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In this case study we explore the concept of translational research: specifically, how common tools were employed in the context of the translational research process to design and implement a formal intervention to address racism at the individual and structural level. This approach to translational research focuses on the implementation of evidence-based interventions to address issues in communities, schools, and other organizations and is ideally suited to support researchers and practitioners in the nation's land-grant institutions. We discuss the suitability of translational research as an approach to identifying and resolving issues and implications for training and day-to-day operations of translational research organizations. Finally, we point to the necessity of incorporating principles of equity and engagement in the translational research process.

The present study aims to investigate the interplays among students' writing self-efficacy, students' research literacy, teachers' immediacy, and teachers' clarity in facilitating the writing enjoyment of EFL postgraduate students in Indonesia. This quantitative research was designed by using Partial Least Square-Structural Equation Modeling (PLS-SEM) as a model analysis. A questionnaire of 40 items adapted from previous studies was used to measure the variables. One hundred fifty EFL postgraduate students in Indonesian universities filled out the questionnaire. Path analyses demonstrated positive relationships among the variables, meaning that students' writing self-efficacy and research literacy and teachers' immediacy and clarity impacted writing enjoyment. Nevertheless, the findings demonstrated that correlations between teachers' immediacy, teachers' clarity and students' writing enjoyment are not statistically significant, indicating that teacher-related factors, namely teachers' immediacy and clarity, may not have significantly impacted students' writing enjoyment. The pedagogical implications and future research directions are examined further.

Recognition that schools should be responsive to children who are impacted by adversity and trauma is burgeoning internationally. However, consensus regarding the necessary components of a trauma-informed school is lacking. This research developed expert-informed and internationally relevant best-practice trauma-informed principles for schools. A four-phase methodology included (i) identification of school-relevant trauma-informed practice programs, (ii) inductive thematic analysis of the main concepts underlying programs, (iii) phrasing of draft Principles and (iv) Principle revision and finalisation via a two-round Delphi survey with international experts. Excellent agreement by experts on the importance of all Principles was achieved (round 1 [greater than or equal to] 86.4%, 2 [greater than or equal to] 92.3%). The final 'International Trauma-Informed Practice Principles for Schools' (ITIPPS) include four Overarching (A-D) and 10 Practice Principles (1-10). Summarised, these include that the school: (A) is student focussed; (B) models compassion and generosity; (C) is understanding and responsive; (D) incorporates recognition of their First Nations peoples in the school's ethos: (1) prioritises safety and wellbeing; (2) models positive relationships; (3) provides a positive culture and connects; (4) consults and collaborates; (5) supports vulnerable students; (6) teaches social and emotional learning; (7) provides trauma-informed practice training; (8) is predictable yet flexible; (9) identifies and nurtures strengths and (10) reflects, changes and grows. The ITIPPS provide clear guidance for education sectors, schools and other settings about appropriate learning environments for children and young people impacted by trauma. Research is now underway in Western Australian schools to pilot test the feasibility and impact of using the ITIPPS within a framework (thoughtfulschools.org.au) to establish trauma-informed schools.

3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population. Participants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function. Males with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment. The 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability. Future studies should assess whether individuals with 3q29del would benefit from early interventions, including occupational therapy.

Objectives: Among Aboriginal children, the year between birth and 1 year of age has the highest mortality rate compared with any other age. Prompt administration of cardiopulmonary resuscitation (CPR) leads to better outcomes and a lower likelihood of ongoing sequalae. Current education on infant CPR is not provided to parents except in certain circumstances in a neonatal intensive care unit. Currently, there are no identified CPR education courses specifically available for Aboriginal or Torres Strait Islander people, meaning that current infant CPR education courses are not culturally responsive. Design: Partnering with an Aboriginal community from the Bindjareb region of the Western Australian Noongar nation, the researchers used a co-design approach and an Aboriginal Participatory Action Research (APAR) design to explore how to deliver culturally safe and responsive infant CPR community education. This resulted in the development of the Koolangka Infant Life Saving Education Framework (KILSEF), which can be used to guide future planning and delivery of culturally safe and responsive community level infant CPR education. Results: The study findings identified that members of the Aboriginal community were very interested in receiving infant CPR education, but the barriers identified from mainstream CPR course delivery need to be removed for the community to benefit from culturally responsive ways of learning. Culturally responsive community CPR education should be provided in culturally safe places and the focus of learning should be on the practical applications of CPR and less on the academic pre-reading and written requirements. Explanations should be provided in lay terms and patience is required to communicate ideas in ways that facilitate understanding, and the course may need to be delivered over several days to accommodate community participant availability. Conclusion: Addressing Aboriginal community concerns and barriers allowed for the implementation of culturally responsive infant resuscitation education which was highly valued by community members and led to increased community confidence and participation in CPR education.

An increasing number of colleges and universities now require graduate student and faculty applicants to submit personal diversity statements for evaluation. Despite their rising use, little is known about how the personal diversity statement writing process is experienced by applicants. For White individuals in particular, their sources of egalitarian motivation may influence affective responses to writing a diversity statement given the content that is typical of these application components and the unease demonstrated in response to diversity-related contexts that is characteristic of White people with a strong external motivation to respond without prejudice. In the present study, White students at an American university participated in a personal diversity statement writing task and self-reported their motivation to respond without prejudice (in advance of the session) and affect (following the writing task). Despite prior research suggesting that they would feel otherwise, participants reported more positive affect compared to negative affect in relation to writing the diversity statement. When considering their sources of motivation, however, White individuals who were more externally motivated to respond without prejudice reported slightly more negative affect in reaction to the diversity statement writing task when compared to those low in external motivation. These findings have implications for the inclusion of personal diversity statements in candidate application materials at various levels of higher education.

Opioid overdose deaths are dramatically increasing in the United States and disproportionately affecting minority communities, with the increasing presence of fentanyl exacerbating this crisis. Developing community coalitions is a long-standing strategy used to address public health issues. However, there is a limited understanding of how coalitions operate amid a serious public health crisis. To address this gap, we leveraged data from the HEALing Communities Study (HCS)--a multisite implementation study aiming to reduce opioid overdose deaths in 67 communities. Researchers analyzed transcripts of 321 qualitative interviews conducted with members of 56 coalitions in the four states participating in the HCS. There were no a priori interests in themes, and emergent themes were identified through inductive thematic analysis and then mapped to the constructs of the Community Coalition Action Theory (CCAT). Themes emerged related to coalition development and highlighted the role of health equity in the inner workings of coalitions addressing the opioid epidemic. Coalition members reported seeing the lack of racial and ethnic diversity within their coalitions as a barrier to their work. However, when coalitions focused on health equity, they noted that their effectiveness and ability to tailor their initiatives to their communities' needs were strengthened. Based on our findings, we suggest two additions to enhance the CCAT: (a) incorporating health equity as an overarching construct that affects all stages of development, and (b) ensuring that data about individuals served are included within the pooled resource construct to enable monitoring of health equity.

Recent criticisms of large-scale summative assessments have claimed that the assessments are biased against historically excluded groups because of the assessments' lack of cultural representation. Accompanying these criticisms is a call for more culturally responsive assessments--assessments that take into account the background characteristics of the students; their beliefs, values, and ethics; their lived experiences; and everything that affects how they learn and behave and communicate. In this paper, we present provisional principles, based on a review of research, that we deem necessary for fostering cultural responsiveness in assessment. We believe the application of these principles can address the criticisms of current assessments.

Introduction: We aimed to assess antibiotic stewardship by quantifying the use of first-dose intravenous (IV) vs oral-only antibiotics and the frequency with which antibiotic class was changed for discharged patients. Secondary aims included the following: evaluation of the relative length of stay (LOS); differences in prescribing patterns between clinician types; differences between academic and community settings; assessment of prescribing patterns among emergency department (ED) diagnoses; and frequency of return visits for patients in each group.Methods: This was a retrospective cohort study including patients presenting to EDs with infections who were discharged from our Midwest healthcare system consisting of 17 community hospitals and one academic center. We included infection type, antibiotic class and route of administration, type of infection, LOS, return visit within two weeks, clinician type, and demographics. Data were collected between June 1, 2018–December 31, 2021 and analyzed using descriptive statistics.Results: We had 77,204 ED visits for patients with infections during the study period, of whom 3,812 received IV antibiotics during their visit. There were more women (62.4%) than men included. Of the 3,812 patients who received IV antibiotics, 1,026 (34.3%) were discharged on a different class of antibiotics than they received. The most common changes were from IV cephalosporin to oral quinolone or penicillin. Patients treated with IV antibiotics prior to discharge had a longer LOS in the ED (median difference of 102 minutes longer for those who received IV antibiotics). There was not a significant difference in the use of IV antibiotics between the academic center and community sites included in the study.Conclusion: Administering IV antibiotics as a first dose prior to oral prescriptions upon discharge is common, as is shifting classes from the IV dose to the oral prescription. This offers an opportunity for intervention to improve antibiotic stewardship for ED patients as well as reduce cost and length of stay.

Guinea pigs (Cavia porcellus) are popular pets and used as laboratory animals, however, their dietary preferences are under-studied. It is important for guinea pig owners and carers to increase the opportunity for good animal welfare by providing personalized and enriching dietary options. Thus, this study aimed to assess the use of paired-stimulus and multiple-stimulus-without-replacement preference assessments to determine the food preferences of seven male guinea pigs and test the validity of the methods by testing the demand for the most- and least preferred foods as reinforcers for climbing an elevated ramp. Generally, the preference assessments identified the same foods as the most preferred for each guinea pig, but not the least preferred foods. Guinea pigs climbed up to the steepest angle for both most and least preferred foods, but a non-linear least squares regression and demand analysis indicated faster climbing and inelastic demand for most preferred foods compared to slower climbing and elastic demand for least preferred foods. Both preference assessment methods were valid in identifying a preferred food, however, the multiple-stimulus-without-replacement assessment was more efficient to conduct. High-preference foods such as parsley and dandelion are recommended as future training reinforcers for guinea pigs and as foods to consider using as enrichment in captive guinea pig systems to encourage good welfare.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

BackgroundTo examine long-term retinal nerve fibre layer thickness (RNFLT) variability and associated clinical factors in African (AD) and European descent (ED) individuals with glaucoma.MethodsThis retrospective cohort study included glaucoma eyes of AD and ED from Diagnostic Innovations in Glaucoma Study/The African Descent and Glaucoma Evaluation Study with ≥4 visits/2 years of follow-up. We calculated optic nerve head RNFLT variability per-examination/visit as the absolute error of its residuals across follow-up. Full, baseline and parsimonious linear-mixed models were fit to evaluate the effects of clinical factors (demographics and ocular characteristics, prior/intervening glaucoma surgeries and cataract extraction (CE), RNFLT thinning rate, scan quality, visit/testing frequency, etc) on RNFLT variability in both races.ResultsThere were 376 and 625 eyes (226 and 349 participants) of AD and ED, and the mean (95% CI) RNFLT variability was 1.62 (1.52, 1.71) µm and 1.42 (1.34, 1.50) µm, respectively (p=0.002). AD and ED had some shared predictors of RNFLT variability, including intraocular pressure fluctuation and scan quality, although the effects varied (p

Background/aimsTo investigate the association between longitudinal changes of foveal avascular zone (FAZ) area and the rate of structural and functional progression in glaucoma.MethodsA longitudinal cohort included 115 eyes (46 glaucoma suspect and 66 primary open-angle glaucoma) of 81 patients having ≥2 year follow-up, and ≥4 visits with optical coherence tomography angiography and visual field (VF). Eyes in the longitudinal cohort with a slope greater than that found in 95 percentile of separate healthy test-retest series for FAZ area were categorised into FAZ progressors; all other eyes were defined as FAZ non-progressors. A generalised linear mixed-effect model was used to investigate the association of FAZ progressors with demographic and clinical characteristics.ResultsFaster ganglion cell complex (GCC) thinning and faster VF mean deviation (MD) loss were found in eyes with FAZ progressors compared with FAZ non-progressors (mean difference: -0.7 (95% CI, -1.4 to -0.1) µm/y; p=0.026, -0.3 (-0.5 to -0.1) dB/y; p=0.017, respectively), while whole image vessel density was not associated with FAZ progressors (p=0.929). SD of intraocular pressure (IOP) and IOP range were also associated with FAZ progressors in separate multivariable models (OR: 1.54 (1.02 to 2.32) per 1 mm Hg higher, p=0.041; OR: 1.20 (1.01 to 1.41) per 1 mm Hg higher; p=0.035, respectively).ConclusionsSignificant FAZ increase was weakly associated with moderately faster rates of both GCC thinning and VF MD loss, but not macular vessel density change in glaucoma eyes. Additional studies are needed to elucidate the pathophysiological associations between macula GCC thinning and FAZ area increases in glaucoma.

BackgroundGestational nutrition can protect against adverse neurodevelopmental outcomes.ObjectivesWe developed a short tool for collecting maternal nutritional intake during pregnancy to facilitate research in this area and compared its retrospective use to prospectively-collected food frequency questionnaires (FFQ).MethodsMaternal nutritional intake was retrospectively assessed using three versions (full interview, full self-administered online, and shortened interview) of the Early Life Exposure Assessment Tool (ELEAT) among participants of the MARBLES pregnancy cohort study of younger siblings of autistic children. Retrospective responses were compared with responses to supplement questions and the validated 2005 Block FFQ prospectively collected in MARBLES during pregnancies 2-7 years prior. ELEAT nutrient values were calculated using reported food intake frequencies and nutrient values from the USDA nutrient database. Correlations between retrospectively- and prospectively-reported intake were evaluated using Kappa coefficients, Youden's J, and Spearman Rank Correlation Coefficients (rs).ResultsMARBLES FFQ dietary intakes were compared among 54 women who completed the ELEAT full form including 12 online, and among 23 who completed the ELEAT short form. Correlations across most foods were fair to moderate. Most ELEAT quantified nutrient values were moderately correlated (rs = 0.3-0.6) with those on the Block FFQ. Supplement questions in both MARBLES and the ELEAT were completed by 114 women. Kappas were moderate for whether or not supplements were taken, but modest for timing. Correlations varied by version and child diagnosis or concerns, and were higher when mothers completed the ELEAT when their child was 4 years old or younger.ConclusionsWith recall up to several years, ELEAT dietary and supplement module responses were modestly to moderately reliable and produced nutrient values moderately correlated with prospectively-collected measures. The ELEAT dietary and vitamin supplements modules can be used to rank participants in terms of intake of several nutrients relevant for neurodevelopment.

When making inferences about the mental lives of others (e.g., others' preferences), it is critical to consider the extent to which the choices we observe are constrained. Prior research on the development of this tendency indicates a contradictory pattern: Children show remarkable sensitivity to constraints in traditional experimental paradigms, yet often fail to consider real-world constraints and privilege inherent causes instead. We propose that one explanation for this discrepancy may be that real-world constraints are often stable over time and lose their salience. The present research tested whether children (N = 133, 5- to 12-year-old mostly US children; 55% female, 45% male) become "less" sensitive to an actor's constraints after first observing two constrained actors (Stable condition) versus after first observing two actors in contexts with greater choice (Not Stable condition). We crossed the "stability" of the constraint with the "type" of constraint: either the constraint was deterministic such that there was only one option available (No Other Option constraint) or, in line with many real-world constraints, the constraint was probabilistic such that there "was" another option, but it was difficult to access (Hard to Access constraint). Results indicated that children in the Stable condition became less sensitive to the probabilistic Hard to Access constraint across trials. Notably, we also found that children's sensitivity to constraints was enhanced in the Not Stable condition regardless of whether the constraint was probabilistic or deterministic. We discuss implications for children's sensitivity to real-world constraints.

Little is known about the implications of cannabis legalization on adolescent health behaviors. This study sought to examine the relationship between recreational cannabis legalization and adolescent sexual risk behaviors. Data on 371,487 respondents who have ever had sexual intercourse from 41 states in the 2005 to 2019 Youth Risk Behavior Survey was linked with data on state-level cannabis policies. Difference-in-differences logistic regression models were conducted. Recreational cannabis legalization was associated with a reduced likelihood of respondents having 2+ sexual partners (adjusted OR [aOR] 0.63, 95% CI [0.47, 0.84]), but had no association with condom use (aOR 0.94, 95% CI [0.80, 1.11]). Changing social norms around cannabis is a potential pathway linking cannabis legalization to a reduction in sexual risk behaviors.

