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Knowing the frequency and characteristics of adverse events (AEs) is key to implementing actions that can prevent their occurrence. However, reporting systems are insufficient for this purpose and epidemiological studies are also required. Currently, the reviewing of clinical records is the gold standard method for knowing the frequency and characteristics of AEs. Research on AEs in a primary care setting has been limited and primarily focuses on specific types of events (medication errors, etc.) or patients. Large studies that search for any kind of AE in all patients are scarce. This study aimed to estimate the prevalence of AEs in the primary care setting and their characteristics., Setting: all 262 primary health-care centres in the Madrid region (Spain) during the last quarter of 2018., Design: cross-sectional descriptive study. Eligible population: subjects over 18 years of age who attended medical consultation over the last year (N = 2 743 719); a randomized sample stratified by age., Main Outcomes: age, sex, occurrence of an AE, number of consultations in the study period, avoidability, severity, place of occurrence, type of event, and contributory factors. The clinical records were reviewed by three teams, each composed of one doctor and one nurse trained and with expertise in patient safety. The SPSS software package (version 26) was used for the statistical analyses. The evaluators reviewed 1797 clinical records. The prevalence of AEs over the study period was 5.0% [95% confidence interval (CI): 4.0%‒6.0%], with higher values in women (5.7%; 95% CI: 4.6%‒6.8%;P = 0.10) and patients over 75 years of age (10.3%; 95% CI: 8.9%‒11.7%; P < 0.001). The overall occurrence per hundred consultations was estimated to be 1.58% (95% CI: 1.28%‒1.94%). Of the detected AEs, 71.3% (95% CI: 62.1%‒80.5%) were avoidable. Additionally, 60.6% (95% CI: 50.7%‒70.5%) were categorized as mild, 31.9% (95% CI: 22.4%‒41.4%) as moderate, and 7.4% (95% CI: 2.1%‒12.7%) as severe. Primary care was the occurrence setting in 76.6% (95% CI: 68.0%‒85.2%) of cases. The overall incidence of AEs related to medication was 53.2% (95% CI: 50.9%‒55.5%). The most frequent types of AEs were prescription errors (28.7%; 95% CI: 19.5%‒37.9%), followed by drug administration errors by patients (17.0%; 95% CI: 9.4%‒24.6%), and clinical assessment errors (11.7%; 95% CI: 5.2%‒18.2%). The most common contributory factors were those related to the patient (80.6%; 95% CI: 71.1%‒90.1%) and tasks (59.7%; 95% CI: 48.0%‒71.4%). A high prevalence of AEs (1 in 66 consultations) was observed, which was slightly higher than that reported in similar studies. About 3 out of 4 such events were considered to be avoidable and 1 out of 13 was severe. Prescription errors, drug administration errors by patients, and clinical assessment errors were the most frequent types of AEs. Graphical Abstract., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Since the first description of Brugada syndrome (BrS), several studies were carried out aimed at diagnosis, arrhythmic risk stratification, and available strategies for sudden death prevention. In high-risk patients, the use of an implantable cardiac defibrillator was an evident option since the first description of the syndrome. Nevertheless, this strategy, while proven, as expected, to be effective in sudden death prevention, does not prevent arrhythmias and may not be an adequate or accepted solution for all patients. The need of a non-pharmacological therapy as a potential solution based on the electrophysiological mechanisms underlying the syndrome, led to search for substrate as target for catheter ablation. Advances in the tools, technology, and technical approach enabled to launch studies aimed at mapping the epicardium of patients with BrS in order to identify and ablate the substrate. As described in previous work and in our experience, an anatomically identifiable electrical substrate, which correspond to the typical ECG, is the ablation target. Complete substrate is better identified in a larger area with sodium-channel-blockers. Ablation of all abnormal electrical potentials is able to normalize the ECG and prevent arrhythmias induction. Encouraging preliminary data, if confirmed by longer follow-up and by multicentre randomized study, could change the whole therapeutic management in BrS patients., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To determine the prevalence and characteristics of bicuspid aortic valve (BAV) among elite athletes and to analyse the effect of long-term exercise training on their aortas., Methods and Results: Consecutive BAV and tricuspid aortic valve (TAV) elite athletes from a population of 5136 athletes evaluated at the Sports Medicine Center of the Spanish National Sports Council were identified using echocardiography. A total of 41 BAV elite athletes were matched with 41 TAV elite athletes, and 41 BAV non-athletic patients from three Spanish tertiary hospitals. Sixteen BAV elite athletes who had undergone at least two cardiac evaluations separated by more than 3 years were selected to assess their clinical course. The prevalence of BAV in elite athletes was 0.8%. The proximal ascending aorta was larger for both BAV groups in comparison to TAV athletes (P = 0.001). No differences in aortic diameters were found between BAV athletes and BAV non-athletes. In BAV elite athletes, the annual growth rates for aortic annulus, sinuses of Valsalva, sinotubular junction, and proximal ascending aorta were 0.04 ± 0.24, 0.11 ± 0.59, 0.14 ± 0.38, and 0.21 ± 0.44 mm/year, respectively. Aortic regurgitation was the only functional abnormality, but no significant progression was found., Conclusion: High-intensity training and sports competition may not aggravate BAV condition during elite athletes' careers. BAV elite athletes with mild-to-moderately dilated aortas may engage in high dynamic cardiovascular exercise without adverse consequences, although an echocardiographic follow-up is recommended., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: The rate of plant decomposition depends on both the decomposition environment and the functional traits of the individual species (e.g. leaf and litter quality), but their relative importance in determining interspecific differences in litter decomposition remains unclear. The aims of this study were to: (a) determine if species from different successional stages grown on soils with low and high nitrogen levels produce leaf and litter traits that decompose differently under identical conditions; and (b) assess which trait of living leaves best relates to litter quality and litter decomposability, Methods: The study was conducted on 17 herbaceous species representative of three stages of a Mediterranean successional sere of Southern France. Plants were grown in monocultures in a common garden under two nitrogen levels. To elucidate how different leaf traits affected litter decomposition a microcosm experiment was conducted to determine decomposability under standard conditions. Tests were also carried out to determine how successional stage and nitrogen supply affected functional traits of living leaves and how these traits then modified litter quality and subsequent litter decomposability., Key Results: The results demonstrated that leaf traits and litter decomposability varied according to species and successional stage. It was also demonstrated that while nitrogen addition affected leaf and litter traits, it had no effect on decomposition rates. Finally, leaf dry matter content stood out as the leaf trait best related to litter quality and litter decomposability, Conclusions: In this study, species litter decomposability was affected by some leaf and litter traits but not by soil nitrogen supply. The results demonstrated the strength of a trait-based approach to predict changes in ecosystem processes as a result of species shifts in ecosystems.

Hexarelin (Hex) is a new synthetic hexapeptide with potent growth hormone (GH)-releasing activity in both animals and men. We evaluated the GH response to a maximal dose of Hex (2 micrograms/kg iv) and GH-releasing hormone (GHRH) (1-29, 1 microgram/kg iv) in 45 short normal children (24 males and 21 females, age 5.9-14 yr, 24 prepubertal and 21 in Tanner stage 2 or 3 of pubertal maturation), in 10 prepubertal obese children (7 males and 3 females, age 7.5-12 yr), and in 5 subjects with organic hypopituitarism (4 males and 1 female, age 8.4-21 yr). In 5 male subjects with constitutional growth delay (age 12.0-13.7 yr), the GH response to Hex was reevaluated 1 week after priming with testosterone enanthate (100 mg im). In all short normal children Hex caused a prompt and clear-cut increase of serum GH concentrations, with peaks occurring between 15-30 min from injection. The GH response to Hex was significantly higher than that observed after GHRH and was not different between males and females or between prepubertal and pubertal subjects. Priming with testosterone resulted in an increased GH response to Hex in all 5 subjects studied. No GH increase was observed in the hypopituitary subjects after either GHRH or Hex administration. In the obese children the GH responses to GHRH and to Hex were significantly lower than in the prepubertal children. Also, in the obese, the GH response to Hex was significantly higher than that observed after GHRH. In all short normal and obese children, but not in the hypopituitary subjects, Hex administration caused a slight but significant increase from baseline of both cortisol and PRL concentrations that returned to the baseline values within 2 h. None of the subjects experienced adverse side effects after Hex administration. This study shows that, in short normal and obese children, Hex is a potent GH-releasing stimulus with potential clinical utility.

Plasma levels of gonadotropins, PRL, T4, and adrenal and gonadal steroids were measured in two groups of 7- to 9-yr-old and 10- to 11-yr-old obese prepubertal girls, and were compared to those found in groups of nonobese girls of the same age. The data found in normal weight subjects confirm the data reported in the literature, showing a significant rise between the 7- to 9- and 10- to 11-yr groups, of FSH, pregnenolone, dehydroepiandrosterone, testosterone, and estradiol plasma levels, while LH, PRL, T4, cortisol, progesterone, 17-hydroxyprogesterone (17P), and androstenedione remained constant. In the obese subjects, pregnenolone and dehydroepiandrosterone levels are notably higher than in the normal girls, in the same range as those found in adult women; furthermore, they show no rise between the two age groups. The obese prepubertal groups had significantly higher progesterone, androstenedione, and PRL levels in comparison with those observed in girls of normal weight, but 17-hydroxyprogesterone, cortisol, testosterone, LH, and T4 were similar in both groups. Estradiol levels were markedly depressed in the obese girls; FSH levels were higher in the younger girls than in normal subjects. These data indicate that in prepubertal obesity, maturation of adrenal gland function (chiefly the delta 5 pathway), is notably enhanced, whereas gonadal secretion of estradiol is impaired in the presence of high levels of FSH and PRL.

The plasma patterns of ACTH, beta-lipotropin (beta LPH) and beta-endorphin (beta EP), in addition to those of cortisol and dehydroepiandrosterone sulfate (DHAS), were studied in 139 prepubertal children (subdivided into different age groups) and 38 adolescents (subdivided according to Tanner's pubertal stages) aged 10-16 yr. The adult control group was composed of 23 females and 12 males aged 17-40 yr. No sex differences were found in ACTH, beta LPH, beta EP, and cortisol plasma levels. ACTH plasma levels were slightly lower in the 1- to 3-yr-old groups than in males at 4-5 yr and females at 8-9 yr. No further significant differences were observed in any of the age or pubertal groups, the concentrations being constantly in the adult range. beta LPH and beta EP plasma levels were lowest at 1-3 yr in both males (beta LPH: 2.1 +/- 0.25, beta EP: 1.85 +/- 0.59 fmol/ml, mean +/- SE) and females (beta LPH: 2.8 +/- 0.31; beta EP: 2.41 +/- 0.41 fmol/ml); plasma levels of both hormones increased progressively in both sexes until Puberty 1 stage of sexual maturation, at which time levels were 7.3 +/- 0.78 and 8.69 +/- 1.0 fmol/ml in males and 7.1 +/- 0.34 and 6.76 +/- 0.13 fmol/ml in females; these levels are similar to adult values. A highly significant linear correlation was found between both beta LPH and beta EP concentrations and the age of the subjects; this was not true for ACTH plasma levels. Cortisol plasma levels were similar in all groups. DHAS plasma levels increased progressively from 1-3 yr to the end of sexual maturation when adult values were reached. During prepuberty, DHAS levels were significantly correlated with both beta LPH and beta EP, but not ACTH. These data indicate that plasma beta LPH and beta EP concentrations, in contrast to ACTH levels, increase progressively throughout prepuberty and suggest that the processing of the parent proopiocortin molecule or secretion of the processed peptides from the anterior pituitary (or other sources) may change from early infancy to adulthood. Furthermore, the correlation between both beta LPH and beta EP with DHAS plasma levels in prepuberty suggests a role of proopiocortin-related peptides in adrenarche.

