FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.

FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here, we use high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results suggest that loss of a translational brake on the synthesis of a subset of synaptic proteins contributes to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD and suggest multiple targets for clinical intervention.

Characterization of a novel mouse platelet transfusion model.

BACKGROUND AND OBJECTIVES: Platelet transfusions are increasing with medical advances. Based on FDA criteria, platelet units are assessed by in vitro measures; however, it is not known how platelet processing and storage duration affect function in vivo. Our study's aim was to develop a novel platelet transfusion model stored in mouse plasma that meets FDA criteria adapted to mice, and transfused fresh and stored platelets are detectable in clots in vivo. STUDY DESIGN AND METHODS: Platelet units stored in mouse plasma were prepared using a modified platelet-rich plasma (PRP) collection protocol. Characteristics of fresh and stored units, including pH, cell count, in vitro measures of activity, including activation and aggregation, and post-transfusion recovery (PTR), were determined. Lastly, a tail transection assay was conducted using mice transfused with fresh or stored units, and transfused platelets were identified by confocal imaging. RESULTS: Platelet units had acceptable platelet and white cell counts and were negative for bacterial contamination. Fresh and 1-day stored units had acceptable pH; the platelets were activatable by thrombin and adenosine diphosphate, agreeable with thrombin, had acceptable PTR, and were present in vivo in clots of recipients after tail transection. In contrast, 2-day stored units had clinically unacceptable quality. CONCLUSION: We developed mouse platelets for transfusion analogous to human platelet units using a modified PRP collection protocol with maximum storage of 1 day for an 'old' unit. This provides a powerful tool to test how process modifications and storage conditions affect transfused platelet function in vivo.

Documentation of Trauma-Informed Care Elements for Young People Hospitalized After Assault Trauma.

INTRODUCTION: Violent traumatic injury, including firearm violence, can adversely impact individual and community health. Trauma-informed care (TIC) can promote resilience and prevent future violence in patients who have experienced trauma. However, few protocols exist to facilitate implementation of TIC for patients who survive traumatic injury. The purpose of the study is to characterize documentation of TIC practices and identify opportunities for intervention in a single academic quaternary care center. METHODS: This study is a retrospective chart review analyzing the documentation of trauma-informed elements in the electronic medical record of a random sample of youth patients (ages 12-23) admitted for assault trauma to the pediatric (n = 50) and adult trauma (n = 200) services between 2016 and mid-2021. Descriptive statistics were used to summarize patient demographics, hospitalization characteristics, and documentation of trauma-informed elements. Chi-square analyses were performed to compare pediatric and adult trauma services. RESULTS: Among pediatric and adult assault trauma patients, 36.0% and 80.5% were hospitalized for firearm injury, respectively. More patients admitted to the pediatric trauma service (96%) had at least one trauma-informed element documented than patients admitted to the adult service (82.5%). Social workers were the most likely clinicians to document a trauma-informed element. Pain assessment and social support were most frequently documented. Safety assessments for suicidal ideation, retaliatory violence, and access to a firearm were rarely documented. CONCLUSIONS: Results highlight opportunities to develop trauma-informed interventions for youth admitted for assault trauma. Standardized TIC documentation could be used to assess risk of violent reinjury and mitigate sequelae of trauma.

Corrigendum: Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica.

This corrects the article DOI: 10.1038/nature24646.

An Introduction to the Semantics and Statistics Behind the Firearm Policy Debates.

It is impossible to fully understand why the United States has consistently failed to protect its citizens from firearm violence until one understands some of the key discrepancies that exist at the center of the firearm policy debate. Differences in language, data categorization, and research related to firearms and their impacts in the United States contribute to confusion and debate between firearm policy advocates and opponents, ultimately stalling progress toward some common goals. As frontline health professionals, emergency nurses must be aware of these nuances in order to be informed advocates for the safety of their patients and their communities. Emergency nurses can use the information from this article to help inform screening and education related to firearm safety and injury prevention. They can also use this information to inform nursing research as well as local and national advocacy efforts related to firearm injuries and deaths.

