Impact of Early Postnatal Androgen Exposure on Voice Development

Background: the impact of early postnatal androgen exposure on female laryngeal tissue may depend on certain characteristics of this exposure. We assessed the impact of the dose, duration, and timing of early androgen exposure on the vocal development of female subjects who had been treated for adrenocortical tumor (ACT) in childhood.Methods: the long-term effects of androgen exposure on the fundamental vocal frequency (F0), vocal pitch, and final height and the presence of virilizing signs were examined in 9 adult (age, 18.4 to 33.5 years) and 10 adolescent (13.6 to 17.8 years) female ACT patients. We also compared the current values with values obtained 0.9 years to 7.4 years after these subjects had undergone ACT surgery, a period during which they had shown normal androgen levels.Results: of the 19 subjects, 17 (89%) had been diagnosed with ACT before 4 years of age, 1 (5%) at 8.16 years, and 1 (5%) at 10.75 years. Androgen exposure (2 to 30 months) was sufficiently strong to cause pubic hair growth in all subjects and clitoromegaly in 74% (14/19) of the subjects, but did not reduce their height from the target value. Although androgen exposure induced a remarkable reduction in F0 (132 Hz) and moderate pitch virilization in 1 subject and partial F0 virilization, resulting in F0 of 165 and 169 Hz, in 2 subjects, the majority had normal F0 ranging from 189 to 245 Hz.Conclusions: Female laryngeal tissue is less sensitive to androgen exposure between birth and adrenarche than during other periods. Differential larynx sensitivity to androgen exposure in childhood and F0 irreversibility in adulthood are age-, concentration-, duration-, and timing-dependent events that may also be affected by exposure to inhibitory or stimulatory hormones. Further studies are required to better characterize each of these factors.Brazilian State of Parana Secretary of Science, Technology and Higher Education (SETI)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Raul Carneiro Hospital Association for Childhood Protection (AHPIRC)American Lebanese Syrian Associated Charities (ALSAC)SETIAHPIRCALSACInst Pesquisa Pele Pequeno Principe, Curitiba, Parana, BrazilHosp Pequeno Principe, Curitiba, Parana, BrazilFac Pequeno Principe, Curitiba, Parana, BrazilInst Voz Maringa, Maringa, Parana, BrazilUniversidade Federal de São Paulo, Dept Fonoaudiol, São Paulo, BrazilClin Voz, Curitiba, Parana, BrazilIrmandade Santa Casa Misericordia São Paulo, São Paulo, BrazilUniv Fed Parana, Dept Saude Comunitaria, BR-80060000 Curitiba, Parana, BrazilUniversidade Federal de São Paulo, Dept Fonoaudiol, São Paulo, BrazilWeb of Scienc

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Synthesis and Study of Fe-Doped Bi2S3 Semimagnetic Nanocrystals Embedded in a Glass Matrix

Iron-doped bismuth sulphide (Bi2−xFexS3) nanocrystals have been successfully synthesized in a glass matrix using the fusion method. Transmission electron microscopy images and energy dispersive spectroscopy data clearly show that nanocrystals are formed with an average diameter of 7–9 nm, depending on the thermic treatment time, and contain Fe in their chemical composition. Magnetic force microscopy measurements show magnetic phase contrast patterns, providing further evidence of Fe incorporation in the nanocrystal structure. The electron paramagnetic resonance spectra displayed Fe3+ typical characteristics, with spin of 5/2 in the 3d5 electronic state, thereby confirming the expected trivalent state of Fe ions in the Bi2S3 host structure. Results from the spin polarized density functional theory simulations, for the bulk Fe-doped Bi2S3 counterpart, corroborate the experimental fact that the volume of the unit cell decreases with Fe substitutionally doping at Bi1 and Bi2 sites. The Bader charge analysis indicated a pseudo valency charge of 1.322|e| on FeBi1 and 1.306|e| on FeBi2 ions, and a spin contribution for the magnetic moment of 5.0 µB per unit cell containing one Fe atom. Electronic band structures showed that the (indirect) band gap changes from 1.17 eV for Bi2S3 bulk to 0.71 eV (0.74 eV) for Bi2S3:FeBi1 (Bi2S3:FeBi2). These results are compatible with the 3d5 high-spin state of Fe3+, and are in agreement with the experimental results, within the density functional theory accuracy

A flow chart summarizing the results of this and other studies investigating the postnatal periods of lowest and greatest larynx sensitivity to androgen exposure and the mechanism of vocal development in response to this exposure.

<p>Pink curves correspond to female F0 spectra and blue curves to male F0 spectra. (1) Normal development of F0 differentiation in males and females. Adrenarche and activation of the hypothalamus–pituitary–gonadal axis (gonadarche) are the main events leading to attainment of adult vocal patterns. At puberty, the larynx, vocal folds, and vocal tract (e.g., the resonance tube up to the oral cavity) acquire increased mass, leading to variable degrees of F0 reduction in men at adrenarche and gonadarche and to partial reduction in women at adrenarche. F0 decreases and then stabilizes between the ages of 14 and 18 years. Mean F0, which is shown for normal male and female Brazilian subjects <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050242#pone.0050242-Leonel1" target="_blank">[4]</a>, slightly decreases with age, as was shown in a study of normal Swedish women <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050242#pone.0050242-PegoraroKrook1" target="_blank">[2]</a> and in other studies (Hollien and Shipp, 1972; Stoicheff, 1981; Hollien et al., 1994), due to steroids and other factors. (2) A hypothesis based on the study results postulating that androgen exposure during pre- and post-pubertal stages in CAH females causes fluctuations in androgen levels and permanent virilization of F0. (3) A good marker identified for the accumulated androgen effect (represented by Tanner stage) is shown for all ACT cases. Each full dot represents 4 months of androgen exposure. Androgen exposure during the pre-pubertal stage leading to decreased F0 was found in only 3 ACT cases (3/19; 15.7%), leading to development of the hypothesis that laryngeal tissue has a low level of sensitivity to androgen exposure during the first 5 postnatal years in females.</p

Timing and characteristics of virilization at ACT diagnosis and time of study.

(1)<p>Cushing’s syndrome. F: female pitch; M+: mild virilization; M++: moderate virilization; NA: not available. Initial F0 was obtained several weeks and 4 years after ACT diagnosis, as reported by Leonel in her thesis in 2003 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050242#pone.0050242-Leonel1" target="_blank">[4]</a>.</p

F0 and vocal pitch of control group.

<p>F0 and vocal pitch of control group.</p