Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia

Mosaicism for FMR1 premutation (PM: 55–199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen

Visitor expenditure estimation for grocery store location planning: a case study of Cornwall

Visitor expenditure is an important driver of demand in many local economies, supporting a range of services and facilities which may not be viable based solely on residential demand. In areas where self-catering accommodation is prevalent visitor demand makes up a considerable proportion of sales and revenue within grocery stores, yet this form of visitor consumption is commonly overlooked in supply and demand-side estimates of visitor spend. As such, store location planning in tourist resorts, decisions about local service provision and the local economic impacts of tourism are based on very limited demand-side estimates of visitor spend. Using Cornwall, South West England as a study area, we outline a methodology and data sources to estimate small-area visitor grocery spend. We use self-catering accommodation provision, utilisation and visitor expenditure rates as key factors driving visitor spend. We identify that the use of visitor accommodation accounts for the spatial and temporal complexities of visitor demand that may be overlooked when using alternative approaches, such as the up-scaling of residential demand. Using a spatial interaction model, we demonstrate that our expenditure estimates can be used to generate store level revenue estimation within tourist resorts, and we make a number of recommendations for service provision and store location planning in these areas

On the importance of parallel magnetic-field fluctuations for electromagnetic instabilities in STEP

This paper discusses the importance of parallel perturbations of the magnetic-field in gyrokinetic simulations of electromagnetic instabilities and turbulence at mid-radius in the burning plasma phase of the conceptual high-β, reactor-scale, tight-aspect-ratio tokamak STEP. Previous studies have revealed the presence of unstable hybrid kinetic ballooning modes (hKBMs) and subdominant microtearing modes at binormal scales approaching the ion Larmor radius. In this STEP plasma it was found that the hKBM requires the inclusion of parallel magnetic-field perturbations to be linearly unstable. Here, the extent to which the inclusion of fluctuations in the parallel magnetic-field can be relaxed is explored through gyrokinetic simulations. In particular, the frequently used MHD approximation (dropping δB∥ and setting the ∇B drift frequency equal to the curvature drift frequency) is discussed and simulations explore whether this approximation is useful for modelling STEP plasmas. It is shown that the MHD approximation can reproduce some of the linear properties of the full STEP gyrokinetic system, but is too stable at low ky and nonlinear simulations using the MHD approximation result in very different transport states. It is demonstrated that the MHD approximation is challenged by the high β′ values in STEP, and that the approximation improves considerably at lower β′ . Furthermore, it is shown that the sensitivity of STEP to δB∥ fluctuations is primarily because the plasma sits close to marginality and it is shown that in slightly more strongly driven conditions the hKBM is unstable without δB∥. Crucially, it is demonstrated that the state of large transport typically predicted by local electromagnetic gyrokinetic simulations of STEP plasmas is not solely due to δB∥ physics

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

On the importance of parallel magnetic-field fluctuations for electromagnetic instabilities in STEP

[ABRIDGED] This paper discusses the importance of parallel perturbations of the magnetic-field in gyrokinetic simulations of electromagnetic instabilities and turbulence at mid-radius in the burning plasma phase of the conceptual high-$\beta$, reactor-scale, tight-aspect-ratio tokamak STEP. Previous studies have revealed the presence of unstable hybrid kinetic ballooning modes (hKBMs) at binormal scales approaching the ion Larmor radius. In this STEP plasma it was found that the hKBM requires the inclusion of parallel magnetic-field perturbations to be linearly unstable. Here, the extent to which the inclusion of fluctuations in the parallel magnetic-field can be relaxed is explored through gyrokinetic simulations. In particular, the frequently used MHD approximation (dropping $\delta \! B_{\parallel}$ and setting the $\nabla B$ drift frequency equal to the curvature drift frequency) is discussed and simulations explore whether this approximation is useful for modelling STEP plasmas. It is shown that the MHD approximation can reproduce some of the linear properties of the full STEP gyrokinetic system, but is too stable at low $k_y$ and nonlinear simulations using the MHD approximation result in very different transport states. It is demonstrated that the MHD approximation is challenged by the high $\beta^{\prime}$ values in STEP, and that the approximation improves considerably at lower $\beta^{\prime}$. Furthermore, it is shown that the sensitivity of STEP to $\delta \! B_{\parallel}$ fluctuations is primarily because the plasma sits close to marginality and it is shown that in slightly more strongly driven conditions the hKBM is unstable without $\delta \! B_{\parallel}.$ Crucially, it is demonstrated that the state of large transport typically predicted by local electromagnetic gyrokinetic simulations of STEP plasmas is not solely due to $\delta \! B_{\parallel}$ physics.Comment: 29th IAEA FEC conferenc

Small steps towards a large framework: a workshop approach

This article follows the progress of a project to support DSNs in meeting Standard 3 of the NSF for Diabetes. The workshop format provided the delegates with the opportunity to discuss shared issues and concerns

Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature

Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident

Chronic constipation in adults: Contemporary perspectives and clinical challenges. 2: Conservative, behavioural, medical and surgical treatment

BACKGROUND: Chronic constipation is a prevalent disorder that affects quality of life of patients and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology and Motility journal supplement devoted to the investigation and management of constipation was published (Neurogastroenterol Motil 2009;21(Suppl 2):1). In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held. The faculty members of this symposium were invited to write two reviews to present a collective synthesis of talks presented and discussions held during this meeting. The first review addresses epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. PURPOSE: The present is the second of these reviews, providing contemporary perspectives and clinical challenges regarding behavioral, conservative, medical, and surgical treatments for patients presenting with constipation. It includes a management algorithm to guide clinical practice

Development and external validation of a head and neck cancer risk prediction model

\ua9 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC. Background: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. Methods: The IARC-ARCAGE European case–control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74–0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61–0.64). Conclusion: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction