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ABSTRACT: The objective of this article is to demonstrate the added value of foot care provided by an RN with foot care training to older adults in their home by focusing on four older adults with diabetic foot ulcers. The RN used a mobile multispectral near-infrared spectroscopy device to enhance the assessment of the diabetic foot ulcers. The Mobile Seniors Wellness Network methodically engaged with English-speaking adults 55 years and older living within a 90-minute radius of the city's community health center. Older adults were referred to the research project through various sources. The participation group included 366 participants with varying holistic healthcare concerns and financial stressors that impacted their ability to age well in place. Over the course of visits by the RN and registered social worker, positive outcomes were facilitated through the collaboration of the participant and the multidisciplinary team, thus enhancing the individual's confidence to remain at home longer. In a time of ongoing provincial health crisis, it may be cost-effective to provide in-home support to those who want to age well in their communities by deploying a Mobile Seniors Wellness Network system throughout the province and enhancing the RN's assessment of feet with a portable and innovative technology tool.
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Pé Diabético , Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Pé Diabético/terapia , Idoso , Masculino , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Feminino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Vida Independente , Idoso de 80 Anos ou maisRESUMO
The FLOW program was designed to facilitate appropriate and safe transitions of patients from specialty mental health (SMH) to primary care (PC) as a method of improving access and reducing appointment burden on veterans who have improved or remitted. In this study, the team evaluated the implementation of FLOW across nine Veterans Affairs (VA) sites using a mixed-methods evaluation in a cluster-randomized stepped wedge trial design. Outcome assessments used data from VA databases, dashboards, and semi-structured interviews and were guided by the Reach, Adoption, Effectiveness, Implementation, and Maintenance (RE-AIM) framework. Across the sites, mean level reach was 1.36% of all specialty mental health patients transitioned to primary care (standard deviation [SD] = 1.05). Mean provider adoption was 10.2% (SD = 8.3%). Approximately 75% of veterans were fully satisfied with their transition and reported shared decision-making in the decision to transition. Rates of transitions did not decrease over the 6-month maintenance period following implementation. These data suggest that FLOW can be successfully implemented and maintained, although there was wide variation in implementation across sites. Future research should examine how to support sites that struggle with implementation.
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Acessibilidade aos Serviços de Saúde , Serviços de Saúde Mental , Atenção Primária à Saúde , United States Department of Veterans Affairs , Veteranos , Humanos , Serviços de Saúde Mental/organização & administração , Estados Unidos , Veteranos/psicologia , Atenção Primária à Saúde/organização & administração , Masculino , Feminino , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de Saúde , Transtornos Mentais/terapia , AdultoRESUMO
The sudden onset of the coronavirus disease led to a rapid expansion of video telehealth to deliver mental healthcare. Although video telehealth was not a new clinical practice, there was limited guidance on how best to modify evidence-based psychotherapies (EBPs) for virtual delivery (a process also referred to as virtualization). The virtualization process for EBPs remains unclear as newly emerging reports on this topic do not consistently report modification decisions. This commentary calls attention to the need to improve documentation practices to allow a greater understanding of modifications needed to maximize the positive effects of EBPs transported to a virtual format. We used the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) to capture details about the nature, process, and outcomes of intervention modifications across a given clinical setting or population. To illustrate the use of the FRAME, we present a case example describing our experiences with transporting a 1-day in-person Acceptance and Commitment Therapy group workshop to a virtual format. Workshop modifications primarily involved changes to the delivery format, administration procedures, and content. The case example walks through how, why, and by whom specific modifications were made as well as the degree to which fidelity was maintained. In the wake of the telemedicine revolution, further investigation into the virtualization process for EBPs is warranted. Improving reporting practices by using the FRAME or a similar adaptation framework will promote a more rigorous study of virtual modifications to EBPs that inform future guidelines and best practices.
Video telehealth rapidly expanded during COVID-19 as a preferred method for delivering mental health treatment. The sudden, unexpected onset of the pandemic left healthcare systems and individual clinicians little time to shift their services to this virtual format. In addition, there was and remains limited information on the most effective ways to modify evidence-based psychotherapies for virtual delivery (a process known as virtualization). To fill this knowledge gap, this commentary calls for improved documentation and evaluation of the virtualization process. We provide a case example demonstrating how to use the Framework for Reporting Adaptations and Modifications-Expandeda comprehensive system to detail the nature and process of treatment modifications within a given context. Routine use of this or similar adaptation models within the field of behavioral and social sciences will provide a better understanding of changes needed to ensure the continuity and integrity of evidence-based psychotherapies modified for video telehealth delivery.
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COVID-19 , Prática Clínica Baseada em Evidências , Psicoterapia , Telemedicina , Humanos , Psicoterapia/métodos , Prática Clínica Baseada em Evidências/métodos , SARS-CoV-2RESUMO
Consuming a diet that meets energy demands and provides essential nutrients promotes a healthy immune system, while both under- and over-nutrition have been associated with immune dysfunction. Military personnel comprise a unique population who frequently endure multi-stressor environments, predisposing them to immune decrements. Additionally, 49% and 22% of active duty U.S. military personnel are classified as overweight and obese, respectively. A literature search on PubMed was conducted to identify studies, reports, review papers, and references within those sources relevant to the topic area. Military personnel experiencing either under- or over-nutrition can suffer from degraded health, readiness, and performance. Insufficient intake of nutrients during military operations increases infection risk and negatively impacts infection recovery. Energy, protein, iron, zinc, and vitamins C and D are nutritional areas of concern that may impact immune competence in a multi-stressor environment. Over-nutrition can promote accretion of excess body fat and obesity, which contributes to a chronic inflammatory state that coincides with immune impairments. Prioritizing efforts to optimize nutrient intake is one approach for reducing disease burden and improving readiness. This review discusses nutritional concerns concomitant to multi-stressor environments that impact immune function, and the relevance of obesity to infectious disease risk in the military population.
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Doenças Transmissíveis , Militares , Humanos , Estado Nutricional , Obesidade/epidemiologia , ImunidadeRESUMO
The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC.
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COVID-19 , Humanos , Ligantes , COVID-19/metabolismo , Ceramidas/metabolismo , Pulmão/metabolismo , Endotélio Vascular/metabolismo , Receptores de Superfície Celular/metabolismo , Proteínas de Transporte/metabolismo , Esfingomielina Fosfodiesterase/metabolismoRESUMO
BACKGROUND: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease. AIM: The presented clinical setting highlights the unmet need for a precise molecular diagnosis of DTC and potential metastatic disease, which should dictate appropriate therapy. MATERIALS AND METHODS: In this article, we present a differential multi-omics model approach, including metabolomics, genomics, and bioinformatic models, to distinguish normal glands from thyroid tumours. Additionally, we are proposing biomarkers that could indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. RESULTS: Normal and tumour thyroid tissue from DTC patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumour cells. The consistency of the DTC metabolic profile allowed us to build a bioinformatic classification model capable of clearly distinguishing normal from tumor thyroid tissues, which might help diagnose thyroid cancer. Moreover, based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intra-tumour heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. DISCUSSION: Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. CONCLUSIONS: Well-designed, prospective translational clinical trials will ultimately show the value of this integrated multi-omics approach and early diagnosis of DTC and potential metastatic PTC.
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Adenocarcinoma , Neoplasias da Glândula Tireoide , Humanos , Radioisótopos do Iodo/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Encurtamento do Telômero , Telômero , Recidiva Local de Neoplasia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND, AIMS AND OBJECTIVES: This scoping review aimed to understand potential barriers and facilitators in transitioning patients from specialty to primary care settings, to inform the implementation of an intervention to promote active consideration of psychiatrically stable patients for transition from the specialty mental health setting back to primary care. METHODS: Guided by Levac and colleagues' six-stage methodological framework for conducting scoping studies, we systematically searched electronic article databases for peer-reviewed literature from January 2000 to May 2016. We included identified articles that discuss findings related to potential barriers and facilitators in transitioning patients from specialty to primary care settings. We performed descriptive and thematic analyses of results to generate emergent codes and their categorizations. RESULTS: Our database search yielded 906 unique articles, 23 of which we included in our scoping review. All but one of the included studies were conducted in North America. Identified potential barriers and facilitators spanned eight emergent themes-(i) primary care accessibility, especially in terms of timely availability of appointments, (ii) clarity in respective roles of specialty care and primary care in managing a patient, (iii) timely exchange of information, (iv) transition process management, (v) perceived ability of primary care providers to manage specialty conditions, (vi) perceived ability of patients to self-manage, (vii) leadership support and (viii) support for implementing initiatives to promote transitions. CONCLUSIONS: Findings from this scoping review enable an increased understanding of current practices and considerations regarding care transitions from specialty to primary care settings. The importance of role clarification, shared clinical information systems, confidence in care competency, and adequate organizational support to promote appropriate transitions were themes most widely reported across the reviewed studies. Few studies specifically examined the transition from specialty mental health to primary care. Future studies should account for mental health-specific symptomatic patterns and recovery trajectories, such as prevalent chronicity and frequency of relapse, in planning and conducting transitions from specialty mental health back to primary care.
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Saúde Mental , Transferência de Pacientes , HumanosRESUMO
Differentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach. TRANSLATIONAL RELEVANCE: In this article, we propose a new integrated metabolic, genomic, and cytopathologic methods to diagnose Differentiated Thyroid Cancer when the conventional methods failed. Moreover, we suggest metabolic and genomic markers to help predict high-risk Papillary Thyroid Cancer. Both might be important tools to avoid unnecessary surgery and/or radioiodine therapy that can worsen the quality of life of the patients more than living with an indolent Thyroid nodule.
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Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).
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Neoplasias da Próstata , RNA Longo não Codificante , Humanos , Masculino , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/genética , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Estudos Retrospectivos , RNA Longo não Codificante/genéticaRESUMO
Sleep restriction alters gut microbiota composition and intestinal barrier function in rodents, but whether similar effects occur in humans is unclear. This study aimed to determine the effects of severe, short-term sleep restriction on gut microbiota composition and intestinal permeability in healthy adults. Fecal microbiota composition, measured by 16S rRNA sequencing, and intestinal permeability were measured in 19 healthy men (mean ± SD; BMI 24.4 ± 2.3 kg/m2, 20 ± 2 years) undergoing three consecutive nights of adequate sleep (AS; 7-9 h sleep/night) and restricted sleep (SR; 2 h sleep/night) in random order with controlled diet and physical activity. α-diversity measured by amplicon sequencing variant (ASV) richness was 21% lower during SR compared to AS (P = 0.03), but α-diversity measured by Shannon and Simpson indexes did not differ between conditions. Relative abundance of a single ASV within the family Ruminococcaceae was the only differentially abundant taxon (q = 0.20). No between-condition differences in intestinal permeability or ß-diversity were observed. Findings indicated that severe, short-term sleep restriction reduced richness of the gut microbiota but otherwise minimally impacted community composition and did not affect intestinal permeability in healthy young men.
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Microbioma Gastrointestinal , Adulto , Masculino , Humanos , RNA Ribossômico 16S/genética , Intestinos , Sono , Fezes , PermeabilidadeRESUMO
INTRODUCTION: Personnel engaged in high-stakes occupations, such as military personnel, law enforcement, and emergency first responders, must sustain performance through a range of environmental stressors. To maximize the effectiveness of military personnel, an a priori understanding of traits can help predict their physical and cognitive performance under stress and adversity. This work developed and assessed a suite of measures that have the potential to predict performance during operational scenarios. These measures were designed to characterize four specific trait-based domains: cognitive, health, physical, and social-emotional. MATERIALS AND METHODS: One hundred and ninety-one active duty U.S. Army soldiers completed interleaved questionnaire-based, seated task-based, and physical task-based measures over a period of 3-5 days. Redundancy analysis, dimensionality reduction, and network analyses revealed several patterns of interest. RESULTS: First, unique variable analysis revealed a minimally redundant battery of instruments. Second, principal component analysis showed that metrics tended to cluster together in three to five components within each domain. Finally, analyses of cross-domain associations using network analysis illustrated that cognitive, health, physical, and social-emotional domains showed strong construct solidarity. CONCLUSIONS: The present battery of metrics presents a fieldable toolkit that may be used to predict operational performance that can be clustered into separate components or used independently. It will aid predictive algorithm development aimed to identify critical predictors of individual military personnel and small-unit performance outcomes.
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PURPOSE: Initial military training (IMT) is a transitionary period wherein immune function may be suppressed and infection risk heightened due to physical and psychological stress, communal living, and sleep deprivation. This study characterized changes in biomarkers of innate and adaptive immune function, and potential modulators of those changes, in military recruits during IMT. METHODS: Peripheral leukocyte distribution and mitogen-stimulated cytokine profiles were measured in fasted blood samples, Epstein-Barr (EBV), varicella zoster (VZV), and herpes simplex 1 (HSV1) DNA was measured in saliva by quantitative polymerase chain reaction as an indicator of latent herpesvirus reactivation, and diet quality was determined using the healthy eating index measured by food frequency questionnaire in 61 US Army recruits (97% male) at the beginning (PRE) and end (POST) of 22-wk IMT. RESULTS: Lymphocytes and terminally differentiated cluster of differentiation (CD)4+ and CD8+ T cells increased PRE to POST, whereas granulocytes, monocytes, effector memory CD4+ and CD8+ T cells, and central memory CD8+ T cells decreased ( P ≤ 0.02). Cytokine responses to anti-CD3/CD28 stimulation were higher POST compared with PRE, whereas cytokine responses to lipopolysaccharide stimulation were generally blunted ( P < 0.05). Prevalence of EBV reactivation was higher at POST ( P = 0.04), but neither VZV nor HSV1 reactivation was observed. Diet quality improvements were correlated with CD8+ cell maturation and blunted proinflammatory cytokine responses to anti-CD3/CD28 stimulation. CONCLUSIONS: Lymphocytosis, maturation of T-cell subsets, and increased T-cell reactivity were evident POST compared with PRE IMT. Although EBV reactivation was more prevalent at POST, no evidence of VZV or HSV1 reactivation, which are more common during severe stress, was observed. Findings suggest increases in the incidence of EBV reactivation were likely appropriately controlled by recruits and immune-competence was not compromised at the end of IMT.
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Militares , Esforço Físico , Privação do Sono , Estresse Psicológico , Feminino , Humanos , Masculino , Antígenos CD28/sangue , Linfócitos T CD8-Positivos/metabolismo , Citocinas/sangue , Estresse Psicológico/imunologia , Privação do Sono/imunologia , Linfócitos T CD4-Positivos/metabolismo , Esforço Físico/imunologiaRESUMO
Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.
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Antineoplásicos , Classe I de Fosfatidilinositol 3-Quinases , GTP Fosfo-Hidrolases , Linfangioma , Anormalidades Linfáticas , Proteínas de Membrana , Tiazóis , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , GTP Fosfo-Hidrolases/genética , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Linfangioma/tratamento farmacológico , Linfangioma/genética , Anormalidades Linfáticas/tratamento farmacológico , Anormalidades Linfáticas/genética , Proteínas de Membrana/genética , Mutação , Análise de Sequência de DNA , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.
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Proteínas de Homeodomínio , Doenças do Sistema Nervoso , Plasticidade Neuronal , Animais , Epigênese Genética , Regulação da Expressão Gênica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Plasticidade Neuronal/genéticaRESUMO
Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662-C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.
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COVID-19 , Vacinas , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Humanos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
BACKGROUND: Physiologic and psychologic stress slow healing from experimental wounds by impairing immune function. OBJECTIVES: We aimed to determine whether supplemental protein and multinutrient supplementation improved wound healing markers after acute stress induced by acute sleep restriction. METHODS: In this single-blind, crossover study in generally healthy young adults (18 males/2 females; mean ± SD age: 19.7 ± 2.30 y), experimental wounds were created by removing the top layer of forearm blisters induced via suction after 48 h of 72-h sleep restriction (2-h nightly sleep), a protocol previously shown to delay wound healing. Skin barrier restoration (measured by transepidermal water loss) assessed wound healing ≤10 d postblistering, and local immune responses were evaluated by serial measurement of cytokine concentrations in fluid collected at wound sites for 48 h postblistering. Participants consumed controlled, isocaloric diets with either 0.900 g · kg-1 · d-1 protein plus placebo (PLA) or 1.50 g · kg-1 · d-1 protein plus multinutrient beverage [l-arginine: 20.0 g/d; l-glutamine: 30.0 g/d; omega-3 (n-3) fatty acids: 1.00 g/d; zinc sulfate: 24.0 mg/d; cholecalciferol: 800 IU/d; and vitamin C: 400 mg/d] (NUT) during sleep restriction and for 4 d afterwards. RESULTS: Skin barrier restoration (primary outcome) was shorter for NUT (median: 3.98 d; IQR: 1.17 d) than for PLA (median: 5.25 d; IQR: 1.05 d) (P = 0.001). Cytokines from wound fluid (secondary outcome) increased over time (main effect of time P ≤ 0.001), except IL-13 (P = 0.07); however, no effects of treatment were observed. CONCLUSIONS: Supplemental nutrition may promote wound healing after sleep restriction in healthy adults including military personnel, the latter of which also have a high incidence of wounds and infection.This trial was registered at clinicaltrials.gov as NCT03525184.
