Nonviral Approaches for Neuronal Delivery of Nucleic Acids

The delivery of therapeutic nucleic acids to neurons has the potential to treat neurological disease and spinal cord injury. While select viral vectors have shown promise as gene carriers to neurons, their potential as therapeutic agents is limited by their toxicity and immunogenicity, their broad tropism, and the cost of large-scale formulation. Nonviral vectors are an attractive alternative in that they offer improved safety profiles compared to viruses, are less expensive to produce, and can be targeted to specific neuronal subpopulations. However, most nonviral vectors suffer from significantly lower transfection efficiencies than neurotropic viruses, severely limiting their utility in neuron-targeted delivery applications. To realize the potential of nonviral delivery technology in neurons, vectors must be designed to overcome a series of extra- and intracellular barriers. In this article, we describe the challenges preventing successful nonviral delivery of nucleic acids to neurons and review strategies aimed at overcoming these challenges

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Using GIS fuzzy-set modelling to integrate social-ecological data to support overall resilience in marine protected area spatial planning: A case study

Marine Protected Areas (MPAs) are useful conservation tools for balancing the complex social-ecological interactions and demands within a given marine area. Often designing, reviewing, and assessing existing MPAs can be a complicated task often based on patchy ecological data, biases towards certain stakeholder groups, and static snapshots of current information. Taking a social-ecological resilience approach, this study has developed an innovative way of using fuzzy-set multi-criteria evaluations in GIS modelling to integrate existing ecological data for a marine area with information from a diverse set of stakeholders to gain an understanding of the overlaps between social and ecological assets within an MPA. Adaptive management frameworks were considered by exploring stakeholder feedback in regards to the current spatial plan and using a social-ecological spatially informed Bayesian Belief Network (BBN) analysis to create a current snapshot of the MPA’s vulnerability. The BBN was then used to predict how climate change may affect sensitive habitats and demonstrates the increase of vulnerability for both habitats and marine species when allowing fishing pressure to occur across the entire MPA. A series of decision-making maps were created that integrated all of this information. Using this current and predicted social-ecological spatial information about an MPA, can assist decision-makers and the local community by giving them the tools to make informed decisions about how to better design an MPA that meets and supports long-term social-ecological resilience.Thank you to the Lesslie Research Scholarship in Landscape Conservation and Ecology grant, the Fenner School of Environment and Society, Australian National University, and the Australian Government Research Training Program Scholarship for funding this research project

Linking the social to the ecological using GIS methods in marine spatial planning and management to support resilience: A review

Marine spatial planning (MSP) has been put forward as a way to more comprehensively manage marine environments by balancing human demands and protecting areas that support ecosystem function. Given the recent motivations for countries to adopt large-scale marine spatial planning approaches, ensuring these plans are grounded in social-ecological resilience theories is essential for long-term success. Drawing upon recent academic attention from a range of disciplinary areas, this review explores current practices and applied examples of published case studies from around the world that have integrated social and ecological spatial information using GIS techniques. This review intended to use these case studies to guide directions of future MSP research that considers social-ecological resilience theories. Five overall themes were uncovered. First, extractive uses, such as fisheries, were often given priority in MSP processes, which even though important, may undermine the social resilience of coastal communities by not supporting the diversity of non-extractive economies. Second, the quality of ecological spatial data used in the studies varied greatly, often with little consideration of how ongoing human demands may influence long-term ecological resilience. Thrid, many GIS techniques were used to integrate social and ecological data including: descriptive maps, site prioritisation techniques, and predictive modelling. Lastly, only a small number of studies considered cross-ecosystem influences and only two incorporated potential climate change impacts on social institutions and marine ecosystems. Overall, there is a need for progressing GIS predictive modelling techniques to assess and link the responses of social and ecological systems to MSP solutions in order to support long-term social-ecological resilience.This work was supported by the Lesslie Endowment, Lesslie Research Scholarship in Landscape Conservation and Ecology grant; the Fenner School of Environment and Society at the Australian National University, PhD Reserach Allocation; and the Australian Department of Education, Government Research Training Program Scholarshi

Understanding the spatial diversity of social uses, dynamics, and conflicts in marine spatial planning

Marine coastal environments are often socially complex public areas that need equitable spatial planning approaches. Understanding the extent of extractive and non-extractive uses and the social dynamics that may be driving patterns of use is essential if the spatial plan is to support the social resilience of a marine area. In this study, a combination of fuzzy-set multi-criteria GIS modelling and negative tie social network analysis were used to explore social uses and conflicts based on sketch-mapping interviews with five key stakeholder groups (ecotourism, Aboriginal Traditional Owners, commercial and recreational fishing, and water sports) within a Marine Protected Area (MPA). Most of the areas within the MPA were regularly used by the stakeholders, with non-extractive and extractive stakeholders occupying similar spatial extents, with each stakeholder group having a different pattern of use. However, stakeholder groups had different levels of perceived priority to access these areas and support of the current spatial management plan, especially within the ecotourism and Aboriginal Traditional Owner groups. The investigation of social conflicts in shaping patterns of use revealed that most stakeholder conflicts do not necessarily occur in areas of overlaps, but generally in areas of high biodiversity and easy access through marine infrastructure. Ecotourism groups had the most perceived conflicts over marine space, which shaped their use towards certain no-take zones that protected high biodiversity and would also provide protection from other conflicting stakeholder uses (e.g., boating, fishing). Overall, the method outlined in this paper presents a way for marine spatial management to consider not only the extent and diversity of social uses in a marine environment but also the spatial-social dynamics that may determine the success of the spatial plan in supporting long-term social resilience.Thank you to the Lesslie Research Scholarship in Landscape Conservation and Ecology grant, the Fenner School of Environment and Society at the Australian National University, and the Australian Government Research Training Program Scholarship for funding this research project

OBSERVATION OF LOW J TRANSITIONS OF LASER ABLATED ALKALI HALIDES

Author Institution: Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455; Institut fur Physikalische Chemie und Elektrochemie, Gottfried-Wilhelm-Leibniz-Universitat Hannover, Callinstrasse 3A, 30167 Hannover, GermanyPulsed nozzle Fourier transform microwave spectroscopy has been used to observe low J transitions (J = 1 $\leftarrow$ 0 and J = 2 $\leftarrow$ 1) of several alkali halides produced by 532 nm laser ablation of pressed pellets. Spectra were readily located using predictions based on literature constants derived from higher J transitions but improvements of 10 to 100 kHz in spectral line positions are obtained. The additional accuracy could prove useful for astrophysical identification. The $^{41}$K isotopologue of KBr has been observed for the first time. Ablation of a mixed pellet of KCl and NaBr produces spectra of NaCl, indicating exchange between species produced by the ablation event. Aspects of the new experimental apparatus will be reported

Acute high-intensity interval running increases markers of gastrointestinal damage and permeability but not gastrointestinal symptoms

Purpose To investigate the effects of high-intensity interval (HIIT) running on markers of gastrointestinal (GI) damage and permeability alongside subjective symptoms of GI discomfort. Methods Eleven male runners completed an acute bout of HIIT (eighteen 400 m runs at 120% VO2max ) where markers of GI permeability, intestinal damage and GI discomfort symptoms were assessed and compared with resting conditions. Results Compared to rest, HIIT significantly increased serum lactulose:rhamnose ratio (0.051 ± 0.016 vs. 0.031 ± 0.021, p = 0.0047; 95% CI = 0.006 - 0.036) and sucrose concentrations (0.388 ± 0.217 vs 0.137 ± 0.148 mg.l-1; pThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author