RESUMEN
BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has significant health implications. Anemia is usually an unseen comorbidity, which could significantly affect outcomes in AECOPD patients, and there is limited data to support this. We conducted this study to assess the effect of anemia on this patient population. METHODS: We performed a retrospective cohort study using the National (Nationwide) Inpatient Sample (NIS) data from 2008 to 2014. Patients with AECOPD and anemia with age >40 years were identified using appropriate International Classification of Diseases, Ninth Revision (ICD-9) codes, excluding transfer out to other hospitals. We calculated the Charlson Comorbidity Index as a measure of associated comorbidities. We analyzed bivariate group comparisons in patients with and without anemia. Odds ratios were calculated using multivariate logistic and linear regression analysis using SAS version 9.4 (2013; SAS Institute Inc. Cary, North Carolina, United States). RESULTS: Among 3,331,305 patients hospitalized with AECOPD, 567,982 (17.0%) had anemia as a comorbidity. The majority of patients were elderly, women, and white. After adjusting for potential confounders in regression, mortality (adjusted OR (aOR) 1.25, 95%CI: 1.18-1.32), length of hospital stay (ß 0.79, 95%Cl 0.76-0.82), and hospitalization cost (ß 6873, 95%Cl 6437-7308) were significantly higher in patients with anemia. In addition, patients with anemia required significantly higher blood transfusion (aOR 16.9, 95%CI 16.1-17.8), invasive ventilator support (aOR 1.72, 95%CI 1.64-1.79), and non-invasive ventilator support (aOR 1.21, 95%CI 1.17-1.26). CONCLUSION: In this first retrospective largest cohort study on this topic, we find anemia is a significant comorbidity associated with adverse outcomes and healthcare burden in hospitalized AECOPD patients. We should focus on close monitoring and management of anemia to improve the outcomes in this population.
RESUMEN
INTRODUCTION: Retinopathy of prematurity (ROP) and infantile hemangiomas (IHs) both have similar proposed pathophysiological mechanisms. IH is more common in preterm than term infants. Hypoxia-induced mediators like vascular endothelial growth factor have been found elevated in children with hemangiomas. The aim of our study was to determine if there is an association between ROP and IH in preterm infants and to investigate racial/ethnic and gender differences of ROP and IHs in this cohort. METHODS: We accessed the national multicenter Kids' Inpatient Database (KID) Healthcare Cost and Utilization Project (HCUP) including admissions at age ≤28 days. Eligible infants were identified by using ICD-9 codes of ROP and IH in infants with gestational age (GA) ≤32 weeks and/or birth weight ≤1,500 g during the years 2003, 2006, 2009, and 2012. A weight-based analysis was performed using SAS Enterprise Guide 7.1 for complex sample design. RESULTS: In the cohort of 1,068,502 eligible infants, the prevalence of IH was 4.7 per 1,000 preterm admissions (<32 weeks). ROP prevalence was 16% for GA ≤26 weeks, 12.5% for GA 27-30 weeks, and 2.7% for GA 31-32 weeks. IH was significantly higher in infants with ROP; this relationship was consistent among all stages of ROP. Regression analysis showed that females are at increased risk of IH with ROP compared to males (adjusted odds ratio [aOR]: 2.00 [1.85-2.56]). White non-Hispanic premature infants had an increased risk of IH with concomitant ROP compared to both African American (aOR: 3.9 [2.63-4.76]) and Hispanic (aOR: 1.2 [1.14-1.38]) infants. However, African American infants had an increased risk of ROP compared to white non-Hispanic infants (aOR: 1.16 [1.07-1.14]). These genders and racial/ethnic disparities were consistent among GA categories. CONCLUSIONS: To our knowledge, this is the largest cohort based on a national multicenter database comparing an association between ROP and IH. A strong association between ROP and IH may suggest similar risk factors and/or pathophysiology. A further role of genetic factors could explain racial/ethnic differences in both conditions despite similar pathogenesis. These findings may open up new bases of research for management and prevention strategies.
RESUMEN
BACKGROUND: The available data regarding morbidity and mortality associated with multiple gestation births is conflicting and contradicting. OBJECTIVE: To compare morbidity, mortality, and length of stay (LOS) outcomes between multiple gestation (twin, triplet and higher-order) and singleton births. METHODS: Data from the national multicenter Kids' Inpatient Database of the Healthcare Cost and Utilization Project from the years 2000, 2003, 2006, 2009, 2012, and 2016 were analyzed using a complex survey design using Statistical Analysis System (SAS) 9.4 (SAS Institute, Cary NC). Neonates with ICD9 and ICD10 codes indicating singletons, twins or triplets, and higher-order multiples were included. Mortality was compared between these groups after excluding transfer outs to avoid duplicate inclusion. To analyze LOS, we included inborn neonates and excluded transfers; who died inpatient and any neonates who appear to have been discharged less than 33 weeks PMA. The LOS was compared by gestational age groups. RESULTS: A total of 22,853,125 neonates were analyzed for mortality after applying inclusion-exclusion criteria; 2.96% were twins, and 0.13% were triplets or more. A total of 22,690,082 neonates were analyzed for LOS. Mean GA, expressed as mean (SD), for singleton, twins and triplets, were 38.30 (2.21), 36.39 (4.21), and 32.72 (4.14), respectively. The adjusted odds for mortality were similar for twin births compared to singleton (aOR: 1.004, 95% CI:0.960-1.051, p = 0.8521). The adjusted odds of mortality for triplet or higher-order gestation births were higher (aOR: 1.33, 95% CI: 1.128-1.575, p = 0.0008) when compared to the singleton births. Median LOS (days) was significantly longer in multiple gestation compared to singleton births overall (singletons: 1.59 [1.13, 2.19] vs. twins 3.29 [2.17, 9.59] vs. triplets or higher-order multiples 19.15 [8.80, 36.38], p < .0001), and this difference remained significant within each GA category. CONCLUSION: Multiple gestation births have higher mortality and longer LOS when compared to singleton births. This population data from multiple centers across the country could be useful in counseling parents when caring for multiple gestation pregnancies.
RESUMEN
We sought to determine whether there are sex-based differences in the requirements for calories or protein for optimal growth during the transition phase (TP) when an extremely low birth weight (ELBW) infant, defined as a preterm infant with a birth weight of < 1000 g, is progressing from parenteral to enteral feeds. A retrospective review of ELBW infants born from 2014 to 2016 was performed at a tertiary NICU. Infants with necrotizing enterocolitis, short bowel syndrome, or chromosomal anomalies were excluded. TP was defined as the period when the infant's enteral feeds were increased from 30 up to 120 ml/kg/day while weaning parenteral nutrition (PN). Effects of sex and protein-calorie intake on the change in growth parameters from the beginning to the end of TP were analyzed. Pre-TP growth percentiles and calorie and protein intake were similar in both sexes. There was a significant (r = 0.22, p = 0.026) correlation of total calorie intake with a change in weight percentiles (wt.pc) for the whole group, but on sex-specific analysis, this correlation was more robust and significant only in girls (r = 0.28, p = 0.015). Protein intake did not correlate with the changes in wt.pc in either sex. Despite a similar intake of calories and protein during the TP, we found a significant decrease in wt.pc only in girls. More extensive studies are needed to understand the sex-based differences in caloric needs and metabolic rate in ELBW infants.
Asunto(s)
Ingestión de Energía , Recien Nacido con Peso al Nacer Extremadamente Bajo , Caracteres Sexuales , Aumento de Peso , Femenino , Humanos , Masculino , Apoyo NutricionalRESUMEN
An extremely premature infant born at a gestational age 24 5/7 and birth weight of 637 g was found to have retained a distal segment of an umbilical venous catheter (UVC) on chest radiograph after removal of the UVC. The catheter was retrieved by interventional radiology on day 10 of life when the baby weighed 660 g. To our knowledge, this is the smallest baby reported to have successfully retrieved catheter percutaneously via femoral access.
RESUMEN
Anti-E alloimmunization is the third most common cause of neonatal hemolytic disease, typically causing mild to moderate hemolytic anemia. We report an unusual case of severe hydrops fetalis and persistent pulmonary hypertension (PPHN) in a neonate with anti-E alloimmunization. Our case emphasizes the importance of close surveillance for development of severe fetal hemolytic anemia and possible need for antenatal intervention. These neonates may also need vigilant monitoring for PPHN.
RESUMEN
OBJECTIVE: To determine in-hospital outcomes of neonates with hypoxic ischemic encephalopathy (HIE) requiring extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: Single-center retrospective study from 2005 to 2016 of neonates ≥35 weeks gestation with moderate/severe HIE, requiring ECMO for persistent pulmonary hypertension of newborn (PPHN). RESULTS: Our cohort (n = 20) received therapeutic hypothermia for moderate (n = 12), severe (n = 5), or undocumented severity (n = 3) of HIE. During ECMO, 30% (n = 6) infants developed intracranial hemorrhage at a median (IQR) duration of 24 (20) hours. Sixteen (80%) infants survived to discharge, among which 15 had MRI performed; 47% (n = 7) had normal MRI, 20% (n = 3) had intracranial hemorrhage and 13% (n = 2), 13% (n = 2) and 7% (n = 1) had NICHD stage 1, 2, and 3 pattern of brain injury respectively. CONCLUSIONS: In this high-risk population of neonates, use of ECMO was safe and efficacious as demonstrated by survival and outcomes.
Asunto(s)
Oxigenación por Membrana Extracorpórea , Hipoxia-Isquemia Encefálica/mortalidad , Hipoxia-Isquemia Encefálica/terapia , Hemorragias Intracraneales/etiología , Síndrome de Circulación Fetal Persistente/etiología , Oxigenación por Membrana Extracorpórea/efectos adversos , Femenino , Mortalidad Hospitalaria , Humanos , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/fisiopatología , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Michigan , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Harlequin ichthyosis (HI) is associated with high mortality. Early systemic retinoids are widely used, although their use remains debatable. We reported two neonates with homozygous mutations in ABCA12 consistent with harlequin ichthyosis who survived to discharge home with intensive care and without use of systemic retinoids.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Ictiosis Lamelar/genética , Ictiosis Lamelar/terapia , Mutación/genética , Femenino , Humanos , Ictiosis Lamelar/diagnóstico , Recién Nacido , Masculino , Retinoides/uso terapéuticoAsunto(s)
Nervios Craneales/diagnóstico por imagen , Leucodistrofia de Células Globoides/diagnóstico por imagen , Edad de Inicio , Nervios Craneales/patología , Femenino , Humanos , Lactante , Leucodistrofia de Células Globoides/patología , Leucodistrofia de Células Globoides/terapia , Imagen por Resonancia Magnética , Nervio Óptico/diagnóstico por imagen , Nervio Óptico/patología , Trasplante de Células MadreRESUMEN
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
RESUMEN
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100â¯nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10â¯mpkâ¯=â¯0⯵Mâ¯h; F%â¯=â¯0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10â¯mpkâ¯=â¯26⯵Mâ¯h; F%â¯=â¯70).
Asunto(s)
Antineoplásicos/farmacología , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirrolidinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To evaluate short-term outcomes in infants born preterm with congenital heart defects (CHDs) and the factors associated with surgery, survival, and length of hospitalization in this population. STUDY DESIGN: We analyzed data from infants born preterm (gestational age <37 weeks) enrolled in the multicenter Kids' Inpatient Database of the Healthcare Cost and Utilization Project who were admitted to the hospital within 30 days after birth. Infants with atrial septal defects were excluded. RESULTS: Of 1 429 762 enrolled infants born preterm, 27 434 (2.0%) with CHDs were included. Overall survival to discharge was 90.5%; 74.0% among infants with critical CHDs and 45.7% among infants with hypoplastic left heart syndrome. Cardiac surgeries were performed in 12.2% of all infants born preterm. Rates of surgical intervention for infants with critical CHDs were lower for very low birth weight (≤1.5 kg) vs larger infants >1.5 kg (27% vs 44%), and only 6.3% of infants born with very low birth weight underwent surgeries in Risk-adjustment for Congenital Heart Surgery categories 4 or greater. Greater birth weight, left-sided lesions, care at children's hospitals, and absence of trisomies were associated with a greater likelihood of surgery. Birth weight <2 kg, nonwhite race, trisomy syndromes, prematurity-related morbidities, and Risk-adjustment for Congenital Heart Surgery category 4 or greater were independent predictors of mortality. Birth weight <2 kg, Risk-adjustment for Congenital Heart Surgery category, morbidities, and sidedness of lesion predicted length of stay. CONCLUSIONS: The high survival rates of infants born preterm with CHDs suggests that a cautiously optimistic approach to surgery may be warranted in all but the most immature infants with the greatest-risk conditions.
Asunto(s)
Cardiopatías Congénitas/cirugía , Enfermedades del Prematuro/cirugía , Bases de Datos Factuales , Femenino , Cardiopatías Congénitas/mortalidad , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/mortalidad , Recién Nacido de muy Bajo Peso , Tiempo de Internación/estadística & datos numéricos , Masculino , Pautas de la Práctica en Medicina/estadística & datos numéricos , Modelos de Riesgos Proporcionales , Ajuste de Riesgo , Resultado del Tratamiento , Estados UnidosRESUMEN
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Descubrimiento de Drogas , Imidazoles/farmacología , Morfolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Artritis Reumatoide/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Modelos Moleculares , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-Actividad , Regulador Transcripcional ERG/antagonistas & inhibidores , Regulador Transcripcional ERG/metabolismoRESUMEN
Introduction Prediction of mortality and morbidity in newborns with congenital diaphragmatic hernia (CDH) is too complex for practical use and may not be accurate. The main objective of this study was to evaluate the usefulness of the CDH Study Group equation and Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE) II score to predict short-term outcomes of newborns with CDH. Materials and Methods Fifty-two neonates were admitted with CDH at Children's Hospital of Michigan from November 2001 to July 2009. Retrospective chart analysis was performed. Predicted survival rates were calculated using the equation published by the CDH Study Group in 2001. SNAPPE II scores were also obtained within 12 hours of admission. Statistical analysis was performed using SPSS statistical package. Results Thirty out of 52 (58%) neonates survived to discharge. SNAPPE II score was significantly lower (p < 0.0001) in survivors (20 ± 15) versus nonsurvivors (41 ± 16). When neonates were stratified according to the CDH Study Group, low-risk patients had a survival rate of 68% (predicted 84%), moderate-risk patients had a survival rate of 43% (predicted 57%), and high-risk patients had a survival rate of 33% (predicted 36%). A total of 83% of the newborns who survived were operated within 48 hours of life, while only 17% of the nonsurvivors were operated within 48 hours of life. Conclusion SNAPPE II scores were better predictors of mortality than the CDH Study Group equation published in 2001. Further exploration is warranted to evaluate validity of survival advantage for those who were operated within 48 hours of life. A future study of combination of prenatal and postnatal factors may help in improved outcomes of the newborns with CDH.
Asunto(s)
Hernias Diafragmáticas Congénitas/mortalidad , Tamizaje Neonatal/métodos , Comorbilidad , Femenino , Hernias Diafragmáticas Congénitas/cirugía , Humanos , Recién Nacido , Masculino , Michigan/epidemiología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de SupervivenciaRESUMEN
Starting from weak µM hits identified through affinity based Automated Ligand Identification System (ALIS) screenings, double digit nM hydroxyaniline amide Erk inhibitors were discovered. This class of compounds had the unique dual mechanism of inhibiting activated and non-activated forms of Erk. They generally had high degree of selectivity in kinase panel tested.
Asunto(s)
Amidas/farmacología , Aminofenoles/farmacología , Descubrimiento de Drogas , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Amidas/síntesis química , Amidas/química , Aminofenoles/síntesis química , Aminofenoles/química , Relación Dosis-Respuesta a Droga , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Antineoplásicos/farmacología , Compuestos Aza/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Piridinas/farmacología , Transferasas Alquil y Aril/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Haplorrinos , Humanos , Ratones , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/patología , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas Quinasa Quinasa PAM/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Mutación , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.