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OBJECTIVE: Virtual reality (VR) can enhance engagement in outpatient physical therapy (PT) through distraction and gamification of movement. This study assessed barriers and facilitators to VR-enhanced PT. METHOD: Data were collected during a feasibility trial of VR-enhanced PT for youth with chronic musculoskeletal pain. Semistructured and informal interviews were conducted with youth participants, their caregivers, and collaborating physical therapists. To analyze transcriptions, content analysis was employed in multiple rounds. Barriers and facilitators to VR implementation were coded using a deductive approach, then an inductive approach was used to identify emergent themes within each deductive code category. RESULTS: We completed interviews with youth participants (n = 9), caregivers (n = 7), and clinician stakeholders (n = 5). Coded barriers included: (1) participant identity and self-narrative inconsistent with the intervention, (2) system-level, structural constraints of healthcare, (3) lack of guidance and leadership from clinicians around VR use, (4) research burnout, (5) expectation violation and disappointment, and (6) missing the optimal treatment window. Coded facilitators included: (1) viewing VR as a bridge to achieving treatment goals, (2) having access to resources, (3) sustained positive experience and immersion in the game, (4) alignment between identity and the intervention, and (5) champion-level collaborations. CONCLUSIONS: This study highlights the importance of considering the VR technology, person using the VR, and the context in which VR is being implemented to optimize uptake and acceptability. Adopting an implementation science lens to the field of VR for chronic pain will enhance the applicability and scale of impact.
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Metamonads are a diverse group of heterotrophic microbial eukaryotes adapted to living in hypoxic environments. All metamonads but one harbour metabolically altered 'mitochondrion-related organelles' (MROs) with reduced functions, however the degree of reduction varies. Here, we generate high-quality draft genomes, transcriptomes, and predicted proteomes for five recently discovered free-living metamonads. Phylogenomic analyses placed these organisms in a group we name the 'BaSk' (Barthelonids+Skoliomonads) clade, a deeply branching sister group to the Fornicata, a phylum that includes parasitic and free-living flagellates. Bioinformatic analyses of gene models shows that these organisms are predicted to have extremely reduced MRO proteomes in comparison to other free-living metamonads. Loss of the mitochondrial iron-sulfur cluster assembly system in some organisms in this group appears to be linked to the acquisition in their common ancestral lineage of a SUF-like minimal system Fe/S cluster pathway by lateral gene transfer. One of the isolates, Skoliomonas litria, appears to have lost all other known MRO pathways. No proteins were confidently assigned to the predicted MRO proteome of this organism suggesting that the organelle has been lost. The extreme mitochondrial reduction observed within this free-living anaerobic protistan clade demonstrates that mitochondrial functions may be completely lost even in free-living organisms.
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Mitocôndrias , Filogenia , Proteoma , Mitocôndrias/metabolismo , Mitocôndrias/genética , Proteoma/metabolismo , Proteoma/genética , Transcriptoma , Eucariotos/genética , Eucariotos/metabolismo , Eucariotos/classificação , Transferência Genética Horizontal , Proteínas Ferro-Enxofre/metabolismo , Proteínas Ferro-Enxofre/genéticaRESUMO
STUDY OBJECTIVE: To assess the rate and characteristics of acute pulmonary embolism (PE) cases diagnosed in the emergency department (ED) following an ED discharge visit within 10 days. METHODS: This is a retrospective analysis of 40 EDs in a statewide clinical registry from 2017 to 2022. We identified adult patients with acute PEs diagnosed in the ED. We assessed PE cases wherein a prior ED visit for the same patient resulting in discharge had taken place within 10 days without interval hospitalization. We then characterized the overall rate of revisit PE cases per overall acute PE cases and per 10,000 ED discharges. We also reported on subgroups of revisit cases where the preceding visit resulted in diagnosis of COVID-19, other cardiopulmonary conditions, and cardiopulmonary symptom codes (eg, chest pain, unspecified). RESULTS: Of 24,525 acute PEs, 1,202 (4.9%, 95% confidence interval [CI] 4.6% to 5.2%) had an ED discharge within the preceding 10 days (2.0 per 10,000 ED discharges, 95% CI 1.9 to 2.1). Two hundred thirty-three (19.4%) were originally discharged with a COVID-19 diagnosis, 107 (8.9%) were originally discharged with another cardiopulmonary condition, and 201 (16.7%) were cases discharged with a nonspecific cardiopulmonary symptom code. Discharges with diagnoses of COVID-19, pneumonia, and pleural effusion had higher rates of revisits with acute PE. CONCLUSION: In this retrospective analysis, about 1 in 20 acute PEs and 2 in 10,000 ED discharges were associated with an ED revisit for acute PE. Some cases may represent potential diagnostic opportunities, whereas others may be progression of disease, risk factors for PE, or unrelated.
