Conjugation Chemistry Markedly Impacts Toxicity and Biodistribution of Targeted Nanoparticles, Mediated by Complement Activation.

Conjugation chemistries are a major enabling technology for the development of drug delivery systems, from antibody-drug conjugates to antibody-targeted lipid nanoparticles inspired by the success of the COVID-19 vaccine. However, here it is shown that for antibody-targeted nanoparticles, the most popular conjugation chemistries directly participate in the activation of the complement cascade of plasma proteins. Their activation of complement leads to large changes in the biodistribution of nanoparticles (up to 140-fold increased uptake into phagocytes of the lungs) and multiple toxicities, including a 50% drop in platelet count.

Lysine 473 Regulates the Progression of SLC7A11, the Cystine/Glutamate Exchanger, through the Secretory Pathway.

System x, the cystine/glutamate exchanger, is a membrane transporter that plays a critical role in the antioxidant response of cells. Recent work has shown that System x localizes to the plasma membrane during oxidative stress, allowing for increased activity to support the production of glutathione. In this study, we used site-directed mutagenesis to examine the role of C-terminal lysine residues (K422, K472, and K473) of xCT (SLC7A11) in regulating System x.

Nanocarriers' repartitioning of drugs between blood subcompartments as a mechanism of improving pharmacokinetics, safety, and efficacy.

For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers.

Enabling non-viral DNA delivery using lipid nanoparticles co-loaded with endogenous anti-inflammatory lipids.

Lipid nanoparticles (LNPs) have transformed genetic medicine, recently shown by their use in COVID-19 mRNA vaccines. While loading LNPs with mRNA has many uses, loading DNA would provide additional advantages such as long-term expression and availability of promoter sequences. However, here we show that plasmid DNA (pDNA) delivery via LNPs (pDNA-LNPs) induces acute inflammation in naïve mice which we find is primarily driven by the cGAS-STING pathway.

Targeting of nanoparticles to the cerebral vasculature after traumatic brain injury.

Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs to the brain. However, there is a potential solution in targeted drug delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following a TBI, the blood-brain barrier (BBB) becomes permeable, which can last for years and allow the leakage of harmful plasma proteins.

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions.

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down-regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by physicochemical targeting in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. Here lung-tropic LNPs are examined, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential.

Trends in price for topical corticosteroids from 2017 to 2021 and the opportunity for cost savings identifiable at the point of care: A retrospective cross-sectional study.

Background: Topical corticosteroids possess numerous generics and similar-strength substitutes. Affordability can impact obtaining the medication prescribed.

Objective: To determine recent trends in topical corticosteroid pricing and potential for cost saving.

Automated measurement of distance-walked as a "sixth vital sign" for detecting infusion reactions during preclinical testing.

Infusion reactions are a major risk for advanced therapeutics (e.g., engineered proteins nanoparticles, etc.

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up- or down-regulate any protein of interest. LNPs have been targeted to specific cell types or organs by physicochemical targeting, in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. In a popular approach, physicochemical targeting is accomplished by formulating with charged lipids.

Elastofibroma Dorsi: Case Series of a Rare Chest Wall Pseudotumor.

Background: Elastofibroma dorsi (EFD) is a pseudotumor of the thoracic wall that can be difficult to diagnose due to its rarity. Prompt recognition can limit unnecessary workup and expedite treatment. This study retrospectively analyzed patients with a diagnosis of EFD, discussing clinical presentations and surgical outcomes.

The contribution of anthropology to the study of Open Dialogue: ethnographic research methods and opportunities.

When Open Dialogue diversifies internationally as an approach to mental healthcare, so too do the research methodologies used to describe, explain and evaluate this alternative to existing psychiatric services. This article considers the contribution of anthropology and its core method of ethnography among these approaches. It reviews the methodological opportunities in mental health research opened up by anthropology, and specifically the detailed knowledge about clinical processes and institutional contexts.

The double-edged sword of 'community' in community-based psychosocial care: reflections on task-shifting in rural Nepal.

Research in the field of Global Mental Health has stoked hopes that 'task-shifting' to community workers can help fill treatment gaps in low-resource settings. The fact that community workers inhabit the same local moral worlds as their clients is widely framed as a boon, with little consideration of the social and ethical dilemmas this might create in the care of chronic, stigmatized conditions. Drawing on 14 months of ethnographic research focused on psychosocial interventions in Nepal, this paper traces how the multiple roles community workers occupied with respect to their clients - clinician, neighbour, and at times kin - came to bear on the care they provided.

Balancing dairy cattle diets for rumen nitrogen and methionine or all essential amino acids relative to metabolizable energy.

Improving the ability of diet formulation models to more accurately predict AA supply while appropriately describing requirements for lactating dairy cattle provides an opportunity to improve animal productivity, reduce feed costs, and reduce N intake. The goal of this study was to evaluate the sensitivity of a new version of the Cornell Net Carbohydrate and Protein System (CNCPS) to formulate diets for rumen N, Met, and all essential AA (EAA). Sixty-four high-producing dairy cattle were randomly assigned to 1 of the 4 following diets in a 14-wk longitudinal study: (1) limited metabolizable protein (MP), Met, and rumen N (Base), (2) adequate Met but limited MP and rumen N (Base + M), (3) adequate Met and rumen N, but limited MP (Base + MU), and (4) adequate MP, rumen N, and balanced for all EAA (Positive).

A Pilot Study of Intralesional Injection of Triamcinolone Acetonide for Desmoid Tumors: Two-Year Outcomes.

Purpose: The purpose of this pilot study was to examine the clinical efficacy and safety of serial triamcinolone injections for the treatment of desmoid tumors.

Patients And Methods: Nine patients were enrolled into this prospective study and underwent three serial ultrasound-guided triamcinolone injections (120 mg) at 6-week intervals. MRI was compared at baseline and every 6 months, out to 24 months.

A retrospective case series of prophylactic neurectomy during total knee arthroplasty.

Introduction: Total knee arthroplasty is a common operation performed to relieve pain and restore functional activity. While overall widely successful, a subset of patients has continued pain postoperatively with no identifiable cause. Neuroma formation has been identified as a possible contributor to this unexplained pain, often necessitating an additional procedure for neuroma removal.

Community health workers and health equity in low- and middle-income countries: systematic review and recommendations for policy and practice.

Background: The deployment of Community Health Workers (CHWs) is widely promoted as a strategy for reducing health inequities in low- and middle-income countries (LMIC). Yet there is limited evidence on whether and how CHW programmes achieve this. This systematic review aimed to synthesise research findings on the following questions: (1) How effective are CHW interventions at reaching the most disadvantaged groups in LMIC contexts? and (2) What evidence exists on whether and how these programmes reduce health inequities in the populations they serve?

Methods: We searched six academic databases for recent (2014-2020) studies reporting on CHW programme access, utilisation, quality, and effects on health outcomes/behaviours in relation to potential stratifiers of health opportunities and outcomes (e.

Development of novel home-based tampon sampling for endometrial cancer: findings from community-based focus groups with Black and White women.

Novel endometrial cancer (EC) early-detection approaches may reduce racial disparities in mortality. We conducted six community-based focus groups with White and Black women ( = 57 participants) in February-March 2020 to explore acceptability of a home-based tampon sampling approach for EC. Participants also completed a survey.

Correcting the Fundamentals of Laparoscopic Surgery "Illusion of Validity" in Laparoscopic Vaginal Cuff Suturing.

Study Objective: The "illusion of validity" is a cognitive bias in which the ability to interpret and predict surgical performance accurately is overestimated. To address this bias, we assessed participants comparing fundamentals of laparoscopic surgery (FLS) and non-FLS tasks with cadaveric vaginal cuff suturing to determine the most representative simulation task for laparoscopic vaginal cuff suturing.

Design: Validity (Messick framework) study comparing FLS and non-FLS tasks with cadaveric vaginal cuff suturing.

Integrating Research into the Undergraduate Curriculum: 3. Research Training in the Upper-level Neuroscience Curriculum.

The benefits of undergraduate training in research are significant. Integration of such training into the undergraduate experience, however, can be challenging at institutions without extensive research programs, and may inadvertently exclude some populations of students. Therefore, inclusion of research into the academic curriculum ensures all students can access this important training.

Integrating Research into the Undergraduate Curriculum: 2. Scaffolding Research Skills and Transitioning toward Independent Research.

Undergraduate research experiences are widely regarded as high-impact practices that foster meaningful mentoring relationships, enhance retention and graduation, and stimulate postbaccalaureate enrollment in STEM graduate and professional programs. Through immersion in a mentored original research project, student develop and apply their skills in critical thinking, problem solving, intellectual independence, communication, collaboration, project ownership, innovation, and leadership. These skills are readily transferable to a wide array of future careers in and beyond STEM that are well-served by evidence-based approaches.

Integrating Research into the Undergraduate Curriculum: 1. Early Research Experiences and Training.

Undergraduate research experiences have emerged as some of the most beneficial high-impact practices in education, providing clear benefits to students that include improved critical thinking and scientific reasoning, increased academic performance, and enhanced retention both within STEM majors and in college overall. These benefits extend to faculty members as well. Several disciplines, including neuroscience, have implemented research as part of their curriculum, yet many research opportunities target late stage undergraduates, despite evidence that early engagement can maximize the beneficial nature of such work.