Inclusive education in the United Arab Emirates (UAE) is evolving with ambitious policies and strategic plans. The extent to which these policies and plans are being embedded into practice in mainstream schools across the country has not been fully captured. This research used an online survey to investigate teachers' perceived competence in implementing inclusive education practices with students with disabilities in mainstream schools and explore its relationship with demographic variables. Participants included 999 teachers from public and private schools across the seven Emirates of the UAE. Greater competence was reported in implementing practices that create an environment conducive to effective learning and less competence in implementing practices that use knowledge of the student. Differences were found between demographic variables and teachers' perceived competence in implementing inclusive education practices with recent professional development in inclusive and/or special education emerging as the most significant predictor. Implications for practice and further research are considered.

In response to COVID-19, educators rapidly pivoted to new and innovative ways of delivering lecture material. The ability to host synchronous lectures on platforms like Zoom gave students continued access to classroom material in the face of an ongoing pandemic. The purpose of this study was to investigate the differences in exam scores between students attending a physiology class (PHSL3051) synchronously via Zoom or asynchronously by viewing recorded lectures posted after class. Students in PHSL3051 were evaluated with four unit exams and one cumulative final exam. Although pooled analysis of all students showed that synchronous lecture viewing positively predicted exam scores, this positive association was even larger when the data were analyzed by gender and ethnicity. For female-identified students and students of color (SOC), attending lectures synchronously was associated with average scores on every unit exam that were higher by 2.7-7.4 percentage points. Moreover, the greater a student's synchronous participation in the course throughout the semester, the better that student's performance on the cumulative final exam was likely to be. These data highlight the need to better understand how different groups of undergraduate students select and respond to different assessment methods used in the same course, which may have long-term effects on their overall performance at 4-year institutions.

The purpose of this study was to evaluate the effects of performance-based feedback delivered via email on teacher candidates' implementation of a multiple stimulus without replacement (MSWO) preference assessment with an adult confederate. Six participants enrolled in a special education teacher preparation program were recruited to participate. After exposure to an introductory MSWO training video, participant fidelity of MSWO administration was measured. Following baseline, performance feedback was delivered via e-mail to each participant after the completion of each research session. Results indicate that performance feedback delivered via e-mail improved fidelity of implementation for all six participants. Implications and future directions are discussed.

Previous research indicates that youth exhibiting antisocial behavior are at risk for utilizing a disproportionate amount of health services compared to youth without these problems. The present study investigates whether being processed by the juvenile justice system and showing callous-unemotional (CU) traits independently predict health service utilization (medical and mental health service use and out-of-home placement) over and above the severity of antisocial behavior across adolescence. A total of 766 participants who had been arrested for the first time in adolescence provided data at ten appointments over a period of seven years. Results showed that self-reported antisocial behavior at the time of arrest predicted increased use of most health service use types over the next seven years (i.e. medicine prescriptions, tests for sexually transmitted infections, mental health service appointments, and out-of-home placements). All except prescription medication use remained significant when controlling for justice system processing and CU traits. Further, justice system processing added significantly to the prediction of medical service appointments. Whereas CU traits were associated with mental health service appointments and out-of-home placements, these did not remain significant when controlling for severity of antisocial behavior. These findings are consistent with prior research documenting the health care costs of antisocial behavior.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

Background and aimsMany agricultural areas are expected to face hotter, drier conditions from climate change. Understanding the mechanisms that crops use to mitigate these stresses can guide breeding for more tolerant plant material. We tested relationships between traits, physiological function in hot conditions and historical climate associations to evaluate these mechanisms for winegrapes. We expected a more negative leaf osmotic potential at full hydration (πo), which reduces leaf turgor loss during drought, and either a metabolically cheaper or more osmoprotectant leaf chemical composition, to allow cultivars associated with hot, dry regions to maintain greater gas exchange in hot growing conditions.MethodsWe measured πo, gas exchange and leaf chemistry for seven commercially important winegrape cultivars that vary widely in historical climate associations. Vines were grown in common-garden field conditions in a hot wine-growing region (Davis, CA, USA) and measured over the hottest period of the growing season (July-September).Key resultsThe value of πo varied significantly between cultivars, and all cultivars significantly reduced πo (osmotically adjusted) over the study period, although osmotic adjustment did not vary across cultivars. The value of πo was correlated with gas exchange and climate associations, but in the direction opposite to expected. Photosynthesis and πo were higher in the cultivars associated with hotter, less humid regions. Leaf chemical composition varied between cultivars but was not related to climate associations.ConclusionsThese findings suggest that maintenance of leaf turgor is not a primary limitation on grapevine adaptation to hot or atmospherically dry growing conditions. Thus, selecting for a more negative πo or greater osmotic adjustment is not a promising strategy to develop more climate-resilient grape varieties, contrary to findings for other crops. Future work is needed to identify the mechanisms increasing photosynthesis in the cultivars associated with hot, dry regions.

