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1.
Cureus ; 16(5): e60436, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38883003

RESUMO

OBJECTIVE: To investigate the perspectives of pediatric otolaryngologists on the impact of the coronavirus disease 2019 (COVID-19) pandemic on their research. METHODS: Two surveys were sent to members of the American Society of Pediatric Otolaryngology (ASPO) in 2019 and 2021 to assess research perspectives before and during the COVID-19 pandemic. The surveys contained questions about research engagement, barriers, time allocation, and shifts in research focus. RESULTS: The COVID-19 pandemic reshaped research within pediatric otolaryngology, with a mixed impact on the amount of time allocated to research endeavors. Almost half of respondents reported a change in research focus to COVID-19-related studies. Protected time and funding were significant pre-pandemic barriers, whereas reduced staff, collaboration opportunities, and enrollment limitations emerged as key pandemic-related obstacles. A personal commitment to research was most strongly correlated with time spent on this endeavor. During the pandemic, women were less likely to report an increase in research activity when compared to men, possibly due to a disproportionate burden of caregiving on women during school closures and stay-at-home orders. CONCLUSION: Overall, the pandemic prompted both increases and decreases in research time allocation, depending on individual circumstances and priorities. Despite new challenges, pediatric otolaryngologists remain committed to research and have continued to remain productive.

2.
Dev Cogn Neurosci ; 68: 101399, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38875770

RESUMO

One in three children in the United States is exposed to insecure housing conditions, including unaffordable, inconsistent, and unsafe housing. These exposures have detrimental impacts on youth mental health. Delineating the neurobehavioral pathways linking exposure to housing insecurity with children's mental health has the potential to inform interventions and policy. However, in approaching this work, carefully considering the lived experiences of youth and families is essential to translating scientific discovery to improve health outcomes in an equitable and representative way. In the current paper, we provide an introduction to the range of stressful experiences that children may face when exposed to insecure housing conditions. Next, we highlight findings from the early-life stress literature regarding the potential neurobehavioral consequences of insecure housing, focusing on how unpredictability is associated with the neural circuitry supporting cognitive and emotional development. We then delineate how community-engaged research (CEnR) approaches have been leveraged to understand the effects of housing insecurity on mental health, and we propose future research directions that integrate developmental neuroscience research and CEnR approaches to maximize the impact of this work. We conclude by outlining practice and policy recommendations that aim to improve the mental health of children exposed to insecure housing.

3.
J Mol Biol ; 436(16): 168640, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38844044

RESUMO

Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how Protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.

4.
J Clin Child Adolesc Psychol ; 53(3): 503-522, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38830059

RESUMO

Despite advances in clinical science, the burden of mental health problems among youth is not improving. To tackle this burden, clinical science with youth needs methods that include youth and family perspectives on context and public health. In this paper, we illustrate how community-engaged research (CEnR) methods center these perspectives. Although CEnR methods are well-established in other disciplines (e.g. social work, community psychology), they are underutilized in clinical science with youth. This is due in part to misperceptions of CEnR as resource-intensive, overly contextualized, incompatible with experimentally controlled modes of inquiry, or irrelevant to understanding youth mental health. By contrast, CEnR methods can provide real-world impact, contextualized clinical solutions, and sustainable outcomes. A key advantage of CEnR strategies is their flexibility-they fall across a continuum that centers community engagement as a core principle, and thus can be infused in a variety of research efforts, even those that center experimental control (e.g. randomized controlled trials). This paper provides a brief overview of this continuum of strategies and its application to youth-focused clinical science. We then discuss future directions of CEnR in clinical science with youth, as well as structural changes needed to advance this work. The goals of this paper are to help demystify CEnR and encourage clinical scientists to consider adopting methods that better consider context and intentionally engage the communities that our work seeks to serve.


Assuntos
Pesquisa Participativa Baseada na Comunidade , Humanos , Adolescente , Criança , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Saúde Mental
5.
Nat Commun ; 15(1): 5028, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866748

RESUMO

Cholesterol-dependent cytolysins (CDCs) comprise a large family of pore-forming toxins produced by Gram-positive bacteria, which are used to attack eukaryotic cells. Here, we functionally characterize a family of 2-component CDC-like (CDCL) toxins produced by the Gram-negative Bacteroidota that form pores by a mechanism only described for the mammalian complement membrane attack complex (MAC). We further show that the Bacteroides CDCLs are not eukaryotic cell toxins like the CDCs, but instead bind to and are proteolytically activated on the surface of closely related species, resulting in pore formation and cell death. The CDCL-producing Bacteroides is protected from the effects of its own CDCL by the presence of a surface lipoprotein that blocks CDCL pore formation. These studies suggest a prevalent mode of bacterial antagonism by a family of two-component CDCLs that function like mammalian MAC and that are wide-spread in the gut microbiota of diverse human populations.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento , Humanos , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Bacteroides/genética , Bacteroides/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Citotoxinas/metabolismo , Microbioma Gastrointestinal , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/imunologia , Animais , Células Eucarióticas/metabolismo
6.
J Behav Health Serv Res ; 51(3): 395-420, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38698193

RESUMO

The onset of the COVID-19 pandemic saw a significant surge in the utilization of telemental health (TMH) services. This narrative review aimed to investigate the efficacy of TMH for serious mood disorders prior to the COVID-19 pandemic. A search across databases was conducted for randomized controlled trials focusing on TMH interventions for mood disorders, encompassing major depressive disorder (MDD) and bipolar disorder (BD). Study and patient characteristics, interventions, and outcomes were extracted. From a pool of 2611 papers initially identified, 17 met the inclusion criteria: 14 focused on MDD, while 4 addressed BD. Among these, 6 papers directly compared TMH interventions to in-person of same treatment, revealing improved access to care and higher rates of appointment follow-up with TMH. Additionally, 6 papers comparing TMH to treatment as usual demonstrated improvements in mood outcomes. Conversely, 3 papers comparing different TMH interventions found no discernible differences in outcomes. Notably, 3 studies evaluated TMH as an adjunct to usual care, all reporting enhancements in depression outcomes. Overall, preliminary evidence suggests that prior to COVID-19, TMH interventions for serious mood disorders facilitated improved access to care and follow-up, with comparable clinical outcomes to traditional in-person interventions. The discussion addresses limitations and provides recommendations for future research in this domain.


Assuntos
COVID-19 , Transtornos do Humor , Telemedicina , Humanos , COVID-19/psicologia , Transtornos do Humor/terapia , Transtornos do Humor/psicologia , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/psicologia , Pandemias , Transtorno Bipolar/terapia , Transtorno Bipolar/psicologia , Serviços de Saúde Mental , SARS-CoV-2 , Resultado do Tratamento , Telessaúde Mental
7.
bioRxiv ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38712280

RESUMO

Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.

8.
Nucleic Acids Res ; 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38797520

RESUMO

Whole-genome bisulfite sequencing (BS-Seq) measures cytosine methylation changes at single-base resolution and can be used to profile cell-free DNA (cfDNA). In plasma, ultrashort single-stranded cfDNA (uscfDNA, ∼50 nt) has been identified together with 167 bp double-stranded mononucleosomal cell-free DNA (mncfDNA). However, the methylation profile of uscfDNA has not been described. Conventional BS-Seq workflows may not be helpful because bisulfite conversion degrades larger DNA into smaller fragments, leading to erroneous categorization as uscfDNA. We describe the '5mCAdpBS-Seq' workflow in which pre-methylated 5mC (5-methylcytosine) single-stranded adapters are ligated to heat-denatured cfDNA before bisulfite conversion. This method retains only DNA fragments that are unaltered by bisulfite treatment, resulting in less biased uscfDNA methylation analysis. Using 5mCAdpBS-Seq, uscfDNA had lower levels of DNA methylation (∼15%) compared to mncfDNA and was enriched in promoters and CpG islands. Hypomethylated uscfDNA fragments were enriched in upstream transcription start sites (TSSs), and the intensity of enrichment was correlated with expressed genes of hemopoietic cells. Using tissue-of-origin deconvolution, we inferred that uscfDNA is derived primarily from eosinophils, neutrophils, and monocytes. As proof-of-principle, we show that characteristics of the methylation profile of uscfDNA can distinguish non-small cell lung carcinoma from non-cancer samples. The 5mCAdpBS-Seq workflow is recommended for any cfDNA methylation-based investigations.

9.
Transl Anim Sci ; 8: txae064, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38770036

RESUMO

In March 2020, the World Health Organization declared COVID-19 a pandemic, which ultimately led to many meat processors temporarily shutting down or reducing processing capacity. This backlog in processing capacity forced many feedlots to retain cattle for longer periods of time and assume the risk of major market fluctuations. The aim of this study was to understand how a dietary insult affects meat quality and muscle metabolism in market-ready steers (590 kg). Sixteen market-ready (590 kg) commercial Angus crossbred steers were subjected to a maintenance diet of either forage or grain for 60 d. Longissimus lumborum (LL) muscle samples were collected immediately postmortem and processed for characteristics reflecting the underlying muscle fiber type and energy state of the tissue. Despite cattle being subjected to a 60-d feeding period, there were no detectable differences (P > 0.05) in carcass characteristics, color of lean, or ultimate pH (pHu). Moreover, our data show that muscle plasticity is rather resilient, as reflected by lack of significance (P > 0.05) in oxidative and glycolytic enzymes, myosin heavy chain isoforms (MyHC), myoglobin, and mitochondrial DNA (mtDNA) contents. These data show that market-ready steers are capable of withstanding a low-input feeding strategy up to 60 d without dramatically impacting underlying muscle characteristics and meat quality development.

10.
Eat Disord ; : 1-22, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38814278

RESUMO

BACKGROUND: Self-stigma of seeking psychological help is a critical factor prohibiting individuals from seeking eating disorder (ED) treatment, but has been widely unexplored in racial/ethnic and sexual minority (SM) samples. The current study examined differences in ED pathology and self-stigma of help-seeking at the intersection of race and gender within a cisgender SM sample. METHODS: Cisgender SM participants (n = 354) identifying as Black, Indigenous, or People of Color (BIPOC; 52%), Asian American and Pacific Islander (AAPI; 24%), or White (24%) were recruited through Prolific Academic. One-way analyses of variance were used to examine differences in the Self-Stigma of Seeking Help Scale (SSOSH) and Eating Pathology Symptom Inventory (EPSI) subscales among men and women in each group. Pearson's correlations explored associations between SSOSH and EPSI subscales within each subgroup. RESULTS: Findings indicated significant between-group differences on the SSOSH and the EPSI subscales of Body Dissatisfaction, Purging, and Excessive Exercise. SSOSH was significantly positively correlated with Body Dissatisfaction in the White SM cis-women group and Binge Eating in the BIPOC SM cis-men group. CONCLUSIONS: Results demonstrate unique, intersectional between-group differences in ED pathology and self-stigma among SM individuals. Further research on the impact of intersectionality on these constructs within larger samples is warranted.

11.
Cureus ; 16(3): e56463, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38638782

RESUMO

Giant colonic diverticulum (GCD) is a well-recognized but infrequently encountered disease in clinical practice. GCD is its own unique entity and differs from commonly seen diverticular disease in both size and management. Initial clinical presentation is typically associated with diverticulitis and symptoms such as abdominal pain, fever, nausea, vomiting, rectal bleeding, or even a palpable abdominal mass. Surgery is the recommended treatment option largely due to the risk of associated complications including colonic perforation. We describe the case of a 56-year-old female diagnosed with a sigmoid GCD that was successfully stabilized medically and definitively treated surgically.

12.
Br J Surg ; 111(4)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38662462

RESUMO

BACKGROUND: The purpose of this study was to compare 3-year overall survival after simultaneous portal (PVE) and hepatic vein (HVE) embolization versus PVE alone in patients undergoing liver resection for primary and secondary cancers of the liver. METHODS: In this multicentre retrospective study, all DRAGON 0 centres provided 3-year follow-up data for all patients who had PVE/HVE or PVE, and were included in DRAGON 0 between 2016 and 2019. Kaplan-Meier analysis was undertaken to assess 3-year overall and recurrence/progression-free survival. Factors affecting survival were evaluated using univariable and multivariable Cox regression analyses. RESULTS: In total, 199 patients were included from 7 centres, of whom 39 underwent PVE/HVE and 160 PVE alone. Groups differed in median age (P = 0.008). As reported previously, PVE/HVE resulted in a significantly higher resection rate than PVE alone (92 versus 68%; P = 0.007). Three-year overall survival was significantly higher in the PVE/HVE group (median survival not reached after 36 months versus 20 months after PVE; P = 0.004). Univariable and multivariable analyses identified PVE/HVE as an independent predictor of survival (univariable HR 0.46, 95% c.i. 0.27 to 0.76; P = 0.003). CONCLUSION: Overall survival after PVE/HVE is substantially longer than that after PVE alone in patients with primary and secondary liver tumours.


Assuntos
Embolização Terapêutica , Hepatectomia , Veias Hepáticas , Neoplasias Hepáticas , Regeneração Hepática , Veia Porta , Humanos , Masculino , Feminino , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Estudos Retrospectivos , Embolização Terapêutica/métodos , Pessoa de Meia-Idade , Regeneração Hepática/fisiologia , Idoso , Hepatectomia/métodos , Taxa de Sobrevida , Análise de Sobrevida , Adulto
13.
Cell Rep ; 43(4): 114029, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38573852

RESUMO

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations.


Assuntos
Microbiota , Fenótipo , Linfócitos T , Animais , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Masculino , Feminino , Camundongos Endogâmicos C57BL
14.
Cureus ; 16(3): e55548, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38576673

RESUMO

Pyoderma gangrenosum (PG) and erythema nodosum (EN) are rare skin conditions associated with inflammatory bowel disease (IBD), with increasing incidence as the disease progresses. We describe three cases of newly diagnosed IBD with cutaneous extraintestinal manifestations (EIMs) at the time of diagnosis. Three previously healthy patients presented with bloody diarrhea and concomitant nodular and ulcerating skin lesions at the onset of diarrhea. Dermatopathology showed PG and EN with endoscopic confirmation of ulcerative colitis. Clinical improvement was achieved with steroids and biological agents. These cases display the importance of a proper review of symptoms and a detailed workup of dermatological lesions prior to assuming infectious etiology.

15.
Plast Reconstr Surg ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563527

RESUMO

BACKGROUND: Conflicting data exist regarding increased perioperative VTE risk while on feminizing hormone therapy. The effect has been poorly studied within the transgender population. Acute perioperative cessation of feminizing hormone therapy often leads to unpleasant side effects and exacerbates gender dysphoria in the perioperative period. We seek to identify the VTE incidence in patients undergoing facial feminization while continuing HRT throughout the time of surgery. METHODS: A 38-year retrospective cohort study within a two-surgeon practice (D.K.O. and J.C.D.) was designed to evaluate postoperative VTE in patients continuing hormone therapy. The primary outcome variable was identified as suffering a VTE postoperatively. RESULTS: 1,715 patients underwent facial feminization surgery within our search window. 953 patients met final inclusion criteria. 1 patient (0.10%) was diagnosed with a VTE postoperatively, comparable to reported literature rates for similar cosmetic and orthognathic procedures. The average Caprini score of all patients was 3.1±1.0 and the average case length was 491.9±111.0 minutes. Subgroup analysis of patients before and after internal practice changes identified 714 (77.7%) patients continuing full dose hormonal therapy perioperatively, 197 (20.7%) patients undergoing hormonal dose reduction to 25-50% perioperatively, and 8 patients who were either not taking hormonal therapy or stopped in the perioperative period. There was no significant difference in VTE incidence between the 3 subgroups (p > 0.99). CONCLUSIONS: Perioperative use of feminizing hormonal therapy does not increase risk for perioperative VTE in patients undergoing facial feminization surgery. Therefore, it is reasonable to continue these medications through the time of surgery.

16.
J Allergy Clin Immunol Glob ; 3(2): 100236, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38590754

RESUMO

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a spectrum of clinical outcomes that may be complicated by severe asthma. Antiviral immunity is often compromised in patients with asthma; however, whether this is true for SARS-CoV-2 immunity and children is unknown. Objective: We aimed to evaluate SARS-CoV-2 immunity in children with asthma on the basis of infection or vaccination history and compared to respiratory syncytial viral or allergen (eg, cockroach, dust mite)-specific immunity. Methods: Fifty-three children from an urban asthma study were evaluated for medical history, lung function, and virus- or allergen-specific immunity using antibody or T-cell assays. Results: Polyclonal antibody responses to spike were observed in most children from infection and/or vaccination history. Children with atopic asthma or high allergen-specific IgE, particularly to dust mites, exhibited reduced seroconversion, antibody magnitude, and SARS-CoV-2 virus neutralization after SARS-CoV-2 infection or vaccination. TH1 responses to SARS-CoV-2 and respiratory syncytial virus correlated with antigen-respective IgG. Cockroach-specific T-cell activation as well as IL-17A and IL-21 cytokines negatively correlated with SARS-CoV-2 antibodies and effector functions, distinct from total and dust mite IgE. Allergen-specific IgE and lack of vaccination were associated with recent health care utilization. Reduced lung function (forced expiratory volume in 1 second ≤ 80%) was independently associated with (SARS-CoV-2) peptide-induced cytokines, including IL-31, whereas poor asthma control was associated with cockroach-specific cytokine responses. Conclusion: Mechanisms underpinning atopic and nonatopic asthma may complicate the development of memory to SARS-CoV-2 infection or vaccination and lead to a higher risk of repeated infection in these children.

17.
Cureus ; 16(3): e55854, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38590480

RESUMO

Duplicated cystic ducts are a rare congenital malformation with less than 20 reported cases before 2019. This malformation is important to identify to reduce the risk of intraoperative complications such as bile duct injuries that can increase postoperative morbidity and mortality. We present the case of a 62-year-old male with duplicated cystic ducts that were ligated during laparoscopic cholecystectomy and subsequently complicated by postoperative biloma formation. Treatment options for biliary leak include endoscopic retrograde cholangiopancreatography (ERCP) with stenting, percutaneous drainage, and duct embolization. Each carries the risk of complications such as infection, duct perforation, and stent/drain displacement. Roux-en-Y hepaticojejunostomy (RHYJ) tends to be the last resort when other minimally invasive procedures fail. It is imperative to identify postoperative complications related to cystic duct anomalies and the various treatment options available should these complications occur.

18.
Front Oncol ; 14: 1332004, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38511142

RESUMO

In clinical oncology, cell-free DNA (cfDNA) has shown immense potential in its ability to noninvasively detect cancer at various stages and monitor the progression of therapy. Despite the rapid improvements in cfDNA liquid biopsy approaches, achieving the required sensitivity to detect rare tumor-derived cfDNA still remains a challenge. For next-generation sequencing, the perceived presentation of cfDNA is strongly linked to the extraction and library preparation protocols. Conventional double-stranded DNA library preparation (dsDNA-LP) focuses on assessing ~167bp double-stranded mononucleosomal (mncfDNA) and its other oligonucleosomal cell-free DNA counterparts in plasma. However, dsDNA-LP methods fail to include short, single-stranded, or nicked DNA in the final library preparation, biasing the representation of the actual cfDNA populations in plasma. The emergence of single-stranded library preparation (ssDNA-LP) strategies over the past decade has now allowed these other populations of cfDNA to be studied from plasma. With the use of ssDNA-LP, single-stranded, nicked, and ultrashort cfDNA can be comprehensively assessed for its molecular characteristics and clinical potential. In this review, we overview the current literature on applications of ssDNA-LP on plasma cfDNA from a potential cancer liquid biopsy perspective. To this end, we discuss the molecular principles of single-stranded DNA adapter ligation, how library preparation contributes to the understanding of native cfDNA characteristics, and the potential for ssDNA-LP to improve the sensitivity of circulating tumor DNA detection. Additionally, we review the current literature on the newly reported species of plasma ultrashort single-stranded cell-free DNA plasma, which appear biologically distinct from mncfDNA. We conclude with a discussion of future perspectives of ssDNA-LP for liquid biopsy endeavors.

19.
Front Immunol ; 15: 1341752, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38524125

RESUMO

Purpose: Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a highly heterogeneous syndrome with distinct phenotypes that impact immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct functional phenotypes of immune cells. In this study, we utilized our Organ-on-Chip assay to categorize sepsis patients into distinct phenotypes using patient data, neutrophil functional analysis, and proteomics. Methods: Following informed consent, neutrophils and plasma were isolated from sepsis patients in the Temple University Hospital ICU (n=45) and healthy control donors (n=7). Human lung microvascular endothelial cells (HLMVEC) were cultured in the Organ-on-Chip and treated with buffer or cytomix ((TNF/IL-1ß/IFNγ). Neutrophil adhesion and migration across HLMVEC in the Organ-on-Chip were used to categorize functional neutrophil phenotypes. Quantitative label-free global proteomics was performed on neutrophils to identify differentially expressed proteins. Plasma levels of sepsis biomarkers and neutrophil extracellular traps (NETs) were determined by ELISA. Results: We identified three functional phenotypes in critically ill ICU sepsis patients based on ex vivo neutrophil adhesion and migration patterns. The phenotypes were classified as: Hyperimmune characterized by enhanced neutrophil adhesion and migration, Hypoimmune that was unresponsive to stimulation, and Hybrid with increased adhesion but blunted migration. These functional phenotypes were associated with distinct proteomic signatures and differentiated sepsis patients by important clinical parameters related to disease severity. The Hyperimmune group demonstrated higher oxygen requirements, increased mechanical ventilation, and longer ICU length of stay compared to the Hypoimmune and Hybrid groups. Patients with the Hyperimmune neutrophil phenotype had significantly increased circulating neutrophils and elevated plasma levels NETs. Conclusion: Neutrophils and NETs play a critical role in vascular barrier dysfunction in sepsis and elevated NETs may be a key biomarker identifying the Hyperimmune group. Our results establish significant associations between specific neutrophil functional phenotypes and disease severity and identify important functional parameters in sepsis pathophysiology that may provide a new approach to classify sepsis patients for specific therapeutic interventions.


Assuntos
Neutrófilos , Sepse , Humanos , Neutrófilos/metabolismo , Células Endoteliais , Proteômica , Biomarcadores/metabolismo , Fenótipo , Gravidade do Paciente
20.
Eat Disord ; : 1-16, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38375554

RESUMO

Prior research has been conflicted on whether gay community involvement serves as a risk or protective factor for body image and eating disorders (EDs) in sexual minority men (SMM), perhaps given that prior research has examined community involvement unidimensionally. The present study examined whether non-appearance-based ("social activism") and appearance-based ("going out/nightlife") community involvement differentially predicted ED prevention outcomes in SMM. SMM (N = 73) enrolled in a randomized controlled trial of an ED prevention program completed measures of community involvement, drive for muscularity, body dissatisfaction, and bulimic symptoms at pre-intervention, post-intervention, and 1-month follow-up. "Social activism" community involvement moderated intervention effects for drive for muscularity and body dissatisfaction scores, but not bulimic symptoms, such that those who placed higher importance on social activism demonstrated expected improvements, while those who placed lower importance on social activism did not exhibit expected improvements. "Going out/nightlife" community involvement did not moderate intervention outcomes; however, greater importance of going out/nightlife was associated with increased body dissatisfaction. Findings support that the impact of community involvement on body image and ED risk for SMM may be nuanced. Encouraging community involvement through activism could help enhance ED prevention efforts for SMM.

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