The case for open science: rare diseases.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally

The Impact of Political Leaders' Profession and Education on Reforms

This paper analyzes whether the educational and professional background of a head of government matters for the implementation of market-liberalizing reforms. Employing panel data over the period 1970-2002, we present empirical evidence based on a novel data set covering profession and education of more than 500 political leaders from 73 countries. Our results show that entrepreneurs, professional scientists, and trained economists are significantly more reform oriented. Contrary, union executives tend to impede reforms. We also highlight interactions between profession and education with time in office and the political leaning of the ruling party

Efficacy of dose-escalated chemoradiation on complete tumour response in patients with locally advanced rectal cancer (RECTAL-BOOST); a phase 2 randomised controlled trial

Purpose Pathological complete tumour response following chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with favourable prognosis and allows organ-sparing treatment strategies. We aimed to investigate the effect of an external radiation boost to the tumour prior to chemoradiation on pathological or sustained clinical complete tumour response in LARC. Methods and materials This multicentre, non-blinded, phase 2, randomised controlled trial followed the trials within cohorts-design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can accept or refuse this), whereas patients in the control group are not notified about the randomisation. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of two radiotherapy centres were eligible. Patients were randomised to no boost or an external radiation boost (5 x 3 Gy) without concurrent chemotherapy directly followed by standard pelvic chemoradiation (25 x 2 Gy with concurrent capecitabine). The primary outcome was pathological complete response (pCR, i.e. ypT0N0) in patients with planned surgery at 12 weeks or, as surrogate for pCR, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCTXXXXXX. Results Between Sept 2014 and July 2018, 128 patients were randomised. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4-stage and a low rectal tumour (31.3% versus 17.2% and 56.3% versus 45.3% respectively), and more patients had a cN2-stage (59.4% versus 70.3% respectively). Rate of pathological or sustained clinical complete tumour response was similar between the groups: 23 of 64 (35.9%, 95%CI 24.3-48.9) in the intervention group versus 24 of 64 (37.5%, 95%CI 25.7-50.5) in the control group (OR=0.94 95%CI 0.46-1.92). Near-complete or complete tumour regression was more common in the intervention group: 34 of 49 (69.4%) versus 24 of 53 (45.3%) in the control group (OR=2.74, 95%CI 1.21-6.18). Grade >3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR=1.22 95%CI 0.35-4.22). Conclusion Dose escalation with an external radiotherapy boost to the tumour prior to neoadjuvant chemoradiation did not increase the pathological or sustained clinical complete tumour response rate in LARC

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Orientaciones específicas para la incorporación de tecnología en procesos de formación de profesores de Ciencias Naturales, Lenguaje y Comunicación, y Matemáticas en contextos de diversidad para el diseño de secuencias de enseñanza aprendizaje

Las Tecnologías de la Información y de la Comunicación (TIC) se han transformado en un elemento de innovación dentro del conocimiento humano. Aplicadas directamente a la disciplina académica, las TIC se han ganado un espacio debido al creciente interés de este tipo de herramientas por parte de los docentes. No obstante, al día de hoy, en Latinoamérica el uso de TIC no es masivo. Su implementación aún está en una etapa inicial, y esto es debido a diversos factores. Algunos tienen que ver con el poco seguimiento que se realiza al implementar este tipo de tecnologías en las instituciones educativas; la limitada formación es una debilidad. En una escuela, el profesor que no ha sido preparado adecuadamente en el uso de TIC difícilmente logrará utilizarlas adecuadamente, y sus metodologías de aula serán, probablemente, idénticas a las que existían previas a su implementación. Existe una gran diferencia entre conocer una herramienta y dominarla; el dominio se logra, por ejemplo, al conocer las ventajas y desventajas que posee una herramienta determinada en conexión directa con los contenidos y las necesidades de los estudiantes. El dominio de las TIC otorga al docente de aula la posibilidad de tomar decisiones que tiendan a la efectividad del proceso educativo, puesto que las TIC no son solo un conjunto de herramientas, sino que, además, son orientables hacia un área u otra dependiendo de factores variables propios del proceso. Teniendo en cuenta el contexto anterior, este documento contiene algunas orientaciones para el uso del material desarrollado en el área de Ciencias Naturales, Lenguaje y Comunicación, y Matemáticas del Proyecto ALTER-NATIVA, el cual va dirigido a la formación de profesores que atienden poblaciones en contexto de diversidad con incorporación de las TIC. Es importante anotar que las actividades que se proponen son una posibilidad distinta de asumir la enseñanza de las ciencias naturales, lo cual a su vez implica reflexión y evaluación constante de la práctica de los docentes de esta área; que los compromete también con los desarrollos tecnológicos actuales, lo cual conlleva analizar y canalizar sus esfuerzos para diseñar y gestionar mecanismos que permitan la incorporación de las TIC en sus prácticas, pues se considera que estas posibilitan colaborar en la construcción de mundos posibles cercanos a los ideales de participación, igualdad y equidad (Alter -nativa , 2012). Estas orientaciones específicas tienen un doble propósito: primero, cobijan algunas recomendaciones, las cuales son una propuesta de uso para aprovechar al máximo el material que se propone en el estudio de las Ciencias Naturales, Lenguaje y Comunicación, y Matemáticas, para las poblaciones objeto de estudio. Para el desarrollo de las actividades planteadas es necesario que los estudiantes para profesor y profesores de escuelas, colegios y universidades de las áreas de Ciencias Naturales, Lenguaje y Comunicación, y Matemáticas, como posibles usuarios de este material, las perciban como un recurso que tiene un potencial y que, para su desarrollo, se hace necesario tener presente el diseño y estructura didáctica, los objetivos temáticos, la infraestructura, los recursos tecnológicos, las necesidades y características de las poblaciones con quien se vaya a utilizar, entre otros aspectos. Y segundo, estas orientaciones tienen como propósito ofrecer elementos para la formación de profesores de Ciencias Naturales, Lenguaje y Comunicación, y Matemáticas en su acción pedagógica y didáctica; se involucran las prácticas profesionales de diseño y elaboración de objetos didácticos y de los objetos virtuales de aprendizaje (OVA) como casos específicos de estos. Tomando como referencia lo anterior, se plantea como objetivos central de este texto el presentar algunas orientaciones que es necesario tener en cuenta a la hora incorporar TIC en la formación de profesores de Ciencias Naturales, Lenguaje y Comunicación, y Matemáticas. De igual forma, unos objetivos específicos serían los siguientes: a) Establecer unas orientaciones que sean consideradas a la hora de usar los recursos virtuales como los Objetos Virtuales de aprendizaje (OVA) que fueron diseñados como parte del proyecto ALTER-NATIVA en el área de ciencias naturales, lenguaje y matemáticas. b) Favorecer el aprendizaje de las ciencias naturales, lenguaje y matemáticas en las poblaciones objeto de estudio a través del uso de las TIC. c) Resaltar la importancia que tiene el uso de las TIC para concebir el aprendizaje como un sistema de interacción y no como transmisión de información solamente. d) Aportar a la reflexión y formación de docentes con una cultura tecnológica que les permita afrontar su labor pedagógica y didáctica en ámbitos de diversidad. e) Proporcionar unos elementos teóricos y de uso de las TIC que les admita la planeación, el diseño, desarrollo, uso y evaluación de objetos virtuales u OVA dentro de un ambiente virtual de aprendizaje

Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Peer reviewe

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe