Search

Abstract Background Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis, affecting 1–4% of adolescents. The Scoliosis Research Society-22R (SRS-22R), a health-related quality-of-life instrument for AIS, has allowed orthopedists to measure subjective patient outcomes before and after corrective surgery beyond objective radiographic measurements. However, research has revealed that there is no significant correlation between the correction rate in major radiographic parameters and improvements in patient-reported outcomes (PROs), making it difficult to incorporate PROs into personalized surgical planning. Methods The objective of this study is to develop an artificial intelligence (AI)-enabled surgical planning and counseling support system for post-operative patient rehabilitation outcomes prediction in order to facilitate personalized AIS patient care. A unique multi-site cohort of 455 pediatric patients undergoing spinal fusion surgery at two Shriners Children’s hospitals from 2010 is investigated in our analysis. In total, 171 pre-operative clinical features are used to train six machine-learning models for post-operative outcomes prediction. We further employ explainability analysis to quantify the contribution of pre-operative radiographic and questionnaire parameters in predicting patient surgical outcomes. Moreover, we enable responsible AI by calibrating model confidence for human intervention and mitigating health disparities for algorithm fairness. Results The best prediction model achieves an area under receiver operating curve (AUROC) performance of 0.86, 0.85, and 0.83 for individual SRS-22R question response prediction over three-time horizons from pre-operation to 6-month, 1-year, and 2-year post-operation, respectively. Additionally, we demonstrate the efficacy of our proposed prediction method to predict other patient rehabilitation outcomes based on minimal clinically important differences (MCID) and correction rates across all three-time horizons. Conclusions Based on the relationship analysis, we suggest additional attention to sagittal parameters (e.g., lordosis, sagittal vertical axis) and patient self-image beyond major Cobb angles to improve surgical decision-making for AIS patients. In the age of personalized medicine, the proposed responsible AI-enabled clinical decision-support system may facilitate pre-operative counseling and shared decision-making within real-world clinical settings.

Abstract Cauliflower is an important winter crop grown in India, its curds are rich in nutritional profile, containing valuable minerals and vitamins. However, cauliflower harvesting is mainly accomplished by hands, which is time-consuming and requires a high labour force. On the other hand, most developed cauliflower harvesters are once over or single pass type, which harvests all plants irrespective of their maturity. So, the selective harvester could improve the cauliflower curds yield, and then decrease the labour requirement. To improve the cutting performance of the selective cauliflower harvester, the working parameters of the chainsaw cutting mechanism need to be considered and optimized. This research investigates the impact of cutting height, feed (push) force, and cutting speed on the efficiency of the cutter during harvest. The Taguchi approach, together with grey relational analysis (GRA), was employed to identify the most favorable combination of operational parameters. In addition, the variance analysis was conducted to statistically examine the impact of multiple parameters. The findings indicated that the feed force was the major parameter that influenced the cutting force, splitting failure levels, and cutting time. The most effective parameter combination consisted of a cutting height of 15 mm, a feed force of 10 N, and a cutting speed of 5 m/s. The grey relational grade of the ideal parameter combination has shown a 0.322 increase in comparison to the grade achieved with the initially selected parameter combination. This setting was further incorporated in the developed selective cauliflower harvester to improve the performance of its cutting mechanism.

Abstract Exposure to ionizing radiation induces cellular and molecular damage leading to a cascade of events resulting in tissue and organ injury. Our study strives to characterize and validate metabolomic changes in preterminal stage (immediately prior to death) samples collected from rhesus macaques lethally irradiated with one of two different doses of radiation. Peripheral blood samples were collected pre-exposure, post-exposure, and at the preterminal stage of nonhuman primates (NHPs that did not survive exposure with 7.2 Gy or 7.6 Gy total-body radiation (LD60-80/60)). We analyzed global metabolomic alterations using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in serum samples collected at various timepoints in relation to radiation exposure. The goal of this study was to validate the metabolic shifts present in samples collected just prior to death, which were reported earlier in a preliminary study with a limited number of samples and a single dose of radiation. Here, we demonstrate that radiation exposure induced significant time-dependent metabolic alterations compared with pre-exposure samples. We observed significant metabolite dysregulation in animals exposed to 7.6 Gy compared to 7.2 Gy. Greater metabolic disruption was observed in the preterminal groups than all of the other post-irradiation timepoints in both cohorts. Metabolomic shifts in these preterminal groups also revealed consistent disturbances in sphingolipid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism pathways. Overall, the sphingolipid metabolism pathway appears to be representative of the preterminal phenotype, confirming the results of our preliminary study. These results offer important and novel insights for identification and validation of biomarkers for lethality, and such observations would be valuable for triage during a radiological/nuclear mass casualty scenario.

Abstract A concern in the field of autism electroencephalography (EEG) biomarker discovery is their lack of reproducibility. In the present study, we considered the problem of learning reproducible associations between multiple features of resting state (RS) neural activity and autism, using EEG data collected during a RS paradigm from 36 to 96 month-old children diagnosed with autism (N = 224) and neurotypical children (N = 69). Specifically, EEG spectral power and functional connectivity features were used as inputs to a regularized generalized linear model trained to predict diagnostic group (autism versus neurotypical). To evaluate our model, we proposed a procedure that quantified both the predictive generalization and reproducibility of learned associations produced by the model. When prioritizing both model predictive performance and reproducibility of associations, a highly reproducible profile of associations emerged. This profile revealed a distinct pattern of increased gamma power and connectivity in occipital and posterior midline regions associated with an autism diagnosis. Conversely, model selection based on predictive performance alone resulted in non-robust associations. Finally, we built a custom machine learning model that further empirically improved robustness of learned associations. Our results highlight the need for model selection criteria that maximize the scientific utility provided by reproducibility instead of predictive performance.

Abstract Background Recent changes in anatomy curricula in undergraduate medical education (UME), including pedagogical changes and reduced time, pose challenges for foundational learning. Consequently, it is important to ask clinicians what anatomical content is important for their clinical specialty, which when taken collectively, can inform curricular development. Methods This study surveyed 55 non-primary care residents in anesthesiology (AN; N = 6), emergency medicine (EM; N = 15), obstetrics and gynecology (OB; N = 13), and orthopedics (OR; N = 21) to assess the importance of 907 anatomical structures across all anatomical regions. Survey ratings by participants were converted into a post-hoc classification system to provide end-users of this data with an intuitive and useful classification system for categorizing individual anatomical structures (i.e., essential, more important, less important, not important). Results Significant variability was observed in the classifications of essential anatomy: 29.1% of all structures were considered essential by OB residents, 37.6% for AN residents, 41.6% for EM residents, and 72.0% for OR residents. Significant differences (with large effect sizes) were also observed between residency groups: OR residents rated anatomy of the back, limbs, and pelvis and perineum anatomy common to both sexes significantly higher, whereas OB residents rated the pelvis and perineum anatomy common to both sexes and anatomy for individuals assigned female at birth highest. Agreement in classifications of importance among residents was observed for selected anatomical structures in the thorax, abdomen, pelvis and perineum (assigned male at birth-specific anatomy), and head and neck. As with the ratings of anatomical structures, OR residents had the highest classification across all nine tissue types (p

Introduction Only 30%–50% of people referred to clinics during community-based eye screening are able to access care in Botswana, India, Kenya and Nepal. The access rate is even lower for certain population groups. This platform trial aims to test multiple, iterative, low-risk public health interventions and simple service modifications with a series of individual randomised controlled trials (RCT) conducted in each country, with the aim of increasing the proportion of people attending.Methods and analysis We will set up a platform trial in each country to govern the running of a series of pragmatic, adaptive, embedded, parallel, multiarm, superiority RCTs to test a series of service modifications suggested by intended service users. The aim is to identify serial marginal gains that cumulatively result in large improvements to equity and access. The primary outcome will be the probability of accessing treatment among the population group with the worst access at baseline. We will calculate Bayesian posterior probabilities of clinic attendance in each arm every 72 hours. Each RCT will continually recruit participants until the following default stopping rules have been met: >95% probability that one arm is best; >95% probability that the difference between the best arm and the arms remaining in the trial is

Our ability to balance upright provides a stable platform to perform daily activities. Balance deficits associated with various clinical conditions may affect activities of daily living, highlighting the importance of quantifying standing balance in ecological environments. Although typically performed in laboratory settings, the growing availability of low-cost inertial measurement units (IMUs) allows the assessment of balance in the real world. However, it is unclear how many IMUs are required to adequately estimate linear displacements of the centre of mass (CoM) at stance widths associated with daily activities. While wearing IMUs on their head, sternum, back, right thigh, right shank, and left shank, 16 participants stood quietly on a force platform in narrow, hip-width, and shoulder-width stances, each for three two-minute trials. Using a multi-segment biomechanical model, we estimated CoM displacements from all possible combinations of the IMUs. We then calculated the correlation between the IMU- and force platform- CoM estimates to determine the minimal number of IMUs needed to estimate CoM sway. Four IMUs were necessary to accurately estimate anteroposterior (AP) and mediolateral (ML) CoM displacements across stance widths. Using IMUs on the back, right thigh, and both shanks, we found strong correlations between the IMU CoM estimation and the force platform CoM estimation in narrow stance (AP: r = 0.92±0.04, RMSE = 2.39±2.08 mm; ML: r = 0.97±0.02, RMSE = 1.16±0.77 mm), hip-width stance (AP: r = 0.93±0.04, RMSE = 2.00±1.18 mm; ML: r = 0.92±0.06, RMSE = 0.92±0.70 mm), and shoulder-width stance (AP: r = 0.93±0.03, RMSE = 1.95±1.66 mm; ML: r = 0.86±0.13, RMSE = 1.39±1.46 mm). These results indicate that IMUs can be used to estimate CoM displacements during quiet standing and that four IMUs are necessary to do so. Using an algorithm based on a simple biomechanical model, researchers and clinicians can estimate whole-body CoM displacements accurately during unperturbed quiet standing. This approach can improve the ecological validity of standing balance research and opens the possibility for assessing/monitoring patients with standing balance deficits.

Abstract The use of digital health technologies to measure outcomes in clinical trials opens new opportunities as well as methodological challenges. Digital outcome measures may provide more sensitive and higher-frequency measurements but pose vital statistical challenges around how such outcomes should be defined and validated and how trials incorporating digital outcome measures should be designed and analysed. This article presents eight methodological questions, exploring issues such as the length of measurement period, choice of summary statistic and definition and handling of missing data as well as the potential for new estimands and new analyses to leverage the time series data from digital devices. The impact of key issues highlighted by the eight questions on a primary analysis of a trial are illustrated through a simulation study based on the 2019 Bellerophon INOPulse trial which had time spent in MVPA as a digital outcome measure. These eight questions present broad areas where methodological guidance is needed to enable wider uptake of digital outcome measures in trials.

Abstract Background Urinary tract infections (UTI) are the most frequently diagnosed infection in residents of long-term care and are a major risk factor for urosepsis, hospitalisation, and death. Translocation of gut pathobionts into the urinary tract is the presumed cause of most UTIs. While specific gut microbiota characteristics have been linked to UTI risk in younger adults, their relevance in aged care residents remains uncertain. Methods The faecal microbiome was assessed in 54 long-term aged care residents with a history of UTIs and 69 residents without a UTI history. Further comparisons were made to microbiome characteristics in 20 younger adults without UTIs. Microbiome characteristics were examined in relation to prior and subsequent UTIs, as well as antibiotic therapy. Results In long-term aged care residents, prior UTI history and exposure to UTI-exclusive antibiotics do not significantly affect microbiome composition or functional capacity. However, exposure to antibiotics unrelated to UTI treatment is associated with distinct microbiota compositional traits. Adjustment for dementia, incontinence, diabetes, and prior antibiotic use finds no microbiota characteristic linked to UTI development. However, prior UTI is identified as a predictor of future UTIs. Comparison with younger adults identifies greater within-participant dispersion in aged care residents, as well as lower microbiota diversity and altered microbiome functional potential. Conclusions No association between the gut microbiome and UTI incidence, as has been reported in younger individuals, is evident in long-term aged care residents. Considerable variability in gut microbiome characteristics, relating to high antibiotic exposure and age-related physiological and immunological factors, could mask such a relationship. However, it cannot be discounted that increased UTI risk in the elderly is independent of microbiome-mediated mechanisms.

The spotted ragged-tooth shark, Carcharias taurus, is widely distributed in subtropical continental coastal seas. In South Africa, it is commonly found along the entire south and east coasts, including the iSimangaliso Wetland Park (IWP) in the far north, which is the largest Marine Protected Area on the South African coast. Pregnant females occur there for much of the year, with the largest aggregations in summer. It is here we used remote underwater photography (RUP), supplemented with in-situ surveys to photo-identify individuals, using unique spot patterns. Three known aggregation sites (Raggie Reef, Quarter-Mile Reef and Mushroom Rocks) were monitored over a 5-year period between 2018 and 2023. We photo-identified 574 individuals (569 females and five males) and registered 1,200 sightings, using images of the right flank. The identification of new individuals persisted throughout the study, with the discovery curve showing no signs of reaching an asymptote. A total of 97% (n = 550) of females observed were noticeably pregnant. Individuals were consistently identified across all sample years and at all three reefs, exhibiting movements among the three monitored sites. The reproductive cycle is generally regarded as 2 years, but some females appeared to have a 2-year rest between pregnancies. Raggie Reef, which lies in the sanctuary zone, emerged as the reef with the highest index of popularity, as individuals were present almost constantly (90% of the sampling days). The findings of this study confirm the crucial role that the IWP plays in the conservation of a species that is globally Critically Endangered.

Background: Breast cancer survivors (BCS) may experience cardiotoxicities from chemotherapy and oral endocrine therapy. Although a few studies have documented that palpitations are prevalent and associated with poorer outcomes, there is limited to no information on BCS’ reporting of palpitations to healthcare providers. Objectives: To compare BCS who did and did not report their palpitations to a healthcare provider and describe how those who did report palpitations recalled their provider responding. Design: This was a cross-sectional, national, electronic, pilot survey of BCS enrolled in the Love Army of Women registry. Methods: Participants ( n = 52 with palpitations) completed standardized and investigator-designed questionnaires. Data were analyzed using frequency and descriptive statistics, chi-square tests, and Mann–Whitney tests. Responses to one open-ended question were analyzed using frequency counts and standard content analysis. Results: Compared to BCS who reported palpitations to a provider ( n = 34), BCS who did not report their palpitations ( n = 18) were significantly more anxious ( p = 0.002) and more likely to feel palpitations as an irregular heartbeat (70.6% versus 38.9%, p = 0.027). Among the 34 BCS who reported palpitations to a provider, 32 completed the open-ended question. Of these 32 BCS, a majority ( n = 27, 84%) indicated their provider recommended cardiac testing and/or referral to a cardiologist. Most ( n = 24) reported completing testing. Test results included diagnosis of a new arrhythmia or other cardiac abnormality ( n = 11, 46%), receipt of a new prescription ( n = 5, 21%), or normal results ( n = 5, 21%). Five (16%) of the 32 BCS did not receive recommendations for testing or referral and felt their provider normalized or dismissed their symptoms. Conclusion: Palpitations are a salient topic for further research and clinical practice recommendations to address cardiac health in BCS.

Abstract The identification and validation of radiation biomarkers is critical for assessing the radiation dose received in exposed individuals and for developing radiation medical countermeasures that can be used to treat acute radiation syndrome (ARS). Additionally, a fundamental understanding of the effects of radiation injury could further aid in the identification and development of therapeutic targets for mitigating radiation damage. In this study, blood samples were collected from fourteen male nonhuman primates (NHPs) that were exposed to 7.2 Gy ionizing radiation at various time points (seven days prior to irradiation; 1, 13, and 25 days post-irradiation; and immediately prior to the euthanasia of moribund (preterminal) animals). Plasma was isolated from these samples and was analyzed using a liquid chromatography tandem mass spectrometry approach in an effort to determine the effects of radiation on plasma proteomic profiles. The primary objective was to determine if the radiation-induced expression of specific proteins could serve as an early predictor for health decline leading to a preterminal phenotype. Our results suggest that radiation induced a complex temporal response in which some features exhibit upregulation while others trend downward. These statistically significantly altered features varied from pre-irradiation levels by as much as tenfold. Specifically, we found the expression of integrin alpha and thrombospondin correlated in peripheral blood with the preterminal stage. The differential expression of these proteins implicates dysregulation of biological processes such as hemostasis, inflammation, and immune response that could be leveraged for mitigating radiation-induced adverse effects.

Abstract Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent’s use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.

Introduction: Local tissue destruction following envenomation from North American snakes, particularly those within the Crotalinae subfamily, has the potential to progress to compartment syndrome. The pathophysiology of venom-induced compartment syndrome (VICS) is a debated topic and is distinct from trauma/reperfusion-induced compartment syndrome. Heterogeneity exists in the treatment practices of VICS, particularly regarding the decision to progress to fasciotomy. Associations with functional outcomes and evolution in clinical practice since the introduction of Crotalidae polyvalent immune Fab (FabAV) have not been well defined. Our goal was to identify the potential gaps in the literature regarding this phenomenon, as well as illuminate salient themes in the clinical characteristics and treatment practices of VICS. Methods: We conducted this systematic scoping-style review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Records were included if they contained data surrounding the envenomation and hospital course of one or more patients who were envenomated by a snake species native to North America and were diagnosed with compartment syndrome from 1980–2020. Results: We included 19 papers: 10 single- or two-patient case reports encompassing 12 patients, and nine chart reviews providing summary statistics of the included patients. In case reports, the median compartment pressure when reported was 60 millimeters of mercury (interquartile range 55–68), 66% underwent fasciotomy, and functional outcomes varied. Use of antivenom appeared to be more liberal with FabAV than the earlier antivenin Crotalidae polyvalent. Rapid progression of swelling was the most commonly reported symptom. Among the included retrospective chart reviews, important data such as compartment pressures, consistent laboratory values, and snake species was inconsistently reported. Conclusions: Venom-induced compartment syndrome is relatively rare. Existing papers generally describe good outcomes even in the absence of surgical management. Significant gaps in the literature regarding antivenom dosing practices, serial compartment pressure measurements, and functional outcomes highlight the need for prospective studies and consistent standardized reporting.

BackgroundMajor depressive disorder (MDD) is common worldwide and can be highly disabling. People with MDD face many barriers to treatment and may not experience full symptom relief even when treated. Therefore, new treatment modalities are needed for MDD. Digital therapeutics (DTx) may provide people with MDD an additional treatment option. ObjectiveThis study aimed to describe a phase 3 remote, multicenter, randomized, masked, sham-controlled trial evaluating the efficacy of a smartphone app–based DTx (CT-152) in adult participants diagnosed with MDD, used as an adjunct to antidepressant therapy (ADT). MethodsParticipants aged 22-64 years with a current primary diagnosis of MDD and an inadequate response to ADT were included. Participants were randomized 1:1 to CT-152 or a sham DTx. CT-152 is a smartphone app–based DTx that delivers a cognitive-emotional and behavioral therapeutic intervention. The core components of CT-152 are the Emotional Faces Memory Task exercises, brief lessons to learn and apply key therapeutic skills, and SMS text messaging to reinforce lessons and encourage engagement with the app. The sham DTx is a digital working memory exercise with emotionally neutral stimuli designed to match CT-152 for time and attention. Participants took part in the trial for up to 13 weeks. The trial included a screening period of up to 3 weeks, a treatment period of 6 weeks, and an extension period of 4 weeks to assess the durability of the effect. Sites and participants had the option of an in-person or remote screening visit; the remaining trial visits were remote. Efficacy was evaluated using the Montgomery-Åsberg Depression Rating Scale, the Generalized Anxiety Disorder-7, Clinical Global Impression–Severity scale, the Patient Health Questionnaire-9, and the World Health Organization Disability Assessment Schedule 2.0. The durability of the effect was evaluated with the Montgomery-Åsberg Depression Rating Scale and Generalized Anxiety Disorder-7 scale. Adverse events were also assessed. Satisfaction, measured by the Participant and Healthcare Professional Satisfaction Scales, and health status, measured by the EQ-5D-5L, were summarized using descriptive statistics. ResultsThis study was initiated in February 2021 and had a primary completion date in October 2022. ConclusionsThis represents the methodological design for the first evaluation of CT-152 as an adjunct to ADT. This study protocol is methodologically robust and incorporates many aspects of conventional pivotal pharmaceutical phase 3 trial design, such as randomization and safety end points. Novel considerations included the use of a sham comparator, masking considerations for visible app content, and outcome measures relevant to DTx. The rigor of this methodology will provide a more comprehensive understanding of the effectiveness of CT-152. Trial RegistrationClinicalTrials.gov NCT04770285; https://clinicaltrials.gov/study/NCT04770285 International Registered Report Identifier (IRRID)RR1-10.2196/56960

Abstract Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses.

Abstract Managing private forests for wildfire resilience is challenging due to conflicting social, economic, and ecological decisions that may result in an increase of surface fuel loads leading to greater fire risk. Due to fire suppression and a changing climate, land managers in fire-prone regions face an increasing threat of high severity fires. Thus, land managers need fuel treatment options that match their forest types and management objectives. One potential option for producers that graze livestock is silvopasture management, where livestock, forages, and overstory vegetation are carefully managed for co-benefits on the same unit of land. This study compared forest composition and structure, fuel types, and vegetative biomass between silvopasture and non-grazed managed forests in Washington, U.S. We show that silvopasture management results in reductions in grass biomass, litter, and duff depth when compared to non-grazed managed forest. These findings point to the integrated nature of silvopasture, where management of overstory composition and structure, understory vegetation, and grazing can reduce fuel loads and potential wildfire risk.

Abstract Tetraopes longhorn beetles are known for their resistance to milkweed plant toxins and their coevolutionary dynamics with milkweed plants (Asclepias). This association is considered a textbook example of coevolution, in which each species of Tetraopes is specialized to feed on one or a few species of Asclepias. A major challenge to investigating coevolutionary hypotheses and conducting molecular ecology studies lies in the limited understanding of the evolutionary history and biogeographical patterns of Tetraopes. By integrating genomic, morphological, paleontological, and geographical data, we present a robust phylogeny of Tetraopes and their relatives, using three inference methods with varying subsets of data, encompassing 2–12 thousand UCE loci. We elucidate the diversification patterns of Tetraopes species across major biogeographical regions and their colonization of the American continent. Our findings suggest that the genus originated in Central America approximately 21 million years ago during the Miocene and diversified from the Mid-Miocene to the Pleistocene. These events coincided with intense geological activity in Central America. Additionally, independent colonization events in North America occurred from the Late Miocene to the early Pleistocene, potentially contributing to the early diversification of the group. Our data suggest that a common ancestor of Tetraopini migrated into North America, likely facilitated by North Atlantic land bridges, while closely related tribes diverged in Asia and Europe during the Paleocene. Establishing a robust and densely sampled phylogeny of Tetraopes beetles provides a foundation for investigating micro- and macroevolutionary phenomena, including clinal variation, coevolution, and detoxification mechanisms in this ecologically important group.

Abstract Exposure to ionizing radiation (IR) presents a formidable clinical challenge. Total-body or significant partial-body exposure at a high dose and dose rate leads to acute radiation syndrome (ARS), the complex pathologic effects that arise following IR exposure over a short period of time. Early and accurate diagnosis of ARS is critical for assessing the exposure dose and determining the proper treatment. Serum microRNAs (miRNAs) may effectively predict the impact of irradiation and assess cell viability/senescence changes and inflammation. We used a nonhuman primate (NHP) model—rhesus macaques (Macaca mulatta)—to identify the serum miRNA landscape 96 h prior to and following 7.2 Gy total-body irradiation (TBI) at four timepoints: 24, 36, 48, and 96 h. To assess whether the miRNA profile reflects the therapeutic effect of a small molecule ON01210, commonly known as Ex-Rad, that has demonstrated radioprotective efficacy in a rodent model, we administered Ex-Rad at two different schedules of NHPs; either 36 and 48 h post-irradiation or 48 and 60 h post-irradiation. Results of this study corroborated our previous findings obtained using a qPCR array for several miRNAs and their modulation in response to irradiation: some miRNAs demonstrated a temporary increased serum concentration within the first 24–36 h (miR-375, miR-185-5p), whereas others displayed either a prolonged decline (miR-423-5p) or a long-term increase (miR-30a-5p, miR-27b-3p). In agreement with these time-dependent changes, hierarchical clustering of differentially expressed miRNAs showed that the profiles of the top six miRNA that most strongly correlated with radiation exposure were inconsistent between the 24 and 96 h timepoints following exposure, suggesting that different biodosimetry miRNA markers might be required depending on the time that has elapsed. Finally, Ex-Rad treatment restored the level of several miRNAs whose expression was significantly changed after radiation exposure, including miR-16-2, an miRNA previously associated with radiation survival. Taken together, our findings support the use of miRNA expression as an indicator of radiation exposure and the use of Ex-Rad as a potential radioprotectant.

Abstract The distribution of the easy-axes in an array of MRAM cells is a vital parameter to understand the switching and characteristics of the devices. By measuring the coercivity as a function of applied-field angle, and remaining close to the perpendicular orientation, a classic Stoner-Wohlfarth approximation has been applied to the resulting variation to determine the standard deviation, $$\sigma $$ σ , of a Gaussian distribution of the orientation of the easy-magnetisation directions. In this work we have compared MRAM arrays with nominal cells sizes of 20 nm and 60 nm and a range of free layer thicknesses. We have found that a smaller diameter cell will have a wider switching-field distribution with a standard deviation $$\sigma = {9.5}^{\circ }$$ σ = 9.5 ∘ . The MRAM arrays consist of pillars produced by etching a multilayer thin film. This value of $$\sigma $$ σ is dominated by pillar uniformity and edge effects controlling the reversal, reinforcing the need for ever-improving etch processes. This is compared to larger pillars, with distributions as low as $$\sigma = {5.5}^{\circ }$$ σ = 5.5 ∘ . Furthermore we found that the distribution broadens from $$\sigma = {5.5}^{\circ }$$ σ = 5.5 ∘ to $$\sigma = {8.5}^{\circ }$$ σ = 8.5 ∘ with free layer thickness in larger pillars and that thinner films had a more uniform easy-axis orientation. For the 20 nm pillars the non-uniform size distribution of the pillars, with a large and unknown error in the free-layer volume, was highlighted as it was found that the activation volume for the reversal of the free layer 930 nm $$^3$$ 3 was larger than the nominal physical volume of the free layer. However for the 60 nm pillars, the activation volume was measured to be equal to one fifth of their physical volume. This implies that the smaller pillars effectively reverse as one entity while the larger pillars reverse via an incoherent mechanism of nucleation and propagation.

Storytelling can enhance stakeholder engagement and support the implementation of the World Health Organization and Pan American Health Organization’s (PAHO) Global Initiative for Childhood Cancer, which aims to improve care globally for children with cancer. The Initiative aligns with the United Nations Sustainable Development Goals, addressing health, education, inequalities and international collaboration. This report describes the design and implementation of a workshop that used storytelling through film to encourage stakeholders in national cancer control plans to engage with the Initiative in its focal countries in Central America, the Dominican Republic and Haiti. A six-step process was used to develop the virtual workshop hosted by PAHO: (i) define the audience; (ii) define the goals of storytelling; (iii) build an appropriate storyline, including choosing a platform and content, and addressing group dynamics and the length of the film; (iv) guide the workshop’s design and implementation with current theoretical frameworks, including the Socioecological Model of Health and the Theory of Change; (v) design interactive group exercises; and (vi) disseminate workshop results. The skills-building component of the day-long workshop included 80 representatives from eight countries in the Region of the Americas, with participants representing pediatric oncology, hospital administration, ministries of health, nonprofit foundations, the scientific community and public health organizations. Outputs from the workshop included (i) a summary report, (ii) an empathy word cloud with live reactions from participants, (iii) qualitative responses (i.e. quotes from participants), (iv) stakeholders’ analyses and (v) a prioritization matrix for country-level strategic activities that could be undertaken to strengthen health systems when caring for children with cancer. The workshop used storytelling through film to try to reduce health inequalities and have a regional impact. Combining art, public health and medicine, the workshop created positive change by sharing real-life experiences. Commitment was fostered among stakeholders through their engagement with the workshop, which aimed to increase their awareness of the need and advocacy to improve health systems and enhance access to health care for this vulnerable population.

The Late Cretaceous of western North America supported diverse dinosaur assemblages, though understanding patterns of dinosaur diversity, evolution, and extinction has been historically limited by unequal geographic and temporal sampling. In particular, the existence and extent of faunal endemism along the eastern coastal plain of Laramidia continues to generate debate, and finer scale regional patterns remain elusive. Here, we report a new centrosaurine ceratopsid, Lokiceratops rangiformis, from the lower portion of the McClelland Ferry Member of the Judith River Formation in the Kennedy Coulee region along the Canada-USA border. Dinosaurs from the same small geographic region, and from nearby, stratigraphically equivalent horizons of the lower Oldman Formation in Canada, reveal unprecedented ceratopsid richness, with four sympatric centrosaurine taxa and one chasmosaurine taxon. Phylogenetic results show that Lokiceratops, together with Albertaceratops and Medusaceratops, was part of a clade restricted to a small portion of northern Laramidia approximately 78 million years ago. This group, Albertaceratopsini, was one of multiple centrosaurine clades to undergo geographically restricted radiations, with Nasutuceratopsini restricted to the south and Centrosaurini and Pachyrostra restricted to the north. High regional endemism in centrosaurs is associated with, and may have been driven by, high speciation rates and diversity, with competition between dinosaurs limiting their geographic range. High speciation rates may in turn have been driven in part by sexual selection or latitudinally uneven climatic and floral gradients. The high endemism seen in centrosaurines and other dinosaurs implies that dinosaur diversity is underestimated and contrasts with the large geographic ranges seen in most extant mammalian megafauna.

BackgroundMultidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations. ObjectiveThe objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers. MethodsThis study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers. ResultsOf the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10). ConclusionsVideo recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers. Trial RegistrationClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403

The SARS-CoV-2 pandemic showed limitations in human outbreak testing. Veterinary diagnostic laboratories (VDLs) possess capabilities to bolster emergency test capacity. Surveys from 26 participating VDLs found human SARS-CoV-2 testing was mutually beneficial, including One Health benefits. VDLs indicated testing >3.8 million human samples during the pandemic, which included some challenges.

Abstract The isolation of specific subpopulations of extracellular vesicles (EVs) based on their expression of surface markers poses a significant challenge due to their nanoscale size ( 10× relative to prior published designs without sacrificing recovery of the target EVs by selecting pore diameter, number of membranes placed in series, and flow rate. We compare TENPO-isolated EVs to those of gold-standard methods of EV isolation and demonstrate its utility for wide application and modularity by targeting subpopulations of EVs from multiple models of disease including lung cancer, pancreatic cancer, and liver cancer.

Bluetongue virus (BTV, Sedoreoviridae: Orbivirus) causes an economically important disease, namely, bluetongue (BT), in domestic and wild ruminants worldwide. BTV is endemic to South India and has occurred with varying severity every year since the virus was first reported in 1963. BT can cause high morbidity and mortality to sheep flocks in this region, resulting in serious economic losses to subsistence farmers, with impacts on food security. The epidemiology of BTV in South India is complex, characterized by an unusually wide diversity of susceptible ruminant hosts, multiple vector species biting midges (Culicoides spp., Diptera: Ceratopogonidae), which have been implicated in the transmission of BTV and numerous co-circulating virus serotypes and strains. BT presence data (1997–2011) for South India were obtained from multiple sources to develop a presence/absence model for the disease. A non-linear discriminant analysis (NLDA) was carried out using temporal Fourier transformed variables that were remotely sensed as potential predictors of BT distribution. Predictive performance was then characterized using a range of different accuracy statistics (sensitivity, specificity, and Kappa). The top ten variables selected to explain BT distribution were primarily thermal metrics (land surface temperature, i.e., LST, and middle infrared, i.e., MIR) and a measure of plant photosynthetic activity (the Normalized Difference Vegetation Index, i.e., NDVI). A model that used pseudo-absence points, with three presence and absence clusters each, outperformed the model that used only the recorded absence points and showed high correspondence with past BTV outbreaks. The resulting risk maps may be suitable for informing disease managers concerned with vaccination, prevention, and control of BT in high-risk areas and for planning future state-wide vector and virus surveillance activities.

Multiple accidents in nuclear power plants and the growing concerns about the misuse of radiation exposure in warfare have called for the rapid determination of absorbed radiation doses (RDs). The latest findings about circulating microRNA (miRNAs) using several animal models revealed considerable promises, although translating this knowledge to clinics remains a major challenge. To address this issue, we randomly divided 36 nonhuman primates (NHPs) into six groups and exposed these groups to six different radiation doses ranging from 6.0-8.5 Gy in increments of 0.5 Gy. Serum samples were collected pre-irradiation as well as three post-irradiation timepoints, namely 1, 2 and 6 days post-total body irradiation (TBI). Generated from a deep sequencing platform, the miRNA reads were multi-variate analyzed to find the differentially expressed putative biomarkers that were linked to RDs, time since irradiation (TSI) and sex. To increase these biomarkers' translational potential, we aligned the NHP-miRNAs' sequences and their functional responses to humans following an in-silico routine. Those miRNAs, which were sequentially and functionally conserved between NHPs and humans, were down selected for further analysis. A linear regression model identified miRNA markers that were consistently regulated with increasing RD but independent TSI. Likewise, a set of potential TSI-markers were identified that consistently shifted with increasing TSI, but independent of RD. Additional molecular analysis found a considerable gender bias in the low-ranges of doses when the risk to radiation-induced fatality was low. Bionetworks linked to cell quantity and cell invasion were significantly altered between the survivors and decedents. Using these biomarkers, an assay could be developed to retrospectively determine the RD and TSI with high translational potential. Ultimately, this knowledge can lead to precise and personalized medicine.

International concern for the human rights of Afghan women has spiked since the Taliban consolidated power in Afghanistan in fall 2021. Yet little is known about how to effectively advocate for women's human rights under this new context. We present findings from a random sample of all adult Afghan internet users' attitudes toward peace, security, gender, and human rights and find significant support for women's human rights as a national priority within Afghanistan, even when controlling for other priorities and even among many men and women aligned with the Taliban. Given that men now have much more political power in Afghan society to protect women's rights, we paid particular attention to men's attitudes toward women's human rights. Our evidence from an embedded survey experiment, building on earlier literature from other countries, demonstrates that fathers of eldest daughters are particularly likely to favor prioritizing women's rights when primed to think about the gender of their eldest children. Thus, the human rights and humanitarian community should spend more time and attention engaging with this demographic, and specifically creating marketing and advocacy strategies that encourage men to think about or act on behalf of their eldest daughters.

Chronic graft-versus-host disease (GVHD) is an immune-mediated disorder that causes significant late morbidity and mortality following allogeneic hematopoietic cell transplantation. The "Close Assessment and Testing for Chronic GVHD (CATCH)" study is a multi-center Chronic GVHD Consortium prospective, longitudinal cohort study designed to enroll patients before hematopoietic cell transplantation and follow them closely to capture the development of chronic GVHD and to identify clinical and biologic biomarkers of chronic GVHD onset. Data are collected pre-transplant and every two months through one-year post-transplant with chart review thereafter. Evaluations include clinician assessment of chronic GVHD and its manifestations, patient-reported outcomes, multiple biospecimens (blood, saliva, tears, buccal mucosa and fecal samples, biopsies of skin and mouth), laboratory testing, and medical record abstraction. This report describes the rationale, design, and methods of the CATCH study, and invites collaboration with other investigators to leverage this resource. trial registration: This study is registered at www.clinicaltrials.gov as NCT04188912.

