Factors influencing transfection efficiency of pIDUA/nanoemulsion complexes in a mucopolysaccharidosis type I murine model

Mucopolysaccharidosis type I (MPS I) is an autosomal disease caused by alpha-l-iduronidase (IDUA) deficiency. This study used IDUA knockout mice as a model to evaluate whether parameters such as dose of plasmid and time of treatment could influence the transfection efficiency of complexes formed with PEGylated cationic nanoemulsions and plasmid (pIDUA), which contains the gene that encodes for IDUA. Formulations were composed of medium chain triglycerides, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]-2000), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), glycerol, and water and were prepared by the adsorption or encapsulation of preformed pIDUA–DOTAP complexes by high-pressure homogenization. A progressive increase in IDUA expression was observed with an increase in the dose and time of transfection for mice treated with both complexes (adsorbed and encapsulated), especially in the liver. Regardless of the complex administered, a significant increase in IDUA activity was detected in lungs and liver compared with nontreated MPS I when a dose of 60 μg was administered and IDUA activity was measured 7 days postadministration. Tissue sections of major organs showed no presence of cell necrosis, inflammatory infiltrate, or an increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed no difference in the number of macrophage cells in treated and nontreated animals, indicating the absence of inflammatory reaction caused by the treatment. The data set obtained in this study allowed establishing that factors such as dose and time can influence transfection efficiency in different degrees and that these complexes did not lead to any lethal effect in the MPS I murine model used

Risk factors for the development of cardiovascular disease in patients with depression in a hospital in Southern Brazil

Introdução: A associação entre depressão e fatores de risco cardiovascular é recorrente. O aumento de risco em deprimidos está relacionado à fatores como obesidade, sedentarismo, dislipidemia, alcoolismo e tabagismo. O objetivo deste trabalho foi identificar a presença de fatores de risco para o desenvolvimento de doenças cardiovasculares em pacientes com quadro de depressão internados em um hospital do sul do Brasil. Métodos: Estudo transversal que envolveu adultos de ambos os sexos internados por episódio depressivo. O estado nutricional foi avaliado pelas medidas antropométricas de peso, altura e circunferência da cintura. Um questionário foi aplicado englobando perfil sociodemográfico, histórico familiar de doenças, consumo de produtos de tabaco e de álcool, atividade física, além do questionário autoaplicável para medida da severidade da depressão. Para avaliação do risco cardiovascular global, foi calculado o escore de Framingham. Os testes qui-quadrado de Pearson (χ2 ) ou exato de Fisher foram utilizados para testar a associação entre as variáveis categóricas, considerando o nível de significância quando p ≤ 0,05 e IC95%. Resultados: Foram avaliados 54 indivíduos, predominantemente mulheres (n = 32), com idade média de 40,2 ± 10,8 anos. A depressão foi classificada como grave na maioria dos pacientes (n = 29). Fatores de risco relacionados ao nível de atividade física (sedentarismo), dislipidemia e estado nutricional (sobrepeso e obesidade) estiveram presentes em 81,5%, 73,1% e 66,7% da amostra, respectivamente. Percentual de risco obtido por meio do escore de Framingham foi encontrado acima do normal em 42,9% dos indivíduos. Depressão leve associou-se positivamente aos pacientes com magreza/eutrofia e, ao serem estratificados como severos e não-severos, o primeiro grupo teve associação positiva com histórico familiar de excesso de peso e hipertensão. Conclusões: Diversos fatores de risco cardiovascular foram encontrados, alertando para a importância do cuidado integral da saúde do paciente e avaliação destes indicadores.Introduction: The association between depression and cardiovascular risk factors is recurrent. Increased risk of depression is related to factors such as obesity, sedentary lifestyle, dyslipidemia, alcoholism, and smoking. The aim of this study was to identify the presence of risk factors for the development of cardiovascular disease in patients with depression admitted to a hospital in southern Brazil. Methods: A cross-sectional study involving adults of both sexes hospitalized for a depressive episode. Nutritional status was assessed by the anthropometric measurements of weight, height and waist circumference. A questionnaire was applied covering sociodemographic data, family history of diseases, consumption of tobacco and alcohol products, and physical activity, in addition to a self-administered questionnaire to measure the severity of depression. The Framingham risk score was calculated for global cardiovascular risk evaluation. Pearson’s chi-square test (χ2 ) or Fisher’s exact Test were used to test the association between categorical variables, considering the level of significance at p ≤ 0.05 and 95% CI. Results: Fifty-four individuals were evaluated, most were women (n = 32), with a mean age of 40.2 ± 10.8 years were evaluated. Depression was classified as severe in most patients (n = 29). Risk factors related to the physical activity level (sedentary lifestyle), dyslipidemia and nutritional status (overweight and obesity) were present in 81.5%, 73.1% and 66.7% of the sample, respectively. Percentage of risk obtained by the Framingham risk score was found above normal in 42.9% of the individuals. Mild depression was positively associated with thin/eutrophic patients and, when stratified as severe and non-severe, the first group had a positive association with family history of overweight and hypertension. Conclusions: Several cardiovascular risk factors were found, alerting to the importance of integral health care for patients and evaluation of these indicators

ALADIN is Required for the Production of Fertile Mouse Oocytes

Asymmetric cell divisions depend on the precise placement of the spindle apparatus. In mammalian oocytes, spindles assemble close to the cell's center, but chromosome segregation takes place at the cell periphery where half of the chromosomes are expelled into small, nondeveloping polar bodies at anaphase. By dividing so asymmetrically, most of the cytoplasmic content within the oocyte is preserved, which is critical for successful fertilization and early development. Recently we determined that the nucleoporin ALADIN participates in spindle assembly in somatic cells, and we have also shown that female mice homozygously null for ALADIN are sterile. In this study we show that this protein is involved in specific meiotic stages, including meiotic resumption, spindle assembly, and spindle positioning. In the absence of ALADIN, polar body extrusion is compromised due to problems in spindle orientation and anchoring at the first meiotic anaphase. ALADIN null oocytes that mature far enough to be fertilized in vitro are unable to support embryonic development beyond the two-cell stage. Overall, we find that ALADIN is critical for oocyte maturation and appears to be far more essential for this process than for somatic cell divisions

Venetoclax ramp-up strategies for chronic lymphocytic leukaemia in the United Kingdom: a real world multicentre retrospective study

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies

LetsTalkShots: personalized vaccine risk communication

IntroductionVaccine hesitancy is a global health threat undermining control of many vaccine-preventable diseases. Patient-level education has largely been ineffective in reducing vaccine concerns and increasing vaccine uptake. We built and evaluated a personalized vaccine risk communication website called LetsTalkShots in English, Spanish and French (Canadian) for vaccines across the lifespan. LetsTalkShots tailors lived experiences, credible sources and informational animations to disseminate the right message from the right messenger to the right person, applying a broad range of behavioral theories.MethodsWe used mixed-methods research to test our animation and some aspects of credible sources and personal narratives. We conducted 67 discussion groups (n = 325 persons), stratified by race/ethnicity (African American, Hispanic, and White people) and population (e.g., parents, pregnant women, adolescents, younger adults, and older adults). Using a large Ipsos survey among English-speaking respondents (n = 2,272), we tested animations aligned with vaccine concerns and specific to population (e.g., parents of children, parents of adolescents, younger adults, older adults).ResultsDiscussion groups provided robust feedback specific to each animation as well as areas for improvements across animations. Most respondents indicated that the information presented was interesting (85.5%), clear (96.0%), helpful (87.0%), and trustworthy (82.2%).DiscussionTailored vaccine risk communication can assist decision makers as they consider vaccination for themselves, their families, and their communities. LetsTalkShots presents a model for personalized communication in other areas of medicine and public health

A cluster randomized trial of a transition intervention for adolescents with congenital heart disease: rationale and design of the CHAPTER 2 study

BACKGROUND: The population of adolescents and young adults with congenital heart disease (CHD) is growing exponentially. These survivors are at risk of late cardiac complications and require lifelong cardiology care. However, there is a paucity of data on how to prepare adolescents to assume responsibility for their health and function within the adult health care system. Evidence-based transition strategies are required. METHODS: The Congenital Heart Adolescents Participating in Transition Evaluation Research (CHAPTER 2) Study is a two-site cluster randomized clinical trial designed to evaluate the efficacy of a nurse-led transition intervention for 16–17 year olds with moderate or complex CHD. The primary endpoint is excess time to adult CHD care, defined as the time interval between the final pediatric cardiology appointment and the first adult CHD appointment, minus the recommended time interval between these appointments. Secondary endpoints include the MyHeart score (CHD knowledge), Transition Readiness Assessment Questionnaire score, and need for catheter or surgical re-intervention. Participants are enrolled in clusters based on week of attendance in the pediatric cardiology clinic. The intervention consists of two one-hour individualized sessions between a cardiology nurse and study participant. Session One focuses on knowledge of the participant’s CHD, review of their cardiac anatomy and prior interventions, and potential late cardiac complications. Session Two focuses on self-management and communication skills through review and discussion of videos and role-play. The study will recruit 120 participants. DISCUSSION: Many adolescents and young adults experience a gap in care predisposing them to late cardiac complications. The CHAPTER 2 Study will investigate the impact of a nurse-led transition intervention among adolescents with CHD. Fidelity of the intervention is a major focus and priority. This study will build on our experience by (i) enrolling at two tertiary care programs, (ii) including a self-management intervention component, and (iii) evaluating the impact of the intervention on time to ACHD care, a clinically relevant outcome. The results of this study will inform pediatric cardiology programs, patients and policy makers in judging whether a structured intervention program provides clinically meaningful outcomes for adolescents and young adults living with CHD. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT0172333

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations