Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA)

OBJECTIVE: To undertake a multicentre epidemiological study reflecting acromegaly in Spain. DESIGN: Voluntary reporting of data on patients with acromegaly to an online database, by the managing physician. METHODS: Data on demographics, diagnosis, estimated date of initial symptoms and diagnosis, pituitary imaging, visual fields, GH and IGF-I concentrations (requested locally), medical, radiotherapy and neurosurgical treatments, morbidity and mortality were collected. RESULTS: Data were included for 1219 patients (60.8% women) with a mean age at diagnosis of 45 years (s.d. 14 years). Reporting was maximal in 1997 (2.1 cases per million inhabitants (c.p.m.) per year); prevalence was globally 36 c.p.m., but varied between 15.7 and 75.8 c.p.m. in different regions. Of 1196 pituitary tumours, most were macroadenomas (73%); 81% of these patients underwent surgery, 45% received radiotherapy and 65% were given medical treatment (somatostatin analogues in 68.3% and dopamine agonists in 31.4%). Cures (GH values (basal or after an oral glucose tolerance test) <2 ng/ml, normal IGF-I, or both) were observed in 40.3% after surgery and 28.2% after radiotherapy. Hypertension (39.1%), diabetes mellitus (37.6%), hypopituitarism (25.7%), goitre (22.4%), carpal tunnel syndrome (18.7%) and sleep apnoea (13.2%) were reported as most frequent morbidities; 6.8% of the patients had cancer (breast in 3.1% of the women and colon in 1.2% of the cohort). Fifty-six patients died at a mean age of 60 years (s.d. 14 years), most commonly of a cardiovascular cause (39.4%); mortality was greater in patients given radiotherapy (hazard ratio 2.29; 95% confidence interval 1.03 to 5.08; P=0.026), and in those in whom GH and IGF-I concentrations were never normal (P<0.001). CONCLUSIONS: This acromegaly registry offers a realistic overview of the epidemiological characteristics, treatment outcome and morbidity of acromegaly in Spain. As active disease and treatment with radiotherapy are associated with an increase in mortality, efforts to control the disease early are desirable.     

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.     

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...     

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.     

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).

     

Advances in electro- and sono-microreactors for chemical synthesis

The anatomy of electrochemical flow microreactors is important to safely perform chemical reactions in order to obtain pure and high yielding substances in a controlled and precise way that excludes the use of supporting electrolytes. Flow microreactors are advantageous in handling unstable intermediates compared to batch techniques and have efficient heat/mass transfer. Electrode nature (cathode and anode) and their available exposed surface area to the reaction mixture, parameters of the spacer, flow rate and direction greatly affects the efficiency of the electrochemical reactor. Solid formation during reactions may result in a blockage and consequently decrease the overall yield, thus limiting the use of microreactors in the field of electrosynthesis. This problem could certainly be overcome by application of ultrasound to break the solids for consistent flow. In this review, we discuss in detail the aforementioned issues, the advances in microreactor technology for chemical synthesis, with possible application of sonochemistry to deal with solid formations. Various examples of flow methods for electrosynthesis through microreactors have been explained in this review, which would definitely help to meet future demands for efficient synthesis and production of various pharmaceuticals and fine chemicals.

The advances in flow microreactor technology for chemical synthesis, with possible application of sonochemistry to deal with solid formations.