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1.
J Am Coll Cardiol ; 83(7): 726-738, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38355242

RESUMO

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.


Assuntos
Técnica de Fontan , Cardiopatias Congênitas , Hepatopatias , Adulto , Humanos , Masculino , Feminino , Estudos Retrospectivos , Cirrose Hepática/genética , Cirrose Hepática/patologia , Hepatopatias/genética , Hepatopatias/cirurgia , Fibrose , Perfilação da Expressão Gênica , RNA , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgia
2.
Pediatr Nephrol ; 39(3): 837-847, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37752381

RESUMO

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in chronic kidney disease-mineral bone disorder and is associated with CKD progression and cardiovascular morbidity. Factors related to CKD-associated anemia, including iron deficiency, can increase FGF23 production. This study aimed to assess whether anemia and/or iron deficiency are associated with increased circulating concentrations of FGF23 in the large, well-characterized Chronic Kidney Disease in Children (CKiD) study cohort. METHODS: Hemoglobin concentrations, iron parameters, C-terminal (total) FGF23, intact FGF23, and relevant covariables were measured in cross-sectional analysis of CKiD study subjects. RESULTS: In 493 pediatric patients with CKD (median [interquartile range] age 13 [9, 16] years), the median estimated glomerular filtration rate was 48 [35, 61] ml/min/1.73 m2, and 103 patients (21%) were anemic. Anemic subjects had higher total FGF23 concentrations than non-anemic subjects (204 [124, 390] vs. 109 [77, 168] RU/ml, p < 0.001). In multivariable linear regression modeling, anemia was independently associated with higher total FGF23, after adjustment for demographic, kidney-related, mineral metabolism, and inflammatory covariables (standardized ß (95% confidence interval) 0.10 (0.04, 0.17), p = 0.002). In the subset of subjects with available iron parameters (n = 191), iron deficiency was not associated with significantly higher total FGF23 concentrations. In the subgroup that had measurements of both total and intact FGF23 (n = 185), in fully adjusted models, anemia was significantly associated with higher total FGF23 (standardized ß (95% CI) 0.16 (0.04, 0.27), p = 0.008) but not intact FGF23 (standardized ß (95% CI) 0.02 (-0.12, 0.15), p = 0.81). CONCLUSIONS: In this cohort of pediatric patients with CKD, anemia was associated with increased total FGF23 levels but was not independently associated with elevated intact FGF23, suggesting possible effects on both FGF23 production and cleavage. Further studies are warranted to investigate non-mineral factors affecting FGF23 production and metabolism in CKD.


Assuntos
Anemia , Deficiências de Ferro , Insuficiência Renal Crônica , Adolescente , Criança , Humanos , Anemia/epidemiologia , Anemia/etiologia , Estudos Transversais , Fatores de Crescimento de Fibroblastos/metabolismo , Ferro , Minerais , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/metabolismo
3.
Am J Cardiol ; 213: 93-98, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38016494

RESUMO

Previous studies have documented longer treatment times and worse outcomes for patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) during the COVID-19 pandemic. The objective of the present study was to evaluate the impact of the COVID-19 pandemic on treatment times and outcomes for patients with STEMI who underwent primary PCI within a regional system of care. This was a retrospective study using data from the Los Angeles County Emergency Medical Services Agency. Data on the emergency medical service activations were abstracted for patients with STEMI from March 19, 2020 to January 31, 2021, during the COVID-19 pandemic and for the same interval the previous year. All adult patients (≥18 years) with STEMI who underwent emergent coronary angiography were included. The primary end point was the first medical contact (FMC) to device time. The secondary end points included treatment time intervals, vascular complications, need for emergent coronary artery bypass surgery, length of hospital stay, and in-hospital mortality. During the study period, 3,017 patients underwent coronary angiography for STEMI, 1,893 patients pre-COVID-19 and 1,124 patients during COVID-19 (40% lower). A total of 2,334 patients (77%) underwent PCI. During the COVID-19 period, rates of PCI were significantly lower compared with the control period (75.1% vs 78.7%, p = 0.02). FMC to device time was shorter during the COVID-19 period compared with the control period (median 77.0 vs 81.0 minutes, p = 0.004). For patients with STEMI complicated by out-of-hospital cardiac arrest, FMC to device time was similar during the COVID-19 period compared with the control period (median 95.0 [33.0] vs 100.0 [40.0] minutes, p = 0.34). Vascular complications, the need for emergent bypass surgery, length of hospital stay, and in-hospital mortality were similar between the periods. In conclusion, in this large regional system of care, we found a relatively small but significant decrease in treatment times, yet overall, similar clinical outcomes for patients with STEMI who underwent primary PCI and were treated during the COVID-19 period compared with a control period. These findings suggest that mature cardiac systems of care were able to maintain efficient care despite the challenges of the COVID-19 pandemic.


Assuntos
COVID-19 , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Adulto , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Intervenção Coronária Percutânea/efeitos adversos , COVID-19/epidemiologia , Los Angeles/epidemiologia , Estudos Retrospectivos , Pandemias , Resultado do Tratamento
4.
Cancer Immunol Res ; 11(12): 1589-1597, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37871333

RESUMO

Transgenic T-cell receptor (TCR) T cell-based adoptive cell therapies for solid tumors are associated with dramatic initial response rates, but there remain many instances of treatment failure and disease relapse. The association of infusion product cytokine profiles with clinical response has not been explored in the context of TCR T-cell therapy products. Single-cell antigen-dependent secretomic and proteomic analysis of preinfusion clinical TCR T-cell therapy products revealed that TNFα cytokine functionality of CD8+ T cells and phospho-STAT3 signaling in these cells were both associated with superior clinical responsiveness to therapy. By contrast, CD4+ T-helper 2 cell cytokine profiles were associated with inferior clinical responses. In parallel, preinfusion levels of IL15, Flt3-L, and CX3CL1 were all found to be associated with clinical response to therapy. These results have implications for the development of therapeutic biomarkers and identify potential targets for enrichment in the design of transgenic TCR T-cell therapies for solid tumors.


Assuntos
Neoplasias , Fator de Necrose Tumoral alfa , Animais , Humanos , Camundongos , Proteômica , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Citocinas , Animais Geneticamente Modificados , Terapia Baseada em Transplante de Células e Tecidos , Camundongos Transgênicos , Fator de Transcrição STAT3
5.
Front Psychol ; 14: 1233901, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37790229

RESUMO

Introduction: Youth in under-resourced communities are more likely to have greater social risk factors for mental health needs yet have less access to needed care. School-based mental health services are effective in treating common disorders such as adolescent depression; however, few have a family-centered approach, which may especially benefit specific populations. Methods: Utilizing a community-partnered approach, we adapted an established, trauma-informed, resilience skill-building family intervention for adolescents with depression. We conducted a small randomized controlled feasibility pilot of an adapted intervention in a large school district that serves predominately low-income, Latinx students in the Southwest United States between 2014-2017. Youth between the ages of 12-18 years old with a Patient Health Questionnaire (PHQ-8) score of 10 or higher, who spoke English or Spanish, were recruited from 12 school mental health clinics. Twenty-five eligible adolescents with depression and their participating caregivers were enrolled and randomly assigned to receive either the adapted intervention, Families OverComing Under Stress for Families with Adolescent Depression (FOCUS-AD), or usual care, Cognitive Behavioral Therapy (CBT) only. Most of the sample was Latinx and female. We evaluated feasibility, acceptability, and preliminary effectiveness. Results: Among participants who completed standardized assessments administered at baseline and approximately five months post-randomization (n = 10 FOCUS-AD, n = 11 CBT only), effectiveness was explored by identifying significant changes over time in adolescent mental health within the FOCUS-AD and CBT only groups and comparing the magnitude of these changes between groups. Nonparametric statistical tests were used. We found the FOCUS-AD intervention to be feasible and acceptable; participant retention was high. Adolescent symptoms of depression (measured by the PHQ-8) improved significantly from baseline to follow-up for youth in both FOCUS-AD (median decrease [MD] = 10, p = 0.02) and control (MD = 6, p = 0.01) groups, with no significant difference across the two groups. Results were similar for symptoms of PTSD (measured by the Child PTSD Symptom Scale; FOCUS-AD MD = 12.5, p = 0.01; CBT only MD = 7, p = 0.04; no significant difference between groups). Conclusion: Family-centered approaches to depression treatment among adolescents living in under-resourced communities may lead to improved mental health, although further research is warranted.

6.
J Am Geriatr Soc ; 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37710405

RESUMO

INTRODUCTION: Despite a growing number of older lesbian, gay, bisexual transgender, and queer (LGBTQ) adults in the United States, education on care for this vulnerable population has historically been inadequate across all levels of training. This research assessed the extent of LGBTQ education in geriatric medicine fellowship curricula across the United States. METHODS: We designed a survey to anonymously collect information from geriatric medicine fellowship programs on LGBTQ curricular content. Eligible participants included all 160 fellowship directors on record with the American Geriatrics Society. The survey addressed demographics of the fellowship program, current state of inclusion of LGBTQ content in didactic curricula and in clinical settings, and other available training opportunities. RESULTS: Out of those contacted, 80 (50%) completed the survey. Of the programs surveyed, 60 (75%) were housed in internal medicine, 19 (24%) were in family medicine, and one was in their own department. Forty-seven fellowships (59%) reported some formal didactic session (e.g., lecture or case based), with the majority of these programs (72%) featuring 1-2 h of formal instruction. Forty-five programs (56%) reported offering no formal clinical experiences. There was less than 50% coverage for all surveyed topics in the required curriculum (range 46% for discrimination to 9% for gender affirming care). Time and lack of expertise were cited as the main barriers to content inclusion. CONCLUSIONS: Curricular content regarding care for LGBTQ older adults is inadequate in geriatric medicine fellowships. Faculty development of current educators and providing standardized guidelines and curricula are steps toward addressing this deficit.

7.
Mayo Clin Proc Innov Qual Outcomes ; 7(5): 411-429, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37731677

RESUMO

Objective: To evaluate the impact of age and COVID-19 variant time period on morbidity and mortality among those hospitalized with COVID-19. Patients and Methods: Patients from the American Heart Association's Get With The Guidelines COVID-19 cardiovascular disease registry (January 20, 2020-February 14, 2022) were divided into groups based on whether they presented during periods of wild type/alpha, delta, or omicron predominance. They were further subdivided by age (young: 18-40 years; older: more than 40 years), and characteristics and outcomes were compared. Results: The cohort consisted of 45,421 hospitalized COVID-19 patients (wild type/alpha period: 41,426, delta period: 3349, and omicron period: 646). Among young patients (18-40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.6; 95% CI, 1.3-2.1), major adverse cardiovascular events (MACE) (OR, 1.8; 95% CI, 1.3-2.5), and in-hospital mortality (OR, 2.2; 95% CI, 1.5-3.3) when compared with presentation during wild type/alpha. Among older patients (more than 40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.2; 95% CI, 1.1-1.3), MACE (OR, 1.5; 95% CI, 1.4-1.7), and in-hospital mortality (OR, 1.4; 95% CI, 1.3-1.6) when compared with wild type/alpha. Among older patients (more than 40 years), presentation during omicron associated with decreased odds of severe COVID-19 (OR, 0.7; 95% CI, 0.5-0.9) and in-hospital mortality (OR, 0.6; 95% CI, 0.5-0.9) when compared with wild type/alpha. Conclusion: Among hospitalized adults with COVID-19, presentation during a time of delta predominance was associated with increased odds of severe COVID-19, MACE, and in-hospital mortality compared with presentation during wild type/alpha. Among older patients (aged more than 40 years), presentation during omicron was associated with decreased odds of severe COVID-19 and in-hospital mortality compared with wild type/alpha.