The response of GH to acute administration of GH-releasing hormone (GHRH) was evaluated in 19 patients with thalassemia major and 8 normal children. In 13 of the 19 patients, GHRH induced a definite increase (greater than 5 ng/ml) in plasma GH levels, with peaks occurring 5-45 min postinjection. In 6 patients there was little or no GH rise after GHRH treatment. Overall, the mean GH response to GHRH of patients with thalassemia was lower than that of normal children. These data indicate that in thalassemia major, in addition to the described defect at the hepatic GH receptor or postreceptor level which impedes generation of somatomedins, there may be a marked impairment in somatotroph function. In one patient in whom the GH response to GHRH was superimposable on that of normal subjects, there was a blunted GH response to insulin hypoglycemia. This finding indicates that functional damage in hypothalamic structures for GH control can also occur in thalassemic patients.

Serum androgens and 17-hydroxyprogesterone concentrations and HLA genotypes were determined in 124 families of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH). In 8 pedigrees, we discovered 16 pubertal or postpubertal family members of either sex who had biochemical evidence of 21-hydroxylase deficiency but were without clinical symptoms of excess virilism, amenorrhea, or infertility. We designated these family members as individuals with cryptic 21-hydroxylase deficiency. Within each generation, the family members with cryptic 21-hydroxylase deficiency were HLA identical. It is proposed that these family members are genetic compounds, having 21-hydroxylase deficiency as a result of two recessive gene defects: 1) a severe 21-hydroxylase gene defect present in the index case with classical CAH (21-OHCAH) and 2) a mild 21-hydroxylase gene defect (21-OHCRYPTIC). Thus, the CAH genotype in the family members with cryptic 21-hydroxylase deficiency is 21-OHCAH/21-OHCRYPTIC. Lod score analysis for linkage between the cryptogenic 21-OH trait and HLA gave a combined Lod score for males and females of theta = 0.00 of 3.409. Close genetic linkage between HLA and 21-OHCRYPTIC was thus established. This study provides support for the previously reported heterogeneity of 21-hydroxylase deficiency which may result from allelic variability at the locus for steroid 21-hydroxylase.

The mechanism underlying the GH-releasing effect of galanin (GAL), a novel 29-amino acid peptide, was investigated in the neonatal rat. The effect of galanin was compared to that of clonidine (CLO), a drug known to release GH via endogenous GHRF. GAL administration (5-25 micrograms/kg BW, sc) induced in 10-day-old pups a clear-cut and dose-related rise in plasma GH 15 min postinjection. CLO (50-450 micrograms/kg BW, sc) induced a marked rise in plasma GH, but no dose-related effect was evident. Inhibition of hypothalamic norepinephrine and epinephrine biosynthesis by DU-18288 (6 mg/kg BW, ip) or selective inhibition of epinephrine biosynthesis by SKF-64139 (50 mg/kg BW, ip) completely abolished the GH-releasing effect of GAL (25 micrograms/kg, sc), but left unaltered the GH rise induced by CLO (150 micrograms/kg, sc). Passive immunization with an anti-GHRF serum decreased basal GH levels and prevented the GH-releasing effect of either GAL or CLO, whereas in pups pretreated with an antisomatostatin serum, CLO, but not GAL, increased the already elevated plasma GH titers. In all these data indicate that in the infant rat 1) GAL is a potent GH secretagogue; 2) the action of GAL is not exerted directly on GHRF- or somatostatin-secreting structures, but requires the intervention of catecholaminergic neurons; 3) the GH-releasing effect of GAL is ultimately exerted via GHRF release, although a mechanism operating to inhibit hypothalamic somatostatin release cannot be ruled out; and 4) differently from GAL, CLO releases GH via postsynaptic stimulation of GHRF-secreting neurons.

Cryptic 21-hydroxylase deficiency has been previously described in asymptomatic family members of patients with classical congenital adrenal hyperplasia (CAH). These family members were detected by high baseline 17-hydroxyprogesterone levels found in the course of family studies. The hormonal responses to ACTH of the family members with cryptic 21-hydroxylase deficiency were determined and compared to the responses of patients with CAH, patients with acquired adrenal hyperplasia, family members predicted to be heterozygous for CAH, family members predicted to be unaffected, and the general population. The ACTH-stimulated levels of 17-hydroxyprogesterone and delta 4-androstenedione in the cryptic family members were elevated above the level of the general population or family members heterozygous for classical CAH, but below that of patients with CAH. The hormonal profile of patients with cryptic 21-hydroxylase deficiency is similar to that of patients with acquired adrenal hyperplasia. The response of family members heterozygous for the cryptic gene (21-OH CRYPTIC/21-OH NORMAL) was indistinguishable from that of family members heterozygous for the classical CAH gene (21-OH CAH/21-OH NORMAL). These studies support our previous proposal that patients with cryptic 21-hydroxylase deficiency are genetic compounds, having one gene for a severe enzyme deficiency and one gene for a mild 21-hydroxylase deficiency. Thus, the 21-hydroxylase genotype in cryptic 21-hydroxylase deficiency is 21-OH CAH/21-OH CRYPTIC.

To study the role of opioid peptides in human obesity, plasma beta-endorphin (beta EP), beta-lipotropin (beta LPH), and cortisol resting values, circadian rhythms, and responses to hypoglycemia were studied in 6 prepubertal and 6 pubertal obese adolescents (at least 40% above ideal body weight) and in 10 normal subjects matched for age, sex, and pubertal development. Baseline plasma beta LPH and beta EP concentrations in both obese children and adolescents were twice as high as those in normal controls, while cortisol levels were not different. Cortisol, beta EP, and beta LPH levels had a clear circadian rhythmicity in all subjects, with the exception of obese pubertal boys whose plasma beta EP concentrations were constant throughout the day. After insulin administration, the fall in blood sugar was similar in all groups. Plasma cortisol and beta EP responses were similar in both obese and normal prepubertal subjects. In obese pubertal adolescents, beta EP did not increase significantly after hypoglycemia, although it did increase in normal weight pubertal subjects. In normal prepubertal subjects, the circadian rhythms of beta EP and beta LPH secretion and release induced by hypoglycemia suggest the presence of a well developed neuroendocrine control of proopiomelanocortin-related peptide secretion. In prepubertal obese children, the increased plasma beta EP and beta LPH levels with the maintenance of their circadian rhythm and responsivity to hypoglycemia suggest overactivity of anterior pituitary secretion. In obese adolescents, in spite of the normal rhythm of beta LPH and cortisol, beta EP levels did not change throughout the day, thus suggesting beta EP secretion from nonpituitary sources in these subjects. The present study indicates a possible direct role for hyperendorphinemia in the induction of overeating in obese children and adolescents.

Administration of human pancreatic GH-releasing factor 1-40 (hpGRF-40) at doses of 1, 10, 20, 100, and 500 ng/100 g BW sc induced in 10-day-old rats a clear-cut rise in plasma GH 15-min post-injection, although the effect was not dose-related and peak GH levels were already present after the lowest GRF dose. In 25-day-old rats, hpGRF induced only a slight rise in plasma GH at the dose of 500 ng/100 g BW sc, whereas it was completely ineffective at the lower doses. In 5-day-old rats, hpGRF (20 ng/100 g BW sc twice daily), administered for 5 days, induced a marked rise in pituitary GH content and plasma GH levels determined 14 h after the last hpGRF injection. In these rats, at the end of treatment, a challenge hpGRF dose (20 ng/100 g BW) induced a rise in plasma GH significantly higher than in infant rats receiving only the challenge hpGRF dose. These data show that: 1) pituitary responsiveness to hpGRF is strikingly higher in infant than in post-weaning rats; 2) in infant rats, subacute administration of hpGRF stimulates GH synthesis and release.

We evaluated the effect of chronic clonidine administration on 24-h integrated GH secretion (IC-GH) in eight children (six boys and two girls; age, 6.0-13.0 yr) with constitutional growth delay (CGD). Clonidine was given orally in a daily dose of 0.1 mg/m2 at bedtime for 6 months; 24-h secretion studies were performed before and after 2 months of treatment. Clonidine caused a significant augmentation (P less than 0.02) of mean IC-GH from 2.6 +/- 0.4 (+/- SE) to 4.6 +/- 0.6 micrograms/L. The increase in IC-GH was mainly the result of increased GH pulse amplitude, which rose from 12.3 +/- 1.3 to 18.2 +/- 2.1 micrograms/L (P less than 0.01). The mean GH pulse amplitude was significantly higher (P less than 0.02) during sleep (15.9 +/- 2.4 micrograms/L) than during the awake hours (8.4 +/- 1.5 micrograms/L) before treatment. During clonidine treatment the mean GH pulse amplitude during the awake hours (15.0 +/- 3.8 micrograms/L) was similar to that during sleep (20.3 +/- 3.1 micrograms/L). GH pulse frequency was not altered by treatment during either the awake or sleep hours. The mean insulin-like growth factor I levels after 2 (1400 +/- 300 U/L) and 6 (1760 +/- 430 U/L) months of treatment were significantly higher (P less than 0.02 and P less than 0.05, respectively) than the pretreatment value (920 +/- 240 U/L). After 2 months of clonidine treatment, growth velocity increased from 3.1 +/- 0.5 to 10.2 +/- 1.0 cm/yr (P less than 0.001), and after 6 months of treatment is was still significantly higher (7.0 +/- 0.7 cm/yr; P less than 0.02) than that before treatment. These results confirm the ability of clonidine to accelerate growth in children with CGD and indicate that clonidine is capable of increasing IC-GH levels. They also reinforce the view that many children with CGD have decreased endogenous GH secretion.

The demonstration that GH-releasing factor (GRF) stimulates GH synthesis and release in rat pups prompted studies to evaluate the effects on the same indices of clonidine (CLO), an alpha 2-adrenoceptor and potent GH secretagogue, purported to act in adult rats via GRF release. Our first aim was to ascertain whether CLO elicits GH release in rat pups via GRF, and if this is the case, to evaluate the ontogenetic development in 1- to 10-day-old pups of the GH response to acute CLO or GRF administration and, finally, the effects of short term CLO or GRF treatment on plasma and pituitary GH concentrations and on the GH response to an acute challenge with the homologous secretagogue. CLO (15 micrograms/100 g BW, sc) induced a clearcut GH rise in 10-day-old rats but not in pups pretreated with a specific anti-GRF serum. Moreover, unlike GRF (10(-8) M), CLO (10(-6) to 10(-5) M) did not stimulate GH release in vitro from anterior pituitaries of 10-day-old rats. In 1-day-old rats, neither CLO (15 micrograms/100 g BW, sc) nor GRF (20 ng/100 g BW, sc) stimulated GH release, whereas significant GH stimulation was elicited by GRF, but not CLO, in 5-day-old rats and by both secretagogues in 10-day-old rats. Short term treatment with CLO (15 micrograms/100 g BW, sc, twice daily) or GRF (20 ng/100 g BW, sc, twice daily) on postnatal days 1 through 5 did not modify either plasma or pituitary GH concentrations 14 h after the last drug administration, but did so when either secretagogue was administered on postnatal days 5 through 9. Finally, an acute challenge with GRF, but not with CLO, induced a further rise in the already elevated plasma GH levels of pups pretreated from postnatal day 5 through 9, but neither secretagogue did so in pups pretreated from postnatal days 1 to 5. Viewed together, these data indicate that in infant rats CLO releases GH via GRF release and that the somatotropes respond earlier to GRF (5 days) than the GRF-secreting structures do to alpha 2-adrenergic stimulation (10 days). Both GRF and CLO stimulate GH synthesis when administered repeatedly. However, whereas repeated GRF treatment has a priming effect on the somatotropes, CLO does not, probably because of down-regulation of hypothalamic alpha 2-adrenoceptors.