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OBJECTIVE: Culture and diversity-related training is critical to the development of competent pediatric psychologists. Evaluation of training efforts have been conducted at the program level, yet evaluation of trainee experiences in culture and diversity-related training remains unassessed. This trainee-led study was the first formal assessment of pediatric psychology trainee experiences of culture and diversity-related training and the impact of training on their own cultural humility. METHODS: Study overview and a survey link was distributed across 2 listservs associated with the American Psychological Association (Division 53, Division 54) and sent directly to directors of graduate, internship, and fellowship training programs with a request to share with trainees. Surveys assessing integration of cultural training and trainee cultural humility were completed. Trainees also provided qualitative feedback regarding their multicultural training and development. RESULTS: Pediatric psychology trainees (N = 90) reported inconsistent integration of culture and diversity topics into their training. Of the 34 training areas assessed, 10 were perceived as thoroughly integrated into formal training by at least half of the respondents. Trainees often sought independent cultural training outside of their programs, and no relationship was detected between perceived integration of cultural training and trainee cultural competence. DISCUSSION: Results indicate room for improvement regarding integration of cultural training and a need to better understand driving forces behind trainees independently seeking training outside of their formal training programs. Moreover, understanding the aspects of training that are most contributory to trainee development is needed given that no relationship between training and development emerged in the current study.
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Microbial hydrogen (H2) cycling underpins the diversity and functionality of diverse anoxic ecosystems. Among the three evolutionarily distinct hydrogenase superfamilies responsible, [FeFe] hydrogenases were thought to be restricted to bacteria and eukaryotes. Here, we show that anaerobic archaea encode diverse, active, and ancient lineages of [FeFe] hydrogenases through combining analysis of existing and new genomes with extensive biochemical experiments. [FeFe] hydrogenases are encoded by genomes of nine archaeal phyla and expressed by H2-producing Asgard archaeon cultures. We report an ultraminimal hydrogenase in DPANN archaea that binds the catalytic H-cluster and produces H2. Moreover, we identify and characterize remarkable hybrid complexes formed through the fusion of [FeFe] and [NiFe] hydrogenases in ten other archaeal orders. Phylogenetic analysis and structural modeling suggest a deep evolutionary history of hybrid hydrogenases. These findings reveal new metabolic adaptations of archaea, streamlined H2 catalysts for biotechnological development, and a surprisingly intertwined evolutionary history between the two major H2-metabolizing enzymes.
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Archaea , Hidrogênio , Hidrogenase , Filogenia , Archaea/genética , Archaea/enzimologia , Proteínas Arqueais/metabolismo , Proteínas Arqueais/química , Proteínas Arqueais/genética , Genoma Arqueal , Hidrogênio/metabolismo , Hidrogenase/metabolismo , Hidrogenase/genética , Hidrogenase/química , Proteínas Ferro-Enxofre/metabolismo , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/química , Modelos Moleculares , Estrutura Terciária de ProteínaRESUMO
Chronic liver diseases, fibrosis, cirrhosis, and HCC are often a consequence of persistent inflammation. However, the transition mechanisms from a normal liver to fibrosis, then cirrhosis, and further to HCC are not well understood. This study focused on the role of the tumor stem cell protein doublecortin-like kinase 1 (DCLK1) in the modulation of molecular factors in fibrosis, cirrhosis, or HCC. Serum samples from patients with hepatic fibrosis, cirrhosis, and HCC were analyzed via ELISA or NextGen sequencing and were compared with control samples. Differentially expressed (DE) microRNAs (miRNA) identified from these patient sera were correlated with DCLK1 expression. We observed elevated serum DCLK1 levels in fibrosis, cirrhosis, and HCC patients; however, TGF-ß levels were only elevated in fibrosis and cirrhosis. While DE miRNAs were identified for all three disease states, miR-12136 was elevated in fibrosis but was significantly increased further in cirrhosis. Additionally, miR-1246 and miR-184 were upregulated when DCLK1 was high, while miR-206 was downregulated. This work distinguishes DCLK1 and miRNAs' potential role in different axes promoting inflammation to tumor progression and may serve to identify biomarkers for tracking the progression from pre-neoplastic states to HCC in chronic liver disease patients as well as provide targets for treatment.
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Quinases Semelhantes a Duplacortina , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular , Cirrose Hepática , Neoplasias Hepáticas , MicroRNAs , Proteínas Serina-Treonina Quinases , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/sangue , Cirrose Hepática/genética , Cirrose Hepática/sangue , Inflamação/genética , Inflamação/sangue , Masculino , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/sangue , Feminino , Doença Crônica , Hepatopatias/sangue , Hepatopatias/genética , Pessoa de Meia-Idade , Carcinogênese/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genéticaRESUMO
Low socioeconomic status (SES) is thought to exacerbate risks for bacterial infections, but global evidence for this relationship has not been synthesized. We systematically reviewed the literature for studies describing participants' SES and their risk of colonization or community-acquired infection with priority bacterial pathogens. Fifty studies from 14 countries reported outcomes by participants' education, healthcare access, income, residential crowding, SES deprivation score, urbanicity, or sanitation access. Low educational attainment, lower than average income levels, lack of healthcare access, residential crowding, and high deprivation were generally associated with higher risks of colonization or infection. There is limited research on these outcomes in low- and middle-income countries (LMICs) and conflicting findings regarding the effects of urbanicity. Only a fraction of studies investigating pathogen colonization and infection reported data stratified by participants' SES. Future studies should report stratified data to improve understanding of the complex interplay between SES and health, especially in LMICs.
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Background: Racial and ethnic disparities in infectious disease burden have been reported in the USA and globally, most recently for COVID-19. It remains unclear whether such disparities also exist for priority bacterial pathogens that are increasingly antibiotic-resistant. We conducted a scoping review to summarize published studies that report on colonization or community-acquired infection with pathogens among different races and ethnicities. Methods: We conducted an electronic literature search of MEDLINE®, Daily, Global Health, Embase, Cochrane Central, and Web of Science from inception to January 2022 for eligible observational studies. Abstracts and full-text publications were screened in duplicate for studies that reported data for race or ethnicity for at least one of the pathogens of interest. Results: Fifty-four observational studies in 59 publications met our inclusion criteria. Studies reported results for Enterobacterales, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus, and were conducted in Australia, Brazil, Israel, New Zealand, and USA. USA studies most often examined Black and Hispanic minority groups with studies regularly reporting a higher risk of these pathogens in Black persons and mixed results for Hispanic persons. Ethnic minority groups (e.g. Bedouins in Israel, Aboriginals in Australia) were often reported to be at a higher risk in other countries. Conclusion: Sufficient evidence was identified in this scoping review justifying future systematic reviews and meta-analyses evaluating the relationship between community-acquired pathogens and race and ethnicity. However, we noted that only a fraction of studies reported data stratified by race and ethnicity, highlighting a substantial gap in the literature.
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BACKGROUND: Few studies have described the insights of frontline health care providers and patients on how the diagnostic process can be improved in the emergency department (ED), a setting at high risk for diagnostic errors. The authors aimed to identify the perspectives of providers and patients on the diagnostic process and identify potential interventions to improve diagnostic safety. METHODS: Semistructured interviews were conducted with 10 ED physicians, 15 ED nurses, and 9 patients/caregivers at two separate health systems. Interview questions were guided by the ED-Adapted National Academies of Sciences, Engineering, and Medicine Diagnostic Process Framework and explored participant perspectives on the ED diagnostic process, identified vulnerabilities, and solicited interventions to improve diagnostic safety. The authors performed qualitative thematic analysis on transcribed interviews. RESULTS: The research team categorized vulnerabilities in the diagnostic process and intervention opportunities based on the ED-Adapted Framework into five domains: (1) team dynamics and communication (for example, suboptimal communication between referring physicians and the ED team); (2) information gathering related to patient presentation (for example, obtaining the history from the patients or their caregivers; (3) ED organization, system, and processes (for example, staff schedules and handoffs); (4) patient education and self-management (for example, patient education at discharge from the ED); and (5) electronic health record and patient portal use (for example, automatic release of test results into the patient portal). The authors identified 33 potential interventions, of which 17 were provider focused and 16 were patient focused. CONCLUSION: Frontline providers and patients identified several vulnerabilities and potential interventions to improve ED diagnostic safety. Refining, implementing, and evaluating the efficacy of these interventions are required.
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Comunicação , Serviço Hospitalar de Emergência , Entrevistas como Assunto , Segurança do Paciente , Pesquisa Qualitativa , Humanos , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/normas , Feminino , Atitude do Pessoal de Saúde , Masculino , Erros de Diagnóstico/prevenção & controle , Melhoria de Qualidade/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Adulto , Pessoa de Meia-IdadeRESUMO
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
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Caquexia , Citocina TWEAK , Macrófagos , Neoplasias Pancreáticas , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/complicações , Citocina TWEAK/metabolismo , Animais , Humanos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral , Atrofia Muscular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Quimiocina CCL5/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Fatores de Necrose Tumoral/metabolismo , Receptores CCR2/metabolismo , Quimiocina CCL2/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Understanding universal aspects of quantum dynamics is an unresolved problem in statistical mechanics. In particular, the spin dynamics of the one-dimensional Heisenberg model were conjectured as to belong to the Kardar-Parisi-Zhang (KPZ) universality class based on the scaling of the infinite-temperature spin-spin correlation function. In a chain of 46 superconducting qubits, we studied the probability distribution of the magnetization transferred across the chain's center, [Formula: see text]. The first two moments of [Formula: see text] show superdiffusive behavior, a hallmark of KPZ universality. However, the third and fourth moments ruled out the KPZ conjecture and allow for evaluating other theories. Our results highlight the importance of studying higher moments in determining dynamic universality classes and provide insights into universal behavior in quantum systems.
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Engineered dissipative reservoirs have the potential to steer many-body quantum systems toward correlated steady states useful for quantum simulation of high-temperature superconductivity or quantum magnetism. Using up to 49 superconducting qubits, we prepared low-energy states of the transverse-field Ising model through coupling to dissipative auxiliary qubits. In one dimension, we observed long-range quantum correlations and a ground-state fidelity of 0.86 for 18 qubits at the critical point. In two dimensions, we found mutual information that extends beyond nearest neighbors. Lastly, by coupling the system to auxiliaries emulating reservoirs with different chemical potentials, we explored transport in the quantum Heisenberg model. Our results establish engineered dissipation as a scalable alternative to unitary evolution for preparing entangled many-body states on noisy quantum processors.
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Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients with GMF and MF with large cell transformation (MFLCT). Skin biopsies from 49 patients (28 GMF and 21 MFLCT) were studied. Patients with GMF were associated with early clinical stage (p = 0.036) and lower levels of lactate dehydrogenase (p = 0.042). An increased percentage of cells positive for Tbet (p = 0.017), RORγT (p = 0.001), and PD-L1 (p = 0.011) was also observed among the GMF specimens, while a stronger PD-1 intensity was detected in cases of MFLCT. In this cohort, LCT, RORγT < 10%, Foxp3 < 10%, age, and advanced stage were associated with worse overall survival (OS) in univariate analysis. GMF demonstrated Th1 (cellular response) and Th17 (autoimmunity) phenotype, seen in early MF and granulomatous processes, respectively, which may be related to the histopathological appearance and biological behavior of GMF. Further studies involving larger series of cases and more sensitive techniques are warranted.
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Micose Fungoide , Neoplasias Cutâneas , Humanos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Neoplasias Cutâneas/patologia , Antígeno B7-H1/metabolismo , Regulação para Cima , Receptor de Morte Celular Programada 1/metabolismo , Fator de Maturação da Glia/metabolismo , Micose Fungoide/patologia , Fatores de Transcrição Forkhead/metabolismoRESUMO
BACKGROUND: Emergency departments (EDs) are susceptible to diagnostic error. Suboptimal communication between the patient and the interdisciplinary care team increases risk to diagnostic safety. The role of communication remains underrepresented in existing diagnostic decision-making conceptual models. METHODS: The authors used eDelphi methodology, whereby data are collected electronically, to achieve consensus among an expert panel of 18 clinicians, patients, family members, and other participants on a refined ED-based diagnostic decision-making framework that integrates several potential opportunities for communication to enhance diagnostic quality. This study examined the entire diagnostic process in the ED, from prehospital to discharge or transfer to inpatient care, and identified where communication breakdowns could occur. After four iterative rounds of the eDelphi process, including a final validation round by all participants, the project's a priori consensus threshold of 80% agreement was reached. RESULTS: The authors developed a final framework that positions communication more prominently in the diagnostic process in the ED and enhances the original National Academies of Sciences, Engineering, and Medicine (NASEM) and ED-adapted NASEM frameworks. Specific points in the ED journey were identified where more attention to communication might be helpful. Two specific types of communication-information exchange and shared understanding-were identified as high priority for optimal outcomes. Ideas for communication-focused interventions to prevent diagnostic error in the ED fell into three categories: patient-facing, clinician-facing, and system-facing interventions. CONCLUSION: This project's refinement of the NASEM framework adapted to the ED can be used to develop communications-focused interventions to reduce diagnostic error in this highly complex and error-prone setting.
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Comunicação , Serviço Hospitalar de Emergência , Serviço Hospitalar de Emergência/organização & administração , Humanos , Erros de Diagnóstico/prevenção & controle , Equipe de Assistência ao Paciente/organização & administraçãoRESUMO
Background: Pulmonary embolism (PE) is a rare yet serious postoperative complication for lung transplant recipients (LTRs). The association between timing and severity of PE and the development of chronic allograft lung dysfunction (CLAD) has not been described. Methods: A single-center, retrospective cohort analysis of first LTRs included bilateral or single lung transplants and excluded multiorgan transplants and retransplants. PEs were confirmed by computed tomography angiography or ventilation/perfusion (VQ) scans. Infarctions were confirmed on computed tomography angiography by a trained physician. The PE severity was defined by the Pulmonary Embolism Severity Index (PESI) score, a 30-d post-PE mortality risk calculator, and stratified by low I and II (0-85), intermediate III and IV (85-125), and high V (>125). PE and PESI were analyzed in the outcomes of overall survival, graft failure, and chronic lung allograft dysfunction (CLAD). Results: We identified 57 of 928 patients (6.14%) who had at least 1 PE in the LTR cohort with a median follow-up of 1623 d. In the subset with PE, the median PESI score was 85 (75.8-96.5). Most of the PESI scores (32/56 available) were in the low-risk category. In the CLAD analysis, there were 49 LTRs who had a PE and 16 LTRs (33%) had infarction. When treating PE as time-dependent and adjusting for covariates, PE was significantly associated with death (hazard ratio [HR] 1.8; 95% confidence interval [CI], 1.3-2.5), as well as increased risk of graft failure, defined as retransplant, CLAD, or death (HR 1.8; 95% CI, 1.3-2.5), and CLAD (HR 1.7; 95% CI, 1.2-2.4). Infarction was not associated with CLAD or death. The PESI risk category was not a significant predictor of death or CLAD. Conclusions: PE is associated with decreased survival and increased hazard of developing CLAD. PESI score was not a reliable predictor of CLAD or death in this lung transplant cohort.
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DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de-repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up-regulation of germline genes and impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de-repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development.