8.
J Obstet Gynecol Neonatal Nurs ; 52(6): 481-490, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37634545

RESUMO

OBJECTIVE: To identify structural factors associated with the receipt of mental health care treatment among Black women in California during pregnancy and after childbirth. DESIGN: Secondary analysis of data from the population-based Listening to Mothers in California survey. PARTICIPANTS: The sample included 194 non-Latina Black women in the postpartum period. METHODS: We used descriptive statistics, including differences between means and logistic regression, to conduct a series of bivariate analyses. RESULTS: Most respondents (84.4%, n = 163) reported symptoms of perinatal mood and anxiety disorders prenatally, and half (50% n = 97) reported symptoms of perinatal mood and anxiety disorders in the postpartum period. Only 12.3% to 14.6% of those who reported symptoms received mental health care treatment. Furthermore, 21.2% (n = 38) of respondents were not screened for postpartum depression. Respondents with private insurance coverage were more likely to report receipt of mental health care after childbirth (OR = 4.6; 95% confidence interval [1.5, 13.5]) compared to respondents with public insurance coverage. CONCLUSION: Our results suggest a high prevalence of unmet mental health needs among non-Latina Black women who lived in California during the perinatal period. Practitioners in clinical settings may be more likely to make referrals to mental health care for women with private insurance coverage in the postpartum period.


Assuntos
Depressão Pós-Parto , Saúde Mental , Gravidez , Feminino , Humanos , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/terapia , Período Pós-Parto/psicologia , California/epidemiologia , Atenção à Saúde , Depressão/psicologia
10.
JMIR Ment Health ; 10: e47084, 2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37477974

RESUMO

BACKGROUND: Although suicide is a leading cause of death among children, the optimal approach for using health care data sets to detect suicide-related emergencies among children is not known. OBJECTIVE: This study aimed to assess the performance of suicide-related International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and suicide-related chief complaint in detecting self-injurious thoughts and behaviors (SITB) among children compared with clinician chart review. The study also aimed to examine variations in performance by child sociodemographics and type of self-injury, as well as develop machine learning models trained on codified health record data (features) and clinician chart review (gold standard) and test model detection performance. METHODS: A gold standard classification of suicide-related emergencies was determined through clinician manual review of clinical notes from 600 emergency department visits between 2015 and 2019 by children aged 10 to 17 years. Visits classified with nonfatal suicide attempt or intentional self-harm using the Centers for Disease Control and Prevention surveillance case definition list of ICD-10-CM codes and suicide-related chief complaint were compared with the gold standard classification. Machine learning classifiers (least absolute shrinkage and selection operator-penalized logistic regression and random forest) were then trained and tested using codified health record data (eg, child sociodemographics, medications, disposition, and laboratory testing) and the gold standard classification. The accuracy, sensitivity, and specificity of each detection approach and relative importance of features were examined. RESULTS: SITB accounted for 47.3% (284/600) of the visits. Suicide-related diagnostic codes missed nearly one-third (82/284, 28.9%) and suicide-related chief complaints missed more than half (153/284, 53.9%) of the children presenting to emergency departments with SITB. Sensitivity was significantly lower for male children than for female children (0.69, 95% CI 0.61-0.77 vs 0.84, 95% CI 0.78-0.90, respectively) and for preteens compared with adolescents (0.66, 95% CI 0.54-0.78 vs 0.86, 95% CI 0.80-0.92, respectively). Specificity was significantly lower for detecting preparatory acts (0.68, 95% CI 0.64-0.72) and attempts (0.67, 95% CI 0.63-0.71) than for detecting ideation (0.79, 95% CI 0.75-0.82). Machine learning-based models significantly improved the sensitivity of detection compared with suicide-related codes and chief complaint alone. Models considering all 84 features performed similarly to models considering only mental health-related ICD-10-CM codes and chief complaints (34 features) and models considering non-ICD-10-CM code indicators and mental health-related chief complaints (53 features). CONCLUSIONS: The capacity to detect children with SITB may be strengthened by applying a machine learning-based approach to codified health record data. To improve integration between clinical research informatics and child mental health care, future research is needed to evaluate the potential benefits of implementing detection approaches at the point of care and identifying precise targets for suicide prevention interventions in children.

11.
J Low Genit Tract Dis ; 27(3): 193-197, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37285236

RESUMO

OBJECTIVE: To evaluate single-pass loop electrosurgical excision procedure (LEEP-SP) versus LEEP with top hat (LEEP-TH) in terms of treatment failure defined as high-grade squamous intraepithelial lesion (HSIL) cytology within 2 years' follow-up. METHODS: This single-institution cohort study used a prospectively collected cervical dysplasia database including all patients who underwent LEEP-SP or LEEP-TH for biopsy-proven cervical intraepithelial neoplasia between 2005 and 2019. RESULTS: Of 340 patients included, 178 underwent LEEP-SP and 162 LEEP-TH. The LEEP-TH patients were more likely to be older (mean age, 40.4 vs 36.5 years; p < .001) and have a positive preprocedure endocervical sampling (68.5% vs 11.8%; p < .001). Positive margins were found in 23 LEEP-SP (12.9%) and in 25 LEEP-TH (15.4%; p = .507). There was no significant difference in depth of excision between LEEP-SP (13.21 ± 23.19 mm) and LEEP-TH (17.37 ± 28.26 mm; p = .138). At 2 years, there was no difference in the rates of HSIL cytology (5.2% vs 6.3%; p = .698), any positive human papillomavirus test, or HSIL cytology (25% vs 15%; p = .284). The 57 patients undergoing repeat excision were more likely to be older (mean age, 40.95 vs 37.52 years; p = .023), have had a LEEP-TH (26.3% vs 73.7%; p < .001), and have initial cytologic HSIL (64.9% vs 35.0%; p < .001). CONCLUSIONS: In this single-institution study, there is no difference in the rate of recurrent HSIL in patients undergoing LEEP-SP versus LEEP-TH. A LEEP-TH may have limited additional benefit over a LEEP-SP in the treatment of cervical HSIL.


Assuntos
Carcinoma de Células Escamosas , Lesões Intraepiteliais Escamosas Cervicais , Lesões Intraepiteliais Escamosas , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Adulto , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Lesões Intraepiteliais Escamosas Cervicais/cirurgia , Lesões Intraepiteliais Escamosas Cervicais/patologia , Estudos de Coortes , Eletrocirurgia/métodos , Displasia do Colo do Útero/patologia , Lesões Intraepiteliais Escamosas/cirurgia , Estudos Retrospectivos , Carcinoma de Células Escamosas/cirurgia
12.
medRxiv ; 2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37333414

RESUMO

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

13.
AMIA Jt Summits Transl Sci Proc ; 2023: 108-117, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37350874

RESUMO

Suicide is the second leading cause of death of U.S. children over 10 years old. Application of statistical learning to structured EHR data may improve detection of children with suicidal behavior and self-harm. Classification trees (CART) were developed and cross-validated using mental health-related emergency department (MH-ED) visits (2015-2019) of children 10-17 years (N=600) across two sites. Performance was compared with the CDC Surveillance Case Definition ICD-10-CM code list. Gold-standard was child psychiatrist chart review. Visits were suicide-related among 284/600 (47.3%) children. ICD-10-CM detected cases with sensitivity 70.7 (95%CI 67.0-74.3), specificity 99.0 (98.8-100), and 85/284 (29.9%) false negatives. CART detected cases with sensitivity 85.1 (64.7-100) and specificity 94.9 (89.2-100). Strongest predictors were suicide-related code, MH- and suicide-related chief complaints, site, area deprivation index, and depression. Diagnostic codes miss nearly one-third of children with suicidal behavior and self-harm. Advances in EHR-based phenotyping have the potential to improve detection of childhood-onset suicidality.

14.
Cancer Immunol Res ; 10(12): 1433-1440, 2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36259217

RESUMO

A major complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents as aphasia, confusion, weakness, somnolence, seizures, and coma. This is similar to the neurologic manifestations of hypophosphatemia, which can result from sudden increases in metabolic demand for phosphorylated intermediates (e.g., refeeding syndrome and sepsis). Given these similarities, we investigated whether CAR T-cell effector metabolic activity is associated with increased extracellular phosphate consumption and a possible association between hypophosphatemia and ICANS. In vitro 4-1BB and CD28 CD19-targeted CAR T-cell effector activity was found to be associated with increased consumption of media phosphorus, which was temporally associated with increased single-cell effector secretomic activity and increased phosphorus-dependent metabolic demand of the CAR T cells. A clinical cohort of 77 patients treated with CD19-targeted CAR T-cell therapy demonstrated a significant anticorrelation between serum phosphorus and ICANS incidence and severity, with earlier onset of hypophosphatemia after CAR T-cell infusion more likely to result in neurotoxicity. These results imply phosphorous level monitoring could alert to the development of ICANS in clinical scenarios. See related Spotlight by Tobin et al., p. 1422.


