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To compare body composition in patients with autonomous cortisol secretion (ACS), non-functioning adrenal incidentalomas (NFAIs) and controls without adrenal tumours.Cross-sectional study of 3 groups: patients with ACS (cortisol post-dexamethasone suppression test (DST)1.8μg/dL), NFAIs (cortisol post-DST ≤1.8μg/dL) and patients without adrenal tumours (controls). Patients of the three groups were matched according to age (±5 years-old), sex and body mass index (±5kg/m25 patients with ACS, 24 NFAIs and 24 controls were enrolled. Based on CT images, a weak positive correlation between serum cortisol post-DST and subcutaneous fat area (r=0.3, P=0.048) was found. As assessed by bioelectrical impedance, lean mass and bone mass were positively correlated with the excretion of total androgens (r=0.56, P0.001; and r=0.58, P0.001, respectively); and visceral mass was positively correlated with the excretion of glucocorticoid metabolites and total glucocorticoids (r=0.28, P=0.031; and r=0.42, P=0.001, respectively). Based on CT imaging evaluation, a positive correlation was observed between lean mass and androgen metabolites (r=0.30, P=0.036); and between visceral fat area, total fat area, and visceral/total fat area ratio and the excretion of glucocorticoid metabolites (r=0.34, P=0.014; r=0.29, P=0.042; and r=0.31, P=0.170, respectively).The USP observed in adrenal tumours, which consists in a low excretion of androgen metabolites and high excretion of glucocorticoid metabolites, is associated with a lower lean mass and bone mass and higher level of visceral mass in patients with adrenal tumours.

OBJECTIVE: Children with complex health needs (CCHN) have both medical (e.g., chronic conditions) and health-related social needs (e.g., potentially adverse social determinants of health) that require ongoing healthcare and support from multiple community service providers. National standards developed for populations defined by health needs (CYSHCN) provide a framework for stakeholders to plan system-level improvements in care delivery for CCHN, but improvement efforts should reflect the priorities of their families and providers. This article describes a process of prioritizing system-level efforts to improve the health and well-being of CCHN and families in North Carolina (NC), using systematic stakeholder engagement and modified Delphi expert ratings. METHODS: We surveyed stakeholders with experience caring for CCHN using an open-ended, 3-item instrument to identify opportunities to improve systems of care. Using directed qualitative content analysis, we synthesized responses into a master list of potential improvement topics. Using a modified Delphi approach, a 16-member advisory committee rated all topics for importance and urgency, on 9-point Likert scales over two rounds; then ratings for each topic were ranked (low, medium, high) to establish relative priority. RESULTS: 47 individuals from 31 counties around NC provided survey responses, yielding 59 improvement topics in 10 domains. Through the modified Delphi method process, 21 topics (36%) received the highest rankings, largely representing access to community- and home-based services, equity, and enhancement of the pediatric workforce. CONCLUSIONS: Priorities identified by stakeholders will inform advocacy, policy, and improvement efforts. Next steps for the coalition include developing improvement projects to implement stakeholder-recommended actions for the highest-priority topics.

The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins. To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker. The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic. Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics.

This report describes the physics case, the resulting detector requirements, and the evolving detector concepts for the experimental program at the Electron-Ion Col- lider (EIC). The EIC will be a powerful new high-luminosity facility in the United States with the capability to collide high-energy electron beams with high-energy proton and ion beams, providing access to those regions in the nucleon and nu- clei where their structure is dominated by gluons. Moreover, polarized beams in the EIC will give unprecedented access to the spatial and spin structure of the proton, neutron, and light ions. The studies leading to this document were com- missioned and organized by the EIC User Group with the objective of advancing the state and detail of the physics program and developing detector concepts that meet the emerging requirements in preparation for the realization of the EIC. The effort aims to provide the basis for further development of concepts for experimen- tal equipment best suited for the science needs, including the importance of two complementary detectors and interaction regions. This report consists of three volumes. Volume I is an executive summary of our findings and developed concepts. In Volume II we describe studies of a wide range of physics measurements and the emerging requirements on detector acceptance and performance. Volume III discusses general-purpose detector concepts and the underlying technologies to meet the physics requirements. These considerations will form the basis for a world-class experimental program that aims to increase our understanding of the fundamental structure of all visible matter.

espanolEl sindrome de ovario poliquistico es la patologia endocrinometabolica mas prevalente en las mujeres en edad fertil. Su diagnostico se basa en la presencia de dos de tres criterios: a) oligoovulacion, b) hiperandrogenismo clinico o bioquimico y c) morfologia poliquistica del ovario en la ecografia transvaginal. El diagnostico exige descartar otras causas secundarias de disfuncion ovulatoria o hiperandrogenismo tales como hiperprolactinemia, hiperplasia suprarrenal congenita no clasica, disfuncion tiroidea, hipercortisolismo, acromegalia o tumores virilizantes suprarrenales u ovaricos. En adolescentes, la disfuncion ovulatoria puede ser normal en el primer ano por inmadurez del eje reproductivo y ademas no se recomienda emplear el criterio ecografico, dada la presencia fisiologica de foliculos ovaricos en mayor cantidad que en adultas. En todos los casos se recomienda, en el momento del diagnostico, realizar un cribado de complicaciones metabolicas que puedan coexistir, incluyendo alteraciones del metabolismo de la glucosa, dislipidemia, esteatosis hepatica e hipertension arterial. EnglishPolycystic ovary syndrome (PCOS) is the most prevalent endocrine-metabolic disease in childbearing age women. Patients are diagnosed with PCOS if they have two of the following three criteria: a) oligo-ovulation, b) clinical or biochemical hyperandrogenism, c) polycystic ovarian morphology (transvaginal ultrasound). Diagnosis requires the exclusion of similar, mimicking disorders, such as hyperprolactinemia, non-classical congenital adrenal hyperplasia, thyroid dysfunction, hypercortisolism, acromegaly or virilizing adrenal or ovarian tumors. Due to the immaturity of the reproductive axis, ovulatory dysfunction may be normal in first pubescent year; being highest the physiological presence of ovarian follicles in these ages, ultrasound criteria are not recommended. Coexisting metabolic complications screening, including: impaired glucose metabolism, dyslipidemia, hepatic steatosis, and high blood pressure, is recommended during diagnosis.

espanolEl hipogonadismo masculino es una condicion clinica que deriva de una produccion insuficiente de testosterona y/o numero de espermatozoides por parte del testiculo como consecuencia de una alteracion a nivel gonadal (HP) o a nivel hipotalamo-hipofisario (secundario o central). Las manifestaciones clinicas variaran segun la edad de instauracion, la gravedad y el tiempo de evolucion. Los adultos mayores con signos, sintomas o hallazgos de laboratorio compatibles deben ser evaluados de manera similar a los adultos jovenes. Concentraciones de testosterona inferiores a 250-300 ng/dl, determinadas por un metodo fiable en dos dias diferentes, establecen su diagnostico. Las concentraciones de gonadotrofinas permitiran diferenciar la etiologia. Si estan elevadas, el origen sera primario testicular, con el sindrome de Klinefelter como causa mas frecuente en adultos jovenes, mientras que concentraciones normales o bajas de gonadotrofinas indican un proceso central o funcional, incluyendo la obesidad grave. Las concentraciones de prolactina deben determinarse en todos los pacientes con hipogonadismo central. EnglishMale hypogonadism is a clinical condition that results from failure to produce physiological concentrations of testosterone and/or normal amounts of sperm; it may be caused by a testicular disease (primary hypogonadism) or a dysfunction of the hypothalamic-pituitary unit (secondary or central hypogonadism). Depending on age, severity and time of evolution of the disease, clinical manifestations will vary. Clinical examination of adult patients with signs, symptoms or compatible laboratory findings is similar to that of young patients. Testosterone concentrations

espanolEl hirsutismo se define como la presencia de exceso de pelo terminal en zonas dependientes de androgenos de la mujer. Para su cuantificacion se emplea la escala de Ferriman-Gallwey modificada, donde se acepta un punto de corte universal ≥ 8, destacando que estos puntos de corte deben ser especificos para cada poblacion y grupo etnico estudiado. El sindrome de ovario poliquistico es la causa mas frecuente de hirsutismo en mujeres en edad fertil. Otras entidades clinicas incluyen el hiperandrogenismo funcional, el hirsutismo idiopatico, la hiperplasia suprarrenal congenita por deficit de 21-hidroxilasa, los tumores virilizantes suprarrenales u ovaricos y los farmacos androgenizantes. Una historia clinica cuidadosa es la herramienta mas util para el diagnostico clinico y etiologico. Una instauracion lenta y progresiva orienta a una causa funcional y/o benigna, mientras que la instauracion brusca y una evolucion rapidamente progresiva, asociando virilizacion, nos obligara a descartar una patologia tumoral. EnglishHirsutism is defined as excess terminal hair growth in androgen-dependent areas of the body in women. Modified Ferriman-Gallwey score is used to classified it, being considered hirsutism a score of ≥ 8; in all times, is mandatory to take in to account, the specific population and ethnic features of the in-study group. In childbearing age women, the most common cause of hirsutism is polycystic ovary syndrome. Functional hyperandrogenism, idiopathic hirsutism, congenital adrenal hyperplasia due to 21-hydroxylase deficiency, virilizing adrenal or ovarian tumors, and androgenizing drugs, are other clinical entities included. The most useful clinical and etiological diagnostic tool is a thorough clinical history. Thus, a slow and progressive onset guides us to a functional and/or benign cause; on the contrary, an abrupt onset, rapidly progressive, associated with virilization, makes it necessary to rule out a tumor pathology.

espanolEl hipogonadismo es una condicion clinica que deriva de un deficit de sintesis de testosterona y/o espermatozoides por el testiculo tras una alteracion, a cualquier nivel, del eje hipotalamo-hipofisis-testicular. El tratamiento con testosterona presenta un marcado beneficio sintomatico, siendo inocuo en la mayoria de los casos. Esta indicado en todos los pacientes con formas clasicas de hipogonadismo primario o secundario y en ciertas condiciones clinicas como aquellos pacientes con virus de inmunodeficiencia humana con perdida de peso acusada, ingesta cronica de glucocorticoides y, de manera muy selectiva, en algunos ancianos con clinica marcada de disfuncion sexual o, en dosis bajas, para proteger su masa osea. Entre sus contraindicaciones se cuentan la enfermedad neoplasica prostatica o de mama, poliglobulia, apnea obstructiva del sueno grave o riesgo cardiovascular importante. Debemos monitorizar periodicamente la eficacia del farmaco y la seguridad del paciente, vigilando concentraciones plasmaticas de testosterona, antigeno prostatico especifico (PSA) y hematocrito. EnglishHypogonadism is a clinical condition resulting from testis failure to produce physiological concentrations of testosterone and/or of sperm caused by a disorder, in any level, of hypothalamic-pituitary-testicular axis. Testosterone-replacement therapy provides, in the most cases, marked symptomatic benefit. It is indicated in all patients with classic forms of primary or secondary hypogonadism and in certain clinical conditions (human immunodeficiency virus patients with marked weight loss, chronic glucocorticoid intake and, very selectively, in some elderly patients with marked sexual dysfunction, or, in low doses, to protect their bone mass). Contraindications are, among others, prostate or breast neoplasms, polycythaemia, obstructive sleep apnea, and uncontrolled congestive heart failure. Both drug efficiency and patient safety have to be monitored, thus, serum testosterone and prostate-specific-antigen concentrations and hematocrit have to be assessed.

espanolLos adenomas hipofisarios (AH) son un grupo heterogeneo de lesiones del sistema nervioso central, generalmente benignas y que ocurren de forma esporadica. Los AH no funcionantes (AHNF) suponen el 25-35% de los AH, siendo los macroadenomas los mas frecuentes en adultos. Los AH gonadotropos silentes son el subtipo mas frecuente, representando el 70-90% de todos los AHNF. Los AHNF causan sintomas por compresion o por deficits hormonales adenohipofisarios. El diagnostico de los AH se basa en las tecnicas de imagen, principalmente en la resonancia magnetica con administracion de contraste. Adicionalmente, se debe realizar un estudio hormonal para descartar alteraciones hormonales, y un estudio neurooftalmologico en aquellos adenomas cercanos o que comprimen el quiasma optico y/o los senos cavernosos, o en pacientes con sintomas visuales. La cirugia transesfenoidal representa el tratamiento de primera linea en los casos sintomaticos o de gran tamano. EnglishPituitary adenomas (PA) are a rare and heterogeneous group, mainly benign, of central nervous system lesions. Non-functioning pituitary adenomas (NFPAs) account for 25-35% of PA; in adulthood macroadenomas are the commonest. Silent gonadotroph adenomas are the most frequent AH's subtype (70-90% of all NFPAs). Symptoms are related with mass effects of the tumor on the surrounding tissues or with hypopituitarism. AHs are diagnosed by imaging tests, mainly contrast magnetic resonance imaging. In order to discard hormone disorders, endocrine analysis has to be performed. Neuro-ophthalmological study has to be carried out in adenomas involving optic chiasm and/or cavernous sinuses, as well as in patients with visual symptoms. Trans-sphenoidal surgery is the primary treatment for symptomatic or large NFPA.

espanolLa homeostasis de los distintos ejes hipotalamo-hipofisarios se mantiene gracias a la interaccion de los circuitos de retroalimentacion positiva y negativa en los que participan las hormonas hipofisarias, senales distales, incluidas las hormonas esteroideas, y aferencias nerviosas de otras regiones cerebrales sobre las neuronas hipofisotroficas. Existen multiples mecanismos que pueden ocasionar una enfermedad del eje hipotalamo-hipofisario; entre ellas se encuentran mutaciones geneticas, alteraciones epigeneticas, procesos inflamatorios, infecciosos y tumorales, trastornos vasculares, traumatismos y diversas situaciones psicogenas. El sindrome hipotalamico puede presentarse con manifestaciones tanto endocrinas como no endocrinas. Una caracteristica clinica habitual es la «obesidad hipotalamica». El diagnostico clinico es complicado, por lo que el diagnostico de confirmacion debe complementarse con distintas pruebas orientadas segun la sospecha clinica; generalmente con un estudio hormonal y radiologico. Es recomendable realizar un abordaje multidisciplinar para tratar los sintomas y deficiencias hormonales y mejorar la calidad de vida de los pacientes. EnglishMaintaining homeostasis in hypothalamic-pituitary axis is accomplished through interlinked positive and negative feedback loops involving both pituitary hormones, distal signals (including steroid hormones), and nerve inputs from other brain regions on hypophysiotropic neurons. Pituitary-hypothalamic axis disorders may be caused by several ways: genetic mutations, epigenetic alterations, inflammatory and tumoral conditions, vascular disorders, traumatisms and different psychogenic situations. Hypothalamic syndrome can present with both endocrine and non-endocrine manifestations. Hypothalamic obesity is a common clinical feature. Clinical diagnosis is complicated. In accordance with clinical suspicion, complementary tests (generally hormonal and radiological study) must be carried out to confirm the diagnosis. In order to treat the symptoms, restore hormone levels and improve the quality of life of patients, multidisciplinary approach is recommended.