The Bioethics of Environmental Injustice: Ethical, Legal, and Clinical Implications of Unhealthy Environments.

Environmental health remains a niche topic in bioethics, despite being a prominent social determinant of health. In this paper we argue that if bioethicists are to take the project of health justice as a serious one, then we have to address environmental injustices and the threats they pose to our bioethics principles, health equity, and clinical care. To do this, we lay out three arguments supporting prioritizing environmental health in bioethics based on bioethics principles including a commitment to vulnerable populations and justice. We also highlight and advocate for environmental law efforts that align with these priorities, focusing specifically on the need for a right to a healthy environment. Our intention is to draw attention to the legal and ethical concepts that underlie the importance of a healthy environment, and urge bioethicists to prioritize both legal and ethical advocacy against environmental injustices in their practice.

Race, Power, and COVID-19: A Call for Advocacy within Bioethics.

Events in 2020 have sparked a reimagination of how both individuals and institutions should consider race, power, health, and marginalization in society. In a response to these developments, we examine the current and past limitations of the ways in which bioethicists have considered race and, more generally, discourses of marginalization. We argue that the foundational principle of justice necessitates that bioethics, as an institution, maintain an active voice against systemic injustice. To carry out this charge, bioethics as a field should promote alternative narratives-"counter storytelling"-to the mainstream voices that have traditionally been heard and accepted, largely without opposition. Additionally, we engage with both Post-Colonial and Critical Race Theory, which we believe are important tools for bioethics in pursuit of equity. Ultimately, we advocate for a proactive form of bioethics that actively resists and denounces injustice and which considers a much wider variety of voices about justice than bioethics has historically considered.

Differential Reactivity of Copper- and Gold-Based Nanomaterials Controls Their Seasonal Biogeochemical Cycling and Fate in a Freshwater Wetland Mesocosm.

Reliable predictions of the environmental fate and risk of engineered nanomaterials (ENMs) require a better understanding of ENM reactivity in complex, biologically active systems for chronic low-concentration exposure scenarios. Here, simulated freshwater wetland mesocosms were dosed with ENMs to assess how their reactivity and seasonal changes in environmental parameters influence ENM fate in aquatic systems. Copper-based ENMs (Kocide), known to dissolve in water, and gold nanoparticles (AuNPs), stable against dissolution in the absence of specific ligands, were added weekly to mesocosm waters for 9 months. Metal accumulation and speciation changes in the different environmental compartments were assessed over time. Copper from Kocide rapidly dissolved likely associating with organic matter in the water column, transported to terrestrial soils and deeper sediment where it became associated with organic or sulfide phases. In contrast, Au accumulated on/in the macrophytes where it oxidized and transferred over time to surficial sediment. A dynamic seasonal accumulation and metal redox cycling were found between the macrophyte and the surficial sediment for AuNPs. These results demonstrate the need for experimental quantification of how the biological and chemical complexity of the environment, combined with their seasonal variations, drive the fate of metastable ENMs.

Size-Based Differential Transport, Uptake, and Mass Distribution of Ceria (CeO2) Nanoparticles in Wetland Mesocosms.

Trace metals associated with nanoparticles are known to possess reactivities that are different from their larger-size counterparts. However, the relative importance of small relative to large particles for the overall distribution and biouptake of these metals is not as well studied in complex environmental systems. Here, we have examined differences in the long term fate and transport of ceria (CeO2) nanoparticles of two different sizes (3.8 vs 185 nm), dosed weekly to freshwater wetland mesocosms over 9 months. While the majority of CeO2 particles were detected in soils and sediments at the end of nine months, there were significant differences observed in fate, distribution, and transport mechanisms between the two materials. Small nanoparticles were removed from the water column primarily through heteroaggregation with suspended solids and plants, while large nanoparticles were removed primarily by sedimentation. A greater fraction of small particles remained in the upper floc layers of sediment relative to the large particles (31% vs 7%). Cerium from the small particles were also significantly more bioavailable to aquatic plants (2% vs 0.5%), snails (44 vs 2.6 ng), and insects (8 vs 0.07 µg). Small CeO2 particles were also significantly reduced from Ce(IV) to Ce(III), while aquatic sediments were a sink for untransformed large nanoparticles. These results demonstrate that trace metals originating from nanoscale materials have much greater potential than their larger counterparts to distribute throughout multiple compartments of a complex aquatic ecosystem and contribute to the overall bioavailable pool of the metal for biouptake and trophic transfer.

Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo.

Abnormal alpha-synuclein (α-synuclein) expression and aggregation is a key characteristic of Parkinson's disease (PD). However, the exact mechanism(s) linking α-synuclein to the other central feature of PD, dopaminergic neuron loss, remains unclear. Therefore, improved cell and in vivo models are needed to investigate the role of α-synuclein in dopaminergic neuron loss. MicroRNA-7 (miR-7) regulates α-synuclein expression by binding to the 3' UTR of the Synuclein Alpha Non A4 Component of Amyloid Precursor (SNCA) gene and inhibiting its translation. We show that miR-7 is decreased in the substantia nigra of patients with PD and, therefore, may play an essential role in the regulation of α-synuclein expression. Furthermore, we have found that lentiviral-mediated expression of miR-7 complementary binding sites to stably induce a loss of miR-7 function results in an increase in α-synuclein expression in vitro and in vivo. We have also shown that depletion of miR-7 using a miR-decoy produces a loss of nigral dopaminergic neurons accompanied by a reduction of striatal dopamine content. These data suggest that miR-7 has an important role in the regulation of α-synuclein and dopamine physiology and may provide a new paradigm to study the pathology of PD.

Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau.

The interneuronal propagation of aggregated tau is believed to play an important role in the pathogenesis of human tauopathies. It requires the uptake of seed-competent tau into cells, seeding of soluble tau in recipient neurons and release of seeded tau into the extracellular space to complete the cycle. At present, it is not known which tau species are seed-competent. Here, we have dissected the molecular characteristics of seed-competent tau species from the TgP301S tau mouse model using various biochemical techniques and assessed their seeding ability in cell and animal models. We found that sucrose gradient fractions from brain lysates seeded cellular tau aggregation only when large (>10 mer) aggregated, hyperphosphorylated (AT8- and AT100-positive) and nitrated tau was present. In contrast, there was no detectable seeding by fractions containing small, oligomeric (<6 mer) tau. Immunodepletion of the large aggregated AT8-positive tau strongly reduced seeding; moreover, fractions containing these species initiated the formation and spreading of filamentous tau pathology in vivo, whereas fractions containing tau monomers and small oligomeric assemblies did not. By electron microscopy, seed-competent sucrose gradient fractions contained aggregated tau species ranging from ring-like structures to small filaments. Together, these findings indicate that a range of filamentous tau aggregates are the major species that underlie the spreading of tau pathology in the P301S transgenic model. Significance statement: The spread of tau pathology from neuron to neuron is postulated to account for, or at least to contribute to, the overall propagation of tau pathology during the development of human tauopathies including Alzheimer's disease. It is therefore important to characterize the native tau species responsible for this process of seeding and pathology spreading. Here, we use several biochemical techniques to dissect the molecular characteristics of native tau protein conformers from TgP301S tau mice and show that seed-competent tau species comprise small fibrils capable of seeding tau pathology in cell and animal models. Characterization of seed-competent tau gives insight into disease mechanisms and therapeutic interventions.

Young people have their say: What makes a youth-friendly general practice?

BACKGROUND: The health of young people can be considered an indicator of the health of Australia's future population. To improve access to healthcare, the perspectives of adolescents on the design and delivery of services need to be championed. The objective of this study was to identify what young people in north-west Tasmania value when seeking healthcare at general practices. METHODS: The study was conducted at a single high school in rural Tasmania. Students aged 16-18 years were invited to participate in an electronic survey seeking their views and preferences for presenting to their general practitioner (GP). RESULTS: One hundred and fifty-five students, with a mean age of 17 years, were surveyed. GPs were the usual healthcare providers for 98.4% of participants, and 86% stated that they would like to discuss mental health, substance use and sexual health with their GP. DISCUSSION: GPs can improve access to care for young people through good communications skills and treating young people as young adults.

A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity.

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.

Examination of the difficulties in emotion regulation scale and its relation to disordered eating in a young female sample.

OBJECTIVE: Difficulties with emotion regulation is considered an important maintaining factor of disordered eating. One of the most commonly used measures of this construct is the Difficulties in Emotion Regulation Scale (DERS). The aim of this study was to explore the factor structure of this measure in young females and to examine its reliability and validity with respect to disordered eating. METHOD: Females aged 17-25 years (M age = 19.6 years, N = 486) were examined in the analyses. Confirmatory factor analyses were conducted followed by regression analyses examining the DERS subscales as predictors of eating disorder severity and disordered eating behaviors. RESULTS: The original 6-factor 36-item model did not fit well and analyses indicated a 6-factor 30-item solution was a more suitable fit for our population. Validity and reliability of the 30-item solution were found to be acceptable. Regression analyses also indicated the 36- and 30-item models were able to adequately predict eating disorder severity and disordered eating behaviors with the "Awareness" and "Goals" subscales being predictors of the former, and the "Impulsivity" subscale being a significant predictor of the latter. DISCUSSION: The overall findings suggest that an abbreviated version of the DERS might be more appropriate than the original version with young females and that this measure exhibits stronger relationships with eating disorder severity and disordered eating behaviors than the longer version. Further examinations of the psychometric properties of the DERS with clinical populations are indicated.

Can first aid training encourage individuals' propensity to act in an emergency situation? A pilot study.

OBJECTIVE: To explore the effect that different activities included in first aid training can have on an individual's propensity to act in a medical emergency. DESIGN: Additional pilot-developed activities were added to a core first aid training session to create six unique groups, including a control group where no activities were added. Participants rated their agreement to pre-identified fears following the course and scored their self-efficacy and willingness to act before, immediately after and 2 months after the course. Change values were compared between groups. SETTING: Three locations in the UK (community halls, schools). PARTICIPANTS: 554 members of the public were recruited using advertising and community groups. A deliberately broad demographic was sought and achieved using targeted approaches where a particular demographic was deficient. INTERVENTION: Each participant attended one British Red Cross first aid course lasting 2 h. MAIN OUTCOME MEASURES: The same questionnaire was completed by all participants before and after each course. Two months later all participants were asked a series of follow-up questions. RESULTS: All courses showed an increase in self-efficacy and willingness to act immediately following the course. The course, which included both factual information relevant to helping in an emergency and 'helper' identity activities, produced significantly more positive responses to pre-identified fears. CONCLUSIONS: Activities which allow the learner to explore and discuss behaviour in an emergency situation can effectively increase the learner's propensity to act. First aid education should be expanded to support the learner to develop both the skill and the will to help.

Confirmation of cannabinoids in forensic toxicology casework by isomer-selective UPLC-MS-MS analysis in urine.

Confirmation of cannabinoid use by forensic toxicology testing in urine has been traditionally focused on ∆9-tetrahydrocannabinol (∆9-THC) with analysis of its major metabolite, 11-nor-9-carboxy-∆9-THC (∆9-cTHC), in free and conjugated forms. Legalization of hemp, however, has led to the widespread production and sale of cannabidiol (CBD) derivatives with psycho-activity, including ∆8-THC and ∆10-THC isomers. The increasing availability and growing use of isomer derivatives necessitate an expanded scope of cannabinoid confirmation test protocols. We report a quantitative, isomer-selective method of cannabinoid confirmation by liquid chromatography-tandem mass spectrometry determination of parent drug isomers (∆8-THC, ∆9-THC, ∆10-THC and CBD) as well as isomeric metabolites (∆8-cTHC and ∆9-cTHC). An efficient C18 phase chromatography on 1.6-µm solid core particles was used with a step gradient for near isocratic separation of both early-eluting THC metabolite isomers and later-eluting CBD and THC isomers. A rapid method of hydrolysis, dilution and analysis was employed for the quantitative co-determination of free and conjugated analytes, using stable isotope internal standardization. Method validation is reported, along with interference assessment from a prior confirmation method. Casework experience with the isomer-selective method revealed a 14% prevalence of ∆8-cTHC positive cases with a pattern of concomitant ∆8-THC and ∆9-THC use. A comparison of ∆8-cTHC and ∆9-cTHC phase two metabolism is also reported.

Occupational Therapy Theory and School-Based Filial Therapy: Intervention Rationale and Formulation.

Background: Emotional-behavioural problems in children present a barrier to engagement and participation in school occupations. Applying practice theory is an essential process to explore the impact of clinical problems and to orient clinical thinking to the domain of occupation. Purpose: Occupational therapy practice theory and frameworks are applied to the formulation of School-Based Filial Therapy, a viable treatment response to emotional-behavioural problems in children. Key issues: Bowen family systems theory, the Occupational Therapy Practice Framework IV and the Canadian Model of Occupational Performance and Engagement are applied to intervention formulation. Implications: School-Based Filial Therapy engages the dynamic interaction of the person, the occupations he/she engages in and the environment via therapeutic medium of play. It is consistent with the Occupational Therapy Practice Framework IV and the Canadian Model of Occupational Performance and Engagement and provides new possibilities as an intervention for occupational therapists working in children's mental health.

Clostridioides difficile infection: a comprehensive review for primary providers.

Clostridioides difficile infection (CDI) is an issue of great concern due to its rising incidence, recurrence, morbidity and impact on healthcare spending. Treatment guidelines have changed in the last few years, and new therapies are being considered. This is a practical review for the primary care practitioner of the latest guidelines for CDI diagnosis, treatment, and emerging therapies.

Application of the Three Rs to challenge assays used in vaccine testing: tenth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement.

This report aims to facilitate the implementation of the Three Rs (reduction, refinement and replacement) in the testing of vaccines for regulatory and other purposes. The focus is predominantly on identification of reduction and refinement opportunities in batch potency testing but the principles described are widely applicable to other situations that involve experimental infections of animals. The report should also help to interpret the requirements of the European Pharmacopoeia with regard to the use of alternative tests, humane endpoints and other refinements. Two specific worked examples, for batch potency testing of Clostridium chauvoei and canine leptospira, with recommendations for harmonisation of international test requirements for these and other vaccines, are provided as appendices online.

Batch safety testing of veterinary vaccines - potential welfare implications of injection volumes.

This study examines the volumes administered by injection during the batch safety testing of veterinary vaccines according to the methods laid down in European Pharmacopoeia monographs. These are compared with maximum dose volumes recommended in good practice guidelines. The volumes administered during safety tests frequently exceeded recommended maximums, giving rise to concerns that these tests may seriously compromise animal welfare. This was particularly the case for live liquid vaccines and for vaccines recommended for intramuscular injection. The volumes used in testing vaccines for avian species exceeded the recommended maximums by the greatest amount. The administration of test doses should be performed in a way that minimises pain and discomfort. The refinement of tests by dividing large dose volumes and delivering them over multiple sites is discussed, but it is recognised that there are technical limitations, which in some cases may cause difficulties with fulfilling the purpose of the tests. Previously, the relevance of batch safety tests has been widely criticised, due to a lack of evidence that they contribute to the safety of veterinary medicines. By showing that the conduct of target animal safety tests can involve injection volumes that compromise the welfare of the animals involved, this analysis highlights the need for a more critical assessment of the necessity and justification for these tests.

Nonviolent offenders' and college students' attachment and social support behaviors: implications for counseling.

This study examines the relationships between adult attachment orientations and the ability to seek social support as factors in mediating behavior. Data were collected on non violent offenders (n = 57) and college students (n = 89). The results indicated the non-normative group of nonviolent offenders reported being more securely attached and having more satisfaction with their social supports than the normative group of college students. Fewer college students reported being securely attached than the nonviolent offenders but had a larger number of social supports. In the insecure categories, nonviolent offenders reported being more dismissively attached whereas college students reported being preoccupied in their attachment orientation. The study suggests that attachment and social-support-seeking behaviors across different populations may be potential factors in designing counseling services that are used for risk classification and needs assessment.

Increased brain bio-distribution and chemical stability and decreased immunogenicity of an engineered variant of GDNF.

Several lines of evidence indicate that Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for dopaminergic neurons. Direct parenchymal administration of GDNF is robustly neuroprotective and neurorestorative in multiple neurotoxin-based animal models (rat and non-human primate (NHP)) of Parkinson's Disease (PD), suggesting its potential as a therapeutic agent. Although small, open-label clinical trials of intra-putamenal administration of bacteria-derived, full length, wild type GDNF (GDNFwt) were efficacious in improving standardized behavioral scores, a double-blinded, randomized controlled trial failed to do so. We hypothesize that the lack of clinical efficacy of GDNFwt in the larger randomized trial was due to poor bio-distribution in the putamen and/or poor chemical stability while in the delivery device for prolonged time periods at 37°C. The development of neutralizing antibodies in some patients may also have been a contributing factor. GDNFv is an engineered form of GDNFwt, expressed and purified from mammalian cells, designed to overcome these limitations, including removal of the N-terminal heparin-binding domain to improve its diffusivity in brain parenchyma by reducing its binding to extracellular matrix (ECM), and key amino acid substitutions to improve chemical stability. Intra-striatal administration of a single injection of GDNFv in the rat produced significantly greater brain distribution than GDNFwt, consistent with reduced binding to ECM. Using liquid chromatography/mass spectrometry (LS/MS) methods GDNFv was shown to have improved chemical stability compared to GDNFwt when stored at 37°C for 4weeks. In addition, GDNFv resulted in lower predicted clinical immunogenicity compared to GDNFwt, as demonstrated by reduced CD4+ T cell proliferation and reduced IL-2-induced secretion in peripheral blood mononucleated cells collected from volunteers representing the world's major histocompatibility complex (MHC) haplotypes. GDNFv was demonstrated to be pharmacologically equivalent to GDNFwt in the key parameters in vitro of GFRα1 receptor binding, c-Ret phosphorylation, neurite outgrowth, and in vivo in its ability to increase dopamine turnover (DA). GDNFv protected dopamine nerve terminals and neurons in a 6-hydroxy-dopamine (6-OHDA) rat model. In summary, we empirically demonstrate the superior properties of GDNFv compared to GDNFwt through enhanced bio-distribution and chemical stability concurrently with decreased predicted clinical immunogenicity while maintaining pharmacological and neurotrophic activity. These data indicate that GDNFv is an improved version of GDNF suitable for clinical assessment as a targeted regenerative therapy for PD.

The role of the 5-HT1D receptor as a presynaptic autoreceptor in the guinea pig.

The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig.