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Conduit pulmonary artery (PA) stiffening is characteristic of pulmonary arterial hypertension (PAH) and is an excellent predictor of mortality due to right ventricular (RV) overload. To better understand the impact of conduit PA stiffening on RV afterload, it is critical to examine the arterial viscoelastic properties, which require measurements of elasticity (energy storage behavior) and viscosity (energy dissipation behavior). Here we hypothesize that PAH leads to frequency-dependent changes in arterial stiffness (related to elasticity) and damping ratio (related to viscosity) in large PAs. To test our hypothesis, PAH was induced by the combination of chronic hypoxia and an antiangiogenic compound (SU5416) treatment in mice. Static and sinusoidal pressure-inflation tests were performed on isolated conduit PAs at various frequencies (0.01-20 Hz) to obtain the mechanical properties in the absence of smooth muscle contraction. Static mechanical tests showed significant stiffening of large PAs with PAH, as expected. In dynamic mechanical tests, structural stiffness (κ) increased and damping ratio (D) decreased at a physiologically relevant frequency (10 Hz) in hypertensive PAs. The dynamic elastic modulus (E), a material stiffness, did not increase significantly with PAH. All dynamic mechanical properties were strong functions of frequency. In particular, κ, E and D increased with increasing frequency in control PAs. While this behavior remained for D in hypertensive PAs, it reversed for κ and E. Since these novel dynamic mechanical property changes were found in the absence of changes in smooth muscle cell content or contraction, changes in collagen and proteoglycans and their interactions are likely critical to arterial viscoelasticity in a way that has not been previously described. The impact of these changes in PA viscoelasticity on RV afterload in PAH awaits further investigation.

Virus is detected in about 80% of upper respiratory tract infections (URTIs) in children and is also detectable in the nasopharynx of 30% of asymptomatic children. The effect of asymptomatic viral infection on the dynamics of bacterial density and colonization of the nasopharynx has not been reported. The current study was performed to assess the presence and density of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the nasopharynx of 4-7-year-old children during URTI and when well. Nasal samples were obtained during 4 surveillance periods when children were asymptomatic and whenever they had symptoms of URTI. Respiratory viruses and bacterial pathogens were identified and quantified using polymerase chain reaction. The proportion of children colonized with all 3 bacteria was higher during visits for acute URTI than during asymptomatic surveillance visits. Mean bacterial densities were significantly higher at all visits for all 3 pathogens when a virus was detected. The differences between the means were 1.0, 0.4, and 0.7 log10 colony-forming unit equivalents per milliliter for S. pneumoniae, H. influenzae, and M. catarrhalis, respectively, compared with visits in which virus was not detected. The percentage of children colonized and density were also higher at asymptomatic visits in which virus was detected than at visits in which virus was not detected. The density and frequency of colonization with S. pneumoniae, H. influenzae, and M. catarrhalis in nasal wash samples increase during periods of both symptomatic and asymptomatic viral infection. Increases in bacterial colonization observed during asymptomatic viral infection were nearly the same magnitude as when children were symptomatic.

Background The body mass index (BMI) is a simple and widely utilized screening tool for obesity in children and adults. The purpose of this investigation was to evaluate if BMI could predict total fat mass (TFM) and percent body fat (%FAT) in a sample of overweight and obese children. Methods In this observational study, body composition was measured by dual energy x-ray absorptiometry (DXA) in 663 male and female overweight and obese children at baseline within a multidisciplinary, pediatric fitness clinic at an academic medical center. Univariate and multivariate regression analyses were conducted to evaluate whether BMI z-score (BMIz) predicts TFM or %FAT. Results The BMIz, sex and age of subjects were identified as significant predictors for both TFM and %FAT. In subjects younger than 9 years, the BMIz was a weak to moderate predictor for both TFM (R 2  = 0.03 for males and 0.26 for females) and %FAT (R 2  = 0.22 for males and 0.38 for females). For subjects between 9 and 18 years, the BMIz was a strong predictor for TFM (R 2 between 0.57 and 0.73) while BMIz remained only moderately predictive for %FAT (R 2 between 0.22 and 0.42). Conclusions These findings advance the understanding of the utility and limitations of BMI in children and adolescents. In youth (9-18y), BMIz is a strong predictor for TFM, but a weaker predictor of relative body fat (%FAT). In children younger than 9y, BMIz is only a weak to moderate predictor for both TFM and %FAT. This study cautions the use of BMIz as a predictor of %FAT in children younger than 9 years.

PurposeWe have previously reported that a plasmid DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) had greater clinical activity when given in combination with pembrolizumab to patients with metastatic, castration-resistant prostate cancer. The current trial was conducted to evaluate vaccination with PD-1 blockade, using nivolumab, in patients with early, recurrent (M0) prostate cancer.MethodsPatients with M0 prostate cancer were treated with pTVG-HP (100 µg administered intradermally) and nivolumab (240 mg intravenous infusion) every 2 weeks for 3 months, and then every 4 weeks for 1 year of total treatment. Patients were then followed for an additional year off treatment. The primary objectives were safety and complete prostate-specific antigen (PSA) response (PSA<0.2 ng/mL).Results19 patients were enrolled. No patients met the primary endpoint of complete PSA response; however, 4/19 (21%) patients had a PSA decline >50%. Median PSA doubling times were 5.9 months pretreatment, 25.6 months on-treatment (p=0.001), and 9.0 months in the subsequent year off-treatment. The overall median radiographic progression-free survival was not reached. Grade 3 or 4 events included adrenal insufficiency, fatigue, lymphopenia, and increased amylase/lipase. 9/19 (47%) patients developed immune-related adverse effects (irAE). The development of irAE and increased CXCL9 were associated with increased PSA doubling time. Quantitative NaF PET/CT imaging showed the resolution of subclinical lesions along with the development of new lesions at each time point.ConclusionsIn this population, combining nivolumab with pTVG-HP vaccination was safe, and immunologically active, prolonged the time to disease progression, but did not eradicate disease. Quantitative imaging suggested that additional treatments targeting mechanisms of resistance may be required to eliminate tumors.Trial registration numberNCT03600350.

Objectives To compare complex quantitative magnetic resonance imaging (MRI) with MR spectroscopy (MRS) for quantification of hepatic steatosis (HS) and determine clinically significant MRI-based thresholds of HS in female youths. Methods This prospective, cross-sectional study was conducted in 132 healthy females (11–22 years, mean 13.3 ± 2). Proton density fat-fraction (PDFF) was measured using complex quantitative MRI and MRS. Body mass index (BMI), fasting labs [glucose, insulin, alanine aminotransferase (ALT), and other metabolic markers] were obtained. Outcomes were measured using regression analysis, Spearman-rank correlation, and receiver operator characteristics (ROC) analysis. HS was defined as MRI-PDFF >5.6 %. Results HS was detected by MRI-PDFF in 15 % of all subjects. Linear regression demonstrated excellent correlation and agreement [r 2  = 0.96, slope = 0.97 (95 %CI: 0.94–1.00), intercept = 0.78 % (95 %CI: 0.58–0.98 %)] between MRI-PDFF and MRS-PDFF. MRI-PDFF had a sensitivity of 100 % (95 %CI: 0.79–1.00), specificity of 96.6 % (95 %CI: 0.91–0.99), and a kappa index of 87 % (95 %CI: 0.75–0.99) for identifying HS. In overweight subjects with HS, MRI-PDFF correlated with ALT (r = 0.84, p  < 0.0001) and insulin (r = 0.833, p  < 0.001), but not with BMI or WC. ROC analysis ascertained an optimal MRI-PDFF threshold of 3.5 % for predicting metabolic syndrome (sensitivity = 76 %, specificity = 83 %). Conclusion Complex quantitative MRI demonstrates strong correlation and agreement with MRS to quantify hepatic triglyceride content in adolescent girls and young women. A low PDFF threshold is predictive of metabolic syndrome in this population. Key points • Confounder-corrected quantitative MRI (ccqMRI) effectively measures hepatic triglyceride content in adolescent girls. • MRS and ccqMRI strongly correlate in liver proton density fat-fraction (PDFF) detection. • A PDFF threshold of 3.5 % may be predictive of paediatric metabolic syndrome.

Background. We estimated the vaccine effectiveness (VE) of tetanus-diphtheria-acellular pertussis vaccine (Tdap) for preventing pertussis among adolescents during a statewide outbreak of pertussis in Wisconsin during 2012. Methods. We used the population-based Wisconsin Immunization Registry (WIR) to construct a cohort of Wisconsin residents born during 1998-2000 and collect Tdap vaccination histories. Reports of laboratory-confirmed pertussis with onset during 2012 were matched to WIR clients. Incidence rate ratios (IRRs) of pertussis and Tdap VE estimates [(1 - IRR)*100%], by year of Tdap vaccine receipt and brand (Boostrix/Adacel), were estimated using Poisson regression. Results. Tdap VE decreased with increasing time since receipt, with VEs of 75.3% (95% confidence interval [CI], 55.2%-86.5%) for receipt during 2012,68.2% (95% CI, 60.9%-74.1%) for receipt during 2011, 34.5% (95% CI, 19.9%-46.4%) for receipt during 2010, and 11.9% (95% CI, -11.1% to 30.1%) for receipt during 2009/2008; point estimates were higher among Boostrix recipients than among Adacel recipients. Among Tdap recipients, increasing time since receipt was associated with increased risk, and receipt of Boostrix (vs Adacel) was associated with decreased risk of pertussis (adjusted IRR, 0.62 [95% CI, .52-74]). Conclusions. Our results demonstrate waning immunity following vaccination with either Tdap brand. Boostrix was more effective than Adacel in preventing pertussis in our cohort, but these findings may not be generalizable to adolescent cohorts that received different diphtheria-tetanus-acellular pertussis vaccines (DTaP) during childhood and should be further examined in studies that include childhood DTaP history.

Metabolic imaging of the relative amounts of reduced NADH and FAD and the microenvironment of these metabolic electron carriers can be used to noninvasively monitor changes in metabolism, which is one of the hallmarks of carcinogenesis. This study combines cellular redox ratio, NADH and FAD lifetime, and subcellular morphology imaging in three dimensions to identify intrinsic sources of metabolic and structural contrast in vivo at the earliest stages of cancer development. There was a significant (P < 0.05) increase in the nuclear to cytoplasmic ratio (NCR) with depth within the epithelium in normal tissues; however, there was no significant change in NCR with depth in precancerous tissues. The redox ratio significantly decreased in the less differentiated basal epithelial cells compared with the more mature cells in the superficial layer of the normal stratified squamous epithelium, indicating an increase in metabolic activity in cells with increased NCR. However, the redox ratio was not significantly different between the superficial and basal cells in precancerous tissues. A significant decrease was observed in the contribution and lifetime of protein-bound NADH (averaged over the entire epithelium) in both low- and high-grade epithelial precancers compared with normal epithelial tissues. In addition, a significant increase in the protein-bound FAD lifetime and a decrease in the contribution of protein-bound FAD are observed in high-grade precancers only. Increased intracellular variability in the redox ratio, NADH, and FAD fluorescence lifetimes were observed in precancerous cells compared with normal cells.

Background The age and sex standardized body mass index (BMIz) is a simple and widely utilized screening tool for obesity in children and adolescents. The purpose of this study was to evaluate the relationship between the BMIz trajectory versus the percent body fat (%FAT) trajectory, and if BMIz could predict significant changes in %FAT in a sample of obese children and adolescents. Methods In this longitudinal observational study, body composition was measured by dual energy x-ray absorptiometry (DXA) in obese children within a multidisciplinary pediatric fitness clinic at an academic medical center over a 3-year time period. Regression analyses were conducted to evaluate the association between changes in BMIz and changes in %FAT. Results Baseline assessment was obtained from 515 participants. The reduction observed in BMIz (2.20 to 2.08, p  < 0.0001) correlated with the reduction in %FAT (38.5 to 35.8%, p  < 0.05) in the first two years. The overall correlation between the slope in BMIz reduction versus %FAT reduction was moderate ( r  = 0.36, p < 0.0001) over the 3-year follow-up period. The sensitivity of BMIz changes for predicting a decrease in %FAT was acceptable (70, 95% CI: 61–78%), however the specificity was poor (42, 95% CI: 31–54%). Conclusions These findings advance the understanding of the utility and limitations of BMIz in children and adolescents. While BMIz may be sensitive to changes in adiposity, it is a weak predictor of these changes in total body fat (%FAT) due to the poor specificity. Therefore, clinicians must exercise caution when monitoring changes in a growing child’s body composition to avoid misclassifying or missing substantial change when utilizing BMIz alone.

ObjectiveTo determine factors associated with nonelective PICC removal and complications.Study designOverall, 1234 PICCs were placed in 918 hospitalized infants <45 weeks postmenstrual age. Outcomes studied include nonelective PICC removal (removal prior to completion of therapy) and line complications. Univariate and multivariate mixed-effects logistic regression analyses were conducted to evaluate the associations between potential predictor variables and clinical outcomesResultsNonelective PICC removal occurred in 28.4% and complications in 34.4% of infants. Nonelective removal (p < 0.001) and complications (p = 0.006) occurred more often with upper than lower extremity PICCs. Malposition in the first 72 h (p = 0.0009) and over time (p = 0.0003) were more common in upper extremity PICCS; however, upper extremity PICCs were associated with a decreased incidence of phlebitis, edema, and perfusion changes (p = 0.03).ConclusionsApproximately one-third of PICCs were associated with complications. When feasible, lower extremity PICCs should be placed as they may be associated with fewer complications.

Objective To identify antenatal and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy (HIE). Study design A single center, retrospective cohort study was conducted for 25,494 singleton births ≥36 weeks’ gestation born between 2009 and 2016. Univariate and multivariate analyses were performed to identify risk factors for HIE. Results Thirty-seven infants met HIE inclusion criteria. Independent antenatal risk factors included primigravida, previous fetal death/stillbirth, antidepressant use, illicit drug use, Rh sensitization, and adjusted gestational weight gain >13.6 kg. Independent intrapartum risk factors identified were placental abruption, ruptured uterus, moderate-to-heavy meconium stained amniotic fluid, and delivery by cesarean-section. An intrapartum risk factor was present in 70.3% of the HIE group compared with 29.6% of the non-HIE group. Conclusion Intrapartum period risk factors appear to be important for the development of HIE. Gestational weight gain may serve as an important modifiable factor to reduce the risk of HIE.