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Abstract Impacts of environmental complexity on affective states in slow-growing broiler chickens (Gallus gallus domesticus) are unknown. Chickens’ performance in judgment bias tests (JBT) can be limited as they are tested individually, causing fear and anxiety. The objectives were to apply a social-pair JBT to assess the effect of environmental complexity on slow-growing broiler chickens` affective states, and assess the impact of fearfulness, anxiety, and chronic stress on JBT performance. Six-hundred Hubbard Redbro broilers were housed in six low-complexity (similar to commercial) or six high-complexity (permanent and temporary enrichments) pens. Twelve chicken pairs were trained (1 pair/pen, n = 24 chickens) using a multimodal approach (visual and spatial cues), with reward and neutral cues of opposing color and location. Three ambiguous cues were tested: near-positive, middle, and near-neutral cues. Approach and pecking behavior were recorded. Eighty-three percent of chickens (20/24) were successfully trained in 13 days. Fearfulness, anxiety, and chronic stress did not impact chickens’ performance. Chickens successfully discriminated between cues. Low-complexity chickens approached the middle cue faster than high-complexity chickens, indicating that they were in a more positive affective state. The environmental complexity provided in this study did not improve affective states in slow-growing broiler chickens compared to a control. A social-pair JBT resulted in excellent learning and testing outcomes in slow-growing broilers.

Abstract Affective state can bias an animal’s judgement. Animals in positive affective states can interpret ambiguous cues more positively (“optimistically”) than animals in negative affective states. Thus, judgement bias tests can determine an animal’s affective state through their responses to ambiguous cues. We tested the effects of environmental complexity and stocking density on affective states of broiler chickens through a multimodal judgement bias test. Broilers were trained to approach reinforced locations signaled by one color and not to approach unreinforced locations signaled by a different color. Trained birds were tested for latencies to approach three ambiguous cues of intermediate color and location. Broilers discriminated between cues, with shorter latencies to approach ambiguous cues closest to the reinforced cue than cues closest to the unreinforced cue, validating the use of the test in this context. Broilers housed in high-complexity pens approached ambiguous cues faster than birds in low-complexity pens–an optimistic judgement bias, suggesting the former were in a more positive affective state. Broilers from high-density pens tended to approach all cues faster than birds from low-density pens, possibly because resource competition in their home pen increased food motivation. Overall, our study suggests that environmental complexity improves broilers’ affective states, implying animal welfare benefits of environmental enrichment.

The diagnostic criteria for autism spectrum disorder in the DSM-5-TR features the option to designate levels of support for social communication (SC) and restricted, repetitive behaviors (RRB). These levels are conceptual in nature, but research indicates standardized assessment outcomes correspond with clinician-assigned levels of support. The purpose of the present study was to identify factors that influence designated levels of support for SC and RRBs when diagnosing autism. Standardized assessment scores across intellectual functioning, adaptive skills, and ASD symptomology were analyzed to determine corresponding levels of support in SC and RRBs assigned by clinicians for 136 autistic children following a comprehensive diagnostic evaluation. At diagnosis, approximately 46% of participants were described as needing substantial support (Level 2) for SC and 49% were described as needing substantial support (Level 2) for RRB. There was a consistent pattern of higher to lower intellectual and adaptive functioning needing Level 1-Level 3 support. Autism assessment results followed a gradient of fewer to greater autism symptoms from Level 1 to Level 3 support. Findings indicated clinician-assigned levels of support for SC and RRB were associated with intellectual functioning, adaptive functioning, autism symptomology, and age, but not sex.

Project INTERprofessional Autism Collaborative Training (INTERACT) is an interprofessional education program designed to prepare graduate students in psychology, special education, and speech-language pathology to work with autistic children with moderate to severe intellectual disabilities. The rising prevalence of autism, coupled with increased appreciation for interprofessional approaches to service delivery, indicates the need for university training programs to prepare graduate students to work interprofessionally with this population; yet descriptions of such programs and their effectiveness are not reported in the literature. In this article, we explain the process through which an interprofessional faculty team developed Project INTERACT, describe the sequence of coursework and team-based clinical experiences that comprise the program, and present preliminary data regarding its effectiveness. Twenty-four graduate students in psychology, special education, and speech-language pathology participated in this quantitative study. We report results from three rating scales that participants completed at program entry, midpoint, and program exit. Participants endorsed positive attitudes toward interprofessional practice and demonstrated high levels of knowledge about autism. Self-rated knowledge and abilities in interprofessional practice increased significantly by program exit. Project INTERACT scholars developed knowledge and skills related to understanding, assessing, and treating autistic children with intellectual disabilities, through the lens of team-based interprofessional collaboration. We discuss implications for practice with Project INTERACT.

Abstract Voltage-gated sodium channels (NaV) are complex macromolecular proteins that are responsible for the initial upstroke of an action potential in excitable cells. Appropriate function is necessary for many physiological processes such as heartbeat, voluntary muscle contraction, nerve conduction, and neurological function. Dysfunction can have life-threatening consequences. During the past decade, there have been significant advancements with ion channel structural characterization by CryoEM, yet descriptions of cytosolic components are often lacking. Many investigations have biophysically characterized reconstituted cytosolic components and their interactions. However, extrapolating the structural alterations and allosteric communication within an intact ion channel can be challenging. To address this, we have developed an all-atom model of the human cardiac sodium channel (NaV1.5) in a lipid bilayer with explicit salt and water. Our simulations contain descriptions of cytosolic components that are poorly predicted by AlphaFold and lacking in many CryoEM structures. Leveraging the latest advancements of the Amber force fields (ff19sb and Lipid21) and water model (OPC), our simulations improved protein backbone torsion angles and generated structural information across time (four independent one-microsecond simulations). Our analysis provided descriptions of lipid and solvent contacts and insight into the C-Terminal Domain - inactivation gate and inactivation gate - latch receptor interactions.

Abstract As renewable energy continues its rapid expansion in the Unites States, multi-decadal hourly datasets of electricity production are needed to asses reliability and resource adequacy of power grids. Recent years have seen the release of grid-cell-level simulated meteorological variables, however these are not extended to the power domain, are not developed from a dynamically consistent numerical weather model, and only cover a historical baseline of less than a decade. To fill this gap, this work provides a dataset of 43 years of coincident plant-level wind and solar power production data. The dataset is designed to be aggregated to appropriate scales of interest for bulk system studies such as Balancing Authorities (BAs), states, and nodes of a production cost model. The dataset covers every plant in the contiguous U.S. that is reported in the U.S. Energy Information Administration (EIA) Form 860 as of 2020. When compared with the EIA-923 monthly generation, we find minimal bias (less than 5%). When compared with BA-reported hourly generation, we find low bias in solar (less than 7%), and slight underdispersion in wind. This coincident multi-decadal historical dataset provides a documented and evaluated multi-resource baseline for studies on reliability, resource adequacy, climate change impacts, and characterization of emergent climate threats on renewable resources.

Abstract The pair production of Higgs bosons at the LHC can give information about the triple Higgs boson coupling. We perform an analytic one-loop calculation of the amplitudes for a pair of Higgs bosons in association with three partons, retaining the exact dependence on the quark mass circulating in the loop. These amplitudes constitute the real radiation corrections in the calculation of Higgs boson pair production at next-to-leading order in the strong coupling. The results of an analytic generalised-unitarity computation are simplified via analytic reconstruction in spinor variables. Compact ansätze for kinematic pole residues are iteratively fitted via p-adic evaluations near said poles and subtracted until no pole remains. A new ansatz construction is introduced to minimally parametrise coefficients of amplitudes with multiple massive external legs. The simplified expressions are faster to evaluate than automatic codes and can lead to more stable results near singular regions.

It is well known that oligodendrocyte-associated Nogo-A protein is an important regulator of axonal outgrowth and an important inhibitor of functional recovery and anatomical plasticity after central nervous system (CNS) injury. Abundant studies of oligodendrocyte-associated Nogo-A function in the uninjured rodent have suggested a role in neuronal development and synaptic function. On the other hand, the roles of neuron-associated (i.e., neuronal) Nogo-A have not been fully investigated. We have previously shown that neuronal Nogo-A influence dendritic spine density and morphology in pyramidal neurons of the intact neocortex. To further examine the role of neuronal Nogo-A in this synaptic population, we designed an RNAi directed against Nogo-A, delivered to the developing rat sensorimotor cortex using a neurotropic viral vector adeno-associated virus (AAV) 2/8. We examined the transduced neocortex for molecules important for synaptic plasticity, including N-Methyl-D-Aspartate (NMDA) receptor subunits GRIN2A; glutamate receptor subunit epsilon-1 (NR2A), and GRIN2B; glutamate receptor subunit epsilon-2 (NR2B), as well as postsynaptic density-95 (PSD-95). Furthermore, we also determined the density of excitatory synapses by examining the presynaptic protein vesicular glutamate transporter 1 (vGLut1) as a marker for potential excitatory synapses. Our results showed that neuronal Nogo-A knockdown in postnatal pyramidal neurons of the sensorimotor cortex led to a significant decrease in NMDA receptor subunits NR2A and NR2B messenger RNA when examined as adults. However, there was no difference in PSD-95 expression in comparison to controls. In addition, the decrease in the number of vGlut1(+) puncta on branches of apical dendrites of pyramidal neurons indicated the loss of synapses that have a strong influence on direct current entering the dendrite. Taken together, these results indicate that neuronal Nogo-A may regulate synaptic plasticity by modulating the components of excitatory synapses. This finding represents a novel role in excitatory synaptic formation for neuronal Nogo-A in developing neurons of the uninjured CNS.

Abstract Aging is associated with systemic chronic, low-grade inflammation, termed ‘inflammaging’. This pattern of inflammation is multifactorial and is driven by numerous inflammatory pathways, including the inflammasome. However, most studies to date have examined changes in the transcriptomes that are associated with aging and inflammaging, despite the fact that inflammasome activation is driven by a series of post-translational activation steps, culminating in the cleavage and activation of caspase-1. Here, we utilized transgenic mice expressing a caspase-1 biosensor to examine age-associated inflammasome activation in various organs and tissues to define these post-translational manifestations of inflammaging. Consistent with other studies, we observe increased inflammation, including inflammasome activation, in aged mice and specific tissues. However, we note that the degree of inflammasome activation is not uniformly associated with transcriptional changes commonly used as a surrogate for inflammasome activation in tissues. Furthermore, we used a skull thinning technique to monitor central nervous system inflammasome activation in vivo in aged mice and found that neuroinflammation is significantly amplified in aged mice in response to endotoxin challenge. Together, these data reveal that inflammaging is associated with both transcriptional and post-translational inflammatory pathways that are not uniform between tissues and establish new methodologies for measuring age-associated inflammasome activation in vivo and ex vivo.

Abstract All newborns undergo minor painful procedures (e.g., injections). Despite strong evidence supporting parents' efficacy to reduce procedural pain (e.g., breastfeeding), parents remain an underutilized resource. Limited evidence‐based resources about infant procedural pain management targeting parents in the perinatal period exist. We co‐created Parenting Pain Away, a website to enhance parents' access to information and participation in procedural pain management following birth. This study aimed to conduct iterative usability testing with the perinatal population to refine Parenting Pain Away based on target users' identified needs and satisfaction. In 2020, parents of healthy newborns or expectant parents from an Atlantic Canadian province, participated in two iterative cycles of usability testing of Parenting Pain Away. Through recorded interviews, participants were directed to use the “Think Aloud” approach (e.g., verbalize what they see, think, feel) as they navigated through the website. Participants completed online questionnaires related to demographics and user satisfaction, measured by the Post Study System Usability Questionnaire (PSSUQ). Descriptive statistics and content analysis were conducted to analyze the data. In total, there were 10 participants with an average age of 29.9 years (SD = 3.9). Participants identified as mothers (n = 7) or fathers (n = 3) and were expecting (n = 6) or had a newborn (n = 4). The PSSUQ overall scores were 1.84 (SD = 0.55) and 1.34 (SD = 0.49) in Cycles 1 and 2, respectively, indicating high user satisfaction on the 7‐point scale. When comparing between the two cycles, the average overall score was lower in Cycle 2, suggesting improved satisfaction. Participants provided positive feedback about the website and suggested major refinements to simplify content and site navigation. Findings from usability testing cycles were used to inform refinements of the Parenting Pain Away in response to participant satisfaction and feedback. Engaging target users in the development process enhanced this website in preparation for further effectiveness testing.

The purpose of this article is to galvanize institutions toward a movement to value teaching excellence in higher education. Colleges and universities that demonstrate this value are Teaching Excellence Colleges and Universities (TECUs), but they have never acted as a group. Many of these institutions lack power in the higher education landscape. However, as a collective, they have the opportunity to forge significant change in higher education. The College Educational Quality (CEQ) study was the first multiinstitutional, cross-disciplinary observational study of college teaching in the United States. CEQ revealed a great deal about college teaching excellence, the institutional contexts where teaching excellence manifests, and why. The CEQ study observed teaching in more than 700 courses across nine 4-year institutions of varying types (e.g., research, liberal arts, public, private, rural, urban, highly ranked, broad access). The CEQ study also surveyed faculty about their teaching practices as well as their institutional context for teaching (e.g., teaching development, culture, policies). Finally, CEQ surveyed students about their perceptions of the teaching in the courses. Across the 7 years of data collection, the author studied eight teaching frameworks that had been previously demonstrated to improve student learning. It is counterintuitive that high-prestige colleges and universities, some institutions that are purported to be higher quality, in fact have lower-quality teaching. Higher education should focus on education. Yet TECUs are often unseen -- hidden gems in a higher education landscape where a proportionally small number of institutions, those that largely do not focus on teaching, hold high-quality reputations, and receive a vast majority of the attention among scholars and funders.

The jigsaw method which utilises peer-teaching in small-group settings permits a facilitator to incorporate active learning strategies into their educational toolbox. In November 2022, we evaluated the impact of the jigsaw method with groups stratified by post-graduate year (PGY) level. We assessed pre and post learner confidence and medical knowledge during a facilitator-led workshop. Participants were stratified into three groups who presented on the following subtopics about osteoporosis in men: (1) history and physical examination (PGY1s), (2) lab work and imaging studies (PGY2s) and (3) management and interventions (PGY3s). We evaluated if stratifying by PGY level impacted learner medical knowledge and confidence in November 2022. We had an 80% response rate from 16 actual participants from a total of 20 possible participants. Authors found a statistically significant increases in residents’ confidence and medical knowledge after the training for all questions, but broad application across a variety of learners is still needed. The jigsaw method showed improvement in learner confidence about osteoporosis in men and may be implemented in teams distributed by PGY levels. Distribution by PGY level allows each team to building on their current training level to educate their peers.

ABSTRACT The oral microbiome is influenced by environmental factors in chronic kidney disease and following kidney transplantation affecting microbial composition, which may have implications for health and recovery. A major driver of oral microbiome perturbation is the accumulation of urea in saliva. We have modelled increased salivary urea concentrations associated with CKD and subsequent reductions that may occur post-transplantation. Oral microbiota were established in constant-depth film fermenters by inoculation with saliva. Duplicate validation runs were maintained with artificial saliva with baseline urea concentrations (0.205 mg/mL) for 21 days. Triplicate treatment runs were then done with baseline urea for 10 days (healthy phase) before urea was increased for 10 days to reflect CKD concentrations (0.92 mg/mL) (CKD phase). This was followed by reversion to baseline urea concentrations (post-transplant phase). Biofilms in primary validation runs reached dynamic stability within 5 days according to viable counting. DNA sequence data indicated minimal taxonomic variation over time and between low and high urea treatments despite background noise indicating changes in bacteria belonging to the family Gemellaceae and the genera TG5 and Leptotrichia. Significant differences in alpha and beta diversity occurred between low and high urea states but not following reversion to a low urea environment. Increased abundance of the TG5 was detected in late model phases, despite apparent count stability, and independent of changes in urea concentrations.IMPORTANCEThis study investigates dynamic changes in the oral microbiome associated with changes in salivary urea concentration, an important factor in chronic kidney disease (CKD). The in vitro system modeled increased urea concentrations and subsequent reductions post-transplantation. The study provides insight into the oral microbial shifts during different simulated clinical phases. Understanding these dynamics is crucial for advancing our comprehension of CKD-associated oral microbiome variations and their potential impact on patient well-being and recovery.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Electroencephalography (EEG) is one of two brain imaging modalities central to the HBCD Study. EEG records electrical signals from the scalp that reflect electrical brain activity. In addition, the EEG signal can be synchronized to the presentation of discrete stimuli (auditory or visual) to measure specific cognitive processes with excellent temporal precision (e.g., event-related potentials; ERPs). EEG is particularly helpful for the HBCD Study as it can be used with awake, alert infants, and can be acquired continuously across development. The current paper reviews the HBCD Study’s EEG/ERP protocol: (a) the selection and development of the tasks (Video Resting State, Visual Evoked Potential, Auditory Oddball, Face Processing); (b) the implementation of common cross-site acquisition parameters and hardware, site setup, training, and initial piloting; (c) the development of the preprocessing pipelines and creation of derivatives; and (d) the incorporation of equity and inclusion considerations. The paper also provides an overview of the functioning of the EEG Workgroup and the input from members across all steps of protocol development and piloting.

Early life experiences can have lasting impacts on an animal’s development. Extensive research evidence aligns across both human and non-human rodent and primate laboratory animals showing negative impacts of early life adversity such as impairments in neurological and behavioural development. Farmed animals experience a range of adversities across their production lifetimes, often early in life, including species atypical social groupings, invasive husbandry procedures, and transport. Correspondingly, farmed animals also demonstrate a wide range of impairments such as stereotypic, injurious, and other abnormal behaviours. An individual, however, needs to experience adversity to be able to develop resilience and coping mechanisms that facilitate dealing with challenges later in life. Not all individuals will experience stress vulnerability following adversity, with some individuals instead developing stress resilience. This mini review collates evidence on the positive effects of early life adversity on improving adaptability in farmed species, both terrestrial and aquatic. While evidence across farmed animal species is currently much less than for humans, laboratory rodents or non-human primates, similar patterns emerge where mild adversity early in life, can improve the adaptability of the animal in the face of future stressors. Many views of optimised welfare posit that farmed animals should be housed in as natural environments as possible to limit many of the typical adversities they face. However, strategic mild exposure to early life adversity may facilitate improved animal welfare under intensive commercial farming conditions. Future research into this area could provide management tools to better predict and promote stress resilience over stress vulnerability.

Abstract Background There is a growing interest in employing community wellness worker models in Indigenous populations to address inequities in healthcare access and outcomes, concerns about shortage in health and mental health human resources, and escalating burden of chronic and complex diseases driving significant increase in health services demand and costs. A thorough review of Indigenous community wellness worker models has yet to be conducted. This rapid review sought to outline the characteristics of a community wellness worker model in Indigenous contexts across the globe, detailing factors shaping implementation challenges and success. Methods A rapid review of the international peer-reviewed and grey literature of OVID Medline, Global Index Medicus, Google, and Google Scholar was conducted from January to June 2022 for Indigenous community wellness/mental health worker models and comparative models. Articles were screened and assessed for eligibility. From eligible articles, data pertaining to study design and sample; description of the program, service, or intervention; model development and implementation; terminology used to describe workers; training features; job roles; funding considerations; facilitators and barriers to success; key findings; outcomes measured; and models or frameworks utilized were extracted. Data were synthesized by descriptive and pattern coding. Results Twenty academic and eight grey literature articles were examined. Our findings resulted in four overarching and interconnected themes: (1) worker roles and responsibilities; (2) worker training, education, and experience; (3) decolonized approaches; and (4) structural supports. Conclusion Community wellness worker models present a promising means to begin to address the disproportionately elevated demand for mental wellness support in Indigenous communities worldwide. This model of care acts as a critical link between Indigenous communities and mainstream health and social service providers and workers fulfill distinctive roles in delivering heightened mental wellness supports to community members by leveraging strong ties to community and knowledge of Indigenous culture. They employ innovative structural solutions to bolster their efficacy and cultivate positive outcomes for service delivery and mental wellness. Barriers to the success of community wellness worker models endure, including power imbalances, lack of role clarity, lack of recognition, mental wellness needs of workers and Indigenous communities, and more.