Objective Social exclusion (such as that experienced by people who are homeless, incarcerated or use drugs) increases morbidity across a range of diseases but is poorly captured in routine data sets. The aim of this study was to use a novel composite variable in a national-level hospital usage dataset to identify social exclusion and to determine whether social exclusion is associated with concurrent venous thromboembolism (VTE) in hospitalised patients in Ireland. Identifying and characterising this association in people who are socially excluded will inform VTE prevention and treatment strategies.Design Retrospective cross-sectional study.Setting Irish Hospital Inpatient Enquiry (HIPE) system, which collects diagnostic information by International Classification of Diseases Tenth Revision code on all hospital admission episodes in the Ireland.Participants All hospital admission episodes involving a VTE diagnosis (in a primary ‘Dx 1’ or secondary ‘Dx 2–30’ coding position) during a 12-month period in the Ireland were identified from consolidated, national-level datasets derived from the Irish HIPE system. Social exclusion was defined as the presence of one or more indicators of homelessness, drug use, incarceration, health hazards due to socioeconomic status or episodes of healthcare terminated prematurely.Results Of 5701 admission episodes involving a VTE diagnosis (in a primary or secondary position) during the study period, 271 (4.8%) related to an individual affected by social exclusion. Among hospitalised individuals identified as being socially excluded based on the novel composite variable, the likelihood of having a concurrent VTE diagnosis was over twofold greater than that observed in the general population (OR 2.14, 95% CI 1.79 to 2.26; p

BackgroundThe prevention of oral health diseases is a key public health issue and a major challenge for racial and ethnic minority groups, who often face barriers in accessing dental care. Daily toothbrushing is an important self-care behavior necessary for sustaining good oral health, yet engagement in regular brushing remains a challenge. Identifying strategies to promote engagement in regular oral self-care behaviors among populations at risk of poor oral health is critical. ObjectiveThe formative research described here focused on creating messages for a digital oral self-care intervention targeting a racially and ethnically diverse population. Theoretically grounded strategies (reciprocity, reciprocity-by-proxy, and curiosity) were used to promote engagement in 3 aspects: oral self-care behaviors, an oral care smartphone app, and digital messages. A web-based participatory co-design approach was used to develop messages that are resource efficient, appealing, and novel; this approach involved dental experts, individuals from the general population, and individuals from the target population—dental patients from predominantly low-income racial and ethnic minority groups. Given that many individuals from racially and ethnically diverse populations face anonymity and confidentiality concerns when participating in research, we used an approach to message development that aimed to mitigate these concerns. MethodsMessages were initially developed with feedback from dental experts and Amazon Mechanical Turk workers. Dental patients were then recruited for 2 facilitator-mediated group webinar sessions held over Zoom (Zoom Video Communications; session 1: n=13; session 2: n=7), in which they provided both quantitative ratings and qualitative feedback on the messages. Participants interacted with the facilitator through Zoom polls and a chat window that was anonymous to other participants. Participants did not directly interact with each other, and the facilitator mediated sessions by verbally asking for message feedback and sharing key suggestions with the group for additional feedback. This approach plausibly enhanced participant anonymity and confidentiality during the sessions. ResultsParticipants rated messages highly in terms of liking (overall rating: mean 2.63, SD 0.58; reciprocity: mean 2.65, SD 0.52; reciprocity-by-proxy: mean 2.58, SD 0.53; curiosity involving interactive oral health questions and answers: mean 2.45, SD 0.69; curiosity involving tailored brushing feedback: mean 2.77, SD 0.48) on a scale ranging from 1 (do not like it) to 3 (like it). Qualitative feedback indicated that the participants preferred messages that were straightforward, enthusiastic, conversational, relatable, and authentic. ConclusionsThis formative research has the potential to guide the design of messages for future digital health behavioral interventions targeting individuals from diverse racial and ethnic populations. Insights emphasize the importance of identifying key stimuli and tasks that require engagement, gathering multiple perspectives during message development, and using new approaches for collecting both quantitative and qualitative data while mitigating anonymity and confidentiality concerns.

Background Components of diet known as fallback foods are argued to be critical in shaping primate dental anatomy. Such foods of low(er) nutritional quality are often non-preferred, mechanically challenging resources that species resort to during ecological crunch periods. An oft-cited example of the importance of dietary fallbacks in shaping primate anatomy is the grey-cheeked mangabey Lophocebus albigena. This species relies upon hard seeds only when softer, preferred resources are not available, a fact which has been linked to its thick dental enamel. Another mangabey species with thick enamel, the sooty mangabey Cercocebus atys, processes a mechanically challenging food year-round. That the two mangabey species are both thickly-enameled suggests that both fallback and routine consumption of hard foods are associated with the same anatomical feature, complicating interpretations of thick enamel in the fossil record. We anticipated that aspects of enamel other than its thickness might differ between Cercocebus atys and Lophocebus albigena. We hypothesized that to function adequately under a dietary regime of routine hard-object feeding, the molars of Cercocebus atys would be more fracture and wear resistant than those of Lophocebus albigena. Methods Here we investigated critical fracture loads, nanomechanical properties of enamel, and enamel decussation in Cercocebus atys and Lophocebus albigena. Molars of Cercopithecus, a genus not associated with hard-object feeding, were included for comparison. Critical loads were estimated using measurements from 2D µCT slices of upper and lower molars. Nanomechanical properties (by nanoindentation) and decussation of enamel prisms (by SEM-imaging) in trigon basins of one upper second molar per taxon were compared. Results Protocone and protoconid critical fracture loads were significantly greater in Cercocebus atys than Lophocebus albigena and greater in both than in Cercopithecus. Elastic modulus, hardness, and elasticity index in most regions of the crown were greater in Cercocebus atys than in the other two taxa, with the greatest difference in the outer enamel. All taxa had decussated enamel, but that of Cercocebus atys uniquely exhibited a bundle of transversely oriented prisms cervical to the radial enamel. Quantitative comparison of in-plane and out-of-plane prism angles suggests that decussation in trigon basin enamel is more complex in Cercocebus atys than it is in either Lophocebus albigena or Cercopithecus cephus. These findings suggest that Cercocebus atys molars are more fracture and wear resistant than those of Lophocebus albigena and Cercopithecus. Recognition of these differences between Cercocebus atys and Lophocebus albigena molars sharpens our understanding of associations between hard-object feeding and dental anatomy under conditions of routine vs. fallback hard-object feeding and provides a basis for dietary inference in fossil primates, including hominins.

Objective Patients with multiple long-term conditions visit various healthcare professionals and are exposed to medication information from various sources causing an increased risk of patients perceiving contradictory medication information. The aims of this study are to: (1) characterise conflicting medication information perceived by patients with long-term conditions, (2) better understand the related impact on patients’ medication self-management and healthcare system navigation and (3) explore ways in which such events could be prevented.Design This study was conducted through qualitative semistructured interviews. Data were analysed using thematic analysis.Setting Community pharmacies and medical centres in Geneva, Switzerland.Participants This study included outpatients from April 2019 to February 2020. Patients were included after participating in a quantitative survey of perceived conflicting information about medications for long-term diseases.Methods Semistructured audiotaped interviews of 20 to 60 min following a pre-established interview guide to explore participants’ perceptions of conflicting information. Interviews were transcribed verbatim, and a thematic analysis was conducted with inductive and deductive coding using MAXQDA (2018, Release 18.2.3).Results Twenty-two patients were interviewed, until data saturation, mentioning indication or need for a medication as the main topic of conflicting information between two healthcare professionals. Perceived conflicting information often resulted from insufficient information provided and poor communication leading to confusion, doubts and medication non-adherence. Patients expected more information and more interprofessional communication on their medications. As a result of conflicting information, most participants learnt or were learning to take an active role and become partners of the healthcare providers.Conclusion The need to strengthen and improve communication and interprofessional collaborative practice among healthcare professionals and with the patient is emerging to increase the quality and consistency of information about medications, and consequently, to ensure better use and experience of medications.

