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The number of diversity, equity, and inclusion (DEI) initiatives in science, technology, engineering, mathematics, and medicine (STEMM) have grown over the last few years. We asked several Black scientists what impact they have and why STEMM still needs them. They answer these questions and describe how DEI initiatives should evolve.
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População Negra , Engenharia , Humanos , TecnologiaRESUMO
B cells expressing potent and broadly neutralizing antibodies to HIV-1 have been found in many infected individuals, suggesting that adaptive immunity has the capacity to defeat viral escape. Gao et al. uncover an intermediate stage in this process when viral escape from one "helper" B cell lineage selects variants that drive a separate B cell lineage toward broad neutralization.
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Vacinas contra a AIDS/química , Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/fisiologiaRESUMO
Effective vaccines induce high-affinity memory B cells and durable antibody responses through accelerated mechanisms of natural selection. Secondary changes in antibody repertoires after vaccine boosts suggest progressive rediversification of B cell receptors (BCRs), but the underlying mechanisms remain unresolved. Here, the integrated specificity and function of individual memory B cell progeny revealed ongoing evolution of polyclonal antibody specificities through germinal center (GC)-specific transcriptional activity. At the clonal and subclonal levels, single-cell expression of the genes encoding the costimulatory molecule CD83 and the DNA polymerase Polη segregated the secondary GC transcriptional program into four stages that regulated divergent mechanisms of memory BCR evolution. Our studies demonstrate that vaccine boosts reactivate a cyclic program of GC function in class-switched memory B cells to remodel existing antibody specificities and enhance durable immunological protection.
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Linfócitos B/imunologia , Centro Germinativo/imunologia , Memória Imunológica/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Anticorpos/imunologia , Formação de Anticorpos/imunologia , Antígenos CD/imunologia , DNA Polimerase Dirigida por DNA/imunologia , Switching de Imunoglobulina/imunologia , Imunoglobulinas/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Gênica/imunologia , Antígeno CD83RESUMO
RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. Although the roles of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using two distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered some GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin positive. The increase in somatostatin-positive interneurons could also be prevented by pharmacological inhibition of the core RAS/MAPK signaling pathway. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes and related disorders.
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Transdução de Sinais , Somatostatina , Alelos , Somatostatina/genética , Somatostatina/metabolismo , Transdução de Sinais/genética , Sistema de Sinalização das MAP Quinases/genética , Interneurônios/metabolismo , Neurônios GABAérgicos/metabolismoRESUMO
Type 1 interferons (IFNs) promote inflammation in the skin but the mechanisms responsible for inducing these cytokines are not well understood. We found that IFN-ß was abundantly produced by epidermal keratinocytes (KCs) in psoriasis and during wound repair. KC IFN-ß production depended on stimulation of mitochondrial antiviral-signaling protein (MAVS) by the antimicrobial peptide LL37 and double stranded-RNA released from necrotic cells. MAVS activated downstream TBK1 (TANK-Binding Kinase 1)-AKT (AKT serine/threonine kinase 1)-IRF3 (interferon regulatory factor 3) signaling cascade leading to IFN-ß production and then promoted maturation of dendritic cells. In mice, the production of epidermal IFN-ß by LL37 required MAVS, and human wounded and/or psoriatic skin showed activation of MAVS-associated IRF3 and induction of MAVS and IFN-ß gene signatures. These findings show that KCs are an important source of IFN-ß and MAVS is critical to this function, and demonstrates how the epidermis triggers unwanted skin inflammation under disease conditions.
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Catelicidinas/metabolismo , Células Dendríticas/fisiologia , Epiderme/patologia , Queratinócitos/imunologia , Mitocôndrias/metabolismo , Psoríase/imunologia , Ferimentos e Lesões/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/genética , Diferenciação Celular , Células Cultivadas , Humanos , Interferon beta/metabolismo , Camundongos , Camundongos Knockout , RNA Interferente Pequeno/genética , Transdução de Sinais , CicatrizaçãoRESUMO
Antibodies are produced across multiple isotypes with distinct properties that coordinate initial antigen clearance and confer long-term antigen-specific immune protection. Here, we interrogate the molecular programs of isotype-specific murine plasma cells (PC) following helper T cell-dependent immunization and within established steady-state immunity. We developed a single-cell-indexed and targeted molecular strategy to dissect conserved and divergent components of the rapid effector phase of antigen-specific IgM+ versus inflammation-modulating programs dictated by type 1 IgG2a/b+ PC differentiation. During antibody affinity maturation, the germinal center (GC) cycle imparts separable programs for post-GC type 2 inhibitory IgG1+ and type 1 inflammatory IgG2a/b+ PC to direct long-term cellular function. In the steady state, two subsets of IgM+ and separate IgG2b+ PC programs clearly segregate from splenic type 3 IgA+ PC programs that emphasize mucosal barrier protection. These diverse isotype-specific molecular pathways of PC differentiation control complementary modules of antigen clearance and immune protection that could be selectively targeted for immunotherapeutic applications and vaccine design.
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Diferenciação Celular , Centro Germinativo , Plasmócitos , Animais , Antígenos , Imunoglobulina G/genética , Imunoglobulina M , Camundongos , Plasmócitos/citologia , Análise de Célula Única , Linfócitos T Auxiliares-IndutoresRESUMO
PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.
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Vacina BCG , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/mortalidade , Masculino , Feminino , Vacina BCG/administração & dosagem , Vacina BCG/uso terapêutico , Administração Intravesical , Seguimentos , Idoso , Pessoa de Meia-Idade , Carcinoma in Situ/patologia , Carcinoma in Situ/terapia , Carcinoma in Situ/tratamento farmacológico , Invasividade Neoplásica , Resultado do Tratamento , Adenoviridae/genética , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
Antibody class defines function in B cell immunity, but how class is propagated into B cell memory remains poorly understood. Here we demonstrate that memory B cell subsets unexpectedly diverged across antibody class through differences in the effects of major transcriptional regulators. Conditional genetic deletion of the gene encoding the transcription factor T-bet selectively blocked the formation and antigen-specific response of memory B cells expressing immunoglobulin G2a (IgG2a) in vivo. Cell-intrinsic expression of T-bet regulated expression of the transcription factor STAT1, steady-state cell survival and transcription of IgG2a-containing B cell antigen receptors (BCRs). In contrast, the transcription factor RORα and not T-bet was expressed in IgA(+) memory B cells, with evidence that knockdown of RORα mRNA expression and chemical inhibition of transcriptional activity also resulted in lower survival and BCR expression of IgA(+) memory B cells. Thus, divergent transcriptional regulators dynamically maintain subset integrity to promote specialized immune function in class-specific memory B cells.
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Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos B/classificação , Citometria de Fluxo , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/química , RNA Mensageiro/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores de Antígenos de Linfócitos B/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/imunologia , Organismos Livres de Patógenos Específicos , Proteínas com Domínio T/genética , Transcrição Gênica/imunologiaRESUMO
Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.
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Linfoma de Célula do Manto , Masculino , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Linfoma de Célula do Manto/patologia , Pirimidinas , Estudos Retrospectivos , Pirazóis/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do Tratamento , Sistema Nervoso Central/patologiaRESUMO
BACKGROUND: Patients undergoing arteriovenous (AV) access creation for hemodialysis often have significant comorbidities. Our goal was to quantify the long-term survival and associated risks factors for long-term mortality in these patients to aid in optimization of goals and expectations. METHODS: The Vascular Implant Surveillance and Interventional Outcomes Network Vascular Quality Initiative Medicare linked data was used to assess long-term survival in the HD registry. Demographics, comorbidities, and interventions were recorded. Because the majority of hemodialysis patients are provided Medicare, Medicare linkage was used to obtain survival data. Multivariable analysis was used to identify independent associations with mortality. RESULTS: There were 13,945 AV access patients analyzed including 10,872 (78%) AV fistulas and 3073 (22%) AV grafts. The median age was 67 years and 56% of patients were male. Approximately one-third had a prior AV access and 44.7% had prior tunneled dialysis catheters. Patients receiving an AV fistula, compared with AV grafts, were more often younger, male, White, obese, independently ambulatory, preoperatively living at home, and less often have a prior AV access and tunneled dialysis catheters (P < .05 for all). The 5-year mortality overall was 62.9% with 61.2% for AV fistulas and 68.8% for AV grafts (P < .001). On multivariable analysis for 5 year mortality, nonambulatory status (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.53-1.83; P < .001), lower extremity access (HR, 1.67; 95% CI, 1.35-2.05; P < .001), human immunodeficiency virus or acquired immunodeficiency syndrome (HR, 1.44; 95% CI, 1.13-1.82; P < .001), White race (HR, 1.43; 95% CI, 1.35-1.51; P < .001), congestive heart failure (HR, 1.33; 95% CI, 1.26-1.41; P < .001), chronic obstructive pulmonary disease (HR, 1.23; 95% CI, 1.15-1.31; P < .001), and AV graft placement (HR, 1.12; 95% CI, 1.02-1.23, P = .016) were most associated with poor survival. Factors associated with improved survival were never smoking (HR, .73; 95% CI, 0.67-0.79; P < .001), prior/quit smoking (HR, .78; 95% CI, 0.72-0.84; P < .001), preoperative home living (HR, .75; 95% CI, 0.68-0.83; P < .001), and hypertension (HR, .89; 95% CI, 0.8-0.99; P = .03). CONCLUSIONS: Long-term survival in Medicare patients undergoing AV access creation is poor with nearly two-thirds of patients having died at 5 years. There are many modifiable risk factors that may improve survival in these patients and give an opportunity for transplantation.
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Derivação Arteriovenosa Cirúrgica , Fístula , Falência Renal Crônica , Idoso , Humanos , Masculino , Estados Unidos/epidemiologia , Feminino , Estudos Retrospectivos , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Medicare , Diálise Renal/efeitos adversos , Fatores de Risco , Fístula/complicações , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Resultado do TratamentoRESUMO
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.
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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 , AdultoRESUMO
BACKGROUND: High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB100-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a). METHODS: Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting. RESULTS: The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis. CONCLUSIONS: These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.
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Anexina A2 , Plasminogênio , Humanos , Plasminogênio/química , Plasminogênio/metabolismo , Lipoproteína(a)/metabolismo , Anexina A2/genética , Dextranos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Transporte , Apolipoproteínas A/metabolismoRESUMO
OBJECTIVE: To characterize the greatest problem or need among individuals with a history of traumatic brain injury (TBI), as compared to individuals with a history of other neurological conditions, mental health conditions, and no history of neurological or mental health conditions. DESIGN: A directed content analysis of open-text responses to a single online survey question using a framework guided by the Mayo-Portland Adaptability Inventory-4. SETTING: Community. PARTICIPANTS: 2,861 community-dwelling adults (nâ¯=â¯274 with TBI; nâ¯=â¯289 with other neurological conditions besides TBI; nâ¯=â¯454 with mental health conditions but no neurological conditions; nâ¯=â¯1,844 controls). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Open-text responses to the survey prompt: "What was your greatest problem or need over the past 2 weeks?" RESULTS: The Participation index comprised the greatest proportion of responses across all four participant groups. A quarter (25.4%) of controls reported None (no problem/need), whereas only 7.9 -10.7% of participants in all other groups reported None. Among all groups, individuals with TBI reported the greatest proportion of problems in the Adjustment and Ability indices. Among people with TBI, Money Management (19.7%), None (10.6%), and Anxiety (7.7%) were the three most frequently reported problems. Compared to individuals with mild TBI (mTBI), individuals with moderate-to-severe TBI (msTBI) reported a higher proportion of problems in the Ability and Adjustment indices. Among individuals with msTBI, the Adjustment index accounted for the greatest proportion of problems. CONCLUSIONS: This study employed a person-centered approach to understanding the greatest needs among individuals with TBI. Qualitative differences were observed between individuals with and without a TBI, between people with mTBI and msTBI, and across genders among people with TBI. These findings can help guide research and policy towards addressing challenges perceived as highly important by people living in the community with TBI.
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BACKGROUND: Significant tricuspid regurgitation (TR) is a predictor of right heart failure (RHF) and increased mortality following left ventricular assist device (LVAD) implantation, however the benefit of tricuspid valve surgery (TVS) at the time of LVAD implantation remains unclear. This study compares early and late mortality and RHF outcomes in patients with significant TR undergoing LVAD implantation with and without concomitant TVS. METHODS: A systematic search of four electronic databases was conducted for studies comparing patients with moderate or severe TR undergoing LVAD implantation with or without concomitant TVS. Meta-analysis was performed for primary outcomes of early and late mortality and RHF. Secondary outcomes included rate of stroke, renal failure, hospital and ICU length of stay. An overall survival curve was constructed using aggregated, reconstructed individual patient data from Kaplan-Meier (KM) curves. RESULTS: Nine studies included 575 patients that underwent isolated LVAD and 308 patients whom received concomitant TVS. Both groups had similar rates of severe TR (46.5% vs. 45.6%). There was no significant difference seen in risk of early mortality (RR 0.90; 95% CI, 0.57-1.42; p = 0.64; I2 = 0%) or early RHF (RR 0.82; 95% CI, 0.66-1.19; p = 0.41; I2 = 57) and late outcomes remained comparable between both groups. The aggregated KM curve showed isolated LVAD to be associated with overall increased survival (HR 1.42; 95% CI, 1.05-1.93; p = 0.023). CONCLUSIONS: Undergoing concomitant TVS did not display increased benefit in terms of early or late mortality and RHF in patients with preoperative significant TR. Further data to evaluate the benefit of concomitant TVS stratified by TR severity or by other predictors of RHF will be beneficial.
