Early electrodiagnosis in the management of neonatal brachial plexus palsy: A systematic review.

Neonatal brachial plexus palsy (NBPP) is a prominent form of newborn morbidity with a potentially disabling persistence. Neurosurgical intervention is indicated in select NBPP patients. Early prognostic assessment would facilitate rational selection of those infants for surgery. We conducted a systematic literature review to determine the prognostic value of early electrodiagnosis (EDx) in NBPP. We included 16 observational studies with a total sample size of 747 children. Risk of bias and quality of evidence were rated. Wide variation was found in EDx techniques, outcome algorithms, and decisionmaking. Nevertheless, the most methodologically sound studies support the use of EDx, at standardized time-frames, as a key prognostic modality for complementing clinical judgment and neuroimaging. An accurate knowledge of the underlying anatomy of the nerve injury helps to counsel families and to guide reconstructive strategy.

Risk factors for neonatal brachial plexus palsy: a systematic review and meta-analysis.

AIM: To provide a comprehensive update on the most prevalent, significant risk factors for neonatal brachial plexus palsy (NBPP). METHOD: Cochrane CENTRAL, MEDLINE, Web of Science, Embase, and ClinicalTrials.gov were searched for relevant publications up to March 2019. Studies assessing risk factors of NBPP in relation to typically developing comparison individuals were included. Meta-analysis was performed for the five most significant risk factors, on the basis of the PRISMA statement and MOOSE guidelines. Pooled odds ratios (ORs), 95% confidence intervals (CIs), and across-study heterogeneity (I2 ) were reported. Reporting bias and quality of evidence was rated. In addition, we assessed the incidence of NBPP. RESULTS: Twenty-two observational studies with a total sample size of 29 419 037 live births were selected. Significant risk factors included shoulder dystocia (OR 115.27; 95% CI 81.35-163.35; I2 =92%), macrosomia (OR 9.75; 95% CI 8.29-11.46; I2 =70%), (gestational) diabetes (OR 5.33; 95% CI 3.77-7.55; I2 =59%), instrumental delivery (OR 3.8; 95% CI 2.77-5.23; I2 =77%), and breech delivery (OR 2.49; 95% CI 1.67-3.7; I2 =70%). Caesarean section appeared as a protective factor (OR 0.13; 95% CI 0.11-0.16; I2 =41%). The pooled overall incidence of NBPP was 1.74 per 1000 live births. It has decreased in recent years. INTERPRETATION: The incidence of NBPP is decreasing. Shoulder dystocia, macrosomia, maternal diabetes, instrumental delivery, and breech delivery are risk factors for NBPP. Caesarean section appears as a protective factor. WHAT THIS PAPER ADDS: The overall incidence of neonatal brachial plexus palsy is 1.74 per 1000 live births. The incidence has declined significantly. Shoulder dystocia, macrosomia, maternal diabetes, instrumental delivery, and breech delivery are the main risk factors. Prevention is difficult owing to unpredictability and often labour-related risk.

RAF2 is a RuBisCO assembly factor in Arabidopsis thaliana.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) catalyzes the reaction between gaseous carbon dioxide (CO2 ) and ribulose-1,5-bisphosphate. Although it is one of the most studied enzymes, the assembly mechanisms of the large hexadecameric RuBisCO is still emerging. In bacteria and in the C4 plant Zea mays, a protein with distant homology to pterin-4α-carbinolamine dehydratase (PCD) has recently been shown to be involved in RuBisCO assembly. However, studies of the homologous PCD-like protein (RAF2, RuBisCO assembly factor 2) in the C3 plant Arabidopsis thaliana (A. thaliana) have so far focused on its role in hormone and stress signaling. We investigated whether A. thalianaRAF2 is also involved in RuBisCO assembly. We localized RAF2 to the soluble chloroplast stroma and demonstrated that raf2 A. thaliana mutant plants display a severe pale green phenotype with reduced levels of stromal RuBisCO. We concluded that the RAF2 protein is probably involved in RuBisCO assembly in the C3 plant A. thaliana.

