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

Cohort profile: the avon longitudinal study of parents and children: ALSPAC mothers cohort

The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile

Measuring quality and outcomes of research collaborations: An integrative review

Introduction: Although the science of team science is no longer a new field, the measurement of team science and its standardization remain in relatively early stages of development. To describe the current state of team science assessment, we conducted an integrative review of measures of research collaboration quality and outcomes. Methods: Collaboration measures were identified using both a literature review based on specific keywords and an environmental scan. Raters abstracted details about the measures using a standard tool. Measures related to collaborations with clinical care, education, and program delivery were excluded from this review. Results: We identified 44 measures of research collaboration quality, which included 35 measures with reliability and some form of statistical validity reported. Most scales focused on group dynamics. We identified 89 measures of research collaboration outcomes; 16 had reliability and 15 had a validity statistic. Outcome measures often only included simple counts of products; publications rarely defined how counts were delimited, obtained, or assessed for reliability. Most measures were tested in only one venue. Conclusions: Although models of collaboration have been developed, in general, strong, reliable, and valid measurements of such collaborations have not been conducted or accepted into practice. This limitation makes it difficult to compare the characteristics and impacts of research teams across studies or to identify the most important areas for intervention. To advance the science of team science, we provide recommendations regarding the development and psychometric testing of measures of collaboration quality and outcomes that can be replicated and broadly applied across studies

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

Efficacy and mechanism of sub-sensory sacral (optimised) neuromodulation in adults with faecal incontinence:Study protocol for a randomised controlled trial

Background: Faecal incontinence (FI) is a substantial health problem with a prevalence of approximately 8% in community-dwelling populations. Sacral neuromodulation (SNM) is considered the first-line surgical treatment option in adults with FI in whom conservative therapies have failed. The clinical efficacy of SNM has never been rigorously determined in a trial setting and the underlying mechanism of action remains unclear. Methods/design: The design encompasses a multicentre, randomised, double-blind crossover trial and cohort follow-up study. Ninety participants will be randomised to one of two groups (SNM/SHAM or SHAM/SNM) in an allocation ratio of 1:1. The main inclusion criteria will be adults aged 18-75 years meeting Rome III and ICI definitions of FI, who have failed non-surgical treatments to the UK standard, who have a minimum of eight FI episodes in a 4-week screening period, and who are clinically suitable for SNM. The primary objective is to estimate the clinical efficacy of sub-sensory SNM vs. SHAM at 32 weeks based on the primary outcome of frequency of FI episodes using a 4-week paper diary, using mixed Poisson regression analysis on the intention-to-treat principle. The study is powered (0.9) to detect a 30% reduction in frequency of FI episodes between sub-sensory SNM and SHAM stimulation over a 32-week crossover period. Secondary objectives include: measurement of established and new clinical outcomes after 1 year of therapy using new (2017 published) optimised therapy (with standardised SNM-lead placement); validation of new electronic outcome measures (events) and a device to record them, and identification of potential biological effects of SNM on underlying anorectal afferent neuronal pathophysiology (hypothesis: SNM leads to increased frequency of perceived transient anal sphincter relaxations; improved conscious sensation of defaecatory urge and cortical/subcortical changes in afferent responses to anorectal electrical stimulation (main techniques: high-resolution anorectal manometry and magnetoencephalography). Discussion: This trial will determine clinical effect size for sub-sensory chronic electrical stimulation of the sacral innervation. It will provide experimental evidence of modifiable afferent neurophysiology that may aid future patient selection as well as a basic understanding of the pathophysiology of FI

Spinocerebellar Ataxia Type 23: A Genetic Update

The spinocerebellar ataxia type 23 locus was identified in 2004 based on linkage analysis in a large, two-generation Dutch family. The age of onset ranged 43–56 years and the phenotype was characterized by a slowly progressive, isolated ataxia. Neuropathological examination revealed neuronal loss in the Purkinje cell layer, dentate nuclei, and inferior olives. Ubiquitin-positive intranuclear inclusions were found in nigral neurons, but were considered to be Marinesco bodies. The disease locus on chromosome 20p13-12.3 was found to span a region of approximately 6 Mb of genomic DNA, containing 97 known or predicted genes. To date, no other families have been described that also map to this SCA locus. Direct sequencing of the coding regions of 21 prioritized candidate genes did not reveal any disease-causing mutation. Apparently, the SCA23 gene is a disease gene with a different function than the genes that have been associated with other known SCA types. Work to elucidate the chromosomal organization of the SCA23 locus will eventually discover the responsible disease gene

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

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

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