Humanizar emprendiendo: homenaje a Rafael Alvira

Este cuaderno contiene "El Instituto y Rafael Alvira" "La carta 9 de Séneca" "Rafael Alvira: la castiza filosofía del hombre que vuelve" "Añoranza del humanismo necesario" "Una reflexión filosófica sobre lo económico: comentario a un texto de Rafael Alvira" "La dimensión societaria de la economía y de la empresa" "Sobre el espíritu aristocrático y el empresario: responsabilidades de ayer, responsabilidades de hoy" "Sobre el sistema de los derechos del hombre: el punto de vista de Charles Péguy" "El hogar familiar: espacio de lo eterno" "¿Filosofar con el martillo o con la empresa?" "Qué queremos decir cuando hablamos de desarrollo" "Tipologías de la información económico-financiera en la empresa. Valores y valoración" "Rafael Alvira y la Universidad de Montevideo" "Breve introducción al examen sistemático de “Cristianismo y empresarialidad”" "La realidad del poder en la familia y en la empresa familiar" "El todo y la parte. Alabanza de la sinécdoque" "Las raíces del liderazgo auténtico. Una fenomenología básica" "Algunas consideraciones sobre el poder político

Whole-genome sequencing holds the key to the success of gene-targeted therapies COMMENT

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.CASE VIGNETTEIn 2017, Ipek (her name is used with permission), an apparently healthy baby girl, was born, but newborn screening (NBS) returned a result of concern: a low T-cell Receptor Excision Circle (TREC) count, raising the possibility immunodeficiency. Her ensuing medical evaluation disclosed no signs of severe combined immune deficiency, the usual target of this screening, but unexpectedly pointed to a different diagnosis: ataxia telangiectasia (A-T), a rare and progressive neurodegenerative disorder. In A-T, pathogenic variants in the ATM gene impair the cell's ability to respond to DNA damage, causing the cerebellum to begin to shrink starting in early childhood. The usual course of the disease includes development of symptoms by age five with development of clumsiness and incoordination. By their teenage years, the abilities to walk, talk, swallow, and coordinate her eye movements are lost. She would likely die as a young adult.No treatments for A-T exist. One of the challenges is that most children are diagnosed only after neurologic symptoms emerge, after significant degeneration has already occurred. But because Ipek was diagnosed at such a young age, she could be enrolled in an investigational trial before major neuronal loss. At age two, Ipek began receiving a series of intrathecal injections of an antisense oligonucleotide, designed by Boston Children's Hospital to suppress the effects of an abnormal splice site created by one of her pathogenic ATM variants (Yu lab, manuscript in review). This therapy promises her an improved long-term outcome that would otherwise have been impossible.In an age burgeoning with promising research studies for rare genetic diseases, this case underscores the importance of early screening for access to investigational trials. Early screening with whole-genome sequencing (WGS) can unlock opportunities for genetically targeted or other experimental therapies, such as the mutation-specific therapy designed for Ipek. For instance, 10%-15% of individuals with A-T have been shown to have splice mutations that could make them eligible for treatment with a splice-modulating ASO (and two-thirds of these cases are only detectable via WGS because they involve deep intronic variants and/or structural genomic rearrangements). In the future, early WGS may unlock opportunities for additional targeted therapies like nonsense readthrough or RNA or genome editing.Functional Genomics of Muscle, Nerve and Brain Disorder

Evidence-Based Consensus and Systematic Review on Reducing the Time to Diagnosis of Duchenne Muscular Dystrophy

Evidence-Based Consensus and Systematic Review on Reducing the Time to Diagnosis of Duchenne Muscular Dystroph

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation

Functional Genomics of Systemic Disorder

Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: A cross-sectional web-based survey

Background Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. Patients, design and setting We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. Results Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54 female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31 and drug-induced TIN in 30 (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28 of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/ min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41 of patients (eGFR �90 mL/ min/1.73 m2), with only 3 having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80 of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18 (n=31) of patients, 21 of whom received mycophenolate mofetil. Conclusions Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88 of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

Personality profiles of cultures: aggregate personality traits

The personality profiles of cultures can be operationalized as the mean trait levels of culture members. College students from 51 cultures rated an individual from their country whom they knew well (N = 12,122). Aggregate scores on Revised NEO Personality Inventory (NEO-PI-R) scales generalized across age and gender groups, yielded a close approximation to the individual-level Five-Factor Model, and correlated with aggregate self-report personality scores and other culture-level variables. Results were not attributable to national differences in economic development or to acquiescence. Geographical differences in scale variances were replicated, but appeared to be artifactual. Findings support the rough scalar equivalence of NEO-PI-R factors and facets across cultures, and suggest that aggregate personality profiles provide insight into cultural differences