Objectives During the last two decades, researchers and funders increasingly recognised the value of engaging patients and communities in research. Despite progress, community engagement remains challenging. There are few examples of successful participant engagement in governance of large-scale research programmes. Here we describe efforts to engage participants as partners in new governance roles in the All of Us Research Program, a precision medicine research initiative which intends to enrol at least one million participants. Using intentional, participant-centric engagement strategies, the All of Us Engagement Core recruited and integrated a diverse group of participants into governance roles including Steering and Executive Committees. Evaluation measures included a survey to assess Consortium Members’ readiness for participant engagement.Results Over a 3-year period, all items on the survey increased (higher readiness). Of the 291 respondents to the 2021 survey, respondents most frequently agreed that participant perspectives are essential (100%), participants understand enough to contribute meaningfully (94%) and participants should be involved in setting goals (96%). Respondents least frequently agreed that participants should have an equal voice in Working Groups (75%), Steering Committee (69%) and Executive Committee (63%).Conclusion In conclusion, participants can be effectively integrated into large-scale research governance, which is associated with increased researcher readiness for engagement.

We report on a highly significant, positive association between anthrax vaccination and occurrence of Gulf War Illness (GWI) in 111 Gulf War veterans (42 with GWI and 69 controls). GWI was diagnosed in 47.1% of vaccinated veterans but only in 17.2% of non-vaccinated veterans (Pearson χ2 = 7.08, p = 0.008; odds ratio = 3.947; relative risk = 2.617), with 1.6x higher GWI symptom severity in vaccinated veterans (p = 0.007, F-test in analysis of covariance). Next, we tested the hypothesis that the susceptibility to GWI following anthrax vaccination could be due to inability to make antibodies against the anthrax protective antigen (PA), the key protein contained in the vaccine. Since the first step in initiating antibody production would be the binding of PA peptide fragments (typically 15-amino acid long [15-mer]) to peptide-binding motifs of human leukocyte antigen (HLA) Class II molecules, we assessed the binding-motif affinities of such HLA specific molecules to all linear 15-mer peptide fragments of the anthrax PA. We identified a total of 58 HLA Class II alleles carried by the veterans in our sample and found that, of those, 18 (31%) were present in the vaccinated group that did not develop GWI but were absent from the vaccinated group who developed GWI. Remarkably, in silico analyses revealed very high binding affinities of peptide-binding motifs of those 18 HLA alleles with fragments of anthrax vaccine PA, leading to the successful production of anti-PA antibodies. Conversely, the absence of these protective HLA alleles points to a reduced ability to develop antibodies against PA, thus resulting in harmful PA persistence and development of GWI.

OBJECTIVES/GOALS: Mechanisms underlying racial and ethnic disparities in rectal cancer care remain poorly understood. We aimed to identify barriers and facilitators to care among rectal cancer patients who identify as Hispanic/Latino (H/L) and to understand how these factors may differ based on rurality, social/physical context, and community support. METHODS/STUDY POPULATION: We utilized qualitative methods and a community-based participatory research framework, including partnership with a community-based organization and oversight from a community advisory board. We developed an initial semi-structured interview guide based on an ecological model of health behavior and then iteratively refined it with the assistance of our partners to incorporate unique aspects of the H/L community in a culturally appropriate manner. Eligible patients and their caregivers are invited to participate in hour-long interviews in both English and Spanish, depending on participants’ preferences. All interviews are recorded, translated, transcribed, and coded. Findings will be compiled and fed back to participantsand community stakeholders as a part of a community forum. RESULTS/ANTICIPATED RESULTS: We identified 6 areas for discussion based on our model: health beliefs (perceived severity, benefit, and barriers; self-efficacy), health literacy, others’ experiences with cancer, patient-provider relationship (patient-provider communication; provider-provider communication; language; cultural competency; discrimination), sources of support, and access to care. Participants are currently being recruited by clinical providers, through flyers in the cancer center, or via outreach from our community partner. We have interviewed 8 participants to date, with discussions ranging from the shock of the initial diagnosis, difficulties with navigating specialty care, and the complexities of shared decision making. We are expecting a total of 30-40 interviews to reach thematic saturation. DISCUSSION/SIGNIFICANCE: We hope to improve our understanding of mechanisms underlying racial and ethnic disparities in rectal cancer care and to identify potential targets for improvement. We plan to use our results to develop community-based policy interventions to improve care delivery, patient experience, and health equity.

This review discusses the expanding application of botulinum neurotoxin in treating neurological conditions. The article specifically explores novel approaches to using non-paralytic botulinum molecules. These new molecules, such as BiTox or el-iBoNT, offer an alternative for patients who face limitations in using paralytic forms of botulinum neurotoxin due to concerns about muscle function loss. We highlight the research findings that confirm not only the effectiveness of these molecules but also their reduced paralytic effect. We also discuss a potential cause for the diminished paralytic action of these molecules, specifically changes in the spatial parameters of the new botulinum molecules. In summary, this article reviews the current research that enhances our understanding of the application of new botulinum neurotoxins in the context of common conditions and suggests new avenues for developing more efficient molecules.

Drug resistance is a challenge in anticancer therapy. In many cases, cancers can be resistant to the drug prior to exposure, that is, possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance without a priori knowledge of its cause. We hypothesized that cell morphology could provide an unbiased readout of drug resistance. To test this hypothesis, we used HCT116 cells, a mismatch repair-deficient cancer cell line, to isolate clones that were resistant or sensitive to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then expanded these clones and measured high-dimensional single-cell morphology profiles using Cell Painting, a high-content microscopy assay. Our imaging- and computation-based profiling pipeline identified morphological features that differed between resistant and sensitive cells. We used these features to generate a morphological signature of bortezomib resistance. We then employed this morphological signature to analyze a set of HCT116 clones (five resistant and five sensitive) that had not been included in the signature training dataset, and correctly predicted sensitivity to bortezomib in seven cases, in the absence of drug treatment. This signature predicted bortezomib resistance better than resistance to other drugs targeting the ubiquitin-proteasome system, indicating specificity for mechanisms of resistance to bortezomib. Our results establish a proof-of-concept framework for the unbiased analysis of drug resistance using high-content microscopy of cancer cells, in the absence of drug treatment.

BackgroundPeople who inject drugs are experiencing syndemic conditions with increasing risk of infection with hepatitis C (HCV) and HIV. However, rates of accessing HCV and HIV testing and treatment among people who inject drugs are low for various reasons, including the criminalization of drug use, which leads to a focus on treating drug use rather than caring for drug users. For many people who inject drugs, health care becomes a form of structural violence, resulting in traumatic experiences, fear of police violence, unmet needs, and avoidance of medical care. There is a clear need for novel approaches to health care delivery for people who inject drugs. ObjectiveThis study aimed to analyze the process of a multidisciplinary team—encompassing health care professionals, community representatives, researchers, and people with lived experience using drugs—that was formed to develop a deep understanding of the experiences of people who inject drugs and local ecosystem opportunities and constraints to inform the cocreation of low-barrier, innovative HCV or HIV care in a rural community. Given the need for innovative approaches to redesigning health care, we sought to identify challenges and tensions encountered in this process and strategies for overcoming these challenges. MethodsAnalysis was based on an in-depth review of meeting notes from the project year, followed by member-checking with the project team to revise and expand upon the challenges encountered and strategies identified to navigate these challenges. ResultsChallenges and tensions included: scoping the project, setting the pace and urgency of the work, adapting to web-based work, navigating ethics and practice of payment, defining success, and situating the project for sustainability. Strategies to navigate these challenges included: dedicated effort to building personal and meaningful connections, fostering mutual respect, identifying common ground to make shared decisions, and redefining successes. ConclusionsWhile cocreated care presents challenges, the resulting program is strengthened by challenging assumptions and carefully considering various perspectives to think creatively and productively about solutions.

BACKGROUND Lower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODS We used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTS The host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSION Lower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDING Support for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.

Healthy expansion of adipose tissue is critical for the maintenance of metabolic health, providing an optimized reservoir for energy storage in the form of triacylglycerol-rich lipoproteins. Dysfunctional adipocytes that are unable to efficiently store lipid can result in lipodystrophy and contribute to nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. Leucine-rich repeat containing protein 8a/SWELL1 functionally encodes the volume-regulated anion channel complex in adipocytes, is induced in early obesity, and is required for normal adipocyte expansion during high-fat feeding. Adipose-specific SWELL1 ablation (Adipo KO) leads to insulin resistance and hyperglycemia during caloric excess, both of which are associated with NAFLD. Here, we show that Adipo-KO mice exhibited impaired adipose depot expansion and excess lipolysis when raised on a variety of high-fat diets, resulting in increased diacylglycerides and hepatic steatosis, thereby driving liver injury. Liver lipidomic analysis revealed increases in oleic acid–containing hepatic triacylglycerides and injurious hepatic diacylglyceride species, with reductions in hepatocyte-protective phospholipids and antiinflammatory free fatty acids. Aged Adipo-KO mice developed hepatic steatosis on a regular chow diet, and Adipo-KO male mice developed spontaneous, aggressive hepatocellular carcinomas (HCCs). These data highlight the importance of adipocyte SWELL1 for healthy adipocyte expansion to protect against NAFLD and HCC in the setting of overnutrition and with aging.

Introduction Metformin is a medication likely to improve measures of cardiometabolic disturbance in young people with mental illness. Evidence also suggests metformin may improve depressive symptoms. This 52-week double-blind randomised control trial (RCT) aims to investigate the efficacy of metformin pharmacotherapy as an adjunct to a healthy lifestyle behavioural intervention in improving cardiometabolic outcomes, and depressive, anxiety and psychotic symptoms in youth with clinically diagnosed major mood syndromes.Methods and analysis At least 266 young people aged 16–25 presenting for mental healthcare for major mood syndromes who are also at risk for poor cardiometabolic outcomes will be invited to participate in this study. All participants will engage in a 12-week sleep–wake, activity and metabolically focused behavioural intervention programme. As an adjunctive intervention, participants will receive either metformin (500–1000 mg) or placebo pharmacotherapy for 52 weeks.Participants will undergo a series of assessments including: (1) self-report and clinician-administered assessments; (2) blood tests; (3) anthropometric assessments (height, weight, waist circumference and blood pressure); and (4) actigraphy. Univariate and multivariate tests (generalised mixed-effects models) will be used to examine changes in primary and secondary outcomes (and associations with predetermined predictor variables).Ethics and dissemination This study has been approved by the Sydney Local Health District Research Ethics and Governance Office (X22-0017). The results of this double-blind RCT will be disseminated into the scientific and broader community through peer-reviewed journals, conference presentations, social media and university websites.Trial registration number Australian New Zealand Clinical Trials Registry (ANZCTR) Number: ACTRN12619001559101p, 12 November 2019.

The Eating Disorders In weight-related Therapy (EDIT) Collaboration brings together data from randomised controlled trials of behavioural weight management interventions to identify individual participant risk factors and intervention strategies that contribute to eating disorder risk. We present a protocol for a systematic review and individual participant data (IPD) meta-analysis which aims to identify participants at risk of developing eating disorders, or related symptoms, during or after weight management interventions conducted in adolescents or adults with overweight or obesity. We systematically searched four databases up to March 2022 and clinical trials registries to May 2022 to identify randomised controlled trials of weight management interventions conducted in adolescents or adults with overweight or obesity that measured eating disorder risk at pre- and post-intervention or follow-up. Authors from eligible trials have been invited to share their deidentified IPD. Two IPD meta-analyses will be conducted. The first IPD meta-analysis aims to examine participant level factors associated with a change in eating disorder scores during and following a weight management intervention. To do this we will examine baseline variables that predict change in eating disorder risk within intervention arms. The second IPD meta-analysis aims to assess whether there are participant level factors that predict whether participation in an intervention is more or less likely than no intervention to lead to a change in eating disorder risk. To do this, we will examine if there are differences in predictors of eating disorder risk between intervention and no-treatment control arms. The primary outcome will be a standardised mean difference in global eating disorder score from baseline to immediately post-intervention and at 6- and 12- months follow-up. Identifying participant level risk factors predicting eating disorder risk will inform screening and monitoring protocols to allow early identification and intervention for those at risk.

SARS-CoV-2 virus induced CoVID-19 pandemic has accelerated the development of diagnostic tools. Devices integrated with electrochemical biosensors may be an interesting alternative to respond to the high demand for testing, particularly in contexts where access to standard detection technologies is lacking. Aptamers as recognition elements are useful due to their stability, specificity, and sensitivity to binding target molecules. We have developed a non-invasive electrochemical aptamer-based biosensor targeting SARS-CoV-2 in human saliva. The aptamer is expected to detect the Spike protein of SARS-CoV-2 wildtype and its variants. Laser-induced graphene (LIG) electrodes coated with platinum nanoparticles were biofunctionalized with a biotin-tagged aptamer. Electrochemical Impedance Spectroscopy (EIS) for BA.1 sensing was conducted in sodium chloride/sodium bicarbonate solution supplemented with pooled saliva. To estimate sensing performance, the aptasensor was tested with contrived samples of UV-attenuated virions from 10 to 10,000 copies/ml. Selectivity was assessed by exposing the aptasensor to non-targeted viruses (hCoV-OC43, Influenza A, and RSV-A). EIS data outputs were further used to select a suitable response variable and cutoff frequency. Capacitance increases in response to the gradual loading of the attenuated BA.1. The aptasensor was sensitive and specific for BA.1 at a lower viral load (10-100 copies/ml) and was capable of discriminating between negative and positive contrived samples (with strain specificity against other viruses: OC43, Influenza A, and RSV-A). The aptasensor detected SARS-CoV-2 with an estimated LOD of 1790 copies/ml in contrived samples. In human clinical samples, the aptasensor presents an accuracy of 72%, with 75% of positive percent of agreement and 67% of negative percent of agreement. Our results show that the aptasensor is a promising candidate to detect SARS-CoV-2 during early stages of infection when virion concentrations are low, which may be useful for preventing the asymptomatic spread of CoVID-19.

In the original publication [...]

Uterine fibroids (leiomyomas) affect Black women disproportionately compared with women of other races and ethnicities in terms of prevalence, incidence, and severity of symptoms. The causes of this racial disparity are essentially unknown. We hypothesized that myometria of Black women are more susceptible to developing fibroids, and we examined the transcriptomic and DNA methylation profiles of myometria and fibroids from Black and White women for comparison. Myometrial samples cluster by race in both their transcriptome and DNA methylation profiles, whereas fibroid samples only cluster by race in the latter. More differentially expressed genes (DEGs) were detected in the Black and White myometrial sample comparison than in the fibroid comparison. Leiomyoma gene set expression analysis identified 4 clusters of DEGs, including a cluster of 24 genes with higher expression in myometrial samples from Black women. One of the DEGs in this group, von Willibrands factor (VWF), was significantly hypomethylated in both myometrial samples from Black women and in all fibroids at 2 CpG probes that are near a putative enhancer site and that are correlated with VWF expression levels. These results suggest that the molecular basis for the disparity in fibroid disease between Black and White women could be found in the myometria before fibroid development and not in the fibroids themselves.