siRNA Delivery to the Glomerular Mesangium Using Polycationic Cyclodextrin Nanoparticles Containing siRNA

There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs

The cost of a single concussion in American high school football: A retrospective cohort study

Aim: The potential financial burden of American football-related concussions (FRC) is unknown. Our objective was to describe the healthcare costs associated with an FRC and determine factors associated with increased costs. Methodology/results: A retrospective cohort study of concussed high school football players presenting between November 2017 and March 2020 was undertaken; 144 male high school football players were included. Total costs were about $115,000, for an average direct healthcare cost of$800.10/concussion. Visiting the emergency department (β = 502.29, 95% CI: 105.79-898.61; p = 0.01), the initial post-concussion symptom scale score (β = 0.39, 95% CI: 0.11-0.66; p = 0.01) and a post-concussion syndrome diagnosis (β = 670.37, 95% CI: 98.96-1241.79; p = 0.02) were each independently associated with total costs. Conclusion: A granular understanding of cost-driving factors associated with FRC is the first step in understanding the cost-effectiveness of prevention and treatment methods

Hospital characteristics associated with highly automated and usable clinical information systems in Texas, United States

<p>Abstract</p> <p>Background</p> <p>A hospital's clinical information system may require a specific environment in which to flourish. This environment is not yet well defined. We examined whether specific hospital characteristics are associated with highly automated and usable clinical information systems.</p> <p>Methods</p> <p>This was a cross-sectional survey of 125 urban hospitals in Texas, United States using the Clinical Information Technology Assessment Tool (CITAT), which measures a hospital's level of automation based on physician interactions with the information system. Physician responses were used to calculate a series of CITAT scores: automation and usability scores, four automation sub-domain scores, and an overall clinical information technology (CIT) score. A multivariable regression analysis was used to examine the relation between hospital characteristics and CITAT scores.</p> <p>Results</p> <p>We received a sufficient number of physician responses at 69 hospitals (55% response rate). Teaching hospitals, hospitals with higher IT operating expenses (>$1 million annually), IT capital expenses (>$75,000 annually) and hospitals with larger IT staff (≥ 10 full-time staff) had higher automation scores than hospitals that did not meet these criteria (p < 0.05 in all cases). These findings held after adjustment for bed size, total margin, and ownership (p < 0.05 in all cases). There were few significant associations between the hospital characteristics tested in this study and usability scores.</p> <p>Conclusion</p> <p>Academic affiliation and larger IT operating, capital, and staff budgets are associated with more highly automated clinical information systems.</p

Kcl Test:an open-source inspired asymptomatic SARS-CoV-2 surveillance programme in an academic institution

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings. Between December 2020 and July 2022, we performed 158277 PCRs for our staff, students, and their household contacts, free of charge. Our average turnaround time was 16 h and 37 min from user registration to result delivery. KCL TEST combined open-source automation and in-house non-commercial reagents, which allows for rapid implementation and repurposing. Importantly, our data parallel those of the UK Office for National Statistics, though we detected a lower positive rate and virtually no delta wave. Our observations strongly support regular asymptomatic community testing as an important measure for decreasing outbreaks and providing safe working spaces. Universities can therefore provide agile, resilient, and accurate testing that reflects the infection rate and trend of the general population. Our findings call for the early integration of academic institutions in pandemic preparedness, with capabilities to rapidly deploy highly skilled staff, as well as develop, test, and accommodate efficient low-cost pipelines.</p

The role of pulmonary arterial stiffness in COPD

AbstractCOPD is the second most common cause of pulmonary hypertension, and is a common complication of severe COPD with significant implications for both quality of life and mortality. However, the use of a rigid diagnostic threshold of a mean pulmonary arterial pressure (mPAP) of ≥25mHg when considering the impact of the pulmonary vasculature on symptoms and disease is misleading. Even minimal exertion causes oxygen desaturation and elevations in mPAP, with right ventricular hypertrophy and dilatation present in patients with mild to moderate COPD with pressures below the threshold for diagnosis of pulmonary hypertension. This has significant implications, with right ventricular dysfunction associated with poorer exercise capability and increased mortality independent of pulmonary function tests.The compliance of the pulmonary artery (PA) is a key component in decoupling the right ventricle from the pulmonary bed, allowing the right ventricle to work at maximum efficiency and protecting the microcirculation from large pressure gradients. PA stiffness increases with the severity of COPD, and correlates well with the presence of exercise induced pulmonary hypertension. A curvilinear relationship exists between PA distensibility and mPAP and pulmonary vascular resistance (PVR) with marked loss of distensibility before a rapid rise in mPAP and PVR occurs with resultant right ventricular failure. This combination of features suggests PA stiffness as a promising biomarker for early detection of pulmonary vascular disease, and to play a role in right ventricular failure in COPD. Early detection would open this up as a potential therapeutic target before end stage arterial remodelling occurs

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Building a Better "Cadillac"

The excise tax on premiums paid for high-cost employer-sponsored plans, also known as the Cadillac tax, is an important provision of the Affordable Care Act (ACA) and should be retained even if the larger law is repealed because it will not only help control the growth of health care spending but also will provide revenues needed to pay for any potential ACA replacement, according to a new paper (PDF) by experts at the Urban Institute and the Center for Health Policy at Brookings. However, the tax should be improved to increase political acceptability and to correct genuine shortcomings in the current law

Sport-Related Concussion: Evaluation, Treatment, and Future Directions

Sport-related concussion (SRC) is a highly prevalent injury predominantly affecting millions of youth through high school athletes every year. In recent years, SRC has received a significant amount of attention due to potential for long-term neurologic sequelae. However, the acute symptoms and possibility of prolonged recovery account for the vast majority of morbidity from SRC. Modifying factors have been identified and may allow for improved prediction of a protracted course. Potential novel modifying factors may include genetic determinants of recovery, as well as radiographic biomarkers, which represent burgeoning subfields in SRC research. Helmet design and understanding the biomechanical stressors on the brain that lead to concussion also represent active areas of research. This narrative review provides a general synopsis of SRC, including relevant definitions, current treatment paradigms, and modifying factors for recovery, in addition to novel areas of research and future directions for SRC research