Assuntos
Hipofosfatemia , Síndromes Neurotóxicas , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T , Antígenos CD19 , Síndromes Neurotóxicas/etiologia , Hipofosfatemia/induzido quimicamente , Fósforo
15.
Ann Surg Oncol ; 29(10): 6407-6414, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35842534

RESUMO

BACKGROUND: In the era of molecular stratification and effective multimodality therapies, surgical staging of the axilla is becoming less relevant for patients with estrogen receptor (ER)-positive early-stage breast cancer (EBC). Therefore, a nonsurgical method for accurately predicting lymph node disease is the next step in the de-escalation of axillary surgery. This study sought to identify epigenetic signatures in the primary tumor that accurately predict lymph node status. PATIENTS AND METHODS: We selected a cohort of patients in The Cancer Genome Atlas (TCGA) with ER-positive, HER2-negative invasive ductal carcinomas, and clinically-negative axillae (n = 127). Clinicopathological nomograms from the Memorial Sloan Kettering Cancer Center (MSKCC) and the MD Anderson Cancer Center (MDACC) were calculated. DNA methylation (DNAm) patterns from primary tumor specimens were compared between patients with pN0 and those with > pN0. The cohort was divided into training (n = 85) and validation (n = 42) sets. Random forest was employed to obtain the combinations of DNAm features with the highest accuracy for stratifying patients with > pN0. The most efficient combinations were selected according to the area under the curve (AUC). RESULTS: Clinicopathological models displayed a modest predictive potential for identifying > pN0 disease (MSKCC AUC 0.76, MDACC AUC 0.69, p = 0.15). Differentially methylated sites (DMS) between patients with pN0 and those with > pN0 were identified (n = 1656). DMS showed a similar performance to the MSKCC model (AUC = 0.76, p = 0.83). Machine learning approaches generated five epigenetic classifiers, which showed higher discriminative potential than the clinicopathological variables tested (AUC > 0.88, p < 0.05). CONCLUSIONS: Epigenetic classifiers based on primary tumor characteristics can efficiently stratify patients with no lymph node involvement from those with axillary lymph node disease, thereby providing an accurate method of staging the axilla.


Assuntos
Neoplasias da Mama , Axila/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Epigênese Genética , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/patologia , Aprendizado de Máquina , Estadiamento de Neoplasias , Nomogramas , Curva ROC , Biópsia de Linfonodo Sentinela
17.
Psychol Trauma ; 14(S1): S82-S90, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34990149

RESUMO

OBJECTIVE: Minoritized students experience high trauma rates which can impact academic outcomes, and experiences may differ between males and females. We investigated the relationship between traumatic stress and academic outcomes by gender among predominantly minoritized students, and whether resilience-building assets can mediate the relationship between traumatic stress and academic outcomes. METHOD: School administrative data were linked to survey data from 9th graders in 2016-2018 across 37 West Coast schools. We examined the association between traumatic stress risk and academic outcomes by gender. Where significant associations were found, mixed effects regression models accounting for school-level variation were fit to assess the role of resilience-building assets as potential mediators of the relationship between traumatic stress risk and academic outcomes. RESULTS: Among 1,750 female and 2,036 male students, we found no significant association between traumatic stress risk and low attendance (<96% days attended). The odds of low grade point average (GPA <2.0) were significantly higher among female students with traumatic stress risk (OR = 1.46, 95% CI [1.16, 1.84]), with no association among males. In models controlling for resilience-building assets, the magnitude of the association between traumatic stress risk and GPA <2.0 among females was reduced. We identified significant mediation for 3 resilience measures: self-efficacy (21.20%; p < .05), school support (18.97%; p < .05), and total internal assets (27.84%; p < .01). CONCLUSIONS: Resilience-building assets may partially mediate the effect of traumatic stress on GPA among females. Resilience initiatives, especially among minoritized female students, may protect against the effect of trauma on academics. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Assuntos
Instituições Acadêmicas , Estudantes , Adolescente , Feminino , Humanos , Masculino , Autoeficácia
18.
Child Adolesc Psychiatr Clin N Am ; 29(4): 601-629, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32891365

RESUMO

Measurement-based care involves the practice of systematically administrating rating scales to patients in order to use the collected information to enhance clinical evaluation, monitor treatment progress, and directly inform decisions relating to each patient's treatment. Rating scales must be psychometrically validated and efficiently administered within the practice setting. Brief rating scales that are available within the public domain may help to optimize workflows and prevent response fatigue. Clinicians should also have a sufficient understanding of the underlying psychometric properties of rating scales to accurately interpret changes in scores over time and use these results to appropriately direct care.


Assuntos
Psiquiatria do Adolescente , Psiquiatria Infantil , Escalas de Graduação Psiquiátrica , Psicometria/normas , Adolescente , Criança , Humanos , Autorrelato
19.
Prev Sci ; 21(8): 1048-1058, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32857298

RESUMO

Behavioral family interventions are an effective way to intervene to prevent negative developmental outcomes for adolescents. Participation in family interventions encompasses behavioral and cognitive/attitudinal dimensions, among others, indicated by retention and engagement, respectively. Two dimensions of participation, retention and engagement, in a family intervention were examined in a sample of newly homeless adolescents and their parents or guardians. Correlates of participation included parents with more income and less perceived family conflict and adolescents with higher endorsement of depression, anxiety, somatization, obsessive-compulsive, phobic, and psychotic symptoms on the Brief Symptom Inventory (BSI). Stronger therapeutic alliance was correlated with being more distressed (i.e., lower income, more hostility), being a female adolescent participant, and having greater comfort discussing sex with parents. Furthermore, parents and adolescents with greater distress and thus greater need were more apt to finish the intervention. The finding that families who were experiencing more distress had higher alliance scores suggests that there is an additional need for development of interventions for families in crisis. Both participant and provider perceptions are also important in development of a strong therapeutic alliance. This study's findings have implications for further exploration of the development of cultural humility and improving mental health literacy among facilitators of behavioral interventions.


Assuntos
Terapia Familiar , Pessoas Mal Alojadas , Pais , Adolescente , Adulto , Terapia Comportamental , Feminino , Humanos , Masculino , Saúde Mental
20.
Suicide Life Threat Behav ; 50(1): 56-71, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31350782

RESUMO

OBJECTIVE: Suicide is a leading cause of adolescent death. Recent data support the efficacy of cognitive-behavioral treatments with strong family components for reducing suicide risk; however, not all youth benefit from current interventions. Identifying predictors of treatment response can inform treatment selection and optimize benefits. METHOD: This study examines predictors of response to a DBT-informed cognitive-behavioral family treatment (SAFETY), among 50 youth with recent suicide attempts/self-harm. Youth and parents were assessed at baseline and post-treatment. RESULTS: Results indicated medium-to-large effect sizes for SAFETY on youth suicidal behavior (SB; defined as suicide attempts, aborted attempts, and planning), depression, hopelessness, social adjustment, and parental depression. Classification tree analysis, with a correct classification rate of 93.3%, and follow-up logistic analyses indicated that 35% of youths reporting active SB at baseline reported active SB at post-treatment, whereas post-treatment SB was rare among youths whose active suicidality had resolved by the baseline assessment (5%). Among youths reporting baseline SB, those endorsing sleep problems were more likely to report post-treatment SB (53%) versus those without sleep problems (0%). CONCLUSIONS: These findings highlight the potential value of personalized treatment approaches based on pretreatment characteristics and the significance of baseline SB and sleep problems for predicting treatment response.


Assuntos
Terapia Cognitivo-Comportamental , Transtorno Depressivo/psicologia , Comportamento Autodestrutivo/psicologia , Ideação Suicida , Tentativa de Suicídio/prevenção & controle , Adolescente , Depressão/psicologia , Terapia Familiar , Feminino , Humanos , Masculino
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