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Ácidos Graxos Ômega-3 , Cicatrização , Adolescente , Adulto , Bebidas , Estudos Cross-Over , Citocinas , Feminino , Humanos , Masculino , Poliésteres/farmacologia , Método Simples-Cego , Sono , Adulto JovemRESUMO
Enhancing dietary omega-3 highly unsaturated fatty acids (n-3 HUFA) intake may confer neuroprotection, brain resiliency, improve wound healing and promote cardiovascular health. This study determined the efficacy of substituting a few common foods (chicken meat, chicken sausage, eggs, salad dressings, pasta sauces, cooking oil, mayonnaise, and peanut butter) lower in omega-6 polyunsaturated fatty acids (n-6 PUFA) and higher in n-3 HUFA in a dining facility on blood fatty acid profile. An eight-week prospective, between-subjects (n = 77), repeated measures, parallel-arm trial was conducted. Participants self-selected foods consumed from conventionally produced foods (control), or those lower n-6 PUFA and higher n-3 HUFA versions (intervention). Changes in blood omega-3 index, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), n-6 PUFA, lipid profile, and food satisfaction were main outcomes. Between-group differences over time were assessed using a linear mixed model to measure the effect of diet on blood serum fatty acids and inflammatory markers. The intervention group achieved a higher omega-3 index score (3.66 ± 0.71 vs. 2.95 ± 0.77; p < 0.05), lower total n-6 (10.1 ± 4.6 vs. 15.3 ± 6.7 µg/mL; p < 0.05), and higher serum concentration of EPA (5.0 ± 1.31 vs. 4.05 ± 1.56 µg/mL; p < 0.05) vs. controls. Satisfaction in intervention foods improved or remained consistent. Substitution of commonly eaten dining facility foods with like-items higher in DHA and EPA and lower in n-6 PUFA can favorably impact fatty acid status and the omega-3 index.
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Ácidos Graxos Ômega-3 , Militares , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Ácidos Graxos , Humanos , Estudos ProspectivosRESUMO
BACKGROUND: Mild traumatic brain injury (mTBI) is a signature wound of Veterans of operations in Iraq and Afghanistan (i.e., OIF/OEF/OND). Most Veterans with mTBI also experience stress-based psychopathology (e.g., depression, posttraumatic stress disorder) and chronic pain. This combination - referred to as polytrauma - results in detrimental long-term effects on social, occupational, and community reintegration. This study will compare the efficacy of a one-day Acceptance and Commitment Training plus Education, Resources, and Support (ACT+ERS) workshop to a one-day active control group (ERS) on symptoms of distress and social, occupational, and community reintegration. We will also examine mediators and moderators of treatment response. METHODS: This is an ongoing randomized clinical trial. 212 OIF/OEF/OND Veterans with polytrauma are being recruited. Veterans are randomly assigned to a one-day ACT+ERS or a one-day ERS workshop with two individualized booster sessions approximately two- and four-weeks post-workshop. Veterans complete assessments prior to the workshop and again at six weeks, three months, and six months post-workshop. Of note, workshops were converted to a virtual format due to the COVID-19 pandemic. RESULTS: The primary outcomes are symptoms of distress and reintegration; secondary outcomes are post-traumatic stress disorder symptoms and pain interference. Secondary analyses will assess whether changes in avoidance at three months mediate changes in distress and reintegration at six months. CONCLUSION: Facilitating the psychological adjustment and reintegration of Veterans with polytrauma is critical. The results of this study will provide important information about the impact of a brief intervention for Veterans with these concerns.
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COVID-19 , Traumatismo Múltiplo , Veteranos , Humanos , Traumatismo Múltiplo/terapia , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2RESUMO
Targeted bacteriophage (phage) particles are potentially attractive yet inexpensive platforms for immunization. Herein, we describe targeted phage capsid display of an immunogenically relevant epitope of the SARS-CoV-2 Spike protein that is empirically conserved, likely due to the high mutational cost among all variants identified to date. This observation may herald an approach to developing vaccine candidates for broad-spectrum, towards universal, protection against multiple emergent variants of coronavirus that cause COVID-19.
RESUMO
Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these "dual-display" phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.