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Immune checkpoint inhibitors (ICPi) have revolutionized cancer immunotherapy but also can induce autoimmune hemolytic anemia (AIHA), a severe disease with high mortality. However, the cellular and molecular mechanism(s) of ICPi-AIHA are unclear, other than being initiated through decreased checkpoint inhibition. Herein, we report ICPi-AIHA in a novel mouse model that shows similar characteristics of known human ICPi-AIHA (e.g., autoantibodies, hemolysis, increased mortality). During ICPi-AIHA, there is the simultaneous reduction of two regulatory T cell populations (FoxP3+ and Tr1 Tregs) and an increase in inflammatory TH17 T cells. Moreover, a novel CD39+CD73-FoxP3-CD25- CD4+ T cell subset (i.e., CD39 single positive [CD39SP]) emerges, and early increases in CD39SP predict AIHA development; CD39 is an ectonuclease that breaks down ATP. Additionally, we found that boosting ATPase activity by injecting recombinant apyrase mitigates AIHA development and significant CD39SP reductions, both suggesting a functional role for CD39 and demonstrating a novel therapeutic approach. Importantly, CD39SP are detectable in multiple mouse models developing AIHA and in patients with AIHA, demonstrating applicability to idiopathic and secondary AIHA. Highlighting broader autoimmunity relevance, ICPi-treated NZB mice experienced accelerated onset and severity of lupus, including AIHA. Moreover, ICPi treatment of healthy B6 animals led to detectable CD39SP and development of autoantibodies against multiple autoantigens including those on red blood cells and platelets. Together, our findings elucidate cellular and molecular mechanisms of ICPi-AIHA, leading to novel diagnostic and therapeutic approaches with translational potential for use in humans being treated with ICPi.
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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.
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Transtorno Autístico/metabolismo , Encéfalo/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Ribossomos/metabolismo , Sinapses/metabolismo , Animais , Transtorno Autístico/fisiopatologia , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Camundongos , Camundongos Knockout , Polirribossomos/metabolismo , Biossíntese de Proteínas , Proteínas de Ligação a RNA , Análise de Sequência de RNARESUMO
Reversible cerebral vasoconstriction syndrome (RCVS) is a rare and understudied transfusion reaction most commonly seen in adult females after correction of chronic, severe anemia. Transfusion-associated RCVS (TA-RCVS) typically presents with thunderclap headaches and one or more systemic (hypertension, nausea/vomiting) or neurologic (seizure, stroke, visual changes) symptoms within a week after red blood cell transfusion. Treatment of RCVS is based on blood pressure control; a recent study suggested that early use of nimodipine could shorten the disease course.
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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.
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Plaquetas , Preservação de Sangue , Transfusão de Plaquetas , Animais , Camundongos , Transfusão de Plaquetas/métodos , Plaquetas/metabolismo , Plaquetas/citologia , Preservação de Sangue/métodos , Humanos , Plasma Rico em Plaquetas/citologia , Modelos AnimaisRESUMO
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.
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Armas de Fogo , Ferimentos por Arma de Fogo , Adulto , Adolescente , Humanos , Criança , Estudos Retrospectivos , Violência , DocumentaçãoRESUMO
This corrects the article DOI: 10.1038/nature24646.
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This study uses Texas's 2017 integration of the state disability and mental health agencies as a case study, combining interviews with Texas agency and advocacy organization leaders to examine perceptions of agency integration and augmented synthetic control analyses of 2014-2020 Medical Expenditure Panel Survey to examine impacts on mental health service use among individuals with co-occurring cognitive disabilities (including intellectual and developmental disabilities) and mental health conditions. Interviewees described the intensive process of agency integration and identified primarily positive (e.g., decreased administrative burden) impacts of integration. Quantitative analyses indicated no effects of integration on receipt of mental health-related services among people with co-occurring conditions. While leaders identified some potentially beneficial impacts of state agency integration, the limited impact of integration beyond the agency suggests that interventions at multiple levels of the service system, including those targeting providers, are needed to better meet the mental health service needs for this population.
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THE PURPOSE: Of this study was to understand emergency nurses' use of frailty to inform care, disposition decision-making, and further assessment. METHODS: A qualitative, descriptive, exploratory approach was used. Field notes from group discussions held during a conference presession on frailty and post-session evaluation data were analyzed. RESULTS: Two common ideas threaded these discussions: frailty as vulnerability to "falling through the cracks" and that of an iceberg. Participants stressed the broad and expansive ramifications of frailty, and lack of structure/process to accurately describe, quantify, and utilize the concept. Participants described issues of physical and emotional/social fragility, including being unable to complete activities of daily living independently; also of concern were the patients' social determinants of health and financial challenges. CONCLUSION: The conceptual understanding of frailty encompassed physical, social, cognitive, and access deficits. Emergency nurses are aware of this concept and would conduct formal frailty screening if provided with training, time, and resources.
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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.
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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.
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Política Pública , Humanos , Viés , Simulação por ComputadorRESUMO
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.
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Dor Crônica , Adulto , Humanos , Estados Unidos/epidemiologia , Dor Crônica/tratamento farmacológico , Dor Crônica/epidemiologia , Analgésicos Opioides/uso terapêutico , Padrões de Prática Médica , Prescrições de Medicamentos , Manejo da DorRESUMO
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.
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Anticoncepcionais Orais Combinados , Potenciação de Longa Duração , Humanos , Feminino , Encéfalo , Plasticidade Neuronal , PeriodicidadeRESUMO
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.
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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.
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Lesões Encefálicas , Acidente Vascular Cerebral , Medicina Transfusional , Humanos , Hemorragia Cerebral/terapia , Acidente Vascular Cerebral/terapia , Cuidados CríticosRESUMO
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.
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Poluentes Atmosféricos , Material Particulado , Material Particulado/análise , Poluentes Atmosféricos/análise , Madeira/química , Chile , Monitoramento Ambiental/métodosRESUMO
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.
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Agricultura , Classe Social , Animais , Agricultura/economia , Agricultura/história , Animais Domésticos , Ásia , América Central , Produção Agrícola/economia , Produção Agrícola/história , Europa (Continente)/etnologia , Características da Família/história , História Antiga , América do Norte , Política , Classe Social/história , HumanosRESUMO
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.
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Lesões Encefálicas Traumáticas , Serviços Médicos de Emergência , Criança , Humanos , Lactente , Estudos Retrospectivos , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Redes Neurais de Computação , Regras de Decisão ClínicaRESUMO
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.
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Bacharelado em Enfermagem , Estudantes de Enfermagem , Humanos , Criança , Aprendizagem Baseada em Problemas , Bacharelado em Enfermagem/métodos , Currículo , Crescimento e DesenvolvimentoRESUMO
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).
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Saúde Pública , Violência no Trabalho , Humanos , Governo Local , Pandemias , Saúde Pública/métodos , Estados Unidos/epidemiologia , Recursos Humanos , Local de TrabalhoRESUMO
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.