First- and Second-Order Analysis for Optimization Problems with Manifold-Valued Constraints

We consider optimization problems with manifold-valued constraints. These generalize classical equality and inequality constraints to a setting in which both the domain and the codomain of the constraint mapping are smooth manifolds. We model the feasible set as the preimage of a submanifold with corners of the codomain. The latter is a subset which corresponds to a convex cone locally in suitable charts. We study first- and second-order optimality conditions for this class of problems. We also show the invariance of the relevant quantities with respect to local representations of the problem

Asociación de la coordinación motriz con la actividad física y el índice de masa corporal en escolares entre 10 y 12 años, en el área urbana del municipio de Zarzal-Valle

Si tan solo al nivel escolar de los niños entre 6 y 12 años se le diera la importancia suficiente al desarrollo de los procesos inherentes a la coordinación como capacidad motriz, se podría dilatar en gran mesura la reducción de dichas capacidades, ya que a medida que se da la maduración infantil y su crecimiento, se va en decadencia de las propias capacidades, así mismo la pérdida de las edades sensibles para su desarrollo, algo a lo que Weineck llama “La ley del tren perdido” que se refiere al tiempo que no se supo aprovechar para desarrollar las capacidades coordinativas, y, que así se pretenda desarrollar posteriormente ya no tendrán la misma efectividad ni adaptabilidad fisiológica. Ruiz Pérez manifiesta, que un déficit madurativo de la coordinación respecto a los niveles correspondientes con la edad cronológica, presenta en el niño deficiencias en el desarrollo de las capacidades coordinativas, evidenciado en trastornos tale como: inconsistencia en sus actuaciones; persistencia; ser incapaces de separar sus actuaciones de las que realizan; asimetrías en las acciones corporales; problemas de equilibrio dinámico, inestabilidad y temor; inestabilidad y falta de control motor tras realizar tareas complejas; sinestesias; incapacidad para seguir ritmos; incapacidad para controlar la fuerza y dificultades en la planificación motriz de las acciones. Los aspectos y limitaciones que pueden afectar a la coordinación motriz son la herencia, el nivel de condición física general, la edad, la fatiga tanto física como psíquica, el nivel de aprendizaje (grado de automatización de los movimientos), el segmento corporal implicado (normalmente los brazos tienen mayor capacidad coordinativa que las piernas), la simetría de movimientos (hemilateral o ambilateral), el sentido de dirección del movimiento (normalmente los movimientos son más fáciles de coordinar hacia delante y en el plano horizontal), etc. La coordinación crea una buena organización de los gestos motores del niño, refiriéndola muchos autores, entre ellos Camerino y Castañer 1992, citados por Pozo (6), como la capacidad de regular de forma precisa la intervención del propio cuerpo en la ejecución de la acción justa y necesaria según lo requiera una acción motriz.If only at the school level of children between 6 and 12 years old enough importance were given to the development of the processes inherent to coordination as motor capacity, the reduction of said capacities could be greatly delayed, since as child maturation and growth occurs, their own abilities decline, likewise the loss of sensitive ages for their development, something that Weineck calls "The Law of the Lost Train" which refers to the time It was known to take advantage of to develop the coordinative capacities, and, that thus it is intended to develop later, they will no longer have the same effectiveness or physiological adaptability. Ruiz Pérez states that a maturational deficit of coordination with respect to the levels corresponding to chronological age, presents deficiencies in the development of coordination skills in the child, evidenced in such disorders as: inconsistency in their actions; persistence; being unable to separate their actions from those they perform; asymmetries in bodily actions; problems of dynamic balance, instability and fear; instability and lack of motor control after performing complex tasks; synesthesia; inability to follow rhythms; inability to control strength and difficulties in motor planning of actions. Aspects and limitations that can affect motor coordination are heredity, general fitness level, age, physical and mental fatigue, learning level (degree of automation of movements), the body segment involved ( normally the arms have greater coordination capacity than the legs), the symmetry of movements (hemilateral or ambilateral), the sense of direction of movement (normally the movements are easier to coordinate forward and in the horizontal plane), etc. Coordination creates a good organization of the child's motor gestures, referred to by many authors, including Camerino and Castañer 1992, cited by Pozo (6), as the ability to precisely regulate the intervention of the body itself in the execution of the action fair and necessary as required by a motor action

Sedimen Larut Dalam Asam Dan Tidak Larut Dalam Asam Di Perairan Teluk Buyat Dan Sekitarnya

Information on water conditions, such as sedimentation, physical factors, and coral reef ecosystem, needs to be understood that the stakeholders could optimally utilize the the area. This study was aimed at determining the sediment content of Buyat Bay and its surroundings dissolved and undissolved in the acid solution. Results found that the terrestrial sediments (Lithogenous) were not soluble in the acid solution and the marine ones (Biogenous) were soluble

Self-assembled coumarin- and 5-fluorouracil-PEG micelles as multifunctional drug delivery systems

The copper(I)-catalyzed azide/alkyne cycloaddition is recognized as one of the most successful click reactions to access self-assembling amphiphilic polymer-drug conjugates (PDCs). In this way, poor water-soluble drugs can be linked covalently to hydrophilic poly(ethylene glycol) (PEG) to obtain PEGylated drug micelles that can be used as versatile carriers for the delivery of diverse therapeutic agents. In this work, two novel amphiphilic PDCs that combine PEG with privileged scaffolds well-known for their anticancer properties, such as coumarin and 5-fluorouracil, have been synthesized and characterized. These conjugates were able to self-assemble into micelles at relatively high critical micellar concentration, probably due to the large portion of hydrophilic PEG. The micelles allowed to load other anticancer drugs (paclitaxel, curcumin, and gemcitabine), providing a unique opportunity to develop promising co-delivery carriers for synergistic cancer therapy. The Korsmeyer-Peppas mathematical model was used for describing the in vitro kinetics of drug release from the micelles. Similar sustained and controlled drug release profiles were obtained for paclitaxel and curcumin in both conjugates, which was attributed to the excellent stability driven by the strong interaction between polymeric conjugates and drugs in the micelle core. In contrast, the high instability observed for the gemcitabine-loaded micelles provided an initial uncontrolled burst release of drug. A preliminary in vitro cytotoxicity study of the micelles against human pancreatic cancer cells PANC-1 and BxPC-3 was also carried out, demonstrating that both coumarin and 5-fluorouracil retain their anticancer properties after conjugation with PEG.La cicloadición de azida/alquino catalizada por cobre (I) se reconoce como una de las reacciones de clic más exitosas para acceder a conjugados de polímero-fármaco anfifílicos (PDC) autoensamblados. De esta manera, los fármacos poco solubles en agua se pueden unir covalentemente al poli(etilenglicol) (PEG) hidrofílico para obtener micelas de fármacos PEGilados que se pueden utilizar como vehículos versátiles para la administración de diversos agentes terapéuticos. En este trabajo, dos PDC anfifílicos novedosos que combinan PEG con andamios privilegiados conocidos por sus propiedades anticancerígenas, como la cumarina .y 5-fluorouracilo, han sido sintetizados y caracterizados. Estos conjugados pudieron autoensamblarse en micelas a una concentración micelar crítica relativamente alta, probablemente debido a la gran porción de PEG hidrofílico. Las micelas permitieron cargar otros medicamentos contra el cáncer (paclitaxel, curcumina y gemcitabina), lo que brinda una oportunidad única para desarrollar portadores de administración conjunta prometedores para la terapia sinérgica contra el cáncer. Se utilizó el modelo matemático de Korsmeyer-Peppas para describir la cinética in vitro de la liberación del fármaco desde las micelas. Se obtuvieron perfiles similares de liberación sostenida y controlada del fármaco para paclitaxel.y curcumina en ambos conjugados, lo que se atribuyó a la excelente estabilidad impulsada por la fuerte interacción entre los conjugados poliméricos y los fármacos en el núcleo de la micela. Por el contrario, la alta inestabilidad observada para las micelas cargadas con gemcitabina proporcionó una liberación inicial descontrolada del fármaco. También se llevó a cabo un estudio preliminar de citotoxicidad in vitro de las micelas contra las células de cáncer de páncreas humano PANC-1 y BxPC-3, demostrando que tanto la cumarina como el 5-fluorouracilo conservan sus propiedades anticancerígenas después de la conjugación con PEG

