Germline-Focused Analysis of Tumour-Only Sequencing: Recommendations from the ESMO Precision Medicine Working Group.

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focused analysis' is performed upon tumour sequencing data and for which variants follow-up analysis of a germline sample is performed. Here we present analyses of paired sequencing data from 17,152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup have generated (i) recommendations regarding germline-focused analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent

Public preferences for digital health data sharing: Discrete choice experiment study in 12 european countries

Background: With new technologies, health data can be collected in a variety of different clinical, research, and public health contexts, and then can be used for a range of new purposes. Establishing the public s views about digital health data sharing is essential for policy makers to develop effective harmonization initiatives for digital health data governance at the European level. Objective: This study investigated public preferences for digital health data sharing. Methods: A discrete choice experiment survey was administered to a sample of European residents in 12 European countries (Austria, Denmark, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom) from August 2020 to August 2021. Respondents answered whether hypothetical situations of data sharing were acceptable for them. Each hypothetical scenario was defined by 5 attributes ("data collector," "data user," "reason for data use," "information on data sharing and consent," and "availability of review process"), which had 3 to 4 attribute levels each. A latent class model was run across the whole data set and separately for different European regions (Northern, Central, and Southern Europe). Attribute relative importance was calculated for each latent class s pooled and regional data sets. Results: A total of 5015 completed surveys were analyzed. In general, the most important attribute for respondents was the availability of information and consent during health data sharing. In the latent class model, 4 classes of preference patterns were identified. While respondents in 2 classes strongly expressed their preferences for data sharing with opposing positions, respondents in the other 2 classes preferred not to share their data, but attribute levels of the situation could have had an impact on their preferences. Respondents generally found the following to be the most acceptable: A national authority or academic research project as the data user; being informed and asked to consent; and a review process for data transfer and use, or transfer only. On the other hand, collection of their data by a technological company and data use for commercial communication were the least acceptable. There was preference heterogeneity across Europe and within European regions. Conclusions: This study showed the importance of transparency in data use and oversight of health-related data sharing for European respondents. Regional and intraregional preference heterogeneity for "data collector," "data user," "reason," "type of consent," and "review" calls for governance solutions that would grant data subjects the ability to control their digital health data being shared within different contexts. These results suggest that the use of data without consent will demand weighty and exceptional reasons. An interactive and dynamic informed consent model combined with oversight mechanisms may be a solution for policy initiatives aiming to harmonize health data use across Europe

Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects

The status of the in vacuum APPLE II IVUE32 at HZB BESSY II

At BESSY II, two new beamlines for RIXS and for X Ray microscopy need a short period variably polarizing undulator. For this purpose, the first in vacuum APPLE II undulator worldwide is under construction. The parameters are as follows period length amp; 955;0 32 mm, periods 78, minimum gap 7mm. The design incorporates a force compensation scheme as proposed by two of the authors at the SRI 2018. All precision parts of the drive chain are located in air. New transverse slides for the transversal slit adjustment have been developed and tested. Optical Micrometers measure the gap and phase positions, similar to the system of the CPMU17 at BESSY II. They provide the signals for motor feedback loops. A new UHV compatible soldering technique, as developed with industry, relaxes fabrication tolerances of magnets and magnet holders and simplifies the magnet assembly. A 10 period prototype has been setup for lifetime tests of the new magnetic keeper design. The paper summarizes the status of the undulator IVUE3

THE DOUBLE-DOUBLE BEND ACHROMAT (DDBA) LATTICE MODIFICATION FOR THE DIAMOND STORAGE RING

Abstract We present an overview of the status of the DDBA project, the various accelerator physics and engineering studies that have been carried out, and plans for the implementation of one or two DDBA cells in Diamond

Estradiol Regulates Energy Balance by Ameliorating Hypothalamic Ceramide-Induced ER Stress

Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in females.</p

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (-3.2 SD score vs. -2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man

Validación del "Cuestionario de ansiedad social para adultos" (CASO-A30) en universitarios españoles: similitudes y diferencias entre carreras universitarias y comunidades autónomas

Resumen: El objetivo de este trabajo es presentar las propiedades psicométricas del ?Cuestionario de ansiedad social para adultos? (CASO-A30) con universitarios y analizar las diferencias y similitudes en ansiedad social en esta muestra. Participaron 15504 estudiantes de 20 carreras universitarias de 17 comunidades autónomas españolas a los que se les aplicó el CASO-A30 y la ?Escala de ansiedad social de Liebowitz, versión de autoinforme? (LSAS-SR). Se obtuvieron cinco dimensiones a través de diversos análisis factoriales y de ecuaciones estructurales del CASO-A30: ?Hablar en público/Interacción con personas de autoridad?, ?Interacción con desconocidos?, ?Interacción con el sexo opuesto?, ?Expresión asertiva de molestia, desagrado o enfado? y ?Quedar en evidencia o en ridículo?. La consistencia interna fue de 0,91 y su validez concurrente (con la LSAS-SR) de 0,66. Se hallaron diferencias significativas entre hombres y mujeres, pero escasas diferencias entre las comunidades autónomas y las carreras. Estos resultados confirman la estructura pentafactorial y las buenas propiedades psicométricas del CASO-A30, que lo convierten en un instrumento adecuado para la evaluación de la ansiedad social en universitarios, tanto generalizada como específica, cuidando las diferencias de sexo.Abstract: This work presents the psychometric properties of the Social Anxiety Questionnaire for Adults (SAQ-A30) with university students and analyses the differences and similarities in social anxiety in the sample. The 15,504 participants, students of 20 degree subjects in 17 Spanish Autonomous Community regions, were applied the SAQ-A30 and the ?Liebowitz Social Anxiety Scale-Self Report? (LSAS-SR). A five-factor structure was obtained through several factor analyses as well as an exploratory structural equation modeling of the SAQ-A30: ?Speaking in public/Talking with people in authority?, ?Interactions with strangers?, ?Interactions with the opposite sex?, ?Assertive expression of annoyance, disgust or displeasure?, and ?Criticism and embarrassment?. Internal consistency was 0.91 and concurrent validity (paired with LSAS-SR) was 0.66. Significant differences were found between males and females, but there was scarce difference between regions and subjects studied. These results confirm the five-factor structure and the good psychometric characteristics of the SAQ-A30, which make it a suitable instrument for assessing both general and specific social anxiety in universities, taking into account sex differences.Este estudio ha sido financiado parcialmente por la Fundación para el Avance de la Psicología Clínica Conductual (FUNVECA), el Ministerio de Ciencia y Tecnología de España (BSO2003-07029/PSCE) y el Fondo Europeo de Desarrollo Regional (FEDER)

The neighbourhood social environment and alcohol use among urban and rural Scottish adolescents

Funding for the Scottish Health Behaviour in School-aged Children was provided by NHS Scotland. This work was also supported by the 600th Anniversary Ph.D. Scholarship which was awarded to Gina Martin by the University of St Andrews.Objectives This research examined the relationship between neighbourhood social environmental characteristics and drinking outcomes among a sample of urban and rural adolescents. Methods From a sample of 1558 Scottish secondary schoolchildren, surveyed as part of the 2010 Health Behaviour in School-aged Children study, we modelled three drinking outcomes on a variety of neighbourhood conditions, including social cohesion, disorder, alcohol outlet density, deprivation, and urban/rurality. Nested and cross-classified multilevel logistic regressions were specified. Results An urban-to-rural gradient was found with non-urban adolescents exhibiting higher odds of having ever drank. Neighbourhood social cohesion related to having ever drank. Among drinkers, those living in accessible small towns had higher odds of weekly drinking and drunkenness compared to urban areas. Higher odds of drunkenness were also found in remote rural areas. Those residing in the least deprived areas had lower odds of weekly drinking. Conclusions In Scotland, inequalities exist in adolescent alcohol use by urban/rurality and neighbourhood social conditions. Findings support regional targeting of public health efforts to address inequalities. Future work is needed to develop and evaluate intervention and prevention approaches for neighbourhoods at risk.Publisher PDFPeer reviewe