Abstract Background The Illumina family of Infinium Methylation BeadChip microarrays has been widely used over the last 15 years for genome-wide DNA methylation profiling, including large-scale and population-based studies, due to their ease of use and cost effectiveness. Succeeding the popular HumanMethylationEPIC BeadChip (EPICv1), the recently released Infinium MethylationEPIC v2.0 BeadChip (EPICv2) claims to extend genomic coverage to more than 935,000 CpG sites. Here, we comprehensively characterise the reproducibility, reliability and annotation of the EPICv2 array, based on bioinformatic analysis of both manifest data and new EPICv2 data from diverse biological samples. Results We find a high degree of reproducibility with EPICv1, evidenced by comparable sensitivity and precision from empirical cross-platform comparison incorporating whole genome bisulphite sequencing (WGBS), and high correlation between technical sample replicates, including between samples with DNA input levels below the manufacturer’s recommendation. We provide a full assessment of probe content, evaluating genomic distribution and changes from previous array versions. We characterise EPICv2’s new feature of replicated probes and provide recommendations as to the superior probes. In silico analysis of probe sequences demonstrates that probe cross-hybridisation remains a significant problem in EPICv2. By mapping the off-target sites at single nucleotide resolution and comparing with WGBS we show empirical evidence for preferential off-target binding. Conclusions Overall, we find EPICv2 a worthy successor to the previous Infinium methylation microarrays, however some technical issues remain. To support optimal EPICv2 data analysis we provide an expanded version of the EPICv2 manifest to aid researchers in understanding probe design, data processing, choosing appropriate probes for analysis and for integration with methylation datasets from previous versions of the Infinium Methylation BeadChip.

Abstract Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

Adoptive immunotherapy with Epstein–Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus. We have developed a peptide-based, virus-free, serum-free closed system to manufacture a bank of virus-specific T cells (VST) for clinical use. We compared these with standard LCL-derived VST using comprehensive characterization and potency assays to determine differences that might influence clinical benefits. Multi-parameter flow cytometry revealed that peptide-derived VST had an expanded central memory population and less exhaustion marker expression than LCL-derived VST. A quantitative HLA-matched allogeneic cytotoxicity assay demonstrated similar specific killing of EBV-infected targets, though peptide-derived EBV T cells had a significantly higher expression of antiviral cytokines and degranulation markers after antigen recall. High-throughput T cell receptor-beta (TCRβ) sequencing demonstrated oligoclonal repertoires, with more matches to known EBV-binding complementary determining region 3 (CDR3) sequences in peptide-derived EBV T cells. Peptide-derived products showed broader and enhanced specificities to EBV nuclear antigens (EBNAs) in both CD8 and CD4 compartments, which may improve the targeting of highly expressed latency antigens in PTLD. Importantly, peptide-based isolation and expansion allows rapid manufacture and significantly increased product yield over conventional LCL-based approaches.

Saltwater crocodiles (Crocodylus porosus) are farmed in Australia primarily for their skins and meat. Commercially, they are raised in group pens as hatchlings and grower crocodiles and then moved to unitised (individual) pens for the final finishing stage when they are several years old. They will exhibit aggressive behaviour towards each other in captivity. Unitised pens can prevent animal injury and teeth marks on the skins but may result in other social restrictions. Research into behavioural housing preferences could assist the industry and inform the process of guideline development for optimal crocodile management and welfare. This study assessed the impacts of two housing systems, unitised or group pens, in 20 commercial finishing crocodiles through measuring behavioural profiles of individuals from video recordings, including housing preference when given a choice. Both pens included water and an above-water shelf, but the crocodiles in unitised pens could also access underneath the shelf. A threat perception test was applied to assess anxiety when housed individually or in groups. However, it was difficult to apply a standardised stimulus to all animals that reliably elicited a behavioural response. Further work would be needed to validate this test for commercial reptiles as the outcomes were not robust. The behavioural observation results showed clear differences in where the crocodiles spent their time across the day and in their activity levels between the pen types. However, interpretation of this variation was confounded by the physical and social differences between the pen types given the inconsistency in shelf access. Behaviours exhibited also differed given there were social opportunities in the group pens where individuals were observed engaged in both aggressive and non-aggressive contact interactions. In the free choice environment, crocodiles spent similar amounts of time in both unitised and group pens, suggesting there were features of both pen types that were attractive to the animals. However, skins were damaged from teeth marks highlighting the physical and economical risks of group housing. Further work could validate behavioural tests to quantify affective state impacts in different housing environments and whether social interactions do provide benefits for improving crocodile welfare.

Purpose: We investigated whether pulmonary metastases from historically considered radioresistant primaries would have inferior local control after radiation therapy than those from nonradioresistant nonlung primaries, and whether higher biologically effective dose assuming alpha/beta=10 (BED10) would be associated with superior local control. Methods and Materials: We identified patients treated with radiation therapy for oligometastatic or oligoprogressive pulmonary disease to 1 to 5 lung metastases from nonlung primaries in 2013 to 2020 at a single health care system. Radioresistant primary cancers included colorectal carcinoma, endometrial carcinoma, renal cell carcinoma, melanoma, and sarcoma. Nonradioresistant primary cancers included breast, bladder, esophageal, pancreas, and head and neck carcinomas. The Kaplan-Meier estimator, log-rank test, and multivariable Cox proportional hazards regression were used to compare local recurrence-free survival (LRFS), new metastasis-free survival, progression-free survival, and overall survival. Results: Among 114 patients, 73 had radioresistant primary cancers. The median total dose was 50 Gy (IQR, 50-54 Gy) and the median number of fractions was 5 (IQR, 3-5). Median follow-up time was 59.6 months. One of 41 (2.4%) patients with a nonradioresistant metastasis experienced local failure compared with 18 of 73 (24.7%) patients with radioresistant metastasis (log-rank P = .004). Among radioresistant metastases, 12 of 41 (29.2%) patients with colorectal carcinoma experienced local failure compared with 6 of 32 (18.8%) with other primaries (log-rank P = .018). BED10 ≥100 Gy was associated with decreased risk of local recurrence. On univariable analysis, BED10 ≥100 Gy (hazard ratio [HR], 0.263; 95% CI, 0.105-0.656; P = .004) was associated with higher LRFS, and colorectal primary (HR, 3.060; 95% CI, 1.204-7.777; P = .019) was associated with lower LRFS, though these were not statistically significant on multivariable analysis. Among colorectal primary patients, BED10 ≥100 Gy was associated with higher LRFS (HR, 0.266; 95% CI, 0.072-0.985; P = .047) on multivariable analysis. Conclusions: Local control after radiation therapy was encouraging for pulmonary metastases from most nonlung primaries, even for many of those classically considered to be radioresistant. Those from colorectal primaries may benefit from testing additional strategies, such as resection or systemic treatment concurrent with radiation.

Summary: Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1−/− tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.