Spontaneous coronary artery dissection in systemic lupus erythematosus: case-based review.

Patients with systemic lupus erythematosus (SLE) present an increased prevalence of coronary heart disease. The majority of cases of acute coronary syndrome (ACS) in patients with SLE are due to atherosclerosis. Less common causes include thrombosis of an angiographically normal coronary artery and coronary vasculitis. Spontaneous coronary artery dissection (SCAD) is a rare cause of ACS in these patients. We report the case of a 53-year-old female diagnosed of SLE presenting with an ACS caused by SCAD. She was treated medically and her clinical course was favorable. A literature search identified seven additional cases of SCAD associated with SLE. The main clinical features found in these reports are revised. ACS caused by SCAD in SLE patients is a condition likely under-reported in literature. SCAD should be suspected in patients with SLE and ACS, especially in younger women without evident cardiovascular risk factors. An early accurate diagnosis of SCAD is key to provide specific treatment, which differs from that of usual atherosclerotic ACS.

LHCSR1 induces a fast and reversible pH-dependent fluorescence quenching in LHCII in Chlamydomonas reinhardtii cells.

To avoid photodamage, photosynthetic organisms are able to thermally dissipate the energy absorbed in excess in a process known as nonphotochemical quenching (NPQ). Although NPQ has been studied extensively, the major players and the mechanism of quenching remain debated. This is a result of the difficulty in extracting molecular information from in vivo experiments and the absence of a validation system for in vitro experiments. Here, we have created a minimal cell of the green alga Chlamydomonas reinhardtii that is able to undergo NPQ. We show that LHCII, the main light harvesting complex of algae, cannot switch to a quenched conformation in response to pH changes by itself. Instead, a small amount of the protein LHCSR1 (light-harvesting complex stress related 1) is able to induce a large, fast, and reversible pH-dependent quenching in an LHCII-containing membrane. These results strongly suggest that LHCSR1 acts as pH sensor and that it modulates the excited state lifetimes of a large array of LHCII, also explaining the NPQ observed in the LHCSR3-less mutant. The possible quenching mechanisms are discussed.

Functional organization of photosystem II antenna complexes: CP29 under the spotlight.

In the first step of the photosynthetic process, light is absorbed by the pigments associated with the antenna proteins, known as light-harvesting complexes (Lhcs), which in vivo are functionally organized as hetero-oligomers. The architecture of the pigments, chlorophylls, and carotenoids bound to each LHC is responsible for the efficient excitation energy transfer resulting in photochemistry. So far, the only LHC studied in depth was LHCII, the most abundant membrane protein of plants, while less information was available for the other antennae. In particular, despite the availability of the structure of CP29 obtained at near atomic resolution in 2011 (Pan et al., 2011), the mismatch in pigment content and spectroscopic properties between CP29 in solution and in the crystal has hampered the possibility to use the structure to interpret the experimental data. In this work, we purified CP29 and its larger assembly (CP29-LHCII-CP24) from the membrane in very mild conditions using a His-tag, and we have studied their pigment binding and spectroscopic properties. In addition, we have performed mutation analysis in vivo to obtain mutants of CP29 lacking individual chlorophylls. The peculiar properties of this antenna support its role in directing the energy flow from the external antennae to the reaction center.

Excitation dynamics and structural implication of the stress-related complex LHCSR3 from the green alga Chlamydomonas reinhardtii.

LHCSR3 is a member of the Light-Harvesting Complexes (LHC) family, which is mainly composed of pigment-protein complexes responsible for collecting photons during the first steps of photosynthesis. Unlike related LHCs, LHCSR3 is expressed in stress conditions and has been shown to be essential for the fast component of photoprotection, non-photochemical quenching (NPQ), in the green alga Chlamydomonas reinhardtii. In plants, which do not possess LHCSR homologs, NPQ is triggered by the PSBS protein. Both PSBS and LHCSR3 possess the ability to sense pH changes but, unlike PSBS, LHCSR3 binds multiple pigments. In this work we have analyzed the properties of the pigments bound to LHCSR3 and their excited state dynamics. The data show efficient excitation energy transfer between pigments with rates similar to those observed for the other LHCs. Application of an exciton model based on a template of LHCII, the most abundant LHC, satisfactorily explains the collected steady state and time-resolved spectroscopic data, indicating that LHCSR3 has a LHC-like molecular architecture, although it probably binds less pigments. The model suggests that most of the chlorophylls have similar energy and interactions as in LHCII. The most striking difference is the localization of the lowest energy state, which is not on the Chlorophyll a (Chl a) 610-611-612 triplet as in all the LHCB antennas, but on Chl a613, which is located close to the lumen and to the pH-sensing region of the protein.

Family chaos and adolescent inflammatory profiles: the moderating role of socioeconomic status.

OBJECTIVE: To test whether family chaos influences adolescents' inflammatory profiles and whether adolescents from low socioeconomic status (SES) environments are at higher risk for experiencing adverse inflammatory profiles from living in chaotic family environments. METHODS: A total of 244 families with an adolescent aged 13 to 16 years participated. Parents completed measures of family SES and family chaos. Both systemic inflammation and stimulated proinflammatory cytokine production in response to bacterial challenge were assessed in adolescents. RESULTS: Our results suggest that SES moderates the detrimental effect of family chaos on systemic inflammation and interleukin-6 (B = -0.010, standard error [SE] = 0.004, p = .026), but not C-reactive protein (B = 0.009, SE = 0.006, p = .11), and on stimulated proinflammatory cytokine production (B = -0.098, SE = 0.044, p = .026) in adolescents, such that a chaotic family environment is positively associated with greater systemic inflammation and greater stimulated proinflammatory cytokine production in adolescents as family SES declines. CONCLUSIONS: These findings indicate that living in chaotic family environments places youth who may be vulnerable based on socioeconomic factors at a potentially higher risk for inflammation-related diseases.

Parental accuracy regarding adolescent daily experiences: relationships with adolescent psychological adjustment and inflammatory regulation.

OBJECTIVE: There is evidence that parents play an important role in their adolescent's health and well-being, but the links between specific daily processes and biological mechanisms relevant to health remain to be determined. In this study, we examined the role of parental accuracy-that is, whether parents who are more accurate about their adolescents' daily experiences have adolescents with better psychological functioning and inflammatory regulation. METHODS: In a 2-week daily diary study of 116 parent-adolescent dyads, we examined whether parental accuracy about their adolescent's daily demands and the positivity of their day together were associated with markers of psychological functioning and with regulation of the inflammatory response in terms of glucocorticoid sensitivity (the extent to which cortisol is able to dampen the production of inflammatory proteins) in adolescents. RESULTS: Adolescents whose daily experiences were perceived more accurately by their parents reported better psychological adjustment (lower stress and depression) and a greater sensitivity of their immune cells to anti-inflammatory signals from cortisol (i.e., diminished production of inflammatory proteins when cells were stimulated with the combination of a bacterial product [lipopolysaccharide] and cortisol; |ß| range, 0.38-0.53, all p values <.041). CONCLUSIONS: Greater parental accuracy regarding adolescents' daily experiences is associated with better adolescent psychological adjustment and a more sensitive anti-inflammatory response to cortisol. These results provide preliminary evidence that parental accuracy regarding their adolescent's daily experiences may be one specific daily parent factor that plays a role in adolescent health and well-being.

[Diagnosis and prognosis of fetal ebstein anomaly]. / Diagnóstico y pronóstico fetales de la anomalía de Ebstein.

