Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this recordSplit-hand/foot malformation type 1 is an autosomal dominant condition with reduced penetrance and variable expression. We report three individuals from two families with split-hand/split-foot malformation (SHFM) in whom next generation sequencing was performed to investigate the cause of their phenotype.Wellcome Trus

Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. To investigate association of genetic loci with CRP levels and risk of coronary heart disease. We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. Risk of coronary heart disease. Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease

An Experimental Area for Short Baseline Neutrino Physics on the CERN Neutrino Beam to Gran Sasso

A new neutrino beam line from the CERN SPS to the Gran Sasso laboratory in Italy is presently under study. The new neutrino beam will allow both long baseline and short baseline neutrino oscillation experiments to be performed. This report presents a conceptual design of the short baseline experimental area to be located at a distance of 1858 m from the neutrino target

Temporal sampling, resetting, and adaptation orchestrate gradient sensing in sperm

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Cell Biology 198 (2012): 1075-1091, doi:10.1083/jcb.201204024.Sperm, navigating in a chemical gradient, are exposed to a periodic stream of chemoattractant molecules. The periodic stimulation entrains Ca2+ oscillations that control looping steering responses. It is not known how sperm sample chemoattractant molecules during periodic stimulation and adjust their sensitivity. We report that sea urchin sperm sampled molecules for 0.2–0.6 s before a Ca2+ response was produced. Additional molecules delivered during a Ca2+ response reset the cell by causing a pronounced Ca2+ drop that terminated the response; this reset was followed by a new Ca2+ rise. After stimulation, sperm adapted their sensitivity following the Weber–Fechner law. Taking into account the single-molecule sensitivity, we estimate that sperm can register a minimal gradient of 0.8 fM/µm and be attracted from as far away as 4.7 mm. Many microorganisms sense stimulus gradients along periodic paths to translate a spatial distribution of the stimulus into a temporal pattern of the cell response. Orchestration of temporal sampling, resetting, and adaptation might control gradient sensing in such organisms as well.This work was supported by the German Research Foundation and the Fonds der Chemischen Industrie.2013-03-1

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

The Impact of the COVID-19 Pandemic on the Psychological Well-Being of Caregivers of People with Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis

The aim of this systematic review was to investigate the effects of the COVID-19 lockdown on the psychological well-being of caregivers of people with dementia or mild cognitive impairment (PwD/MCI). Electronic databases were searched from inception to August 2022 for observational studies investigating the COVID-19 lockdown and psychological well-being of caregivers of PwD/MCI. Summary estimates of standardized mean differences (SMD) in psychological well-being scores pre- versus during COVID-19 were calculated using a random-effects model. Fifteen studies including 1702 caregivers (65.7% female, mean age 60.40 ± 12.9 years) with PwD/MCI were evaluated. Five studies found no change in psychological well-being parameters, including depression, anxiety, distress, caregiver burden, and quality of life. Ten studies found a worsening in at least one parameter: depression (six studies, n = 1368; SMD = 0.40; 95%CI: 0.09–0.71; p = 0.01, I2 = 86.8%), anxiety (seven studies, n = 1569; SMD = 1.35; 95%CI: 0.05–2.65; I2 = 99.2%), caregiver distress (six studies, n = 1320, SMD = 3.190; 95%CI: 1.42–4.95; p &lt; 0.0001; I2 = 99.4%), and caregiver burden (four studies, n = 852, SMD = 0.34; 95%CI: 0.13–0.56; p = 0.001; I2 = 54.1%) (p &lt; 0.05). There was an increase in depression, anxiety, caregiver burden, and distress in caregivers of PwD/MCI during the lockdown in the COVID pandemic. This could have longer term consequences, and it is essential that caregivers’ psychological well-being is assessed and supported, to benefit both themselves and those for whom they care

Insights from computational modeling in inflammation and acute rejection in limb transplantation

Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection. © 2014 Wolfram et al

Diatreta Cups, Light in Roman Dining Spaces

Cage cups or Diatreta are ancient Roman glass vessels produced by creating a thick blown blank of glass that, once cooled down, is taken to a glass cutter or diatretarii. The latter would cut and carve away most of the glass leaving a transparent vessel inside and an open-work decoration separated through thin posts of glass. The work is very delicate and exclusive, produced within limited space in time with no record of similar vessels until the late 1800 (Donald B. Harden & Toynbee 1959, p.181). Many of these glass objects have good-will inscriptions or decorations that express the importance of drinking. As for their provenance, most –when found in context- have been found in pagan burials. Nevertheless some fragments have been found in Christian environments or with Christian motifs like the Szekszárd cup. The location of these finds is mostly in the Rhine area –northern Empire, when Milan was one of its capitals (Aquaro 2004)- but the actual extent of finds expand throughout the 4th century extent of the Roman Empire. Considering their typological analysis there are basically two types, beaker and bowl. Beakers are considered drinking vessels as they either display a legend or a mythological reference to drink or wine. Whereas a general consensus agrees that open bowl-form cups were hanging lamps (Whitehouse 1988, p.28) since the 1986 find of a diatreta bowl with copper alloy hanging attachments. It is clear these were luxury objects to be used in special occasions and spaces. The aim of this paper is to understand the space were socialisation and drinking took place and the importance of luxurious objects to adorn, display and use. The paper will also put forward the idea that the beaker shaped diatreta vessels, usually considered for drinking, could have been lamps that encouraged drinking and good will to the guests. This paper is structured to first consider an introduction to late luxury Roman glass and then analysing the typological shape of all, or most of the diatreta currently known; secondly, through assessment by the means of comparison, analyse the writings or decorations the vessels were endowed with. Thirdly, by describing and understanding the people and the space were these vessels would have been used, emphasise the beauty of illuminating such spaces with these vessels. According to Herodotus in his historical investigation –5th century-, dress habits and food regime are elements of extreme importance to understand a people (Caporusso et al. 2011, p.12). This idea is not only valid for Herodotus’ time but it is something anthropology uses time and again to explain different aspects in people’s way of life. Through food and its environment, the dining space, this paper will aim to put the cage cups into a social context in order to give emphasis to the hypothesis of light versus wine

Management of behavioural and psychological symptoms of dementia:a pragmatic scoping review of European guidelines and literature

Purpose:Dementia prevalence within the European Union (EU) is expected to double by 2050. Behavioural and Psychological Symptoms of Dementia (BPSD) are common, causing burden to patients and caregivers. This pragmatic scoping review aims to synthesize recommendations of European BPSD management guidelines and literature, highlighting areas of consensus and disagreement.Methods:An electronic literature search, including Medline, PsychINFO, and CINAHL, and Internet search for grey literature were undertaken to identify published BPSD guidelines from the EU, European Economic Area (EEA) and UK, supplemented by contacting EU member countries of European Geriatric Medicine Society (EuGMS).Results:The literature search found 11 papers describing BPSD management. Of the 32 countries of interest, 22 guidelines were sourced (five confirmed no guidelines, five did not respond). There was a general consensus between the guidelines, as all recommended comprehensive assessment and individualised approaches, with non-pharmacological therapies as first line, but there was disagreement around specific therapies. Psycho-education was most commonly recommended (15 countries). There was general agreement that pharmacological treatment should be used as an adjunct to non-pharmacological interventions, but recommendations differed between medication groups. Short-term atypical antipsychotics were most commonly recommended, especially risperidone (18 countries). 15 countries recommended acetylcholinesterase inhibitors and 12 memantine. 16 countries recommended the use of SSRIs. Recommendations for the use of sedative medications and antiepileptics varied.Conclusions:This study provides a broad, inclusive overview of current European guidelines for the management of BPSD, demonstrating significant variability. Clinical practice in dementia care throughout Europe needs to be optimised and standardised

Cognitive frailty:a useful concept or a source of confusion? Insights from a survey of European geriatricians

BACKGROUND: This report examines how European geriatricians understand the concept of 'cognitive frailty', which was first formally defined by the International Academy on Nutrition and Aging (IANA) and the International Association of Gerontology and Geriatrics (IAGG) in 2013.METHODS: An online survey about delirium, dementia and frailty relationships and pathways was distributed across Europe through appropriate professional groups. Eligible participants were geriatricians or trainees in their final two years of specialist geriatric training, in a European country. Snowball sampling was used. In total, 440 people replied to the survey, of which 324 responded to the section on cognitive frailty. Respondents were predominantly female and there was a marked under-representation of Eastern European participants.RESULTS: From a list of possible definitions, only one in four of the 324 respondents identified cognitive frailty as defined by the IANA and the IAGG, i.e., a combination of physical frailty and mild cognitive impairment. Almost two thirds of those who stated that they currently use the term in their work did not choose the IANA-IAGG definition. After the definition was shared with respondents, only 44% strongly agreed with it as an apt description of cognitive frailty, with some considering it too narrow (by omitting delirium and dementia) while others considered it too broad (by including physical frailty).CONCLUSIONS: There is no clear consensus opinion among geriatricians in Europe on the definition of 'cognitive frailty'. While there is some core support for the IANA-IAGG definition, it is not intuitive to those not already familiar with the term. The variance in the current understanding of cognitive frailty among geriatricians suggests the time is right for a meaningful debate on this issue. While there is ongoing, growing research on a shared pathophysiology between physical frailty and cognitive impairment, further studies are required to evaluate the added benefit of this particular conceptual theorization in older persons care rather than its single components, and if beneficial, how awareness, understanding and correct usage of the concept can be improved.</p