Serum total IgE and specific IgE to Dermatophagoides pteronyssinus, but not eosinophil cationic protein, are more likely to be elevated in elderly asthmatic patients.

Serum IgE (total and five specific) and eosinophil cationic protein (ECP) levels were compared in elderly physician-diagnosed patients with asthma with non-asthmatic controls matched by age and gender to ascertain whether elevated levels are indicators of asthma in the elderly. All subjects and controls were non-smokers. The subjects were participants in the Florida Geriatric Research Program (FGRP), a longitudinal aging study that tracks the health status of people 65 years and older. Frozen sera from 33 randomly selected asthmatic patients and 21 controls, none of whom had any other chronic respiratory disease, such as chronic obstructive pulmonary disease (COPD), all between the ages of 65 and 90, were assessed for total IgE; five specific IgE concentrations (for cat, ragweed, German cockroach, Dermatophagoides pteronyssinus (Dp) and live oak); and ECP levels using the Pharmacia Unicap System. The odds of an elderly asthmatic patient having a total IgE of > 100 KU/L were higher than that for a non-asthmatic patient (odds ratio (OR) = 13.0; Mantel-Haenszel (MH) p = 0.005). The odds of elderly asthmatic patients having at least one positive serum specific IgE compared to elderly age-matched non-asthmatic patients were higher (OR = 21.2; MH p = 0.001). Among the five specific IgE concentrations, only IgE for Dp was higher in asthmatic than in non-asthmatic patients (OR = 13.00; MH p = 0.005). The ECP level was not significantly different between elderly asthmatic and non-asthmatic patients (asthmatic mean = 20.7 microg/L, SE = 0.48; control mean = 19.5 microg/L. SE = 0.76) (mean for younger adults 4.4 microg/L, Pharmacia Diagnostics). The serum of elderly asthmatic patients is more likely to have elevated total IgE and a positive specific IgE to Dp. ECP is elevated in elderly subjects but is not an indicator of asthma.     

Admixed phenotype of NEDD4L associated periventricular nodular heterotopia: A case report

Rationale:Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene.Patient concerns:We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband''s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.Diagnoses:The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband''s genome that absented in any other analyzed family member, suggesting its de novo origin.Interventions and outcomes:The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.Lessons:We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.     

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

We consider dosing regimens designed to cure patients by eradicating colony forming units (CFU) such as bacteria. In the field of “population” pharmaco-kinetics/dynamics (PK/PD), inter-individual variability (IIV) of patients is estimated using model parameter statistical distributions. We consider a more probabilistic approach to IIV called stochastic process theory, motivated by the fact that tumor treatment planning uses both approaches. Stochastic process PD can supply additional insights and suggest different dosing regimens due to its emphasis on the probability of complete CFU eradication and its predictions on “pure chance” fluctuations of CFU number per patient when treatment has reduced this integer to less than ~100. To exemplify the contrast between stochastic process PD models and standard deterministic PD models, which track only average CFU number, we analyze, neglecting immune responses, neonatal intravenous gentamicin dosing regimens directed against Escherichia coli. Our stochastic calculations predict that the first dose is crucial for CFU eradication. For example, a single 6 mg/kg dose is predicted to have a higher eradication probability than four daily 4 mg/kg doses. We conclude: (1) neonatal gentamicin dosing regimens with larger first doses but smaller total doses deserve investigation; (2) in general, if standard PK/PD models predict average CFU number drops substantially below 100, the models should be modified to incorporate stochastic effects more accurately, and will then usually make more favorable, or less unfavorable, predictions for front boosting (“hit hard early”). Various caveats against over-interpreting the calculations are given.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9715-3) contains supplementary material, which is available to authorized users.KEY WORDS: anti-bacterial dosing regimens, front boosting, PK/PD eradication probability, small-number stochastic fluctuations, stochastic birth-death cell population dynamics     

Measurement Invariance of the Brief Resilient Coping Scale (BRCS) in Peruvian and Spanish Older Adults

Journal of Cross-Cultural Gerontology - Although the Brief Resilient Coping Scale (BRCS) has been validated in some European and American countries, there are no studies that evaluate its factorial...     

PENTA guidelines for the use of antiretroviral therapy in paediatric HIV infection. Pediatric European Network for Treatment of AIDS

Objective

To produce European Guidelines for the use of antiretroviral therapy (ART) in HIV‐infected children.

Design

Systematic literature review using Medline, the major antiretroviral conference reports, and IDSA recommendations on guideline production.

Setting

Pediatric European Network for Treatment of AIDS (PENTA) Steering Committee.

Outcome measure

Guidelines have been produced for the use of antiretroviral therapy in HIV‐infected children in Europe. Recommendations on when to start ART and which ART to start, with dosages and a summary of the relevant literature, have been produced.

Conclusions

These guidelines are aimed at assisting paediatricians in Europe with ART prescribing, and provide a more cautious approach to starting therapy than current paediatric USA guidelines.

     

Closed-loop regulation of arterial pressure after acute brain death

The purpose of this concept study was to investigate the possibility of automatic mean arterial pressure (MAP) regulation in a porcine heart-beating brain death (BD) model. Hemodynamic stability of BD donors is necessary for maintaining acceptable quality of donated organs for transplantation. Manual stabilization is challenging, due to the lack of vasomotor function in BD donors. Closed-loop stabilization therefore has the potential of increasing availability of acceptable donor organs, and serves to indicate feasibility within less demanding patient groups. A dynamic model of nitroglycerine pharmacology, suitable for controller synthesis, was identified from an experiment involving an anesthetized pig, using a gradient-based output error method. The model was used to synthesize a robust PID controller for hypertension prevention, evaluated in a second experiment, on a second, brain dead, pig. Hypotension was simultaneously prevented using closed-loop controlled infusion of noradrenaline, by means of a previously published controller. A linear model of low order, with variable (uncertain) gain, was sufficient to describe the dynamics to be controlled. The robustly tuned PID controller utilized in the second experiment kept the MAP within a user-defined range. The system was able to prevent hypertension, exceeding a reference of 100 mmHg by more than 10%, during 98% of a 12 h experiment. This early work demonstrates feasibility of the investigated modelling and control synthesis approach, for the purpose of maintaining normotension in a porcine BD model. There remains a need to characterize individual variability, in order to ensure robust performance over the expected population.     

Myocardial tissue remodeling after orthotopic heart transplantation: a pilot cardiac magnetic resonance study

After orthotopic heart transplantation (OHT), the allograft undergoes characteristic alterations in myocardial structure, including hypertrophy, increased ventricular stiffness, ischemia, and inflammation, all of which may decrease overall graft survival. Methods to quantify these phenotypes may clarify the pathophysiology of progressive graft dysfunction post-OHT. We performed cardiac magnetic resonance (CMR) with T1 mapping in 26 OHT recipients (mean age 47?±?7 years, 30?% female, median follow-up post-OHT 6 months) and 30 age-matched healthy volunteers (mean age 50.5?±?15 years; LVEF 63.5?±?7?%). OHT recipients had a normal left ventricular ejection fraction (LVEF 65.3?±?11?%) with higher LV mass relative to age-matched healthy volunteers (114?±?27 vs. 85.8?±?18 g; p?<?0.001). There was no late gadolinium enhancement in either group. Both myocardial extracellular volume fraction (ECV) and intracellular lifetime of water (τ_ic), a measure of cardiomyocyte hypertrophy, were higher in patients post-OHT (ECV: 0.39?±?0.06 vs. 0.28?±?0.03, p?<?0.0001; τ_ic: 0.12?±?0.08 vs. 0.08?±?0.03, p?<?0.001). ECV was associated with LV mass (r?=?0.74, p?<?0.001). In follow-up, OHT recipients with normal biopsies by pathology (ISHLT grade 0R) in the first year post-OHT exhibited a lower ECV relative to patients with any rejection ≥2R (0.35?±?0.02 for 0R vs. 0.45?±?0, p?<?0.001). Higher ECV but not LVEF was significantly associated with a reduced rejection-free survival. After OHT, markers of tissue remodeling by CMR (ECV and τ_ic) are elevated and associated with myocardial hypertrophy. Interstitial myocardial remodeling (by ECV) is associated with cellular rejection. Further research on the impact of graft preservation and early immunosuppression on tissue-level remodeling of the allograft is necessary to delineate the clinical implications of these findings.     

Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data

Purpose

The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.

Methods

We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume.

Results

Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P?=?0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P?=?0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P?=?0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher V_T.

Conclusions

Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).