Oral microbial signatures associated with age and frailty in Canadian adults.

This study aimed to assess the association between the oral microbiome, age, and frailty. Data and saliva samples were obtained from male and female participants aged 35-70 years (n = 1357). Saliva samples were analysed by 16S rRNA gene sequencing and differences in microbial diversity and community compositions were examined in relation to chronological age and the frailty index (FI). Most alpha diversity measures (Richness, Shannon Diversity, Faith's Phylogenetic Diversity) showed an inverse association with frailty, whereas a positive association was observed with age and Shannon Diversity and Evenness. A further sex-stratified analysis revealed differences in measures of microbial diversity and composition. Multiple genera were detected as significantly differentially abundant with increasing frailty and age by at least two methods. With age, the relative abundance of Veillonella was reduced in both males and females, whereas increases in Corynebacterium appeared specific to males and Aggregatibacter, Fusobacterium, Neisseria, Stomatobaculum, and Porphyromonas specific to females. Beta diversity was significantly associated with multiple mental health components of the FI. This study shows age and frailty are differentially associated with measures of microbial diversity and composition, suggesting the oral microbiome may be a useful indicator of increased risk of frailty or a potential target for improving health in ageing adults.

Network analysis of S-nitrosylated synaptic proteins demonstrates unique roles in health and disease.

Nitric oxide can covalently modify cysteine thiols on target proteins to alter that protein's function in a process called S-nitrosylation (SNO). S-nitrosylation of synaptic proteins plays an integral part in neurotransmission. Here we review the function of the SNO-proteome at the synapse and whether clusters of SNO-modification may predict synaptic dysfunction associated with disease. We used a systematic search strategy to concatenate SNO-proteomic datasets from normal human or murine brain samples. Identified SNO-modified proteins were then filtered against proteins reported in the Synaptome Database, which provides a detailed and experimentally verified annotation of all known synaptic proteins. Subsequently, we performed an unbiased network analysis of all known SNO-synaptic proteins to identify clusters of SNO proteins commonly involved in biological processes or with known disease associations. The resulting SNO networks were significantly enriched in biological processes related to metabolism, whereas significant gene-disease associations were related to Schizophrenia, Alzheimer's, Parkinson's and Huntington's disease. Guided by an unbiased network analysis, the current review presents a thorough discussion of how clustered changes to the SNO-proteome influence health and disease.

Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.

Interrogation of the human cortical peptidome uncovers cell-type specific signatures of cognitive resilience against Alzheimer's disease.

Alzheimer's disease (AD) is characterised by age-related cognitive decline. Brain accumulation of amyloid-ß plaques and tau tangles is required for a neuropathological AD diagnosis, yet up to one-third of AD-pathology positive community-dwelling elderly adults experience no symptoms of cognitive decline during life. Conversely, some exhibit chronic cognitive impairment in absence of measurable neuropathology, prompting interest into cognitive resilience-retained cognition despite significant neuropathology-and cognitive frailty-impaired cognition despite low neuropathology. Synapse loss is widespread within the AD-dementia, but not AD-resilient, brain. Recent evidence points towards critical roles for synaptic proteins, such as neurosecretory VGF, in cognitive resilience. However, VGF and related proteins often signal as peptide derivatives. Here, nontryptic peptidomic mass spectrometry was performed on 102 post-mortem cortical samples from individuals across cognitive and neuropathological spectra. Neuropeptide signalling proteoforms derived from VGF, somatostatin (SST) and protachykinin-1 (TAC1) showed higher abundance in AD-resilient than AD-dementia brain, whereas signalling proteoforms of cholecystokinin (CCK) and chromogranin (CHG) A/B and multiple cytoskeletal molecules were enriched in frail vs control brain. Integrating our data with publicly available single nuclear RNA sequencing (snRNA-seq) showed enrichment of cognition-related genes in defined cell-types with established links to cognitive resilience, including SST interneurons and excitatory intratelencephalic cells.

Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry.

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

Lower Prevalence of Diabetic Ketoacidosis at Diagnosis in Research Participants Monitored for Hyperglycemia.