BACKGROUND: Fetal echocardiography is possible to confirm with great certainty the diagnosis, in utero, Ebstein's anomaly, as well as determine its perinatal prognosis. OBJECTIVE: Review the experience of 16 cases diagnosed with Ebstein's anomaly, using fetal echocardiography, analyzing "forecast echocardiographic parameters" set by Pavlova, Huhta and Barre. MATERIAL AND METHOD: retrospective and descriptive analysis. We analysed echocardiographic parameters and its correlation with the perinatal development of 16 cases diagnosed with Ebstein's anomaly. RESULTS: Maternal age of our patients was 27.94 +/- 5.7 years, gestational age 31.3 +/- 3.6.) Mortality: in-utero 37.5% (n = 6), neonatal 50% (n = 8), survived 12.5% (n = 2). Cardiothoracic index 0.61 +/- 0.074, relationship foramen oval/heart atrial 0.6 +/- 0.015; obstruction to the way out of the right ventricle in 14 cases (87.5%). The deceased 81% presented degree of valvular displacement > 2.5; relationship RV/LV 2.24 +/- 0.37). CONCLUSIONS: Cardiothoracic index fetal stage > 0.55, relationship oval foramen/interatrial septum < 0.3, obstruction to the way out and a degree of valvular displacement > 2.5, absence of back flow in arteriosus ductus and a ratio RV/LV > 2 are poor prognostic factors for Ebstein's anomaly.

Three-Dimensional Upper Limb Movement Analysis in Children and Adolescents With Brachial Plexus Birth Injury: A Systematic Review.

BACKGROUND: To synthesize the current evidence on clinical use of three-dimensional upper limb movement analysis (3D-ULMA) in children and adolescents with brachial plexus birth injury (BPBI). METHODS: MEDLINE, Embase, and Web of Science were searched for relevant studies up to April 2022. An automatic e-mail alert was installed to ensure no eligible article was missed. Articles evaluating 3D-ULMA in children and adolescents with BPBI were included. Covidence web-based platform was used for blind screening of eligible articles. Twenty-one observational studies with a final sample size of 609, encompassing 493 BPBI cases, met the inclusion criteria. Data were extracted using a custom form to support standardized extraction conforming to the Cochrane Checklist of items. Risk of bias was assessed using the Newcastle-Ottawa Scale, the Strengthening the Reporting of Observational Studies in Epidemiology checklist, and a specifically established quality assessment form for kinematic analysis studies. RESULTS: Study setups differed, including six different types of kinematic devices. Twelve studies used the (modified) Mallet positions for their 3D-ULMA. Throughout the studies, 3D-ULMA was used for various purposes. The Newcastle-Ottawa Scale scored 16 articles with five stars or more, indicating fair to moderate quality. CONCLUSIONS: This systematic review summarizes the different 3D-ULMA kinematic devices, test protocols, and their clinical use for BPBI. The use of 3D-ULMA provides valuable, objective, and quantified data to clinicians with regard to movement strategies; it complements existing clinical scales and can be implemented to evaluate effectiveness of therapy interventions. Implications for future research and clinical practice are discussed.

Vaccine-carditis study: Spanish multicenter registry of inflammatory heart disease after COVID-19 vaccination.

INTRODUCTION AND OBJECTIVES: Vaccines against SARS-CoV-2 have been a major scientific and medical achievement in the control of the COVID-19 pandemic. However, very infrequent cases of inflammatory heart disease have been described as adverse events, leading to uncertainty in the scientific community and in the general population. METHODS: The Vaccine-Carditis Registry has included all cases of myocarditis and pericarditis diagnosed within 30 days after COVID-19 vaccination since August 1, 2021 in 29 centers throughout the Spanish territory. The definitions of myocarditis (probable or confirmed) and pericarditis followed the consensus of the Centers for Disease Control and the Clinical Practice Guidelines of the European Society of Cardiology. A comprehensive analysis of clinical characteristics and 3-month evolution is presented. RESULTS: From August 1, 2021, to March 10, 2022, 139 cases of myocarditis or pericarditis were recorded (81.3% male, median age 28 years). Most cases were detected in the 1st week after administration of an mRNA vaccine, the majority after the second dose. The most common presentation was mixed inflammatory disease (myocarditis and pericarditis). 11% had left ventricular systolic dysfunction, 4% had right ventricular systolic dysfunction, and 21% had pericardial effusion. In cardiac magnetic resonance studies, left ventricular inferolateral involvement was the most frequent pattern (58%). More than 90% of cases had a benign clinical course. After a 3-month follow-up, the incidence of adverse events was 12.78% (1.44% mortality). CONCLUSIONS: In our setting, inflammatory heart disease after vaccination against SARS-CoV-2 predominantly affects young men in the 1st week after the second dose of RNA-m vaccine and presents a favorable clinical course in most cases.

Regulation of light harvesting in the green alga Chlamydomonas reinhardtii: the C-terminus of LHCSR is the knob of a dimmer switch.

Feedback mechanisms that dissipate excess photoexcitations in light-harvesting complexes (LHCs) are necessary to avoid detrimental oxidative stress in most photosynthetic eukaryotes. Here we demonstrate the unique ability of LHCSR, a stress-related LHC from the model organism Chlamydomonas reinhardtii, to sense pH variations, reversibly tuning its conformation from a light-harvesting state to a dissipative one. This conformational change is induced exclusively by the acidification of the environment, and the magnitude of quenching is correlated to the degree of acidification of the environment. We show that this ability to respond to different pH values is missing in the related major LHCII, despite high structural homology. Via mutagenesis and spectroscopic characterization, we show that LHCSR's uniqueness relies on its peculiar C-terminus subdomain, which acts as a sensor of the lumenal pH, able to tune the quenching level of the complex.

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

BACKGROUND: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64-82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. METHODS/DESIGN: Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. DISCUSSION: If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8-4.6 million (€2.05-5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects. TRIAL REGISTRATION: EudraCT number: 2020-001006-39.

Automatic detection of foreign body objects in neurosurgery using a deep learning approach on intraoperative ultrasound images: From animal models to first in-human testing.

Objects accidentally left behind in the brain following neurosurgical procedures may lead to life-threatening health complications and invasive reoperation. One of the most commonly retained surgical items is the cotton ball, which absorbs blood to clear the surgeon's field of view yet in the process becomes visually indistinguishable from the brain parenchyma. However, using ultrasound imaging, the different acoustic properties of cotton and brain tissue result in two discernible materials. In this study, we created a fully automated foreign body object tracking algorithm that integrates into the clinical workflow to detect and localize retained cotton balls in the brain. This deep learning algorithm uses a custom convolutional neural network and achieves 99% accuracy, sensitivity, and specificity, and surpasses other comparable algorithms. Furthermore, the trained algorithm was implemented into web and smartphone applications with the ability to detect one cotton ball in an uploaded ultrasound image in under half of a second. This study also highlights the first use of a foreign body object detection algorithm using real in-human datasets, showing its ability to prevent accidental foreign body retention in a translational setting.

MitraClip improves cardiopulmonary exercise test in patients with systolic heart failure and functional mitral regurgitation.

AIMS: The aim of this study is to evaluate changes in cardiopulmonary exercise test (CPET) after percutaneous mitral valve repair (PMVR) with MitraClip in patients with heart failure with reduced ejection fraction who are potentially candidates for heart transplantation or destination left ventricular assist device. METHODS AND RESULTS: Prospective registry of all consecutive patients with heart failure with reduced ejection fraction and functional mitral regurgitation (MR) underwent elective PMVR between October 2015 and March 2018 in our institution. Patients with preserved or mid-range left ventricular ejection fraction (>40%), advanced age (>75 years old), or severe co-morbidities (end-stage organ damage) were not included. Treadmill exercise testing with respiratory gas exchange analysis was carried out in 11 patients (male, 72.7%; median age, 67 years old) within the month prior to the procedure and at 6 month follow-up. PMVR was successfully performed in all patients. At 6 month follow-up, PMVR was associated with an improvement in New York Heart Association functional class (P = 0.021) and a reduction in MR severity (P = 0.013) and N-terminal pro-brain natriuretic peptide levels (2805 [1878-5022] vs. 1485 [654-3032] pg/mL; P = 0.012). All patients completed pre-procedural and post-procedural CPET, and all the studies showed a respiratory exchange ratio ≥1 and were consistent with sufficient exercise effort. Compared with pre-procedural CPET, patients showed a significant increase in exercise time (295 [110-335] vs. 405 [261-540] s; P = 0.047), VO2 (9.8 [9.1-13.4] vs. 13.5 [12.1-16.8] mL/kg/min; P = 0.033), ventilatory anaerobic threshold (510 [430-950] vs. 850 [670-1070] mL/kg/min; P = 0.033), peak O2 pulse (7.2 [4.3-8.6] vs. 8.3 [6.2-11.8] mL/beat; P = 0.033), and workload (5 [3-6] vs. 6 [5-8] metabolic equivalents; P = 0.049). CONCLUSIONS: Percutaneous mitral valve repair with MitraClip was associated with an enhancement in cardiopulmonary performance in patients with systolic heart failure and secondary MR.

Revisiting the Role of Xanthophylls in Nonphotochemical Quenching.

Photoprotective nonphotochemical quenching (NPQ) of absorbed solar energy is vital for survival of photosynthetic organisms, and NPQ modifications significantly improve plant productivity. However, the exact NPQ quenching mechanism is obscured by discrepancies between reported mechanisms, involving xanthophyll-chlorophyll (Xan-Chl) and Chl-Chl interactions. We present evidence of an experimental artifact that may explain the discrepancies: strong laser pulses lead to the formation of a novel electronic species in the major plant light-harvesting complex (LHCII). This species evolves from a high excited state of Chl a and is absent with weak laser pulses. It resembles an excitonically coupled heterodimer of Chl a and lutein (or other Xans at site L1) and acts as a de-excitation channel. Laser powers, and consequently amounts of artifact, vary strongly between NPQ studies, thereby explaining contradicting spectral signatures attributed to NPQ. Our results offer pathways toward unveiling NPQ mechanisms and highlight the necessity of careful attention to laser-induced artifacts.

[Approach to illness and death of Vadinienses in roman Hispania (I-IV centuries)]. / Aproximación a la enfermedad y muerte de los Vadinienses en la Hispania romana (siglos I-IV).

The Vadinienses were a Cantabrian people who lived between the first and fourth centuries in the north of the Iberian Peninsula, northeast of the present province of León and the corresponding part of the current territory of Asturias. In this paper we study the possible causes of illness and death of the Vadinienses represented in their gravestones. The analysis of Vadinienses epitaphs shows that two-thirds of the deaths occurred in people between the ages of 20-30, a finding that is not interpreted as representative of the usual age of death at that time. The most likely causes of death are infections and violent deaths in sports competitions or work accidents. Analyzing females independently, almost half of the deceased were under the age of 20, being the main possibilities the deaths related to pregnancy and childbirth at very early ages.

Los vadinienses fueron un pueblo cántabro que habitó entre los siglos I y IV en el norte de la península ibérica -noreste de la actual provincia de León y la parte correspondiente de la actual Asturias-. En este trabajo se estudian las posibles causas de enfermedad y muerte de la población vadiniense representada en sus lápidas funerarias. Dos terceras partes de los vadinienses, según los datos de sus epitafios, murieron entre los 20-30 años, hallazgo que no se interpreta como representativo de la edad de muerte habitual en la época. Se consideran como las causas de muerte más probables las infecciones y las muertes violentas en competiciones deportivas o en accidentes laborales. Cuando se analiza de modo independiente al sexo femenino, casi la mitad de las fallecidas lo hicieron antes de los 20 años de edad, valorando como principales posibilidades las muertes relacionadas con embarazos y partos en edades muy precoces.