Validating human induced pluripotent stem cell-specific quality control tests for the release of an intermediate drug product in a Good Manufacturing Practice quality system.

One of the challenges in Good Manufacturing Practice (GMP)-compliant human induced pluripotent stem cell (hiPSC) production is the validation of quality control (QC) tests specific for hiPSCs, which are required for GMP batch release. This study presents a comprehensive description of the validation process for hiPSC-specific GMP-compliant QC assays; more specifically, the validation of assays to assess the potential presence of residual episomal vectors (REVs), the expression of markers of the undifferentiated state and the directed differentiation potential of hiPSCs. Critical aspects and specific acceptance criteria were formulated in a validation plan prior to assay validation. Assay specificity, sensitivity and reproducibility were tested, and the equipment used for each assay was subjected to performance qualification. A minimum input of 20 000 cells (120 ng of genomic DNA) was defined for accurate determination of the presence of REVs. Furthermore, since vector loss in hiPSC lines is a passage-dependent process, we advocate screening for REVs between passages eight and 10, as testing at earlier passages might lead to unnecessary rejection of hiPSC lines. The cutoff value for assessment of markers of the undifferentiated state was set to the expression of at least three individual markers on at least 75% of the cells. When multi-color flow cytometry panels are used, a fluorescence minus one control is advised to ensure the control for fluorescent spread. For the assay to assess the directed differentiation potential, the detection limit was set to two of three positive lineage-specific markers for each of the three individual germ layers. All of our assays proved to be reproducible and specific. Our data demonstrate that our implemented analytical procedures are suitable as QC assays for the batch release of GMP-compliant hiPSCs.

Good Manufacturing Practice-compliant human induced pluripotent stem cells: from bench to putative clinical products.

BACKGROUND AIMS: Few human induced pluripotent stem cell (hiPSC) lines are Good Manufacturing Practice (GMP)-compliant, limiting the clinical use of hiPSC-derived products. Here, we addressed this by establishing and validating an in-house platform to produce GMP-compliant hiPSCs that would be appropriate for producing both allogeneic and autologous hiPSC-derived products. METHODS: Our standard research protocol for hiPSCs production was adapted and translated into a GMP-compliant platform. In addition to the generation of GMP-compliant hiPSC, the platform entails the methodology for donor recruitment, consent and screening, donor material procurement, hiPSCs manufacture, in-process control, specific QC test validation, QC testing, product release, hiPSCs storage and stability testing. For platform validation, one test run and three production runs were performed. Highest-quality lines were selected to establish master cell banks (MCBs). RESULTS: Two MCBs were successfully released under GMP conditions. They demonstrated safety (sterility, negative mycoplasma, endotoxins <5.0 EU/mL and negative adventitious agents), cell identity (>75% of cells expressing markers of undifferentiated state, identical STR profile, normal karyotype in >20 metaphases), purity (negative residual vectors and no plasmid integration in the genome) and potency (expression of at least two of the three markers for each of the three germ layers). In addition, directed differentiation to somitoids (skeletal muscle precursors) and six potential clinical products from all three germ layers was achieved: pancreatic islets (endoderm), kidney organoids and cardiomyocytes (mesoderm), and keratinocytes, GABAergic interneurons and inner-ear organoids (ectoderm). CONCLUSIONS: We successfully developed and validated a platform for generating GMP-compliant hiPSC lines. The two MCBs released were shown to differentiate into clinical products relevant for our own and other regenerative medicine interests.

Transición en las enfermedades crónicas gastrointestinales. Del cuidado pediátrico al del adulto / Transition in chronic gastrointestinal diseases. From pediatric to adult care

Los avances tecnológicos y del conocimiento hicieron que un mayor número de pacientes con enfermedad crónica gastrointestinal pasen de ser atendidos por el pediatra al control por los médicos de adultos durante una de las etapas más vulnerables de la vida: la adolescencia. El Grupo de Trabajo de Transición del Comité de Gastroenterología de la Sociedad Argentina de Pediatría realizó una búsqueda de literatura exhaustiva y convocó a especialistas referentes del país, con el objeto de unificar los criterios basados en la evidencia y la experiencia. De esta manera, se proponen una serie de recomendaciones para todo el equipo de salud (pediatra, gastroenterólogo infantil, nutricionista, gastroenterólogo de adultos, psicólogo, enfermería), incluso para pacientes y familias, que faciliten el proceso de transición y optimicen el seguimiento, el control, la prevención de complicaciones y la calidad de vida de los pacientes con enfermedades crónicas gastrointestinales

Technological advances and the globalization of knowledge have led to a considerable increase in the number of patients with chronic gastrointestinal disease who transition from pediatric to adult care during one of the most vulnerable life stages: adolescence. The Transition Working Group of the Gastroenterology Committee of the Sociedad Argentina de Pediatría conducted an exhaustive literature search and summoned leading specialists in the most frequent chronic pathologies from all over the country to unify criteria based on evidence and experience. As a result, a series of recommendations are proposed for the whole health team (pediatrician, pediatric gastroenterologist, nutritionist, adult gastroenterologist, psychologist, and nurse) including patients and families, to facilitate the transition process, optimize follow-up, prevent complications, and improve the quality of life of patients with chronic gastrointestinal diseases.

[Transition in chronic gastrointestinal diseases. From pediatric to adult care]. / Transición en las enfermedades crónicas gastrointestinales. Del cuidado pediátrico al del adulto.

Technological advances and the globalization of knowledge have led to a considerable increase in the number of patients with chronic gastrointestinal disease who transition from pediatric to adult care during one of the most vulnerable life stages: adolescence. The Transition Working Group of the Gastroenterology Committee of the Sociedad Argentina de Pediatría conducted an exhaustive literature search and summoned leading specialists in the most frequent chronic pathologies from all over the country to unify criteria based on evidence and experience. As a result, a series of recommendations are proposed for the whole health team (pediatrician, pediatric gastroenterologist, nutritionist, adult gastroenterologist, psychologist, and nurse) including patients and families, to facilitate the transition process, optimize follow-up, prevent complications, and improve the quality of life of patients with chronic gastrointestinal diseases.

Los avances tecnológicos y del conocimiento hicieron que un mayor número de pacientes con enfermedad crónica gastrointestinal pasen de ser atendidos por el pediatra al control por los médicos de adultos durante una de las etapas más vulnerables de la vida: la adolescencia. El Grupo de Trabajo de Transición del Comité de Gastroenterología de la Sociedad Argentina de Pediatría realizó una búsqueda de literatura exhaustiva y convocó a especialistas referentes del país, con el objeto de unificar los criterios basados en la evidencia y la experiencia. De esta manera, se proponen una serie de recomendaciones para todo el equipo de salud (pediatra, gastroenterólogo infantil, nutricionista, gastroenterólogo de adultos, psicólogo, enfermería), incluso para pacientes y familias, que faciliten el proceso de transición y optimicen el seguimiento, el control, la prevención de complicaciones y la calidad de vida de los pacientes con enfermedades crónicas gastrointestinales.

Satellite ligand effects on magnetic exchange in dimers. A structural, magnetic and theoretical investigation of Cu2L2X4 (L = methylisothiazolinone and X = Cl-, Br-).

Halide-bridged polymers have gained significant interest due to their diverse properties and potential applications. Stacked Cu2L2X4 dimers, where L is an organic ligand and X can be Cl- or Br-, are of interest because a chloride analogue where L = 2-pyridone, had previously been reported to exhibit bulk ferromagnetism, which augured great potentiality for this class of compounds. The synthesis, structural characterization, magnetic susceptibility measurements, and computational studies of two isostructural CuClMI (MI = methylisothiazolinone) and CuBrMI polymers of Cu(II), along with a related CuClPYR (PYR = 2-pyridone) is reported. CuClMI and CuBrMI were found to exhibit AFM bulk properties, due to FM/AFM alternating chains along the halide-bridged polymer axis, while FM bulk properties were confirmed for CuClPYR exhibiting a FM spin ladder. In combination with a benzamide analogue, CuClBA, three O-donor amides, CuClMI, CuClBA and CuClPYR were analyzed and revealed that the kinetic exchange is affected by the identity, but more importantly, the orientation of the satellite ligands. The torsional angle of the ligand with the dimer plane is shown to significantly affect the magnetic exchange in the dimer, and between dimers, explaining the reported FM bulk properties of CuClPYR. This finding is exceedingly important, as it suggests that a spin device can be constructed to flip between singlet/triplet states by manipulating the orientation of the satellite/terminal ligand.

