Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63.

Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value < 1 × 10-5) with CTRCD in case-control and extreme phenotypes analyses, respectively. The 3q28 locus (rs rs7652759, P = 5.64 × 10-6) in the case-control analysis was the strongest signal, with up to 64 SNPs above the suggestive significance threshold. The rs7652759, an intergenic variant between TPRG1 and TP63 genes, was the only variant validated in the replication cohort (P-value = 0.01). Functional mapping of this significant locus revealed up to 5 new genes potentially involved in the CTRCD. We identified the intergenic region near TP63 as a novel CTRCD susceptibility locus. In the future, the genotyping of these markers could be considered in new CTRCD risk scores to improve preventive strategies in cardio-oncology.

Examining the Role of Cultural and Family Factors in Substance Use Risk Among Indian American Youth.

INTRODUCTION: Although Indian Americans constitute the second-largest immigrant group in the United States, there is a paucity of information about Indian American youth, particularly with respect to substance use risk. We examined the relationship of social factors to permissive substance use beliefs (a proxy for substance use risk since they can lead to adulthood substance use and misuse) and family functioning. METHODS: The study used structural equation modeling to examine the prevalence of permissive substance use beliefs in a sample of Indian American youth ages 12-17 (N = 223) and examined the degree to which discrimination, bicultural identity integration, and endorsement of the model minority stereotype were associated with permissive substance use beliefs. RESULTS: Findings suggest that bicultural identity integration (B = 0.267 [SE = 0.112], p = 0.01) and discrimination (B = 0.294 [SE = 0.087], p = 0.001) are positively associated with permissive substance use beliefs. Bicultural identity integration (B = 0.415 [SE = 0.090], p = 0.0001) was positively associated with family support (B= -0.329 [SE = 0.108], p = 0.002) which, in turn, was associated with less permissive substance use beliefs. In contrast, endorsement of the model minority stereotype (B = 0.351 [SE = 0.090], p = 0.001) was positively associated with family closeness (B = 0.232 [SE = 0.927], p = 0.01) which, in turn, was associated with family support and then with less permissive substance use beliefs. CONCLUSIONS: Discrimination and bicultural identity integration emerged as key constructs related to substance use risk among Indian American youth. These youth could benefit from culturally appropriate prevention programming that addresses the negative impact of discrimination and its effect on permissive substance use beliefs and highlights protective factors.

Design, Synthesis, and Structure-Activity Relationship Studies of New Quinone Derivatives as Antibacterial Agents.

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae, while compound 28 demonstrated higher potency against MRSA than vancomycin.

Benefits in quality of life following an obstructive sleep apnea screening and treatment program in patients with acute ischemic stroke. / Beneficios en la calidad de vida de un programa de cribado y tratamiento de apnea obstructiva del sueño en pacientes con ictus isquémico agudo.

INTRODUCTION: Obstructive sleep apnea (OSA) has been proposed as a factor that worsens stroke prognosis. Our aim was to determine if an OSA intervention could improve quality of life (QOL, first objective) and modified Rankin score (mRS, second objective). PATIENTS AND METHODS: The intervention group of this quasi-experimental study included patients with acute ischemic stroke <72 hours who underwent polygraphy and Continuous Positive Airway Pressure (CPAP) and hygienic-dietary measures if required. The control group followed routine clinical practice. The Short Form 36 Health Survey (SF-36) and mRS were applied at the sixth month after stroke in both groups. RESULTS: Fifty-five vs. sixty-two patients were included in the intervention and control group respectively. In the intervention group, 64.71% of patients accepted the proposed CPAP (16 cases with a good adherence). An improvement in SF-36 items was detected in the intervention group: physical functioning (p = 0.008), role physical (p = 0.002), bodily pain (p = 0.008), general health (p <0.001), vitality (p = 0.001) and role emotional (p = 0.015). In a per-protocol analysis, all these improvements were verified in the group of patients treated with good CPAP adherence (p < 0.05 in all the same SF-36 items). The percentage of patients with physical component summatory = 50 was higher in the intervention group (p = 0.003). There were no differences in the median of mRS (p = 0.262). CONCLUSIONS: Although more evidence is needed, a significant improvement in QOL was suggested after our OSA intervention, particularly in patients with good CPAP adherence.

TITLE: Beneficios en la calidad de vida de un programa de cribado y tratamiento de apnea obstructiva del sueño en pacientes con ictus isquémico agudo.Introducción. La apnea obstructiva del sueño (AOS) se ha propuesto como un factor de mal pronóstico en el ictus. Pretendemos determinar si una intervención sobre la AOS puede mejorar las escalas de calidad de vida (primer objetivo) y de discapacidad (segundo objetivo). Pacientes y métodos. El grupo de intervención de este estudio cuasi experimental incluye a pacientes con ictus isquémico agudo menor de 72 horas de evolución a quienes se les realizó poligrafía, así como presión positiva continua en las vías aéreas (CPAP) y medidas higienicodietéticas si se requerían. En el grupo de control se siguió la práctica clínica habitual. Se aplicaron las escalas Short Form 36 Health Survey (SF-36) y modified Rankin Score (mRS) en el sexto mes del ictus en ambos grupos. Resultados. Se incluyó a 55 y a 62 pacientes en el grupo de intervención y en el de control, respectivamente. En el grupo de intervención, el 64,71% de los pacientes aceptó la CPAP indicada (16 casos con buena adhesión). Se detectó una mejoría en los ítems de la escala SF-36 en el grupo de intervención: funcionamiento físico (p = 0,008), rol físico (p = 0,002), dolor corporal (p = 0,008), salud general (p menor de 0,001), vitalidad (p = 0,001) y rol emocional (p = 0,015). En un análisis por protocolo, todas estas mejorías se comprobaron en el grupo de pacientes tratados con CPAP con buena adhesión (p menor de 0,05 en todos los ítems de la SF-36). El porcentaje de pacientes con el sumatorio del componente físico = 50 fue más alto en el grupo de intervención (p = 0,003). No había diferencias en la mediana de la mRS (p = 0,262). Conclusiones. Aunque se necesitan más evidencias, nuestro estudio sugiere una mejoría significativa de la calidad de vida tras nuestra intervención en la AOS, especialmente en pacientes con buena adhesión a la CPAP.

Intraventricular hemorrhage as complication after spinal surgery. Case report.

Remote intracranial hemorrhage (ICH) is a rare but dreaded complication after spinal surgery. The physiopathology of this phenomenon is closely related to a loss of cerebrospinal fluid (CSF) after an incidental durotomy during spine surgery. The most common remote ICH location is cerebellar, but few articles report intraventricular hemorrhage. Its clinic is associated with cerebral hypotension due to decreased CSF, mainly headache, dysarthria, hemiparesis, an impaired level of awareness and seizures. The diagnosis of remote ICH after a non-cranial surgery can be a challenge to anesthesiologists, this pathology should be suspected face an immediate neurological deterioration after anesthetic awakening. Non-specific symptoms make it difficult to identify the origin of intracranial hemorrhagic from other differential diagnoses. We present a patient with an impaired level of awareness and seizures who suffered a hemorrhage in the right ventricle with cerebral and cerebellar edema in the immediate postoperative period after spinal surgery.

Bilateral serous retinal detachment in a patient with atypical presentation of preeclampsia due to HELLP syndrome.

Exudative retinal detachment (ERD) is a rare complication that occurring in 1% of patients with preeclampsia, its incidence is increased when it is associated with HELLP syndrome. Preeclampsia is defined by the development of arterial hypertension and proteinuira occurs after 20 weeks of gestation until postpartum. HELLP syndrome (low platelets, hemolysis and elevated liver enzymes) is a severe form of preeclampsia. ERD in preeclampsia is related to choroidal ischaemia, in the vast majority of the cases associated with hypertensive retinopathy. However, it has been proposed that the combination of hypertension with a microangiopathic hemolysis, hipercoagulability and hypoalbuminemia are the main factors contributing to the development of ERD. Its treatment includes a rapid resolution of labor to reverse ocular manifestations and prevent visual sequels. We describe the case of a pregnant woman with atypical preeclampsia who, in the postpartum of a cesarean, presented an ERD concomitantly with a HELLP syndrome.

Intraventricular hemorrhage as complication after spinal surgery. Case report. / Hemorragia intraventricular como complicación tras una cirugía espinal. Caso clínico.

Remote intracranial hemorrhage (ICH) is a rare but dreaded complication after spinal surgery. The physiopathology of this phenomenon is closely related to a loss of cerebrospinal fluid (CSF) after an incidental durotomy during spine surgery. The most common remote ICH location is cerebellar, but few articles report intraventricular hemorrhage. Its clinic is associated with cerebral hypotension due to decreased CSF, mainly headache, dysarthria, hemiparesis, an impaired level of awareness and seizures. The diagnosis of remote ICH after a non-cranial surgery can be a challenge to anesthesiologists, this pathology should be suspected face an immediate neurological deterioration after anesthetic awakening. Non-specific symptoms make it difficult to identify the origin of intracranial hemorrhagic from other differential diagnoses. We present a patient with an impaired level of awareness and seizures who suffered a hemorrhage in the right ventricle with cerebral and cerebellar edema in the immediate postoperative period after spinal surgery.

Bilateral serous retinal detachment in a patient with atypical presentation of preeclampsia due to HELLP syndrome. / Desprendimiento de retina exudativo bilateral en paciente con presentación atípica de preeclampsia por síndrome de HELLP.

Exudative retinal detachment (ERD) is a rare complication that occurring in 1% of patients with preeclampsia, its incidence is increased when it is associated with HELLP syndrome. Preeclampsia is defined by the development of arterial hypertension and proteinuira occurs after 20 weeks of gestation until postpartum. HELLP syndrome (low platelets, hemolysis and elevated liver enzymes) is a severe form of preeclampsia. ERD in preeclampsia is related to choroidal ischaemia, in the vast majority of the cases associated with hypertensive retinopathy. However, it has been proposed that the combination of hypertension with a microangiopathic hemolysis, hipercoagulability and hypoalbuminemia are the main factors contributing to the development of ERD. Its treatment includes a rapid resolution of labor to reverse ocular manifestations and prevent visual sequels. We describe the case of a pregnant woman with atypical preeclampsia who, in the postpartum of a cesarean, presented an ERD concomitantly with a HELLP syndrome.

Incidence of venous thromboembolic events in cancer patients receiving immunotherapy: a single-institution experience.

BACKGROUND: Cancer and cancer therapies have been associated with an increased incidence of venous thromboembolic events (VTE). However, the incidence of VTE in patients on immunotherapy has not been well characterized. The aim of this study was to assess the incidence of VTE in cancer patients receiving immunotherapy and ascertain its prognostic utility. MATERIALS AND METHODS: We conducted a single-institution retrospective study, including all cancer patients treated with anti-Programmed cell Death 1 (PD-1), anti-Programmed cell Death Ligand-1 (PD-L1), anti-Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4), a combination of anti-PD-1/anti-PD-L1 and anti-CTLA4 or a combination including any of these drugs with chemotherapy, antiangiogenic agents or both between June 2013 and April 2019 at La Paz University Hospital, Madrid (Spain). RESULTS: We selected 229 patients. VTE occurred in 16 of 229 patients (7%). VTE occurred more frequently in patients with lung cancer followed by melanoma. Female sex and melanoma were independently associated with an increased risk of VTE. 12 of 16 VTE (75%) were symptomatic. Progressive disease to immunotherapy [HR 31.60 (95% CI 11.44-87.22), p = 0.00], lung cancer [HR 2.55 (95% CI 1.34-4.86), p = 0.00] and melanoma [HR 2.42 (1.20-4.86), p = 0.01] were independently associated with shorter OS. VTE occurrence was not independently associated with shorter OS [HR 1.33 (95% CI 0.63-2.80), p = 0.44]. CONCLUSIONS: The incidence of VTE in cancer patients receiving immunotherapy in our study appeared to be similar to the incidence previously reported in other series of cancer patients treated with systemic therapies. VTE occurrence did not correlate with the prognosis. Further and prospective studies are needed to derive definitive conclusions.

[Descriptive study of hepatic steatosis and associated morbidity in Primary Care. (ESTEATOAP Study)]. / Estudio descriptivo de la esteatosis hepática y la morbilidad asociada en atención primaria. (Estudio ESTEATOAP).

