RESUMO
Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.
Assuntos
Neoplasias Gastrointestinais/patologia , Tumor de Músculo Liso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de ProgressãoRESUMO
RESEARCH QUESTION: Is minority race associated with worse oocyte donation outcomes? DESIGN: Retrospective analysis of 926 oocyte recipients who underwent a donor cycle with fresh embryo transfer at a single fertility centre between January 2009 and June 2015. Race was self-reported. To adjust for repeat donors within the sample, mixed models were used to analyse donor parameters and recipient outcomes. The recipient outcome models were adjusted for age, body mass index and primary infertility diagnosis. RESULTS: The study consisted of 767 (82.8%) White, 41 (4.4%) Black, 63 (6.8%) Asian and 55 (5.9%) Hispanic women. Compared with White recipients, the adjusted odds ratio (aOR) for clinical pregnancy was 0.39 (95% confidence interval [CI] 0.19-0.79) for Black, 0.55 (95% CI 0.31-0.98) for Hispanic and 0.88 (95% CI 0.51-1.53) for Asian recipients. The aOR for live birth was 0.47 (95% CI 0.23-0.98) for Black, 0.58 (95% CI 0.32-1.06) for Hispanic and 0.62 (95% 0.35-1.09) for Asian recipients. A subgroup analysis restricted to cycles with racially concordant donors and recipients showed that the odds of clinical pregnancy and live birth were further reduced among Black recipients, with aOR of 0.28 (95% CI 0.09-0.81) and 0.30 (95% CI 0.09-0.98), respectively. CONCLUSIONS: Black and Hispanic oocyte donation recipients experience lower clinical pregnancy rates and Black recipients experience lower live birth rates compared with White recipients. Racially discordant donor oocyte cycles involving donors and recipients of different races present an opportunity to further investigate the cause of disparity.
Assuntos
Coeficiente de Natalidade , Negro ou Afro-Americano , Disparidades nos Níveis de Saúde , Nascido Vivo , Doação de Oócitos , População Branca , Adulto , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos RetrospectivosRESUMO
OBJECTIVE: The objective of this study was to study provider attitudes of and perceived barriers to the clinical use of pharmacogenomics before and during participation in an implementation program. PARTICIPANTS AND METHODS: From 2012 to 2017, providers were recruited. After completing semistructured interviews (SSIs) about pharmacogenomics, providers received training on and access to a clinical decision support tool housing patient-specific pharmacogenomic results. Thematic analysis of SSI was conducted (inter-rater reliability κ≥0.75). Providers also completed surveys before and during study participation, and provider-perceived barriers to pharmacogenomic implementation were analyzed. RESULTS: Seven themes emerged from the SSI (listed from most frequent to least): decision-making, concerns with pharmacogenomic adoption, outcome expectancy, provider knowledge of pharmacogenomics, patient attitudes, individualized treatment, and provider interest in pharmacogenomics. Although there was prestudy enthusiasm among all providers, concerns with clinical utility, time, results accession, and knowledge of pharmacogenomics were frequently stated at baseline. Despite this, adoption of pharmacogenomics was robust, as patient-specific results were accessed at 64% of visits, and medication changes were influenced by provided pharmacogenomic information 42% of the time. Providers reported they had enough time to evaluate the information and the results were easily understood on 74 and 98% of surveys, respectively. Nevertheless, providers consistently felt there was insufficient pharmacogenomic information for most drugs they prescribed and clear guidelines for using pharmacogenomic information were lacking. CONCLUSION: Despite initial concerns about adequate time and knowledge for adoption, providers frequently utilized pharmacogenomic results. Provider-perceived barriers to wider use included lack of clear guidelines and evidence for most drugs, highlighting important considerations for the field of pharmacogenomics.
Assuntos
Tomada de Decisão Clínica , Genoma Humano/efeitos dos fármacos , Farmacogenética , Guias como Assunto , Pessoal de Saúde , Humanos , Testes Farmacogenômicos , Medicina de Precisão , Inquéritos e QuestionáriosRESUMO
Effective doctor-patient communication is critical for disease management, especially when considering genetic information. We studied patient-provider communications after implementing a point-of-care pharmacogenomic results delivery system to understand whether pharmacogenomic results are discussed and whether medication recall is impacted. Outpatients undergoing preemptive pharmacogenomic testing (cases), non-genotyped controls, and study providers were surveyed from October 2012-May 2017. Patient responses were compared between visits where pharmacogenomic results guided prescribing versus visits where pharmacogenomics did not guide prescribing. Provider knowledge of pharmacogenomics, before and during study participation, was also analyzed. Both providers and case patients frequently reported discussions of genetic results after visits where pharmacogenomic information guided prescribing. Importantly, medication changes from visits where pharmacogenomics influenced prescribing were more often recalled than non-pharmacogenomic guided medication changes (OR = 3.3 [1.6-6.7], p = 0.001). Case patients who had separate visits where pharmacogenomics did and did not, respectively, influence prescribing more often remembered medication changes from visits where genomic-based guidance was used (OR = 3.4 [1.2-9.3], p = 0.02). Providers also displayed dramatic increases in personal genomic understanding through program participation (94% felt at least somewhat informed about pharmacogenomics post-participation, compared to 61% at baseline, p = 0.04). Using genomic information during prescribing increases patient-provider communications, patient medication recall, and provider understanding of genomics, important ancillary benefits to clinical use of pharmacogenomics.
Assuntos
Prescrições de Medicamentos/normas , Farmacogenética/normas , Medicamentos sob Prescrição/normas , Comunicação , Gerenciamento Clínico , Recall de Medicamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Relações Médico-Paciente , Sistemas Automatizados de Assistência Junto ao Leito/normas , Medicina de Precisão/normas , Pesquisa/normasRESUMO
BACKGROUND: The patient-centered medical home (PCMH) is a widely adopted primary care model. However, it is unclear whether changes in provider and staff perceptions of clinic PCMH capability are associated with changes in provider and staff morale, job satisfaction, and burnout in safety net clinics. OBJECTIVE: To determine how provider and staff PCMH ratings changed under a multi-year PCMH transformation initiative and assess whether changes in provider and staff PCMH ratings were associated with changes in morale, job satisfaction, and burnout. DESIGN: Comparison of baseline (2010) and post-intervention (2013-2014) surveys. SETTING: Sixty clinics in five states. PARTICIPANTS: Five hundred thirty-six (78.2%) providers and staff at baseline and 589 (78.3%) post-intervention. INTERVENTION: Collaborative learning sessions and on-site coaching to implement PCMH over 4 years. MEASUREMENTS: Provider and staff PCMH ratings on 0 (worst) to 100 (best) scales; percent of providers and staff reporting good or better morale, job satisfaction, and freedom from burnout. RESULTS: Almost half of safety net clinics improved PCMH capabilities from the perspective of providers (28 out of 59, 47%) and staff (25 out of 59, 42%). Over the same period, clinics saw a decrease in the percentage of providers reporting high job satisfaction (- 12.3% points, p = .009) and freedom from burnout (- 10.4% points, p = .006). Worsened satisfaction was concentrated among clinics that had decreased PCMH rating, with those clinics seeing far fewer providers report high job satisfaction (- 38.1% points, p < 0.001). LIMITATIONS: Control clinics were not used. Individual-level longitudinal survey administration was not feasible. CONCLUSION: If clinics pursue PCMH transformation and providers do not perceive improvement, they may risk significantly worsened job satisfaction. Clinics should be aware of this potential risk of PCMH transformation and ensure that providers are aware of PCMH improvements.
Assuntos
Esgotamento Profissional/psicologia , Pessoal de Saúde/psicologia , Pessoal de Saúde/tendências , Satisfação no Emprego , Moral , Assistência Centrada no Paciente/tendências , Adolescente , Adulto , Atitude do Pessoal de Saúde , Esgotamento Profissional/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Centrada no Paciente/métodos , Atenção Primária à Saúde/métodos , Atenção Primária à Saúde/tendências , Provedores de Redes de Segurança/métodos , Provedores de Redes de Segurança/tendências , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND & AIMS: Guidelines recommend that all colorectal tumors be assessed for mismatch repair deficiency, which could increase identification of patients with Lynch syndrome. This is of particular importance for minority populations, in whom hereditary syndromes are under diagnosed. We compared rates and outcomes of testing all tumor samples (universal testing) collected from a racially and ethnically diverse population for features of Lynch syndrome. METHODS: We performed a retrospective analysis of colorectal tumors tested from 2012 through 2016 at 4 academic centers. Tumor samples were collected from 767 patients with colorectal cancer (52% non-Hispanic white [NHW], 26% African American, and 17% Hispanic patients). We assessed rates of tumor testing, recommendations for genetic evaluation, rates of attending a genetic evaluation, and performance of germline testing overall and by race/ethnicity. We performed univariate and multivariate regression analyses. RESULTS: Overall, 92% of colorectal tumors were analyzed for mismatch repair deficiency without significant differences among races/ethnicities. However, minority patients were significantly less likely to be referred for genetic evaluation (21.2% for NHW patients vs 16.9% for African American patients and 10.9% for Hispanic patients; P = .02). Rates of genetic testing were also lower among minority patients (10.7% for NHW patients vs 6.0% for AA patients and 3.1% for Hispanic patients; P < .01). On multivariate analysis, African American race, older age, and medical center were independently associated with lack of referral for genetic evaluation and genetic testing. CONCLUSION: In a retrospective analysis, we found that despite similar rates of colorectal tumor analysis, minority patients are less likely to be recommended for genetic evaluation or to undergo germline testing for Lynch syndrome. Improvements in institutional practices in follow up after tumor testing could reduce barriers to diagnosis of Lynch diagnosis in minorities.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/estatística & dados numéricos , Testes Genéticos/estatística & dados numéricos , Síndromes Neoplásicas Hereditárias/diagnóstico , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Idoso , Etnicidade , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Grupos Raciais , Estudos RetrospectivosAssuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Aconselhamento Genético/estatística & dados numéricos , Testes Genéticos/estatística & dados numéricos , Estudos Transversais , Feminino , Predisposição Genética para Doença , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados UnidosRESUMO
Glycosylation affects the circulatory half-lives of therapeutic proteins. However, the effects of an additional N-glycosylation in the unstructured region or the loop region of alpha-1 antitrypsin (A1AT) on the circulatory half-life of the protein are largely unknown. In this study, we investigated the role of an additional N-glycosylation site (Q4N/D6T, Q9N, D12N/S14T, A70N, G148T, R178N, or V212N) to the three naturally occurring N-glycosylation sites in human A1AT. A single-dose (445 µg/kg) pharmacokinetic study using male Sprague-Dawley rats showed that, among the seven recombinant A1AT (rA1AT) mutants, Q9N and D12N/S14T showed the highest serum concentration and area under the curve values, as well as similar circulatory half-lives that were 2.2-fold higher than plasma-derived A1AT and 1.7-fold higher than wild-type rA1AT. We further characterized the Q9N mutant regarding the N-glycan profile, sialic acid content, protease inhibitory activity, and protein stability. The results indicate that an additional N-glycosylation in the flexible N-terminal region increases the circulatory half-life of rA1AT without altering its protease inhibitory activity. Our study provides novel insight into the use of rA1AT for the treatment of emphysema with an increased injection interval relative to the clinically used plasma-derived A1AT.
Assuntos
alfa 1-Antitripsina/farmacologia , alfa 1-Antitripsina/farmacocinética , Animais , Enfisema/tratamento farmacológico , Enfisema/metabolismo , Glicosilação , Meia-Vida , Humanos , Masculino , Mutação de Sentido Incorreto , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , alfa 1-Antitripsina/genéticaRESUMO
OBJECTIVES: To compare health care use and spending of Medicaid enrollees seen at federally qualified health centers versus non-health center settings in a context of significant growth. METHODS: Using fee-for-service Medicaid claims from 13 states in 2009, we compared patients receiving the majority of their primary care in federally qualified health centers with propensity score-matched comparison groups receiving primary care in other settings. RESULTS: We found that health center patients had lower use and spending than did non-health center patients across all services, with 22% fewer visits and 33% lower spending on specialty care and 25% fewer admissions and 27% lower spending on inpatient care. Total spending was 24% lower for health center patients. CONCLUSIONS: Our analysis of 2009 Medicaid claims, which includes the largest sample of states and more recent data than do previous multistate claims studies, demonstrates that the health center program has provided a cost-efficient setting for primary care for Medicaid enrollees.
Assuntos
Financiamento Pessoal/economia , Medicaid/estatística & dados numéricos , Provedores de Redes de Segurança/economia , Provedores de Redes de Segurança/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde/economia , Atenção Primária à Saúde/estatística & dados numéricos , Estados UnidosRESUMO
BACKGROUND: Trastuzumab has shown a survival benefit in cases of Her2-positive gastroesophageal cancer (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, these low-throughput assays often produce discordant or equivocal results. METHODS: We developed a targeted proteomic assay based on selected reaction monitoring mass spectrometry (SRM-MS) and quantified levels (amol/µg) of Her2-SRM protein in cell lines (n = 27) and GEC tissues (n = 139). We compared Her2-SRM protein expression with IHC/FISH, seeking to determine optimal SRM protein expression cutoffs in order to identify HER2 gene amplification. RESULTS: After demonstrating assay development, precision, and stability, Her2-SRM protein measurement was observed to be highly concordant with the HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM expression of the covariates Met, Egfr, Her3, and HER2 heterogeneity, as well as their interactions (cell lines r (2) = 0.9842; FFPE r (2) = 0.7643). In GEC tissues, Her2-SRM protein was detected at any level in 71.2 % of cases. ROC curves demonstrated that Her2-SRM protein levels have a high specificity (100 %) at an upper-level cutoff of >750 amol/µg and sensitivity of 75 % at a lower-level cutoff of <450 amol/µg for identifying HER2 FISH-amplified tumors. An "equivocal zone" of 450-750 amol/µg of Her2-SRM protein was analogous to IHC2+ but represented fewer cases (9-16 % of cases versus 36-41 %). CONCLUSIONS: Compared to IHC, targeted SRM-Her2 proteomics provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer equivocal cases. Along with its multiplex capability for other relevant oncoproteins, these results demonstrate a refined HER2 protein expression assay for clinical application.
Assuntos
Hibridização in Situ Fluorescente/métodos , Proteômica/métodos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Amplificação de Genes , Humanos , Técnicas Imunoenzimáticas , Neoplasias Gástricas/patologiaRESUMO
STUDY QUESTION: Does an association exist between high normal numbers of CGG trinucleotide repeats on the fragile X mental retardation 1 (FMR1) gene and diminished ovarian reserve (DOR)? SUMMARY ANSWER: This large data set demonstrated that a high normal number of CGG repeats (35-54 repeats) on the FMR1 gene was not significantly correlated with DOR. WHAT IS KNOWN ALREADY: The FMR1 premutation (55-200 repeats) is a known cause of primary ovarian insufficiency. However, the relationship between high normal CGG repeat numbers (35-54 repeats) and ovarian reserve has yet to be conclusively demonstrated. STUDY DESIGN, SIZE, DURATION: This is a retrospective data analysis conducted between January 2012 and February 2014 that included 1287 women. Over 1140 women had complete data. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women, excluding oocyte donors, who presented to a large private practice specializing in reproductive endocrinology and infertility for treatment and who underwent both fragile X and ovarian reserve testing were included. All fragile X testing was performed using triplet repeat PCR, with confirmation of positives by Southern blot. CGG repeat numbers from both alleles were recorded, and the allele with the higher number of repeats was used for statistical calculations. We did not differentiate between patients with one or two high normal alleles. Women with >54 CGG repeats were excluded from the analysis. For our analysis, we considered both a 'high normal' number of CGG repeats (35-44) and an intermediate number of GCC repeats (45-54) as 'high normal'. Ovarian reserve testing was carried out on Cycle Day 2 or 3 and included measurements of FSH, anti-Müllerian hormone (AMH) and antral follicle count (AFC). A generalized linear regression model assuming gamma distribution and log link function that controlled for age was used to assess correlation between CGG repeat number and FSH, AMH and AFC. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, there was a significant correlation between increasing age and increasing FSH and decreasing AFC and AMH for the patients in this study. For every 1-year increase in age, FSH increased by a factor of 1.04, AFC decreased by a factor of 0.93 and AMH decreased by a factor of 0.89. After controlling for age, there was no significant correlation between FMR1 CGG trinucleotide repeat number and FSH (P = 0.23), AFC (P = 0.14) or AMH (P = 0.53). Three subgroup analyses were also performed. We found a significant relationship between increasing CGG repeat number and decreasing AMH levels (P = 0.01) in women >44 years old. The second subgroup analysis included only Caucasian patients and found no significant correlation between CGG repeat number and DOR. In a subgroup analysis comparing women with at least one allele <26 repeats, at least one allele >35 and women with both alleles between 29 and 32, there were no significant associations regarding ovarian reserve in any of these groups. LIMITATIONS, REASONS FOR CAUTION: One limitation of this study is that it involved a heterogeneous population of infertile women with mixed diagnoses. Factors that could affect ovarian reserve, such as medical comorbidities, prior surgeries, family history and endometriosis, were not accounted for. Finally, there was a lack of racial diversity, with Caucasians representing 67.8% of the total population. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study are generalizable to an infertility population and are in line with several previously published studies. Women who are found to have high normal CGG repeat numbers can be counseled that this is not causative for DOR. Further studies are needed to investigate whether increasing CGG repeat numbers are associated with ovarian responsiveness to gonadotrophin stimulation or IVF outcome.
Assuntos
Hormônio Antimülleriano/sangue , Proteína do X Frágil da Deficiência Intelectual/genética , Infertilidade Feminina/genética , Reserva Ovariana/genética , Repetições de Trinucleotídeos/genética , Adulto , Fatores Etários , Feminino , Humanos , Infertilidade Feminina/sangue , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Churches may provide a familiar and accessible setting for chronic disease self-management education and social support for Latinos with diabetes. OBJECTIVE: We assessed the impact of a multi-faceted church-based diabetes self-management intervention on diabetes outcomes among Latino adults. DESIGN: This was a community-based, randomized controlled, pilot study. SUBJECTS: One-hundred adults with self-reported diabetes from a Midwestern, urban, low-income Mexican-American neighborhood were included in the study. INTERVENTIONS: Intervention participants were enrolled in a church-based diabetes self-management program that included eight weekly group classes led by trained lay leaders. Enhanced usual care participants attended one 90-minute lecture on diabetes self-management at a local church. OUTCOME MEASURES: The primary outcome was change in glycosylated hemoglobin (A1C). Secondary outcomes included changes in low-density lipoproteins (LDL), blood pressure, weight, and diabetes self-care practices. KEY RESULTS: Participants' mean age was 54 ± 12 years, 81 % were female, 98 % were Latino, and 51 % were uninsured. At 3 months, study participants in both arms decreased their A1C from baseline (-0.32 %, 95 % confidence interval [CI]: -0.62, -0.02 %). The difference in change in A1C, LDL, blood pressure and weight from baseline to 3-month and 6-month follow-up was not statistically significant between the intervention and enhanced usual care groups. Intervention participants reported fewer days of consuming high fat foods in the previous week (-1.34, 95 % CI: -2.22, -0.46) and more days of participating in exercise (1.58, 95 % CI: 0.24, 2.92) compared to enhanced usual care from baseline to 6 months. CONCLUSIONS: A pilot church-based diabetes self-management intervention did not reduce A1C, but resulted in decreased high fat food consumption and increased participation in exercise among low-income Latino adults with diabetes. Future church-based interventions may need to strengthen linkages to the healthcare system and provide continued support to participants to impact clinical outcomes.
Assuntos
Catolicismo , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/terapia , Intervenção Médica Precoce/métodos , Comportamentos Relacionados com a Saúde/etnologia , Hispânico ou Latino/etnologia , Autocuidado/métodos , Adulto , Idoso , Pressão Sanguínea/fisiologia , Exercício Físico/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
BACKGROUND: To investigate the incidence of second malignant neoplasms (SMN) for patients with neuroblastoma, we analyzed patients from the SEER database according to three treatment eras (Era 1: 1973-1989, Era 2: 1990-1996, and Era 3: 1997-2006) corresponding to the introduction of multi-agent chemotherapy, risk-based treatment, and stem cell transplant. PROCEDURES: The SEER database was mined for all patients with neuroblastoma or ganglioneuroblastoma. Cumulative incidence of SMN was calculated with death as a competing risk. A poisson regression model was used to estimate incidence rate ratios and 95% confidence intervals to compare the rates of SMN between patients in different Eras. RESULTS: The analytic cohort included 2,801 patients. Thirty-four patients developed a SMN, accounting for 1.2% of all patients. Of the patients who developed a SMN, 47.1% received radiation for their primary neuroblastoma. Fourteen of the SMN were carcinomas, and 10 were hematologic malignancies, with six cases of acute myelogenous leukemia. There was no difference in the incidence of SMN in Era 1 compared to Era 3 (P = 0.48). The cumulative incidence of SMN at 30 years for high-risk patients was 10.44% (95% CI 3.98-20.52%) compared to 3.57% (95% CI 1.87-6.12%) for non-high-risk patients (P < 0.001). CONCLUSIONS: This study showed no increase in the incidence of SMNs for children treated in the most recent treatment era as compared to earlier Eras. However, as the risk for developing SMN does not plateau, the number of SMNs will likely continue to rise in the cohort of patients treated after 1996. Comprehensive follow-up care for these survivors will be important.
Assuntos
Segunda Neoplasia Primária/epidemiologia , Neuroblastoma/complicações , Lesões por Radiação/epidemiologia , Radioterapia/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , Estadiamento de Neoplasias , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/mortalidade , Neuroblastoma/mortalidade , Neuroblastoma/radioterapia , Prognóstico , Lesões por Radiação/etiologia , Lesões por Radiação/mortalidade , Fatores de Risco , Programa de SEER , Taxa de Sobrevida , Adulto JovemRESUMO
Advances in high throughput technology have enabled the generation of unprecedented amounts of genomic data (e.g., next-generation sequence data, transcriptomics, metabolomics, and proteomics), which promises to unravel the genetic architecture of complex traits. These discoveries may lead to novel therapeutic targets, guide disease prevention, and enable personalized medicine. However, the pace of data generation surpasses the ability to process and analyze the vast amounts of data. For example, in a typical study of transcription regulation, the relationship between more than 1 million genetic variants and 10,000 transcript levels are explored, requiring tens of billions of tests. In order to address this problem, we propose a fast, accurate, and robust method that can assess the significance of associations between quantitative phenotypes and genotypes. The method is an extension of the allelic test commonly used in case-control studies for the analysis of quantitative traits. We show the asymptotic equivalence of the proposed test to linear regression results. We also reduce a generalized linear regression problem to the comparison of two groups, which can handle nonnormal and survival time phenotypes.
Assuntos
Alelos , Estudo de Associação Genômica Ampla/métodos , Genômica , Genótipo , Humanos , Nefropatias/genética , Modelos Lineares , Fenótipo , Locos de Características Quantitativas/genética , Taxa de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: Few studies have evaluated whether the patient-centered medical home (PCMH) supports patient activation and none have evaluated whether support for patient activation differs among racial and ethnic groups or by health status. This is critical because activation is lower on average among minority patients and those in poorer health. OBJECTIVE: To assess the association between clinic PCMH characteristics and patient perception of clinic support for patient activation, and whether that association varies by patients' self-reported race/ethnicity or health status. PARTICIPANTS: A total of 214 providers/staff and 735 patients in 24 safety net clinics across 5 states. MEASURES: Provider/staff surveys produced a 0-100 score for PCMH characteristics. Patient surveys used the patient activation subscale of the Patient Assessment of Chronic Illness Care to produce a 0-100 score for patient perception of clinic support for patient activation. RESULTS: Across all patients, we did not find a statistically significant association between PCMH score and clinic support for patient activation. However, among the subgroup of minority patients in fair or poor health, a 10-point higher PCMH score was associated with a 14.5-point (CI, 4.4, 24.5) higher activation score. CONCLUSIONS: In a population of safety net patients, higher-rated PCMH characteristics were not associated with patients' perception of clinic support for activation among the full study population; however, we found a strong association between PCMH characteristics and clinic support for activation among minority patients in poor/fair health status. The PCMH may be promising for reducing disparities in patient activation for ill minority patients.
Assuntos
Doença Crônica/etnologia , Etnicidade , Assistência Centrada no Paciente/organização & administração , Relações Profissional-Paciente , Avaliação de Programas e Projetos de Saúde/métodos , Provedores de Redes de Segurança/organização & administração , Colorado , Pesquisa sobre Serviços de Saúde , Nível de Saúde , Humanos , Idaho , Massachusetts , Oregon , PennsylvaniaRESUMO
BACKGROUND: The Risk Analysis Index (RAI) is a frailty assessment tool based on an accumulation of deficits model. We mapped RAI to data from the Society of Thoracic Surgeons (STS) Database to determine whether RAI correlates with postoperative outcomes following lung cancer resection. METHODOLOGY/PRINCIPAL FINDINGS: This was a national database retrospective observational study based on data from the STS Database. Study patients underwent surgery 2018 to 2020. RAI was divided into four increasing risk categories. The associations between RAI and each of postoperative complications and administrative outcomes were examined using logistic regression models. We also compared the performance of RAI to established risk indices (American Society of Anesthesiology (ASA) and Charlson Comorbidity Index (CCI)) using areas under the Receiver Operating Characteristic (ROC) curves (AUC). Results: Of 29,420 candidate patients identified in the STS Database, RAI could be calculated for 22,848 (78%). Almost all outcome categories exhibited a progressive increase in marginal probability as RAI increased. On multivariable analyses, RAI was significantly associated with an incremental pattern with almost all outcomes. ROC analyses for RAI demonstrated "good" AUC values for mortality (0.785; 0.748) and discharge location (0.791), but only "fair" values for all other outcome categories (0.618 to 0.690). RAI performed similarly to ASA and CCI in terms of AUC score categories. CONCLUSIONS/SIGNIFICANCE: RAI is associated with clinical and administrative outcomes following lung cancer resection. However, its overall accuracy as a surgical risk predictor is only moderate and similar to ASA and CCI. We do not recommend routine use of RAI for assessment of individual patient risk for major lung resection.
Assuntos
Neoplasias Pulmonares , Complicações Pós-Operatórias , Humanos , Neoplasias Pulmonares/cirurgia , Feminino , Masculino , Idoso , Medição de Risco/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Curva ROC , Bases de Dados Factuais , Pneumonectomia/efeitos adversos , Fatores de Risco , Fragilidade/epidemiologiaRESUMO
Importance: Meticulous postoperative flap monitoring is essential for preventing flap failure and achieving optimal results in free flap operations, for which physical examination has remained the criterion standard. Despite the high reliability of physical examination, the requirement of excessive use of clinician time has been considered a main drawback. Objective: To develop an automated free flap monitoring system using artificial intelligence (AI), minimizing human involvement while maintaining efficiency. Design, Setting, and Participants: In this prognostic study, the designed system involves a smartphone camera installed in a location with optimal flap visibility to capture photographs at regular intervals. The automated program identifies the flap area, checks for notable abnormalities in its appearance, and notifies medical staff if abnormalities are detected. Implementation requires 2 AI-based models: a segmentation model for automatic flap recognition in photographs and a grading model for evaluating the perfusion status of the identified flap. To develop this system, flap photographs captured for monitoring were collected from patients who underwent free flap-based reconstruction from March 1, 2020, to August 31, 2023. After the 2 models were developed, they were integrated to construct the system, which was applied in a clinical setting in November 2023. Exposure: Conducting the developed automated AI-based flap monitoring system. Main Outcomes and Measures: Accuracy of the developed models and feasibility of clinical application of the system. Results: Photographs were obtained from 305 patients (median age, 62 years [range, 8-86 years]; 178 [58.4%] were male). Based on 2068 photographs, the FS-net program (a customized model) was developed for flap segmentation, demonstrating a mean (SD) Dice similarity coefficient of 0.970 (0.001) with 5-fold cross-validation. For the flap grading system, 11â¯112 photographs from the 305 patients were used, encompassing 10â¯115 photographs with normal features and 997 with abnormal features. Tested on 5506 photographs, the DenseNet121 model demonstrated the highest performance with an area under the receiver operating characteristic curve of 0.960 (95% CI, 0.951-0.969). The sensitivity for detecting venous insufficiency was 97.5% and for arterial insufficiency was 92.8%. When applied to 10 patients, the system successfully conducted 143 automated monitoring sessions without significant issues. Conclusions and Relevance: The findings of this study suggest that a novel automated system may enable efficient flap monitoring with minimal use of clinician time. It may be anticipated to serve as an effective surveillance tool for postoperative free flap monitoring. Further studies are required to verify its reliability.
Assuntos
Inteligência Artificial , Retalhos de Tecido Biológico , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Fotografação/métodos , Monitorização Fisiológica/métodos , Monitorização Fisiológica/instrumentação , Adulto Jovem , Adolescente , Procedimentos de Cirurgia Plástica/métodos , Reprodutibilidade dos TestesRESUMO
Recent insights have identified adrenergic (ADRN) and mesenchymal (MES) cell lineages as distinct biologic cell types and T-cell inflammation as a prognostic marker in neuroblastoma. We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers for informing ongoing efforts to improve therapeutic approaches for children with high-risk neuroblastoma. We identified lineage-specific, single-stranded super-enhancers to define ADRN and MES specific genes. Publicly available RNA-seq of diagnostic tumor biopsies was used in Discovery and Validation cohorts. Each tumor was assigned a relative MES score and T-cell-inflamed (TCI) score. Survival was assessed using the Kaplan-Meier method, and differences were assessed by the log-rank test. Inflammation scores were correlated with MES scores and anticorrelated with MYCN-amplification in both cohorts. Among patients with high-risk, ADRN tumors, those with TCI tumors had superior overall survival to those with non-inflamed tumors. A similar, but non-significant, trend was observed in the Validation cohort. Conversely, there was no difference according to TCI status in the MES cohort in either the Discover or Validation Cohorts. High inflammation scores were correlated with improved survival in some patients with high-risk, ADRN but not MES neuroblastoma. Our findings bolster support for further developing T-cell based immunotherapy-based approaches for children with high-risk neuroblastoma of varying MES and ADRN expression.
RESUMO
In rodent model systems, the sequential changes in lung morphology resulting from hyperoxic injury are well characterized and are similar to changes in human acute respiratory distress syndrome. In the injured lung, alveolar type two (AT2) epithelial cells play a critical role in restoring the normal alveolar structure. Thus characterizing the changes in AT2 cells will provide insights into the mechanisms underpinning the recovery from lung injury. We applied an unbiased systems-level proteomics approach to elucidate molecular mechanisms contributing to lung repair in a rat hyperoxic lung injury model. AT2 cells were isolated from rat lungs at predetermined intervals during hyperoxic injury and recovery. Protein expression profiles were determined by using iTRAQ with tandem mass spectrometry. Of the 959 distinct proteins identified, 183 significantly changed in abundance during the injury-recovery cycle. Gene ontology enrichment analysis identified cell cycle, cell differentiation, cell metabolism, ion homeostasis, programmed cell death, ubiquitination, and cell migration to be significantly enriched by these proteins. Gene set enrichment analysis of data acquired during lung repair revealed differential expression of gene sets that control multicellular organismal development, systems development, organ development, and chemical homeostasis. More detailed analysis identified activity in two regulatory pathways, JNK and miR 374. A novel short time-series expression miner algorithm identified protein clusters with coherent changes during injury and repair. We concluded that coherent changes occur in the AT2 cell proteome in response to hyperoxic stress. These findings offer guidance regarding the specific molecular mechanisms governing repair of the injured lung.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Hiperóxia/metabolismo , Estresse Oxidativo/fisiologia , Proteômica , Alvéolos Pulmonares/metabolismo , Mucosa Respiratória/metabolismo , Lesão Pulmonar Aguda/genética , Algoritmos , Animais , Células Cultivadas , Modelos Animais de Doenças , Hiperóxia/genética , Masculino , Oxigênio/toxicidade , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , TranscriptomaRESUMO
Human alpha-1-antitrypsin (α1AT) is a glycoprotein with protease inhibitor activity protecting tissues from degradation. Patients with inherited α1AT deficiency are treated with native α1AT (nAT) purified from human plasma. In the present study, recombinant α1AT (rAT) was produced in Chinese hamster ovary (CHO) cells and their glycosylation patterns, inhibitory activity and in vivo half-life were compared with those of nAT. A peptide mapping analysis employing a deglycosylation reaction confirmed full occupancy of all three glycosylation sites and the equivalency of rAT and nAT in terms of the protein level. N-glycan profiles revealed that rAT contained 10 glycan structures ranging from bi-antennary to tetra-antennary complex-type glycans while nAT displayed six peaks comprising majorly bi-antennary glycans and a small portion of tri-antennary glycans. In addition, most of the rAT glycans were shown to have only core α(1 - 6)-fucose without terminal fucosylation, whereas only minor portions of the nAT glycans contained core or Lewis X-type fucose. As expected, all sialylated glycans of rAT were found to have α(2 - 3)-linked sialic acids, which was in sharp contrast to those of nAT, which had mostly α(2 - 6)-linked sialic acids. However, the degree of sialylation of rAT was comparable to that of nAT, which was also supported by an isoelectric focusing gel analysis. Despite the differences in the glycosylation patterns, both α1ATs showed nearly equivalent inhibitory activity in enzyme assays and serum half-lives in a pharmacokinetic experiment. These results suggest that rAT produced in CHO cells would be a good alternative to nAT derived from human plasma.