Disbudding prevents horn growth in calves through thermal or chemical cauterization and causes damage that is painful for weeks following the procedure. Current pain management strategies are only effective from 1 to 2 h (local anesthetic) to 1 to 3 d (nonsteroidal anti-inflammatory drugs). A potential practical solution for addressing longer-term pain may be to administer ethanol as a cornual nerve block. When administered at a high concentration, ethanol damages the functionality of peripheral nerves, promoting localized long-lasting analgesia. It is also thought to be painful, thus ethanol may be combined with lidocaine, as a mixed solution or administered beforehand. We tested the use of an ethanol cornual nerve block for anesthesia around the horn bud in 2 pilot studies. We used different concentrations and amounts of ethanol (100% and 70%) in combination with different ratios of lidocaine in our attempt to identify an effective block. In pilot 1, 14 nondisbudded calves were administered 2 to 4 mL of 100% ethanol below the bony ridge on each side of the head to block the cornual nerve at 3 to 10 d of age (n = 28 horn buds) and observed for 5 wk. The duration of loss of sensation was evaluated using pinprick tests 10 min, 1, 3, and 7 d after the block, and then weekly thereafter until 35 d or full sensation had returned. Pinprick tests consisted of lightly pressing a needle in 10 evenly spaced locations around the base of the horn bud (0 responses = no sensation, 1-5 responses = partial sensation, 6-10 responses = full sensation). Pilot 2 looked at the 24 h after the injection and consisted of 9 nondisbudded calves (5 mL of 2:1, 70% ethanol and 2% lidocaine per horn bud) and 6 disbudded individuals (5 mL of 100% ethanol, 70% ethanol, or 2% lidocaine per horn bud). All treatments were administered at the calf level. Anesthesia was checked 10 min after the injection and 4 or 16 h later. In pilot 1, on the day of the ethanol injection (0 d), there was no sensation in 85% of horn buds. Sensation began to return as early as 1 d after blocking, with only 50%, 21%, and 3% of horn buds having no sensation at 1, 7, and 35 d, respectively. Partial sensation was present in 25%, 17%, and 10% of horn buds at these time points. In pilot 2, 27.8% of horn buds in the nondisbudded group had no sensation, whereas 33.3% had partial sensation 10 min after the injection. In the disbudded calves 10 min after the injection, 100% of horn buds from the 100% ethanol group had partial sensation and 100% of horn buds administered 70% ethanol had full sensation. Four or sixteen hours later, 100% of horn buds had full sensation. Together, in these pilot studies, ethanol provided inconsistent anesthesia when used for a cornual nerve block.

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of the dystrophin-glycoprotein complex (DGC) that links the intracellular actin cytoskeleton with the extracellular matrix. It is also associated with integrin α7β1, the predominant integrin expressed in skeletal muscle. As a tetraspanin-like protein with four transmembrane spanning domains, SSPN functions as a scaffold to facilitate protein-protein interactions at the cell membrane. Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy are caused by the loss of dystrophin at the muscle cell surface and a concomitant loss of the entire DGC, including SSPN. SSPN overexpression ameliorates Duchenne muscular dystrophy in the mdx murine model, which supports SSPN being a viable therapeutic target. Other rescue studies support SSPN as a biomarker for the proper assembly and membrane expression of the DGC. Highly specific and robust antibodies to SSPN are needed for basic research on the molecular mechanisms of SSPN rescue, pre-clinical studies, and biomarker evaluations in human samples. The development of SSPN antibodies is challenged by the presence of its four transmembrane domains and limited antigenic epitopes. To address the significant barrier presented by limited commercially available antibodies, we aimed to generate a panel of robust SSPN-specific antibodies that can serve as a resource for the research community. We created antibodies to three SSPN protein epitopes, including the intracellular N- and C-termini as well as the large extracellular loop (LEL) between transmembrane domains 3 and 4. We developed a panel of rabbit antibodies (poly- and monoclonal) against an N-terminal peptide fragment of SSPN. We used several assays to show that the rabbit antibodies recognize mouse SSPN with a high functional affinity and specificity. We developed mouse monoclonal antibodies against the C-terminal peptide and the large extracellular loop of human SSPN. These antibodies are superior to commercially available antibodies and outperform them in various applications, including immunoblotting, indirect immunofluorescence analysis, immunoprecipitation, and an ELISA. These newly developed antibodies will significantly improve the quality and ease of SSPN detection for basic and translational research.