AimTo co-create parental presence practice recommendations across Canadian NICUs during pandemics caused by respiratory pathogens such as COVID-19.MethodsRecommendations were developed through evidence, context, Delphi and Values and Preferences methods. For Delphi 1 and 2, participants rated 50 items and 20 items respectively on a scale from 1 (very low importance) to 5 (very high). To determine consensus, evidence and context of benefits and harms were presented and discussed within the Values and Preference framework for the top-ranked items. An agreement of 80% or more was deemed consensus.ResultsAfter two Delphi rounds (n = 59 participants), 13 recommendations with the highest rated importance were identified. Consensus recommendations included 6 strong recommendations (parents as essential caregivers, providing skin-to-skin contact, direct or mothers' own expressed milk feeding, attending medical rounds, mental health and psychosocial services access, and inclusion of parent partners in pandemic response planning) and 7 conditional recommendations (providing hands-on care tasks, providing touch, two parents present at the same time, food and drink access, use of communication devices, and in-person access to medical rounds and mental health and psychosocial services).ConclusionThese recommendations can guide institutions in developing strategies for parental presence during pandemics caused by respiratory pathogens like COVID-19

Abstract Background Long-term opioid use is associated with dependency, addiction, and serious adverse events. Although a framework to reduce inappropriate opioid prescribing exists, there is no consensus on prescribing indicators for preventable opioid-related problems in patients with chronic pain in primary care in the UK. This study aimed to identify opioid prescription scenarios for developing indicators for prescribing opioids to patients with chronic pain in primary care. Methods Scenarios of opioid prescribing indicators were identified from a literature review, guidelines, and government reports. Twenty-one indicators were identified and presented in various opioid scenarios concerning opioid-related harm and adverse effects, drug-drug interactions, and drug-disease interactions in certain disease conditions. After receiving ethics approval, two rounds of electronic Delphi panel technique surveys were conducted with 24 expert panellists from the UK (clinicians, pharmacists, and independent prescribers) from August 2020 to February 2021. Each indicator was rated on a 1–9 scale from inappropriate to appropriate. The score’s median, 30th and 70th percentiles, and disagreement index were calculated. Results The panel unanimously agreed that 15 out of the 21 opioid prescribing scenarios were inappropriate, primarily due to their potential for causing harm to patients. This consensus was reflected in the low appropriateness scores (median ranging from 1 to 3). There were no scenarios with a high consensus that prescribing was appropriate. The indicators were considered inappropriate due to drug-disease interactions (n = 8), drug-drug interactions (n = 2), adverse effects (n = 3), and prescribed dose and duration (n = 2). Examples included prescribing opioids during pregnancy, concurrently with benzodiazepines, long-term without a laxative prescription and prescribing > 120-mg morphine milligram equivalent per day or long-term duration over 3 months after surgery. Conclusions The high agreement on opioid prescribing indicators indicates that these potentially hazardous consequences are relevant and concerning to healthcare practitioners. Future research is needed to evaluate the feasibility and implementation of these indicators within primary care settings. This research will provide valuable insights and evidence to support opioid prescribing and deprescribing strategies. Moreover, the findings will be crucial in informing primary care practitioners and shaping quality outcome frameworks and other initiatives to enhance the safety and quality of care in primary care settings.

Historical gold mining operations between the 1860s and 1940s have left substantial quantities of arsenic- and mercury-rich tailings near abandoned mines in remote and urban areas of Nova Scotia, Canada. Large amounts of materials from the tailings have entered the surface waters of downstream aquatic ecosystems at concentrations that present a risk to benthos. We used paleolimnological approaches to examine long-term trends in sedimentary metal(loid) concentrations, assess potential sediment toxicity, and determine if geochemical recovery has occurred at four lakes located downstream of three productive gold-mining districts. During the historical mining era, sedimentary total arsenic and mercury concentrations and enrichment factors increased substantially at all downstream lakes that received inputs from tailings. Similarly, chromium, lead, and zinc concentrations increased in the sediments after mining activities began and the urbanization that followed. The calculated probable effects of concentration quotients (PEC-Qs) for sediments exceeded the probable biological effects threshold (PEC-Q > 2) during the mining era. Although sedimentary metal(loid) concentrations have decreased for most elements in recent sediments, relatively higher PEC-Q and continued exceedance of Canadian Interim Sediment Quality Guidelines suggest that complete geochemical recovery has not occurred. It is likely that surface runoff from tailing fields, urbanization, and climate-mediated changes are impacting geochemical recovery trajectories.

Abstract Background Patients who self-harm may consult with primary care nurses, who have a safeguarding responsibility to recognise and respond to self-harm. However, the responses of nursing staff to self-harm are poorly understood, and opportunities to identify self-harm and signpost towards treatment may be missed. It is unclear how to support nursing staff to implement national guidelines. Aims Among primary care nursing staff to: [1] Examine reported barriers and enablers to nurses’ use of, and adherence to, national guidance for self-harm; and [2] Recommend potential intervention strategies to improve implementation of the NICE guidelines. Methods Twelve telephone interviews partly structured around the capabilities, opportunities and motivations model of behaviour change (COM-B) were conducted with primary care nurses in the United Kingdom. The Theoretical Domains Framework was used as an analytical framework, while the Behaviour Change Wheel was used to identify exemplar behaviour change techniques and intervention functions. Results Nursing staff identified a need to learn more about risk factors (knowledge), and strategies to initiate sensitive conversations about self-harm (cognitive and interpersonal skills) to support their professional competencies (professional role and identity). Prompts may support recall of the guidance and support a patient centred approach to self-harm within practices (memory, attention, and decision making). GPs, and other practice nurses offer guidance and support (social influences), which helps nurses to navigate referrals and restricted appointment lengths (environmental context and influences). Conclusions Two converging sets of themes relating to information delivery and resource availability need to be targeted. Nine groups of behaviour change techniques, and five intervention functions offer candidate solutions for future intervention design. Key targets for change include practical training to redress conversational skill gaps about self-harm, the integration of national guidance with local resources and practice-level protocols to support decision-making, and creating opportunities for team-based mentoring.

Abstract Objectives Lemniscal (motor‐related) and spinothalamic (neuropathic pain‐related) somatosensory abnormalities affect different subsets of adults with cerebral palsy (CP). Lemniscal/motor abnormalities are associated with posterior thalamic radiation white matter disruption in individuals with CP and white matter injury. We tested the hypothesis that neuropathic pain symptoms in this population are rather associated with injury of the somatosensory (posterior group nuclei) thalamus. Methods In this cross‐sectional study, communicative adults with CP and bilateral white matter injury and neurotypical control participants volunteered to self‐report pain symptoms and undergo research MRI. Posterior group thalamic nuclei volume was computed and correlated against neuropathic pain scores. Results Participants with CP (n = 6) had, on average, 24% smaller posterior group thalamic volumes (95% CI: [10%–39%]; corrected p = 0.01) than control participants. More severe volume loss was correlated with more severe neuropathic pain scores (ρ = −0.87 [−0.99, −0.20]; p = 0.02). Interpretation Association with thalamic volume loss suggests that neuropathic pain in adults with CP may frequently be central neuropathic pain. Complementing assessments of white matter microstructure, regional brain volumes hold promise as diagnostic biomarkers for central neuropathic pain in individuals with structural brain disorders.

Understanding the molecular mechanisms of differentiation is important for regenerative medicine and developmental biology. This study aims to characterise the role of the glycolysis/oxidative phosphorylation balance as a driver of mesenchymal stem cell (MSC) differentiation. Cells were maintained in normal conditions or stimulated towards the MSC trilineage cell types over 21 days. Multispectral imaging of cell autofluorescence was applied as a non-invasive methodology to continuously image cultures in situ. Spectral signals for collagen, NAD(P)H, and flavins were unmixed. MSCs cultured under chondrogenic conditions exhibited increased collagen levels relative to controls. Following osteogenic induction, MSCs showed increased collagen levels relative to controls during the earlier stages of culture; however, control cells increased their collagen levels as they became confluent. MSCs cultured under adipogenic conditions exhibited lower levels of collagen than controls. The redox ratio (RR; NAD(P)H/flavins) immediately decreased during chondrogenesis, with this early effect persisting throughout the culture compared to control cells, which appeared to increase their RR, similar to osteogenesis. Adipogenesis resulted in a small increase in RR on day 2 relative to control cells, followed by a persistent decrease. Chondrogenic and adipogenic differentiation favoured oxidative phosphorylation, whereas osteogenesis and MSC overgrowth resulted in a glycolytic metabolism. Following consideration of these findings, as well as the diverse reports in the literature, it is concluded that neither enhanced oxidative phosphorylation nor glycolysis are fundamental to the canonical modes of differentiation, and researchers should avoid interpreting shifts as indicating differentiation.

Abstract Background and Objectives Because much of the work in academic medicine is done by committee, early career URiM faculty, are often asked to serve on multiple committees, including diversity work that may not be recognized as important. They may also be asked to serve on committees to satisfy a diversity “check box,” and may be asked more often than their non-URiM peers to serve in this capacity. We sought to describe the committee experiences of early career URiM faculty, hypothesizing that they may see committee service as a minority tax. Methods Participants in the Leadership through Scholarship Fellowship (LTSF) were asked to share their experiences with committee service in their careers after participating in a faculty development discussion. Their responses were analyzed and reported using qualitative, open, axial, and abductive reasoning methods. Results Four themes, with eight sub-themes (in parenthesis), emerged from the content analysis of the LTSF fellows responses to the prompt: Time commitment (Timing of committee work and lack of protected time for research and scholarship), URiM Committee service (Expectation that URiM person will serve on committees and consequences for not serving), Mentoring issues (no mentoring regarding committee service, faculty involvement is lacking and the conflicting nature of committee work) and Voice (Lack of voice or acknowledgement). Conclusions Early career URiM faculty reported an expectation of serving on committees and consequences for not serving related to their identity, but other areas of committee service they shared were not connected to their URiM identity. Because most of the experiences were not connected to the LTSF fellows’ URiM identity, this group has identified areas of committee service that may affect all early career faculty. More research is necessary to determine how committee service affects URiM and non-URiM faculty in academic family medicine.

Abstract We present compact analytic results for tree-level amplitudes containing a t t ¯ $$ t\overline{t} $$ pair accompanied by up to four massless partons, t t ¯ gg $$ t\overline{t} gg $$ , t t ¯ ggg $$ t\overline{t} ggg $$ , t t ¯ gggg $$ t\overline{t} gggg $$ , t t ¯ q q ¯ $$ t\overline{t}q\overline{q} $$ , t t ¯ q q ¯ g $$ t\overline{t}q\overline{q}g $$ , t t ¯ q q ¯ gg $$ t\overline{t}q\overline{q} gg $$ and t t ¯ q q ¯ q ′ q ¯ ′ $$ t\overline{t}q\overline{q}{q}^{\prime }{\overline{q}}^{\prime } $$ . The results, obtained using BCFW on-shell recursion, are based both on previous published results and on the new calculations performed in this paper. These amplitudes are sufficient to calculate the production of a t t ¯ $$ t\overline{t} $$ pair and zero, one, or two light parton jets, with the option to include the tree-level decays t → bνe + and t ¯ $$ \overline{t} $$ → b ¯ e $$ \overline{b}e $$ − ν ¯ $$ \overline{\nu} $$ efficiently. Our results are part of the NNLO corrections to t t ¯ $$ t\overline{t} $$ production including the decay correlations for on-shell top quarks.

Abstract Background Interferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway. Methods We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death. Results We show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins. Conclusions Our results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

BackgroundStaffing and resource shortages, especially during the COVID-19 pandemic, have increased stress levels among health care workers. Many health care workers have reported feeling unable to maintain the quality of care expected within their profession, which, at times, may lead to moral distress and moral injury. Currently, interventions for moral distress and moral injury are limited. ObjectiveThis study has the following aims: (1) to characterize and reduce stress and moral distress related to decision-making in morally complex situations using a virtual reality (VR) scenario and a didactic intervention; (2) to identify features contributing to mental health outcomes using wearable, physiological, and self-reported questionnaire data; and (3) to create a personal digital phenotype profile that characterizes stress and moral distress at the individual level. MethodsThis will be a single cohort, pre- and posttest study of 100 nursing professionals in Ontario, Canada. Participants will undergo a VR simulation that requires them to make morally complex decisions related to patient care, which will be administered before and after an educational video on techniques to mitigate distress. During the VR session, participants will complete questionnaires measuring their distress and moral distress, and physiological data (electrocardiogram, electrodermal activity, plethysmography, and respiration) will be collected to assess their stress response. In a subsequent 12-week follow-up period, participants will complete regular assessments measuring clinical outcomes, including distress, moral distress, anxiety, depression, and loneliness. A wearable device will also be used to collect continuous data for 2 weeks before, throughout, and for 12 weeks after the VR session. A pre-post comparison will be conducted to analyze the effects of the VR intervention, and machine learning will be used to create a personal digital phenotype profile for each participant using the physiological, wearable, and self-reported data. Finally, thematic analysis of post-VR debriefing sessions and exit interviews will examine reoccurring codes and overarching themes expressed across participants’ experiences. ResultsThe study was funded in 2022 and received research ethics board approval in April 2023. The study is ongoing. ConclusionsIt is expected that the VR scenario will elicit stress and moral distress. Additionally, the didactic intervention is anticipated to improve understanding of and decrease feelings of stress and moral distress. Models of digital phenotypes developed and integrated with wearables could allow for the prediction of risk and the assessment of treatment responses in individuals experiencing moral distress in real-time and naturalistic contexts. This paradigm could also be used in other populations prone to moral distress and injury, such as military and public safety personnel. Trial RegistrationClinicalTrials.gov NCT05923398; https://clinicaltrials.gov/study/NCT05923398 International Registered Report Identifier (IRRID)DERR1-10.2196/54180

