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Abstract Objectives The objective of this study is to validate a hypothesis that a non‐invasive optical imaging assay targeting genomic VPAC receptors on malignant cells shed in voided urine will represent either benign prostatic hyperplasia (BPH) or prostatic cancer (PCa). Risk for BPH in men 50–70 years old is 50–70% and PCa is 17%. BPH and PCa can coexist in 20% of men with BPH. Most commonly practiced methods to diagnose BPH do not distinguish BPH from PCa. Patients (or Materials) and Methods Males with BPH (N = 97, 60.8 ± 6.3 years, prostate‐specific antigen 0.7 ± 0.4 ng/mL) and without oncologic disease (N = 35, 63.4 ± 5.8 years, prostate‐specific antigen

Abstract Background Australian Aboriginal and Torres Strait Islander women with diabetes in pregnancy (DIP) are more likely to have glycaemic levels above the target range, and their babies are thus at higher risk of excessive fetal growth. Shoulder dystocia, defined by failure of spontaneous birth of fetal shoulder after birth of the head requiring obstetric maneuvers, is an obstetric emergency that is strongly associated with DIP and fetal size. The aim of this study was to investigate the epidemiology of shoulder dystocia in Aboriginal babies born to mothers with DIP. Methods Stratifying by Aboriginal status, characteristics of births complicated by shoulder dystocia in women with and without DIP were compared and incidence and time-trends of shoulder dystocia were described. Compliance with guidelines aiming at preventing shoulder dystocia in women with DIP were compared. Post-logistic regression estimation was used to calculate the population attributable fractions (PAFs) for shoulder dystocia associated with DIP and to estimate probabilities of shoulder dystocia in babies born to mothers with DIP at birthweights > 3 kg. Results Rates of shoulder dystocia from vaginal births in Aboriginal babies born to mothers with DIP were double that of their non-Aboriginal counterparts (6.3% vs 3.2%, p 4.5 kg were lower in the Aboriginal women (28.6% vs 43.1%, p = 0.004). PAFs indicated that 13.4% (95% CI: 9.7%-16.9%) of shoulder dystocia cases in Aboriginal (2.7% (95% CI: 2.1%-3.4%) in non-Aboriginal) women were attributable to DIP. Probability of shoulder dystocia among babies born to Aboriginal mothers with DIP was higher at birthweights > 3 kg. Conclusions Aboriginal mothers with DIP had a higher risk of shoulder dystocia and a stronger association between birthweight and shoulder dystocia. Many cases were recurrent. These factors should be considered in clinical practice and when counselling women.

IntroductionEpstein-Barr virus (EBV) is an oncogenic human herpesvirus associated with ~350,000 cases of lymphoid and epithelial malignancies every year, and is etiologically linked to infectious mononucleosis and multiple sclerosis. Despite four decades of research, no EBV vaccine candidate has yet reached licensure. Most previous vaccine attempts focused on a single viral entry glycoprotein, gp350, but recent data from clinical and pre-clinical studies, and the elucidation of viral entry mechanisms, support the inclusion of multiple entry glycoproteins in EBV vaccine design.MethodsHere we generated a modified vaccinia Ankara (MVA)-vectored EBV vaccine, MVA-EBV5-2, that targets five EBV entry glycoproteins, gp350, gB, and the gp42gHgL complex. We characterized the genetic and translational stability of the vaccine, followed by immunogenicity assessment in BALB/c mice and rhesus lymphocryptovirus-negative rhesus macaques as compared to a gp350-based MVA vaccine. Finally, we assessed the efficacy of MVA-EBV5-2-immune rhesus serum at preventing EBV infection in human CD34+ hematopoietic stem cell-reconstituted NSG mice, under two EBV challenge doses.ResultsThe MVA-EBV5-2 vaccine was genetically and translationally stable over 10 viral passages as shown by genetic and protein expression analysis, and when administered to female and male BALB/c mice, elicited serum EBV-specific IgG of both IgG1 and IgG2a subtypes with neutralizing activity in vitro. In Raji B cells, this neutralizing activity outperformed that of serum from mice immunized with a monovalent MVA-vectored gp350 vaccine. Similarly, MVA-EBV5-2 elicited EBV-specific IgG in rhesus macaques that were detected in both serum and saliva of immunized animals, with serum antibodies demonstrating neutralizing activity in vitro that outperformed serum from MVA-gp350-immunized macaques. Finally, pre-treatment with serum from MVA-EBV5-2-immunized macaques resulted in fewer EBV-infected mice in the two challenge experiments than pretreatment with serum from pre-immune macaques or macaques immunized with the monovalent gp350-based vaccine.DiscussionThese results support the inclusion of multiple entry glycoproteins in EBV vaccine design and position our vaccine as a strong candidate for clinical translation.

The common murre (Uria aalge) is a species of seabird particularly vulnerable to several environmental stressors, including parasitic infection and oil contamination. However, the molecular response to these stressors is severely understudied. This study investigated the common murre’s transcriptomic responses to these stressors. Blood samples were collected from common murres undergoing rehabilitation at International Bird Rescue in Fairfield, CA. Total RNA was extracted from these samples, followed by library preparation and Illumina sequencing to generate whole transcriptome data. Differential gene expression analysis was conducted using DeSeq2 to identify genes significantly altered in response to oil contamination and parasitic infection. Differential gene expression analysis revealed 194 genes shared between oil-contaminated and infected birds, including key immune-related genes, such as ANXA2, LY96, and LY86. These genes play vital roles in mediating the production of pro-inflammatory cytokines. Gene Set Enrichment Analysis indicated significant alterations in stress, immune, and inflammatory responses, with additional lipid metabolism changes in contaminated birds. Our findings highlight the detrimental effects that these stressors have on wild birds. These findings suggest a generalized stress response and specific metabolic adaptations to oil exposure, providing insights for seabird conservation.

Abstract Debris flows and floods generated by rainfall runoff occur in rocky mountainous landscapes and burned steeplands. Flow type is commonly identified post‐event through interpretation of depositional structures, but these may be poorly preserved or misinterpreted. Prior research indicates that discharge magnitude is commonly amplified in debris flows relative to floods due to volumetric bulking and increased frictional resistance. Here, we use this flow amplification to develop a metric (Q*) to separate debris flows from floods based on the ratio of observed peak discharge to the theoretical maximum water discharge from rainfall runoff. We compile 642 observations of floods and debris flows and demonstrate that Q* distinguishes flow type to ∼92% accuracy. Q* allows for accurate identification of debris flows through simple channel cross‐section surveys rather than through qualitative interpretation of deposits, and therefore should increase the performance of models and engineered structures that require accurate flow‐type observations.

Per- and polyfluoroalkyl substances (PFAS) are a widespread and persistent class of contaminants posing significant environmental and human health concerns. Comprehensive understanding of the modes of action underlying toxicity among structurally diverse PFAS is mostly lacking. To address this need, we recently reported on our application of developing zebrafish to evaluate a large library of PFAS for developmental toxicity. In the present study, we prioritized 15 bioactive PFAS that induced significant morphological effects and performed RNA-sequencing to characterize early transcriptional responses at a single timepoint (48 h post fertilization) after early developmental exposures (8 h post fertilization). Internal concentrations of 5 of the 15 PFAS were measured from pooled whole fish samples across multiple timepoints between 24–120 h post fertilization, and additional temporal transcriptomics at several timepoints (48–96 h post fertilization) were conducted for Nafion byproduct 2. A broad range of differentially expressed gene counts were identified across the PFAS exposures. Most PFAS that elicited robust transcriptomic changes affected biological processes of the brain and nervous system development. While PFAS disrupted unique processes, we also found that similarities in some functional head groups of PFAS were associated with the disruption in expression of similar gene sets. Body burdens after early developmental exposures to select sulfonic acid PFAS, including Nafion byproduct 2, increased from the 24–96 h post fertilization sampling timepoints and were greater than those of sulfonamide PFAS of similar chain lengths. In parallel, the Nafion byproduct 2-induced transcriptional responses increased between 48 and 96 h post fertilization. PFAS characteristics based on toxicity, transcriptomic effects, and modes of action will contribute to further prioritization of PFAS structures for testing and informed hazard assessment.

# Background Stretching programs are designed to improve hamstring flexibility by attempting to mechanically increase the length of the target tissue. However, other manual treatment approaches such as those utilized in Total Motion Release (TMR®), could be beneficial by identifying body asymmetries to assess and treat soft tissue impairments leading to diminished extensibility. # Purpose The purpose of this study was to determine the effectiveness of the TMR® Fab 6 assessment and treatment to increase hamstring flexibility in healthy participants following one session of TMR®. # Study Design Observational Cohort study # Methods A convenience sample of 20 healthy participants (10 males, 10 females) were recruited from three institutions. Following collection of demographic information and a brief medical history, each participant performed a five minute warm-up on the stationary bike at a moderate intensity (80-90 RPMs) followed immediately by the bilateral performance of the Active Knee Extension Test (AKET) and Passive Straight Leg Raise (PSLR) to assess hamstring muscle length. Participants were randomly placed in the TMR® or control group. The TMR® group completed the “Fab 6” evaluation and treatment, while the control group performed one repetition of standing active hip flexion every 30-seconds for 15-minutes with both knees in full extension. Upon completion of treatment, control and TMR® groups were immediately re-evaluated on the AKET and the PSLR in the same order and fashion as baseline testing. Participants were asked to return in 24-hours for the same objective measurements as previously described. # Results A significant time by group interaction was identified across all variables (p ≤ 0.001) for AKET and PSLR except the PSLR preferred leg from post-treatment to 24hr follow-up. The most significant increase in the AKET occurred in the TMR® group between baseline and post-treatment of the non-preferred leg (12.15°±2.94) when compared to the control group (7.15°±1.56). # Conclusion The results of the study suggest that implementing a regionally interdependent treatment approach like TMR® results in significant improvements in hamstring extensibility and hip ROM compared to the control group. # Level of evidence 3

Abstract Background Post-overdose outreach programs engage overdose survivors and their families soon after an overdose event. Staff implementing these programs are routinely exposed to others’ trauma, which makes them vulnerable to secondary traumatic stress (STS) and compassion fatigue. The purpose of this study was to explore experiences of STS and associated upstream and downstream risk and protective factors among program staff. Methods We conducted a post-hoc analysis of semi-structured interviews with post-overdose outreach program staff in Massachusetts. Transcripts were analyzed using a multi-step hybrid inductive-deductive approach to explore approaches and responses to outreach work, factors that might give rise to STS, and compassion fatigue resilience. Findings were organized according to the three main constructs within Ludick and Figley’s compassion fatigue resilience model (empathy, secondary traumatic stress, and compassion fatigue resilience). Results Thirty-eight interviews were conducted with staff from 11 post-overdose outreach programs in Massachusetts. Within the empathy construct, concern for others’ well-being emerged as a motivator to engage in post-overdose outreach work – with staff trying to understand others’ perspectives and using this connection to deliver respectful and compassionate services. Within the secondary traumatic stress construct, interviewees described regular and repeated exposure to others’ trauma – made more difficult when exposures overlapped with staff members’ personal social spheres. Within the compassion fatigue resilience construct, interviewees described the presence and absence of self-care practices and routines, social supports, and workplace supports. Job satisfaction and emotional detachment from work experiences also arose as potential protective factors. Interviewees reported inconsistent presence and utilization of formal support for STS and compassion fatigue within their post-overdose outreach teams. Conclusion Post-overdose outreach program staff may experience secondary traumatic stress and may develop compassion fatigue, particularly in the absence of resilience and coping strategies and support. Compassion fatigue resilience approaches for post-overdose outreach staff warrant further development and study.

Abstract Background Benzodiazepines are a class of medications that are being frequently prescribed in Canada but carry significant risk of harm. There has been increasing clinical interest on the potential “sparing effects” of medical cannabis as one strategy to reduce benzodiazepine use. The objective of this study as to examine the association of medical cannabis authorization with benzodiazepine usage between 2013 and 2021 in Alberta, Canada. Methods A propensity score matched cohort study with patients on regular benzodiazepine treatment authorized to use medical cannabis compared to controls who do not have authorization for medical cannabis. A total of 9690 medically authorized cannabis patients were matched to controls. To assess the effect of medical cannabis use on daily average diazepam equivalence (DDE), interrupted time series (ITS) analysis was used to assess the change in the trend of DDE in the 12 months before and 12 months after the authorization of medical cannabis. Results Over the follow-up period after medical cannabis authorization, there was no overall change in the DDE use in authorized medical cannabis patients compared to matched controls (− 0.08 DDE, 95% CI: − 0.41 to 0.24). Likewise, the sensitivity analysis showed that, among patients consuming ≤5 mg baseline DDE, there was no change immediately after medical cannabis authorization compared to controls (level change, − 0.04 DDE, 95% CI: − 0.12 to 0.03) per patient as well as in the month-to-month trend change (0.002 DDE, 95% CI: − 0.009 to 0.12) per patient was noted. Conclusions This short-term study found that medical cannabis authorization had minimal effects on benzodiazepine use. Our findings may contribute ongoing evidence for clinicians regarding the potential impact of medical cannabis to reduce benzodiazepine use. Highlights • Medical cannabis authorization had little to no effect on benzodiazepine usage among patients prescribed regular benzodiazepine treatment in Alberta, Canada. • Further clinical research is needed to investigate the potential impact of medical cannabis as an alternative to benzodiazepine medication.

Abstract The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on July 15, 2022, to provide a forum to discuss industry and regulator CMC challenges associated with emergency use authorizations.

Graphene and related materials (graphene oxide, reduced graphene oxide) as a subclass of carbon materials and their composites have been examined in various functions as materials in supercapacitor electrodes. They have been suggested as active masses for electrodes in electrochemical double-layer capacitors, tested as conducting additives for redox-active materials showing only poor electronic conductivity, and their use as a coating of active materials for corrosion and dissolution protection has been suggested. They have also been examined as a corrosion-protection coating of metallic current collectors; paper-like materials prepared from them have been proposed as mechanical support and as a current collector of supercapacitor electrodes. This entry provides an overview with representative examples. It outlines advantages, challenges, and future directions.

Abstract It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed all available medications and may benefit from HSCT. The increasing experience with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remission or reduced burden of disease. Longer follow-up, however, is needed to better define the long-term outcomes. The discussion at the NextGen 2022 conference was focused on the optimal timing for the procedure, the need for a good control of inflammatory SJIA activity prior to HSCT, and the role of the reduced intensity conditioning regimens as there was a remote concern that such regimens might increase the risk of SJIA relapse after the transplantation. There was unanimous agreement about the importance of long-term registries to address these questions.

Abstract Since IL-18 has recently emerged as a biomarker associated with refractory disease course in SJIA, the focus of the discussion was the feasibility of the biomarker-driven drug development to SJIA. Overall, there was broad agreement on the conclusion that IL-18 is a uniquely specific biomarker for many of the subsets of SJIA most in need of new therapies, and it may define a class of diseases mediated by IL-18 excess. The consensus was that leveraging IL-18 remains our most promising “lead” for use in refractory SJIA as it may mechanistically explain the disease pathophysiology and lead to more targeted therapies.

Background: During takotsubo syndrome (TS), QTc prolongation is common, reflecting repolarization injury and providing the substrate for torsades de pointes (TdP). TdP has been reported sporadically in TS, yet QTc prolongation and TdP risk are often overlooked during management. Objectives: In TS patients, we sought to document TdP incidence, characteristics of patients with TdP, and association of QTc with postdischarge survival. Methods: Among consecutive TS patients at a single institution, we documented admission and discharge QTc, TdP incidence, and postdischarge 1-year mortality from 2006 to 2019. For perspective regarding TdP-TS risk, we characterized all published TdP cases from 2003 to 2022. Results: Of 259 patients, median age was 68 (range: 59-77) years; 92% were female. The QTc interval was prolonged (≥460 ms) on admission in 129 (49.8%) patients and at discharge in 140 (54%) patients. QTc was ≥500 ms either on admission or at discharge in 98 (37.8%) patients. In-hospital TdP incidence was 0.8%. Postdischarge mortality was associated with admission but not discharge, QTc: 98% survival at 1-year postdischarge.

Research has identified a positive relationship between physical activity and neuropsychological functioning across the lifespan. The present study further examined the relationship between physical activity, depression, anxiety, and cognitive functioning in community-dwelling older adults (ages 65–96) who completed an outpatient neuropsychological evaluation ( N = 526). Psychometrically sound and validated measures were used to assess depression, anxiety, and cognitive functioning. Analyses of covariance (ANCOVA) were conducted to examine differences between individuals who reported regularly engaging in physical activity and those who did not, after adjusting for demographic variables (age, education, and gender). Results indicated that physical activity was associated with better scores on measures of depression, anxiety, and cognitive functioning. Effect sizes for total scores on all measures were large, but there was a sizeable range of effect sizes (from small to large) for various cognitive domains. Smallest effect sizes were observed for subtests measuring language skills and visuospatial abilities, whereas largest effect sizes were seen in processing speed and memory. Results suggest that engaging in physical activity may be a beneficial non-pharmacological intervention for older adults. These findings underscore the importance of integrating physical activity programs in community and healthcare settings to foster mental and cognitive health in older populations.

Background: While historical rate of decline in kidney function is informally used by clinicians to estimate risk of future adverse clinical outcomes especially kidney failure, in people with type 2 diabetes the epidemiology and independent association of historical eGFR slope on risk is not well described. Objective: Determine the association of eGFR slope and risk of clinically important outcomes. Design Setting and Patients: Observational population-based cohort with type 2 diabetes in Alberta. Measurement and Methods: An Alberta population-based cohort with type 2 diabetes was assembled, characterized, and observed over 1 year (2018) for clinical outcomes of ESKD, first myocardial infarction, first stroke, heart failure, and disease-specific and all-cause hospitalization and mortality. Kidney function was defined using KDIGO criteria using the most recent eGFR and albuminuria measured in the preceding 18 months; annual eGFR slope utilized measurements in the 3 years prior and was parameterized using three methods (percentiles, and linear term with and without missingness indicator). Demographics, laboratory results, medications, and comorbid conditions using validated definitions were described. In addition to descriptive analysis, odds ratios from fully adjusted logistic models regressing outcomes on eGFR slope are reported; the marginal risk of clinical outcomes was also determined. Results: Among 336 376 participants with type 2 diabetes, the median annual eGFR slope was −0.41 mL/min/1.73 m 2 (IQR −1.67, 0.62). In fully adjusted models, eGFR slope was independently associated with many adverse clinical outcomes; among those with ≤10th percentile of slope (median −4.71 mL/min/1.73 m 2 ) the OR of kidney failure was 2.22 (95% CI 1.75, 2.82), new stroke 1.23 (1.08, 1.40), heart failure 1.42 (1.27, 1.59), MI 0.98 (0.77, 1.23) all-cause hospitalization 1.31 (1.26, 1.36) and all-cause mortality 1.56 (1.44, 1.68). For every −1 mL/min/1.73 m 2 in eGFR slope, the OR of outcomes ranged from 1.01 (0.98, 1.05 for new MI) to 1.09 (1.08, 1.10 for all-cause mortality); findings were significant for 10 of the 13 outcomes considered. Limitations: Causality cannot be established with this study design. Conclusions: These findings support consideration of the rate of eGFR decline in risk stratification and may inform clinicians and policymakers to optimize treatment and inform health care system planning.

Background. Small stature and female sex correlate to decreased deceased donor liver transplant (DDLT) access and higher waitlist mortality. However, efforts are being made to improve access and equity of allocation under the new continuous distribution (CD) system. Liver anteroposterior diameter (APD) is a method used by many centers to determine size compatibility for DDLT but is not recorded systematically, so it cannot be used for allocation algorithms. We therefore seek to correlate body surface area (BSA) and height to APD in donors and recipients and compare waitlist outcomes by these factors to support their use in the CD system. Methods. APD was measured from single-center DDLT recipients and donors with cross-sectional imaging. Linear, Pearson, and PhiK correlation coefficient were used to correlate BSA and height to APD. Competing risk analysis of waitlist outcomes was performed using United Network for Organ Sharing data. Results. For 143 pairs, donor BSA correlated better with APD than height (PhiK = 0.63 versus 0.20). For recipient all comers, neither BSA nor height were good correlates of APD, except in recipients without ascites, where BSA correlated well (PhiK = 0.63) but height did not. However, among female recipients, BSA, but not height, strongly correlated to APD regardless of ascites status (PhiK = 0.80 without, PhiK = 0.70 with). Among male recipients, BSA correlated to APD only in those without ascites (PhiK = 0.74). In multivariable models, both BSA and height were predictive of waitlist outcomes, with higher values being associated with increased access, decreased delisting for death/clinical deterioration, and decreased living donor transplant (model concordance 0.748 and 0.747, respectively). Conclusions. Taken together, BSA is a good surrogate for APD and can therefore be used in allocation decision making in the upcoming CD era to offset size and gender-based disparities among certain candidate populations.

Introduction: Protective associations of greenspace with Parkinson’s disease (PD) have been observed in some studies. Visual exposure to greenspace seems to be important for some of the proposed pathways underlying these associations. However, most studies use overhead-view measures (e.g., satellite imagery, land-classification data) that do not capture street-view greenspace and cannot distinguish between specific greenspace types. We aimed to evaluate associations of street-view greenspace measures with hospitalizations with a PD diagnosis code (PD-involved hospitalization). Methods: We created an open cohort of about 45.6 million Medicare fee-for-service beneficiaries aged 65 + years living in core based statistical areas (i.e. non-rural areas) in the contiguous US (2007–2016). We obtained 350 million Google Street View images across the US and applied deep learning algorithms to identify percentages of specific greenspace features in each image, including trees, grass, and other green features (i.e., plants, flowers, fields). We assessed yearly average street-view greenspace features for each ZIP code. A Cox-equivalent re-parameterized Poisson model adjusted for potential confounders (i.e. age, race/ethnicity, socioeconomic status) was used to evaluate associations with first PD-involved hospitalization. Results: There were 506,899 first PD-involved hospitalizations over 254,917,192 person-years of follow-up. We found a hazard ratio (95% confidence interval) of 0.96 (0.95, 0.96) per interquartile range (IQR) increase for trees and a HR of 0.97 (0.96, 0.97) per IQR increase for other green features. In contrast, we found a HR of 1.06 (1.04, 1.07) per IQR increase for grass. Associations of trees were generally stronger for low-income (i.e. Medicaid eligible) individuals, Black individuals, and in areas with a lower median household income and a higher population density. Conclusion: Increasing exposure to trees and other green features may reduce PD-involved hospitalizations, while increasing exposure to grass may increase hospitalizations. The protective associations may be stronger for marginalized individuals and individuals living in densely populated areas.

Background Professionalism is a complex and multifaceted component of medical education. Historically, students have learned about professionalism informally and as part of the hidden curriculum. Currently, professionalism is increasingly prominent in formal curricula, but uncertainty remains regarding optimal professionalism pedagogies. In this study, the authors explored medical students’ exposure to professional topics and considered factors that enabled students to correctly recognize and manage these issues. Methods Convenience sampling was used to recruit medical students from existing clinical attachments at the authors’ hospital. A semi-structured interview format was used to explore participants’ awareness of professional issues within fictional vignettes created using published regulatory guidance. The interview transcripts and interview guide field notes were then analyzed. Results The data suggest that students require a combination of didactic teaching and experiential learning to reliably recognize and manage professional issues. Didactic teaching alone enabled topic recognition, but with uncertainty about management strategies. Experiential learning alone led to erratic recognition of the subject and reliance upon role modeling to guide its management. This work stimulates faculty development to enhance teaching professionalism. Conclusions Undergraduate medical education on professionalism must be introduced into the formal curriculum. Didactic teaching is required to scaffold experiential learning. Failure to do so renders students unable to reliably recognize or manage professional issues encountered in clinical practice. Further research questions were identified to progress this work.

Mathematical models describing the spatial spreading and invasion of populations of biological cells are often developed in a continuum modelling framework using reaction–diffusion equations. While continuum models based on linear diffusion are routinely employed and known to capture key experimental observations, linear diffusion fails to predict well-defined sharp fronts that are often observed experimentally. This observation has motivated the use of nonlinear degenerate diffusion; however, these nonlinear models and the associated parameters lack a clear biological motivation and interpretation. Here, we take a different approach by developing a stochastic discrete lattice-based model incorporating biologically inspired mechanisms and then deriving the reaction–diffusion continuum limit. Inspired by experimental observations, agents in the simulation deposit extracellular material, which we call a substrate, locally onto the lattice, and the motility of agents is taken to be proportional to the substrate density. Discrete simulations that mimic a two-dimensional circular barrier assay illustrate how the discrete model supports both smooth and sharp-fronted density profiles depending on the rate of substrate deposition. Coarse-graining the discrete model leads to a novel partial differential equation (PDE) model whose solution accurately approximates averaged data from the discrete model. The new discrete model and PDE approximation provide a simple, biologically motivated framework for modelling the spreading, growth and invasion of cell populations with well-defined sharp fronts. Open-source Julia code to replicate all results in this work is available on GitHub.

Abstract Individual‐level differences in animal spatial behavior can lead to differential exposure to risk. We assessed the risk‐exposure of a reintroduced population of kākā (Nestor meridionalis) in a fenced reserve in New Zealand by GPS tracking 10 individuals and comparing the proportion of each individual's home range beyond the reserve's fence in relation to age, sex, and fledging origin. To estimate dynamic space use, we used a sweeping window framework to estimate occurrence distributions (ODs) from temporally overlapping snapshots. For each OD, we calculated the proportion outside the reserve's fence to assess temporal risk exposure, and the area, centroid, and overlap to represent the behavioral pattern of space use. Home range area declined significantly and consistently with age, and the space use of juvenile kākā was more dynamic, particularly in relation to locational changes of space use. The wider‐ranging and more dynamic behavior of younger kākā resulted in more time spent outside the reserve, which aligned with a higher number of incidental mortality observations. Quantifying both home range and dynamic space use is an effective approach to assess risk exposure, which can provide guidance for management interventions. We also emphasize the dynamic space use approach, which is flexible and can provide insights into a species' spatial ecology.

Tissue flossing is an emerging myofascial intervention used by sports medicine professionals with a growing body of research evidence. Sports medicine professionals may use tissue flossing to increase myofascial mobility, improve joint ROM, enhance athletic performance, and reduce pain. Despite the increasing use, there is no consensus on clinical practice recommendations for this intervention. The purpose of this commentary is to discuss proposed clinical practice recommendations for tissue flossing and to encourage sports medicine professionals and researchers to contribute their expertise to further develop best practices. # Level of Evidence 5

Abstract Background We previously demonstrated that a heuristic (i.e., evidence-based, rounded yet practical) cadence threshold of ≥ 100 steps/min was associated with absolutely-defined moderate intensity physical activity (i.e., ≥ 3 metabolic equivalents [METs]) in older adults 61–85 years of age. Although it was difficult to ascertain achievement of absolutely-defined vigorous (6 METs) intensity, ≥ 130 steps/min was identified as a defensible threshold for this population. However, little evidence exists regarding cadence thresholds and relatively-defined moderate intensity indicators, including ≥ 64% heart rate [HR] maximum [HRmax = 220-age], ≥ 40% HR reserve [HRR = HRmax-HRresting], and ≥ 12 Borg Scale Rating of Perceived Exertion [RPE]; or vigorous intensity indicators including ≥ 77%HRmax, ≥ 60%HRR, and ≥ 14 RPE. Purpose To analyze the relationship between cadence and relatively-defined physical activity intensity and identify relatively-defined moderate and vigorous heuristic cadence thresholds for older adults 61–85 years of age. Methods Ninety-seven ostensibly healthy adults (72.7 ± 6.9 years; 49.5% women) completed up to nine 5-min treadmill walking bouts beginning at 0.5 mph (0.8 km/h) and progressing by 0.5 mph speed increments (with 2-min rest between bouts). Directly-observed (and video-recorded) steps were hand-counted, HR was measured using a chest-strapped monitor, and in the final minute of each bout, participants self-reported RPE. Segmented mixed model regression and Receiver Operating Characteristic (ROC) curve analyses identified optimal cadence thresholds associated with relatively-defined moderate (≥ 64%HRmax, ≥ 40%HRR, and ≥ 12 RPE) and vigorous (≥ 77%HRmax, ≥ 60%HRR, and ≥ 14 RPE) intensities. A compromise between the two analytical methods, including Youden’s Index (a sum of sensitivity and specificity), positive and negative predictive values, and overall accuracy, yielded final heuristic cadences. Results Across all relatively-defined moderate intensity indicators, segmented regression models and ROC curve analyses identified optimal cadence thresholds ranging from 105.9 to 112.8 steps/min and 102.0-104.3 steps/min, respectively. Comparable values for vigorous intensity indicators ranged between126.1-132.1 steps/min and 106.7–116.0 steps/min, respectively. Regardless of the relatively-defined intensity indicator, the overall best heuristic cadence threshold aligned with moderate intensity was ≥ 105 steps/min. Vigorous intensity varied between ≥ 115 (greater sensitivity) or ≥ 120 (greater specificity) steps/min. Conclusions Heuristic cadence thresholds align with relatively-defined intensity indicators and can be useful for studying and prescribing older adults’ physiological response to, and/or perceived experience of, ambulatory physical activity. Trial registration Clinicaltrials.gov NCT02650258. Registered 24 December 2015.

Pier 52 along New York’s Hudson River doesn’t exist. Yet, it has a phantasmic presence in the form of David Hammons’art installation Day’s End—a skeletal recreation of the pier’s former dimensions that haunts the luxuryscape along the river. The piece is hardly noticeable and probably appears to most passersby as an infrastructural relic of an earlier economic regime. The installation contrasts sharply with the ostentatious and hypervisible Little Island a block to the north. Little Island is a cutting-edge futurepark rising out of the river on mushrooming concrete stems—the hallucination of billionaire brand mogul Barry Diller. Little Island exemplifies the contemporary urban economy premised on the ocular capture of pre-designed experiences. This essay frames such architecture as a breed of wealth pollution that has enclosed the city in glossy Instagram panoramas and ushered in a dystopic paralysis of imagination.

Research misconduct erodes the trust of the stake holders in the social science research enterprise. In order to return confidence and trust in social science research findings, we must emphasize research integrity through education and transparency. This essay discusses three fundamental components of research misconduct to raise awareness of examples of fabrication and falsification misconduct by several prominent social science researchers.

Abstract Significant advances in computational ethology have allowed the quantification of behaviour in unprecedented detail. Tracking animals in social groups, however, remains challenging as most existing methods can either capture pose or robustly retain individual identity over time but not both. To capture finely resolved behaviours while maintaining individual identity, we built NAPS (NAPS is ArUco Plus SLEAP), a hybrid tracking framework that combines state‐of‐the‐art, deep learning‐based methods for pose estimation (SLEAP) with unique markers for identity persistence (ArUco). We show that this framework allows the exploration of the social dynamics of the common eastern bumblebee (Bombus impatiens). We provide a stand‐alone Python package for implementing this framework along with detailed documentation to allow for easy utilization and expansion. We show that NAPS can scale to long timescale experiments at a high frame rate and that it enables the investigation of detailed behavioural variation within individuals in a group. Expanding the toolkit for capturing the constituent behaviours of social groups is essential for understanding the structure and dynamics of social networks. NAPS provides a key tool for capturing these behaviours and can provide critical data for understanding how individual variation influences collective dynamics.

Hip Disability and Osteoarthritis Outcome Survey (HOOS) was developed as a region- and disease-specific outcome to assess hip disability. Despite the use of the HOOS in clinical practice and research, psychometric analyses of the scale in a large dataset of patients have not been performed. As such, the purposes of this study were to assess the structural validity of the HOOS in patients who underwent a total hip arthroplasty. Data were obtained from the Surgical Outcome System (SOS) global registry. Confirmatory factor analysis (CFA) was conducted to assess the scale structure of the 40-item HOOS and exploratory factor analysis (EFA) was conducted to identify a parsimonious scale structure. The parsimonious model identified was subjected to multi-group and longitudinal invariance testing and LGC modeling. The original five-factor, 40-item HOOS did not meet recommended model fit indices values (CFI = 0.822, TLI = 0.809, IFI = 0.822, RMSEA = 0.085). Alternate model generation identified an alternative model (i.e., HOOS-9). Sound model fit was identified for the HOOS-9 (CFI = 0.974, TLI = 0.961, RMSEA = 0.046). Invariance testing criteria were also met between groups (i.e., age and sex) and across time. Lastly, a nonlinear growth trajectory was identified in responses pertaining to hip disability. The original scale structure of the 40-item HOOS was not supported. The HOOS-9 met contemporary model fit recommendations, along with multi-group and longitudinal invariance testing. Our findings support the preliminary use of the HOOS-9 to assess hip function and disability in research and clinical practice.

Optical fiber is increasingly used for both communication and distributed sensing of temperature and strain in environmental studies. In this work, we demonstrate the viability of unreinforced fiber tethers (bare fiber) for Raman-based distributed temperature sensing in deep ocean and deep ice environments. High-pressure testing of single-mode and multimode optical fiber showed little to no changes in light attenuation over pressures from atmospheric to 600 bars. Most importantly, the differential attenuation between Stokes and anti-Stokes frequencies, critical for the evaluation of distributed temperature sensing, was shown to be insignificantly affected by fluid pressures over the range of pressures tested for single-mode fiber, and only very slightly affected in multimode fiber. For multimode fiber deployments to ocean depths as great as 6000 m, the effect of pressure-dependent differential attenuation was shown to impact the estimated temperatures by only 0.15 °K. These new results indicate that bare fiber tethers, in addition to use for communication, can be used for distributed temperature or strain in fibers subjected to large depth (pressure) in varying environments such as deep oceans, glaciers and potentially the icy moons of Saturn and Jupiter.

IntroductionIn vivo studies of cancer biology and assessment of therapeutic efficacy are critical to advancing cancer research and ultimately improving patient outcomes. Murine cancer models have proven to be an invaluable tool in pre-clinical studies. In this context, multi-parameter flow cytometry is a powerful method for elucidating the profile of immune cells within the tumor microenvironment and/or play a role in hematological diseases. However, designing an appropriate multi-parameter panel to comprehensively profile the increasing diversity of immune cells across different murine tissues can be extremely challenging.MethodsTo address this issue, we designed a panel with 13 fixed markers that define the major immune populations –referred to as the backbone panel– that can be profiled in different tissues but with the option to incorporate up to seven additional fluorochromes, including any marker specific to the study in question.ResultsThis backbone panel maintains its resolution across different spectral flow cytometers and organs, both hematopoietic and non-hematopoietic, as well as tumors with complex immune microenvironments.DiscussionHaving a robust backbone that can be easily customized with pre-validated drop-in fluorochromes saves time and resources and brings consistency and standardization, making it a versatile solution for immuno-oncology researchers. In addition, the approach presented here can serve as a guide to develop similar types of customizable backbone panels for different research questions requiring high-parameter flow cytometry panels.

Librarians and archivists are often early adopters and experimenters with new technologies. Our field is also interested in critically engaging with technology, and we are well-positioned to be leaders in the slow and careful consideration of new technologies. Therefore, as librarians and archivists have begun using artificial intelligence (AI) to enhance library services, we also aim to interrogate the ethical issues that arise while using AI to enhance collection description and discovery and streamline reference services and teaching. The IMLS-funded Responsible AI in Libraries and Archives project aims to create resources that will help practitioners make ethical decisions when implementing AI in their work. The case studies in this special issue are one such resource. Seven overarching ethical issues come to light in these case studies—privacy, consent, accuracy, labor considerations, the digital divide, bias, and transparency. This introduction reviews each issue and describes strategies suggested by case study authors to reduce harms and mitigate these issues.

Objective: Centers for Medicare and Medicaid Services (CMS) has requested hospitals collect and report patient-reported outcomes (PROs) beginning in 2024 including the Hip Disability and Osteoarthritis Outcome Score Joint Replacement (HOOS-JR). However, scale structural validity of the HOOS-JR has minimally been assessed. The purpose of this study was to assess internal consistency, structural validity, and multi-group invariance properties of the HOOS-JR in a large sample of patients who underwent a total hip arthroplasty (THA). Methods: A cross-sectional study using the Surgical Outcomes System was retrospectively queried for patients who underwent a THA. Internal consistency was assessed using Cronbach's alpha and McDonald's Omega. A confirmatory factor analysis (CFA) was performed on the HOOS-JR using a priori cut-off values. Multi-group invariance testing was also performed on the sample of patients across sex and age groups. Results: Internal consistency was acceptable for 6-item (alpha ​= ​0.88; omega ​= ​0.88) and 5-item (alpha ​= ​0.86; omega ​= ​0.86) HOOS-JR. The one-factor, 6-item CFA did not meet the recommended fit indices. The one-factor, 5-item CFA had acceptable fit for the sample data. Invariance testing criteria were met between the age groups; however, scalar invariance was not met for sex. Conclusion: The 6-item HOOS-JR did not meet contemporary model fit indices indicating that scale refinement is warranted. The 5-item met most goodness-of-fit indices and invariance criteria. However, further scale refinement may be warranted as localized fit issues were identified.

Space-borne passive microwave (PMW) data provide rich information on atmospheric state, including cloud structure and underlying surface properties. However, PMW data are sparse and limited due to low Earth orbit collection, resulting in coarse Earth system sampling. This study demonstrates that Bayesian deep learning (BDL) is a promising technique for predicting synthetic microwave (MW) data and its uncertainties from more ubiquitously available geostationary infrared observations. Our BDL models decompose predicted uncertainty into aleatoric (irreducible) and epistemic (reducible) components, providing insights into uncertainty origin and guiding model improvement. Low and high aleatoric uncertainty values are characteristic of clear sky and cloudy regions, respectively, suggesting that expanding the input feature vector to allow richer information content could improve model performance. The initially high average epistemic uncertainty metrics quantified by most models indicate that the training process would benefit from a greater data volume, leading to improved performance at most studied MW frequencies. Using quantified epistemic uncertainty to select the most useful additional training data (a training dataset size increase of 3.6%), the study reduced the mean absolute error and root mean squared error by 1.74% and 1.38%, respectively. The broader impact of this study is the demonstration of how predicted epistemic uncertainty can be used to select targeted training data. This allows for the curation of smaller, more optimized training datasets and also allows for future active learning studies.

Histone variants are paralogs that replace canonical histones in nucleosomes, often imparting novel functions. However, how histone variants arise and evolve is poorly understood. Reconstruction of histone protein evolution is challenging due to large differences in evolutionary rates across gene lineages and sites. Here we used intron position data from 108 nematode genomes in combination with amino acid sequence data to find disparate evolutionary histories of the three H2A variants found in Caenorhabditis elegans: the ancient H2A.ZHTZ-1, the sperm-specific HTAS-1, and HIS-35, which differs from the canonical S-phase H2A by a single glycine-to-alanine C-terminal change. Although the H2A.ZHTZ-1 protein sequence is highly conserved, its gene exhibits recurrent intron gain and loss. This pattern suggests that specific intron sequences or positions may not be important to H2A.Z functionality. For HTAS-1 and HIS-35, we find variant-specific intron positions that are conserved across species. Patterns of intron position conservation indicate that the sperm-specific variant HTAS-1 arose more recently in the ancestor of a subset of Caenorhabditis species, while HIS-35 arose in the ancestor of Caenorhabditis and its sister group, including the genus Diploscapter. HIS-35 exhibits gene retention in some descendent lineages but gene loss in others, suggesting that histone variant use or functionality can be highly flexible. Surprisingly, we find the single amino acid differentiating HIS-35 from core H2A is ancestral and common across canonical Caenorhabditis H2A sequences. Thus, we speculate that the role of HIS-35 lies not in encoding a functionally distinct protein, but instead in enabling H2A expression across the cell cycle or in distinct tissues. This work illustrates how genes encoding such partially-redundant functions may be advantageous yet relatively replaceable over evolutionary timescales, consistent with the patchwork pattern of retention and loss of both genes. Our study shows the utility of intron positions for reconstructing evolutionary histories of gene families, particularly those undergoing idiosyncratic sequence evolution.

Wastewater-based epidemiology is a promising public health tool that can yield a more representative view of the population than case reporting. However, only about 80% of the U.S. population is connected to public sewers, and the characteristics of populations missed by wastewater-based epidemiology are unclear. To address this gap, we used publicly available datasets to assess sewer connectivity in the U.S. by location, demographic groups, and economic groups. Data from the U.S. Census' American Housing Survey revealed that sewer connectivity was lower than average when the head of household was American Indian and Alaskan Native, White, non-Hispanic, older, and for larger households and those with higher income, but smaller geographic scales revealed local variations from this national connectivity pattern. For example, data from the U.S. Environmental Protection Agency showed that sewer connectivity was positively correlated with income in Minnesota, Florida, and California. Data from the U.S. Census' American Community Survey and Environmental Protection Agency also revealed geographic areas with low sewer connectivity, such as Alaska, the Navajo Nation, Minnesota, Michigan, and Florida. However, with the exception of the U.S. Census data, there were inconsistencies across datasets. Using mathematical modeling to assess the impact of wastewater sampling inequities on inferences about epidemic trajectory at a local scale, we found that in some situations, even weak connections between communities may allow wastewater monitoring in one community to serve as a reliable proxy for an interacting community with no wastewater monitoring, when cases are widespread. A systematic, rigorous assessment of sewer connectivity will be important for ensuring an equitable and informed implementation of wastewater-based epidemiology as a public health monitoring system.

Background The extent to which sex, racial, and ethnic groups receive advanced heart therapies equitably is unclear. We estimated the population rate of left ventricular assist device (LVAD) and heart transplant (HT) use among (non‐Hispanic) White, Hispanic, and (non‐Hispanic) Black men and women who have heart failure with reduced ejection fraction (HFrEF). Methods and Results We used a retrospective cohort design combining counts of LVAD and HT procedures from 19 state inpatient discharge databases from 2010 to 2018 with counts of adults with HFrEF. Our primary outcome measures were the number of LVAD and HT procedures per 1000 adults with HFrEF. The main exposures were sex, race, ethnicity, and age. We used Poisson regression models to estimate procedure rates adjusted for differences in age, sex, race, and ethnicity. In 2018, the estimated population of adults aged 35 to 84 years with HFrEF was 69 736, of whom 44% were women. Among men, the LVAD rate was 45.6, and the HT rate was 26.9. Relative to men, LVAD and HT rates were 72% and 62% lower among women (P0.05) or higher (P

Abstract Dermatomyositis is a rare disease characterized by progressive muscle weakness and skin rashes. Estimates of incidence and prevalence are fundamental measures in epidemiology, but few studies have been conducted on dermatomyositis. To address this knowledge gap, we conducted a population-based study to determine the contemporary incidence (between 2013 and 2019) and prevalence (2019) of adults living with dermatomyositis using administrative health data in Alberta, Canada. We also described disease-related medication use, as there are very few approved medications for the treatment of dermatomyositis, and no Canadian therapeutic guidelines. The average age- and sex-standardized annual incidence of dermatomyositis was 2.8–3.0 cases per 100,000 adults, and prevalence was 28.6 cases per 100,000 adults, which is greater than reported in other cohorts. Dermatomyositis-related medication use decreased from 73% in the first year to 46% in the eighth year after diagnosis. Glucocorticoids were the most commonly used drug class, often taken concurrently with various immunomodulatory agents; this medication use aligns with empirically-based recommendations and the few therapeutic guidelines for dermatomyositis. Considering that Alberta may have one of the highest rates of dermatomyositis among adults, further research on the burden of disease is warranted for planning within the health care system.

The Hip Dysfunction and Osteoarthritis Outcome Score for Joint Replacement (HOOS-JR) was developed as a short-form survey to measure progress after total hip arthroplasty (THA). However, the longitudinal validity of the scale structure pertaining to the modified five-item HOOS-JR has not been assessed. Therefore, the purpose of this study was to evaluate the structural validity, longitudinal invariance properties, and latent growth curve (LGC) modeling of the modified five-item HOOS-JR in a large multi-site sample of patients who underwent a THA. A longitudinal study was conducted using data from the Surgical Outcome System (SOS) database. Confirmatory factor analyses (CFAs) were conducted to assess the structural validity and longitudinal invariance across five time points. Additionally, LGC modeling was performed to assess the heterogeneity of the recovery patterns for different subgroups of patients. The resulting CFAs met most of the goodness-of-fit indices (CFI = 0.964–0.982; IFI = 0.965–0.986; SRMR = 0.021–0.035). Longitudinal analysis did not meet full invariance, exceeding the scalar invariance model (CFIDIFF = 0.012; χ2DIFF test = 702.67). Partial invariance requirements were met upon release of the intercept constraint associated with item five (CFIDIFF test = 0.010; χ2DIFF = 1073.83). The equal means model did not pass the recommended goodness-of-fit indices (CFIDIFF = 0.133; χ2DIFF = 3962.49). Scores significantly changed over time, with the highest scores identified preoperatively and the lowest scores identified at 2- and 3-years postoperatively. Upon conclusion, partial scalar invariance was identified within our model. We identified that patients self-report most improvements in their scores within 6 months postoperatively. Females reported more hip disability at preoperative time points and had faster improvement as measured by the scores of the modified five-item HOOS-JR.

Abstract Introduction A better understanding of current acute pain-driven analgesic practices within the emergency department (ED) and upon discharge will provide foundational information in this area, as few studies have been conducted in Canada. Methods Administrative data were used to identify adults with a trauma-related ED visit in the Edmonton area in 2017/2018. Characteristics of the ED visit included time from initial contact to analgesic administration, type of analgesics dispensed during and upon being discharged home directly from the ED (≤ 7 days after), and patient characteristics. Results A total of 50,950 ED visits by 40,505 adults with trauma were included. Analgesics were administered in 24.2% of visits, of which non-opioids were dispensed in 77.0% and opioids were dispensed in 49.0%. Time to analgesic initiation occurred more than 2 h after first contact. Upon discharge, 11.5% received a non-opioid and 15.2% received an opioid analgesic, among whom 18.5% received a daily dose ≥ 50 morphine milligram equivalents (MME) and 30.2% received > 7 days of supply. Three hundred and seventeen adults newly met criteria for chronic opioid use after the ED visit, among whom 43.5% received an opioid dispensation upon discharge; of these individuals, 26.8% had a daily dose ≥ 50 MME and 65.9% received > 7 days of supply. Conclusions Findings can be used to inform optimization of analgesic pharmacotherapy practices for the treatment of acute pain, which may include reducing the time to initiation of analgesics in the ED, as well as close consideration of recommendations for acute pain management upon discharge to provide ideal patient-centered, evidence-informed care.

Abstract TRIUMF is one of the only laboratories in the world able to produce both lead-203 (203Pb, t1/2 = 51.9 h) and 212Pb (t1/2 = 10.6 h) onsite via its 13 and 500 MeV cyclotrons, respectively. Together, 203Pb and 212Pb form an element-equivalent theranostic pair that potentiate image-guided, personalized cancer treatment, using 203Pb as a single-photon emission computed tomography (SPECT) source, and 212Pb for targeted alpha therapy. In this study, improvements to 203Pb production were accomplished by manufacturing electroplated, silver-backed thallium (Tl) targets to improve target thermal stability, which allow for higher currents during irradiation. We implemented a novel, two-column purification method that employs selective Tl precipitation (203Pb only) alongside extraction and anion exchange chromatography to elute high specific activity and chemical purity 203/212Pb in a minimal volume of dilute acid, without the need for evaporation. Optimization of the purification method translated to improvements in radiolabeling yields and apparent molar activity of lead chelators TCMC (S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) and Crypt-OH, a derivative of a [2.2.2]-cryptand.

Abstract The sympathetic nervous system is crucial for controlling multiple cardiac functions. However, a comprehensive, detailed neuroanatomical map of the sympathetic innervation of the heart is unavailable. Here, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical distribution of the sympathetic postganglionic innervation in whole atria of C57Bl/6 J mice. We found that (1) 4–5 major extrinsic TH-IR nerve bundles entered the atria at the superior vena cava, right atrium (RA), left precaval vein and the root of the pulmonary veins (PVs) in the left atrium (LA). Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the atria with the greatest density of innervation near the sinoatrial node region (P

Objectives The objectives of this study were to describe medication use, treatment patterns and adherence, as well as acute exacerbations of chronic obstructive pulmonary disease (AECOPD) among adults living with COPD.Methods A retrospective observational study using administrative data (linked by unique person-level personal health numbers) between 1 April 2007 and 31 March 2018 from Alberta, Canada was performed. Individuals aged ≥35 years who had been living with COPD ≥1 year on 1 April 2017 (index date) were identified. COPD-related medication use was determined on the index date (baseline), and medication use, treatment patterns, adherence and AECOPD were measured during the 1-year postindex observation period; descriptive statistics were applied.Results Among the total cohort (n=192 814), 59% were not using a COPD-related medication at baseline; among those using medication, the most common (>10%) classes were short acting bronchodilators only (29%), dual inhaled corticosteroids/long acting beta2 agonists (ICS/LABA, 27%), combined ICSs/LABA/long acting muscarinic antagonist (ICS/LABA/LAMA, 21%) and LAMA monotherapy (12%). During the observation period, those with baseline COPD medication use had low adherence (42% were adherent (medication possession ratio ≥0.80) to their baseline medication class) and AECOPD were common (13%–40%); 66% of those with ≥1 dispensation for an additional medication class had a step-up in therapy that was concordant with guideline recommendations.Conclusions In this population-based study, the majority of individuals identified as living with COPD were not taking any COPD-related medication, while in those who were taking medication, adherence was low, deficits in alignment to guideline-recommended therapy were observed and many had AECOPD. Strategies for earlier identification of undertreatment, consideration of guideline-based knowledge transfer strategies and mechanisms to improve long-term medication adherence may improve outcomes.

While the surrogate fuel approach has been successfully applied to the simulation of the combustion behaviors of complex gasoline and jet fuels, its application to diesel fuels has been challenging. One of the main challenges derives from the large molecular size of the representative surrogate components necessary to simulate diesel blends, as the development of detailed chemical kinetic models and their validation becomes more complex. In this study, a new surrogate mixture that emulates the chemical and physical properties of a well-characterized diesel fuel is proposed. An optimization procedure was used to select surrogate components that can match both the physical and chemical properties of the target diesel fuel comprehensively. The surrogate fuel mixture composition was designed to have fuel properties (e.g., boiling point, cloud point, etc.) that enable its use in future diesel engine experiments. A detailed kinetic model for the surrogate fuel mixture was developed by combining well-validated sub-mechanisms of each surrogate component from Lawrence Livermore National Laboratory. The ability of the surrogate mixture and kinetic model to emulate ignition delay times was assessed by comparing the simulated results with measurements for the target diesel fuel. Comparison of the experimental and simulated ignition delay times shows that the current surrogate mixture and kinetic model well capture the autoignition response of the target diesel fuel at varying conditions of pressure, temperature, oxygen concentration, and fuel concentration. The current study is one of the first to demonstrate the efficacy of detailed chemical kinetics for diesel range fuels by assembling validated sub-mechanisms for palette compounds and successfully simulating the autoignition characteristics of a target diesel fuel. The experimental ignition delay times of diesel measured with a rapid compression machine, the surrogate mixture, and the kinetic model developed shall aid in progress of understanding diesel ignition under engine relevant conditions.

BACKGROUND Macrophage activation syndrome (MAS) is a life-threatening complication of Still’s disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS.METHOD We profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies.RESULTS Bulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell, and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 — both elevated in MAS patients — synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response.CONCLUSION MAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.

Mineral weathering is an important soil-forming process driven by the interplay of water, organisms, solution chemistry, and mineralogy. The influence of hillslope-scale patterns of water flux on mineral weathering in soils is still not well understood, particularly in humid postglacial soils, which commonly harbor abundant weatherable primary minerals. Previous work in these settings showed the importance of lateral hydrologic patterns to hillslope-scale pedogenesis. In this study, we hypothesized that there is a corresponding relationship between hydrologically driven pedogenesis and chemical weathering in podzols in the White Mountains of New Hampshire, USA. We tested this hypothesis by quantifying the depletion of plagioclase in the fine fraction (≤2 mm) of closely spaced, similar-age podzols along a gradient in topography and depth to bedrock that controls lateral water flow. Along this gradient, laterally developed podzols formed through frequent, episodic flushing by upslope groundwater, and vertically developed podzols formed through characteristic vertical infiltration. We estimated the depletion of plagioclase-bound elements within the upper mineral horizons of podzols using mass transfer coefficients (τ) and quantified plagioclase losses directly through electron microscopy and microprobe analysis. Elemental depletion was significantly more pronounced in the upslope lateral eluvial (E horizon-dominant) podzols relative to lateral illuvial (B horizon-dominant) and vertical (containing both E and B horizons) podzols downslope, with median Na losses of ∼74 %, ∼56 %, and ∼40 %, respectively. When comparing genetic E horizons, Na and Al were significantly more depleted in laterally developed podzols relative to vertically developed podzols. Microprobe analysis revealed that ∼74 % of the plagioclase was weathered from the mineral pool of lateral eluvial podzols, compared to ∼39 % and ∼23 % for lateral illuvial podzols and vertically developed podzols, respectively. Despite this intense weathering, plagioclase remains the second most abundant mineral in soil thin sections. These findings confirm that the concept of soil development as occurring vertically does not accurately characterize soils in topographically complex regions. Our work improves the current understanding of pedogenesis by identifying distinct, short-scale gradients in mineral weathering shaped by local patterns of hydrology and topography.

Purpose: Patients with pancreatic cancer undergoing chemoradiation therapy may experience acute and chronic side effects. We conducted an exploratory analysis of patients with locally advanced pancreatic cancer (LAPC) undergoing definitive chemoradiation to identify factors influencing the occurrence of gastrointestinal (GI) bleeding, short-term radiation side effects, patterns of failure, and survival. Methods and Materials: Under an institutional review board–approved protocol, we retrospectively studied patients with LAPC treated with chemoradiation. Statistical models were used to test associations between clinical characteristics and outcomes, including upper GI bleeding, radiation treatment breaks, and weight loss during therapy. Results: Between 1999 and 2012, 211 patients were treated with radiation for pancreatic cancer. All patients received concurrent chemotherapy with either gemcitabine (174) or 5-fluorouracil (27), and 67 received intensity modulated radiation therapy (IMRT). Overall, 18 patients experienced an upper GI bleed related to treatment, with 70% of bleeds occurring in the stomach or duodenum, and among those patients, 11 (61%) patients had a pancreatic head tumor and 17 (94%) patients had a metallic biliary stent. IMRT was associated with decreased risk of postradiation nausea (odds ratio, 0.27 [0.11, 0.67], P = .006) compared with 3-dimensional conformal radiation. Regarding long-term toxicities, patients with a metallic biliary stent at the time of radiation therapy were at a significantly higher risk of developing upper GI bleeding (unadjusted hazard ratio [HR], 15.41 [2.02, 117.42], P = .008), even after controlling for radiation treatment modality and prescribed radiation dose (adjusted HR, 17.38 [2.26, 133.58], P = .006). Furthermore, biliary stent placement was associated with a higher risk of death (HR, 1.99 [1.41, 2.83], P < .001) after adjusting for demographic, treatment-related, and patient-related variables. Conclusions: Metallic biliary stents may be associated with an increased risk of upper GI bleeding and mortality. Furthermore, IMRT was associated with less nausea and short-term toxicity compared with 3-dimensional conformal therapy.

Summary: Background: Diagnosis of skin cancer requires medical expertise, which is scarce. Mobile phone-powered artificial intelligence (AI) could aid diagnosis, but it is unclear how this technology performs in a clinical scenario. Our primary aim was to test in the clinic whether there was equivalence between AI algorithms and clinicians for the diagnosis and management of pigmented skin lesions. Methods: In this multicentre, prospective, diagnostic, clinical trial, we included specialist and novice clinicians and patients from two tertiary referral centres in Australia and Austria. Specialists had a specialist medical qualification related to diagnosing and managing pigmented skin lesions, whereas novices were dermatology junior doctors or registrars in trainee positions who had experience in examining and managing these lesions. Eligible patients were aged 18–99 years and had a modified Fitzpatrick I–III skin type; those in the diagnostic trial were undergoing routine excision or biopsy of one or more suspicious pigmented skin lesions bigger than 3 mm in the longest diameter, and those in the management trial had baseline total-body photographs taken within 1–4 years. We used two mobile phone-powered AI instruments incorporating a simple optical attachment: a new 7-class AI algorithm and the International Skin Imaging Collaboration (ISIC) AI algorithm, which was previously tested in a large online reader study. The reference standard for excised lesions in the diagnostic trial was histopathological examination; in the management trial, the reference standard was a descending hierarchy based on histopathological examination, comparison of baseline total-body photographs, digital monitoring, and telediagnosis. The main outcome of this study was to compare the accuracy of expert and novice diagnostic and management decisions with the two AI instruments. Possible decisions in the management trial were dismissal, biopsy, or 3-month monitoring. Decisions to monitor were considered equivalent to dismissal (scenario A) or biopsy of malignant lesions (scenario B). The trial was registered at the Australian New Zealand Clinical Trials Registry ACTRN12620000695909 (Universal trial number U1111–1251–8995). Findings: The diagnostic study included 172 suspicious pigmented lesions (84 malignant) from 124 patients and the management study included 5696 pigmented lesions (18 malignant) from the whole body of 66 high-risk patients. The diagnoses of the 7-class AI algorithm were equivalent to the specialists’ diagnoses (absolute accuracy difference 1·2% [95% CI –6·9 to 9·2]) and significantly superior to the novices’ ones (21·5% [13·1 to 30·0]). The diagnoses of the ISIC AI algorithm were significantly inferior to the specialists’ diagnoses (–11·6% [–20·3 to –3·0]) but significantly superior to the novices’ ones (8·7% [–0·5 to 18·0]). The best 7-class management AI was significantly inferior to specialists’ management (absolute accuracy difference in correct management decision –0·5% [95% CI –0·7 to –0·2] in scenario A and –0·4% [–0·8 to –0·05] in scenario B). Compared with the novices’ management, the 7-class management AI was significantly inferior (–0·4% [–0·6 to –0·2]) in scenario A but significantly superior (0·4% [0·0 to 0·9]) in scenario B. Interpretation: The mobile phone-powered AI technology is simple, practical, and accurate for the diagnosis of suspicious pigmented skin cancer in patients presenting to a specialist setting, although its usage for management decisions requires more careful execution. An AI algorithm that was superior in experimental studies was significantly inferior to specialists in a real-world scenario, suggesting that caution is needed when extrapolating results of experimental studies to clinical practice. Funding: MetaOptima Technology.

The common snipe (Gallinago gallinago) is a wader that breeds in subarctic regions from Iceland to Russia, and for which global populations are in decline. We studied snipe breeding in western Iceland between 1998 and 2020, locating nests and ringing birds annually. In 2019 and 2020, we deployed geolocators on nesting adults to estimate the timing of their annual migration and the location of overwintering areas. Birds moved principally between breeding locations in Iceland to wintering areas in Ireland, although some birds may winter farther north. We also found that apparent annual adult survival averaged 66%, but was higher in years with warmer, wetter winters. Given the similarity of our survival estimates to those from snipe elsewhere, we suggest that adult survival is unlikely a major contributor to declining populations, and other factors like habitat loss may be of more concern.

Abstract The establishment of an exotic pest may require displacing local species with a similar niche. The potential of Trogoderma granarium to displace Trogoderma inclusum was explored in a stored product setting. We performed direct competition experiments varying commodity and temperature over different durations. At nine weeks T. inclusum outproduced T. granarium on all commodities at any temperature. However the proportion of T. granarium versus T. inclusum was greater at 32 °C compared to 25 °C. The nine-week production of T. granarium was best on wheat, while rice was optimal for T. inclusum. After 25 weeks, when adults were used at the start of competition, T. inclusum maintained an advantage in the direct competition. If larvae were used to initiate the competition for 25 weeks, the two species coexisted well at 25 °C, but T. granarium nearly excluded T. inclusum at 32 °C. Thus T. inclusum performs better in competition over shorter intervals when resources are plentiful, but T. granarium can be more successful over longer time periods, particularly when late instar larvae are involved. The finding suggests a real threat of introductions of T. granarium larvae to establish populations within grain storage infrastructure where T. inclusum is common.

Mobile media are fundamental to social life in a growing number of ways. Beyond the mundane, the technology has come to play a meaningful role in protests and emergent demonstrations worldwide, including recent cases of political violence among far-right groups in the U.S. Drawing from the folk theory tradition, this study samples Alt-Right supporters to investigate how perceived essence of mobile media, particularly as a tool for collective action, is associated with willingness to engage in racially motivated and extreme political action in offline and online contexts. Findings reveal that perceptions of the mobile phone as a tool for collective action are associated with greater intentions to participate in online and offline activity explicitly in support of White people. Additionally, we find cases where links between essence and intentions are strengthened among those reporting higher levels of micro-coordination, or use of mobile media for coordinating with others in daily life. The findings indicate how everyday life perceptions and practices function and interact in ways that help explain willingness to join racially motivated calls to action among this group. The discussion offers implications for studying mobile media and collective action more broadly, especially in the context of under-researched political groups.

Abstract Trogoderma granarium Everts, the khapra beetle, native to the Indian subcontinent, is one of the world’s most destructive pests of stored food products. Early detection of this pest facilitates prompt response towards the invasion and prevents the need for costly eradication efforts. Such detection requires proper identification of T. granarium, which morphologically resembles some more frequently encountered, non-quarantine congeners. All life stages of these species are difficult to distinguish using morphological characters. Additionally, biosurveillance trapping can result in the capture of large numbers of specimens awaiting identification. To address these issues, we aim to develop an array of molecular tools to rapidly and accurately identify T. granarium among non-target species. Our crude, cheap DNA extraction method performed well for Trogoderma spp. and is suitable for downstream analyses including sequencing and real-time PCR (qPCR). We developed a simple quick assay usingrestriction fragment length polymorphism to distinguish between T. granarium and the closely related, congeneric T. variabile Ballion and T. inclusum LeConte. Based on newly generated and published mitochondrial sequence data, we developed a new multiplex TaqMan qPCR assay for T. granarium with improved efficiency and sensitivity over existing qPCR assays. These new tools benefit regulatory agencies and the stored food products industry by providing cost- and time-effective solutions to enhance the identification of T. granarium from related species. They can be added to the existing pest detection toolbox. The selection of which method to use would depend on the intended application.