M15 is a globular cluster with a known spread in neutron-capture elements. This paper presents abundances of neutron-capture elements for 62 stars in M15. Spectra were obtained with the Michigan/Magellan Fiber System spectrograph, covering a wavelength range from ∼4430 to 4630 Å. Spectral lines from Fe i, Fe ii, Sr i, Zr ii, Ba ii, La ii, Ce ii, Nd ii, Sm ii, Eu ii, and Dy ii were measured, enabling classifications and neutron-capture abundance patterns for the stars. Of the 62 targets, 44 are found to be highly Eu-enhanced r-II stars, another 17 are moderately Eu-enhanced r-I stars, and one star is found to have an s-process signature. The neutron-capture patterns indicate that the majority of the stars are consistent with enrichment by the r-process. The 62 target stars are found to show significant star-to-star spreads in Sr, Zr, Ba, La, Ce, Nd, Sm, Eu, and Dy, but no significant spread in Fe. The neutron-capture abundances are further found to have slight correlations with sodium abundances from the literature, unlike what has been previously found; follow-up studies are needed to verify this result. The findings in this paper suggest that the Eu-enhanced stars in M15 were enhanced by the same process, that the nucleosynthetic source of this Eu pollution was the r-process, and that the r-process source occurred as the first generation of cluster stars was forming.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

OBJECTIVES: We aim to estimate geographic variability in total numbers of infections and infection fatality ratios (IFR; the number of deaths caused by an infection per 1,000 infected people) when the availability and quality of data on disease burden are limited during an epidemic. METHODS: We develop a noncentral hypergeometric framework that accounts for differential probabilities of positive tests and reflects the fact that symptomatic people are more likely to seek testing. We demonstrate the robustness, accuracy, and precision of this framework, and apply it to the United States (U.S.) COVID-19 pandemic to estimate county-level SARS-CoV-2 IFRs. RESULTS: The estimators for the numbers of infections and IFRs showed high accuracy and precision; for instance, when applied to simulated validation data sets, across counties, Pearson correlation coefficients between estimator means and true values were 0.996 and 0.928, respectively, and they showed strong robustness to model misspecification. Applying the county-level estimators to the real, unsimulated COVID-19 data spanning April 1, 2020 to September 30, 2020 from across the U.S., we found that IFRs varied from 0 to 44.69, with a standard deviation of 3.55 and a median of 2.14. CONCLUSIONS: The proposed estimation framework can be used to identify geographic variation in IFRs across settings.

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Type 2 diabetes mellitus (T2DM) is a common comorbidity among Parkinsons disease (PD) patients. Yet, little is known about dysregulated pathways that are unique in PD patients with T2DM. We applied high-resolution metabolomic profiling in serum samples of 636 PD and 253 non-PD participants recruited from Central California. We conducted an initial discovery metabolome-wide association and pathway enrichment analysis. After adjusting for multiple testing, in positive (or negative) ion mode, 30 (25) metabolic features were associated with T2DM in both PD and non-PD participants, 162 (108) only in PD participants, and 32 (7) only in non-PD participants. Pathway enrichment analysis identified 17 enriched pathways associated with T2DM in both the PD and non-PD participants, 26 pathways only in PD participants, and 5 pathways only in non-PD participants. Several amino acid, nucleic acids, and fatty acid metabolisms were associated with T2DM only in the PD patient group suggesting a possible link between PD and T2DM.