Identifying Optimal Methods for Addressing Confounding Bias When Estimating the Effects of State-level Policies.

BACKGROUND: Policy evaluation studies that assess how state-level policies affect health-related outcomes are foundational to health and social policy research. The relative ability of newer analytic methods to address confounding, a key source of bias in observational studies, has not been closely examined. METHODS: We conducted a simulation study to examine how differing magnitudes of confounding affected the performance of 4 methods used for policy evaluations: (1) the two-way fixed effects difference-in-differences model; (2) a 1-period lagged autoregressive model; (3) augmented synthetic control method; and (4) the doubly robust difference-in-differences approach with multiple time periods from Callaway-Sant'Anna. We simulated our data to have staggered policy adoption and multiple confounding scenarios (i.e., varying the magnitude and nature of confounding relationships). RESULTS: Bias increased for each method: (1) as confounding magnitude increases; (2) when confounding is generated with respect to prior outcome trends (rather than levels), and (3) when confounding associations are nonlinear (rather than linear). The autoregressive model and augmented synthetic control method had notably lower root mean squared error than the two-way fixed effects and Callaway-Sant'Anna approaches for all scenarios; the exception is nonlinear confounding by prior trends, where Callaway-Sant'Anna excels. Coverage rates were unreasonably high for the augmented synthetic control method (e.g., 100%), reflecting large model-based standard errors and wide confidence intervals in practice. CONCLUSIONS: In our simulation study, no single method consistently outperformed the others, but a researcher's toolkit should include all methodologic options. Our simulations and associated R package can help researchers choose the most appropriate approach for their data.

Effects of Opioid Prescribing Cap Laws on Opioid and Other Pain Treatments Among Persons with Chronic Pain.

BACKGROUND: Many states have adopted laws that limit the amount or duration of opioid prescriptions. These limits often focus on prescriptions for acute pain, but there may be unintended consequences for those diagnosed with chronic pain, including reduced opioid prescribing without substitution of appropriate non-opioid treatments. OBJECTIVE: To evaluate the effects of state opioid prescribing cap laws on opioid and non-opioid treatment among those diagnosed with chronic pain. DESIGN: We used a difference-in-differences approach that accounts for staggered policy adoption. Treated states included 32 states that implemented a prescribing cap law between 2017 and 2019. POPULATION: A total of 480,856 adults in the USA who were continuously enrolled in medical and pharmacy coverage from 2013 to 2019 and diagnosed with a chronic pain condition between 2013 and 2016. MAIN MEASURES: Among individuals with chronic pain in each state: proportion with at least one opioid prescription and with prescriptions of a specific duration or dose, average number of opioid prescriptions, average opioid prescription duration and dose, proportion with at least one non-opioid chronic pain prescription, average number of such prescriptions, proportion with at least one chronic pain procedure, and average number of such procedures. KEY RESULTS: State laws limiting opioid prescriptions were not associated with changes in opioid prescribing, non-opioid medication prescribing, or non-opioid chronic pain procedures among patients with chronic pain diagnoses. CONCLUSIONS: These findings do not support an association between state opioid prescribing cap laws and changes in the treatment of chronic non-cancer pain.

Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives.

INTRODUCTION: The combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. METHODS: Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions: days 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. RESULTS: Visually induced LTP was greater on day 21 than day 3 (p = 0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between days 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. CONCLUSIONS: This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders.

Transfusion medicine approaches for spontaneous intracerebral hemorrhage patients.