Thiamine pharmaconutrition in sepsis: Monotherapy, combined therapy, or neither? Current evidence on safety and efficacy.

Sepsis is a life-threatening condition characterized by multiorgan dysfunction due to an exaggerated host response to infection associated with a homeostatic failure. In sepsis, different interventions, aimed at improving clinical outcomes, have been tested over the past decades. Among these most recent strategies, intravenous high-dose micronutrients (vitamins and/or trace elements) have been investigated. According to current knowledge, sepsis is characterized by low thiamine levels, which are associated with illness severity, hyperlactatemia, and poor clinical outcomes. However, caution is needed about the clinical interpretation of thiamine blood concentration in critically ill patients, and the inflammatory status, based on C-reactive protein levels, should always be measured. In sepsis, parenteral thiamine has been administered as monotherapy or in combination with vitamin C and corticosteroids. Nevertheless, most of those trials failed to report clinical benefits with high-dose thiamine. The purpose of this review is to summarize the biological properties of thiamine and to examine current knowledge regarding the safety and efficacy of high-dose thiamine as pharmaconutrition strategy when administering singly or in combination with other micronutrients in critically ill adult patients with sepsis or septic shock. Our examination of the most up-to-date evidence concludes that Recommended Daily Allowance supplementation is relatively safe for thiamine-deficient patients. However, current evidence does not support pharmaconutrition with high-dose thiamine as a single therapy or as combination therapy aimed at improving clinical outcomes in critically ill septic patients. The best nutrient combination still needs to be determined, based on the antioxidant micronutrient network and the multiple interactions among different vitamins and trace elements. In addition, a better understanding of the pharmacokinetic and pharmacodynamic profiles of intravenous thiamine is needed. Future well-designed and powered clinical trials are urgently warranted before any specific recommendations can be made regarding supplementation in the critical care setting.

Low temperature structures and magnetic interactions in the organic-based ferromagnetic and metamagnetic polymorphs of decamethylferrocenium 7,7,8,8-tetracyano-p-quinodimethanide, [FeCp*2]˙+[TCNQ]˙.

To identify the genesis of the differing magnetic behaviors for the ferro- (FO) and metamagnetic (MM) polymorphs of [FeCp*2][TCNQ] (Cp* = pentamethylcyclopentadienide; TCNQ = 7,7,8,8-tetracyano-p-quinodimethane) the low temperature (18 ± 1 K) structures of each polymorph were determined from high-resolution synchrotron powder diffraction data. Each polymorph possesses chains of alternating S = 1/2 [FeCp*2]˙+ cations and S = 1/2 [TCNQ]˙+, but with differing relative orientations. These as well as an additional paramagnetic polymorph do not thermally interconvert. In addition, the room and low (<70 ± 10 K) temperature structures of the MM polymorph, MMRT and MMLT, respectively, differ from that previously reported at 167 K (-106 °C) MM structure, and no evidence of either phase transition was previously noted even from the magnetic data. This transition temperature and enthalpy of this phase transition for MMRT⇌MM was determined to be 226.5 ± 0.4 K (-46.7 ± 0.4 °C) and 0.68 ± 0.04 kJ mol-1 upon warming, respectively, from differential calorimetry studies (DSC). All three MM phases are triclinic (P1[combining macron]) with the room temperature phase having a doubled unit cell relative to the other two. The lower temperature phase transition involves a small rearrangement of the molecular ions and shift in lattice parameters. These three MM and FO polymorphs have been characterized and form extended 1-D chains with alternating S = 1/2 [FeCp*2]˙+ cations, and S = 1/2 [TCNQ]˙- anions, whereas the fifth, paramagnetic (P) polymorph possesses S = 0 π-[TCNQ]22- dimers. At 18 ± 1 K the intrachain FeFe separations are 10.738(2) and 10.439(3) Å for the FO and MMLT polymorphs, respectively. The key structural differences between FO and MMLT at 18 ± 1 K are the 10% shorter interchain NN and the 2.8% shorter intrachain FeFe separation present for MMLT. Computational analysis of all nearest-neighbor spin couplings for the 18 K structures of FO and MMLT indicates that the intrachain [FeCp*2]˙+[TCNQ]˙- spin couplings (H = -2Si·Sj) are the strongest (4.95 and 6.5 cm-1 for FO and MMLT, respectively), as previously hypothesized, and are ferromagnetic due to their S = 1/2 spins residing in orthogonal orbitals. The change in relative [TCNQ]˙-[TCNQ]˙- orientations leads to a computed change from the ferromagnetic interaction (0.2 cm-1) for FO to an antiferromagnetic interaction (-0.1 cm-1) for MMLT in accord with its observed antiferromagnetic ground state. Hence, the magnetic ground state cannot be solely described by the dominant magnetic interactions.

Prevalence, severity, and clinical correlates of food neophobia in Salvadorian youth.

Food neophobia (FN) describes problematic fear-based avoidance/restriction of novel foods. Using the novel parent-reported Measure of Food Neophobia (MFN), the authors examined FN symptoms and impairment in 305 Salvadorian children and explored clinical correlates. Factor analysis supported the MFN's designed structure to inquire about FN symptoms and FN impairment. At least one FN symptom was observed in 91% of the sample; however, only 9% were rated as having moderate or greater impairment. Demographic variables were not associated with FN; however, FN was positively correlated with internalizing, externalizing, inattention, health anxiety, and obsessive-compulsive symptoms. Inattention symptoms and health anxiety emerged as significant predictors of FN symptoms, while FN symptoms were the only significant predictor of FN impairment. The present study supports the MFN and provides information about FN in a general population, including the prevalence of clinically significant symptoms and association with psychological domains. Continued investigation of FN is still needed.

Novel Semi-Interpenetrated Polymer Networks of Poly(3-Hydroxybutyrate-co-3-Hydroxyvalerate)/Poly (Vinyl Alcohol) with Incorporated Conductive Polypyrrole Nanoparticles.

This paper reports the preparation and characterization of semi-interpenetrating polymer networks (semi-IPN) of poly(3-hydroxybutirate-co-3-hydroxyvalerate), PHBV, and poly (vinyl alcohol), PVA, with conductive polypirrole (PPy) nanoparticles. Stable hybrid semi-IPN (PHBV/PVA 30/70 ratio) hydrogels were produced by solvent casting, dissolving each polymer in chloroform and 1-methyl-2-pyrrolidone respectively, and subsequent glutaraldehyde crosslinking of the PVA chains. The microstructure and physical properties of this novel polymeric system were analysed, including thermal behaviour and degradation, water sorption, wettability and electrical conductivity. The conductivity of these advanced networks rose significantly at higher PPy nanoparticles content. Fourier transform infrared spectroscopy (FTIR) and calorimetry characterization indicated good miscibility and compatibility between all the constituents, with no phase separation and strong interactions between phases. A single glass transition was observed between those of pure PHBV and PVA, although PVA was dominant in its contribution to the glass transition process. Incorporating PPy nanoparticles significantly reduced the hydrogel swelling, even at low concentrations, indicating molecular interactions between the PPy nanoparticles and the hydrogel matrix. The PHBV/PVA semi-IPN showed higher thermal stability than the neat polymers and PHBV/PVA blend, which also remained in the tertiary systems.

Tratamiento intervencionista con stents en recién nacidos con cardiopatías congénitas complejas / Interventionist treatment with stents in newborns with complex congenital heart disease

Introducción: La colocación de stents mediante cateterismo cardiaco en recién nacidos con ciertas cardiopatías congénitas complejas constituye un puente hacia la cirugía correctiva, paliativa o trasplante cardiaco. Objetivo: Evaluar el resultado del implante percutáneo de stents en pacientes recién nacidos con cardiopatías congénitas complejas. Presentación de los casos: Se colocó stents en cinco pacientes; a uno de ellos en la aorta y a los cuatros restantes en el ductus arterioso. Un primer paciente con hipoplasia de cavidades izquierdas en el que predominaba el bajo gasto se le colocó stent en el ductus e inmediatamente se le condujo al salón de operaciones para cerclaje pulmonar. Otro paciente con la misma enfermedad, pero en el que predominaba el hiperflujo pulmonar, se intervino de forma inversa, medió 47 días entre uno y otro proceder. A un tercer paciente, portador de coartación aórtica, se le colocó stent en la aorta y se le hizo cerclaje pulmonar 14 días después del proceder hemodinámico. Las condiciones clínicas del cuarto paciente, con síndrome de hipoplasia de cavidades izquierdas solo permitió colocar stent en el ductus. Esta paciente fallece en evento no relacionado con el cateterismo cardiaco. El último paciente intervenido, portador de una atresia pulmonar, tolera la colocación del stent en el ductus y la evolución clínica posterior demostró que no requería realizar cerclaje pulmonar. Conclusiones: La colocación de stent en el grupo de pacientes analizado es factible y el momento de su implante según el evento hemodinámico apremiante pudiera ser una forma alternativa del cateterismo cardiaco(AU)

Introduction: The paliative placing of stents by cardiac catetherism in new borns with specific congenital hearts diseases is a bridge through a new kind of corrective, paliative surgery or heart transplant. Objective: To evaluate the result of the percutaneous implant of stents in newborn patients with complex congenital heart diseases. Cases presentation: There were placed stents in 5 patients, to one of them in the aorta and to the other four in the ductus arteriosus. The first patient with hypoplasia of the left cavities in which low output predominated had an stent placing in the ductus and he was immediately taken to OR to perform a pulmonary cerclage. Another patients with the same disease but with predominance of pulmonary hyperflow was intervened in the inverse way; there were 47 days between both procedures. A third patient, carrier of aortic coarctation, had an stent placing in the aorta and he also had pulmonary cerclage 14 days after the hemodynamic procedure. The clinical conditions of the fourth patient, who had syndrome of left cavities´ hypoplasia, just allowed to place the stent in the ductus. This patients died in a procedure not related to heart catetherism. The last intervened patient, who was a carrier of pulmonary atresia, tolerated the stent placing in the ductus and the subsequent clinical evolution showed that it was not needed pulmonary cerclage. Conclusions: The stent placing in the analized group of patients is suitable and the moment for its implantation according to the hemodynamic event can be an alternative form of heart catetherism(AU)

Development and testing of a 3D-printable polylactic acid device to optimize a water bioremediation process.

In the present work, a remediation bioprocess based on the use of a native isolate of Chlorella vulgaris immobilized in an alginate matrix inside a polylactic acid (PLA) device is proposed. This microalga immobilized in alginate beads was previously shown to be useful for the reduction of several chemical and microbial contaminants present in the highly polluted water from the Matanza-Riachuelo watershed. However, these beads had a relatively short shelf life in the natural environment. To overcome this limitation, a 3D-printed PLA device was designed. PLA is a biocompatible and biodegradable material suitable for biotechnological applications. We used Erlenmeyers and stirred-tank bioreactors fed batch with Murashige Skoog (MS) culture medium or water from the Cildáñez stream (one of the water bodies of the aforementioned watershed) to estimate the growth kinetics parameters and the bioremediation capacity of immobilized-microalgal cells as an unconfined system (UcS) or a confined system (CfS) inside PLA devices on Cildáñez water. Although alga's growth parameters were maximum in the UcS fed with MS medium as substrate, successful bioremediation of the target water was possible using the CfS: all inorganic nitrogen forms and total phosphorus were reduced at least by 90% after 5 days of bioprocess in an agitated bioreactor, whereas aerobic mesophilic bacteria decreased by about 85%. The number of coliforms also decreased. Standardized cytotoxicity tests using Allium cepa seeds carried out to prove the effectiveness of the bioremediation process, confirmed the high degree of decontamination achieved by the use of immobilized microalga confined in a 3D-printable PLA-device.

Cierre de la comunicación interauricular por cateterismo intervencionista con dispositivo Amplatzer en pediatría / Atrial Septal defect closure by interventional catheterization with Amplatzer device in Pediatrics

Introducción: El cateterismo intervencionista corrige las cardiopatías complejas, donde el dispositivo Amplatzer es el más usado y está disponible en Cuba. Objetivo: Evaluar el cateterismo intervencionista con Amplatzer, en el cierre de la comunicación interauricular ostium secundum. Métodos: Estudio de evaluación, longitudinal y prospectivo en 92 pacientes. El cierre de la comunicación por cateterismo con Amplatzer, se realizó en el Cardiocentro Pediátrico William Soler (2010-2016). Se utilizaron variables demográficas, ecocardiográficas (transtorácicas y transesofágicas) antes, durante y al año del cateterismo. Se observaron las complicaciones. La evaluación clínica y ecocardiográfica se realizó al año poscateterismo. Los pacientes a quienes se les realizó el proceder en el 2016, se evaluaron a los 6 meses. Resultados: Se encontraron diferencias significativas en el sexo (p<0,05): femenino 64,1 por ciento con homogeneidad para la edad (p= 0,244): media 9,8 años ( 5 desviaciones estándar. Precateterismo: 28,3 por ciento eran desnutridos y 17,4 por ciento delgados; poscateterismo la desnutrición mejoró significativamente (p= 0,000): desnutridos 9,8 por ciento y delgados 8,7 por ciento. El diámetro medio del defecto por ecocardiografía transcateterismo fue significativo (p= 0,000). Transcateterismo: 98,9 por ciento con cierre de defecto, 16,3 por ciento con insuficiencia tricúspidea y 4,3 por ciento con insuficiencia mitral. Poscateterismo: 98,9 por ciento con Amplatzer bien colocado. Hubo complicaciones inmediatas en 8,7 por ciento (arritmias, derrame pericárdico y embolización). Al año se detectó cortocircuito residual pequeño (n= 1) e insuficiencias valvulares auriculoventriculares (n= 3). La evolución fue satisfactoria (n= 91). Conclusiones: La evolución del cierre de la comunicación interauricular ostium secundum con dispositivo Amplatzer es satisfactoria, con mejoras de la desnutrición(AU)

Introduction: The interventional catheterization corrects complex heart diseases, and the Amplatzer device is the most widely used and is available in Cuba. Objective: To assess the interventional catheterization with Amplatzer device in the ostium secundum atrial septal closure. Methods: Longitudinal and prospective evaluation study in 92 patients. The closure of the communication by Amplatzer catheterization was performed in the William Soler Pediatric Cardiocenter of (2010-2016). Demographic and echocardiographic (transthoracic and transesophageal) variables were used before, during, and at the year of the catheterization. Complications were observed. Clinical and echocardiographic assessment was made a year after catheterism. The patients who underwent the procedure in 2016 were evaluated at 6 months. Results: Significant differences were found in the sex (p< 0.05): Female 64.1 t percent with homogeneity of the age (p= 0.244): average 9.8 years ( 5 standard deviations. Pre-catheterism: 28.3 percent were malnourished and 17.4 percent thin; post-catheterism: malnutrition improved significantly (p= 0.000): 9.8 percent malnourished and 8.7 percent thin. The average diameter of the defect by transcatheter echocardiography was significant (p= 0.000). Transcatheter: 98.9 percent : with default closure, 16.3 percent with tricuspid insufficiency and 4.3 percent with mitral regurgitation. Post-catheterism: 98.9 percent with Amplatzer device correctly positioned. There were immediate complications in 8.7 percent (arrhythmia, pericardial effusion, and embolization). A year after, small residual short circuit was detected (n= 1), and atrioventricular valve regurgitation (n= 3). The evolution was satisfactory (n= 91). Conclusions: The evolution of ostium secundum atrial septal defect´s closure with Amplatzer device is satisfactory and improves malnutrition(AU)

Parents' Knowledge, Attitudes, and Experiences in Child Sexual Abuse Prevention in El Salvador.

Childhood sexual abuse (CSA), a global public health problem, is often underreported especially in low-income countries such as El Salvador, and prevention efforts are needed. The purpose of this study was to examine knowledge, attitudes and experiences of CSA prevention and characteristics related to greater knowledge and openness to engaging in child abuse prevention among Salvadoran parents. Salvadoran parents (N = 478) completed questionnaires regarding demographics, definition and signs and symptoms of child abuse, personal experiences of CSA, CSA prevention training, and knowledge, attitudes and practices about preventing CSA. Most parents were knowledgeable about CSA, viewed CSA prevention as their responsibility, and had talked with their children about CSA, although 65.7% incorrectly believed that children are more likely to be abused by strangers. Parents with lower income were less knowledgeable and willing to participate in CSA prevention. CSA programing needs to involve parents and specifically target low-income parents.

Impact of Transcatheter Device Closure of Atrial Septal Defect on Atrial Arrhythmias Propensity in Young Adults.

Atrial septal defect (ASD) is a condition that requires early intervention because of the consequences over the right-side heart. Chronic atrial stretching promotes atrial conduction delay and the imbalance of the conduction homogeneity, which lead to the propensity to atrial arrhythmias (AA). We aim to evaluate the impact of transcatheter closure of ASD on atrial vulnerability markers leading to late AA in young adults. We conducted a prospective, longitudinal study in one hundred patients (mean age 25.2 ± 5.4 years) who underwent transcatheter closure of ASD at Cardiocentro Pediátrico William Soler. P-wave maximum (Pmax) and P-wave dispersion (Pd) were analyzed from 12-lead electrocardiogram. Left-side and right-side intraatrial and interatrial electromechanical delay (EMD) were measured with tissue Doppler imaging. Both electrocardiographic and echocardiographic analyses were performed during the study period. Compared to baseline, there was a significant reduction in P max (p ≤ 0.001) and Pd (p ≤ 0.001) after 3 months of procedure. All atrial electromechanical coupling parameters significantly reduced at 6 months of ASD closure and tend to remain at lower values till the last evaluation. Over 9.2 ± 1.6 years of follow-up, 15 subjects (15%) developed AA, of which intraatrial reentrant tachycardia (66.6%) became the main rhythm disturbance. Intra-right atrial EMD ≥ 16 ms (HR 4.08, 95% CI 1.15-14.56; p = 0.03) and Pd 45 ms (HR 1.66, 95% CI 1.06-2.59; p = 0.02) were identified as predictors of late AA. Transcatheter device closure of ASD in young adults promotes a significant reduction of electrocardiographic and echocardiographic markers of AA vulnerability, which persist during the long-term follow-up. Nevertheless, Pd and interatrial EMD were identified as independent risk factors of AA.

The magnetic fingerprint of dithiazolyl-based molecule magnets.

Magnetic bistability in organic-radical based materials has attracted significant interest due to its potential application in electronic devices. The first-principles bottom-up study herein presented aims at elucidating the key factors behind the different magnetic response of the low and high temperature phases of four different switchable dithiazolyl (DTA)-based compounds. The drastic change in the magnetic response upon spin transition is always due to the changes in the JAB magnetic interactions between adjacent radicals along the π-stacks of the crystal, which in turn are driven mostly by the changes in the interplanar distance and degree of lateral slippage, according to the interpretation of a series of magneto-structural correlation maps. Furthermore, specific geometrical dispositions have been recognized as a ferromagnetic fingerprint in such correlations. Our results thus show that an appropriate substitution of the chemical skeleton attached to the DTA ring could give rise to new organic materials with dominant ferromagnetic interactions.

Origin of Bistability in the Butyl-Substituted Spirobiphenalenyl-Based Neutral Radical Material.