OBJECTIVE: To study the recorded prevalence of hepatic steatosis in Primary Care, as well as the proportion of patients diagnosed with fatty liver diseases (FLD) including simple non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) versus steatosis by other causes. In addition, the proportion of cardiometabolic morbidities associated with NAFLD liver was studied. MATERIAL AND METHODS: A descriptive observational study was carried out on a population that included all patients with a recorded diagnosis of hepatic steatosis in an urban health centre that serves a population of 25,747 over the age of 14. A sample size of 229 patients was calculated. The demographic and clinical characteristics associated with hepatic steatosis are described. RESULTS: The prevalence of steatosis was 2.17% and 1.51% for NAFLD. The mean age was 62.42 years. The study included 114 (50.2%) women and 113 (49.8%) males. NAFLD was found in 147 (64.8%), and 64 (28.2%) were steatosis due to other causes. The proportion of patients with NAFLD and high transaminases was 24.13%, and the proportion of patients with NAFLD and GGT elevation was 18.6%. A high proportion of NAFLD had been found with cardiometabolic risk factors: 93.9% overweight and obesity, 55.1% diabetes, 54.4% hypertension, 32.9% metabolic syndrome, 35.2% hypertriglyceridaemia, and HDL risk 19.6%. A significant association was found between cardiometabolic risk factors and NAFLD in diabetes, obesity, and metabolic syndrome. DISCUSSION: Prevalence was only 1.51%, perhaps because of the low importance given to this disease. There is a high proportion of NAFLD with cardiometabolic risk factors and more in the general population. If all the causes of steatosis are considered there is a significant association between obesity, diabetes mellitus, and metabolic syndrome with NAFLD. CONCLUSIONS: The recorded prevalence of NAFLD is much lower than that of population studies, and a high presence of cardiometabolic factors has been found in these patients.

Conjugation of NMR and SAXS for flexible and multidomain protein structure determination: From sample preparation to model refinement.

Experimental information from small angle X-ray scattering (SAXS) is conjugated with nuclear magnetic resonance (NMR) spectroscopy data for the improvement of protein structure determination, particularly for flexible, multidomain or intrinsically disordered proteins. Individually, each of these techniques presents capabilities and limitations: NMR excels in local information, providing atomic resolution, but is limited by protein size, whereas SAXS yields a global envelope of the protein with lower resolution, but revealing domain positions. Different conjugation methodologies use the complementarity of both techniques' independent constraints to achieve comprehensive protein structure determination and resolve dynamics at a moderate computational expense.

Conjugation of NMR and SAXS for multidomain protein structure determination: from sample preparation to model refinement / Conjugación de NMR y SAXS para la determinación estructural de proteínas multidominio: de la preparación de muestras al refinamiento de modelo

Abstract Experimental information from small angle X-ray scattering (SAXS) is conjugated with nuclear magnetic resonance (NMR) spectroscopy data for the improvement of protein structure determination, particularly for flexible, multidomain or intrinsically disordered proteins. Individually, each of these techniques presents capabilities and limitations: NMR excels in local information, providing atomic resolution, but is limited by protein size, whereas SAXS yields a global envelope of the protein with lower resolution, but revealing domain positions. Different conjugation methodologies use the complementarity of both technique´s independent constraints to accomplish a comprehensive protein structure determination and dynamics understanding at a moderate computational expense.

Resumen Se conjuga información experimental proveniente de dispersión de rayos X a ángulos pequeños (SAXS) con la espectroscopía de resonancia magnética nuclear (NMR) para perfeccionar la determinación de la estructura protéica, en particular de proteínas flexibles, de multidominio o intrínsecamente desordenadas. Individualmente, cada una de estas técnicas presenta capacidades y limitaciones: NMR se destaca en la información local, proporcionando resolución atómica, pero está limitada por el tamaño de la proteína, mientras que SAXS produce una envoltura global de la proteína con una resolución menor pero revelando las posiciones de los dominios. Las diferentes metodologías de conjugación utilizan la complementariedad de las restricciones independientes de ambas técnicas para seguir estrategias adecuadas de acuerdo con la proteína, logrando una determinación integral de la estructura y una comprensión de las dinámicas del sistema proteico a un costo computacional moderado.

[Health literacy in childhood and adolescence: An overview and current state of research]. / Health Literacy bei Kindern und Jugendlichen : Ein Überblick über den aktuellen Forschungsstand.

BACKGROUND: Health literacy is multidisciplinary and brings together many concepts, and is of increasing importance for disease protection, health promotion, and prevention, and for health policy within Europe. Although its importance is increasingly recognised, adults are mostly the target audience, whereas children and adolescents, in addition to education and schools, have so far been neglected. OBJECTIVES: The aim is to give an overview of the state of the art in childhood and adolescence health literacy research, and to identify any existing gaps. MATERIALS: A literature review has been performed to identify the relevant research data. RESULTS: Limitations in developmental and age-adjusted conceptual frameworks and a lack of prevalence data, however, significantly impede our understanding of the meaning of health literacy in children and adolescents. School health promotion programmes could serve as a platform for effective health literacy education, beginning in early childhood. CONCLUSIONS: In addition to compatibility with a broader literacy perspective, the proximity to several theories of health promotion and defined concepts, and the importance of school health promotion and education, it is vital to focus research on current gaps in the understanding of health literacy determinants, health literacy as a determinant of health, and in terms of the design and systematic implementation of intervention programmes.

Use of bevacizumab as a first-line treatment for metastatic breast cancer.

OBJECTIVE: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.

Trends and Disparities in Mortality Among Spanish-Born and Foreign-Born Populations Residing in Spain, 1999-2008.

Spain's immigrant population has increased 380% in the last decade, accounting for 13.1% of the total population. This fact has led her to become during 2009 the eighth recipient country of international immigrants in the world. The aim of this article is to describe the evolution of mortality and the main causes of death among the Spanish-born and foreign-born populations residing in Spain between 1999 and 2008. Age-standardised mortality rates (ASRs), average age and comparative mortality ratios among foreign-born and Spanish-born populations residing in Spain were computed for every year and sub-period by sex, cause of death and place of birth as well as by the ASR percentage change. During 1999-2008 the ASR showed a progressive decrease in the risk of death in the Spanish-born population (-17.8% for men and -16.6% for women) as well as in the foreign-born one (-45.9% for men and -35.7% for women). ASR also showed a progressive decrease for practically all the causes of death, in both populations. It has been observed that the risk of death due to neoplasms and respiratory diseases among immigrants is lower than that of their Spanish-born counterparts, but risk due to external causes is higher. Places of birth with the greater decreases are Northern Europe, Eastern Europe, Western Europe, Southern Europe, and Latin America and the Caribbean. The research shows the differences in the reduction of death risk between Spanish-born and immigrant inhabitants between 1999 and 2008. These results could contribute to the ability of central and local governments to create effective health policy. Further research is necessary to examine changes in mortality trends among immigrant populations as a consequence of the economic crisis and the reforms in the Spanish health system. Spanish data sources should incorporate into their records information that enables them to find out the immigrant duration of permanence and the possible impact of this on mortality indicators.

Enhanced immobilization of gold nanoclusters on graphite.

The immobilization of individual biological molecules by metal nanoparticles requires that the particles themselves be immobilized. We introduce a new technique for immobilization of gold clusters based on their binding to small tunnels in a graphite support, themselves created by the implantation of small clusters. These tunnels are shown to perform as more effective cluster immobilization sites than point defects on the surface of graphite. The method is tested with atomic force microscopy (AFM) (both contact and noncontact mode) scanning. Size-selected clusters with 923, 561, 309, and 147 atoms have been immobilized and imaged with high-resolution, noncontact AFM.

[Acute lung injury as a consequence of fresh frozen plasma administration in a patient with factor XII deficiency]. / Lesión pulmonar aguda como consecuencia de la transfusión de plasma fresco congelado en un paciente con déficit de factor xii.

Along with the complete blood count, the coagulation tests are those most demanded before a surgical procedure. The activated partial thromboplastin time (APPT) quantifies the intrinsic and common coagulation pathways, including factors XII, XI, IX, VIII, X, V and II. Factor XII deficiency is associated with a prolonged APPT and an increase in thromboembolic phenomena, without increasing the intraoperative bleeding risk. A 20 year old man with factor XII deficiency was receiving two units of fresh frozen plasma because of an APPT of 100 seconds, with the intention of normalizing it before an urgent surgery procedure, and the fear of intraoperative bleeding. An hour after starting the transfusion the patient developed an acute lung injury (ALI) compatible with the diagnosis of a transfusion related acute lung injury (TRALI). The surgery continued without complications, and the patient was admitted to the resuscitation unit for 72 h, needing respiratory support. If the APTT is prolonged in the absence of bleeding, the presence of a non-specific circulating anticoagulant, a deficiency of factor XI, XII and VIII (associated to Von Willebrand disease) must be ruled out. Therefore, in the case presented here, the administration of hemoderivatives was unnecessary and can have consequences as serious as the one that the patient presented, a transfusion related acute lung injury.