PURPOSE OF REVIEW: Spontaneous intracerebral hemorrhage (ICH) is the deadliest stroke subtype. Acute treatments necessitate rapid hemorrhage control to minimize secondary brain injury. Here, we discuss the overlap of transfusion medicine and acute ICH care relating to diagnostic testing and therapies relevant for coagulopathy reversal and secondary brain injury prevention. RECENT FINDINGS: Hematoma expansion (HE) is the largest contributor to poor outcomes after ICH. Conventional coagulation assays to diagnose coagulopathy after ICH does not predict HE. Given the testing limitations, empiric pragmatic hemorrhage control therapies have been trialed but have not improved ICH outcomes, with some therapies even causing harm. It is still unknown whether faster administration of these therapies will improve outcomes. Alternative coagulation tests (e.g., viscoelastic hemostatic assays, amongst others) may identify coagulopathies relevant for HE, currently not diagnosed using conventional assays. This provides opportunities for rapid, targeted therapies. In parallel, ongoing work is investigating alternative treatments using transfusion-based or transfusion-sparing pharmacotherapies that can be implemented in hemorrhage control strategies after ICH. SUMMARY: Further work is needed to identify improved laboratory diagnostic approaches and transfusion medicine treatment strategies to prevent HE and optimize hemorrhage control in ICH patients, who appear particularly vulnerable to the impacts of transfusion medicine practices.

On the Ability of the N-O Bond to Support a Stable Stereogenic Axis: Peptide-Catalyzed Atroposelective N-Oxidation.

During studies of atroposelective, peptide-catalyzed N-oxidations of pyridines, we observed lower-than-expected barriers to atropisomerization for these stereodynamic processes under the reaction conditions. Mechanistic studies indicate a hydrogen bond-assisted racemization mechanism intrinsic to both the starting materials and products. We also identified a protonation-dependent barrier to rotation that operates for the starting materials alone. Nonetheless, several substrates were amenable to atroposelective N-oxidations via kinetic resolution, yielding krel values of up to 12.6 and the isolation of one N-oxide with >99:1 er after recrystallization.

Development of Spatio-Temporal Land Use Regression Models for Fine Particulate Matter and Wood-Burning Tracers in Temuco, Chile.

Biomass burning is common in much of the world, and in some areas, residential wood-burning has increased. However, air pollution resulting from biomass burning is an important public health problem. A sampling campaign was carried out between May 2017 and July 2018 in over 64 sites in four sessions, to develop a spatio-temporal land use regression (LUR) model for fine particulate matter (PM) and wood-burning tracers levoglucosan and soluble potassium (Ksol) in a city heavily impacted by wood-burning. The mean (sd) was 46.5 (37.4) µg m-3 for PM2.5, 0.607 (0.538) µg m-3 for levoglucosan, and 0.635 (0.489) µg m-3 for Ksol. LUR models for PM2.5, levoglucosan, and Ksol had a satisfactory performance (LOSOCV R2), explaining 88.8%, 87.4%, and 87.3% of the total variance, respectively. All models included sociodemographic predictors consistent with the pattern of use of wood-burning in homes. The models were applied to predict concentrations surfaces and to estimate exposures for an epidemiological study.

Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica.

How wealth is distributed among households provides insight into the fundamental characters of societies and the opportunities they afford for social mobility. However, economic inequality has been hard to study in ancient societies for which we do not have written records, which adds to the challenge of placing current wealth disparities into a long-term perspective. Although various archaeological proxies for wealth, such as burial goods or exotic or expensive-to-manufacture goods in household assemblages, have been proposed, the first is not clearly connected with households, and the second is confounded by abandonment mode and other factors. As a result, numerous questions remain concerning the growth of wealth disparities, including their connection to the development of domesticated plants and animals and to increases in sociopolitical scale. Here we show that wealth disparities generally increased with the domestication of plants and animals and with increased sociopolitical scale, using Gini coefficients computed over the single consistent proxy of house-size distributions. However, unexpected differences in the responses of societies to these factors in North America and Mesoamerica, and in Eurasia, became evident after the end of the Neolithic period. We argue that the generally higher wealth disparities identified in post-Neolithic Eurasia were initially due to the greater availability of large mammals that could be domesticated, because they allowed more profitable agricultural extensification, and also eventually led to the development of a mounted warrior elite able to expand polities (political units that cohere via identity, ability to mobilize resources, or governance) to sizes that were not possible in North America and Mesoamerica before the arrival of Europeans. We anticipate that this analysis will stimulate other work to enlarge this sample to include societies in South America, Africa, South Asia and Oceania that were under-sampled or not included in this study.

A deep neural network framework to derive interpretable decision rules for accurate traumatic brain injury identification of infants.

