FeMV is a cathepsin-dependent unique morbillivirus infecting the kidneys of domestic cats.

Feline morbillivirus (FeMV) is a recently discovered pathogen of domestic cats and has been classified as a morbillivirus in the Paramyxovirus family. We determined the complete sequence of FeMVUS5 directly from an FeMV-positive urine sample without virus isolation or cell passage. Sequence analysis of the viral genome revealed potential divergence from characteristics of archetypal morbilliviruses. First, the virus lacks the canonical polybasic furin cleavage signal in the fusion (F) glycoprotein. Second, conserved amino acids in the hemagglutinin (H) glycoprotein used by all other morbilliviruses for binding and/or fusion activation with the cellular receptor CD150 (signaling lymphocyte activation molecule [SLAM]/F1) are absent. We show that, despite this sequence divergence, FeMV H glycoprotein uses feline CD150 as a receptor and cannot use human CD150. We demonstrate that the protease responsible for cleaving the FeMV F glycoprotein is a cathepsin, making FeMV a unique morbillivirus and more similar to the closely related zoonotic Nipah and Hendra viruses. We developed a reverse genetics system for FeMVUS5 and generated recombinant viruses expressing Venus fluorescent protein from an additional transcription unit located either between the phospho-protein (P) and matrix (M) genes or the H and large (L) genes of the genome. We used these recombinant FeMVs to establish a natural infection and demonstrate that FeMV causes an acute morbillivirus-like disease in the cat. Virus was shed in the urine and detectable in the kidneys at later time points. This opens the door for long-term studies to address the postulated role of this morbillivirus in the development of chronic kidney disease.

Cognitive Functioning and Psychosocial Outcomes in Adults with Complex Congenital Heart Disease: A Cross-sectional Pilot Study.

Adults with complex congenital heart disease (CHD) are at risk for cognitive dysfunction. However, associations between cognitive dysfunction and psychosocial outcomes are poorly defined. Between June and November 2022, we prospectively recruited 39 adults with complex CHD who completed a computerized cognitive assessment (Cogstate) and validated psychosocial scales measuring psychological distress, health-related quality of life (HRQOL), and resilience. Participants had a mean age of 36.4 ± 11.2 years. Over half (62%) were women, most (79%) had complex biventricular CHD, and 21% had Fontan physiology. Prevalence of cognitive dysfunction was greatest in the domains of attention (29%), working memory (25%), and psychomotor speed (21%). Adjusting for age and sex, Pearson partial correlations between Cogstate z-scores and self-reported cognitive problems were small. Participants who lived in the most disadvantaged areas and those with a below-average annual household income had lower global cognitive z-scores (p = 0.02 and p = 0.03, respectively). Two-thirds (64%) reported elevated symptoms of depression, anxiety, and/or stress. Small correlations were observed between psychological distress and cognitive performance. Greater resilience was associated with lower psychological distress (r ≥ -0.5, p < 0.001) and higher HRQOL (r = 0.33, p = 0.02). Our findings demonstrate that adults with complex CHD have a high risk of cognitive dysfunction, though may not recognize or report their cognitive challenges. Lower socioeconomic status may be an indicator for those at risk of poorer cognitive functioning. Psychological distress is common though may not be a strong correlate of performance-based cognitive functioning. Formal cognitive evaluation in this patient population is essential. Optimizing resilience may be a protective strategy to minimize psychological distress and bolster HRQOL.

Community workshops increase advance care planning knowledge, appointment of legal proxies and completion of end-of life written plans.

Advance Care Planning involves having conversations, completing documents detailing individuals' end-of life treatment and care preferences, and appointing legal proxies who make health, lifestyle, or financial decisions. Although beneficial outcomes have been demonstrated, community rates of Advance Care Planning remain low. We developed a theoretically based workshop to increase knowledge and change behaviors in relation to Advance Care Planning; 347 participants completed the workshop. Advance Care Planning knowledge and action significantly improved three months post workshop. The intervention increased Advance Care Planning knowledge and changed behaviors.

COVID-19 in New South Wales children during 2021: severity and clinical spectrum.

OBJECTIVES: To describe the severity and clinical spectrum of coronavirus disease 2019 (COVID-19) in children during the 2021 New South Wales outbreak of the Delta variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN, SETTING: Prospective cohort study in three metropolitan Sydney local health districts, 1 June - 31 October 2021. PARTICIPANTS: Children under 16 years of age with positive SARS-CoV-2 nucleic acid test results admitted to hospital or managed by the Sydney Children's Hospital Network (SCHN) virtual care team. MAIN OUTCOME MEASURES: Age-specific SARS-CoV-2 infection frequency, overall and separately for SCHN virtual and hospital patients; rates of medical and social reason admissions, intensive care admissions, and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 per 100 SARS-CoV-2 infections; demographic and clinical factors that influenced likelihood of hospital admission. RESULTS: A total of 17 474 SARS-CoV-2 infections in children under 16 were recorded in NSW, of whom 11 985 (68.6%) received SCHN-coordinated care, including 459 admitted to SCHN hospitals: 165 for medical reasons (1.38 [95% CI, 1.17-1.59] per 100 infections), including 15 admitted to intensive care, and 294 (under 18 years of age) for social reasons (2.45 [95% CI, 2.18-2.73] per 100 infections). In an analysis that included all children admitted to hospital and a random sample of those managed by the virtual team, having another medical condition (adjusted odds ratio [aOR], 7.42; 95% CI, 3.08-19.3) was associated with increased likelihood of medical admission; in univariate analyses, non-asthmatic chronic respiratory disease was associated with greater (OR, 9.21; 95% CI, 1.61-174) and asthma/viral induced wheeze with lower likelihood of admission (OR, 0.38; 95% CI, 0.18-0.78). The likelihood of admission for medical reasons declined from infancy to 5-11 years, but rose again for those aged 12-15 years. Sex and Indigenous status did not influence the likelihood of admission. CONCLUSION: Most SARS-CoV-2 infections (Delta variant) in children were asymptomatic or associated with mild disease. Hospitalisation was relatively infrequent, and most common for infants, adolescents, and children with other medical conditions. More children were hospitalised for social than for medical reasons.

Program for the Education and Enrichment of Relational Skills for adolescents with an acquired brain injury: A randomized controlled trial.

AIM: To test the efficacy of a group social skills intervention on social functioning in adolescents with a brain injury. METHOD: Thirty-six adolescents (mean age 14y, SD 1y 8mo, age range 12y 1mo-16y 3mo; 17 females) with acquired brain injury (ABI; ≥12mo postintervention; n=19) or cerebral palsy (n=17) were randomly allocated to the Program for the Education in Enrichment of Relational Skills (PEERS) or usual care. The primary outcome was the Social Skills Improvement System-Rating Scales (SSIS-RS). Secondary outcomes were scores derived from the Test of Adolescent Social Skills Knowledge-Revised (TASSK-R), Social Responsiveness Scale, Second Edition, and Quality of Socialization Questionnaire. Between-group differences postintervention and at the 26-week retention time point were compared using linear mixed modelling for continuous outcomes and Poisson regression for count data. RESULTS: There were no between-group differences on the primary outcome (SSIS-RS). Regarding the secondary outcomes, the PEERS-exposed group achieved significantly greater improvements on the TASSK-R (mean difference [MD]=6.8, 95% confidence interval [CI]=4.8-8.8, p<0.001), which were maintained at the 26-week retention time point (MD=8.1, 95% CI=6.0-10.2, p<0.001). PEERS was also associated with a significant increase in parent-reported invited get-togethers at 26 weeks (incidence rate ratio=4.0, 95% CI=1.0-16.0, p=0.05). INTERPRETATION: Adolescents with brain injury who completed the PEERS learned and retained social knowledge and increased social participation.

Using a Community Workgroup Approach to Increase Access to Physical Activity in an Underresourced Urban Community.

Background. Regular physical activity is associated with improved physical and psychosocial well-being. Increasing access to physical activity in underresourced communities requires collaborative, community-engaged methods. One such method is community workgroups. Purpose. The purpose of this article is to describe implementation, strengths, challenges, and results of the workgroup approach as applied to increasing access to physical activity, using our recent study as an illustrative example. Method. A 1-day conference was held in April 2017 for community leaders. The first half of the conference focused on disseminating results of a multifaceted community assessment. The second half entailed community workgroups. Workgroups focused on applying community assessment results to develop strategies for increasing access to physical activity, with plans for ongoing workgroup involvement for strategy refinement and implementation. A professional artist documented the workgroup process and recommendations via graphic recording. Results. Sixty-three community leaders attended the conference and participated in the workgroups. Workgroup participants reported that greater macrosystem collaboration was critical for sustainability of physical activity programming and that, particularly in underresourced urban communities, re-imagining existing spaces (rather than building new spaces) may be a promising strategy for increasing access to physical activity. Discussion. Considered collectively, the community workgroup approach provided unique insight and rich data around increasing access to physical activity. It also facilitated stakeholder engagement with and ownership of community health goals. With careful implementation that includes attention to strengths, challenges, and planning for long-term follow-up, the community workgroup approach can be used to develop health promotion strategies in underresourced communities.

Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).

In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.

Lead identification and characterization of hTrkA type 2 inhibitors.

Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.

Attention to faces in social context in children with neurofibromatosis type 1.

AIM: To examine visual attention to faces within social scenes in children with neurofibromatosis type 1 (NF1) and typically developing peers. METHOD: Using eye-tracking technology we investigated the time taken to fixate on a face and the percentage of time spent attending to faces relative to the rest of the screen within social scenes in 24 children with NF1 (17 females, seven males; mean age 10y 4mo [SD 1y 9mo]). Results were compared with those of 24 age-matched typically developing controls (11 females, 13 males; mean age 10y 3mo [SD 2y]). RESULTS: There was no significant between-group differences in time taken to initially fixate on a face (p=0.617); however, children with NF1 spent less time attending to faces within scenes than controls (p=0.048). Decreased attention to faces was associated with elevated autism traits in children with NF1. INTERPRETATION: Children with NF1 spend less time attending to faces than typically developing children when presented in social scenes. Our findings contribute to a growing body of literature suggesting that abnormal face processing is a key aspect of the social-cognitive phenotype of NF1 and appears to be related to autism spectrum disorder traits. Clinicians should consider the impact of reduced attention to faces when designing and implementing treatment programmes for social dysfunction in this population. WHAT THIS PAPER ADDS: Children with neurofibromatosis type 1 (NF1) demonstrated atypical gaze behaviour when attending to faces. NF1 gaze behaviour was characterized by normal initial fixation on faces but shorter face dwell time. Decreased attention to faces was associated with elevated autism traits in the sample with NF1.

Long-Term Neuropsychological Outcomes of Childhood Onset Acute Disseminated Encephalomyelitis (ADEM): a Meta-Analysis.

The long-term neurocognitive prognosis of childhood onset acute disseminated encephalomyelitis (ADEM) is unclear. This review and quantitative synthesis of the available literature examined whether there are long-term impacts of childhood ADEM on neurocognitive functioning. A search of online databases (MEDLINE, EMBASE, EBSCO CINAHL, PsycINFO and the Cochrane Database of Systematic Reviews) from their inception to October 2015 and reference lists identified 13 papers eligible for inclusion in the systematic review; seven of these were eligible for inclusion in meta-analyses. The systematic review indicated that, at a group level there is a positive long-term neuropsychological outcome from childhood onset ADEM. However, despite the apparent absence of long-term negative impacts of ADEM at a group level, at an individual level impairments in the areas of IQ, attention, executive functioning, processing speed, learning and memory, visuospatial skills and internalising symptoms were found in up to 43% of patients when aggregated across the studies. No significant negative effect of ADEM for any of the neuropsychological domains examined was found in meta-analyses. However, the effects for Processing Speed (r mean = -0.296 (CI 95% = -0.605-0.013)) and Internalising symptoms (r mean = 0.242 (CI 95% = -0.014-0.564)) approached significance (p = 0.06), suggesting a trend towards ADEM leading to long-term reduced processing speed and elevated internalising symptoms. Together, our findings suggest that despite a generally positive neurocognitive outcome post childhood ADEM there are a subset of individuals who can suffer from ongoing specific cognitive impairments. Clinical implications and research priorities are discussed.

The neuropsychological profile of children with basal ganglia encephalitis: a case series.

Inflammatory basal ganglia encephalitis (BGE) is a rare but distinct entity of putative autoimmune aetiology, with specific basal ganglia inflammation and acute movement disorders. Unlike most brain injuries, BGE is a radiologically pure basal ganglia syndrome. The current study systematically describes the neuropsychological outcomes of four paediatric cases of BGE, and thus the neuropsychological outcomes of focal basal ganglia insult in childhood. Although all patients made significant motor recoveries, all four cases displayed executive dysfunction, fine motor difficulties, and anxiety. Three out of four cases displayed attention deficits. The case who received intravenous immunoglobulin (IVIg) treatment and steroids during the acute phase of the disease had the best cognitive outcome. These findings highlight the need for detailed neuropsychological assessment and long-term follow-up.

The opossum MHC genomic region revisited.

The gray short-tailed opossum Monodelphis domestica is one of the few marsupial species for which a high quality whole genome sequence is available and the major histocompatibility complex (MHC) region has been annotated. Previous analyses revealed only a single locus within the opossum MHC region, designated Modo-UA1, with the features expected for encoding a functionally classical class I α-chain. Nine other class I genes found within the MHC are highly divergent and have features usually associated with non-classical roles. The original annotation, however, was based on an early version of the opossum genome assembly. More recent analyses of allelic variation in individual opossums revealed too many Modo-UA1 sequences per individual to be accounted for by a single MHC class I locus found in the genome assembly. A reanalysis of a later generation assembly, MonDom5, revealed the presence of two additional loci, now designated Modo-UA3 and UA4, in a region that was expanded and more complete than in the earlier assembly. Modo-UA1, UA3, and UA4 are all transcribed, although Modo-UA4 transcripts are rarer. Modo-UA4 is also relatively non-polymorphic. Evidence presented support the accuracy of the later assembly and the existence of three related class I genes in the opossum, making opossums more typical of mammals and most tetrapods by having multiple apparent classical MHC class I loci.

Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. METHODS: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). FINDINGS: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. INTERPRETATION: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FUNDING: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).

Reflections from the forgotten frontline: 'The reality for children and staff in residential care' during COVID-19.

Currently, 78,150 children are in care in England, with 11% of the most vulnerable living in 2,460 residential homes due to multitype traumas. These children require safe and secure trauma-informed therapeutic care. However, the children's residential care workforce delivering this vital care is an unrepresented, under-researched and largely unsupported professional group. The workforce undertakes physically and emotionally challenging work in difficult conditions, exacerbated by the COVID-19 pandemic. Practitioner wellbeing is directly associated with outcomes for children. Therefore, we sought to understand how experiences within the workforce could improve overall working conditions, and thus outcomes for staff and children. Thirty participants took part in a survey, providing feedback on their experiences and the situations they faced during the English lockdown April-June 2020. Two participants also opted to take part in a teleconference interview, rather than survey, although were asked the same questions. Data were analysed through thematic analysis. A stakeholder advisory board supported the project, including frontline staff, care leavers, service managers and policy researchers. The advisory board assisted in reflecting on the data from the survey and interviews to generate a complete analysis. Overall, staff require facilitated safe spaces for peer-support, reflective and emotionally supportive supervision. An organisational awareness that staff wellbeing is intrinsically connected to the wellbeing and therapeutic outcomes of the children they care for is essential. Further, staff require a sense of belongingness to feel safe and competent in their role due to a lack of external recognition and professional representation or validation. Based on the findings of the study and an iterative process with the stakeholder advisory board, we created a Wellbeing Charter for adoption within organisations to promote and protect the wellbeing of this vital workforce. The COVID-19 pandemic has exposed professional, financial and environmental inequalities that affect these frontline workers. Implementing organisational, statutory and policy-driven initiatives to prioritise their wellbeing are essential for the vulnerable children they care for.

Corticosteroids to safely reduce neonatal respiratory morbidity after late preterm and term planned caesarean section birth? A randomised placebo-controlled feasibility study.

OBJECTIVES: To assess the feasibility of conducting a randomised placebo-controlled trial of corticosteroids prior to planned caesarean section from 35+0 to 39+6 weeks. DESIGN: A triple-blind, placebo-controlled, parallel, trial randomised at the participant level (1:1 ratio). Additional feasibility data obtained by questionnaires from trial participants and women who declined trial participation, and focus groups with local site researchers and clinicians. SETTING: Three obstetric units in New Zealand including tertiary and secondary care; public and private care, and research active and non-active units. PARTICIPANTS: Women undergoing a planned caesarean section from 35+0 to 39+6 weeks; local site researchers and clinicians. INTERVENTIONS: Two doses of 11.4 mg betamethasone or saline placebo. Questionnaires and focus group meetings. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: trial recruitment rate of eligible women. SECONDARY OUTCOMES: trial recruitment by gestational age, site and delivery indication; proportion of babies who completed measurements of blood glucose concentrations as per protocol; overall incidence neonatal respiratory distress requiring >60 min of respiratory support; overall incidence of neonatal hypoglycaemia, and barriers and enablers to trial participation by participants, researchers and clinicians. RESULTS: The recruitment rate was 8.9% (88/987) overall and 11.2% (88/789) for those approached about the trial. Neonatal blood glucose concentrations were measured as per protocol in 87/92 (94.6%) babies. For potential participants, key enablers to participation were contributing to research, a feeling of relevance and a good understanding; key barriers were a lack of understanding and concerns over safety. For researchers and clinicians, themes representing enablers and barriers included relevance, communication and awareness, influences on women's decision-making, resource challenges and trial process practicalities. CONCLUSIONS: Some women are willing to participate in a randomised placebo-controlled trial of corticosteroids prior to a planned caesarean section birth at late preterm and term gestations. Participation in such a trial can be enhanced.

The nicotinic acetylcholine receptors of the parasitic nematode Ascaris suum: formation of two distinct drug targets by varying the relative expression levels of two subunits.

Parasitic nematodes are of medical and veterinary importance, adversely affecting human health and animal welfare. Ascaris suum is a gastrointestinal parasite of pigs; in addition to its veterinary significance it is a good model of the human parasite Ascaris lumbricoides, estimated to infect approximately 1.4 billion people globally. Anthelmintic drugs are essential to control nematode parasites, and nicotinic acetylcholine receptors (nAChRs) on nerve and muscle are the targets of cholinergic anthelmintics such as levamisole and pyrantel. Previous genetic analyses of nematode nAChRs have been confined to Caenorhabditis elegans, which is phylogenetically distinct from Ascaris spp. and many other important parasites. Here we report the cloning and expression of two nAChR subunit cDNAs from A. suum. The subunits are very similar in sequence to C. elegans UNC-29 and UNC-38, are expressed on muscle cells and can be expressed robustly in Xenopus oocytes to form acetylcholine-, nicotine-, levamisole- and pyrantel-sensitive channels. We also demonstrate that changing the stoichiometry of the receptor by injecting different ratios of the subunit cRNAs can reproduce two of the three pharmacological subtypes of nAChR present in A. suum muscle cells. When the ratio was 5:1 (Asu-unc-38ratioAsu-unc-29), nicotine was a full agonist and levamisole was a partial agonist, and oocytes responded to oxantel, but not pyrantel. At the reverse ratio (1:5 Asu-unc-38ratioAsu-unc-29), levamisole was a full agonist and nicotine was a partial agonist, and the oocytes responded to pyrantel, but not oxantel. These results represent the first in vitro expression of any parasitic nicotinic receptor and show that their properties are substantially different from those of C. elegans. The results also show that changing the expression level of a single receptor subunit dramatically altered the efficacy of some anthelmintic drugs. In vitro expression of these subunits may permit the development of parasite-specific screens for future anthelmintics.

Coastal dunes as a sink and secondary source of marine plastics: A study at Perran Beach, southwest England.

Plastic food packaging and containers (n = 263) have been retrieved from the scarped foredunes at Perran Beach, SW England, following a storm surge. Samples displayed evidence of cracking, scratching, discolouration, staining and hydroxyl and carbonyl stretching, but legible text indicating their origin, dates of manufacture/expiration, packaging codes and logos, coupled with online product searches, allowed 25 food packets and 87 containers to be aged. Estimates of food packaging age spanned a 43-year period (1975-2018), with a median age of 25 years, while estimates for containers spanned 57 years (1962-2019), with a median age of 19 years. Plastic derived from local littering and offshore sources appears to be trapped within the foredunes for years to decades and subsequently released as "fresh" beach litter following surges sufficient to effect scarping. Dunal systems may act as significant reservoirs of historical plastics and play a critical role in their recycling and retention in the coastal zone.

Transport, weathering and pollution of plastic from container losses at sea: Observations from a spillage of inkjet cartridges in the North Atlantic Ocean.

Observations of beached polypropylene inkjet cartridges, spilled from a ship container lost in the North Atlantic Ocean, have been compiled through calls on international social media. Within a period of four years from the spillage, a total of about 1500 cartridges was reported in locations as far apart as Florida and northern Norway. The distribution of cartridges reflected the principal surface currents in the ocean, with some carried by the Azores and Canary currents around the North Atlantic Gyre, and others transported northwards with the North Atlantic and Norwegian currents. Along the shorelines of the UK and Ireland, there was a clear, preferential accumulation of cartridges on west- and south-facing coasts, consistent with the direction of the North Atlantic current and the heading of the principal winds. Dates of first sightings in various regions throughout the North Atlantic (and as reported on social media) suggested that cartridges traveled on average at around 6-13 cm s-1. These observations and estimates were largely consistent with simulations of the dispersion of free floating, neutrally buoyant particles from the spillage site derived from PlasticAdrift, an empirical model based on drifter tracking data. Microscopic and X-ray fluorescence analyses of selected cartridges revealed a high degree of exterior weathering, resulting in chalking and embrittlement of the polypropylene and the formation of microplastics rich in Ti, chemical fouling of interior ink foams (where still present) by Fe oxides, and, in some cases, the presence of an electronic chip containing Cu, Au and brominated compounds. Significantly, the latter characteristic renders cartridges as electrical and electronic waste and means that current, conventional regulations on plastic cargo lost at sea are not applicable here. More generally, the study highlights the potential usefulness of social media-led citizen science to marine research, and inadequacies in the relevance and robustness of instruments and conventions that deal with plastic waste in the ocean.

In Pursuit of an Allosteric Human Tropomyosin Kinase A (hTrkA) Inhibitor for Chronic Pain.

Human ß-nerve growth factor (ß-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit ß-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.