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Objective: Our objective was to determine the feasibility and preliminary efficacy of a behavioral nudge on adoption of a clinical decision support (CDS) tool. Materials and Methods: We conducted a pilot cluster nonrandomized controlled trial in 2 Emergency Departments (EDs) at a large academic healthcare system in the New York metropolitan area. We tested 2 versions of a CDS tool for pulmonary embolism (PE) risk assessment developed on a web-based electronic health record-agnostic platform. One version included behavioral nudges incorporated into the user interface. Results: A total of 1527 patient encounters were included in the trial. The CDS tool adoption rate was 31.67%. Adoption was significantly higher for the tool that included behavioral nudges (39.11% vs 20.66%; P < .001). Discussion: We demonstrated feasibility and preliminary efficacy of a PE risk prediction CDS tool developed using insights from behavioral science. The tool is well-positioned to be tested in a large randomized clinical trial. Trial Registration: Clinicaltrials.gov (NCT05203185).
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BACKGROUND: Although monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma disproportionately affect Black individuals, few epidemiological studies have been conducted on these plasma cell disorders in Africa. Here we describe the prevalence of MGUS in Eswatini and compare our results to the landmark Olmsted County, Minnesota study. METHODS: Between 2016 and 2017, 13 339 residents of Eswatini participated in the Swaziland HIV Incidence Measurement Survey, from which a nationally representative biorepository was created. Plasma samples were then randomly selected and analyzed for MGUS. MGUS prevalence in Eswatini was compared with that of Olmsted County. In addition, demographic and HIV-related associations with MGUS were assessed. RESULTS: Of the 515 samples randomly selected, the median age was 50 years (range = 35-80 years); 60% were female; and 38.6% were HIV positive, of whom 82.4% were on antiretroviral therapy. We found that 68 participants had evidence of MGUS, for a prevalence of 13.2%. HIV status was not significantly associated with MGUS (odds ratio = 1.05, 95% confidence interval = 0.62 to 1.77), but among HIV-positive individuals, MGUS was less frequent for patients on antiretroviral therapy (adjusted odds ratio = 0.31, 95% confidence interval = 0.11 to 0.82). The prevalence of conventional MGUS was similar between Eswatini and Olmsted County (3.4% vs 3.2%-3.4%), whereas the incidence of light-chain MGUS was significantly greater in Eswatini (12.3% vs 0.8%). CONCLUSION: Our study suggests that the incidence of MGUS is similar between ethnicities and raises the question of whether the current definition of light-chain MGUS reliably reflects a true monoclonal protein precursor state. Perhaps the current definition of light-chain MGUS may be capturing alternate etiologies, such as untreated HIV infection.
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Infecciones por VIH , Gammopatía Monoclonal de Relevancia Indeterminada , Humanos , Femenino , Masculino , Prevalencia , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/epidemiología , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Anciano , Adulto , Anciano de 80 o más Años , Infecciones por VIH/epidemiología , Infecciones por VIH/complicaciones , Esuatini/epidemiología , Minnesota/epidemiología , Mieloma Múltiple/epidemiología , Incidencia , Oportunidad RelativaRESUMEN
Importance: Oropharyngeal dysphagia is common in hospitalized patients with Alzheimer disease and related dementias (ADRD). Although the use of thick liquids in patients with dysphagia has been shown to reduce aspiration on direct visualization, there is no clear evidence that this practice translates into improved clinical outcomes. Objectives: To determine whether a diet of thick liquids compared with thin liquids is associated with improved outcomes in hospitalized patients with ADRD and dysphagia. Design, Setting, and Participants: This cohort study included adults aged 65 years and older with ADRD who were admitted to the medicine service across 11 diverse hospitals in New York between January 1, 2017, and September 20, 2022, with clinical suspicion of dysphagia during hospitalization and survival for at least 24 hours after hospital arrival. Patients were grouped according to whether at least 75% of their hospital diet consisted of a thick liquid diet or a thin liquid diet. Propensity score matching was used to balance covariates across the 2 groups for the following covariates: demographics (eg, age, sex), baseline clinical characteristics (eg, Charlson Comorbidity Index), and acute presentation (eg, respiratory diagnosis, illness severity, delirium). Main Outcomes and Measures: Hospital outcomes included mortality (primary outcome), respiratory complications (eg, pneumonia), intubation, and hospital length of stay (LOS). Results: Of 8916 patients with ADRD and dysphagia included in the propensity score matched analysis, the mean (SD) age was 85.7 (8.0) years and 4829 were female (54.2%). A total of 4458 patients receiving a thick liquid diet were matched with 4458 patients receiving a thin liquid diet. There was no significant difference in hospital mortality between the thick liquids and thin liquids groups (hazard ratio, 0.92; 95% CI, 0.75-1.14]; P = .46). Compared with patients receiving thin liquids, patients receiving thick liquids were less likely to be intubated (odds ratio [OR], 0.66; 95% CI, 0.54-0.80), but they were more likely to have respiratory complications (OR, 1.73; 95% CI, 1.56-1.91). Conclusions and Relevance: This cohort study emphasizes the need for prospective studies that evaluate whether thick liquids are associated with improved clinical outcomes in hospitalized patients with ADRD and dysphagia.
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Enfermedad de Alzheimer , Trastornos de Deglución , Hospitalización , Humanos , Trastornos de Deglución/etiología , Femenino , Masculino , Enfermedad de Alzheimer/complicaciones , Anciano , Anciano de 80 o más Años , Hospitalización/estadística & datos numéricos , Mortalidad Hospitalaria , Demencia/complicaciones , Estudios de Cohortes , Tiempo de Internación/estadística & datos numéricos , DietaRESUMEN
BACKGROUND: Most patients with COVID-19 report experiencing one or more symptoms after acute infection subsides, known as post-acute sequelae of SARS-CoV-2 infection (PASC). Though research has examined PASC after acute COVID-19, few studies have examined PASC over a longer follow-up duration or accounted for rates of symptoms and diagnoses before COVID-19 infection, and included those not actively seeking treatment for PASC. To determine what symptoms and diagnoses are occurring at higher rates after acute COVID-19 infection from a more inclusive sample, we extracted electronic hospital records (EHR) data from 13,033 adults with previously known diagnoses and symptoms. METHODS: The sample was comprised of patients who had a positive PCR test for SARS-CoV-2 between March 1, 2020, and December 31, 2020, and follow-up was conducted through November 29, 2021. All patients in the sample had medical appointments ≥4 weeks before and ≥4 weeks after their positive PCR test. At these appointments, all ICD-10 codes recorded in the EHR were classified into 21 categories based on the literature and expert review. Conditional logistic regression models were used to quantify the odds of these symptoms and diagnostic categories following COVID-19 infection relative to visits occurring before infection. The sample was comprised of 28.0% adults over 65 and was 57.0% female. After the positive PCR test, the most recorded diagnoses and symptoms were dyspnea and respiratory failure, myositis, musculoskeletal pain/stiffness, anxiety, and depression. RESULTS: Results from regression analyses showed increased odds of diagnosis for 15 of the 21 categories following positive PCR. Relative to pre-COVID, the diagnoses and symptoms with the greatest odds after a positive PCR test were loss of smell or taste [OR (95% CI) = 6.20 (3.18-12.09)], pulmonary fibrosis [3.50 (1.59-7.68)], and dyspnea/respiratory failure [2.14 (1.92-2.40)]. Stratification of these analyses by age, gender, race, and ethnicity showed similar results. CONCLUSION: The increased symptoms and diagnoses detected in the current study match prior analyses of PASC diagnosis and treatment-seeking patients. The current research expands upon the literature by showing that these symptoms are more frequently detected following acute COVID-19 than before COVID-19. Further, our analyses provide a broad snapshot of the population as we were able to describe PASC among all patients who tested positive for COVID-19.
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COVID-19 , Insuficiencia Respiratoria , Adulto , Humanos , Femenino , Masculino , COVID-19/diagnóstico , SARS-CoV-2 , Síndrome Post Agudo de COVID-19 , DisneaRESUMEN
PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quinasa 6 Dependiente de la CiclinaRESUMEN
Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an important cause of heart failure in older individuals. Misfolding and deposition of transthyretin or prealbumin protein causes ATTR-CM in the context of a normal (wild-type) or variant TTR sequence. Variant ATTR-CM is most commonly caused by the substitution of valine for isoleucine at position 122 in transthyretin (Val122Ile or pV142I, almost exclusively observed in individuals of West African ancestry), demonstrated in 3.4% of self-identified Black individuals in the United States with an estimated 1.5 million carriers. Despite the large number of known pV142I carriers, the proportion of older Black patients with heart failure attributable to ATTR-CM remains unknown. Methods To address this knowledge gap, the SCAN-MP (Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations) study was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL139671) to enroll a targeted population of self-identified, community-dwelling Black or Caribbean Hispanic patients (many of whom are of West African ancestry) >60 years of age with heart failure and identify ATTR-CM by noninvasive nuclear imaging. The principal objective of SCAN-MP is to determine the prevalence of ATTR-CM in this population. Secondary objectives will explore TTR genotype, demographics, progression of variant versus wild-type ATTR-CM, and biochemical mechanisms of transthyretin amyloid fibril formation. Conclusions The SCAN-MP study is the largest, prospective study of cardiac amyloidosis in Black and Hispanic individuals. Both wild-type and variant ATTR-CM are now treatable with the US Food and Drug-approved drug tafamidis. The insights gained from SCAN-MP are likely to improve those at risk for or afflicted with ATTR-CM. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03812172.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Insuficiencia Cardíaca , Humanos , Anciano , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/complicaciones , Prealbúmina/genética , Prealbúmina/metabolismo , Estudios Prospectivos , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/genética , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/complicaciones , Poblaciones Minoritarias, Vulnerables y Desiguales en SaludRESUMEN
BACKGROUND: Lung cancer screening (LCS) decreases lung cancer mortality. However, its benefit may be limited by nonadherence to screening. Although factors associated with LCS nonadherence have been identified, to the best of our knowledge, no predictive models have been developed to predict LCS nonadherence. The purpose of this study was to develop a predictive model leveraging a machine learning model to predict LCS nonadherence risk. METHODS: A retrospective cohort of patients who enrolled in our LCS program between 2015 and 2018 was used to develop a model to predict the risk of nonadherence to annual LCS after the baseline examination. Clinical and demographic data were used to fit logistic regression, random forest, and gradient-boosting models that were internally validated on the basis of accuracy and area under the receiver operating curve. RESULTS: A total of 1875 individuals with baseline LCS were included in the analysis, with 1264 (67.4%) as nonadherent. Nonadherence was defined on the basis of baseline chest computed tomography (CT) findings. Clinical and demographic predictors were used on the basis of availability and statistical significance. The gradient-boosting model had the highest area under the receiver operating curve (0.89, 95% confidence interval = 0.87 to 0.90), with a mean accuracy of 0.82. Referral specialty, insurance type, and baseline Lung CT Screening Reporting & Data System (LungRADS) score were the best predictors of nonadherence to LCS. CONCLUSIONS: We developed a machine learning model using readily available clinical and demographic data to predict LCS nonadherence with high accuracy and discrimination. After further prospective validation, this model can be used to identify patients for interventions to improve LCS adherence and decrease lung cancer burden.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Estudios Retrospectivos , Detección Precoz del CáncerRESUMEN
Gene sets are being increasingly leveraged to make high-level biological inferences from transcriptomic data; however, existing gene set analysis methods rely on overly conservative, heuristic approaches for quantifying the statistical significance of gene set enrichment. We created Nonparametric analytical-Rank-based Enrichment Analysis (NaRnEA) to facilitate accurate and robust gene set analysis with an optimal null model derived using the information theoretic Principle of Maximum Entropy. By measuring the differential activity of ~2500 transcriptional regulatory proteins based on the differential expression of each protein's transcriptional targets between primary tumors and normal tissue samples in three cohorts from The Cancer Genome Atlas (TCGA), we demonstrate that NaRnEA critically improves in two widely used gene set analysis methods: Gene Set Enrichment Analysis (GSEA) and analytical-Rank-based Enrichment Analysis (aREA). We show that the NaRnEA-inferred differential protein activity is significantly correlated with differential protein abundance inferred from independent, phenotype-matched mass spectrometry data in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), confirming the statistical and biological accuracy of our approach. Additionally, our analysis crucially demonstrates that the sample-shuffling empirical null models leveraged by GSEA and aREA for gene set analysis are overly conservative, a shortcoming that is avoided by the newly developed Maximum Entropy analytical null model employed by NaRnEA.
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Patients with heart failure (HF) often have multiple chronic conditions and are at increased risk for severe disease and mortality when infected by SARS-CoV-2, the virus that causes COVID-19. Furthermore, disparities in outcomes with COVID-19 have been associated with both racial/ethnic identity but also social determinants of health. Among older, urban-dwelling, minority patients with HF, we sought to characterize medical and non-medical factors associated with SARS-CoV-2 infection. Patients with HF living in Boston and New York City over 60 years of age participating in the Screening for Cardiac Amyloidosis with Nuclear Imaging (SCAN-MP) study between 12/1/2019 and 10/15/2021 (n = 180) were tested for nucleocapsid antibodies to SARS-CoV-2 and queried for symptomatic infection with PCR verification. Baseline testing included the Kansas City Cardiomyopathy Questionnaire (KCCQ), assessment of health literacy, biochemical, functional capacity, echocardiography, and a novel survey tool that determined living conditions, perceived risk of infection, and attitudes towards COVID-19 mitigation. The association of infection with prevalent socio-economic conditions was assessed by the area deprivation index (ADI). There were 50 overall cases of SARS-CoV-2 infection (28%) including 40 demonstrating antibodies to SARS-CoV-2 (indicative of prior infection) and 10 positive PCR tests. There was no overlap between these groups. The first documented case from New York City indicated infection prior to January 17, 2020. Among active smokers, none tested positive for prior SARS-CoV-2 infection (0 (0%) vs. 20 (15%), p = 0.004) vs. non-smokers. Cases were more likely to be taking ACE-inhibitors/ARBs compared to non-cases (78% vs 62%, p = 0.04). Over a mean follow-up of 9.6 months, there were 6 total deaths (3.3%) all unrelated to COVID-19. Death and hospitalizations (n = 84) were not associated with incident (PCR tested) or prior (antibody) SARS-CoV-2 infection. There was no difference in age, co-morbidities, living conditions, attitudes toward mitigation, health literacy, or ADI between those with and without infection. SARS-CoV-2 infection was common among older, minority patients with HF living in New York City and Boston, with evidence of infection documented in early January 2020. Health literacy and ADI were not associated with infection, and there was no increased mortality or hospitalizations among those infected with SARS-CoV-2.
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COVID-19 , Insuficiencia Cardíaca , Determinantes Sociales de la Salud , Anciano , Humanos , Persona de Mediana Edad , Anticuerpos , COVID-19/etnología , Insuficiencia Cardíaca/etnología , SARS-CoV-2 , Boston/epidemiología , Ciudad de Nueva York/epidemiologíaRESUMEN
Inhibiting individual histone deacetylase (HDAC) is emerging as well-tolerated anticancer strategy compared with pan-HDAC inhibitors. Through preclinical studies, we demonstrated that the sensitivity to the leading HDAC6 inhibitor (HDAC6i) ricolinstat can be predicted by a computational network-based algorithm (HDAC6 score). Analysis of ~3,000 human breast cancers (BCs) showed that ~30% of them could benefice from HDAC6i therapy. Thus, we designed a phase 1b dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in patients with metastatic BC (MBC) (NCT02632071). Study results showed that the two agents can be safely combined, that clinical activity is identified in patients with HR+/HER2- disease and that the HDAC6 score has potential as predictive biomarker. Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6i's. Mechanistically, we have linked the anticancer activity of HDAC6i's to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.
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Neoplasias de la Mama , Humanos , Femenino , Histona Desacetilasa 6/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéuticoRESUMEN
In this issue of NEJM Evidence, Gaudet et al. present the safety profile and pharmacodynamics of ARO-APOC3, a small interfering RNA therapeutic that inhibits apolipoprotein C-III (APOC3) mRNA expression in a phase I trial.1 Assignment to treatment was based on fasting levels of triglycerides. The trial included two double-blinded cohorts with 52 randomly assigned healthy participants and 40 patients with hypertriglyceridemia assigned to escalating doses of ARO-APOC3 at 10, 25, 50, or 100 mg or placebo in a single- and/or repeat-dose (days 1 and 29) regimen. An open-label cohort of patients with chylomicronemia was treated with ARO-APOC3 at 50 mg.
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Triglicéridos , Humanos , Triglicéridos/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase I como AsuntoRESUMEN
OBJECTIVE: Smell and taste alteration are closely linked to infection with SARS-CoV-2 and may be associated with a more indolent disease course. Serologic response rates among individuals with mild disease remains limited. We sought to identify whether chemosensory changes associated with COVID-19 were predictive of a serologic response. STUDY DESIGN: Cross-sectional study. METHODS: The sample consisted of 306 adults (≥18 years old) volunteering for convalescent plasma donation following perceived COVID-19 illness from April-June 2020. Documentation of COVID-19 PCR status, clinical symptoms at time of illness, and treatment course occurred at the time of serologic analysis, where we assessed chemosensory function using patient-perceived deficits. We implemented previously validated ELISA screening to determine serologic status regarding anti-Spike immunoglobulins. Statistical analysis using stepwise logistic models were employed to identify predictive factors of serologic response. RESULTS: Of 306 patients undergoing serologic and chemosensory evaluation, 196 (64.1%) and 195 (63.7%) reported subjective olfactory and taste dysfunction, respectively, during the first two weeks of COVID-19 infection. In unadjusted models, the odds of developing suprathreshold IgG antibody titers were 1.98 times higher among those who reported altered smell (95% CI 1.14-3.42, p = 0.014) and 2.02 times higher among those with altered taste (95% CI 1.17-3.48, p = 0.011) compared to those with normal smell and taste. Multivariable logistic models adjusting for sex, age, race/ethnicity, symptom duration, smoking status and comorbidities index demonstrated that altered smell and taste remained significant predictors of positive anti-spike IgG response (smell OR = 1.90, 95% CI 1.05-3.44, p = 0.033; taste OR = 2.01, 95% CI = 1.12-3.61, p = 0.019). CONCLUSION: Subjective chemosensory dysfunction, as self-reported smell or taste deficiency, is highly predictive of serologic response following SARS-CoV-2 infection. This information may be useful for patient counseling. Additional longitudinal research should be performed to better understand the onset and duration of the serologic response in these patients.
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COVID-19 , Trastornos del Olfato , Adulto , Humanos , Adolescente , SARS-CoV-2 , COVID-19/complicaciones , Estudios Transversales , Trastornos del Gusto/etiología , Trastornos del Gusto/diagnóstico , Trastornos del Olfato/diagnóstico , OlfatoRESUMEN
Introduction: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. Materials and Methods: This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib. Results: 34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome. Conclusions: The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease.
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BACKGROUND: Both multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance (MGUS), occur twice as often within Black compared with White populations, suggesting that racial disparities lie within the development of MGUS. Nonetheless, MGUS has been studied mainly in White cohorts; the study that first described the natural history of MGUS was conducted in 97.3% White Olmsted County, Minnesota. METHODS: We determined the prevalence of MGUS among 386 Black South African (SA) men >30 years at Chris Hani Baragwanath Hospital in Johannesburg. We conducted serum protein electrophoresis and free light chain quantification to define MGUS by the same criteria as the Olmsted County studies. We also investigated the association between MGUS and various clinical factors, including human immunodeficiency virus (HIV) infection and smoking. RESULTS: We found the prevalence of MGUS to be 8.03% [95% confidence interval (CI), 5.32-10.74], nearly 1.6-fold higher than in the White Olmsted County male population. In a univariable logistic regression model, MGUS was associated with HIV status (OR, 2.39; 95% CI, 0.95-5.49), but in an adjusted model that included body mass index and cigarette use, the association was not statistically significant. Those who were current (vs. never) cigarette smokers were more likely to have MGUS in both univariable (OR, 5.60; 95% CI, 2.16-17.42) and multivariable models (OR, 4.49; 95% CI, 1.63-14.56). CONCLUSIONS: The prevalence of MGUS in Black SA men is substantially higher than in White populations and may be associated with HIV status and cigarette use. IMPACT: Racial disparities in MGUS exist and may be associated with potentially modifiable risk factors.
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Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Paraproteinemias , Masculino , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/epidemiología , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Prevalencia , Sudáfrica/epidemiología , Paraproteinemias/epidemiología , Paraproteinemias/complicaciones , Cadenas Ligeras de Inmunoglobulina , Factores de RiesgoRESUMEN
Objective: To use magnetic resonance imaging (MRI) to quantify the follicle number per ovary (FNPO) using biplanar measurements and determine the ovarian volume (OV) using three-dimensional measurements in adolescents and young adults with polycystic ovary syndrome (PCOS) and controls and compare the differences between these groups; to examine the relationships between FNPO and OV and metabolic markers associated with PCOS; to compare OV obtained by use of MRI and ultrasound between young patients with PCOS and controls. Design: Cross-sectional study. Setting: Outpatient within a major medical center in New York City. Patients: Adolescent girls and young women aged 13-25 years with PCOS (n = 16) and body mass index-, age-, and ethnicity-comparable control subjects (n = 15). Interventions: None. Main Outcome Measures: The OV and FNPO by use of MRI, OV by use of transabdominal pelvic ultrasound, anthropometric measurements, and biochemical and hormonal evaluation. Results: The FNPO was higher in participants with PCOS (23.7 ± 4.6 follicles) than in controls (15.2 ± 4 follicles) when adjusted for menstrual age. The OV by use of ultrasound was higher in participants with PCOS (11.7 ± 5.6 mL) than in controls (8.1 ± 3.4 mL); however, OV by use of MRI did not differ between the groups. The OV by use of MRI and ultrasound correlated in participants with PCOS (r = 0.62) but not in controls. Conclusions: Our results are in line with prior studies showing that FNPO may be a more sensitive measure of polycystic ovary morphology than OV. The results of this study support the use of ovarian k, a promising diagnostic tool for PCOS, in young patients.
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Heart failure with preserved ejection fraction is a heterogeneous clinical syndrome that includes distinct subtypes with different pathophysiologies, genetics, and treatment. Distinguishing heart failure with preserved ejection fraction caused by transthyretin cardiac amyloidosis (ATTR-CA) is critical given its specific treatment. We analyzed a single-center retrospective cohort to determine the association of body mass index (BMI) with a composite of either ATTR-CA or the valine-to-isoleucine substitution (Val122Ile) variant genotype (ATTR-CA+Val122Ile). These BMI differences were prospectively evaluated in the multicenter Screening for Cardiac Amyloidosis using nuclear imaging for Minority Populations (SCAN-MP) study of Black and Hispanic patients with heart failure. The association of BMI with ATTR-CA+Val122Ile was compared by Wilcoxon rank sum analysis and combined with age, gender, and maximum left ventricle wall thickness in multivariable logistic regression. In the retrospective analysis (n = 469), ATTR-CA+Val122Ile was identified in n = 198 (40%), who had a lower median BMI (25.8 kg/m2, interquartile range [IQR] 23.4 to 28.9) than other patients (27.1 kg/m2, IQR 23.9 to 32.0) (p <0.001). In multivariable logistic regression, BMI <30 kg/m2 (odds ratio 2.6, 95% confidence interval 1.5 to 4.5) remained independently associated with ATTR-CA+Val122Ile with a greater association in Black and Hispanic patients (odds ratio 5.8, 95% confidence interval 1.7 to 19.6). In SCAN-MP (n = 201), 17 (8%) had either ATTR-CA (n = 10) or were Val122Ile carriers (n = 7) with negative pyrophosphate scans. BMI was lower (25.4 kg/m2 [IQR 24.3 to 28.2]) in ATTR-CA+Val122Ile patients than in non-amyloid patients (32.7 kg/m2 [28.3 to 38.6]) (p <0.001), a finding that persisted in multivariable analysis (p = 0.002). In conclusion, lower BMI is associated with ATTR-CA+Val122Ile in heart failure with increased left ventricle wall thickness, particularly in Black and Hispanic patients, and may aid in the identification of those benefiting from ATTR-CA evaluation.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Cardiopatías , Insuficiencia Cardíaca , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/genética , Índice de Masa Corporal , Hispánicos o Latinos , Humanos , Prealbúmina/genética , Estudios RetrospectivosRESUMEN
Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3+ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3+CD8+ cytotoxic T cells (CTLs, p = .0079), CD3+CD4+FOXP3- T helper cells (Th, p = .0010), and CD3+CD4+FOXP3+ regulatory T cells (Tregs, p = .0089) with no difference in CD68+ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.
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Carcinoma Ductal Pancreático , Melanoma , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Factores de Transcripción Forkhead , Humanos , Melanoma/terapia , Terapia Neoadyuvante , Neoplasias Pancreáticas/terapia , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Talimogene Laherparepvec (OncoVEXmGMCSF), an oncolytic virus, immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1), and BRAF inhibition (BRAFi), are all clinically approved for treatment of melanoma patients and are effective through diverse mechanisms of action. Individually, these therapies also have an effect on the tumor immune microenvironment (TIME). Evaluating the combination effect of these three therapies on the TIME can help determine when combination therapy is most appropriate for further study. In this study, we use a transgenic murine melanoma model (Tyr::CreER; BRAFCA/+; PTENflox/flox), to evaluate the TIME in response to combinations of BRAFi, anti-PD1, and OncoVEXmGMCSF. We find that mice treated with the triple combination BRAFi + anti-PD1 + OncoVEXmGMCSF have decreased tumor growth compared to BRAFi alone and prolonged survival compared to control. Flow cytometry shows an increase in percent CD8 + /CD3 + cytotoxic T Lymphocytes (CTLs) and a decrease in percent FOXP3 + /CD4 + T regulatory cells (Tregs) in tumors treated with OncoVEXmGMCSF compared to mice not treated with OncoVEXmGMCSF. Immunogenomic analysis at 30d post-treatment shows an increase in Th1 and interferon-related genes in mice receiving OncoVEXmGMCSF + BRAFi. In summary, treatment with combination BRAFi + anti-PD1 + OncoVEXmGMCSF is more effective than any single treatment in controlling tumor growth, and groups receiving OncoVEXmGMCSF had more tumoral infiltration of CTLs and less intratumoral Tregs in the TIME. This study provides rational basis to combine targeted agents, oncolytic viral therapy, and checkpoint inhibitors in the treatment of melanoma.