Background We assessed whether a sustained period of intensive glucose control with hybrid closed-loop for 12 months following diagnosis of type 1 diabetes in children and adolescents can preserve C-peptide secretion compared to standard insulin therapy. Methods In an open-label, multicentre, randomised, parallel trial, youth aged 10–16.9 years were randomised within 21 days of type 1 diabetes diagnosis to hybrid closed-loop or standard insulin therapy (control). Primary end point was the difference in mixed-meal C-peptide area under the curve 12 months post diagnosis. Key secondary end points included time spent in target glucose range, glycated haemoglobin and time spent below target glucose range at 12 months. Analysis was by intention to treat. The Closed Loop from Onset in Type 1 Diabetes consortium secured external funding for participants to continue on beyond 12 months, but the funding by National Institute for Health and Care Research and the results reported here refer only to the 12 months follow-up. Results We randomised 97 participants (mean ± standard deviation age 12 ± 2 years), 51 to closed-loop and 46 to control therapy. There was no difference in C-peptide area under the curve at 12 months between groups [geometric mean (interquartile range) closed-loop (n = 46): 0.35 pmol/ml (0.16, 0.49) vs. control (n = 37): 0.46 pmol/ml (0.22, 0.69); mean adjusted difference –0.06 (95% confidence interval –0.14 to 0.03); p = 0.19]. The proportion of time in target range 3.9–10.0 mmol/l based on 14-day masked LibrePro (Abbott Diabetes Care, Maidenhead, UK) sensor glucose data at 12 months was 10 percentage points (95% confidence interval 2 to 17) higher in the closed-loop group (64 ± 14%) compared to control group (54 ± 23%). Arithmetic mean glycated haemoglobin A1c was lower in the closed-loop group by 4 mmol/mol (0.4%) [95% confidence interval 0 to 8 mmol/mol (0.0% to 0.7%)] at 12 months. The mean difference in time spent 10.0 mmol/l was 11 percentage points (95% CI 3 to 19 percentage points) lower in the CL group compared to the control group at 12 months. Glucose variability measured by standard deviation (SD) was similar between CL and control groups, while coefficient of variation of glucose was 4 percentage points higher in the CL group at 12 months (95% CI 1 to 8 percentage points). The primary end point was similar in a per-protocol analysis using data from randomised participants in the CL group with at least 60% CL use and those in the control group who did not start insulin pump therapy. Total daily insulin dose was similar between treatment groups, but there was a greater proportion of basal insulin (mean ± SD closed-loop 0.52 ± 0.31 U/kg/day, control 0.37 ± 0.26 U/kg/day) to bolus insulin (mean ± SD closed-loop 0.44 ± 0.22 U/kg/day, control 0.46 ± 0.23 U/kg/day) in the CL group at 12 months. Blood pressure, lipid profile and BMI percentile were similar between treatment groups. In the CL group, median CL use was 66% (IQR 44–80) over the 12-month period. In the control group, 10% of participants (n = 4) were using insulin pump therapy and 57% (n = 21) were using a flash or real-time continuous glucose sensor at 12 months post diagnosis. Three severe hypoglycaemic events occurred in the CL group (two participants), and one in the control group; one DKA occurred in the CL group and none in the control group. The number of other AEs (CL group 34, control group 37) and SAEs (CL group 2, control group 4) was similar between groups. Responses to the Pediatric Quality of Life Inventory (PedsQL), hypoglycaemia fear survey (HFS), problem areas in diabetes (PAID) and Strengths and Difficulties Questionnaires (SDQs) were similar between treatment groups in both children and parents at 12 months. Scores for the INSPIRE (INsulin Dosing Systems: Perceptions, Ideas, Reflections and Expectations) questionnaire were high in children, teenagers and parents, suggesting positive expectancies regarding automated insulin delivery in this population. In-depth interviews of 18 youths and 21 parents with ≥ 12 months’ experience of using CL technology were undertaken. Interviews explored the impact of using CL systems on diabetes management practices and everyday family life. As reported by Lawton et al. Participants reported very few disruptions to their lives when using a closed-loop system. Reports of family conflict were minimal as the closed-loop enabled dietary flexibility and glucose levels to be checked effortlessly. Adolescents described doing ‘normal’ activities without worrying about high or low glucose, and parents reported allowing them to do so unsupervised because the closed-loop would regulate their glucose and keep them safe. Some adolescents expressed concerns about the visibility of components and, to avoid stigma, described curtailing activities such as swimming. Participants described how the closed-loop enabled adolescents to be in control of, or create distance from, their diabetes. Lawton J, Kimbell B, Rankin D, Ashcroft NL, Varghese L, Allen JM, et al.; CLOuD Consortium. Health professionals’ views about who would benefit from using a closed-loop system: a qualitative study. Diabet Med: J Br Diabet Assoc 2020;37(6):1030–7. Interviews of multidisciplinary healthcare professionals (n = 22) providing support to trial participants explored the benefits, issues and challenges arising from introducing and using CL systems to support diabetes self-management. Lawton et al. reported that interviewees described how, compared with other insulin regimens, teaching and supporting individuals to use a closed-loop system could be initially more time-consuming. However, they also noted that after an initial adjustment period, users had less need for initiating contact with the clinical team compared with people using pumps or multiple daily injections. Interviewees highlighted how a lessened need for ad hoc clinical input could result in new challenges; specifically, they had fewer opportunities to reinforce users’ diabetes knowledge and skills and detect potential psychosocial problems. Lawton et al. (2020) We explored health professionals’ views about who would benefit from using a CL system. Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the CL system in ways they had not anticipated. This included educated, technologically competent individuals who over-interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefited from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre-selection criteria and ideally all individuals should be given the chance to try the technology. Conclusions The CLOuD study demonstrates that CL glucose control over a period of 12 months does not slow the decline in C-peptide secretion in children and adolescents with new-onset type 1 diabetes. Mean time in range was 10 percentage points higher and mean HbA1c was 0.4% (4 mmol/mol) lower in the CL group compared with the control group at 12 months, but these end points did not reach the pre-specified significance thresholds and it is possible that a greater improvement in glucose control with attainment of normoglycaemia could prevent the decline in C-peptide secretion. Further work may be needed to definitively rule out a role of glycaemic burden in the decline of C-peptide secretion. Total daily exogenous insulin requirements, a surrogate marker of residual insulin secretion, were similar between groups at all time points after diagnosis. This comparison may be hampered by any between-group differences in glycaemic control. It is likely that factors other than glycaemic control, such as autoimmune response, determine the rate of C-peptide decline following diagnosis of type 1 diabetes. It is possible that other factors act in concert with dysglycaemia on C-peptide secretion. The present study demonstrates that hybrid CL is effective in new-onset type 1 diabetes in youth and can safely accommodate the variability in exogenous insulin requirements which occur with beta-cell recovery post diagnosis. Glycaemic control was sustained over 12 months in the CL group, whereas glycaemic control started to deteriorate in the control group at 6 to 9 months after diagnosis. At 12 months post diagnosis, only 56% of youth in the control group (78% in the CL group) were able to achieve a HbA1c of

Summary: Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.

BackgroundDiets rich in minimally processed plant-based foods are recommended to breast cancer patients, and some may have an interest in whole-food, plant-based (WFPB) diets that avoid animal-based foods, added fats, and refined sugars. Within WFPB diets, the intakes of isoflavones, omega-6 polyunsaturated fatty acids (n-6 PUFAs), and omega-3 polyunsaturated FAs (n-3 PUFAs), which have been discussed in reference to breast cancer outcomes, have not been well characterized.MethodsWomen with stage IV breast cancer on stable therapy were randomized 2:1 into (1) a WFPB intervention (N = 21) or (2) usual care (N = 11) for 8 weeks. Three meals per day were provided. Outcomes presented here include dietary intake of isoflavones, n-3 and n-6- PUFAs, which were assessed using three-day food records at baseline and 8 weeks. Baseline and 8-week mean intake within groups were compared using the Wilcoxon signed-rank test and between control and intervention groups by a two-sample t-test.ResultsThe WFPB intervention participants increased their daily consumption of total isoflavones from a mean of 0.8 mg/day to 14.5 mg/day (p

The weaning of beef calves in yards places multiple stressors on the animals, and environmental enrichment may help mitigate some of these stressors and improve animal welfare. This trial assessed the impacts of enrichment provision to beef calves during yard weaning using measures of biological functioning, behaviour, and affective state. Overall, calves utilised the brush more than the other provided enrichments, which were a hanging rope and a ball. Enrichment influenced the behaviours of calves during both an attention bias test, with enriched calves exhibiting behaviours associated with greater anxiety, and a novel object recognition test, with enriched calves spending less time interacting with objects. In their home pens, enriched calves performed more drinking and grooming behaviours. However, no significant differences were seen between treatments for body weight, faecal cortisol metabolites, and internal body temperature. Enrichment also did not influence any longer-term measurements of body weight, flight speed, or crush score. The study design was impacted by mud, requiring the regrouping of the animals. Thus, some results should be interpreted with caution. Overall, this study demonstrates that further work is required into the assessment of affective states for these animals as it could not be confirmed whether the results seen indicate that calf welfare was improved or impaired through enrichment provision.

Objectives: Type one diabetes (T1D) in children places substantial responsibility on parents as caregivers. This study investigated caregiver burden in parents of children with T1D by exploring the financial, physical, social, spiritual, and emotional or psychological problems they experienced. Methods: We conducted a qualitative scoping review of the databases PsycINFO, PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), EBSCO CINAHL, ProQuest Dissertations and Theses Global, and SCOPUS. Of 119 full text articles assessed for eligibility, 18 peer-reviewed qualitative studies were included. Studies were considered relevant if they focused on diabetes management and parental burden or the experience of caregiving for a child with T1D. Results: Using thematic analysis, six interrelated themes were identified: (a) experiencing chronic sorrow, (b) assuming responsibility for glucose highs and lows, (c) managing T1D and nighttime sleep disturbances, (d) making career sacrifices and choices to optimize T1D care, (e) navigating social experiences postdiagnosis, and (f) discovering new sources of support through online platforms. Conclusions: This synthesis highlights an all-encompassing experience involved in caretaking for a child with T1D. Caregiving duties lead to a constant sense of vigilance, especially due to fear of hypoglycemic incidents. Parents commonly experience challenges with balancing work demands with T1D management, which lead to career and financial sacrifices. Their burden of care is exacerbated by a lack of reliable respite care but helped somewhat by online peer support. Future research is needed on the care burden differences between mothers and fathers and how sociodemographic factors affect how caregiver burden is experienced.

Abstract Background Individuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation in long-term pain after mTBIs is not fully elucidated. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes in inflammatory processes following mTBIs and their effects on TBI-related pain. Methods We utilized a recently developed transgenic caspase-1 luciferase reporter mouse model to monitor caspase-1 activation through a thinned skull window in the in vivo setting following three closed-head mTBI events. Organotypic coronal brain slice cultures and acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context of inflammation signal. Mechanical allodynia was assessed by mechanical withdrawal threshold to von Frey and thermal hyperalgesia withdrawal latency to radiant heat. Mouse grimace scale (MGS) was used to detect spontaneous or non-evoked pain. In some experiments, mice were prophylactically treated with MCC950, a potent small molecule inhibitor of NLRP3 inflammasome assembly to inhibit injury-induced inflammatory signaling. Bioluminescence spatiotemporal dynamics were quantified in the head and hind paws, and caspase-1 activation was confirmed by immunoblot. Immunofluorescence staining was used to monitor the progression of astrogliosis and microglial activation in ex vivo brain tissue following repetitive closed-head mTBIs. Results Mice with repetitive closed-head mTBIs exhibited significant increases of the bioluminescence signals within the brain and paws in vivo for at least one week after each injury. Consistently, immunoblotting and immunofluorescence experiments confirmed that mTBIs led to caspase-1 activation, astrogliosis, and microgliosis. Persistent changes in MGS and hind paw withdrawal thresholds, indicative of pain states, were observed post-injury in the same mTBI animals in vivo. We also observed enhanced inflammatory responses in ex vivo brain slice preparations and DRG for at least 3 days following mTBIs. In vivo treatment with MCC950 significantly reduced caspase-1 activation-associated bioluminescent signals in vivo and decreased stimulus-evoked and non-stimulus evoked nociception. Conclusions Our findings suggest that the inflammatory states in the brain and peripheral nervous system following repeated mTBIs are coincidental with the development of nociceptive sensitization, and that these events can be significantly reduced by inhibition of NLRP3 inflammasome activation.

Abstract The Multi-mode Acoustic Gravitational wave Experiment (MAGE) is a high frequency gravitational wave detection experiment. In its first stage, the experiment features two near-identical quartz bulk acoustic wave resonators that act as strain antennas with spectral sensitivity as low as 6.6 × 10−21 [strain]/ $$\sqrt{\text {Hz}}$$ Hz in multiple narrow bands across MHz frequencies. MAGE is the successor to the initial path-finding experiments; GEN 1 and GEN 2. These precursor runs demonstrated the successful use of the technology, employing a single quartz gravitational wave detector that found significantly strong and rare transient features. As the next step to this initial experiment, MAGE will employ further systematic rejection strategies by adding an additional quartz detector such that localised strains incident on just a single detector can be identified. The primary goals of MAGE will be to target signatures arising from objects and/or particles beyond that of the standard model, as well as identifying the source of the rare events seen in the predecessor experiment. The experimental set-up, current status and future directions for MAGE are discussed. Calibration procedures of the detector and signal amplification chain are presented. The sensitivity of MAGE to gravitational waves is estimated from knowledge of the quartz resonators. Finally, MAGE is assembled and tested in order to determine the thermal state of its new components.