One of the most remarkable bistable materials reported so far is made of π dimers of a butyl-substituted spirobiphenalenyl boron radical (butyl-SBP). The phase transition of this material, which is accompanied by changes in its optical, conductive, and magnetic properties, occurs with a hysteretic loop 25 K wide centered at 335 K. Herein, a computational study is presented aimed at deciphering the origin of this hysteresis. The phase transition of butyl-SBP consists of a spin transition of the constituent π dimers coupled with an order-disorder transition involving the butyl chains linked to the nitrogen atoms of the superimposed phenalenyl rings of the π dimer. Below 335 K, the terminal methyl group of the butyl chains adopts a gauche conformation with respect to the methylene unit bonded to the nitrogen atom. Above 335 K, the methyl group is in an anti conformation and exhibits dynamic disorder. The gauche→anti conformational rearrangement triggers the spin transition of the π dimers and is responsible for the hysteretic behavior of butyl-SBP. Specifically, the onset of the phase transition in the heating mode, and thus, the width of the hysteresis loop, are governed by the high energy cost and strong structural cooperative effects associated with this conformational change. Our results show that coupling a spin switch with a conformational switch in a molecular crystal provides a promising strategy in the design of new bistable materials.

Ferromagnetic Exchange in Bichloride Bridged Cu(II) Chains: Magnetostructural Correlations between Ordered and Disordered Systems.

The synthesis, structure, magnetic properties, and theoretical analysis of a new phase of dichloro(2-chloro-3-methylpyridine)copper(II) (2) and its isomorphous analogue dichloro(2-bromo-3-methylpyridine)copper(II) (3) are reported. Both complexes crystallize in the orthorhombic space group Pbca and present square pyramidal Cu(II) ions bridged into chains by chloride ions with each copper(II) bearing a single pyridine ligand. Variable temperature magnetic susceptibility measurements were well fit by a uniform one-dimensional ferromagnetic chain model with 2, J = 69.0(7) K, C = 0.487 emu-K/mol-Oe; 3, J = 73.9(4) K, C = 0.463 emu-K/mol-Oe (H = -JΣSi·Sj Hamiltonian). The experimental J-values were confirmed via theoretical calculations. Comparison to a known disordered polymorph of dichloro(2-chloro-3-methylpyridine)copper(II), 1, shows marked differences as there are significant antiferromagnetic next-nearest neighbor interactions in 1 in addition to randomness induced by the disorder which provide a distinctly different magnetic response. The differences in magnetic behavior are attributed principally to the structural difference in the Cu(II) coordination sphere, 1 being significantly closer to trigonal-bipyramidal, whose difference changes both the nearest and next-nearest neighbor interactions.

Understanding room-temperature π-dimerisation of radical ions: intramolecular π-[TTF]22+ in functionalised calix[4]arenes.

Long, multicentre π-dimers of radical ions are weakly bound and can only be observed in solution at low temperature. However, recent supramolecular approaches induce the extra stabilisation required to preserve them at room temperature, by different means depending on the approach. In particular, π-[TTF]22+ dimers (TTF = tetrathiafulvalene) were detected upon oxidation of a TTF-based calix[4]arene in acetonitrile solution at room temperature, manifesting intramolecular [R-TTF]˙+[R-TTF]˙+ interactions (Chem. Commun. 2006, 2, 2233). In this work, the reasons behind the remarkable formation of these π-dimers in the calix[4]arene, [calix], molecule are unravelled by means of DFT calculations. We first demonstrate that the properties of the π-[R-TTF]22+ dimers are preserved in the [calix]2+. Most importantly, our results show that the π-dimerised and non-dimerised forms of the [calix]2+ are isoenergetic at room temperature, and that the activation energy for this process is ca. 9.5 kcal mol-1. Hence, both forms coexist in equilibrium at 298 K, as the intramolecular nature of the interaction ensures a high reaction rate. The role of the Na+ cation in preventing the π-[R-TTF]22+ dimerisation of the [calix]2+ receptor is also examined, unveiling that this effect is mostly due to the electrostatic repulsion induced by the cation. Finally, we provide a revision on room-temperature stable supramolecular long, multicentre π-dimers of radical ions, a class of systems with great potential as molecular switches.