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Fears of negative evaluation (FNEs) and fears of positive evaluation (FPEs) comprise a bivalent model of evaluation that can explain the aetiology and maintenance of Social Anxiety Disorder (SAD). In this study, we examined an extended version of this model which incorporates two related cognitive processes (concerns about reprisal and discounting of positive outcomes) as partial mediators of the effects of FNEs and FPEs. We built on earlier work by including a broader measure of social anxiety across different social situations and comparing models for groups of participants with and without probable SAD. Structural equation modelling was utilised to test the model in a sample of 890 university students (74.8% female, mean age 29.49). We replicated the findings of Cook et al. in the overall sample and in the group with probable SAD. FNEs and FPEs predicted social anxiety directly and were serially mediated by concerns about reprisal and discounting positive outcomes. The model was also a good fit for those without SAD; however, in the model, FNEs were no longer a direct predictor of social anxiety. The findings confirm the utility of the extended bivalent model and have implications for psychoevolutionary accounts of social anxiety.

Abstract Background This scoping study explored patients’ preoperative perspectives of their expectations, their tolerance for risk, and what factors may influence their decision to undergo hallux valgus surgery. Methods Recently consented patients for hallux valgus surgery at a tertiary public hospital were recruited for this mixed-methods study. Firstly, semi-structured interviews were undertaken to explore attitudes, perceptions, feelings about risk, and expectations of surgery. Following the interview, questionnaires assessing demographics, pain, and health-related quality of life were completed. The data were analysed using NVivo and SPSS. Results Seven participants (Five women; mean age 63, range 47–79, years) were recruited for this study. Foot pain was rated as moderate to high, but catastrophisation and sensitisation were low. Surgery was viewed a definitive resolution and expectations were high. Participants with higher pain had higher expectations and the experience of others was used to judge the chance of a successful outcome. Conclusion People with high foot pain and hallux valgus may have higher expectations of a successful operation. Expectations and acceptance of risk in people having surgery for hallux valgus are optimistic.

Abstract Staphylococcus aureus is an important human commensal which persistently colonizes up to 30% of the human population, predominantly within the nasal cavity. The commensal lifestyle of S. aureus is complex, and the mechanisms underpinning colonization are not fully understood. S. aureus can induce an immunosuppressive environment in the nasal tissue (NT) by driving IL-10 and IL-27 to facilitate nasal colonization, indicating that S. aureus has the capacity to modulate the local immune environment for its commensal habitation. Mounting evidence suggests commensal bacteria drive type 1 interferons (IFN-I) to establish an immunosuppressive environment and whilst S. aureus can induce IFN-I during infection, its role in colonization has not yet been examined. Here, we show that S. aureus preferentially induces IFN signaling in macrophages. This IFN-I in turn upregulates expression of proapoptotic genes within macrophages culminating in caspase-3 cleavage. Importantly, S. aureus was found to drive phagocytic cell apoptosis in the nasal tissue during nasal colonization in an IFN-I dependent manner with colonization significantly reduced under caspase-3 inhibition. Overall, loss of IFN-I signaling significantly diminished S. aureus nasal colonization implicating a pivotal role for IFN-I in controlling S. aureus persistence during colonization through its ability to induce phagocyte apoptosis. Together, this study reveals a novel strategy utilized by S. aureus to circumvent host immunity in the nasal mucosa to facilitate nasal colonization.

Abstract Background Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, PFDR

Abstract Background Diabetes-specific quality of life (QoL) questionnaires are commonly used to assess the impact of diabetes and its management on an individual’s quality of life. While several valid and reliable measures of diabetes-specific QoL exist, there is no consensus on which to use and in what setting. Furthermore, there is limited evidence of their acceptability to people with diabetes. Our aim was to explore perceptions of adults with type 1 diabetes (T1D) toward five diabetes-specific QoL measures. Methods Adults (aged 18 + years) with T1D living in Australia or the United Kingdom (UK) were eligible to take part in ‘YourSAY: QoL’, an online cross-sectional survey. Recruitment involved study promotion on diabetes-related websites and social media, as well as direct invitation of people with T1D via a hospital client list (UK only). In random order, participants completed five diabetes-specific QoL measures: Audit of Diabetes-Dependent Quality of Life (ADDQoL-19); Diabetes Care Profile: Social and Personal Factors subscale (DCP); DAWN Impact of Diabetes Profile (DIDP); Diabetes-Specific Quality of Life Scale: Burden Subscale (DSQoLS); Diabetes Quality of Life Questionnaire (Diabetes QOL-Q). They were invited to provide feedback on each questionnaire in the form of a brief free-text response. Responses were analysed using inductive, thematic template analysis. Results Of the N = 1,946 adults with T1D who completed the survey, 20% (UK: n = 216, Australia: n = 168) provided qualitative responses about ≥ 1 measure. All measures received both positive and negative feedback, across four themes: (1) clarity and ease of completion, e.g., difficulty isolating impact of diabetes, dislike of hypothetical questions, and preference for ‘not applicable’ response options; (2) relevance and comprehensiveness, e.g., inclusion of a wide range of aspects of life to improve personal relevance; (3) length and repetition, e.g., length to be balanced against respondent burden; (4) framing and tone, e.g., preference for respectful language and avoidance of extremes. Conclusions These findings suggest opportunities to improve the relevance and acceptability of existing diabetes-specific QoL measures, and offer considerations for developing new measures, which need to be better informed by the preferences of people living with diabetes.

Early Cenomanian (100.5–95.7 Ma) ammonite faunas from East and North-East Greenland collected by the late Simon Kelly and colleagues are described. The assemblages are dominated by typically boreal Schloenbachia varians (J. Sowerby 1817). Also present are Parapuzosia (Austiniceras) austeni (Sharpe 1855) and species of more typically Tethyan genera. These include Phylloceras (Hypophylloceras) lombardense (Joly 2000), Gaudryceras (Gaudryceras) cassisianum (d’Orbigny 1850), Gaudryceras (Mesogaudryceras) leptonema (Sharpe 1855), and the hypermorphic tetragonitine Titanoleioceras boreale gen. et sp. nov. Previously known only from Geographical Society Ø and Traill Ø, the newly described material extends the distribution of these early Cenomanian faunas northwards to Hold with Hope and south to the Kangerlussuaq Basin. The phylloceratids, gaudryceratids, and tetragonitids in these assemblages are probably not preserved in their preferred original habitats, but rather drifted to their respective sites of burial during or after their lifetime.

Abstract 3D printing technologies such as fused filament fabrication (FFF) offer great opportunities to enable the fabrication of complex geometries without access to a workshop or knowledge of machining. By adding filler materials to the raw filaments used for FFF, the material properties of the plastic can be adapted. With the addition of neutron absorbing particles, filaments can be created that enable 3D printing of neutron shielding with arbitrary geometry. Two materials for FFF are presented with different mixing ratios of hexagonal Boron nitride (h-BN) and Polylactic acid (PLA). BNPLA25 with 25 %wt h-BN and BNPLA35 with 35 %wt h-BN are compared to the commercially available Addbor N25 material. To qualify the applicability of BNPLA25 and BNPLA35 as shielding material for neutron instrumentation, such as neutron imaging, we investigated the overall neutron attenuation, the influence of non-optimized print settings, as well as characterized the incoherent neutron scattering and the microstructure using neutron imaging, and time-of-flight small-angle-neutron-scattering. Finally, the tensile strength of the material was determined in standardized tensile tests. The measured neutron attenuation shows excellent agreement with analytical calculations, thus validating both the material composition and the calculation method. Approximately 6 mm (8 mm) BNPLA35 are needed for $$1\times 10^{-3}$$ 1 × 10 - 3 transmission of a cold (thermal) neutron beam. Lack of extrusion due to suboptimal print settings can be compensated by increased thickness, clearly visible defects can be mitigated by 11–18% increase in thickness. Incoherent scattering is shown to be strongly reduced compared to pure PLA. The tensile strength of the material is shown not to be impacted by the h-BN filler. The good agreement between the measured attenuation and calculation, combined with the adoption of safety factor enables the quick and easy development as well as the performance estimation of shielding components. BNPLA is uniquely suited for 3D printing neutron shielding because of the combination of non-abrasive h-BN particles in standard PLA, which results in a filament that can be printed with almost any off-the-shelf printer and virtually no prior experience in 3D printing. This mitigates the slightly lower attenuation observed as compared to filaments containing $${\hbox {B}_{4}}\hbox {C}$$ B 4 C , which is highly abrasive and requires extensive additive manufacturing experience.

Bowlby remained attached to his psychoanalytic roots and conceptualised treatment in terms of one-to-one relationships, albeit acknowledging the need for a family formulation. Bowlby's five therapeutic tasks were never adapted to the current understanding of working with the relationships fostering the development and maintenance of children's attachment strategies. This paper goes through each of Bowlby's five tasks and adapts them to our current understanding of development, with consequences for prioritising family approaches, rather than a secure base alone with a therapist. In doing so I will review the process of achieving security, seeing it as more similar to an allostatic process than a state of homeostasis.

Abstract Garnet peridotite xenoliths have been rarely reported from suboceanic mantle. Petrographic and geochemical characteristics of garnet-bearing oceanic peridotite xenoliths provide precious information on dynamics of the suboceanic lithosphere and asthenosphere interaction. We examined a lherzolite xenolith included in olivine nephelinite lava from Aitutaki Island, a member of the Cook-Austral volcanic chain. The lherzolite xenolith contains reddish fine-grained (

Background: The Democratic Republic of Congo (DRC) has faced emerging infectious diseases such as Ebola, Mpox and Yellow fever, and antimicrobial resistance is a growing concern. To address these issues, in 2011 the country embarked on implementing the One Health (OH) approach at the national and provincial levels. This study investigates OH institutionalization and implementation in the DRC, describes the process of OH decentralization, and identifies the opportunities and challenges of sustaining these efforts. Methods: We conducted a qualitative study based on literature, document review and key informant interviews. The literature search targeted PubMed, Google Scholar and the document depository of the national One Health platform (NOHP). Key informant identified at the national level included ministry representatives, OH platform members and donors supporting OH implementation. These interviews were conducted in-person and online, recorded, transcribed, and imported into Dedoose software (version 9.2.006) for coding. Content analysis was performed to identify activities, processes, and achievements during the implementation of OH in DRC. Findings: Results of the literature and document review (n = 72) and analysis of stakeholder interviews (n = 24) indicate that a national OH platform, initiated in 2011, is hosted at the Ministry of Higher Education and coordinates other sectors. It comprises governmental departments, academic institutions, and civil society organizations working at the human, animal, and environment sectors. The governance structure includes a national coordinator, a permanent secretariat, technical working groups, and subnational entities at provincial and territorial levels. Following the establishment of the national OH platform, a structured process foresees to facilitate OH implementation at the provincial and territorial levels. Achievements up to today include the development of training programs, establishment of OH committees in some provinces, assessments of workforce needs, formulation of a national strategy, development of governance manuals, and support to the Mpox response coordination.Nevertheless, OH implementation in the DRC faces challenges, including leadership tensions at the national level, inadequate domestic funding, limited training and capacity building for professionals, and insufficient infrastructure for data collection and sharing. Strengthening leadership and coordination, advocating for domestic resource mobilization, and strengthening infrastructure for data collection and sharing while ensuring equity across sectors is essential for advancing the OH agenda and ensuring its efficacy.

Macaques (Macaca spp.) are reported in human-wildlife interaction in anthropogenic areas. The management of human-macaque interactions (HMI) requires an understanding of various perspectives and knowledge. One Health (OH) is a transdisciplinary approach to address the well-being and health of animals, humans, and ecosystems, which supports sustainable management through its three pillars: economy, ecology, and society. Thus, the OH approach could be applied to HMI management. To explore the HMI management within the context of the OH approach, we examined articles related to the management of HMI from 2013 to 2022 following the systematic review by PRISMA guidelines. Ninety-four publications were included in the study. Then, we extracted information on HMI framing, management activities, species, and location and categorized HMI framings and management activities into themes of three OH domains and three pillars of sustainability. We noticed an underrepresentation of the society and economy pillars in HMI management and the ecosystem health domain was the least explored in both the HMI and management activities. When we connected publications addressing all three pillars with OH domains in management activities, the number focused on ecosystem health (3/13) remained limited. The most frequently reported HMI theme was “crop feeding”(n=42) and management activities were “HMI management” (n=42). Most publications lacked any form of evaluation of the HMI management. The challenges to better consider ecosystem health in the HMI and to promote participatory governance present an opportunity to apply the OH approach in wildlife conservation and management.

ABSTRACTThe nuclear envelope (NE) separates translation and transcription and is the location of multiple functions, including chromatin organization and nucleocytoplasmic transport. The molecular basis for many of these functions have diverged between eukaryotic lineages. Trypanosoma brucei, a member of the early branching eukaryotic lineage Discoba, highlights many of these, including a distinct lamina and kinetochore composition. Here, we describe a cohort of proteins interacting with both the lamina and NPC, which we term lamina-associated proteins (LAPs). LAPs represent a diverse group of proteins, including two candidate NPC-anchoring pore membrane proteins (POMs) with architecture conserved with S. cerevisiae and H. sapiens, and additional peripheral components of the NPC. While many of the LAPs are Kinetoplastid specific, we also identified broadly conserved proteins, indicating an amalgam of divergence and conservation within the trypanosome NE proteome, highlighting the diversity of nuclear biology across the eukaryotes, increasing our understanding of eukaryotic and NPC evolution.

Background Patients with pulmonary vascular disease (PVD) often suffer from nocturnal hypoxaemia, but also from sleep apnoea. Short-term use of acetazolamide increases ventilation due to metabolic acidosis and also reduces loop gain. We investigated whether prolonged use of acetazolamide improves sleep disordered breathing in PVD. Methods In a randomised controlled crossover trial, patients with PVD were randomly assigned to acetazolamide 250 mg and placebo twice daily for 5 weeks. Patients underwent respiratory polygraphy at baseline and at the end of each intervention phase. Outcomes of interest were the effect of acetazolamide on mean nocturnal oxygen saturation (SpO2), time with oxygen saturation 5 events·h−1 was reduced from 75% to 60% and with AHI >15 events·h−1 from 30% to 15%. Two patients discontinued the study because of mild side-effects. Conclusions Acetazolamide given for 5 weeks reduces nocturnal hypoxaemia in PVD to a clinically relevant level and reduces the proportion of patients with obstructive sleep apnoea.

Background Hypoxia is a trigger for sympathetic activation and autonomic cardiovascular dysfunction. Pulmonary vascular disease (PVD) is associated with hypoxaemia, which increases with altitude. The aim was to investigate how exposure of patients with PVD to hypobaric hypoxia at altitude affects autonomic cardiovascular regulation. Methods In a randomised crossover study, patients with PVD were studied for 1 day and one night at an altitude of 2500 m (hypobaric hypoxia) and low altitude at 470 m in a random order. Outcomes were heart rate variability (HRV) in the time domain and in the frequency domain (low frequency (LF)/high frequency (HF) and LF/HF) and heart rate (HR) during day and night and baroreflex sensitivity (BRS). Results In 25 patients with PVD (72% pulmonary arterial hypertension and 28% distal chronic thromboembolic pulmonary hypertension; mean±sd age 60.7±13.6 years), exposure to altitude resulted in significant increases in awake HR by 9.4 bpm (95% confidence interval (CI) 6.3–12.4, p

DNA metabarcoding and morphological taxonomic (microscopic) analysis of the gut contents was used to examine diet diversity of seven species of fishes collected from mesopelagic depths (200-1000 m) in the NW Atlantic Ocean Slope Water during Summer 2018 and 2019. Metabarcoding used two gene regions: V9 hypervariable region of nuclear 18S rRNA and mitochondrial cytochrome oxidase I (COI). V9 sequences were classified into 14 invertebrate prey groups, excluding fish due to predator swamping. Ecological network analysis was used to evaluate relative strengths of predator-prey linkages. Multivariate statistical analysis revealed consistently distinct diets of four fish species in 2018 and/or 2019: Argyropelecus aculeatus, Chauliodus sloani, Hygophum hygomii, and Sigmops elongatus. Three other species analyzed (Malacosteus niger, Nemichthys scolopaceus, and Scopelogadus beanii) showed more variability between sampling years. COI sequences were classified into eight invertebrate prey groups, within which prey species were detected and identified. Considering all predator species together, a total of 77 prey species were detected with a minimum of 1,000 COI sequences, including 22 copepods, 18 euphausiids, and 7 amphipods. Morphological prey counts were classified into seven taxonomic groups, including a gelatinous group comprised of soft-bodied organisms. The ocean twilight zone or is home to exceptional diversity and biomass of marine fish, which are key players in deep sea food webs. This study used integrative morphological-molecular analysis to provide new insights into trophic relationships and sources of productivity for mesopelagic fishes, including identification of key prey species, recognition of the importance of gelatinous prey, and characterization of differences in diet among fish predators in the NW Atlantic Slope Water.

While earlier first-generation epigenetic aging clocks were trained to estimate chronological age as accurately as possible, more recent next-generation clocks incorporate DNA methylation information more pertinent to health, lifestyle, and/or outcomes. Recently, we produced a non-invasive next-generation epigenetic clock trained using Infinium MethylationEPIC data from more than 8,000 diverse adult buccal samples. While this clock correlated with various health, lifestyle, and disease factors, we did not assess its ability to capture mortality. To address this gap, we applied CheekAge to the longitudinal Lothian Birth Cohorts of 1921 and 1936. Despite missing nearly half of its CpG inputs, CheekAge was significantly associated with mortality in this longitudinal blood dataset. Specifically, a change in one standard deviation corresponded to a hazard ratio (HR) of 1.21 (FDR q = 1.66e-6). CheekAge performed better than all first-generation clocks tested and displayed a comparable HR to the next-generation, blood-trained DNAm PhenoAge clock (HR = 1.23, q = 2.45e-9). To better understand the relative importance of each CheekAge input in blood, we iteratively removed each clock CpG and re-calculated the overall mortality association. The most significant effect came from omitting the CpG cg14386193, which is annotated to the gene ALPK2. Excluding this DNA methylation site increased the FDR value by nearly threefold (to 4.92e-06). We additionally performed enrichment analyses of the top annotated CpGs that impact mortality to better understand their associated biology. Taken together, we provide important validation for CheekAge and highlight novel CpGs that underlie a newly identified mortality association.

Abstract Background Epigenetic scores (EpiScores), reflecting DNA methylation (DNAm)-based surrogates for complex traits, have been developed for multiple circulating proteins. EpiScores for pro-inflammatory proteins, such as C-reactive protein (DNAm CRP), are associated with brain health and cognition in adults and with inflammatory comorbidities of preterm birth in neonates. Social disadvantage can become embedded in child development through inflammation, and deprivation is overrepresented in preterm infants. We tested the hypotheses that preterm birth and socioeconomic status (SES) are associated with alterations in a set of EpiScores enriched for inflammation-associated proteins. Results In total, 104 protein EpiScores were derived from saliva samples of 332 neonates born at gestational age (GA) 22.14 to 42.14 weeks. Saliva sampling was between 36.57 and 47.14 weeks. Forty-three (41%) EpiScores were associated with low GA at birth (standardised estimates |0.14 to 0.88|, Bonferroni-adjusted p-value

Abstract Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes that link substrate release and opening of the cytoplasmic gate and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.

Abstract Carbonaceous material (CM) undergoes progressive changes that reflect its thermal history. These changes are in general irreversible and provide valuable information for understanding diagenetic and metamorphic processes of crustal rocks. Among various approaches to quantify these changes, the R2 ratio, area ratio of specific peaks in CM Raman spectra, is widely used to estimate the maximum temperature of intermediate- to moderately high-grade metamorphism. The calculation of the R2 ratio requires peak deconvolution of the original spectrum, and the results depend on the details of how this is carried out. However, a clear protocol for selecting appropriate initial conditions has not been established and obtaining a reliable temperature estimate depends at least in part on the experience and skill of the operator. In this study, we developed a Python code that automatically calculates the R2 ratio from CM Raman spectra. Our code produces R2 ratios that are generally in good agreement with those of Aoya et al. (J Metamorph Geol 28:895–914, 2010, https://doi.org/10.1111/j.1525-1314.2010.00896.x ) for the same Raman data, with much less time and effort than was the case in the previous studies. We have confirmed that the code is also applicable to other previous datasets from both contact and regional metamorphic regions. The overall trend of the recalculated data indicates that samples with R2 greater than ~ 0.7 are not sensitive to the changes in CM maturity and thus should not be used for the calibration of an R2-based geothermometer. We propose a modified geothermometer for contact metamorphism that is strictly applicable to samples with R2 from 0.023 to 0.516, with the proviso that a laser with a wavelength of 532 nm should be used. A slight extrapolation of the newly proposed geothermometer up to R2 of 0.57 provides a temperature estimate that is consistent with the geothermometer of Kaneki and Kouketsu (Island Arc 31:e12467, 2022; https://doi.org/10.1111/iar.12467 ); the boundary between the two geothermometers corresponds to a temperature of 391 °C.

A 2022 canine gastroenteritis outbreak in the United Kingdom was associated with circulation of a new canine enteric coronavirus closely related to a 2020 variant with an additional spike gene recombination. The variants are unrelated to canine enteric coronavirus–like viruses associated with human disease but represent a model for coronavirus population adaptation.

Abstract Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.

Abstract Background To tag large marine vertebrates, without the need to catch them, avoiding using barbs for tag retention, and precisely controlling tag location, the remote Tag Attachment Device on a pole (TADpole) was developed. This allows single-pin tags (Finmount, Wildlife Computers) to be attached to the dorsal fins of free-swimming large marine vertebrates. Results TADpole comprises a pole-mounted holster that carries a tag. It uses compressed air, and a micro-controller, to rapidly insert a stainless-steel pin through a corrodible metal retaining ring in the first tag attachment wing, the animal’s dorsal fin, and then a press fit Delrin retaining ring in the tag wing on the other side of the fin. Tagging only occurs when the trailing edge of the dorsal fin touches a trigger bar in the holster, ensuring optimal pin placement. It was developed using fins from cadavers, then trialed on briefly restrained coastal dolphins that could be followed in successive days and weeks, and then on free-swimming animals in the field. The latter showed very short touch/response intervals and highlighted the need for several iterative revisions of the pneumatic system. This resulted in reducing the total time from triggering to tag application to ~ 20 ms. Subsequent efforts expanded the TADpole’s applicability to sharks. One free-swimming Atlantic spotted dolphin, two white sharks, and one whale shark were then tagged using the TADpole. Conclusions Being able to tag free-swimming dolphins and sharks remotely and precisely with satellite-linked telemetry devices may contribute to solving conservation challenges. Sharks were easier to tag than dolphins. Dolphin touch-to-response times were 28 ms or less. Delphinid skin has unique polymodal axon bundles that project into the epidermis, perhaps a factor in their uniquely fast response, which is 10 × faster than humans. Their primary reaction to tagging is to abduct the flippers and roll the fin out of the TADpole holster. This device has the potential to deliver high-quality tag data from large vertebrates with dorsal fins without the stress and logistics associated with catch-and-release, and without the trauma of tags that use barbs for retention. It also collects a dorsal fin biopsy core.

Abstract Background Kinetic modeling of 18F-florbetaben provides important quantification of brain amyloid deposition in research and clinical settings but its use is limited by the requirement of arterial blood data for quantitative PET. The total-body EXPLORER PET scanner supports the dynamic acquisition of a full human body simultaneously and permits noninvasive image-derived input functions (IDIFs) as an alternative to arterial blood sampling. This study quantified brain amyloid burden with kinetic modeling, leveraging dynamic 18F-florbetaben PET in aorta IDIFs and the brain in an elderly cohort. Methods 18F-florbetaben dynamic PET imaging was performed on the EXPLORER system with tracer injection (300 MBq) in 3 individuals with Alzheimer’s disease (AD), 3 with mild cognitive impairment, and 9 healthy controls. Image-derived input functions were extracted from the descending aorta with manual regions of interest based on the first 30 s after injection. Dynamic time-activity curves (TACs) for 110 min were fitted to the two-tissue compartment model (2TCM) using population-based metabolite corrected IDIFs to calculate total and specific distribution volumes (VT, Vs) in key brain regions with early amyloid accumulation. Non-displaceable binding potential ( $$ {BP}_{ND})$$ was also calculated from the multi-reference tissue model (MRTM). Results Amyloid-positive (AD) patients showed the highest VT and VS in anterior cingulate, posterior cingulate, and precuneus, consistent with $$ {BP}_{ND}$$ analysis. $$ {BP}_{ND} $$ and VT from kinetic models were correlated (r² = 0.46, P

Background: Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at elevated risk of developing psychiatric illness owing to both genetic predisposition and increased burden of environmental stress. Emerging evidence indicates a disruption of brain network connectivity in young offspring of patients with bipolar disorder and schizophrenia, but the age trajectories of these brain networks in this high-familial-risk population remain to be elucidated. Methods: A total of 271 T1-weighted and diffusion-weighted scans were obtained from 174 offspring of at least 1 parent diagnosed with bipolar disorder (n = 74) or schizophrenia (n = 51) and offspring of parents without severe mental illness (n = 49). The age range was 8 to 23 years; 97 offspring underwent 2 scans. Anatomical brain networks were reconstructed into structural connectivity matrices. Network analysis was performed to investigate anatomical brain connectivity. Results: Offspring of parents with schizophrenia had differential trajectories of connectivity strength and clustering compared with offspring of parents with bipolar disorder and parents without severe mental illness, of global efficiency compared with offspring of parents without severe mental illness, and of local connectivity compared with offspring of parents with bipolar disorder. Conclusions: The findings of this study suggest that familial high risk of schizophrenia is related to deviations in age trajectories of global structural connectome properties and local connectivity strength.

The structural integrity of myelin sheaths in the central nervous system (CNS) is crucial for the maintenance of its function. Electron microscopy (EM) is the gold standard for visualizing individual myelin sheaths. However, the tissue processing involved can induce artifacts such as shearing of myelin, which can be difficult to distinguish from true myelin abnormalities. Spectral confocal reflectance (SCoRe) microscopy is an imaging technique that leverages the differential refractive indices of compacted CNS myelin in comparison to surrounding parenchyma to detect individual compact myelin internodes with reflected light, positioning SCoRe as a possible complementary method to EM to assess myelin integrity. Whether SCoRe is sensitive enough to detect losses in myelin compaction when myelin quantity is otherwise unaffected has not yet been directly tested. Here, we assess the capacity of SCoRe to detect differences in myelin compaction in two mouse models that exhibit a loss of myelin compaction without demyelination: microglia-deficient mice (Csf1r-FIREΔ/Δ) and wild-type mice fed with the CSF1R inhibitor PLX5622. In addition, we compare the ability to detect compact myelin sheaths using SCoRe in fixed-frozen versus paraffin-embedded mouse tissue. Finally, we show that SCoRe can successfully detect individual sheaths in aged human paraffin-embedded samples of deep white matter regions. As such, we find SCoRe to be an attractive technique to investigate myelin integrity, with sufficient sensitivity to detect myelin ultrastructural abnormalities and the ability to perform equally well in tissue preserved using different methods.

Abstract Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E–17 and 1.78E–11) and WBFFM (p = 2.88E–08 and 8.24E–12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass.

Abstract Background Epigenetic Scores (EpiScores) for blood protein levels have been associated with disease outcomes and measures of brain health, highlighting their potential usefulness as clinical biomarkers. They are typically derived via penalised regression, whereby a linear weighted sum of DNA methylation (DNAm) levels at CpG sites are predictive of protein levels. Here, we examine 84 previously published protein EpiScores as possible biomarkers of cross-sectional and longitudinal measures of general cognitive function and brain health, and incident dementia across three independent cohorts. Results Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, P FDR

Abstract DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Abstract Background Lymphangioleiomyomatosis (LAM) is common in tuberous sclerosis complex (TSC) yet under recognised with management mostly based upon evidence obtained from patients with sporadic LAM. We performed a prospective audit of patients with TSC-LAM attending a national referral centre to inform management guidelines. Methods The UK LAM Centre was established in 2011 and conducts a prospective audit of pre-defined quality outcomes for all subjects. Audit data are reported on all patients with TSC-LAM and a comparator population of patients with sporadic LAM. Results Between 2011 and 2022, 73 patients were seen with TSC-LAM. All were women with a mean (SD) age of 39 (12) years. Referral rates were similar over the study period including after the introduction of CT screening. Median age of diagnosis with TSC was 11 years (range 0–70) with one third diagnosed with TSC as adults. Compared with all TSC patients in the ‘TOSCA’ registry, TSC-LAM patients tended to have been diagnosed with TSC at an older age, had fewer neuro-cognitive manifestations and were more likely to have angiomyolipoma. The most common presentations of TSC-LAM were following workup for angiomyolipoma, pneumothorax or dyspnoea with only one fifth detected after CT screening. Baseline FEV1 and DLCO at first assessment were reduced to 77 and 63% predicted respectively and were similar to patients with sporadic LAM. During follow-up, FEV1 fell by a mean of 81 ml/year and DLCO fell by 0.309 mmol/ml/kPa/year in patients not being treated with an mTOR inhibitor. 55% required treatment with either sirolimus or Everolimus for LAM or angiomyolipoma respectively. For those treated with an mTOR inhibitor, mean FEV1 fell by 3 ml/year and DLCO increased by 0.032 mmol/ml/kPa/year and was similar to sporadic LAM. Risk of death due to LAM or need for lung transplant in patients with TSC-LAM was 0.67%/year. Conclusions Despite screening recommendations, LAM is often diagnosed in TSC after symptoms develop which may delay treatment. Complications including pneumothorax and loss of lung function are significant and similar to sporadic LAM. Work is needed to implement the recommended CT screening for LAM and improve respiratory care for TSC-LAM.

Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Abstract Background Seizure emergencies (ie, status epilepticus [SE] and cluster seizures [CS]), are common challenging disorders with complex pathophysiology, rapidly progressive drug‐resistant and self‐sustaining character, and high morbidity and mortality. Current treatment approaches are characterized by considerable variations, but official guidelines are lacking. Objectives To establish evidence‐based guidelines and an agreement among board‐certified specialists for the appropriate management of SE and CS in dogs and cats. Animals None. Materials and Methods A panel of 5 specialists was formed to assess and summarize evidence in the peer‐reviewed literature with the aim to establish consensus clinical recommendations. Evidence from veterinary pharmacokinetic studies, basic research, and human medicine also was used to support the panel's recommendations, especially for the interventions where veterinary clinical evidence was lacking. Results The majority of the evidence was on the first‐line management (ie, benzodiazepines and their various administration routes) in both species. Overall, there was less evidence available on the management of emergency seizure disorders in cats in contrast to dogs. Most recommendations made by the panel were supported by a combination of a moderate level of veterinary clinical evidence and pharmacokinetic data as well as studies in humans and basic research studies. Conclusions and Clinical Relevance Successful management of seizure emergencies should include an early, rapid, and stage‐based treatment approach consisting of interventions with moderate to preferably high ACVIM recommendations; management of complications and underlying causes related to seizure emergencies should accompany antiseizure medications.

Abstract The distribution of different stress states in the subducting slab indicated by centroid moment tensor solutions for intra-slab earthquakes can help constrain the rheological properties of the slabs. A comparison of slabs in the western and eastern Pacific realms shows contrasting patterns in the stress states down to depths of ~ 350 km. The majority of slabs in the western Pacific show a pair of down-dip compression (DC) and down-dip tension (DT) domains in the upper and lower parts of the slab reflecting the effects of the slab unbending during progressive subduction. In contrast, slabs in the eastern Pacific show predominantly in-plane DT stress irrespective of slab geometry. Two-dimensional numerical simulations assuming constant slab thickness and viscosity indicate that the development of slabs with in-plane DT stress at depths of 100–300 km requires the slabs to be thin and have a low viscosity (1023 Pa s). Weak slabs bend easily and tend to fold when they encounter increased resistance to downward movement at the 660-km boundary. The associated DC stresses are not transmitted up the slab so negative buoyancy of the slab and DT stress dominates at intermediate depths for this type of slab. Most experimentally derived rheological parameters predict a high viscosity (> 1024 Pa s) for such slabs. However, two-dimensional numerical simulations using temperature- and pressure-dependent viscosity show that a relatively low activation energy (~ 110 kJ/mol) for diffusion creep is a possible explanation for the observed distribution of stresses in the slabs. Such low activation energies are compatible with recent experimental work on diffusion creep of polyphase mantle materials in which a low effective activation energy for creep results from a slow grain growth due to pinning effect of the secondary phase. The simulations provide a mechanical explanation for the observed dominantly DT stress state at 100–300 km depths for young slabs and paired DT and DC stress states at the same depth range for old slabs. Graphical Abstract

Many new methods for single atom skeletal editing of heterocycles have been developed in the past few years with obvious applications to discovery chemistry. In this perspective, we assess the recent advances in this field and the potential application to lead exploration campaigns.

Objective: To investigate the ventilatory and circulatory differences between eccentric (ECC) and concentric (CON) cycling exercise at submaximal, low-dose intensity from onset to end-exercise in healthy middle-aged participants. Design: Randomized controlled crossover trial. Setting: The participants underwent 1 ECC and 1 CON test according to stepwise incremental exercise protocols at identical, submaximal intensities. Breath-by-breath analyses of ventilatory gas exchange and echocardiography were used to assess cardiopulmonary function during exercise. Participants: 24 healthy middle-aged, untrained participants (14 women, 10 men, 50±14 years) were included. Interventions: 1 ECC and 1 CON test at submaximal intensities. Main Outcome Measure: The main outcome was oxygen uptake (V'O2). Results: The V'O2 increase was reduced by -422 mL/min (-52%, 95% confidence interval: -513 to -292, P

Dynamic PET allows quantification of physiological parameters through tracer kinetic modeling. For dynamic imaging of brain or head and neck cancer on conventional PET scanners with a short axial field of view, the image-derived input function (ID-IF) from intracranial blood vessels such as the carotid artery (CA) suffers from severe partial volume effects. Alternatively, optimization-derived input function (OD-IF) by the simultaneous estimation (SIME) method does not rely on an ID-IF but derives the input function directly from the data. However, the optimization problem is often highly ill-posed. We proposed a new method that combines the ideas of OD-IF and ID-IF together through a kernel framework. While evaluation of such a method is challenging in human subjects, we used the uEXPLORER total-body PET system that covers major blood pools to provide a reference for validation. Methods: The conventional SIME approach estimates an input function using a joint estimation together with kinetic parameters by fitting time activity curves from multiple regions of interests (ROIs). The input function is commonly parameterized with a highly nonlinear model which is difficult to estimate. The proposed kernel SIME method exploits the CA ID-IF as a priori information via a kernel representation to stabilize the SIME approach. The unknown parameters are linear and thus easier to estimate. The proposed method was evaluated using 18F-fluorodeoxyglucose studies with both computer simulations and 20 human-subject scans acquired on the uEXPLORER scanner. The effect of the number of ROIs on kernel SIME was also explored. Results: The estimated OD-IF by kernel SIME showed a good match with the reference input function and provided more accurate estimation of kinetic parameters for both simulation and human-subject data. The kernel SIME led to the highest correlation coefficient (R = 0.97) and the lowest mean absolute error (MAE = 10.5 %) compared to using the CA ID-IF (R = 0.86, MAE = 108.2 %) and conventional SIME (R = 0.57, MAE = 78.7 %) in the human-subject evaluation. Adding more ROIs improved the overall performance of the kernel SIME method. Conclusion: The proposed kernel SIME method shows promise to provide an accurate estimation of the blood input function and kinetic parameters for brain PET parametric imaging.

A novel multi-technique approach has been applied for the identification and mapping of wild orchids using a combination of remote sensing and spectral image analysis. The five orchid species identified were the common spotted-orchid (Dactylorhiza fuchsia), heath spotted-orchid (Dactylorhiza maculata), pyramidal orchid (Anacamptis pyramidalis), heath fragrant-orchid (Gymnadenia borealis), and the dark-red helleborine (Epipactis atrorubens). Field studies have been done using a hand-held spectrometer operating in the 400–700 nm visible spectrum, photogrammetry using a digital camera as well as a multispectral image camera operating at the specific spectral bands of 450 nm (blue), 560 nm (green), 650 nm (red), 730 nm (red edge) and 840 nm (near-infrared) attached to an unmanned aerial vehicle Data analysis, using the hand-held spectrometer, followed by pattern recognition using principal component analysis and partial least squares-discriminant analysis, have identified the key distinguishing wavelengths for identification of the 5 orchid types as 400, 410, 420 and 560 nm. The use of remote sensing, using the UAV-MSI, and application of a dedicated spectral index has enabled field identification of the orchids. Finally, object-based image analysis of field gathered photogrammetry imagery, has enabled use of shape, size, and color to identify and distinguish orchid species. The developed data analytic tool, using random forest classification, can be used to identify and characterize wild orchids across multiple sites within their short lifespan with an accuracy of 86%. Any longer-term study would provide invaluable information on the diversity and complexity of orchid habitat, population variation both intra- and inter-site location, as well as the impact of climate change.

Abstract Background Epigenetic scores (EpiScores) can provide biomarkers of lifestyle and disease risk. Projecting new datasets onto a reference panel is challenging due to separation of technical and biological variation with array data. Normalisation can standardise data distributions but may also remove population-level biological variation. Results We compare two birth cohorts (Lothian Birth Cohorts of 1921 and 1936 — nLBC1921 = 387 and nLBC1936 = 498) with blood-based DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examine the effect of 16 normalisation methods on a novel BMI EpiScore (trained in an external cohort, n = 18,413), and Horvath’s pan-tissue DNA methylation age, when the cohorts are normalised separately and together. The BMI EpiScore explains a maximum variance of R 2=24.5% in BMI in LBC1936 (SWAN normalisation). Although there are cross-cohort R 2 differences, the normalisation method makes a minimal difference to within-cohort estimates. Conversely, a range of absolute differences are seen for individual-level EpiScore estimates for BMI and age when cohorts are normalised separately versus together. While within-array methods result in identical EpiScores whether a cohort is normalised on its own or together with the second dataset, a range of differences is observed for between-array methods. Conclusions Normalisation methods returning similar EpiScores, whether cohorts are analysed separately or together, will minimise technical variation when projecting new data onto a reference panel. These methods are important for cases where raw data is unavailable and joint normalisation of cohorts is computationally expensive.

Abstract Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Abstract Igneous rocks associated with the Cretaceous to Paleogene volcanic arc in SW Japan show ages that young from west to east in a direction parallel to the Median Tectonic Line suggesting corresponding translation of a heat source traditionally interpreted in terms of oblique subduction of a spreading ridge. However, recent oceanic plate reconstructions suggest ridge subduction may be younger than the main arc activity. Age compilations of 1227 points of felsic to intermediate Cretaceous and Cenozoic igneous rocks from the Japan arc show arc magmatism that can be separated into an early active period 130–60 Ma (stage 1), a subsequent period of quiescence 60–46 Ma (stage 2), which is followed by a resumption of igneous activity from 46 Ma onward (stage 3). In southwest Japan, the orientations of the magmatic arcs of stages 1 and 3 show and angular discordance of about 20°. The lack of active arc magmatism and the occurrence patterns of adakitic and high-Mg andesitic magmas indicate that ridge subduction occurred during stage 2. The arc age distribution pattern of stage 1 is explained by the slab shallowing related to a younging of the subducting slab as the ridge approaches. Furthermore, the obliquity of the arcs formed at stages 1 and 3 is explained by a 20° clockwise rotation of the inner zone of southwest Japan during the ridge-subduction phase. Oceanic plate reconstructions show counterclockwise rotation in the subduction direction after the ridge subduction phase, and coupling of the subducting oceanic plate with the upper plate would support microplate rotation in the inner zone. The new proposed tectonic reconstructions provide a framework to related Paleogene subduction of an active spreading ridge along the east Asia margin not only to the distribution of granitic bodies but also to rift-related basin formation on the eastern margin of the Eurasian continent and to rotation of crustal blocks indicated by paleomagnetic data of Cretaceous terranes.

Background: Atlanto-axial (AA) subluxation can be a complex syndrome in dogs. Accurate identification and assessment of this condition is key to providing treatment and resolution. Aim: The purpose of this retrospective study was to describe the magnetic resonance imaging (MRI) characteristics of AA subluxation and associated neurologic deficits. Methods: A multicenter review of dogs with a diagnosis of AA subluxation was conducted, evaluating signalment, neurologic grade, duration of signs, and MRI characteristics. MRI characteristics included degree of spinal cord compression and joint subluxation, integrity of odontoid ligaments, presence of a dens, spinal cord signal intensity, and presence of syringohydromyelia, hydrocephalus, and Chiari-like malformation. A control population with normal AA joints was also evaluated. MR images of 42 dogs with AA subluxation were compared to 26 age and breed-matched control dogs. Results: Affected dogs had a median age of 27 months and median weight of 2.7 kg, and the most commonly affected breed was Yorkshire terrier (47.5%). Spinal cord signal hyperintensity, increased AA joint size, and cross-sectional cord compression at the level of the dens and mid-body C2 were associated with AA subluxation. No associations were found between cord compression, appearance of the dens, or cord signal intensity and neurologic grade. Affected dogs did not have a higher incidence of Chiari-like malformation, syringohydromyelia, or hydrocephalus than control dogs, and their neurologic grade was not associated with MRI findings. Lack of a dens and/or odontoid ligaments was associated with larger subluxations. Conclusion: Dogs with clinical signs of AA subluxation were significantly more likely to have intramedullary hyperintensity at the level of compression (p=0.0004), an increased AA joint cavity size (p=0.0005), and increased spinal cord compression at the level of dens and mid-body C2 (p=1.4mm and a subluxation distance >2.5mm as cutoffs for MRI diagnosis of AA subluxation in dogs. No differences were noted between dogs with AA subluxation and control dogs regarding syringohydromyelia, hydrocephalus, and Chiari-like malformation. [Open Vet J 2023; 13(9.000): 1091-1098]

This paper presents software for calculating the optimal mass of samples with complex compositions (e.g. supported metal catalysts) for X-ray absorption spectroscopy (XAS) and scattering measurements. The ability to calculate the sample mass and other relevant parameters needed for an XAS measurement allows experimentalists to be better prepared in terms of detector selection, energy range of scan and overall time needed to complete the measurement, thus increasing efficiency. CatMass builds on existing sample mass calculators allowing users to determine the optimum sample preparation, collection geometry, usable energy range for a scan and approximate edge step of the absorption event. Visualization tools present the absorption calculation results in a format familiar to XAS experimentalists, with the added ability to save calculations and plots for future reference or recalculation. CatMass is a program broadly applicable in catalysis and is helpful for users with complex samples due to composition/stoichiometry or multiple competing elements.

Abstract Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Abstract Background Randomised controlled trials are often beset by problems with poor recruitment and retention. Information to support decisions on trial participation is usually provided as printed participant information sheets (PIS), which are often long, technical, and unappealing. Multimedia information (MMI), including animations and videos, may be a valuable alternative or complement to a PIS. The Trials Engagement in Children and Adolescents (TRECA) study compared MMI to PIS to investigate the effects on participant recruitment, retention, and quality of decision-making. Methods We undertook six SWATs (Study Within A Trial) within a series of host trials recruiting children and young people. Potential participants in the host trials were randomly allocated to receive MMI-only, PIS-only, or combined MMI + PIS. We recorded the rates of recruitment and retention (varying between 6 and 26 weeks post-randomisation) in each host trial. Potential participants approached about each host trial were asked to complete a nine-item Decision-Making Questionnaire (DMQ) to indicate their evaluation of the information and their reasons for participation/non-participation. Odds ratios were calculated and combined in a meta-analysis. Results Data from 3/6 SWATs for which it was possible were combined in a meta-analysis (n = 1758). Potential participants allocated to MMI-only were more likely to be recruited to the host trial than those allocated to PIS-only (OR 1.54; 95% CI 1.05, 2.28; p = 0.03). Those allocated to combined MMI + PIS compared to PIS-only were no more likely to be recruited to the host trial (OR = 0.89; 95% CI 0.53, 1.50; p = 0.67). Providing MMI rather than PIS did not impact on DMQ scores. Once children and young people had been recruited to host trials, their trial retention rates did not differ according to intervention allocation. Conclusions Providing MMI-only increased the trial recruitment rate compared to PIS-only but did not affect DMQ scores. Combined MMI + PIS instead of PIS had no effect on recruitment or retention. MMIs are a useful tool for trial recruitment in children and young people, and they could reduce trial recruitment periods.

Alternaria solani is the second most devastating foliar pathogen of potato crops worldwide, causing premature defoliation of the plants. This disease is currently prevented through the regular application of detrimental crop protection products and is guided by early warnings based on weather predictions and visual observations by farmers. To reduce the use of crop protection products, without additional production losses, it would be beneficial to be able to automatically detect Alternaria solani in potato fields. In recent years, the potential of deep learning in precision agriculture is receiving increasing research attention. Convolutional Neural Networks (CNNs) are currently the state of the art, but also come with challenges, especially regarding in-field robustness. This stems from the fact that they are often trained on datasets that are limited in size or have been recorded in controlled environments, not necessarily representative of real-world settings. We collected a dataset consisting of ultra-high-resolution modified RGB UAV-imagery of both symptomatic and non-symptomatic potato crops in the field during various years and disease stages to cover the great variability in agricultural data. We developed a convolutional neural network to perform in-field detection of Alternaria, defined as a binary classification problem. Our model achieves a similar accuracy as several state-of-the-art models for disease detection, but has a much lower inference time, which enhances its practical applicability. By using training data of three consecutive growing seasons (2019, 2020 and 2021) and test data of an independent fourth year (2022), an F1 score of 0.93 is achieved. Furthermore, we evaluate how different properties of the dataset such as its size and class imbalance impact the obtained accuracy.

Background: Lower childhood intelligence test scores are reported in some studies to be associated with higher risk of depression in adulthood. The reasons for the association are unclear. This longitudinal data-linkage study explored the relationship between childhood intelligence (at age ∼11) and risk of depression in later-life (up to age ∼85), and whether childhood family structure and adulthood socio-economic and geographical factors accounted for some of this association. Methods: Intelligence test scores collected in the Scottish Mental Survey 1947 were linked to electronic health records (hospital admissions and prescribing data) between 1980 and 2020 (n = 53,037), to identify diagnoses of depression. Mixed-effect Cox regression models were used to explore the relationship between childhood intelligence test scores and risk of depression in later-life. Analyses were also adjusted for childhood family structure (size of family) and adulthood socio-economic and geographical factors (Carstairs index, urban/rural). Results: Twenty-seven percent of participants were diagnosed with depression during follow-up (n = 14,063/53,037). Greater childhood intelligence test scores were associated with a reduced risk of depression in an unadjusted analysis (HR = 0.95, 95% CI = 0.93 to 0.97, P

IntroductionChronic rhinosinusitis causes severe symptoms that can affect patient quality of life. Endoscopic sinus surgery can be effective in improving symptoms, although surgical outcomes can be compromised post-operatively, and revision surgery is required in a proportion of patients. This study compares outcomes and healthcare resource use in patients undergoing sinus surgery with or without Chitogel as a post-operative dressing.MethodsA retrospective cohort study was conducted using deidentified audit data from adult patients with severe chronic rhinosinusitis, who underwent endoscopic sinus surgery between January 2016 and December 2021. Patients in the intervention group received Chitogel as a post-operative dressing, and control patients received standard best-practice care. Cox Proportional Hazards survival analysis was used to compare revision surgery rates and time to revision between treatment groups. The rate of revision surgery was used to estimate potential health sector savings associated with use of Chitogel following surgery compared to the control arm, considering initial treatment costs and the cost of revision surgery.ResultsOver 18–24 months, patients treated with Chitogel demonstrated significantly lower rates of revision surgery (p = 0.035), and a trend towards decreased use of post-operative steroids, compared to control. Potential health sector savings due to reduced rates of revision surgery following use of Chitogel are estimated as NZ $753,000 per 100 patients.ConclusionSevere chronic rhinosinusitis patients treated with Chitogel had lower rates of revision surgery within the first 18–24 months post-operative. These findings suggest that use of Chitogel can improve long-term patient outcomes and should improve health system efficiency.