RESUMEN
BACKGROUND AND AIMS: Purines are building blocks for the cellular genome, and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumors, and impacting tumorigenesis remains elusive. APPROACH AND RESULTS: Transcriptomic and metabolomic analyses of purine biosynthesis and purine degradation pathways were performed in the tumor and associated nontumor liver tissues obtained from 62 patients with HCC, one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated, while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DNA damage repairing (DDR) machinery through upregulating RNA N6-methyladenosine (m 6 A) modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in 5 independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo . CONCLUSIONS: Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Purinas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Daño del ADN/genética , Reparación del ADN/genética , Epigénesis Genética/genética , Regulación de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Purinas/metabolismoRESUMEN
BACKGROUND: The incidence of second stage cesarean delivery has been rising globally because of the failure or the anticipated difficulty of performing instrumental delivery. Yet, the best way to interpret the figure and its optimal rate remain to be determined. This is because it is strongly influenced by the practice of other 2 modes of birth, namely cesarean delivery performed before reaching the second stage and assisted vaginal birth during the second stage. In this regard, a bubble chart that can display 3-dimensional data through its x-axis, y-axis, and the size of each plot (presented as a bubble) may be a suitable method to evaluate the relationship between the rates of these 3 modes of births. OBJECTIVE: This study aimed to conduct an epidemiologic study on the incidence of second stage cesarean deliveries rates among >300,000 singleton term births in 10 years from 8 obstetrical units and to compare their second stage cesarean delivery rates in relation to their pre-second stage cesarean delivery rates and assisted vaginal birth rates using a bubble chart. STUDY DESIGN: The territory-wide birth data collected between 2009 and 2018 from all 8 public obstetrical units (labelled as A to H) were reviewed. The inclusion criteria were all singleton pregnancies with cephalic presentation that were delivered at term (≥37 weeks' gestation). Pre-second stage cesarean delivery rate was defined as all elective cesarean deliveries and those emergency cesarean deliveries that occurred before full cervical dilatation was achieved as a proportion of the total number of births. The second stage cesarean delivery rate and assisted vaginal birth rate were calculated according to the respective mode of delivery as a proportion of the number of cases that reached full cervical dilatation. The rates of these 3 modes of births were compared among the parity groups and among the 8 units. Using a bubble chart, each unit's second stage cesarean delivery rate (y-axis) was plotted against its pre-second stage cesarean delivery rate (x-axis) as a bubble. Each unit's second stage cesarean delivery to assisted vaginal birth ratio was represented by the size of the bubble. RESULTS: During the study period, a total of 353,434 singleton cephalic presenting term pregnancies were delivered in the 8 units, and 180,496 (51.1%) were from nulliparous mothers. When compared with the multiparous group, the nulliparous group had a significantly lower pre-second stage cesarean delivery rate (18.58% vs 21.26%; P<.001) but a higher second stage cesarean delivery rate (0.79% vs 0.22%; P<.001) and a higher assisted vaginal birth rate (17.61% vs 3.58%; P<.001). Using the bubble of their averages as a reference point in the bubble chart, the 8 units' bubbles were clustered into 5 regions indicating their differences in practice: unit B and unit H were close to the average in the center. Unit A and unit F were at the upper right corner with a higher pre-second stage cesarean delivery rate and second stage cesarean delivery rate. Unit D and unit E were at the opposite end. Unit C was at the upper left corner with a low pre-second stage cesarean delivery rate but a high second stage cesarean delivery rate, whereas unit G was at the opposite end. Unit C and unit G were also in the extremes in terms of pre-second stage cesarean delivery to assisted vaginal birth ratio (0.09 and 0.01, respectively). Although some units seemed to have very similar second stage cesarean delivery rates, their obstetrical practices were differentiated by the bubble chart. CONCLUSION: The second stage cesarean delivery rate must be evaluated in the context of the rates of pre-second stage cesarean delivery and assisted vaginal birth. A bubble chart is a useful method for analyzing the relationship among these 3 variables to differentiate the obstetrical practice between different units.
RESUMEN
BACKGROUND: The shared provider responsibility between married couples does not translate to equally shared division of childcare (CC) and household labor. While some marriages contain highly positive aspects, marriages may also simultaneously contain both positive and negative aspects. The negativity in these relationships can negate the positivity and could potentially lead to the detriment of mothers' health. PURPOSE: We examined mothers' ambulatory blood pressure (ABP) associated with their marital relationship quality and perceived equity with her spouse on CC and household tasks. METHODS: We investigate these associations using a mixed multilevel model analysis on a sample of 224 mothers in heterosexual marriages, all of whom had children under the age of 18 years currently living in the home. RESULTS: Mothers' perception of equity in the division of CC responsibilities contributed to lower ABP. Additionally, mothers in supportive marital relationships (low negativity and high positivity) had lower ABP than those in ambivalent relationships (both high negativity and positivity). There was a crossover interaction such that the effect of relationship quality on ABP was moderated by the perception of equity in the division of CC. For mothers who report doing all the CC, they had lower ABP if they had a supportive marital relationship compared with mothers in ambivalent relationships. Whereas mothers who report more equity in CC and have a supportive relationship have higher ABP compared with mothers in ambivalent relationships. CONCLUSIONS: This study has implications related to dynamics within marital relationships. These results demonstrate important relational influences on mothers' ABP.
Married mothers disproportionately shoulder the responsibilities of childcare (CC) and household labor. This inequity of the division of family responsibilities can negatively affect the relationship between husbands and wives with marital satisfaction being higher when the load is more equally shared between partners. Additionally, marital satisfaction is associated with numerous health benefits including lower blood pressure. We examined mothers' ambulatory blood pressure (ABP) associated with their marital relationship quality and perceived equity with her spouse on CC and household tasks on a sample of 224 mothers in heterosexual marriages. Mothers' perception of equity in the division of CC responsibilities contributed to lower ABP. Additionally, mothers in supportive marital relationships had lower ABP than those reporting less supportive relationships. There was an interaction between the perception of equity in the division of CC and the effect that relationship quality had on mothers' ABP. Mothers who reported doing all the CC had lower ABP if they had a supportive marital relationship compared with mothers in less supportive relationships. Whereas mothers who reported more equity in CC and had a supportive relationship had higher ABP compared with mothers in less supportive relationships.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Matrimonio , Femenino , Niño , Humanos , Adolescente , Presión Sanguínea/fisiología , Conducta Social , MadresRESUMEN
BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.
Asunto(s)
Distrofia Muscular de Cinturas , Sarcoglicanopatías , Humanos , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , Fenotipo , Músculo Esquelético , Mutación/genética , Proteínas del Tejido Nervioso/genética , Chaperonas Moleculares/genética , Proteínas del Choque Térmico HSP40/genética , Pentosiltransferasa/genética , Anoctaminas/genéticaRESUMEN
INTRODUCTION/AIMS: Scoliosis is a common comorbidity among individuals diagnosed with a dystrophinopathy. We examined associations between clinical predictors and scoliosis in childhood-onset dystrophinopathy. METHODS: The progression and treatment of scoliosis were obtained from data collected by the US population-based Muscular Dystrophy Surveillance, Tracking, and Research Network. Associations between loss of independent ambulation (LoA) and corticosteroid use and scoliosis outcomes (ages at or exceeding Cobb angle thresholds [10°, 20°, 30°]; surgery) were estimated using Kaplan-Meier curve estimation and extended Cox regression modeling. RESULTS: We analyzed curvature data for 513 of 1054 individuals ascertained. Overall, approximately one-half had at least one radiograph and one-quarter had a curvature of at least 20°. The average maximum curvature was 25.0° (SD = 21.5°) among all individuals and 42.8° (SD = 18.8°) among those recommended for surgery. Higher adjusted hazards ratio of curvature (aHR(curvature) [95% confidence interval]) were found among individuals with LoA compared to those without LoA (aHR(10) = 6.2 [4.4, 8.7], aHR(20) = 15.3 [7.4, 31.7], aHR(30) = 31.6 [7.7, 128.9]), among individuals who did not use corticosteroids compared to those who did (aHR(10) = 1.2 [0.9, 1.7], aHR(20) = 1.8 [1.1, 2.7], aHR(30) = 2.3 [1.3, 4.0]), and among non-ambulatory individuals who used corticosteroids after LoA compared to those who did not (aHR(10) = 1.8 [1.2, 2.8], aHR(20) = 1.6 [1.0, 2.6], aHR(30) = 3.6 [1.6, 7.9]). Scoliosis surgery among individuals with LoA who did not use corticosteroids was more than double compared to those who used (aHR = 2.3 [1.3, 4.2]). DISCUSSION: Our retrospective observational study suggests corticosteroids may delay spinal curvature progression and need for scoliosis surgery. Continuing corticosteroids after LoA also showed potential benefits of delaying curvature progression, additional studies are needed to confirm this finding or address the magnitude of benefit.
Asunto(s)
Distrofia Muscular de Duchenne , Escoliosis , Corticoesteroides/uso terapéutico , Humanos , Masculino , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/epidemiología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Escoliosis/complicaciones , Escoliosis/diagnóstico por imagen , Escoliosis/epidemiologíaRESUMEN
INTRODUCTION: The 21st century was marked by a dramatic increase in adolescent e-cigarette use in the United States (US). The popularity of non-traditional flavor types, including fruit and pastry, is thought to contribute toward growing product use nationally, leading to a variety of federal and state regulations limiting the use of non-traditional flavors in the US. The relationship between flavor type and increased adolescent use suggests a possible link between flavor use and addiction and harm perception. This study assessed if the flavor type used when initiating e-cigarette use predicted addiction and harm perceptions. METHODS: The study utilized data from the multi-wave youth Population Assessment of Tobacco Health Study. It explored the impact initiating e-cigarette use with traditional versus non-traditional flavor types among cigarette users on the outcome variables: e-cigarette addiction and harm perception. Both e-cigarette addiction and harm perception were measured using self-report, Likert scale questionnaires. Descriptive statistics characterized the study variables and linear regression analyses performed to test whether flavor initiation type is associated with addiction and harm perception. RESULTS: The study sample consisted of 1,043 youth (weighted N = 1,873,617) aged 12 to 17 years who reported at least one instance of e-cigarette use. After adjusting for age, age of onset, sex, race and annual household income there was no statistically significant difference in addiction levels between those initiating with traditional versus non-traditional flavors (p = 0.294). Similarly, traditional versus non-traditional flavor initiation did not show a statistically significant difference in adolescent e-cigarette harm perceptions (p = 0.601). CONCLUSIONS: Traditionally flavored e-cigarette initiation produces similar risk for addiction and harm perceptions as non-traditionally flavored initiation. These findings suggest that banning non-traditional flavors alone may be ineffective in curbing e-cigarette addiction and harm perception. Additional research is needed to better understand which e-cigarette product characteristics and behaviors may be associated with greater addiction and reduced harm perceptions.
Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Productos de Tabaco , Vapeo , Adolescente , Aromatizantes , Humanos , Percepción , Estados Unidos/epidemiología , Vapeo/epidemiologíaRESUMEN
INTRODUCTION: Past studies examined factors associated with rural practice, but none employed newer machine learning (ML) methods to explore potential predictors. The primary aim of this study was to identify factors related to practice in a rural area. Secondary aims were to capture a more precise understanding of the demographic characteristics of the healthcare professions workforce in Utah (USA) and to assess the viability of ML as a predictive tool. METHODS: This study incorporated four datasets - the 2017 dental workforce, the 2016 physician workforce, the 2014 nursing workforce and the 2017 pharmacy workforce - collected by the Utah Medical Education Council. Supervised ML techniques were used to identify factors associated with practice location, the outcome variable of interest. RESULTS: The study sample consisted of 11 259 healthcare professionals with an average age of 46.6 years, of which 36.6% were males and 94.5% Caucasian. Four ML methods were applied to assess model performance by comparing accuracy, sensitivity, specificity and area under the receiver operating characteristic (ROC) curve. Of the methods used, support vector machine performed the best (accuracy 99.7%, precision 100%, sensitivity 100%, specificity 99.4% and ROC 0.997). The models identified income and rural upbringing as the top factors associated with rural practice. CONCLUSION: By far, income emerged as the most important factor associated with rural practice, suggesting that attractive income offers might help rural communities address health professional shortages. Rural upbringing was the next most important predictive factor, validating and updating earlier research. The performance of the ML algorithms suggests their usefulness as a tool to model other databases for individualized prediction.
Asunto(s)
Servicios de Salud Rural , Atención a la Salud , Personal de Salud , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Ubicación de la Práctica Profesional , Recursos HumanosRESUMEN
[18 F]ß-CFT is a positron emission tomography (PET) ligand for imaging of dopamine transporter. It was proved to be a sensitive PET marker to detect presynaptic dopaminergic hypofunction in Parkinson's disease. In recent years, copper-mediated 18 F-fluorination of aryl boronic esters has been successful in some molecules containing aromatic groups. In this study, we describe the novel synthetic strategy of [18 F]ß-CFT by copper-mediated nucleophilic radiofluorination with pinacol-derived aryl boronic esters upon reaction with [18 F]KF/K222 and Cu (OTf)2 (py)4 . The radiolabeling protocol was optimized with [18 F]fluoride elution method and amount of copper catalyst used. [18 F]ß-CFT is obtained from boronic ester precursors in 2.2% to 10.6% non-isolated radiochemical yield (RCY). Purified [18 F]ß-CFT with >99% radiochemical purity (RCP) and high molar activity was obtained in validation runs. The radiolabeling procedure is straightforward and can easily be adapted for clinical use.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana PlasmáticaRESUMEN
BACKGROUND: Orthodontics prevent and treat facial, dental, and occlusal anomalies. Untreated orthodontic problems can lead to significant dental public health issues, making it important to understand expenditures for orthodontic treatment. This study examined orthodontic expenditures and trends in the United States over 2 decades. METHODS: This study used data collected by the Medical Expenditure Panel Survey to examine orthodontic expenditures in the United States from 1996 to 2016. Descriptive statistics for orthodontic expenditures were computed and graphed across various groups. Trends in orthodontic expenditures were adjusted to the 2016 United States dollar to account for inflation and deflation over time. Sampling weights were applied in estimating per capita and total expenditures to account for non-responses in population groups. RESULTS: Total orthodontic expenditures in the United States almost doubled from $11.5 billion in 1996 to $19.9 billion in 2016 with the average orthodontic expenditure per person increasing from $42.69 in 1996 to $61.52 in 2016. Black individuals had the lowest per capita orthodontic visit expenditure at $30.35. Out-of-pocket expenses represented the highest total expenditure and although the amount of out-of-pocket expenses increased over the years, they decreased as a percentage of total expenditures. Public insurance increased the most over the study period but still accounted for the smallest percentage of expenditures. Over the course of the study, several annual decreases were interspersed with years of increased spending CONCLUSION: While government insurance expenditure increased over the study period, out of pocket expenditures remained the largest contributor. Annual decreases in expenditure associated with economic downturns and result from the reliance on out-of-pocket payments for orthodontic care. Differences in spending among groups suggest disparities in orthodontic care among the US population.
Asunto(s)
Gastos en Salud , Seguro , Negro o Afroamericano , Demografía , Atención Odontológica , Humanos , Estados UnidosRESUMEN
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy. The high expression of BART-miRNAs (miR-BARTs) during latent EBV infection in NPC strongly supports their pathological importance in cancer progression. Recently, we found that several BART-miRNAs work co-operatively to modulate the DNA damage response (DDR) by reducing Ataxia-telangiectasia-mutated (ATM) activity. In this study, we further investigated the role of miR-BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down-regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2-3p, BART12, BART17-5p and BART19-3p in BRCA1 expression. The ectopic expression of these four miR-BARTs suppressed endogenous BRCA1 expression in EBV-negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR-BARTs activities in C666-1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR-BART17-5p and miR-BART19-3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR-BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
Asunto(s)
Proteína BRCA1/genética , Resistencia a Antineoplásicos/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/genética , MicroARNs , Carcinoma Nasofaríngeo/etiología , ARN Viral , Animales , Proteína BRCA1/metabolismo , Ciclo Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Interacciones Huésped-Patógeno/genética , Humanos , Inmunohistoquímica , Ratones , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/etiología , Neoplasias Nasofaríngeas/patología , Interferencia de ARNRESUMEN
BACKGROUND: The coronavirus disease (COVID-19) pandemic led to substantial public discussion. Understanding these discussions can help institutions, governments, and individuals navigate the pandemic. OBJECTIVE: The aim of this study is to analyze discussions on Twitter related to COVID-19 and to investigate the sentiments toward COVID-19. METHODS: This study applied machine learning methods in the field of artificial intelligence to analyze data collected from Twitter. Using tweets originating exclusively in the United States and written in English during the 1-month period from March 20 to April 19, 2020, the study examined COVID-19-related discussions. Social network and sentiment analyses were also conducted to determine the social network of dominant topics and whether the tweets expressed positive, neutral, or negative sentiments. Geographic analysis of the tweets was also conducted. RESULTS: There were a total of 14,180,603 likes, 863,411 replies, 3,087,812 retweets, and 641,381 mentions in tweets during the study timeframe. Out of 902,138 tweets analyzed, sentiment analysis classified 434,254 (48.2%) tweets as having a positive sentiment, 187,042 (20.7%) as neutral, and 280,842 (31.1%) as negative. The study identified 5 dominant themes among COVID-19-related tweets: health care environment, emotional support, business economy, social change, and psychological stress. Alaska, Wyoming, New Mexico, Pennsylvania, and Florida were the states expressing the most negative sentiment while Vermont, North Dakota, Utah, Colorado, Tennessee, and North Carolina conveyed the most positive sentiment. CONCLUSIONS: This study identified 5 prevalent themes of COVID-19 discussion with sentiments ranging from positive to negative. These themes and sentiments can clarify the public's response to COVID-19 and help officials navigate the pandemic.
Asunto(s)
Infecciones por Coronavirus/economía , Infecciones por Coronavirus/psicología , Recolección de Datos , Aprendizaje Automático , Pandemias/economía , Neumonía Viral/economía , Neumonía Viral/psicología , Opinión Pública , Medios de Comunicación Sociales/estadística & datos numéricos , COVID-19 , Infecciones por Coronavirus/epidemiología , Humanos , Neumonía Viral/epidemiología , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: To identify concepts and constructs important to parents of children with Pierre Robin Sequence (PRS). DESIGN: Qualitative study. SETTING: All children received some care at a tertiary hospital with additional care at outside facilities. Interviews were conducted in nonclinical locations, including remote locations. PARTICIPANTS: Parents of children <5 years old with a diagnosis of PRS. Prior treatments included observation, positioning, nasal trumpet, mandibular distraction osteogenesis, tracheostomy, and gastrostomy. INTERVENTION: Semi-structured interviews with individuals (4) and with groups (focus groups, 4) were conducted using open-ended questions and non-leading prompts. Transcripts were analyzed with iterative open and axial coding. Concepts and constructs were identified and refined into codes and central themes. Interviews were conducted until thematic saturation was achieved. RESULTS: Sixteen parents were interviewed. Their experiences were coded into 5 main themes, which can be summarized as: (1) child's symptoms/well-being, (2) parents' grief/isolation, (3) family stress, (4) relationships with providers, and (5) psychological and technical growth. Difficulty with feeding, weight gain, and breathing problems were core physical issues described by participants with associated intense fear. Participants described frustration from not only lack of care coordination, slow diagnoses, and poor communication but also gratitude for providers who served as advocates. Participants described gradual development of knowledge/competencies. CONCLUSIONS: Families of children with PRS have experiences that profoundly affect their lives. Child's physical symptoms/well-being and parents' psychosocial well-being provide content for a future PRS-specific quality-of-life instrument. Concepts that emerged also provide a framework to improve parents' experience and enhance their children's quality of care.
Asunto(s)
Osteogénesis por Distracción , Síndrome de Pierre Robin , Niño , Preescolar , Humanos , Mandíbula , Padres , Investigación CualitativaRESUMEN
Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28-8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28-8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28-8 and SP263 assays. In conclusion, the 22C3, 28-8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.
Asunto(s)
Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/inmunología , Inmunohistoquímica/métodos , Neoplasias Hepáticas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: The development of a disease-specific patient-reported outcome for Charcot-Marie-Tooth disease is an important step in the preparation for therapeutic trials. This study describes the development of the Charcot-Marie-Tooth Health Index (CMTHI). METHODS: Inherited Neuropathy Consortium Contact Registry participants were queried on the symptoms that most impacted their lives. The CMTHI was developed based on these responses. Factor analysis, assessment of test-retest reliability, known group validity, and patient interviews were utilized to refine the instrument. RESULTS: The final CMTHI contains 18 themes that capture Charcot-Marie-Tooth disease (CMT) burden. The CMTHI has a high internal consistency and test-retest reliability. The CMTHI was able to discriminate between patient groups expected to have different disease burden. The CMTHI was able to discriminate levels of disability as measured by the CMT examination score and the mobility-Disability Severity Index. INTERPRETATION: The CMTHI represents a valid and reliable outcome to assess patient-reported disease burden in CMT. Ann Neurol 2018;84:225-233.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/diagnóstico , Medición de Resultados Informados por el Paciente , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios/normas , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros/normas , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.
Asunto(s)
Distrofia Miotónica/fisiopatología , Distrofia Miotónica/psicología , Actividades Cotidianas , Adolescente , Adulto , Cuidadores , Niño , Preescolar , Comunicación , Costo de Enfermedad , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Femenino , Dedos/fisiopatología , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/fisiopatología , Mano/fisiopatología , Humanos , Masculino , Limitación de la Movilidad , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Miotonía/etiología , Miotonía/fisiopatología , Distrofia Miotónica/complicaciones , Medición de Resultados Informados por el Paciente , Adulto JovenRESUMEN
BACKGROUND: Routine assessment of photophobia in the clinical setting may underestimate the presence and severity of this condition. We aimed to develop and validate a questionnaire to improve evaluation of the impact of photophobia on activities of daily living, and to determine the relationship of this questionnaire to psychophysical assessment of light sensitivity thresholds. METHODS: We developed the 17-item Utah Photophobia Symptom Impact Scale (UPSIS-17) and compared its psychometric properties to the 8-item Korean Photophobia Questionnaire (KUMC-8). Ninety five subjects with or without light sensitivity completed both questionnaires; 72 also completed laboratory-based assessment of light sensitivity thresholds. We used Rasch analysis to evaluate instrument targeting, including internal consistency and reliability. Correlation analysis was used to assess the relationship between questionnaire scores and light sensitivity thresholds. RESULTS: We observed correlation between UPSIS-17 and KUMC-8, r = 0.72 (p < 0.0001). Higher UPSIS-17 scores correlated with light sensitivity thresholds, r = -0.42 (p < 0.0001), whereas KUMC-8 scores did not significantly correlate with light sensitivity thresholds, r = -0.21 (p = 0.072). UPSIS-17 showed better instrument targeting than KUMC-8 on Rasch analysis. Person-item maps allowed for identification of questions that could be removed without affecting questionnaire validity measures. CONCLUSION: This study resulted in a shortened, 12-item questionnaire. The UPSIS-12 retained significant correlation with both the KUMC-8 and light sensitivity thresholds, yielding a simpler tool for symptom assessment, while retaining validity. This expanded tool may be useful in clinical, as well as research settings, for collection of data about disability due to photophobia.
Asunto(s)
Fotofobia , Evaluación de Síntomas/instrumentación , Actividades Cotidianas , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fotofobia/diagnóstico , Psicometría/instrumentación , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Marriage is associated with lower cardiovascular morbidity and mortality, but quality matters. Marriages characterized by ambivalent behaviors (containing both highly positive and highly negative behaviors concurrently) may not confer the same cardiovascular benefits as characterized by purely positive behavior. Ambivalence is assumed to take time to develop but couples in the early years of marriage may already exhibit ambivalent behaviors and thus be at increased risk for future cardiovascular events. PURPOSE: The purpose of this study was to determine the frequency of spouse and own ambivalent behavior, the impact on interpersonal (i.e., responsiveness, disclosure, affective interactions) processes, and ambulatory blood pressure (ABP) in individuals in the early years of marriage. METHODS: In 84 young married couples, objective and subjective ambivalence, interpersonal functioning, and ABP over a 24-hr period were assessed. RESULTS: As predicted, ambivalence developed early in marriage. Regarding interpersonal processes, spousal and own objective ambivalent behavior was associated with lower spousal responsiveness (p < .01), disclosure (p < .05), and more negative (p < .03) and less positive interactions (p < .001). Physiologically, ambivalent spousal behavior was associated with higher systolic blood pressure (p = .02) and higher diastolic blood pressure (p = .04). Measures of subjective ambivalence were congruent. CONCLUSIONS: Early marriages already contain ambivalent behavior; in such cases, individuals may not receive the cardiovascular protection of a supportive marriage.
Asunto(s)
Presión Sanguínea/fisiología , Emociones/fisiología , Relaciones Interpersonales , Esposos , Adulto , Monitoreo Ambulatorio de la Presión Arterial , Femenino , Humanos , Masculino , Matrimonio , Adulto JovenRESUMEN
Objective: Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in patients with type 1 diabetes (T1D) not using a continuous glucose monitoring (CGM) system. The current study investigated the prevalence of IAH and its relationship with severe hypoglycemia in T1D patients using CGM systems. Methods: This cross-sectional observational study enrolled 135 patients with T1D and ongoing real-time CGM use. A survey was conducted to assess hypoglycemia awareness with the Gold, Clarke, and Pedersen-Bjergaard questionnaires and the 6-month history of severe hypoglycemia. Other diabetes histories and the CGM glucose data were collected. Results: The Gold, Clarke, and Pedersen-Bjergaard questionnaires demonstrated the overall prevalence of IAH/abnormal awareness to be 33.3%, 43.7%, and 77.0%, respectively. Participant age and duration of T1D were consistently related to IAH or hypoglycemia unawareness with all three questionnaires (P<.05). Amongst the patients using CGM for >6 months, 24.5% were found to have at least one episode of severe hypoglycemia in the preceding 6 months. IAH identified by the Gold and Clarke questionnaires and hypoglycemia unawareness identified by the Pedersen-Bjergaard questionnaire were related to 6-, 4.63-, and 5.83-fold increased risk of severe hypoglycemia (P = .001, .004, and .013), respectively. IAH identified by the Gold/Clarke questionnaires was associated with a longer duration of CGM glucose <54 mg/dL and higher glucose coefficients of variation (P<.05). Conclusion: IAH is highly prevalent and related to a higher risk for severe hypoglycemia in T1D patients using CGM. Abbreviations: CGM = continuous glucose monitoring; CI = confidence interval; HAAF = hypoglycemia-associated autonomic failure; HbA1c = hemoglobin A1C; IAH = impaired awareness of hypoglycemia; T1D = type 1 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1 , Hipoglucemia , Glucemia , Automonitorización de la Glucosa Sanguínea , Estudios Transversales , Hemoglobina Glucada , Humanos , Factores de RiesgoRESUMEN
PURPOSE: The Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity Computer Adaptive Test (UE CAT) was recently updated to version 2.0 (v2.0). We hypothesized that the PROMIS UE CAT v2.0 would exhibit improved performance characteristics compared with the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) when administered to a nonshoulder upper extremity patient population. METHODS: The UE CAT v2.0, Physical Function (PF) CAT v2.0, and the QuickDASH were each prospectively administered via tablet computer to all patients presenting to a tertiary hand and upper extremity clinic between April 2017 and October 2017. Patient responses were analyzed, and the mean, range, floor and ceiling effect, and correlations between instruments were calculated. RESULTS: Among 825 patients, the mean UE CAT v2.0 score was 38.3 (SD 10.7) with a range of 15 to 61 and interquartile range of 15.4. The UE CAT v2.0 had a strong correlation with the QuickDASH (r = -0.749) and the PF CAT v2.0 (r = 0.719). No patient scored between 56 and 60, indicating a gap in scoring in that range. The UE CAT v2.0 demonstrated a floor effect of 1%, a ceiling effect of 6.9%, and a high internal consistency with a Cronbach alpha of 0.99. CONCLUSIONS: The PROMIS UE CAT v2.0 demonstrated improved ceiling effects, range, and a decreased gap in scoring compared with prior versions. Limitations of the PROMIS UE CAT v2.0 are still present, but updates have led to an incremental improvement over prior versions, demonstrating the ability to influence PROMIS instrument performance through upgrades. CLINICAL RELEVANCE: The updated PROMIS UE CAT v2.0 still demonstrates a ceiling effect and gap in scores at the upper end of the instrument, both of which may limit discrimination between different levels of upper extremity function for high-functioning patients.
Asunto(s)
Evaluación de la Discapacidad , Medición de Resultados Informados por el Paciente , Extremidad Superior/fisiopatología , Computadoras de Mano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Programas InformáticosRESUMEN
PURPOSE: In light of recently-proposed quality measures for carpal tunnel release (CTR), elucidating the minimal clinically important difference (MCID) for selected outcome measures will be important when interpreting treatment responses. Our purpose was to estimate the MCID of the Patient-Reported Outcomes Measurement Information System (PROMIS) instruments and the short Disabilities of the Arm, Shoulder, and Hand (QuickDASH) following CTR. METHODS: Adult patients undergoing isolated unilateral CTR between July 2014 and October 2016 were identified. Outcomes included the PROMIS Upper Extremity (UE) Computer Adaptive Test (CAT), Physical Function (PF) CAT, QuickDASH, and Pain Interference (PI) CAT. For inclusion, pretreatment baseline (within 60 days of surgery) and postoperative (6-90 days) UE or PF CAT scores were required, as well as a response on a 5-point Likert scale to the question "How much relief and/or improvement do you feel you have experienced as a result of your treatment?" The MCID was calculated using SD and minimum detectable change (MDC) distribution methods. RESULTS: In response to the Likert scale question, 88.6% of patients reported improvement at a mean of 14.8 days after surgery. The infrequency of patients reporting no change (5 of 44; 11.4%) precluded calculation of a statistically sound anchor-based MCID value. The MCID values, as calculated using the one-half SD method, were 3.6, 4.6, 10.4, and 3.4 for the UE CAT, PF CAT, QuickDASH, and PI CAT, respectively. CONCLUSIONS: We have calculated MCID values for the UE CAT, PF CAT, QuickDASH, and PI CAT for patients undergoing CTR. Although the small number of patients reporting no change and minimal change after surgery precluded an anchor-based MCID calculation, we report estimates using the one-half SD method for the MCID following CTR. CLINICAL RELEVANCE: These MCID estimates will be helpful when interpreting CTR clinical outcomes and for powering prospective trials.