reinforcement learning.

Agency beliefs influence how humans learn from different contexts and outcomes. Research demonstrates that stressors, such as exposure to early-life adversity (ELA), are associated with both agency beliefs and learning, but how these processes interact remains unclear. The current study investigated whether exposure to ELA influences agency and interacts with reinforcement learning in adults.

Recovery Time and Success: A Comparative Study of Robotic and Manual Total Hip Arthroplasty Outcomes.

Background: Despite the growing utilization of robotic-assisted total hip arthroplasty (rTHA), major debate remains regarding its comparative effectiveness in achieving optimal patient outcomes compared to manual total hip arthroplasty (mTHA). This study aimed to compare both the rate and time to achieve minimal clinically important difference (MCID) between rTHA and mTHA.

Methods: We conducted a retrospective analysis comparing 341 rTHAs with a 1:3 propensity score-matched cohort of 1,023 mTHAs performed from 2016 to 2022.