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Abstract Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.

Abstract Objective The objective of this study is to determine whether a sleep and health improvement programme (SHIP) to promote healthy sleep, eating and physical activity would be feasible, acceptable and have a positive impact on lifestyle behaviours for prostate cancer survivors and caregivers. Methods We recruited 50 participants for a single group 3‐month pre‐post pilot study. The SHIP intervention included (1) website about sleep, nutrition and physical activity (≥1 view/week), (2) two email newsletters with goal‐setting exercises and resources and (3) midpoint health coach call. The primary outcome was changes in validated sleep scales; secondary outcomes included changes in diet, physical activity and concentration from baseline to 3 months. Results Of 50 participants enrolled, median age was 65, 30% were Black and 8% were Hispanic. Thirty‐four patients and 7 family caregivers completed the pilot study (82%). Following the intervention, we observed a statistically significant improvement in the Sleep Hygiene Index (pre: 15, post: 13, p

Objective Quality of care (QoC) delivery in rheumatoid arthritis (RA) continues to suffer from various challenges (eg, delay in diagnosis and referral) that can lead to poor patient outcomes. This study aimed to identify good practice interventions that address these challenges in RA care in North America. Methods The study was conducted in three steps: (1) literature review of existing publications and guidelines (April 2005 to April 2021) on QoC in RA; (2) in‐person visits to >50 individual specialists and health care professionals across nine rheumatology centers in the United States and Canada to identify challenges in RA care and any corresponding good practice interventions; and (3) collation and organization of findings of the two previous methods by commonalities to identify key good practice interventions, followed by further review by RA experts to ensure key challenges and gaps in RA care were captured. Results Several challenges and eight good practice interventions were identified in RA care. The interventions were prioritized based on the perceived positive impact on the challenges in care and ease of implementation. High‐priority interventions included the use of technology to improve care, streamlining specialist treatment, and facilitating comorbidity assessment and care. Other interventions included enabling patient access to optimal medication regimens and improving patient self‐management strategies. Conclusion Learnings from the study can be implemented in other rheumatology centers throughout North America to improve RA care. Although the study was completed before the COVID‐19 pandemic, the findings remain relevant.

Abstract Sixteen percent of patients referred for cardiology evaluation are found to have no cause for palpitations. Studies show that hypertension intricately influences “heart rate” and “contractility,?” the key components of “palpitation.” While the prevalence of hypertension is 22.4% in 18–39‐year‐olds, the relationship between palpitations and hypertension remains unknown in this age group. In our study, we assessed the incidence and prevalence of hypertension over 5 years in 18–40‐year‐olds referred for palpitations who had no known arrhythmic cause for palpitations between January 1, 206 and December 31, 2017. We found that over a period of 2.2 (0.7–4.1) years, an additional 56% patients were diagnosed with stage 1 (65/130) and stage 2 (28/130) hypertension, increasing the prevalence from 16% at the start of the study period to 72% at the end of the study period (p

Abstract Immune checkpoint inhibitors block the interaction between a receptor on one cell and its ligand on another cell, thus preventing the transduction of an immunosuppressive signal. While inhibition of the receptor–ligand interaction is key to the pharmacological activity of these drugs, it can be technically challenging to measure these intercellular interactions directly. Instead, target engagement (or receptor occupancy) is commonly measured, but may not always be an accurate predictor of receptor–ligand inhibition, and can be misleading when used to inform clinical dose projections for this class of drugs. In this study, a mathematical model explicitly representing the intercellular receptor–ligand interaction is used to compare dose prediction based on target engagement or receptor–ligand inhibition for two checkpoint inhibitors, atezolizumab and magrolimab. For atezolizumab, there is little difference between target engagement and receptor–ligand inhibition, but for magrolimab, the model predicts that receptor–ligand inhibition is significantly less than target engagement. The key variables explaining the difference between these two drugs are the relative concentrations of the target receptors and their ligands. Drug‐target affinity and receptor–ligand affinity can also have divergent effects on target engagement and inhibition. These results suggest that it is important to consider ligand–receptor inhibition in addition to target engagement and demonstrate the impact of using modeling for efficacious dose estimation.

Objective Patients with early rheumatoid arthritis (RA) may present with more tender than swollen joints, which can persist. Elevated tender‐swollen joint difference (TSJD) is often challenging, because there may be multiple causes and it may contribute to overestimating disease activity. Little is known about the phenotype and impact of TSJDs on patient function. Our objective was to evaluate the impact of TSJD on functional outcomes in early RA and to see whether associations vary by joint size. Methods Data were from patients with active, early RA (≤12 months) enrolled in the Canadian Early Arthritis Cohort, who completed assessments of general function (Multidimensional Health Assessment Questionnaire [MDHAQ]), upper extremity (UE) function (Quality of Life in Neurological Disorders [Neuro‐QoL] UE scale), and work/activity impairment (Work Productivity and Activity Impairment RA) over their first year of follow‐up. A total of 28 joint counts were performed. TSJDs were calculated. Adjusted associations between TSJDs and functional outcomes were estimated in separate multivariable linear mixed effects models. Separate analyses were performed for large‐ versus small‐joint TSJD. Results Patients (N = 547) were 70% female, mean age 56 (SD 15) years, mean disease duration 5.3 (SD 2.9) months. At baseline, 287 (52%) had TSJD >0 (43% involved large joints and 34% small joints), decreasing to 32% at 12 months. A one‐point increase in TSJD was significantly associated with worse function (MDHAQ: adjusted mean change 0.10, 95% confidence interval [CI] 0.08–0.13; Neuro‐QoL UE function T score: adjusted mean change −0.59, 95% CI −0.76 to −0.43; and greater work impairment: adjusted mean change 1.95%, 95% CI 0.85%–3.05%). Higher large‐joint TSJDs were associated with the worst functional outcomes. Conclusion Having more tender than swollen joints is common in early RA and is associated with worse function, most notably when involving large joints. Early identification and targeted intervention strategies may be needed.

Abstract Many of the world's iconic, endangered and endemic species rely on large, contiguous landscapes for their survival. In the US West, working ranches are integral to large landscape conservation goals and there are numerous influences on ranchers' conservation actions, including their relational values, perceived self‐efficacy and property rights concerns. Using survey data from 681 ranchers in eastern Idaho and western Montana, we sought to answer the question: How do relational values, property rights orientations, perceived efficacy and public lands dependence affect reported conservation actions on private ranch lands? Conservation adoption varied widely by action, with invasive plant removal having the highest (92%) and conifer removal the lowest (21%) rates of adoption. Conservation adoption was higher among ranchers who believe they are responsible for conserving nature, believe their land should be used to provide environmental benefits to the region, have higher perceived self‐efficacy, lower property rights concerns and higher incomes. Programmes encouraging the adoption of conservation on private lands could benefit from message framing that resonates with the worldviews of landowners and land managers. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Given that terrestrial ecosystems globally are facing the loss of biodiversity from land use conversion, invasive species, and climate change, effective management requires a better understanding of the drivers and correlates of biodiversity. Increasingly, biodiversity is co‐managed with aboveground carbon storage because high biodiversity in animal species is observed to correlate with high aboveground carbon storage. Most previous investigations into the relationship of biodiversity and carbon co‐management do not focus on the biodiversity of the species rich plant kingdom, which may have tradeoffs with carbon storage. To examine the relationships of plant species richness with aboveground tree biomass carbon storage, we used a series of generalized linear models with understory plant species richness and diversity data from the USDA Forest Service Forest Inventory and Analysis dataset and high‐resolution modeled carbon maps for the Tongass National Forest. Functional trait data from the TRY database was used to understand the potential mechanisms that drive the response of understory plants. Understory species richness and community weighted mean leaf dry matter content decreased along an increasing gradient of tree biomass carbon storage, but understory diversity, community weighted mean specific leaf area, and plant height at maturity did not. Leaf dry matter content had little variance at the community level. The decline of understory plant species richness but not diversity to increases in aboveground biomass carbon storage suggests that rare species are excluded in aboveground biomass carbon dense areas. These decreases in understory species richness reflect a tradeoff between the understory plant community and aboveground carbon storage. The mechanisms that are associated with observed plant communities along a gradient of biomass carbon storage in this forest suggest that slower‐growing plant strategies are less effective in the presence of high biomass carbon dense trees in the overstory.

ABSTRACT Background Approximately one‐third of US adults have a tattoo, and the prevalence is increasing. Tattooing can result in long‐term exposure to carcinogens and inflammatory and immune responses. Methods We examined tattooing and risk of hematologic cancers in a population‐based case–control study with 820 cases diagnosed 2019–2021 and 8200 frequency‐matched controls, ages 18–79 years. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable‐adjusted logistic regression models. Results The prevalence of tattooing was 22% among Hodgkin lymphoma (HL) cases, 11% among non‐Hodgkin lymphoma (NHL) cases, 16% among myeloid neoplasm cases, and 15% among controls. Though there were no clear patterns of associations between ever receiving a tattoo and risk of HL, NHL, or myeloid neoplasms overall, in analyses restricted to ages 20–60 years, ever receiving a tattoo (OR 2.06 [95% CI 1.01, 4.20]) and receiving a tattoo 10+ years prior (OR 2.64 [95% CI 1.23, 5.68]) were associated with an aggregated group of rarer mature B‐cell NHLs. We also observed elevated risks for a 10+ year latency for myelodysplastic syndromes and chronic myeloid leukemia (OR 1.48 [95% CI 0.40, 5.41], and OR 1.24 [95% CI 0.45, 3.43], respectively). Conclusions Though estimates were imprecise, we found some suggestive evidence that tattooing may be associated with an increased risk of certain hematologic cancer subtypes. With an estimated 46% prevalence of tattooing in US individuals ages 30–49, additional studies are needed to understand the degree to which these exposures may be associated with hematologic cancer risk.

Abstract The preservation of genetic variation is fundamental in biodiversity conservation, yet its importance for population viability remains contentious. Mixed‐source reintroductions, where individuals are translocated into a single vacant habitat from multiple genetically divergent and often depauperate populations, provide an opportunity to evaluate how genetic variation and hybridization influence individual and relative population fitness. Population genetic theory predicts that individuals with higher genetic variation and hybrids among populations should have higher fitness. We tested these two hypotheses by analyzing individual and population‐scale data for westslope cutthroat trout (Oncorhynchus clarkii lewisi) in four mixed‐source reintroductions. We observed more hybrid and fewer nonhybrid offspring than expected across four independent mixed‐source reintroductions. We also found clear evidence that heterozygosity influenced individual reproductive and relative population fitness. Overall, we found a strong, positive relationship between genetic variation, hybridization, and transplant fitness, emphasizing the importance of genetic variation and population mixing in conservation.

Abstract Because it can lead to retaliatory killing, livestock depredation by large carnivores is among the foremost threats to carnivore conservation, and it severely impacts human well‐being worldwide. Ongoing climate change can amplify these human–wildlife conflicts, but such issues are largely unexplored, though are becoming increasingly recognized. Here, we assessed how the availability of primary resources and wild prey interact to shape large carnivore selection for livestock rather than wild prey (i.e., via prey switching or apparent competition). Specifically, we combined remotely sensed estimates of primary resources (i.e., water availability and primary productivity), wild prey movement, and 7 years (2015–2021) of reports for livestock depredation by African lions (Panthera leo) in the Makgadikgadi Pans ecosystem, Botswana. Although livestock depredation did not vary between wet versus dry seasons, analyses at finer temporal scales revealed higher incidences of livestock depredation when primary production, water availability, and wild prey availability were lower, though the effects of wild prey availability were mediated by water availability. Increased precipitation also amplified livestock depredation events despite having no influence on wild prey availability. Our results suggest that livestock depredation is influenced by the diverse responses of livestock, wild prey, and lions to primary resource availability, a driver that is largely overlooked or oversimplified in studies of human–carnivore conflict. Our findings provide insight into tailoring potential conflict mitigation strategies to fine‐scale changes in resource conditions to efficiently reduce conflict and support human livelihoods.

Abstract The loss and degradation of forests and other ecosystems worldwide threaten both global biodiversity and the livelihoods of people who use natural resources. Understanding how natural resource use impacts landscape provisioning services for both people and wildlife is thus critical for designing comprehensive resource management strategies. We used data from community focus groups, botanical plots and an inventory of plant species consumed by the Critically Endangered red‐ruffed lemur (Varecia rubra) to assess the availability of key provisioning services for people and endemic wildlife on the Masoala Peninsula, a rainforest transformation landscape, in northeastern Madagascar (Masoala National Park and 13 surrounding communities). We constructed Poisson regression mixed models to evaluate the impact of community factors (i.e. community population size, plot distance to community) and changes over time on the count and species richness of timber trees, medicinal plants and red‐ruffed lemur food trees within botanical plots. Over three‐quarters of all plant species could be used for at least one purpose by local communities (n = 238 species). Of the 59 V. rubra food tree species, only 15% had no reported human use. Timber and ruffed lemur food tree availability declined both with community population size and time and were predicted to be lower outside of Masoala National Park. In contrast, medicinal plant availability was not strongly predicted by any tested factors. Provisioning service availability also differed strongly across sites, suggesting that additional, untested proxies of human pressure likely also have an effect. Our results highlight the importance of evaluating natural resource availability from a community‐based perspective and by resource purpose to inform forest landscape restoration efforts that can support both people and wildlife. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Introduction Research indicates that the immobilisation mask required for radiation therapy (RT) for head and neck cancers can provoke intense anxiety. However, little is known about the rates of this anxiety, whether it changes over a course of treatment and how it is managed in clinical practice. This study aimed to describe the rates and patterns of situational anxiety in patients undergoing RT for head and neck cancer and the use of anxiety management interventions in current clinical practice in a major regional cancer setting in New South Wales, Australia. Methods Situational anxiety rates and patterns were assessed at five time points using the State‐Trait Anxiety Inventory prior to treatment planning (SIM), the first three treatment sessions (Tx 1, Tx 2 and Tx 3) and treatment 20 (Tx 20). Sessions were observed to record the use of general supportive interventions (music and support person) and anxiety‐specific interventions (break from the mask, relaxation techniques and anxiolytic medication). Sociodemographic and clinical information was extracted from the medical record. Results One hundred and one patients were recruited. One‐third had clinically significant anxiety at any of the first three time points (33.3–40%), and a quarter at Tx 3 (26.4%) and Tx 20 (23.4%). Of the sample, 55.4% had available data for categorisation into one of four pattern groups: ‘No Anxiety’ (46.4%); ‘Decreasing Anxiety’ (35.7%); ‘Increasing Anxiety’ (7.1%); and ‘Stable High Anxiety’ (10.7%). Most participants had social support present at SIM (53.5%) and listened to music during treatment (86.7–92.9%). Few participants received relaxation techniques alone (1.2–2.3%). Anxiolytic medication was provided for 10% of patients at some stage during the treatment journey and 5% required a break from the mask at SIM, with frequency decreasing throughout the treatment course. Conclusions In this regional cancer setting, situational anxiety was common, but generally decreased throughout treatment. Some patients experience persistent or increasing anxiety, with up to 10% of patients receiving specific anxiety management interventions.

Abstract Viral vectors and lipofection‐based gene therapies have dispersion‐dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close‐field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of “naked” plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near‐field conductivity (“conductivity‐clamping”–CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic‐ready bionics‐derived CC‐GET device achieved neurotrophin‐encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics‐based hearing. The performance of CC‐GET is evaluated in the brain, an organ problematic for pulsed electric field‐based plasmid DNA delivery, due to high required currents causing Joule‐heating and damaging electroporation. Here CC‐GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red‐shifted channelrhodopsin and a genetically‐encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

Abstract Currently 1677 species are listed under the U.S. Endangered Species Act (ESA), yet only a small percentage have been delisted due to recovery. In the fall of 2021, the U.S. Fish and Wildlife Service proposed delisting 23 species due to extinction. Tracking changes in species ‘recovery status over time is critical to understanding species’ statuses, informing adaptive management strategies, and assessing the performance of the ESA to prevent further species loss. In this paper, we describe four key obstacles in tracking species recovery status under the ESA. First, ESA 5‐year reviews lack a standardized format and clear documentation. Second, despite having been listed for decades, many species still suffer major data gaps in their biology and threats, rendering it difficult if not impossible to track progress towards recovery. Third, many species have continued declining after listing, yet given the above (1 & 2), understanding potential causes (proximate and/or ultimate) can be difficult. Fourth, many species currently have no path to clear recovery, which represents a potential failing of the process. We conclude with a discussion of potential policy responses that could be addressed to enhance the efficacy of the ESA.

Abstract The Endangered Species Act (ESA) provides legal protection to imperiled populations and their associated habitats. As a part of this process, listed species must undergo a general status review (also called 5‐Year Review) to assess the progress toward recovery every 5 years. However, almost all 5‐year reviews result in a status of “no change,” prompting scientists to question if the review process is robust enough to detect changes in recovery. The U.S. Fish and Wildlife Service (USFWS) was therefore interested in developing a standardized metric for monitoring more nuanced recovery progress as part of the status review. In collaboration with the USFWS, over 75 biologists from five different organizations developed and tested a set of novel metrics to summarize recovery progress of listed species by considering current and future conditions, threats, and conservation measures. We found that, although the majority of species had reviews with a recommendation of no change, scorers were able to use the metrics to interpret more nuanced changes in the 3Rs (resiliency, redundancy, and representation), threats, and conservation measures than in the status review. Our results suggest that these metrics could illuminate more nuanced areas of recovery and decline in species' conditions, but consistency among scorers and status reports should be a focus of future development. Our approach offers a rigorous set of metrics to systematically track the recovery progress of all ESA species.

Abstract Public lands across the United States are managed for multiple uses, resources, and values ranging from energy development to rare plant conservation. Intensified energy development and other land use changes across the Southwestern United States have increased the need for proactive management to mitigate impacts to rare plants. Habitat suitability models can inform decision‐making and lead to more effective conservation of rare plants and their habitats, but high‐quality models that are suited for use at local scales are lacking for many species. Our team of scientists and managers developed ensembles of habitat suitability models for five rare plant species in New Mexico using a coproduced, iterative framework complemented by comprehensive ground truthing and tailoring of products for use in public land decisions. Our process resulted in substantial differences from initial models through changes to environmental predictors, species occurrence and background data, and development of new species‐specific predictors. Involving species experts and end users in model development can strengthen the process and resulting model and build understanding and trust in final products. Both factors can promote use of models to inform public land permitting and planning decisions that may affect rare plants, including by guiding development away from highly suitable habitats.

Abstract Freshwater ecosystems are complex, diverse, and face multiple imminent threats that have led to changes in both structure and function. It is urgent that we develop and standardize monitoring tools that allow for rapid and comprehensive assessment of freshwater communities to understand their changing dynamics and inform conservation. Environmental DNA surveys offer a means to inventory and monitor aquatic diversity, yet most studies focus on one or a few taxonomic groups because of technical challenges. In this study, we (1) create an eDNA metabarcoding dataset (natural water bodies) with 14 validated primer pairs; (2) create a free online, user‐friendly tool for primer selection that can be used for any metabarcoding data (SNIPe); and (3) using SNIPe, explore our dataset to derive subsets of informative, cost‐effective primer pairs that maximize detection of freshwater diversity. We first evaluated the completeness of public reference sequence databases and the efficiency of 14 primer pairs in silico, in vitro on five mock communities (mix of DNA from tissues of select taxa), in vivo on water samples from aquarium samples with known taxonomic composition, and finally in vivo on water samples from freshwater systems in Eastern Canada. Results from analyses using SNIPe revealed that 13 or 14 primer pairs are necessary to recover 100% of the species in water samples (natural systems), but that four primer pairs are sufficient to recover almost 75% of taxa with little overlap. Our work highlights the power of eDNA metabarcoding for reconstructing freshwater communities, including prey, parasite, pathogen, invasive, and declining species. It also emphasizes the importance of marker choice on species resolution, and primer characteristics and filtering parameters on detection success and accuracy of biodiversity estimates. Together, these results highlight the usefulness of eDNA for freshwater monitoring and should prompt more studies of tools to survey all communities.

Abstract Post‐traumatic stress disorder (PTSD) is associated with increased cardiovascular disease (CVD) risk. Compared with males, females are twice as likely to develop PTSD after trauma exposure, and cardiovascular reactivity to stress is a known risk factor for CVD. We aimed to examine hemodynamic responses to acute mental stress in trauma‐exposed females with and without a clinical diagnosis of PTSD. We hypothesized that females with PTSD would have higher heart rate (HR), blood pressure (BP), and lower blood flow velocity (BFV) responsiveness compared with controls. We enrolled 21 females with PTSD and 21 trauma‐exposed controls. We continuously measured HR using a three‐lead electrocardiogram, BP using finger plethysmography, and brachial BFV using Doppler ultrasound. All variables were recorded during 10 min of supine rest, 5 min of mental arithmetic, and 5 min of recovery. Females with PTSD were older, and had higher BMI and higher resting diastolic BP. Accordingly, age, BMI, and diastolic BP were covariates for all repeated measures analyses. Females with PTSD had a blunted brachial BFV response to mental stress (time × group, p = 0.005) compared with controls, suggesting greater vasoconstriction. HR and BP responses were comparable. In conclusion, our results suggest early impairment of vascular function in premenopausal females with PTSD.

Background Cardiac amyloidosis (CA) is frequently found in older patients with aortic stenosis (AS). However, the prevalence of AS among patients with CA is unknown. The objective was to study the prevalence and prognostic impact of AS among patients with CA. Methods and Results We conducted a retrospective analysis of a prospective registry comprising 976 patients with native aortic valves who were confirmed with wild type transthyretin amyloid (ATTRwt), hereditary variant transthyretin amyloid (ATTRv), or immunoglobulin light‐chain (AL) CA. CA patients' echocardiograms were re‐analyzed focusing on the aortic valve. Multivariable Cox regression analysis was performed to assess the mortality risk associated with moderate or greater AS in ATTRwt CA. The crude prevalence of AS among patients with CA was 26% in ATTRwt, 8% in ATTRv, and 5% in AL. Compared with population‐based controls, all types of CA had higher age‐ and sex‐standardized rate ratios (SRRs) of having any degree of AS (AL: SRR, 2.62; 95% Confidence Interval (CI) [1.09–3.64]; ATTRv: SRR, 3.41; 95%CI [1.64–4.60]; ATTRwt: SRR, 10.8; 95%CI [5.25–14.53]). Compared with hospital controls, only ATTRwt had a higher SRR of having any degree of AS (AL: SRR, 0.97, 95%CI [0.56–1.14]; ATTRv: SRR, 1.27; 95%CI [0.85–1.44]; ATTRwt: SRR, 4.01; 95%CI [2.71–4.54]). Among patients with ATTRwt, moderate or greater AS was not associated with increased all‐cause death after multivariable adjustment (hazard ratio, 0.71; 95%CI [0.42–1.19]; P=0.19). Conclusions Among patients with CA, ATTRwt but not ATTRv or AL is associated with a higher prevalence of patients with AS compared with hospital controls without CA, even after adjusting for age and sex. In our population, having moderate or greater AS was not associated with a worse outcome in patients with ATTRwt.

Abstract Background Concurrent ectopic pregnancies in differing anatomical locations are a rarity. It is imperative to be able to identify these cases as extrauterine pregnancies require emergent evaluation and treatment. Case We describe a case of suspected ruptured ectopic pregnancy in a low‐risk multiparous female found to have ipsilateral ovarian and tubal ectopic pregnancies on laparoscopy and subsequent pathology. Conclusion Although the co‐occurrence of these pregnancies presented as a diagnostic challenge, preoperative ultrasound imaging increased our suspicion in conjunction with laparoscopic findings. Thorough examination of the uterus and bilateral adnexa during laparoscopy is essential in identifying pathology and reducing morbidity. Furthermore, sampling or removal of suspicious concomitant lesions may aid in diagnosis. Following beta HCG trends may provide additional information in patients with unclear findings on laparoscopy.

Abstract Public lands are often managed for multiple uses ranging from energy development to rare plant conservation. Habitat models can help land managers assess and mitigate potential effects of projects on rare plants, but it is unclear how models are currently being used. Our goal was to better understand how staff in the Bureau of Land Management currently use habitat models to inform their decisions, and perceived challenges and benefits associated with that use. We first examined litigation documents to determine whether the agency has been challenged on its use of data for rare plants and found no relevant legal challenges. Second, we analyzed model use in National Environmental Policy Act (NEPA) documents and found no clear citations of habitat models. Finally, we conducted interviews with agency staff who analyze potential effects of proposed actions on rare plants in NEPA documents. The primary challenges interviewees faced in using models related to data organization and access, model quality and accuracy, and institutional capacity. Interviewees believed models could be used more to inform decisions and actions to conserve rare plants and rare plant habitat on public lands and recommended improving staff access to models, creating models for additional species, and addressing staffing limitations.

Abstract Autonomic dysfunction is a common complication of type 2 diabetes mellitus (T2DM). However, the character of dysfunction varies in different reports. Differences in measurement methodology and complications might have influenced the inconsistent results. We sought to evaluate comprehensively the relationship between abnormal glucose metabolism and autonomic function at rest and the response to exercise in healthy individuals and T2DM patients. We hypothesized that both sympathetic and parasympathetic indices would decrease with the progression of abnormal glucose metabolism in individuals with few complications related to high sympathetic tone. Twenty healthy individuals and 11 T2DM patients without clinically evident cardiovascular disease other than controlled hypertension were examined. Resting muscle sympathetic nerve activity (MSNA), heart rate variability, spontaneous cardiovagal baroreflex sensitivity (CBRS), sympathetic baroreflex sensitivity and the MSNA response to handgrip exercise were measured. Resting MSNA was lower in patients with T2DM than in healthy control subjects (P = 0.011). Resting MSNA was negatively correlated with haemoglobin A1c in all subjects (R = −0.45, P = 0.024). The parasympathetic components of heart rate variability and CBRS were negatively correlated with glycaemic/insulin indices in all subjects and even in the control group only (all, P

Abstract The New Zealand's Greenshell™ mussel (Perna canaliculus) aquaculture industry is being affected by summer mortality events associated with increasing seawater temperatures and pathogens. In this study, challenge experiments were conducted to investigate, for the first time, the effects of pathogen coinfection on the survivability and haemolymph immune responses of juvenile and adult mussels. Animals were injected with marine broth (control), Vibrio mediterranei, Photobacterium swingsii, or a mixture of V. mediterranei and P. swingsii. Then, mussel survival was monitored for 72 h, and haemolymph was sampled for bacterial quantification and metabolomics analyses at 24‐ and 48‐h post challenge. Coinfected adults and juveniles showed 100% mortality. Bacterial colony counts in haemolymph decreased as infection time continued, especially in juveniles. The haemolymph metabolome of mussels exposed to single bacterial species and coinfection showed response changes largely within energy metabolism. Mussels infected with V. mediterranei exhibited increased metabolites linked to the glutathione pathway, branched‐chain amino acids, and others over time, supporting structural functions. Conversely, mussels infected with P. swingsii showed no metabolic differences over time. The coinfection group exhibited large decreases in important metabolites, such as fatty acids as an alternative energy source and amino acids to support immune functions and protein synthesis.

Abstract The Gulf of Carpentaria and Torres Strait in north‐eastern Australia support globally significant seagrass ecosystems that underpin fishing and cultural heritage of the region. Reliable data on seagrass distribution are critical to understanding how these ecosystems are changing, while managing for resilience. Spatial data on seagrass have been collected since the early 1980s, but the early data were poorly curated. Some was not publicly available, and some already lost. We validated and synthesized historical seagrass spatial data to create a publicly available database. We include a site layer of 48,612 geolocated data points including information on seagrass presence/absence, sediment, collection date, and data custodian. We include a polygon layer with 641 individual seagrass meadows. Thirteen seagrass species are identified in depths ranging from intertidal to 38 m below mean sea level. Our synthesis includes scientific survey data from 1983 to 2022 and provides an important evidence base for marine resource management.

Abstract 1. Conserving species' ability to traverse the landscape is vital for maintaining biodiversity in the face of global change. Connectivity conservation requires identifying important pathways for species' movements and aligning societal support for conservation of those pathways. Contemporary connectivity analyses emphasize the impacts of topography, vegetation and human footprint on species' movements; but largely ignore the role that attitudes, economics and institutions play in practitioners' ability to conserve those movements. 2. We introduce implementation resistance as an analogue of biophysical resistance that combines social, economic and institutional factors that promote or impede connectivity conservation. We demonstrate the utility of integrating implementation resistance as a means of choosing between competing connectivity conservation strategies using wolves in Colorado (USA) as a case study. 3. Our analysis of five potential corridor locations based on biophysical costs revealed substantial differences in the social costs associated with implementing each corridor despite relatively minimal differences in the biophysical costs. 4. Our comparison of hypothetical interventions to reduce implementation resistance illustrates that interventions that reduce conflicts between land use and wolves may substantially reduce overall resistance, those reductions are not as well aligned with connectivity priorities as those resulting from changes in land management agency policy. 5. Our results highlight the need to design conservation interventions that fit both the social and ecological landscape and provide a framework for developing robust, interdisciplinary methods that facilitate implementable connectivity conservation. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Introduction The paediatric radiation therapy group (PRTG) provided a multidisciplinary network to support patients accessing radiation therapy (RT). This study aims to evaluate the use and efficacy of behaviour therapy practices used by the PRTG. Methods A retrospective cross‐sectional review of general anaesthetic (GA) utilisation for paediatric patients was completed between 1 January 2010 and 30 June 2014. The PRTG incorporated behavioural therapy techniques into all appointments but offered additional play appointments to children unable to comply with the requirements of RT. This aimed to increase their compliance and minimise GA use. Results Two‐hundred and seventy‐four patients had 5402 occasions of service, of which 1361 were delivered under GA (25.2%). Two‐hundred and fifty‐seven patients met the eligibility criteria. Patients under 8 years who required GA for their entire treatment reduced for each year of increase in age (odds ratio 0.37, 95% confidence interval 0.27–0.51, P

Abstract Objectives To explore the perceptions of patients and healthcare professionals on Raman‐faecal immunochemical test (FIT) as an alternative test for colorectal cancer exclusion in primary care. Design Semi‐structured interviews within a feasibility study. Setting Patients presenting to primary care with colorectal symptoms and healthcare professionals working in primary and secondary care. Participants A total of 23 patients and 12 healthcare professionals. Methods Patient participants were asked to complete a novel combined Raman‐FIT test before being seen in secondary care. This study sought their opinions about the test. We also sought the views of healthcare professionals. Findings Patients and healthcare professionals agreed that Raman‐FIT was a suitable test to be given in primary care. It aligned with routine practice and was a simple test for most patients to complete. Conclusions Patients are willing and able to complete the Raman‐FIT test in primary care. Raman‐FIT may accelerate access to diagnosis with the potential to improve cancer outcomes. Patient and Public Involvement Lay members (J. H. and I. H.) with experience and knowledge of colorectal cancer and screening contributed to developing, undertaking, and disseminating all aspects of the research. They were supported to collaborate as equal members of the research team. They were involved in developing the study as coapplicants, using personal experience to ensure that the research and its methods were relevant to the patient and public needs. Both prepared participant information sheets, coanalysed data, and contributed to study reporting and dissemination through papers, conference presentations and a lay summary.

Abstract Here, an in vitro characterization of a family of prazole derivatives that covalently bind to the C73 site on Tsg101 and assay their ability to inhibit viral particle production is presented. Structurally, increased steric bulk on the 4‐pyridyl of the prazole expands the prazole site on the UEV domain toward the β‐hairpin in the Ub‐binding site and is coupled to increased inhibition of virus‐like particle production in HIV‐1. Increased bulk also increased toxicity, which is alleviated by increasing flexibility. Further, the formation of a novel secondary Tsg101 adduct for several of the tested compounds and the commercial drug lansoprazole. The secondary adduct involved the loss of the 4‐pyridyl substituent to form an irreversible species, with implications for increasing the half‐life of the active species or its specificity toward Tsg101 UEV. It is also determined that sulfide derivatives display effective viral inhibition, presumably through cellular sulfoxidation, allowing for delayed conversion within the cellular environment, and identify SARS‐COV‐2 as a target of prazole inhibition. These results open multiple avenues for the design of prazole derivatives for antiviral applications.

Abstract INTRODUCTION Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large‐scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. METHODS Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi‐omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system‐level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome‐wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease‐associated biology. This rank‐and‐organize approach, performed genome‐wide, allows the characterization of aggregations of AD risk across biological domains. RESULTS The top AD‐risk‐associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. DISCUSSION This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.

Abstract Demographic histories are frequently a product of the environment, as populations expand or contract in response to major environmental changes, often driven by changes in climate. Meso‐ and bathy‐pelagic fishes inhabit some of the most temporally and spatially stable habitats on the planet. The stability of the deep‐pelagic could make deep‐pelagic fishes resistant to the demographic instability commonly reported in fish species inhabiting other marine habitats, however the demographic histories of deep‐pelagic fishes are unknown. We reconstructed the historical demography of 11 species of deep‐pelagic fishes using mitochondrial and nuclear DNA sequence data. We uncovered widespread evidence of population expansions in our study species, a counterintuitive result based on the nature of deep‐pelagic ecosystems. Frequency‐based methods detected potential demographic changes in nine species of fishes, while extended Bayesian skyline plots identified population expansions in four species. These results suggest that despite the relatively stable nature of the deep‐pelagic environment, the fishes that reside here have likely been impacted by past changes in climate. Further investigation is necessary to better understand how deep‐pelagic fishes, by far Earth's most abundant vertebrates, will respond to future climatic changes.

Abstract Extracellular vesicles (EVs) have been proposed to play dual roles in cellular homeostasis, functioning both to remove unwanted intracellular molecules, and to enable communication between cells as a means of modulating cellular responses in different physiological and pathological scenarios. EVs contain a broad range of cargoes, including multiple biotypes of RNA, which can vary depending on the cell status, and may function as signalling molecules. In this study, we carried out comparative transcriptomic analysis of Drosophila EVs and cells, demonstrating that the RNA profile of EVs is distinct from cells and shows dose‐dependent changes in response to oxidative stress. We identified a high abundance of snoRNAs in EVs, alongside an enrichment of intronic and untranslated regions (UTRs) of mRNAs under stress. We also observed an increase in the relative abundance of either aberrant or modified mRNAs under stress. These findings suggest that EVs may function both for the elimination of specific cellular RNAs, and for the incorporation of RNAs that may hold signalling potential.

Abstract Background and Aims Lack of provider (physicians and advanced practice providers) participation in fall risk assessment was theorized to be contributing to rising rates of falls with injury at our institution. This project sought to identify if attitudinal barriers to inpatient provider participation in fall risk assessment were similar to those identified in other clinical settings. Methods Barriers to provider participation in fall risk assessment were identified in the literature. These were mapped to the Theoretical Domains Framework (TDF) domains to assist with interpretation of the data. A 10‐item survey using a 5‐point Likert scale (strongly agree to strongly disagree) with two open‐ended questions was developed using these barriers. The survey was distributed via email to all providers on the Medical Staff in July 2021. Results The response rate was 9.1% (188/2062). 72.6% (95% confidence interval [CI]: 65.6, 78.5) of providers at our institution did agree that fall risk assessment was within their role and 72% (95% CI: 66.1, 78.5) agreed that assessment can prevent falls. Nearly half felt that they lacked formal training in fall risk assessment (48.1% [95% CI: 41.1, 55.1]) and 52.2% (95% CI: 44.6, 58.6) agreed that other aspects of patient care took priority over falls assessment. These barriers correlated best with the TDF domains of Beliefs about Capabilities and Beliefs about Consequences. Conclusions Survey results indicate that interventions focused on increasing provider motivation and capability regarding fall risk assessment and helping providers prioritize fall risk assessment are potential targets for future quality improvement projects.

ABSTRACT: There are now abundant data demonstrating disparities in acute stroke management and prognosis; however, interventions to reduce these disparities remain limited. This special report aims to provide a critical review of the current landscape of disparities in acute stroke care and highlight opportunities to use implementation science to reduce disparities throughout the early care continuum. In the prehospital setting, stroke symptom recognition campaigns that have been successful in reducing prehospital delays used a multilevel approach to education, including mass media, culturally tailored community education, and professional education. The mobile stroke unit is an organizational intervention that has the potential to provide more equitable access to timely thrombolysis and thrombectomy treatments. In the hospital setting, interventions to address implicit biases among health care providers in acute stroke care decision‐making are urgently needed as part of a multifaceted approach to advance stroke equity. Implementing stroke systems of care interventions, such as evidence‐based stroke care protocols at designated stroke centers, can have a broader public health impact and may help reduce geographic, racial, and ethnic disparities in stroke care, although further research is needed. The long‐term impact of disparities in acute stroke care cannot be underestimated. The consistent trend of longer time to treatment for Black and Hispanic people experiencing stroke has direct implications on long‐term disability and independence after stroke. A learning health system model may help expedite the translation of evidence‐based interventions into clinical practice to reduce disparities in stroke care.

Abstract Background The long‐term effect of implantable vagus nerve stimulators (VNS) on seizures has not been evaluated in epileptic dogs. Objectives Report seizure frequency in medication‐resistant epileptic dogs before and after VNS implantation. Animals Twelve client‐owned dogs with idiopathic epilepsy and >1 seizure day per 3 weeks despite 3 months of appropriate use of 2 antiseizure medications and seizure diaries maintained 6 months before and >12 months after VNS implantation. Methods Uncontrolled, open‐label, before and after study. Mean monthly seizures and inter‐seizure periods obtained from contemporaneous seizure diaries in the 6 months before implantation were compared with 0 to 6 months, 7 to 12 months, and subsequent 12‐month periods after implantation. The number of dogs with >50% decrease in seizure frequency, >3 times increase in inter‐ictal period interval, and seizure freedom for >3 months at the time of death or last follow‐up were recorded. Results Five of 12 dogs were euthanized 50% decrease in seizure frequency until last follow‐up, starting at a median of 37 to 48 months after implantation (range, 0‐6 to 61‐72 months) and a >3‐fold increase in mean inter‐seizure interval starting a median of 25 to 36 months after implantation (range, 0‐6 months to 49‐60 months), 3/7 dogs were seizure‐free at death or last follow‐up. Conclusions and Clinical Importance Monthly seizure frequencies decreased and inter‐seizure intervals increased in all dogs 2 to 3 years after VNS implantation, but a high proportion were euthanized before this time point. Prospective clinical trials are required to establish causality and the magnitude of this association.

Abstract Objective Use of computational fluid dynamic (CFD) simulations to measure the changes in upper airway geometry and aerodynamics during (a) an episode of Exercise‐Induced Laryngeal Obstruction (EILO) and (b) speech therapy exercises commonly employed for patients with EILO. Methods Magnetic resonance imaging stills of the upper airway including the nasal and oral cavities from an adult female were used to re‐construct three‐dimensional geometries of the upper airway. The CFD simulations were used to compute the maximum volume flow rate (l/s), pressure (Pa), airflow velocity (m/s) and area of cross‐section opening in eight planes along the vocal tract, separately for inhalation and exhalation. Results Numerical predictions from three‐dimensional geometrical modeling of the upper airway suggest that the technique of nose breathing for inhalation and pursed lip breathing for exhalation show most promising pressure conditions and cross‐sectional diameters for rescue breathing exercises. Also, if EILO is due to the constriction at the vocal fold level, then a quick sniff may also be a proper rescue inhalation exercise. EILO affects both the inspiratory and the expiratory phases of breathing. Conclusions A prior knowledge of the supraglottal aerodynamics and the corresponding upper airway geometry from CFD analysis has the potential to assist the clinician in choosing the most effective rescue breathing technique for optimal functional outcome of speech therapy intervention in patients with EILO and in understanding the pathophysiology of EILO on a case‐by‐case basis with future studies. Level of Evidence 4

Abstract Introduction Hemimegalencephaly is a syndrome of dysplastic cortical formation, with hamartomatous overgrowth of a cerebral hemisphere, classically associated with intractable focal epilepsy, hemiparesis, and hemianopia. While often cryptogenic, associations with various proliferative syndromes have been implicated, such as in our patients. Patient Description We present a newborn with intractable focal epilepsy due to hemimegalencephaly caused by an inherited mutation in nitrogen permease regulator‐like 3 (NPRL3). He underwent anatomic hemispherectomy. His phenotype was more severe than that of other family member, which is consistent with recent studies suggesting that NPRL3 and other genes implicated in familial focal epilepsy with variable foci (FFEVF) produce a phenotypic range. Conclusions Hemimegalencephaly can produce intractable focal epilepsy and has been associated with various genetic causes, including NPRL3 mutations. We describe the fifth patient with hemimegalencephaly secondary to NPRL3 and the only one to undergo anatomic hemispherectomy. Given the small number of documented patients, more research is needed to elucidate the role of interventions such as sirolimus and palliative surgical procedures such as hemispherectomy.

Abstract Background Urologic guidelines universally recommend increasing fluid intake for kidney stone prevention. Increased voided volume is thought to help reduce stone recurrence and severity, but supporting evidence is limited. Patients and Methods Nephrolithiasis outcomes and 24‐h urine data for patients from the Registry for Stones of the Kidney and Ureter (ReSKU), a registry of nephrolithiasis patients collected between 2015 and 2020, were retrospectively analysed. Outcome was stone events, either an office visit where a patient reports symptomatic passage of stones or surgery for stone removal. Results We identified 450 stone patients with 24‐h urine and kidney stone outcome data. There was no significant difference in 24‐h voided volume between patients with one stone event and patients with two or more stone events. On multivariable logistic regression, after controlling for age, gender, BMI, and 24‐h sodium and creatinine per kilogram, no significant associations were found between voided volume and stone events. There was a statistically significant negative correlation noted between voided volume and stone events in calcium oxalate dihydrate stone formers (Spearman R = −0.42, p = 0.04), but not others. Conclusions Twenty‐four‐hour voided volume was not associated with stone events in a large institutional cohort, and subset analysis reveals that some stone formers may benefit more from increased voided volume than others; identifying such patients represents a novel precision medicine opportunity.

Abstract Hypoxia in coastal waters and lakes is widely recognized as a detrimental environmental issue, yet we lack a comparable understanding of hypoxia in rivers. We investigated controls on hypoxia using 118 million paired observations of dissolved oxygen (DO) concentration and water temperature in over 125,000 locations in rivers from 93 countries. We found hypoxia (DO

Abstract Introduction Transvaginal mesh (mesh) surgeries have been used to treat stress urinary incontinence (incontinence) and/or pelvic organ prolapse (prolapse). In Australia, as in many other countries, the harms caused by mesh eventually prompted individual and collective attempts to achieve redress. The rise of mesh surgery as a procedure, the experience of mesh‐affected women and the formal inquiries and legal actions that followed all occurred in social, cultural and discursive contexts. One strategy to understand these contexts is to track how the mesh and key actors in the mesh stories have been portrayed in mass media sources. We conducted a media analysis of the most highly read Australian newspapers and online news media platforms, focusing on how mesh and the interaction of stakeholders in mesh stories were presented to the Australian public. Method We searched systematically in the top 10 most‐read print and online media outlets in Australia. We included all articles that mentioned mesh, from the date of first use of mesh in Australia to the date of our final search (1996–2021). Result After early scant media reporting focusing on the benefits of mesh procedures, major Australian medicolegal processes created a hook to shift reporting about mesh. The news media then played a significant role in redressing women's experienced epistemic injustice, including by amplifying previously ignored evidence of harm. This created an opportunity for previously unreported suffering to be revealed to powerful actors, in settings beyond the immediate control and epistemic authority of healthcare stakeholders, validating women's testimony and creating new hermeneutic resources for understanding mesh. Over time, media reports show healthcare stakeholders responding sympathetically to these new understandings in public discourse, contrasting with their statements in earlier media coverage. Conclusion We argue that mass media reporting, in synergy with medicolegal actions and the Australian Senate Inquiry, appears to have provided women with greater epistemic justice, giving their testimony privileged epistemic status such that it was considered by powerful actors. Although medical reporting is not recognised in the hierarchy of evidence embedded in the medical knowledge system, in this case, media reporting appears to have contributed to shaping medical knowledge in significant ways. Patient or Public Contribution We used publicly available data, print and online media outlets, for our analysis. Therefore, this manuscript does not contain the direct contribution of patients, service users, caregivers, people with lived experience or members of the public.

Abstract Microplastics (MPs) have become an environmental concern in recent years, with most research focused on the physiological effects of exposure. Comparatively little consideration has been given to the potential behavioral impacts of exposure, which may also have fitness consequences for individuals. Moreover, MPs can serve as vectors for endocrine‐disrupting chemicals and other locally co‐occurring contaminants known to impair behavioral responses. This project aimed to determine whether MPs alone or in association with a common environmental EDC (17‐alpha ethinyl estradiol; EE2) alter reproductive behavior and decision‐making in fish. Male and female fathead minnows (Pimephales promelas) were exposed to MPs associated with either a low (10 ng/L; MPEE2 10) or high (50 ng/L, MPEE2 50) concentration of EE2, or MPs without EE2 (MPvirgin) for 30 days via a dietary feeding protocol. Behavioral trials were conducted on Day 31 to determine the effects of exposure on male–female social interactions. The expression of male sexually selected traits, including courtship, was unaffected by exposure. However, non‐exposed females in all treatment groups trended toward discrimination against exposed males, which reached statistical significance for the MPEE2 50 group. Female fish exposed to MPs, alone or in association with EE2, were equally likely to approach and associate with non‐exposed and exposed males. The results from this study suggest that MPs may alter social behavior in fishes and that the behavioral impacts of exposure may be more strongly pronounced in females than males. Such individual‐level changes in fitness have the potential to impact population size, with downstream effects on the broader aquatic community.

Abstract Introduction Disparities in the uptake of routine and COVID‐19 vaccinations have been observed in migrant populations, and attributed to issues of mistrust, access and low vaccine confidence. Participatory research approaches and behaviour change theory hold the potential for developing tailored vaccination interventions that address these complex barriers in partnership with communities and should be explored further. Methods This study used a theory‐informed, community‐based participatory research approach to co‐design a culturally tailored behaviour change intervention aimed at increasing COVID‐19 vaccine uptake among Congolese migrants in London, United Kingdom (2021–2022). It was designed and led by a community‐academic partnership in response to unmet needs in the Congolese community as the COVID‐19 pandemic started. Barriers and facilitators to COVID‐19 vaccination, information and communication preferences, and intervention suggestions were explored through qualitative in‐depth interviews with Congolese migrants, thematically analysed, and mapped to the theoretical domains framework (TDF) and the capability, opportunity, motivation, behaviour model to identify target behaviours and strategies to include in interventions. Interventions were co‐designed and tailored in workshops involving Congolese migrants. Results Thirty‐two Congolese adult migrants (24 (75%) women, mean 14.3 (SD: 7.5) years in the United Kingdom, mean age 52.6 (SD: 11.0) years) took part in in‐depth interviews and 16 (same sample) took part in co‐design workshops. Fourteen barriers and 10 facilitators to COVID‐19 vaccination were identified; most barrier data related to four TDF domains (beliefs about consequences; emotion; social influences and environmental context and resources), and the behavioural diagnosis concluded interventions should target improving psychological capability, reflective and automatic motivations and social opportunities. Strategies included culturally tailored behaviour change techniques based on education, persuasion, modelling, enablement and environmental restructuring, which resulted in a co‐designed intervention comprising community‐led workshops, plays and posters. Findings and interventions were disseminated through a community celebration event. Conclusions Our study demonstrates how behavioural theory can be applied to co‐designing tailored interventions with underserved migrant communities through a participatory research paradigm to address a range of health issues and inequalities. Future research should build on this empowering approach, with the goal of developing more sensitive vaccination services and interventions which respond to migrant communities' unique cultural needs and realities. Patient or Public Contribution Patient and public involvement (PPI) were embedded in the participatory study design and approach, with community members co‐producing all stages of the study and co‐authoring this paper. An independent PPI board (St George's Migrant Health Research Group Patient and Public Involvement Advisory Board) comprising five adult migrants with lived experience of accessing healthcare in the United Kingdom were also consulted at significant points over the course of the study.

Abstract Objective Governments use vaccination mandates, of different degrees of coerciveness, to encourage or require childhood vaccination. We elicited the views of well‐informed community members on the public acceptability of using childhood vaccination mandates in Australia. Methods Four community juries were conducted in Canberra, Launceston, Cairns and Melbourne, Australia between 2021 and 2022. We recruited 51 participants from diverse backgrounds, genders and ages through random digit dialling and social media. Two juries were held in metropolitan areas, and two in regional/rural settings. Outcome measures included jury verdicts and reasons in response to structured questions. Results All juries were concerned about collective protection and individual rights but prioritised the former over the latter. A majority in all juries supported mandates but juries disagreed with respect to the appropriate mandate types. All juries endorsed using the least restrictive or coercive means to encourage vaccination (providing incentives or education, e.g.) before imposing penalties such as financial losses and school exclusions. The overriding view was that it is fairer to place a direct burden on parents rather than children and that mandates should be designed to avoid inequitable impacts on less advantaged groups in society. Many jurors found conscientious objection acceptable as a controlled option for resolute refusers, provided that overall vaccination coverage remains high. Conclusion This paper gives policymakers access to the reasons that Australians have for supporting or opposing different mandates under conditions of high knowledge, understanding and deliberation regarding policy options. Sustaining high rates of vaccination requires high levels of co‐operation between governments, public health actors and the public. Our findings highlight the importance of considering public values in the design and implementation of vaccination mandates. Patient and Public Involvement We sought input from individuals who did and did not vaccinate during the study design. The views and perspectives of nonvaccinating parents were presented in the evidence to juries. We deliberately excluded nonvaccinating individuals from participating, as the divisive and often hostile nature of the topic, and their minority status, made it difficult to ensure they would feel safe as members of the jury without overrepresenting their perspective in the sample. Two related projects engaged directly with these parents.

Abstract Negative interactions between humans and venomous snakes are increasing, with the World Health Organization committed to halving snakebite deaths and disabilities by 2030. Evidence‐based strategies are thus urgently required to reduce snakebite events in high‐risk areas, while promoting snake conservation. Understanding the factors that drive the adoption of snakebite prevention measures is critical for the effective implementation of snakebite management strategies. We conducted in‐person questionnaires (n = 535 respondents) with rural agricultural communities within the Thiruvarur District of Tamil Nadu, India, a national snakebite hotspot. Using a health belief model framework, we explored current snakebite prevention measures and factors impacting their adoption. The majority of respondents reported using multiple snakebite prevention measures. Perceived self‐efficacy and perceived risk frequency of snakebites were important overall predictors of future adoption, whereas education, gender, relative wealth, and current adoption were important for specific measures. Achieving international commitments to support human–snake coexistence will require collective and collaborative action (e.g., governments, donor agencies, civil society organizations, researchers, and communities) underpinned by behavioural insights and context‐specific solutions.

Abstract Introduction Age is the greatest risk factor for Alzheimer's disease (AD). A limitation of randomized control trials in AD is a lack of specificity in the age ranges of participants who are enrolled in studies of disease‐modifying therapies. We aimed to apply Emax (i.e., maximum effect) modeling as a novel approach to identity ideal treatment windows. Methods Emax curves were fitted to longitudinal cognitive data of 101 participants with AD and 1392 healthy controls. We included the Mini‐Mental State Examination (MMSE) and tests of verbal fluency and executive functioning. Results In people with AD, the earliest decline in the MMSE could be detected in the 67–71 age band while verbal fluency declined from the 41–45 age band. In healthy controls, changes in cognition showed a later trajectory of decline. Discussion Emax modeling could be used to design more efficient trials which has implications for randomized control trials targeting the earlier stages of AD.

Abstract INTRODUCTION Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss‐of‐function GRN mutations. METHODS A first‐in‐human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple‐dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss‐of‐function GRN mutation (FTD‐GRN). RESULTS Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple‐dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD‐GRN to levels that approximated those seen in healthy volunteers. DISCUSSION Data from the first‐in‐human phase 1 study support further development of latozinemab for the treatment of FTD‐GRN. Highlights GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD). Latozinemab is being developed as a PGRN‐elevating therapy. Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial. Latozinemab increased PGRN levels in the CNS of symptomatic FTD‐GRN participants.

Abstract INTRODUCTION In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field. METHODS During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic. RESULTS The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de‐risk clinical pipeline, and (4) centralize data management. DISCUSSION In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines.

Abstract The water‐limited potential yield of wheat (Triticum aestivum L.) may be largely dependent on plant transpiration behavior. Research into plant transpiration dynamics is limited due to the difficulty of monitoring water use over an extended period of time. The advent of fully automated gravimetric platforms makes this research possible. The methods for using this equipment to study transpiration of wheat in water‐deficit environments are not well established. The objective of this greenhouse study was to develop a methodology to evaluate plant transpiration under terminal water stress using a gravimetric platform. Using a plant–pot system designed to limit nonplant water loss, the methodology proved capable of monitoring plant transpiration over a 42‐day period and detected significant differences between well‐watered and water‐stressed treatments. However, the high degree of variation in transpiration limited the system's ability to detect significant differences between genotypes of similar watering regimes. Both environmental and human error likely contributed to the observed variation. Recommendations are provided to reduce this variation and improve upon the methodology for future studies. This work lays the foundation for further research into plant water use and the identification of genotypes capable of high transpiration despite exposure to water‐deficit conditions.

Abstract The Hagberg–Perten falling number (HFN) method is the international standard used to evaluate the damage to wheat (Triticum aestivum) grain quality due to preharvest sprouting (PHS) and late maturity alpha‐amylase (LMA). However, the HFN test requires specialized laboratory facilities and is time consuming. Spectrometers were known as a potential tool for quick HFN assessment, but none of the studies have validated the assessment results across different datasets. In this study, an independent validation was conducted using independent samples and spectral instruments. The calibration set had 462 grain samples of 92 varieties grown at 24 locations in 2019 and examined using a near‐infrared spectrometer. In the validation set, 19 varieties collected from 10 locations in 2 years that experienced either PHS or LMA were scanned with a hyperspectral camera. The association between spectra and HFN was modeled by partial least square regression. As a result, the independent validation correlation accuracy was r = 0.72 and a mean absolute error of 56 s. Furthermore, this study showed a cost‐effective alternative using only 10 spectral bands to predict HFN, and it achieved better performance than the full spectrum of the hyperspectral system. In conclusion, this is the first study that showed the potential that wheat HFN could be predicted on an independent dataset measured by a different instrument. The result suggested that spectrometers can potentially serve as a faster alternative for plant breeders to develop varieties resistant to PHS and LMA, and for growers to screen damaged grains in transportation processes.