Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Segmental lesions along blaschko´s lines in an elderly man

Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple keratotic and crusted papules over seborrheic areas, along with a variable involvement of oral mucosa, palmoplantar region, and nails. Segmental subtypes (type 1 and 2) are uncommon clinically limited forms of DD that usually present at middle age with few cutaneous lesions following Blaschko´s lines. We report a case of extensive multi segmental DD type 1 that developed in an elderly man, an unusual clinical onset of DD that dermatologists should bear in mind

Whitish oral lesions in a heavy pipe smoker

Classically known as the "Great Imitator", the diagnosis of syphilis continues to be an enormous challenge. We describe a case of isolated oral lesions as the sole presentation of secondary syphilis and only clinical clue to previously undiagnosed human immunodeficiency virus infection. The current increase in new cases of syphilis is leading to reemergence of forgotten old scenarios, which physicians should bear in mind within the differential diagnosis of their daily practice

Whitish oral lesions in a heavy pipe smoker

Classically known as the "Great Imitator", the diagnosis of syphilis continues to be an enormous challenge. We describe a case of isolated oral lesions as the sole presentation of secondary syphilis and only clinical clue to previously undiagnosed human immunodeficiency virus infection. The current increase in new cases of syphilis is leading to reemergence of forgotten old scenarios, which physicians should bear in mind within the differential diagnosis of their daily practice

Segmental lesions along blaschko´s lines in an elderly man

Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple keratotic and crusted papules over seborrheic areas, along with a variable involvement of oral mucosa, palmoplantar region, and nails. Segmental subtypes (type 1 and 2) are uncommon clinically limited forms of DD that usually present at middle age with few cutaneous lesions following Blaschko´s lines. We report a case of extensive multi segmental DD type 1 that developed in an elderly man, an unusual clinical onset of DD that dermatologists should bear in mind

Influence of the COVID-19 lockdown on Spanish professional soccer teams’ external demands according to their on-field ranking

The main objective of this study was to analyse the changes in external demand parameters (e.g., total distance, high-speed running distance, accelerations/decelerations) in Spanish professional soccer teams after the COVID-19 lockdown considering their on-field ranking (i.e., teams whose ranking worsened after the COVID-19 lockdown [WRS] vs. teams that improved their ranking after the COVID-19 lockdown [IMP]). A total of 23,527 individual match observations were collected on players competing during the 2019/20 season in the First Spanish Professional soccer League (LaLiga). Goalkeepers and players who participated for less than 10 minutes in each match were excluded. Relative total distance (TD/min), distance covered at 21–24 km·h-1 (HIRD/min) and > 24 km·h-1 per minute (VHIRD/min), high metabolic load distance (HMLD), and the number of accelerations (3 m/s2 ) and decelerations (< 3 m/s2 ) performed were analysed by the ChryonHego video tracking system. These variables were analysed during two differentiated periods, before the COVID-19 lockdown (i.e., 27 matches) and after the COVID-19 lockdown (i.e., 11 matches), and teams were classified into two groups according to their ranking (i.e., WRS vs. IMP). R-Studio was employed for data analysis and a mixed linear model was conducted. A decrease in external demands in all teams after the COVID-19 lockdown was observed, and this decrease was greater in WRS. These results suggest that, after an inactive period (i.e., the COVID-19 lockdown), teams that return with better physical performance, mainly related to high-intensity actions, have more possibilities of improving their final qualifying position

3-烷基，3-二氢-1H-异吲哚-1-酮的不对称合成

3-烷基-2，3-二氢-1H-异吲哚-1-酮(I)类化合物存在于许多天然有机物和生理活性物质的核心结构中,具有广阔的医学和生化应用前景。此外,这类化合物还可作为不对称合成的手性辅助剂,还原后可作为手性配体,在不对称合成中具有潜在的应用前景。本论文的目的是在本实验室以往研究工作的基础上，开发手性异吲哚酮合成子的合成路线，建立一种灵活多用的合成方法，以期为不对称合成提供新型手性辅助剂,用于不对称合成反应。首先，从邻苯二甲酸酐(II)和（R）-（-）-苯基甘氨醇(III)出发,合成了N–取代邻苯二甲酰亚胺(V)。把V的羟基用苄基保护后的产物VI进行还原烷基化反应,即格氏试剂加成—三氟化硼合乙醚催化下...The 3-substituted-2,3-dihydro-1H-isoindol-1-ones (I) are found as core units in many natural and/or bioactive compounds, they have broad prospect in fields of medicine and biochemistry. After amide carbonyl reduction, they can serve as a group of promising chiral auxiliaries in asymmetric synthesis. Our laboratory has developed a general method for the asymmetric synthesis of pyrrolidines, 2-pyrro...学位：理学硕士院系专业：化学化工学院化学系_有机化学学号：19972501

Programas y enfoques para enseñar a pensar

En el presente documento se trata el problema de la enseñanza de las habilidades del pensamiento si se quiere dotar al alumnado de instrumentos y recursos eficaces para encarar el futuro con capacidad crítica. Se dirige fundamentalmente a los profesionales de la educación de niveles no universitarios que estén interesados por la enseñanza de las habilidades del pensamiento en el aula. Se pretende facilitar y hacer más accesible al profesorado información relevante sobre un conjunto de interesantes programas que ofrecen una visión sintética sobre este tema, analizando a la vez sus parámetros teóricos, el nivel científico de que gozan, su nivel de operatividad práctica, el tipo de instrumentación que requieren para su puesta en funcionamiento, etc.AndalucíaCentro del Profesorado de Málaga. Biblioteca; Calle Noé, 3; 29007 Málaga; +34951924214; +34952334092; [email protected]