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OBJECTIVE: To identify neurobehavioral symptom profiles among persons with chronic traumatic brain injury (TBI) using the Behavioral Assessment Screening Tool (BAST) and to consider participant characteristics that differ between profile groups. SETTING: Community. PARTICIPANTS: Participants (n = 615) were English-speaking adults (≥18) and had a self-reported history of at least one TBI of any severity. DESIGN: Secondary analysis of cross-sectional data. MAIN MEASURES: The BAST measures neurobehavioral symptoms in the domains of Negative Affect, Fatigue, Executive Dysfunction, Impulsivity, and Substance Misuse. RESULTS: Using latent profile analysis (LPA), we identified 3 different neurobehavioral profiles. Overall symptom frequency and differences in the pattern of symptom frequency across domains differentiated the profile groups. Average domain scores differed significantly across the profiles (P < .001) for all domains except Fatigue (P = .076). Those in profile 3 (High-Risk group) reported the most frequent symptoms across all domains (similar Negative Affect frequency as profile 1). Substance Misuse was especially high in this group. Compared to profile 2 (High Negative Affect group), participants in profile 1 (Moderate-Risk group) endorsed significantly more frequent (and more variable) symptoms across all BAST domains, particularly Impulsivity and Substance Misuse. Participants in profile 2 endorsed the least frequent symptoms across all domains. Demographic comparison showed that groups differed based on gender, age, and injury severity (mild vs moderate-severe), with profile 3 composed of the most men and the most persons in early adulthood, and profile 2 composed of the most women and those with mild TBI. CONCLUSIONS: We differentiated 3 neurobehavioral symptom profiles among persons with chronic TBI and determined differences in sociodemographic factors between the groups. Future research should focus on validating these profiles in another sample of individuals with chronic TBI. Characterizing persons according to multidimensional symptom profiles could allow for more tailored approaches to predict and prevent long-term negative outcomes.
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OBJECTIVES: To determine the association between self-reported emotional and cognitive symptoms and participation outcomes in chronic traumatic brain injury (TBI) and to explore the relative contribution of self-reported versus performance-based cognition to participation outcomes. SETTING: Community. PARTICIPANTS: Community-dwelling adults ( n = 135) with a lifetime history of mild to severe TBI. DESIGN: Secondary analysis of a cross-sectional study on neurobehavioral symptoms in chronic TBI. MAIN MEASURES: Behavioral Assessment Screening Tool (BAST) (Negative Affect, Fatigue, Executive Dysfunction, Impulsivity, Substance Abuse subscales) measured self-reported neurobehavioral symptoms; Participation Assessment with Recombined Tools (Productivity, Social Relations, and Out and About) measured self-reported participation outcomes; and Brief Test of Adult Cognition by Telephone (BTACT) measured performance-based cognition (Episodic Memory and Executive Function summary scores) in a subsample ( n = 40). RESULTS: The BAST Executive Dysfunction was significantly associated with less frequent participation and had the strongest effect on participation in all participation domains. No other BAST subscales were associated with participation, after adjusting for all subscale scores and age, with the exception of BAST Impulsivity, which was associated with more frequent Social Relationships. Exploratory analysis in the sample including the BTACT revealed that, after accounting for subjective Executive Dysfunction using the BAST, performance-based Executive Function was associated with Productivity and Working Memory was associated with Social Relations, but neither was associated with being Out and About; the BAST Executive Dysfunction remained significant in all models even after including BTACT scores. CONCLUSIONS: Self-reported Executive Dysfunction contributed to participation outcomes after mild to severe TBI in community-dwelling adults, whereas self-reported emotional and fatigue symptoms did not. Performance-based cognition measures may capture different variability in participation after injury.
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Lesões Encefálicas Traumáticas , Cognição , Adulto , Humanos , Estudos Transversais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Participação da Comunidade , FadigaRESUMO
A key role of chromatin kinases is to phosphorylate histone tails during mitosis to spatiotemporally regulate cell division. Vaccinia-related kinase 1 (VRK1) is a serine-threonine kinase that phosphorylates histone H3 threonine 3 (H3T3) along with other chromatin-based targets. While structural studies have defined how several classes of histone-modifying enzymes bind to and function on nucleosomes, the mechanism of chromatin engagement by kinases is largely unclear. Here, we paired cryo-electron microscopy with biochemical and cellular assays to demonstrate that VRK1 interacts with both linker DNA and the nucleosome acidic patch to phosphorylate H3T3. Acidic patch binding by VRK1 is mediated by an arginine-rich flexible C-terminal tail. Homozygous missense and nonsense mutations of this acidic patch recognition motif in VRK1 are causative in rare adult-onset distal spinal muscular atrophy. We show that these VRK1 mutations interfere with nucleosome acidic patch binding, leading to mislocalization of VRK1 during mitosis, thus providing a potential new molecular mechanism for pathogenesis.
Assuntos
Histonas , Nucleossomos , Cromatina/genética , Microscopia Crioeletrônica , DNA/genética , DNA/metabolismo , Histonas/genética , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Fosforilação , Proteínas Serina-Treonina Quinases , Treonina/metabolismoRESUMO
Introduction: Initial continuous intravenous (CIV) tacrolimus (0.03 mg/kg/day based on ideal body weight [IBW]) has been favored for graft versus host disease (GVHD) prevention in allogeneic stem cell transplant patients due to the consistent, steady-state degree of immunosuppression; however, this method poses many logistical challenges. We implemented intermittent (IIV) tacrolimus at a starting dose of 0.015 mg/kg IBW twice daily over 4â h. To our knowledge this is the first retrospective comparison of CIV to IIV tacrolimus. Objectives: The primary objective was to evaluate the safety of IIV tacrolimus in comparison to CIV with respect to nephrotoxicity and neurotoxicity. The secondary objectives were to compare the incidence of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at day +180, outcomes including relapse and overall survival, cell engraftment, and reactivation of cytomegalovirus and Epstein-Barr virus. Methods: This retrospective, single-center review evaluated adults who received an allogeneic stem cell transplant patients between January 1, 2020, and December 31, 2022. Results: Fifty-one unique patients were eligible for evaluation - 28 in the IIV cohort and 23 in the CIV group. The number of patients who developed nephrotoxicity and neurotoxicity were comparable between groups with no significant differences noted. No severe neurotoxicity was identified in either population. Secondary objectives revealed no significant difference in GVHD incidence or survival outcomes. Conclusion: IIV tacrolimus is comparable to CIV in terms of safety while also maintaining similar outcomes at day +180. IIV is a safe and feasible alternative to CIV in adult allogeneic stem cell transplant recipients.
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The incidence of human illness due to Salmonella Infantis reported to Foodborne Diseases Active Surveillance Network and the prevalence of Infantis on chicken carcasses reported by the United States Department of Agriculture Food Safety and Inspection Service have increased significantly in the past decade. However, the trends do not appear coincident, as would be expected if the increased prevalence in chicken led to the increase in the incidence of human illness. Salmonella Infantis incidence and prevalence trends are analyzed using penalized B-spline methods for generalized additive regression models. The association between the two time series is analyzed using time-lagged rank-order cross-correlation. Geographic variations in reported incidence and trends are also explored. The increase in human incidence of Salmonella Infantis began circa 2011. The increase in chicken carcass prevalence began circa 2015. A 4-year lag on chicken carcass prevalence maximizes the rank-order cross-correlation with the incidence of illness. While chicken consumption undoubtedly contributes to the incidence of human illness due to Salmonella Infantis, the initial increase in reported illness was likely due to one or more other transmission pathways. Other potential transmission pathways include non-chicken foodborne, waterborne, person-to-person, animal contact, and environmental.
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A reliable non-invasive biomarker for endometriosis is highly likely in the coming years. In the lead-up to this, clinicians need to be aware of commercially available tests as they become accessible, be aware of the level of evidence to support them and be prepared to counsel and manage patients who present with the results of such tests. One such test gaining popularity in Europe was developed using a machine-based learning algorithm to analyse thousands of microRNAs based on a 200-patient cohort with suspected endometriosis in France. We explore the background science for this commercially available test; outline the questions that remain to be answered; and caution against its use outside of a research setting.