Sound speed is a critical parameter in ocean acoustic studies, as it determines the propagation and interpretation of recorded sounds. The potential for exploiting oceanic vessel noise as a sound source of opportunity to estimate ocean sound speed profile is investigated. A deep learning-based inversion scheme, relying upon the underwater radiated noise of moving vessels measured by a single hydrophone, is proposed. The dataset used for this study consists of Automatic Identification System data and acoustic recordings of maritime vessels transiting through the Santa Barbara Channel between January 2015 and December 2017. The acoustic recordings and vessel descriptors are used as predictors for regressing sound speed for each meter in the top 200 m of the water column, where sound speeds are most variable. Multiple (typically ranging between 4 and 10) transits were recorded each day; therefore, this dataset provides an opportunity to investigate whether multiple acoustic observations can be leveraged together to improve inversion estimates. The proposed single-transit and multi-transit models resulted in depth-averaged root-mean-square errors of 1.79 and 1.55 m/s, respectively, compared to the seasonal average predictions of 2.80 m/s.

The Facility for Rare Isotope Beams (FRIB) began operation with 1 kW beam power for scientific users in May 2022 upon completion of 8 years of project construction. The ramp-up to the ultimate beam power of 400 kW, planned over a 6-year period, will enable the facility to reach its full potential for scientific discovery in isotope science and applications. In December 2023, a record-high beam power of 10.4 kW uranium was delivered to the target. Technological developments and accelerator improvements are being made over the entire facility and are key to completion of the power ramp-up. Major technological developments entail the phased deployment of high-power beam-intercepting systems, including the charge strippers, the charge selection systems, the production target, and the beam dump, along with support systems, including non-conventional utilities (NCU) and remote handling facilities. Major accelerator improvements include renovations to aging legacy systems associated with experimental beam lines and system automation for improved operational efficiency and better machine availability. Experience must be gained to safely handle the increased radiological impacts associated with high beam power; extensive machine studies and advanced beam tuning procedures are needed to minimize uncontrolled beam losses for the desired operating conditions. This paper discusses the technological developments and accelerator improvements with emphasis on major R&D efforts.

COVID-19 pandemic-related traumatic stress (PRTS) symptoms are reported in various populations, but risk factors in older adults with chronic medical conditions, remain understudied. We therefore examined correlates and pre-pandemic predictors of PRTS in older adults with hypertension during COVID-19. Participants in California, aged 61-92 years (n = 95), participated in a pre-pandemic healthy aging trial and later completed a COVID-19 assessment (May to September 2020). Those experiencing ⩾1 PRTS symptom (n = 40), and those without PRTS symptoms (n = 55), were compared. The PRTS+ group had poorer mental and general health and greater impairment in instrumental activities of daily living. Pre-pandemic biomarkers of vascular inflammation did not predict increased odds of PRTS; however, greater pre-pandemic anxiety and female gender did predict PRTS during COVID-19. Our findings highlight PRTS as a threat to healthy aging in older adults with hypertension; targeted approaches are needed to mitigate this burden, particularly for females and those with pre-existing anxiety.

What is the connection between the cultural evolution of a language and the rapid processing response to that language in the brains of individual learners? In an iterated communication study that was conducted previously, participants were asked to communicate temporal concepts such as "tomorrow," "day after," "year," and "past" using vertical movements recorded on a touch screen. Over time, participants developed simple artificial 'languages' that used space metaphorically to communicate in nuanced ways about time. Some conventions appeared rapidly and universally (e.g., using larger vertical movements to convey greater temporal durations). Other conventions required extensive social interaction and exhibited idiosyncratic variation (e.g., using vertical location to convey past or future). Here we investigate whether the brain's response during acquisition of such a language reflects the process by which the language's conventions originally evolved. We recorded participants' EEG as they learned one of these artificial space-time languages. Overall, the brain response to this artificial communication system was language-like, with, for instance, violations to the system's conventions eliciting an N400-like component. Over the course of learning, participants' brain responses developed in ways that paralleled the process by which the language had originally evolved, with early neural sensitivity to violations of a rapidly-evolving universal convention, and slowly developing neural sensitivity to an idiosyncratic convention that required slow social negotiation to emerge. This study opens up exciting avenues of future work to disentangle how neural biases influence learning and transmission in the emergence of structure in language.