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BACKGROUND: To determine normative data by forced oscillation technique (FOT) in non-sedated normal term neonates and test the hypothesis that infants with transient tachypnea of the newborn (TTN) have higher resistance (R) and lower reactance (X) on day 1. METHODS: Healthy term infants (n = 138) and infants with TTN (n = 17) were evaluated on postnatal days 1 through 3 (NCT03346343). FOT was measured with a mask using a TremoFlo C-100 Airwave System™. R, X, and area under the reactance curve (AX) were measured at prime frequencies 7-41 Hz for 8 s. RESULTS: In all, 86% of control infants had adequate measurements (coherence >0.8, CV < 0.25) on day 1. Infants with TTN had higher resistance at 13 Hz (TTN 32.5 cm H2O·s/L [95% CI 25.5-39.4]; controls 23.8 cm H2O·s/L [95% CI 22.2 to 25.3], P = 0.007) and lower reactance from 17 to 37 Hz (TTN -35.1 to -10.5; controls -26.3 to -6.1, P < 0.05). In healthy controls, lung mechanics were unchanged from days 1 to 3. In TTN, lung mechanics normalized on days 2 and 3. CONCLUSIONS: FOT is feasible in neonates and distinguishes normal control infants from those with TTN on postnatal day 1. Oscillometry offers a non-invasive, longitudinal technique to assess lung mechanics in newborns.
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Volumen Espiratorio Forzado , Pulmón/fisiopatología , Oscilometría/métodos , Pruebas de Función Respiratoria/métodos , Mecánica Respiratoria , Taquipnea/fisiopatología , Resistencia de las Vías Respiratorias , Asma , Femenino , Humanos , Recién Nacido , Masculino , Estudios Prospectivos , Espirometría , Capacidad VitalRESUMEN
BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).
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Glucocorticoides/administración & dosificación , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/cirugía , Prednisona/administración & dosificación , Timectomía , Adolescente , Adulto , Anciano , Terapia Combinada , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/clasificación , Índice de Severidad de la Enfermedad , Método Simple Ciego , Resultado del Tratamiento , Adulto JovenRESUMEN
Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms, there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators, has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small-molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyperresponsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor TM5275 may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling.
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Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma/tratamiento farmacológico , Piperazinas/uso terapéutico , Inactivadores Plasminogénicos/uso terapéutico , para-Aminobenzoatos/uso terapéutico , Animales , Asma/patología , Citocinas/biosíntesis , Eosinófilos/efectos de los fármacos , Femenino , Fibrinólisis/efectos de los fármacos , Ovalbúmina/administración & dosificación , Ovalbúmina/uso terapéutico , Piperazinas/administración & dosificación , Inactivadores Plasminogénicos/administración & dosificación , para-Aminobenzoatos/administración & dosificaciónRESUMEN
G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin and were then treated focally with 5 Gy radiation. Treatment was well tolerated, and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean: 23 months; range: 11-51 months). Six of the nine patients had stable disease or partial response for at least one time point. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% confidence interval: 3.0-12.7). In conclusion, this study showed the safety and the potential for clinical response of single-dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.
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Terapia Genética , Glioma/genética , Glioma/radioterapia , Herpesvirus Humano 1/genética , Adulto , Femenino , Glioma/diagnóstico por imagen , Glioma/virología , Herpesvirus Humano 1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Viroterapia Oncolítica/efectos adversos , Virus Oncolíticos/genética , Virus Oncolíticos/patogenicidad , Radiografía , Replicación Viral/genéticaRESUMEN
OBJECTIVE: To investigate the optimal gestational age to deliver pregnant people with chronic hypertension to improve perinatal outcomes. METHODS: We conducted a planned secondary analysis of a randomized controlled trial of chronic hypertension treatment to different blood pressure goals. Participants with term, singleton gestations were included. Those with fetal anomalies and those with a diagnosis of preeclampsia before 37 weeks of gestation were excluded. The primary maternal composite outcome included death, serious morbidity (heart failure, stroke, encephalopathy, myocardial infarction, pulmonary edema, intensive care unit admission, intubation, renal failure), preeclampsia with severe features, hemorrhage requiring blood transfusion, or abruption. The primary neonatal outcome included fetal or neonatal death, respiratory support beyond oxygen mask, Apgar score less than 3 at 5 minutes, neonatal seizures, or suspected sepsis. Secondary outcomes included intrapartum cesarean birth, length of stay, neonatal intensive care unit admission, respiratory distress syndrome (RDS), transient tachypnea of the newborn, and hypoglycemia. Those with a planned delivery were compared with those expectantly managed at each gestational week. Adjusted odds ratios (aORs) with 95% CIs are reported. RESULTS: We included 1,417 participants with mild chronic hypertension; 305 (21.5%) with a new diagnosis in pregnancy and 1,112 (78.5%) with known preexisting hypertension. Groups differed by body mass index (BMI) and preexisting diabetes. In adjusted models, there was no association between planned delivery and the primary maternal or neonatal composite outcome in any gestational age week compared with expectant management. Planned delivery at 37 weeks of gestation was associated with RDS (7.9% vs 3.0%, aOR 2.70, 95% CI, 1.40-5.22), and planned delivery at 37 and 38 weeks was associated with neonatal hypoglycemia (19.4% vs 10.7%, aOR 1.97, 95% CI, 1.27-3.08 in week 37; 14.4% vs 7.7%, aOR 1.82, 95% CI, 1.06-3.10 in week 38). CONCLUSION: Planned delivery in the early-term period compared with expectant management was not associated with a reduction in adverse maternal outcomes. However, it was associated with increased odds of some neonatal complications. Delivery timing for individuals with mild chronic hypertension should weigh maternal and neonatal outcomes in each gestational week but may be optimized by delivery at 39 weeks.
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Edad Gestacional , Hipertensión , Humanos , Femenino , Embarazo , Adulto , Recién Nacido , Parto Obstétrico , Complicaciones Cardiovasculares del Embarazo/terapia , Resultado del Embarazo , Factores de Tiempo , Cesárea/estadística & datos numéricos , Enfermedad Crónica , Adulto JovenRESUMEN
OBJECTIVE: To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. METHODS: We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding. RESULTS: Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine. CONCLUSION: No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.
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Antihipertensivos , Hipertensión , Labetalol , Nifedipino , Resultado del Embarazo , Humanos , Embarazo , Femenino , Labetalol/administración & dosificación , Labetalol/efectos adversos , Labetalol/uso terapéutico , Nifedipino/administración & dosificación , Nifedipino/efectos adversos , Nifedipino/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Adulto , Hipertensión/tratamiento farmacológico , Recién Nacido , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Hipertensión Inducida en el Embarazo/tratamiento farmacológico , Administración Oral , Recién Nacido Pequeño para la Edad Gestacional , Preeclampsia/tratamiento farmacológico , Enfermedad CrónicaRESUMEN
OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.
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Antihipertensivos , Hipertensión , Complicaciones Cardiovasculares del Embarazo , Humanos , Femenino , Embarazo , Recién Nacido , Adulto , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Resultado del Embarazo , Presión Arterial , Hipertensión Inducida en el Embarazo/tratamiento farmacológicoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric liver disease in the developed world, with primary care providers caring for many at-risk children. The prevalence of NAFLD varies widely by race and ethnicity. OBJECTIVE: To explore racial differences in screening and referral patterns for NAFLD among a high-risk pediatric population. METHODS: This retrospective cohort study studied primary care patients at Children's of Alabama aged 5-17 years with BMI ≥ 85th percentile from 2008 to 2018. The main outcomes of interest were screening for NAFLD with alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and referral to Hepatology, Endocrinology, or Weight Management clinics. RESULTS: Of 666 children with BMI ≥ 85th percentile, 65% were screened at least once for NAFLD during the designated study period. Liver enzyme screening was performed in 54% of Hispanic Whites, 50% of non-Hispanic Whites, and 74% of African Americans (p-value < 0.001). African American patients had the lowest rate of abnormal liver enzymes (defined as ALT and/or AST > 1 × upper limit of normal). Among all patients with abnormal liver enzymes, 87% of non-Hispanic Whites, 92% of Hispanic Whites, and 17% of African Americans were referred (p-value < 0.0001). CONCLUSIONS: Significant differences exist in NAFLD screening and referral practices by race/ethnicity. African Americans were far less likely to be referred for abnormal screening labs than their counterparts of other races. Awareness of these differences may allow for more intentional efforts to standardize practices, ensuring all patients receive care according to established guidelines.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Niño , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Etnicidad , Estudios Retrospectivos , Derivación y Consulta , Atención Primaria de SaludRESUMEN
OBJECTIVE: To evaluate the association between maternal blood pressure (BP) below 130/80 mm Hg compared with 130-139/80-89 mm Hg and pregnancy outcomes. METHODS: We conducted a planned secondary analysis of CHAP (Chronic Hypertension and Pregnancy), an open label, multicenter, randomized controlled trial. Participants with mean BP below 140/90 mm Hg were grouped as below 130/80 mm Hg compared with 130-139/80-89 mm Hg by averaging postrandomization clinic BP throughout pregnancy. The primary composite outcome was preeclampsia with severe features, indicated preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The secondary outcome was small for gestational age (SGA). RESULTS: Of 2,408 patients in CHAP, 2,096 met study criteria; 1,328 had mean BP 130-139/80-89 mm Hg and 768 had mean BP below 130/80 mm Hg. Participants with mean BP below 130/80 mm Hg were more likely to be older, on antihypertensive medication, in the active treatment arm, and to have lower BP at enrollment. Mean clinic BP below 130/80 mm Hg was associated with lower frequency of the primary outcome (16.0% vs 35.8%, adjusted relative risk 0.45; 95% CI 0.38-0.54) as well as lower risk of severe preeclampsia and indicated birth before 35 weeks of gestation. There was no association with SGA. CONCLUSION: In pregnant patients with mild chronic hypertension, mean BP below 130/80 mm Hg was associated with improved pregnancy outcomes without increased risk of SGA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.
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Hipertensión , Preeclampsia , Nacimiento Prematuro , Embarazo , Humanos , Recién Nacido , Femenino , Preeclampsia/epidemiología , Preeclampsia/etiología , Nacimiento Prematuro/epidemiología , Placenta , Resultado del Embarazo , Retardo del Crecimiento Fetal , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/complicacionesRESUMEN
The matricellular protein osteopontin (OPN), expressed in various cancer types and elevated in the blood of cancer patients, is thought to have different functions when derived from host versus cancer cells. To assess the effect of host-derived OPN on growth of cancers of epithelial origin, we established a line of cutaneous squamous cell carcinoma (SCC) cells, named ONSC, which lacks the OPN gene and develops SCC in syngeneic wild-type (WT) and OPN-null mice. At 8 and/or 10 week after subcutaneous injection of ONSC cells in mice, however, there was a lower tumor incidence in WT mice, suggesting that host-derived OPN is associated with suppression of early growth of extrinsic cancer cells. Histological, immunohistochemical, biochemical and hematological analyses were performed on the tumor microenvironment and blood from tumor-bearing mice during the first week after implantation. Host-derived OPN suppression of extrinsic ONSC cell progression is likely mediated through elicitation of an early innate inflammatory response, through its function as a chemoattractant and/or by enhancing survival of inflammatory cells. Further, consistent with a previous report, the serum levels of host-derived OPN, which are elevated during the early phase of tumor growth in mice implanted with ONSC, appear to reflect an anti-tumor progression effect.
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Carcinoma de Células Escamosas/metabolismo , Osteopontina/fisiología , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Inflamación , Ratones , Ratones Transgénicos , Osteopontina/sangre , Microambiente TumoralRESUMEN
OBJECTIVE: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase. METHODS: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24-week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2-sample test were used for analyses, along with Kaplan-Meier estimates and log rank tests. RESULTS: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF-treated patients versus 30% of placebo-treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%). CONCLUSION: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.
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Inmunidad Adaptativa/efectos de los fármacos , Supresores de la Gota/administración & dosificación , Gota/tratamiento farmacológico , Ácido Micofenólico/administración & dosificación , Polietilenglicoles/administración & dosificación , Urato Oxidasa/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Gota/inmunología , Supresores de la Gota/inmunología , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/inmunología , Prueba de Estudio Conceptual , Resultado del Tratamiento , Urato Oxidasa/inmunologíaRESUMEN
Importance: Despite a high disease burden, there is no effective treatment for respiratory syncytial virus (RSV) infection. Objectives: To determine whether administration of azithromycin (AZM) to children with RSV-induced respiratory failure is safe and to define the effect of AZM therapy on nasal matrix metalloproteinase 9 (MMP-9) levels. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 trial was conducted at a single tertiary pediatric intensive care unit from February 2016 to February 2019. The study included children with RSV infection who were admitted to the pediatric intensive care unit and required respiratory support via positive pressure ventilation (invasive and noninvasive). A total of 147 children were screened; 90 were excluded for not meeting inclusion criteria, having an absent legal guardian, lacking pharmacy support, or having a language barrier and 9 declined participation, resulting in 48 patients enrolled in the study. Intervention: Receipt of standard dose AZM (10 mg/kg/d), high-dose AZM (20 mg/kg/d), or a matching placebo of normal saline intravenously for 3 days. Main Outcomes and Measures: Nasal and endotracheal samples were collected at baseline as well as at 24 hours and 48 hours after start of treatment. The secondary outcome was to determine treatment effect on clinical outcome measures, including days of positive pressure ventilation and length of hospital stay. Results: A total of 48 patients were enrolled in the trial, with a median (range) age at randomization of 12 (1 to 125) months; 36 participants (75.0%) were younger than 2 years. Overall, 26 participants (54.2%) were boys, and 29 (60.4%) had a comorbidity. A total of 16 patients were randomized into each trial group (ie, placebo, standard-dose AZM, and high-dose AZM). Baseline demographic characteristics were comparable among the 3 groups. Both doses of AZM were safe, with no adverse events observed. No difference in nasal MMP-9 levels were observed between treatment groups. Among those who required mechanical ventilation and received high-dose AZM, endotracheal active and total MMP-9 levels were lower on day 3. Compared with baseline, active and total MMP-9 levels in endotracheal aspirates were 1.0 log lower in the high-dose AZM group (active MMP-9: 99.8% CI, -1.28 to -0.64; P < .001; total MMP-9: 99.8% CI, -1.37 to -0.57; P < .001). Patients who received high-dose AZM had fewer median (interquartile range) hospital days compared with those receiving the placebo (8 [6-14] days vs 11 [8-20] days; mean ratio estimate, 0.57; 95% CI, 0.38-0.87; P = .01). Conclusions and Relevance: In this phase 2 randomized clinical trial, both doses of AZM were safe. While nasal MMP-9 levels were unchanged among treatment groups, endotracheal MMP-9 levels were lower among those who received high-dose AZM. The positive secondary clinical outcome, while exploratory, provides insight for end points in a multicenter randomized trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02707523.
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Antibacterianos/administración & dosificación , Azitromicina/administración & dosificación , Insuficiencia Respiratoria/tratamiento farmacológico , Administración Intravenosa , Antibacterianos/farmacocinética , Azitromicina/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico , Masculino , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Respiración con Presión Positiva , Insuficiencia Respiratoria/etiología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Carga Viral/efectos de los fármacosRESUMEN
OBJECTIVE: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG). METHODS: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups. RESULTS: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone. CONCLUSIONS: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone. CLINICALTRIALSGOV IDENTIFIER: NCT00294658. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.
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Inmunosupresores/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Prednisona/uso terapéutico , Timectomía , Adolescente , Adulto , Animales , Terapia Combinada , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Miastenia Gravis/cirugía , Prednisona/administración & dosificación , Prednisona/efectos adversos , Ratas , Método Simple Ciego , Síndrome de Abstinencia a Sustancias/etiología , Timoma/complicaciones , Timoma/cirugía , Neoplasias del Timo/complicaciones , Neoplasias del Timo/cirugía , Adulto JovenRESUMEN
OBJECTIVES: To compare contraception use in 18-30-year-old women living with and without HIV. We also explored factors associated with contraceptive use. STUDY DESIGN: We reviewed outpatient medical records for women living with HIV aged 18-30â¯years seen in one of two university-affiliated HIV-subspecialty clinics in Birmingham, Alabama, between July 2015 and June 2016. We selected an age-matched sample of women living without HIV seen in one of two university-affiliated non-HIV primary care clinics as the comparator group and focused our analysis on women with a documented discussion of contraception in clinic. For women with more than one clinic visit during the 1-year study period, the most recent visit was used for analysis. Multinominal and binary logistic regressions were used to identify factors associated with contraception use, and models were adjusted for HIV status. RESULTS: This study included 197 women (58 HIV-positive, 139 HIV-negative). Short-acting contraception methods were the most common methods used by women with (41.4%) and without HIV (47.5%, p=.43). Long-acting reversible contraception (LARC) use was 14% among women with HIV and 32% among women without HIV (p=.12). Contraception use predictors included HIV status, mental health comorbidities, obesity and number of pregnancies. CONCLUSION: Documented contraceptive method use among 18-30-year -old women seen in clinics in urban Alabama varied by HIV status. Women with HIV were less likely to use LARC methods compared to women without HIV. IMPLICATIONS: Future studies should focus on identifying factors that influence contraceptive choice and which methods are offered to young women in the South. Providers should document contraception discussions at each visit and remove any barriers to LARC provision.
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Conducta Anticonceptiva/estadística & datos numéricos , Anticonceptivos Femeninos/clasificación , Infecciones por VIH/epidemiología , Anticoncepción Reversible de Larga Duración/estadística & datos numéricos , Adulto , Alabama/epidemiología , Anticoncepción/métodos , Femenino , Humanos , Modelos Logísticos , Estudios Retrospectivos , Adulto JovenRESUMEN
The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O3) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development.
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Envejecimiento/fisiología , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Apolipoproteína E3 , Exposición a Riesgos Ambientales/efectos adversos , Trastornos de la Memoria/etiología , Ozono/efectos adversos , Animales , Apolipoproteína E4 , Genotipo , Masculino , Estrés Oxidativo , Factores de RiesgoRESUMEN
BACKGROUND: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. METHODS: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. FINDINGS: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. INTERPRETATION: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke.
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Miastenia Gravis/terapia , Prednisona/uso terapéutico , Adulto , Femenino , Humanos , Estudios Longitudinales , Masculino , Miastenia Gravis/cirugía , Timectomía/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-ß peptide (Aß) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aß load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aß load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aß out of the brain, as well as plasma Aß42 are increased, whereas the expression and processing of full-length amyloid-ß protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aß40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aß accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aß in the brain.