OBJECTIVE: We aimed to develop a robust framework to model the complex association between clinical features and traumatic brain injury (TBI) risk in children under age two, and identify significant features to derive clinical decision rules for triage decisions. METHODS: In this retrospective study, four frequently used machine learning models, i.e., support vector machine (SVM), random forest (RF), deep neural network (DNN), and XGBoost (XGB), were compared to identify significant clinical features from 24 input features associated with the TBI risk in children under age two under the permutation feature importance test (PermFIT) framework by using the publicly available data set from the Pediatric Emergency Care Applied Research Network (PECARN) study. The prediction accuracy was determined by comparing the predicted TBI status with the computed tomography (CT) scan results since CT scan is the gold standard for diagnosing TBI. RESULTS: At a significance level of [Formula: see text], DNN, RF, XGB, and SVM identified 9, 1, 2,  and 4 significant features, respectively. In a comparison of accuracy (Accuracy), the area under the curve (AUC), and the precision-recall area under the curve (PR-AUC), the permutation feature importance test for DNN model was the most powerful framework for identifying significant features and outperformed other methods, i.e., RF, XGB, and SVM, with Accuracy, AUC, and PR-AUC as 0.915, 0.794, and 0.974, respectively. CONCLUSION: These results indicate that the PermFIT-DNN framework robustly identifies significant clinical features associated with TBI status and improves prediction performance. The findings could be used to inform the development of clinical decision tools designed to inform triage decisions.

Experiential Learning of Childhood Growth and Development Through a Pediatric Play Project.

ABSTRACT: The adoption of a new undergraduate nursing curriculum granted the opportunity to develop a new method for teaching growth and development. The Pediatric Play Project was designed as part of clinical experience where students explored principles of growth and development by designing a toy or play activity for a hospitalized pediatric patient. Students exhibited immense creativity while meeting learning outcomes, and the project received positive feedback from students and faculty. With minor refinement of the project, students will continue to gain understanding of the nurse's role in promoting growth and development for the hospitalized child.

Pandemic-Related Workplace Violence and Its Impact on Public Health Officials, March 2020‒January 2021.

Objectives. To characterize the experience and impact of pandemic-related workplace violence in the form of harassment and threats against public health officials. Methods. We used a mixed methods approach, combining media content and a national survey of local health departments (LHDs) in the United States, to identify harassment against public health officials from March 2020 to January 2021. We compared media-portrayed experiences, survey-reported experiences, and publicly reported position departures. Results. At least 1499 harassment experiences were identified by LHD survey respondents, representing 57% of responding departments. We also identified 222 position departures by public health officials nationally, 36% alongside reports of harassment. Public health officials described experiencing structural and political undermining of their professional duties, marginalization of their expertise, social villainization, and disillusionment. Many affected leaders remain in their positions. Conclusions. Interventions to reduce undermining, ostracizing, and intimidating acts against health officials are needed for a sustainable public health system. We recommend training leaders to respond to political conflict, improving colleague support networks, providing trauma-informed worker support, investing in long-term public health staffing and infrastructure, and establishing workplace violence reporting systems and legal protections. (Am J Public Health. 2022;112(5):736-746. https://doi.org/10.2105/AJPH.2021.306649).

Reimagining public safety: Public opinion on police reform and gun violence prevention by race and gun ownership in the United States.

Inequitable experiences of community gun violence and victimization by police use of force led to nationwide calls to "reimagine public safety" in 2020. In January 2021, we examined public support among U.S. adults for 7 policy approaches to reforming policing and investing in community gun violence prevention. Using a nationally representative sample (N = 2778), with oversampling for Black Americans, Hispanic Americans, and gun owners, we assessed support overall and by racial, ethnic, and gun owner subgroups. Overall, we found majority support for funding and implementing police and mental health co-responder models (66% and 76%, respectively), diversion from incarceration for people with symptoms of mental illness (72%), stronger laws to assure police accountability (72%), and funding for community-based and hospital-based gun violence prevention programs (69% and 60%, respectively). Support for redirecting funding from the police to social services was more variable (44% overall; White: 35%, Black: 60%, Hispanic: 43%). For all survey items, support was strongest among Black Americans. Gun owners overall reported lower support for public safety reforms and investments than respondents who did not own guns, but this distinction was found to be driven by White gun owners. The views of Black gun owners were indistinguishable from Black non-owners and were similar to White non-owners on most issues. These findings suggest that broad public support exists for innovative violence reduction strategies and public safety reforms.

National support for gun policies among U.S. adults in 2019 and 2021.

Gun-related deaths and gun purchases were at record highs in 2020. In light of the COVID-19 pandemic, public protests against police violence, and a tense political environment, which may influence policy preferences, we aimed to understand the current state of support for gun policies in the U.S. We fielded a national public opinion survey in January 2019 and January 2021 using an online panel to measure support for 34 gun policies among U.S. adults. We compared support over time, by gun ownership status, and by political party affiliation. Most respondents supported 33 of the 34 gun regulations studied. Support for seven restrictive policies declined from 2019 to 2021, driven by reduced support among non-gun owners. Support declined for three permissive policies: allowing legal gun carriers to bring guns onto college campuses or K-12 schools and stand your ground laws. Public support for gun-related policies decreased from 2019 to 2021, driven by decreased support among Republicans and non-gun owners.

National support for gun policies among U.S. adults in 2019 and 2021.

Gun-related deaths and gun purchases were at record highs in 2020. In light of the COVID-19 pandemic, public protests against police violence, and a tense political environment, which may influence policy preferences, we aimed to understand the current state of support for gun policies in the U.S. We fielded a national public opinion survey in January 2019 and January 2021 using an online panel to measure support for 34 gun policies among U.S. adults. We compared support over time, by gun ownership status, and by political party affiliation. Most respondents supported 33 of the 34 gun regulations studied. Support for seven restrictive policies declined from 2019 to 2021, driven by reduced support among non-gun owners. Support declined for three permissive policies: allowing legal gun carriers to bring guns onto college campuses or K-12 schools and stand your ground laws. Public support for gun-related policies decreased from 2019 to 2021, driven by decreased support among Republicans and non-gun owners.

Asymmetric Catalysis Mediated by Synthetic Peptides, Version 2.0: Expansion of Scope and Mechanisms.

Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759-5812). The overarching goal of this new Review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C-C bond formation, in which peptides have been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.

Cancer Screening Among Adults With and Without Serious Mental Illness: A Mixed Methods Study.

BACKGROUND: Persons with serious mental illness (SMI) die 10-20 years earlier than the general population; cancer is the second leading cause of death. Differences in cancer screening between SMI and the general population are not well understood. OBJECTIVES: To describe receipt of cancer screening among individuals with versus without SMI and to explore clinicians' perceptions around cancer screening for people with SMI. METHODS: Mixed-methods study using 2010-2017 MarketScan commercial insurance administrative claims data and semi-structured clinician interviews. In the quantitative analyses, we used multivariate logistic regression analyses to calculate the likelihood of receiving cervical, breast, colorectal, or prostate cancer screening among people with versus without SMI, defined as schizophrenia or bipolar disorder. We conducted semi-structured interviews with 17 primary care physicians and 15 psychiatrists. Interview transcripts were coded using a hybrid deductive/inductive approach. RESULTS: Relative to those without SMI, individuals with SMI were less likely to receive screening for cervical cancer [adjusted odds ratio (aOR): 0.80; 95% confidence interval (CI): 0.80-0.81], breast cancer (aOR: 0.79; 95% CI: 0.78-0.80), colorectal cancer (aOR: 0.90; 95% CI: 0.89-0.91), and prostate cancer (aOR: 0.85; 95% CI: 0.84-0.87). Clinicians identified 5 themes that may help explain the lower rates of cancer screening in persons with SMI: access to care, available support, prioritization of other issues, communication, and patient concerns. CONCLUSIONS: People with SMI were less likely to receive 4 common types of cancer screening. Improving cancer screening rates in the SMI population will likely require a multidisciplinary approach to overcome barriers to screening.