Mutations related to Antiretroviral Resistance identified by ultra-deep sequencing in HIV-1 infected children under Structured Interruptions of HAART

Altres ajuts: CONACYT/GCPS/44519Although Structured Treatment Interruptions (STI) are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM's) at levels under limit of detection of conventional genotyping (<20% of quasispecies) could increase the risk of virologic failure. In this work, we analyzed the protease and reverse transcriptase regions of the pol gene by ultra-deep sequencing in pediatric patients under STI with the aim of determining the presence of high- and low-abundance DRM's in the viral rebounds generated by the STI. High-abundance mutations in protease and high- and low-abundance mutations in reverse transcriptase were detected but no one of these are directly associated with resistance to antiretroviral drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM's during STI

Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy

Objective: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. TRIM63 has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in TRIM63 and the development of HCM. Methods: TRIM63 was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls. Results: Sixteen index cases with rare homozygous or compound heterozygous variants in TRIM63 (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%). Conclusion: TRIM63 appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction

Predictores de riesgo en una cohorte española con cardiolaminopatías. Registro REDLAMINA

[Abstract] Introduction and objectives. According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) < 45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria. Methods. The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure. Results. We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF < 45% (P = .001) and NSVT (P < .001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF < 45% (P < .001). Conclusions. In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF < 45%. Therefore, female carriers of missense variants with either NSVT or LVEF < 45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.[Resumen] Introducción y objetivos. Según las guías de muerte súbita, se debe considerar un desfibrilador automático implantable (DAI) para los pacientes con miocardiopatía dilatada debida a variantes en el gen de la lamina (LMNA) con al menos 2 factores: varones, fracción de eyección del ventrículo izquierdo (FEVI) < 45%, taquicardia ventricular no sostenida (TVNS) y variantes no missense. Nuestro objetivo es describir las características clínicas de una cohorte española de pacientes con cardiolaminopatías (registro REDLAMINA) y evaluar los criterios de riesgo vigentes. Métodos. Se evaluó la relación entre factores de riesgo y eventos cardiovasculares en una cohorte de 140 portadores de variantes en LMNA (54 probandos, 86 familiares, edad ≥ 16 años). Se consideró: a) evento arrítmico mayor (EAM) si hubo descarga apropiada del DAI o muerte súbita, y b) muerte por insuficiencia cardiaca, incluidos los trasplantes. Resultados. Se identificaron 11 variantes nuevas y 21 previamente publicadas. La FEVI < 45% (p = 0,001) y la TVNS (p < 0,001) se relacionaron con los EAM, pero no el sexo o el tipo de variante (missense frente a no missense). La FEVI < 45% (p < 0,001) fue el único factor relacionado con la muerte por insuficiencia cardiaca. Conclusiones. En el registro REDLAMINA, los únicos 2 predictores asociados con EAM fueron la TVNS y la FEVI < 45%. No se debería considerar grupo de bajo riesgo a las portadoras de variantes missense con TVNS o FEVI < 45%. Es importante individualizar la estratificación del riesgo de los portadores de variantes missense en LMNA, porque no todas tienen el mismo pronóstico.This study received a grant from the Proyecto de investigación de la Sección de Insuficiencia Cardiaca 2017 from the Spanish Society of Cardiology and grants from the Instituto de Salud Carlos III (ISCIII) [PI14/0967, PI15/01551, AC16/0014] and ERA-CVD Joint Transnational Call 2016 (Genprovic). Grants from the ISCIII and the Ministerio de Economía y Competitividad de España (Spanish Department of Economy and Competitiveness) are supported by the Plan Estatal de I+D+i 2013-2016: Fondo Europeo de Desarrollo Regional (FEDER) “Una forma de hacer Europa”