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Antineoplásicos , Melanoma , Viroterapia Oncolítica , Virus Oncolíticos , Animales , Antineoplásicos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Melanoma/tratamiento farmacológico , Ratones , Proteínas Proto-Oncogénicas B-raf/genética , Microambiente TumoralRESUMEN
BACKGROUND: Few studies have examined the longer-term psychological impact of COVID-19 in healthcare workers (HCWs). PURPOSE: We examined the 10-week trajectory of insomnia symptoms in HCWs during the COVID-19 pandemic. METHODS: HCWs completed a web-based survey at baseline (9 April-11 May 2020) and every 2 weeks for 10 weeks. The main outcome was the severity of insomnia symptoms in the past week. Multivariable-adjusted generalized estimating equation analyses examined factors associated with insomnia symptoms. RESULTS: n = 230 completed surveys at baseline. n = 155, n = 130, n = 118, n = 95, and n = 89 completed follow-ups at weeks 2, 4, 6, 8, and 10, respectively. Prevalence of insomnia symptoms of at least moderate severity was 72.6% at baseline, and 63.2%, 44.6%, 40.7%, 34.7%, and 39.3% at weeks 2, 4, 6, 8, and 10, respectively. In multivariable analyses, factors significantly associated with increased odds of insomnia symptoms were younger age (OR: 0.98, 95% CI: 0.96-1.00), working in a COVID-facing environment (OR: 1.75, 95% CI: 1.15-2.67) and hours worked (OR: 1.16, 95% CI: 1.06-1.27). CONCLUSIONS: The initial high rates of insomnia symptoms improved as time passed from the peak of local COVID-19 cases but four out of ten HCWs still had moderate-to-severe insomnia symptoms ten weeks after baseline.
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COVID-19 , Trastornos del Inicio y del Mantenimiento del Sueño , Ansiedad , Estudios Transversales , Depresión , Personal de Salud , Humanos , Estudios Longitudinales , Salud Mental , Ciudad de Nueva York/epidemiología , Pandemias , SARS-CoV-2 , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiologíaRESUMEN
BACKGROUND: Prevalence, incidence, and factors associated with posttraumatic stress disorder (PTSD) symptoms at follow-up among healthcare workers after the first wave of the COVID-19 pandemic are unknown. METHODS: A web survey invitation was sent to healthcare worker listservs at a NYC medical center (April, 2020). The Primary Care (PC)-PTSD questionnaire was used to screen for PTSD symptoms at baseline and then every 2 weeks for 10 weeks. Incidence and prevalence of PTSD symptoms were determined at each time point. Multivariable generalized estimating equation models were performed to investigate the factors associated with a positive PC-PTSD screen at follow-up. RESULTS: Median age (interquartile range) of N = 230 participants was 36 (31-48) years; 79.6% were women; 82.6% worked in COVID-19-focused settings. The prevalence of PTSD symptoms decreased from 55.2% at baseline to 25.0% at 10 weeks (p < 0.001). Among participants who had a baseline negative screen for PTSD symptoms, the incidence of PTSD at 10 weeks was 12.2% (p-trend 0.034). In multivariable-adjusted analyses, being a nurse (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.06-2.71), female (OR: 3.00, 95% CI: 1.59, 5.72), and working in a COVID-19-focused location (OR: 1.51, 95% CI: 1.02, 2.21) were associated with increased odds of PTSD symptoms at 10-weeks. CONCLUSIONS: PTSD symptoms improved over 3 months following the first wave of the COVID-19 pandemic. However, one out of four NYC healthcare workers still had an increased risk for PTSD at 10-weeks. Screening healthcare workers for PTSD symptoms should be considered during the COVID-19 pandemic.