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DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Feminino , Camundongos , Gravidez , Animais , Metilação de DNA/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Ativação Transcricional , Placenta/metabolismo , Camundongos Transgênicos , Trofoblastos/metabolismo , Células GerminativasRESUMO
Importance: Pediatric readiness is essential for all emergency departments (EDs). Children's experience of care may differ according to operational challenges in children's hospitals, community hospitals, and rural EDs caused by recurring and sometimes unpredictable viral illness surges. Objective: To describe wait times, lengths of stay (LOS), and ED revisits across diverse EDs participating in a statewide quality collaborative during a surge in visits in 2022. Design, Setting, and Participants: This retrospective cohort study included 25 EDs from the Michigan Emergency Department Improvement Collaborative data registry from January 1, 2021, through December 31, 2022. Pediatric (patient age <18 years) encounters for viral and respiratory conditions were analyzed, comparing wait times, LOS, and ED revisit rates for children's hospital, urban pediatric high-volume (≥10% of overall visits), urban pediatric low-volume (<10% of overall visits), and rural EDs. Exposures: Surge in ED visit volumes for children with viral and respiratory illnesses from September 1 through December 31, 2022. Main Outcomes and Measures: Prolonged ED visit wait times (arrival to clinician assigned, >4 hours), prolonged LOS (arrival to departure, >12 hours), and ED revisit rate (ED discharge and return within 72 hours). Results: A total of 2â¯761â¯361 ED visits across 25 EDs in 2021 and 2022 were included. From September 1 to December 31, 2022, there were 301â¯688 pediatric visits for viral and respiratory illness, an increase of 71.8% over the 4 preceding months and 15.7% over the same period in 2021. At children's hospitals during the surge, 8.0% of visits had prolonged wait times longer than 4 hours, 8.6% had prolonged LOS longer than 12 hours, and 42 revisits occurred per 1000 ED visits. Prolonged wait times were rare among other sites. However, prolonged LOS affected 425 visits (2.2%) in urban high-pediatric volume EDs, 133 (2.6%) in urban pediatric low-volume EDs, and 176 (3.1%) in rural EDs. High visit volumes were associated with increased ED revisits across sites. Conclusions and Relevance: In this cohort study of more than 2.7 million ED visits, a pediatric viral illness surge was associated with different pediatric acute care across EDs in the state. Clinical management pathways and quality improvement efforts may more effectively mitigate dangerous clinical conditions with strong collaborative relationships across EDs and setting of care.
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Serviços Médicos de Emergência , Viroses , Criança , Humanos , Adolescente , Estudos de Coortes , Estudos Retrospectivos , Serviço Hospitalar de Emergência , Tratamento de Emergência , Viroses/epidemiologia , Viroses/terapiaRESUMO
While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1.
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Quinases Semelhantes a Duplacortina , Neoplasias , Humanos , Epigênese Genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Isoformas de Proteínas/metabolismo , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismoRESUMO
Archamoebae comprises free-living or endobiotic amoebiform protists that inhabit anaerobic or microaerophilic environments and possess mitochondrion-related organelles (MROs) adapted to function anaerobically. We compared in silico reconstructed MRO proteomes of eight species (six genera) and found that the common ancestor of Archamoebae possessed very few typical components of the protein translocation machinery, electron transport chain and tricarboxylic acid cycle. On the other hand, it contained a sulphate activation pathway and bacterial iron-sulphur (Fe-S) assembly system of MIS-type. The metabolic capacity of the MROs, however, varies markedly within this clade. The glycine cleavage system is widely conserved among Archamoebae, except in Entamoeba, probably owing to its role in catabolic function or one-carbon metabolism. MRO-based pyruvate metabolism was dispensed within subgroups Entamoebidae and Rhizomastixidae, whereas sulphate activation could have been lost in isolated cases of Rhizomastix libera, Mastigamoeba abducta and Endolimax sp. The MIS (Fe-S) assembly system was duplicated in the common ancestor of Mastigamoebidae and Pelomyxidae, and one of the copies took over Fe-S assembly in their MRO. In Entamoebidae and Rhizomastixidae, we hypothesize that Fe-S cluster assembly in both compartments may be facilitated by dual localization of the single system. We could not find evidence for changes in metabolic functions of the MRO in response to changes in habitat; it appears that such environmental drivers do not strongly affect MRO reduction in this group of eukaryotes.