The implementation of embedded researchers in policy, public services, and commercial settings: a systematic evidence and gap map.

BACKGROUND: Embedding researchers into policy and other settings may enhance research capacity within organisations to enable them to become more research active. We aimed to generate an evidence map on evaluations of embedded researcher interventions to (i) identify where systematic reviews and primary research are needed and (ii) develop conceptual understandings of 'embedded researchers'. We define 'embedded researchers' through a set of principles that incorporate elements such as the aim of activities, the types of relationships and learning involved, and the affiliations and identities adopted. METHODS: We included studies published across all sectors, searching fourteen databases, other web sources and two journals for evaluations published between 1991 and spring 2021. Data were extracted using a coding tool developed for this study. We identified new typologies of embedded researcher interventions through undertaking Latent Class Analysis. RESULTS: The map describes 229 evaluations spanning a variety of contexts. Our set of principles allowed us to move beyond a narrow focus on embedded researchers in name alone, towards consideration of the wide range of roles, activities, identities, and affiliations related to embedded researchers. We identified 108 different allied terms describing an embedded researcher. Embedded researcher activity spanned a continuum across lines of physical, cultural, institutional, and procedural embeddedness (from weaker to more intense forms of embeddedness) and took a range of forms that bridge or blur boundaries between academia and policy/practice. CONCLUSIONS: We developed a broad map of international embedded researcher activity in a wide range of sectors. The map suggests that embedded researcher interventions occupy a broader suite of models than previously acknowledged and our findings also offer insight on the type and nature of this literature. Given the clear policy interest in this area, a better understanding of the processes involved with becoming embedded within an organisation is needed. Further work is also necessary to address the challenges of evaluating the work of embedded researchers, including consideration for which outcome measures are most appropriate, to better understand their influence.

Understanding structure activity relationships of Good HEPES lipids for lipid nanoparticle mRNA vaccine applications.

Lipid nanoparticles (LNPs) have shown great promise as delivery vehicles to transport messenger ribonucleic acid (mRNA) into cells and act as vaccines for infectious diseases including COVID-19 and influenza. The ionizable lipid incorporated within the LNP is known to be one of the main driving factors for potency and tolerability. Herein, we describe a novel family of ionizable lipids synthesized with a piperazine core derived from the HEPES Good buffer. These ionizable lipids have unique asymmetric tails and two dissimilar degradable moieties incorporated within the structure. Lipids tails of varying lengths, degrees of unsaturation, branching, and the inclusion of additional ester moieties were evaluated for protein expression. We observed several key lipid structure activity relationships that correlated with improved protein production in vivo, including lipid tails of 12 carbons on the ester side and the effect of carbon spacing on the disulfide arm of the lipids. Differences in LNP physical characteristics were observed for lipids containing an extra ester moiety. The LNP structure and lipid bilayer packing, visualized through Cryo-TEM, affected the amount of protein produced in vivo. In non-human primates, the Good HEPES LNPs formulated with an mRNA encoding an influenza hemagglutinin (HA) antigen successfully generated functional HA inhibition (HAI) antibody titers comparable to the industry standards MC3 and SM-102 LNPs, demonstrating their promise as a potential vaccine.

Pan-SARS neutralizing responses after third boost vaccination in non-human primate immunogenicity model.

The emergence of SARS-CoV-2 variants, especially Beta and Delta, has raised concerns about the reduced protection from previous infection or vaccination based on the original Wuhan-Hu-1 (D614) virus. To identify promising regimens for inducing neutralizing titers towards new variants, we evaluated monovalent and bivalent mRNA vaccines either as primary vaccination or as a booster in nonhuman primates (NHPs). Two mRNA vaccines, D614-based MRT5500 and Beta-based MRT5500ß, tested in sequential regimens or as a bivalent combination in naïve NHPs produced modest neutralizing titers to heterologous variants. However, when mRNA vaccines were administered as a booster to pre-immune NHPs, we observed a robust increase in neutralizing titers with expanded breadth towards all tested variants, and notably SARS-CoV-1. The breadth of the neutralizing response was independent of vaccine sequence or modality, as we further showed either MRT5500 or recombinant subunit Spike protein (with adjuvant) can serve as boosters to induce broadly neutralizing antibodies in the NHPs primed with MRT5500. The data support the notion that a third vaccination is key to boosting existing titers and improving the breadth of antibodies to address variants of concern, including those with an E484K mutation in the Receptor Binding Domain (RBD) (Beta, Gamma).

Field evidence that ecosystem service projects support biodiversity and diversify options.

Ecosystem service approaches to conservation are being championed as a new strategy for conservation, under the hypothesis that they will broaden and deepen support for biodiversity protection. Where traditional approaches focus on setting aside land by purchasing property rights, ecosystem service approaches aim to engage a much wider range of places, people, policies, and financial resources in conservation. This is particularly important given projected intensification of human impacts, with rapid growth in population size and individual aspirations. Here we use field research on 34 ecosystem service (ES) projects and 26 traditional biodiversity (BD) projects from the Western Hemisphere to test whether ecosystem service approaches show signs of realizing their putative potential. We find that the ES projects attract on average more than four times as much funding through greater corporate sponsorship and use of a wider variety of finance tools than BD projects. ES projects are also more likely to encompass working landscapes and the people in them. We also show that, despite previous concern, ES projects not only expand opportunities for conservation, but they are no less likely than BD projects to include or create protected areas. Moreover, they do not draw down limited financial resources for conservation but rather engage a more diverse set of funders. We also found, however, that monitoring of conservation outcomes in both cases is so infrequent that it is impossible to assess the effectiveness of either ES or BD approaches.

Development of multivalent mRNA vaccine candidates for seasonal or pandemic influenza.

Recent approval of mRNA vaccines for emergency use against COVID-19 is likely to promote rapid development of mRNA-based vaccines targeting a wide range of infectious diseases. Compared to conventional approaches, this vaccine modality promises comparable potency while substantially accelerating the pace of development and deployment of vaccine doses. Already demonstrated successfully for single antigen vaccines such as for COVID-19, this technology could be optimized for complex multi-antigen vaccines. Herein, utilizing multiple influenza antigens, we demonstrated the suitability of the mRNA therapeutic (MRT) platform for such applications. Seasonal influenza vaccines have three or four hemagglutinin (HA) antigens of different viral subtypes. In addition, influenza neuraminidase (NA), a tetrameric membrane protein, is identified as an antigen that has been linked to protective immunity against severe viral disease. We detail the efforts in optimizing formulations of influenza candidates that use unmodified mRNA encoding full-length HA or full-length NA encapsulated in lipid nanoparticles (LNPs). HA and NA mRNA-LNP formulations, either as monovalent or as multivalent vaccines, induced strong functional antibody and cellular responses in non-human primates and such antigen-specific antibody responses were associated with protective efficacy against viral challenge in mice.

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

Assessment of clotrimazole gels for in vitro stability and in vivo retention in the frontal sinus of dogs.

OBJECTIVE: To evaluate the stability and retention of viscous formulations of the antifungal drug clotrimazole in vitro and to evaluate retention times, absorption, and histologic response to these compounds when placed in the frontal sinus of dogs. ANIMALS: 6 male Beagles. PROCEDURES: 1% clotrimazole gels were formulated with hydroxypropyl cellulose, poloxamer, and carboxymethylcellulose sodium bases. Commercially available 1% clotrimazole creams were also evaluated. Each compound was incubated at 37 degrees C in a funnel. Volume retained and clotrimazole stability were evaluated for 4 weeks. Six compounds were then chosen for in vivo evaluation. The frontal sinuses of 6 dogs were filled with 1 of the 6 compounds. Computed tomographic evaluation was performed weekly for up to 4 weeks to evaluate gel retention. Blood samples were collected to evaluate clotrimazole absorption. Following euthanasia, sinuses were examined histologically. RESULTS: Commercially available clotrimazole creams were not retained in funnels in vitro. In vivo, hydroxypropyl cellulose- and carboxymethylcellulose-based gels resulted in the most severe inflammatory response and were retained the longest. Poloxamer-based gels had a shorter retention time and were associated with less inflammation. Clotrimazole was minimally absorbed. Despite a marked inflammatory response to several of the clotrimazole-containing gels, no notable adverse clinical responses were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Poloxamer gels had the most promise for improving drug contact within the frontal sinus of dogs, while limiting the inflammatory response. Poloxamer gels have the additional benefit of improved handling as a result of reverse gelation (ie, they gel when warmed to 37 degrees C).

The impacts of the global gag rule on global health: a scoping review.

BACKGROUND: The 1984 Mexico City Policy is a U.S. federal policy that has prohibited foreign nongovernmental organizations that receive U.S. international family planning assistance from using their own, non-U.S. funds to provide, counsel on, or refer for abortion services as a method of family planning, or advocate for the liberalization of abortion laws- except in cases of rape, incest, and life endangerment. The policy became known as the global gag rule (GGR) due to its silencing effect on abortion advocacy. Historically, it has only been attached to family planning funding, until 2017 when a presidential memorandum expanded the policy to nearly all US$8.8 billion in global health foreign assistance. In light of the aforementioned expansion, this scoping review aimed to describe and map the impacts of the GGR on global health, which in turn would identify research and policy gaps. This is the first time that all of the existing literature on the policy's impact has been synthesized into one article and comprehensively reviewed. METHODS: The review utilized Arksey and Malley's five-stage methodological framework to conduct a scoping review. Fourteen peer-reviewed databases and 25 grey literature sources were searched for publications between January 1984 and October 2017. Organizations and individuals working on GGR research and impact were also contacted to access their works from the same time period. These publications reported on impacts of the global gag rule on 14 domains in global health. RESULTS: The searches yielded 1355 articles, of which 43 were included. Overall, 80% of the identified sources were qualitative. The misunderstanding, miscommunication, and chilling effect of the policy underpinned the GGR's impacts. The frequently reported impacts on family planning delivery systems (34 articles) and the loss of U.S. funding (21 articles) were often related. Sources reported on the impact of the GGR on HIV and AIDS programs, advocacy and coalition spaces, and maternal and child health. Only three studies (6.9%) quantified associations between the GGR and abortion rates, concluding that the policy does not decrease rates of abortion. DISCUSSION: The GGR's development and implementation was consistently associated with poor impacts on health systems' function and outcomes. More peer-reviewed and quantitative research measuring and monitoring the policy's impact on health outcomes are needed. More research and policy analysis exploring the GGR's development and its implementation on the ground will improve knowledge on GGR consequences, and potentially shape its reform.

Vehicle effects on in vitro transdermal absorption of sevoflurane in the bullfrog, Rana catesbeiana.

The experimental objectives were to identify a vehicle which produces a homogenous formulation when combined with the anesthetic solution sevoflurane and understand the dermal absorption of sevoflurane in silastic membranes and amphibian skin in vitro utilizing a flow-through diffusion system. Seven vehicles were evaluated in varying ratios with 5 formulations resulting in the desired homogenous consistency for practical application. Sevoflurane diffusion across silastic membranes was influenced by pluronic/lecithin organogel (PLO), pluronic F 127 20% gel, and sterile lube. Flux and permeability across silastic membranes were significantly greater in sterile lube than in the other formulations. While no significant vehicle effects were observed in bullfrog skin, the flux-time profiles suggest that sevoflurane diffusion in bullfrog skin may be positively influenced by PLO. Future in vivo studies are required to assess sevoflurane retention after removal of these formulations to more accurately control the plane of anesthesia in amphibians.

The phenotypic spectrum of SCN8A encephalopathy.

OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations. METHODS: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data. RESULTS: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges. CONCLUSION: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.

Characterizing the subjective, psychomotor, and physiological effects of oral propoxyphene in non-drug-abusing volunteers.

BACKGROUND: The subjective, psychomotor, and physiological effects of a widely prescribed prescription opioid, propoxyphene, have not been studied in a population of non-drug-abusing people. The drug also has potential for abuse and it was of interest in the present study to determine if the drug had any abuse liability-related subjective effects in this population. METHODS: Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo; 50 mg propoxyphene napsylate; 100 mg propoxyphene napsylate; 200 mg propoxyphene napsylate; 40 mg morphine sulfate; and 2 mg lorazepam. Measures were assessed before and for 300 min after drug administration. RESULTS: Both morphine and lorazepam produced subjective effects. There were no statistically significant subjective effects obtained with any dose of propoxyphene in the group as a whole, but approximately 30-50% of the subjects did appear to experience subjective effects from the drug. Drug liking was not consistently observed in this subset. Propoxyphene, unlike lorazepam, did not impair psychomotor or cognitive performance. Both propoxyphene and morphine produced miosis. CONCLUSIONS: There was a lack of statistically significant subjective effects of propoxyphene in the group as a whole, including a propoxyphene dose that was twice as high as the typical clinically-prescribed dose of 100 mg. However, there were some subjects who did report effects, consistent with the notion that patients differ in their sensitivity to opioid effects.

Pharmacokinetics and pharmacodynamics of furosemide after oral administration to horses.

Furosemide is the most common diuretic drug used in horses. Furosemide is routinely administered as IV or IM bolus doses 3-4 times a day. Administration PO is often suggested as an alternative, even though documentation of absorption and efficacy in horses is lacking. This study was carried out in a randomized, crossover design and compared 8-hour urine volume among control horses that received placebo, horses that received furosemide at 1 mg/kg PO, and horses that received furosemide at 1 mg/kg IV. Blood samples for analysis of plasma furosemide concentrations, PCV, and total solids were obtained at specific time points from treated horses. Furosemide concentrations were determined by reversed-phase high-performance liquid chromatography with fluorescent detection. Systemic availability of furosemide PO was poor, erratic, and variable among horses. Median systemic bioavailability was 5.4% (25th percentile, 75th percentile: 3.5, 9.6). Horses that received furosemide IV produced 7.4 L (7.1, 7.7) of urine over the 8-hour period. The maximum plasma concentration of 0.03 microg/mL after administration PO was not sufficient to increase urine volume compared with control horses (1.2 L [1.0, 1.4] PO versus 1.2 L [1.0, 1.4] control). There was a mild decrease in urine specific gravity within 1-2 hours after administration of furosemide PO, and urine specific gravity was significantly lower in horses treated with furosemide PO compared with control horses at the 2-hour time point. Systemic availability of furosemide PO was poor and variable. Furosemide at 1 mg/kg PO did not induce diuresis in horses.

The eyes have it: long-distance dispersal by an intraorbital leech parasite of birds.

A leech was found parasitizing the ocular orbit of a common redstart captured during a faunistic survey of Antikythira in the Aegean Sea during the spring migration of 2012. Morphological and molecular characterizations placed the leech in the mucous-membrane specific leech family Praobdellidae and definitively as the species Parapraobdella lineata. This is the first record of any leech parasitizing a passerine bird, Phoenicurus phoenicurus , and the first of a praobdellid leech on any avian host.

Dipstick urinalysis for the emergency department evaluation of urinary tract infections in infants aged less than 2 years.

BACKGROUND: The clinical diagnosis of urinary tract infection (UTI) in infants under the age of 2 years is challenging because of the nonspecific symptoms and signs in this age group. Prompt diagnosis and treatment is critical, and although dipstick testing allows rapid testing, there is some doubt about its use in infants. We sought to show the use of the dipstick test in identifying or excluding UTI in infants under the age of 2 years presenting to the emergency department with a febrile illness. METHODS: We conducted a retrospective diagnostic cohort study for over a 12-month period in a UK Paediatric Emergency Department, including all febrile children who had a urine dipstick and a quantitative culture as part of their diagnostic workup. The gold standard was the quantitative culture. RESULTS: Three hundred and twenty-one samples were eligible for inclusion. The mean age of the children included was 9.3 months. Sixty-three percent were female children. A test positive for nitrite, leucocyte esterase and blood gave a specificity of 97.12% [95% confidence interval (CI): 94.17-98.60] and a positive likelihood ratio of 15.13 (95% CI: 6.99-32.76). A test negative for nitrite, LE, blood and protein had a sensitivity of 97.44% (95% CI: 91.12-99.29) and a negative likelihood ratio of 0.10 (95% CI: 0.02-0.39). CONCLUSION: In febrile infants who were below 2 years of age, dipstick urinalysis shows promising results in identifying or ruling out a UTI.

A critical analysis of ecosystem services as a tool in conservation projects: the possible perils, the promises,and the partnerships.

Human modifications of the environment are growing in number and geographic extent, expanding to all of the Earth's surfaces and affecting the vast majority of the Earth's natural resources. Increases in demand for resources, growing levels of poverty, and more extensive urbanization, among other changes, lead to a need to move beyond parks and classic conservation approaches to incorporate humans and working landscapes more directly in conservation efforts. One approach to do this is to focus on ecosystem services, the benefits ecosystems provide to humans. Here conservation projects that focus only on biodiversity are analytically compared with those that include ecosystem-service goals to dispel myths and explore promises. Projects conducted by The Nature Conservancy, the world's largest conservation organization, are used, and it is demonstrated that not only do ecosystem-service approaches engage new landscapes, stakeholders, and funding sources, but that they do so without neglecting traditional biodiversity goals and the traditional approaches of protection and preservation. Seven case studies that uniquely create a broker-type structure to determine how to distribute money for the provision of particular services to the satisfaction of a wide range of stakeholder interests are focused on. It is found that all use local, independent leadership to initiate partnership formation, which then leads to the creation of a separate institutional entity that has legal rights to determine fund provision. The activities encouraged by these entities, and which therefore appear to satisfy a wide array of interests, are supporting education, rewarding best management practice, creating jobs, and monitoring outcomes.

Calpain inhibitors protect against axonal degeneration in a model of anti-ganglioside antibody-mediated motor nerve terminal injury.

Miller Fisher syndrome-associated anti-GQ1b ganglioside antibodies produce an acute complement-dependent neuroexocytic effect at the mouse neuromuscular junction (NMJ) that closely resembles the effect of alpha-latrotoxin (LTx). This pathophysiological effect is accompanied by morphological disruption of the nerve terminal involving the loss of major cytoskeletal components, including neurofilament. Both LTx and the membrane attack complex of complement form membrane pores that allow free ionic movement and we have previously hypothesized that Ca2+ ingress and the subsequent activation of Ca2+-dependent proteases, calpains, may lead to substrate degradation resulting in structural disorganization of the terminal. Here, we treated mouse NMJs in hemidiaphragm preparations with anti-GQ1b antibodies and complement, or with LTx in the presence and absence of extracellular Ca2+, and studied possible neuroprotective effects of the calpain inhibitors calpeptin and calpain inhibitor V. Both Ca2+ depletion and calpain inhibition protected the cytoskeleton from degradation, as assessed by immunohistological and ultrastructural analysis. Calpain inhibitors may therefore be useful therapeutically in limiting nerve terminal and axonal injury in autoimmune peripheral neuropathy and in human latrodectism.