CONTEXT: In Colorado children, the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) has been increasing over time. OBJECTIVE: Evaluate the prevalence of and factors involved in DKA at T1D diagnosis among participants followed in monitoring research studies before diagnosis compared to patients from the community. SETTING AND PARTICIPANTS: Patients < 18 years diagnosed with T1D between 2005 and 2021 at the Barbara Davis Center for Diabetes. OUTCOME: Prevalence of and factors associated with DKA at diagnosis among participants in preclinical monitoring studies compared to those diagnosed in the community. RESULTS: Of 5049 subjects, 164 were active study participants, 42 inactive study participants, and 4843 were community patients. Active study participants, compared to community patients, had lower HbA1c (7.3% vs 11.9%]; P < 0.001) and less frequently experienced DKA (4.9% vs 48.5%; P < 0.001), including severe DKA (1.2% vs 16.2%; P < 0.001). Inactive study participants had intermediate levels for both prevalence and severity of DKA. DKA prevalence increased in community patients, from 44.0% to 55%, with less evidence for a temporal trend in study participants. DKA prevalence was highest in children <2 years (13% in active study participants vs 83% in community patients). In community patients, younger age (P = 0.0038), public insurance (P < 0.0001), rural residence (P < 0.0076), higher HbA1c (P < 0.0001), and ethnicity minority status (P < 0.0001) were associated with DKA at diagnosis. CONCLUSIONS: While DKA prevalence increases in community patients over time, it stayed <5% in active research participants, who have a 10 times lower prevalence of DKA at diagnosis, including in minorities.

Intraoperative Epiphyseal Perfusion Monitoring Does Not Reliably Predict Osteonecrosis Following Treatment of Unstable SCFE.

BACKGROUND: Avascular necrosis (AVN) remains the most dreaded complication of unstable slipped capital femoral epiphysis (SCFE) treatment. Newer closed reduction techniques (with perfusion monitoring) have emerged as a technically straightforward means to address residual SCFE deformity while still minimizing the risk of osteonecrosis. However, limited data exists regarding the reliability of intraoperative epiphyseal perfusion monitoring to predict the development of AVN. The purpose of this study was to evaluate its reliability. METHODS: We retrospectively reviewed all patients with unstable SCFE who underwent closed or open reduction with epiphyseal perfusion monitoring using an intracranial pressure (ICP) probe from 2015 to 2023 at a single institution with a minimum 6-month radiographic follow-up. Demographic, clinical, and radiographic data were recorded, including duration of symptoms, type of reduction, capsulotomy performed, presence of a waveform on ICP monitoring after epiphyseal fixation, and development of AVN on follow-up radiographs. RESULTS: Our cohort included 33 hips (32 patients), of which 60.6% (n=20) were male. The average age was 12.5±1.8 years, with a median follow-up of 15.8 months. Eleven hips were treated with open reduction using the modified Dunn technique (10 hips) or anterior approach (1 hip), and 22 hips were treated with inadvertent (5 hips) or purposeful closed reduction using the Leadbetter technique (17 hips). Overall, 8 of the 33 hips in our series (24.2%) developed AVN, 6 of which (20%) had a pulsatile waveform on intraoperative epiphyseal perfusion monitoring. The overall rate of AVN after closed reductions was 31.8% (7 of 22 hips); the incidence of AVN after closed reduction with a detectable waveform was 30% (6 of 20 hips). There was no significant association between time to surgery ( P =0.416) or type of reduction ( P =0.218) and the incidence of AVN. CONCLUSIONS: In this series, intraoperative epiphyseal perfusion monitoring did not reliably predict the development of osteonecrosis. To our knowledge, this is the first study to report AVN after demonstrable intraoperative epiphyseal perfusion following closed reduction of unstable slips. LEVEL OF EVIDENCE: Level IV: case series-therapeutic study.

Child Opportunity Index and Pediatric Intensive Care Outcomes: A Multicenter Retrospective Study in the United States.

OBJECTIVES: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS). DESIGN: Retrospective cohort study. SETTING: Fifteen PICUs in the United States. PATIENTS: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance. CONCLUSIONS: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood.

Air pollution mortality benefits of sustained COVID-19 mobility restrictions in Australian cities.

OBJECTIVES: Emissions from road traffic, power generation and industry were substantially reduced during pandemic lockdown periods globally. Thus, we analysed reductions in traffic-related air pollution in Australian capital cities during March-April 2020 and then modelled the mortality benefits that could be realised if similar reductions were sustained by structural policy interventions. STUDY DESIGN: Satellite, air pollution monitor and land use observations were used to estimate ground-level nitrogen dioxide (NO2) concentrations in all Australian capital cities during: (a) a typical year with no prolonged air pollution events; (b) a hypothetical sustained reduction in NO2 equivalent to the COVID-19 lockdowns. METHODS: We use the WHO recommended NO2 exposure-response coefficient for mortality (1.023, 95 % CI: 1.008-1.037, per 10 µg/m3 annual average) to assess gains in life expectancy and population-wide years of life from reduced exposure to traffic-related air pollution. RESULTS: We attribute 1.1 % of deaths to anthropogenic NO2 exposures in Australian cities, corresponding to a total of 13,340 years of life lost annually. Although COVID-19-related reductions in NO2 varied widely between Australian cities during April 2020, equivalent and sustained reductions in NO2 emissions could reduce NO2-attributable deaths by 27 %, resulting in 3348 years of life gained annually. CONCLUSIONS: COVID-19 mobility restrictions reduced NO2 emissions and population-wide exposures in Australian cities. When sustained to the same extent by policy interventions that reduce fossil fuel consumption by favouring the uptake of electric vehicles, active travel and public transport, the health, mortality and economic benefits will be measurable in Australian cities.

What Are the Psychosocial Effects of Pavlik Harness Treatment? A Prospective Study on Perceived Impact on Families and Maternal-Infant Bonding.

BACKGROUND: The Pavlik harness (PH) is the most common treatment for infants with developmental dysplasia of the hip. Although success rates are high when used appropriately, brace treatment may impact family function and parental bonding. The purpose of this study was to prospectively determine how PH treatment affected these psychosocial variables. METHODS: This is a prospective, single-surgeon study at a tertiary-care, urban, academic children's hospital between November 2022 and March 2023. All patients newly treated with a Pavlik were eligible. Caregivers were administered the Postpartum Bonding Questionnaire and the Revised Impact on Family Scale (rIOFS) at the baseline visit and 2- and 6 weeks following treatment initiation. Demographic and treatment-specific information was collected through surveys and retrospective chart review. Descriptive statistics and bivariate analysis were used. RESULTS: A total of 55 caregiver-child dyads were included in the final analysis. Most patients were female (89%) and/or first-born (73%). Forty (73%) hips were diagnosed as having stable dysplasia. rIOFS scores steadily improved from baseline, through 2- and 6 weeks posttreatment initiation. Six-week rIOFS scores were significantly lower than both baseline ( P= 0.002) and 2 weeks ( P =0.018). Average parental bonding scores also improved steadily throughout treatment and did not surpass the threshold of clinical concern at any time. Neither full-time harness use (24 h/d vs. 23 h/d based upon clinical stability) nor age at treatment initiation had a statistically significant effect on parental bonding or family functioning (all P >0.05). Additional demographic variables such as birth order, parental history of anxiety/depression, and relative socioeconomic disadvantage also had no significant effect on psychosocial outcomes. CONCLUSION: PH treatment did not significantly impact maternal-fetal bonding or family dynamics. Relative to other pediatric diseases, PH treatment has an impact on family life greater than that of single-leg spica, but less than that of school-age children with chronic medical illnesses. As PH treatment is a widely used treatment for infantile developmental dysplasia of the hip, this study provides information that clinicians may use to more accurately counsel families and assuage parental concerns. LEVELS OF EVIDENCE: Level IV-prospective uncontrolled cohort study.

New Classification for Pediatric Proximal Fifth Metatarsal Fractures.

Proximal fifth metatarsal fractures are the most common foot fractures in children. Attempts to classify these injuries are misapplied and inadequately predict outcomes. This is the first study to identify factors associated with healing in pediatric fifth metatarsal fractures. In this retrospective cohort study (N = 305), proximal fifth metatarsal fractures were classified on radiographs by location on the bone, alignment (transverse or oblique), displacement (>2 mm), and completion through the bone. Based on the literature, they were secondarily sorted by category: apophyseal, intra-articular metaphyseal, extra-articular metaphyseal, and diaphyseal. Primary outcomes included times to healing, indicated by clinical symptoms, immobilization, and return to sports, as well as radiographic callus formation, bridging, and remodeling. Healing times were compared by ANOVA and linear regression. Location had a significant effect on times of immobilization and return to sports, but alignment, displacement, and completion were not associated with healing. When re-classified, the categories were also associated with immobilization and return to sports. Apophyseal fractures healed fastest and diaphyseal fractures required the most time to heal. There was no difference between extra- and intra-articular fractures. For every year of age, symptoms resolved about 2 days sooner. Neither gender nor body mass index (BMI) was positively or negatively associated with healing times. In conclusion, classifying fractures by apophyseal, metaphyseal, and diaphyseal is the most concise, accurate, and useful system. This is the largest series of nonoperatively treated proximal fifth metatarsal fractures in children and a robust standard to which surgical management can be compared.

Microbial hitchhikers harbouring antimicrobial-resistance genes in the riverine plastisphere.

BACKGROUND: The widespread nature of plastic pollution has given rise to wide scientific and social concern regarding the capacity of these materials to serve as vectors for pathogenic bacteria and reservoirs for Antimicrobial Resistance Genes (ARG). In- and ex-situ incubations were used to characterise the riverine plastisphere taxonomically and functionally in order to determine whether antibiotics within the water influenced the ARG profiles in these microbiomes and how these compared to those on natural surfaces such as wood and their planktonic counterparts. RESULTS: We show that plastics support a taxonomically distinct microbiome containing potential pathogens and ARGs. While the plastisphere was similar to those biofilms that grew on wood, they were distinct from the surrounding water microbiome. Hence, whilst potential opportunistic pathogens (i.e. Pseudomonas aeruginosa, Acinetobacter and Aeromonas) and ARG subtypes (i.e. those that confer resistance to macrolides/lincosamides, rifamycin, sulfonamides, disinfecting agents and glycopeptides) were predominant in all surface-related microbiomes, especially on weathered plastics, a completely different set of potential pathogens (i.e. Escherichia, Salmonella, Klebsiella and Streptococcus) and ARGs (i.e. aminoglycosides, tetracycline, aminocoumarin, fluoroquinolones, nitroimidazole, oxazolidinone and fosfomycin) dominated in the planktonic compartment. Our genome-centric analysis allowed the assembly of 215 Metagenome Assembled Genomes (MAGs), linking ARGs and other virulence-related genes to their host. Interestingly, a MAG belonging to Escherichia -that clearly predominated in water- harboured more ARGs and virulence factors than any other MAG, emphasising the potential virulent nature of these pathogenic-related groups. Finally, ex-situ incubations using environmentally-relevant concentrations of antibiotics increased the prevalence of their corresponding ARGs, but different riverine compartments -including plastispheres- were affected differently by each antibiotic. CONCLUSIONS: Our results provide insights into the capacity of the riverine plastisphere to harbour a distinct set of potentially pathogenic bacteria and function as a reservoir of ARGs. The environmental impact that plastics pose if they act as a reservoir for either pathogenic bacteria or ARGs is aggravated by the persistence of plastics in the environment due to their recalcitrance and buoyancy. Nevertheless, the high similarities with microbiomes growing on natural co-occurring materials and even more worrisome microbiome observed in the surrounding water highlights the urgent need to integrate the analysis of all environmental compartments when assessing risks and exposure to pathogens and ARGs in anthropogenically-impacted ecosystems. Video Abstract.

Increased LPS-Induced Fever and Sickness Behavior in Adult Male and Female Rats Perinatally Exposed to Morphine.

As a result of the current opioid crisis, the rate of children born exposed to opioids has skyrocketed. Later in life, these children have an increased risk for hospitalization and infection, raising concerns about potential immunocompromise, as is common with chronic opioid use. Opioids can act directly on immune cells or indirectly via the central nervous system to decrease immune system activity, leading to increased susceptibility, morbidity, and mortality to infection. However, it is currently unknown how perinatal opioid exposure (POE) alters immune function. Using a clinically relevant and translatable model of POE, we have investigated how baseline immune function and the reaction to an immune stimulator, lipopolysaccharide, is influenced by in utero opioid exposure in adult male and female rats. We report here that POE potentiates the febrile and neuroinflammatory response to lipopolysaccharide, likely as a consequence of suppressed immune function at baseline (including reduced antibody production). This suggests that POE increases susceptibility to infection by manipulating immune system development, consistent with the clinical literature. Investigation of the mechanisms whereby POE increases susceptibility to pathogens is critical for the development of potential interventions for immunosuppressed children exposed to opioids in utero.

Cross-study analyses of microbial abundance using generalized common factor methods.

BACKGROUND: By creating networks of biochemical pathways, communities of micro-organisms are able to modulate the properties of their environment and even the metabolic processes within their hosts. Next-generation high-throughput sequencing has led to a new frontier in microbial ecology, promising the ability to leverage the microbiome to make crucial advancements in the environmental and biomedical sciences. However, this is challenging, as genomic data are high-dimensional, sparse, and noisy. Much of this noise reflects the exact conditions under which sequencing took place, and is so significant that it limits consensus-based validation of study results. RESULTS: We propose an ensemble approach for cross-study exploratory analyses of microbial abundance data in which we first estimate the variance-covariance matrix of the underlying abundances from each dataset on the log scale assuming Poisson sampling, and subsequently model these covariances jointly so as to find a shared low-dimensional subspace of the feature space. CONCLUSIONS: By viewing the projection of the latent true abundances onto this common structure, the variation is pared down to that which is shared among all datasets, and is likely to reflect more generalizable biological signal than can be inferred from individual datasets. We investigate several ways of achieving this, demonstrate that they work well on simulated and real metagenomic data in terms of signal retention and interpretability, and recommend a particular implementation.

Change Score and Subscore Precision and Reliability of the Children's Depression Inventory.

The Child Depression Inventory (CDI) is often used to assess change in depression over time, but no studies estimate the reliability of CDI change scores nor its five subscores. Our study investigated the reliability of change scores for both the total score on the CDI as well as its five subscores. We examined CDI responses from 186 maltreated children and estimated change score reliability for relative (e.g., comparison) and absolute (e.g., diagnosis) purposes. We also conducted subscore utility analysis, which determines if subscores have adequate reliability and provide information beyond the total score. We found that the total change score had acceptable reliability of .70 for our sample for both relative and absolute interpretations. In addition, the total score was a better predictor of true subscore values than the observed subscores-suggesting subscores did not add value over the total score, and that the reliability of changes in subscores was too low to be useful for any purpose. In summary, we found that the total CDI change scores were useful for assessing change in studies that examine relative or absolute change, and we advise caution when interpreting CDI subscores based on our analysis.

Deer management influences perception of avian plumage in temperate deciduous forests.

Many animals use visual signals to communicate; birds use colorful plumage to attract mates and repel intruders. Visual signal conspicuousness is influenced by the lighting environment, which can be altered by human-induced changes. For example, deer-management efforts can affect vegetation structure and light availability. Whether these changes alter animal communication is still unknown. We investigated the effect of deer management on forest light and the contrast of understory birds against the forest background. We modeled visual perception using: (1) an ultraviolet-sensitive (UVS) avian model and plumage parameters representative of red, yellow, and blue birds (2) species-specific turkey visual and plumage parameters, and (3) individual-specific brown-headed cowbird visual and plumage parameters. Deer management led to greater light irradiance and lowered forest background reflectance. Management increased chromatic contrasts in the UVS model, primarily in deciduous forests and low understory, and across all habitat types in turkey and cowbird models. Deer management did not affect achromatic contrasts in the UVS model, but was associated with lower contrast in mixed forests for turkeys and across habitats for cowbirds. Together, this suggests that management of deer browsing is likely to impact visual signaling for a wide range of avian species. However, we also suspect that species- and individual-specific parameters increased the resolution of models, warranting consideration in future studies. Further work should determine if differences in visual perception translate to biologically relevant consequences. Our results suggest that, at least for some species, deer browsing and anthropogenic change may impose an evolutionary driver on visual communication.

Mechanical assessment of proprietary and improvised pelvic binders for use in the prehospital environment.

INTRODUCTION: Pelvic fractures often result from high-energy trauma and are associated with a 10% mortality rate and significant morbidity. Pelvic binders are applied in suspected pelvic injury to stabilise fractured bone, decrease bleeding and potentiate tamponade. A binder must hold the pelvis with sufficient force for this effect to be achieved. This study aims to quantify the ability of proprietary and improvised pelvic binders to hold a target tensile force over time. METHODS: The ability of three proprietary and three improvised binders to hold a binding force for 2 hours was tested. A uniaxial materials testing machine was used to tension each binder to 150 N and then hold the displacement for 2 hours; the drop in tension over time was recorded for each binder. The ability to hold tension above 130 N after 2 hours was set as the metric of binder performance. RESULTS: The median tension at 2 hours was above 130 N for the SAM Pelvic Sling II and T-POD Pelvic Stabilisation Device and was below 130 N for the Prometheus Pelvic Splint, field-expedient pelvic splint (FES) and the Personal Clothing System-Multi-Terrain Pattern Combat Trousers binders. The tension in the improvised FES after 2 hours was approximately at the target 130 N; however, in 40% of the tests, it held above 130 N. CONCLUSIONS: Binders varied in their ability to maintain sufficient tension to treat a pelvic fracture over the 2-hour testing period. The FES performed well under our testing regime; with relatively low cost and weight, it represents a good alternative to proprietary binders for the austere environment.

Content Validity of a High-Fidelity Surgical Middle Ear Simulator: A Randomized Prospective International Multicenter Trial.

OBJECTIVE: After demonstration of face validity of a surgical middle ear simulator (SMS) previously, we assessed the content validity of the simulator with otolaryngology residents. STUDY DESIGN: Multicenter randomized prospective international study. SETTING: Four academic institutions. METHODS: Novice participants were randomized into control, low-fidelity (LF), and high-fidelity (HF) groups. Control and LF produced 2 recordings from 2 attempts, and HF produced 4 recordings from 10 attempts, with trials 1, 4, 7, and 10 used for scoring. Three blinded experts graded videos of the simulated stapedectomy operation using an objective skills assessment test format consisting of global and stapedotomy-specific scales. RESULTS: A total of 152 recordings from 61 participants were included. Baseline characteristics did not differ significantly between groups. Depending on the step of the operation, inter-rater reliability ranged from 24 to 90%. For LF and HF, years of training was significantly associated with improved scores in certain objective skills assessment test subparts. HF outperformed the control group on stapes and global scores ( p < 0.05). The HF group demonstrated improvement in global score over trials, but plateaued after four trials. Scores varied greatly for participants from different institutions in certain operative steps, such as transecting incudostapedial joints, likely due to differences in instrumentation and time elapsed since manufacture. CONCLUSION: Practice with SMS led to better performance in both global and stapes-specific scores. Further studies are needed to examine construct validity and to create otology-appropriate grading systems. Variables like instrumentation and decline in flexibility of the simulator after 12 months greatly affect performance on the simulator.

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

Background: Eating Disorders (ED) affect up to 5% of youth and are associated with reward system alterations and compulsive behaviors. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and/or purging. The presumed mechanism of action is blockade of reward activation; however, not all patients respond, and the optimal dose is unknown. Developing a tool to detect objective drug response in the brain will facilitate drug development and therapeutic optimization. This pilot study evaluated neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED. Methods: Youth aged 13-21 with binge/purge ED completed functional magnetic resonance imaging (fMRI) pre- and post-oral naltrexone. fMRI detected blood oxygenation-level dependent (BOLD) signal at rest and during two reward probes (monetary incentive delay, MID, and passive food view, PFV) in predefined regions of interest associated with reward and inhibitory control. Effect sizes for Δ%BOLD (post-naltrexone vs. baseline) were estimated using linear mixed effects modeling. Results: In 12 youth (16-21 years, 92% female), BOLD signal changes were detected following naltrexone in the nucleus accumbens during PFV (Δ%BOLD -0.08 ± 0.03; Cohen's d -1.06, p = 0.048) and anterior cingulate cortex during MID (Δ%BOLD 0.06 ± 0.03; Cohen's d 1.25, p = 0.086). Conclusion: fMRI detected acute reward pathway modulation in this small sample of adolescents with binge/purge ED. If validated in future, larger trials, task-based Δ%BOLD detected by fMRI may serve as a pharmacodynamic biomarker of opioid antagonism to facilitate the development of novel therapeutics targeting the reward pathway, enable quantitative pharmacology trials, and inform drug dosing. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04935931, NCT#04935931.