C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.

Background and Objectives: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion. Methods: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing. Results: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds. Discussion: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.

Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Understanding reasons for image rejection by radiologists and radiographers.

INTRODUCTION: A core element of a radiographer's role is the decision on whether a radiograph is sufficient for diagnosis, or a repeat examination is needed. Studies illustrate the disagreement on the diagnostic value of radiographs between radiographers and radiologists, which may influence repeat examinations. This study investigates if parameters contributing to image quality are possible determinants to explain the difference between professions. METHODS: A total of 74 radiographers and radiologists from three different countries assessed three data sets (chest PA, hip HBL, c-spine lateral), each containing 25 radiographs. All observers scored image quality in terms of anatomical visualisation, positioning, collimation, detector exposure and judged the diagnostic value using the ACR RadLex classification. All assessments were performed on a clinically relevant display. Visual grading characteristics were used to compare image quality evaluations between groups. RESULTS: Radiographers scored the visualisation of anatomical structures lower than radiologists though the difference was not statistically significant. A difference in classification using the RadLex categories - with radiographers rejecting more radiographs - was demonstrated. Only the subjective evaluation of the detector exposure correlated statistically with RadLex ratings. There was no difference between radiographers and radiologists when reviewing patient positioning and collimation. CONCLUSION: Radiographers and radiologists agree on the visualisation of anatomical structures, but radiographers are more critical towards the diagnostic value. Within the criteria studied, the evaluation of anatomical structures does not explain the difference. Radiographs have a higher change of being rejected if the observer (subjectively) assessed the detector exposure as inappropriate. This correlation is stronger for radiographers.

Potential eligibility for Aducanumab therapy in an Irish specialist cognitive service-Utilising cerebrospinal fluid biomarkers and appropriate use criteria.

OBJECTIVES: Aducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti-amyloid agent. METHODS: Retrospective analysis was undertaken of patients with positive AD-biomarker CSF analysis. Data available at time of CSF analysis was reviewed to determine hypothetical eligibility for Aducanumab. RESULTS: Seventy patients had positive AD-CSF biomarkers. Forty nine of these were seen in the Gerontology-led service, with 21 in the neurology cohort. Average patient age was 70 years old. Forty patients (57%) met eligibility criteria for Aducanumab therapy by AUC guidelines. CONCLUSION: We highlight the patients within our service who would be appropriate for Aducanumab or similar anti-amyloid agents should licencing be granted in the European Union, and the need to develop the resources and capacity to deliver this or other emerging disease modifying AD therapies. CLINICAL TRIAL REGISTRATION: All patients in the combined cognitive clinic provide consent re willingness to be contacted re research.

Brachiocephalic artery aneurysm plaque rupture, stroke & repair.

A 70 year old left-handed man presented to his general practitioner with abnormal left arm movements, left hemianopia and loss of balance. He was found to have an isolated brachiocephalic artery aneurysm, measuring 3.5 cm, with associated plaque rupture, contributing to recurrent episodes of transient ischemic attack. He was discussed extensively by a multidisciplinary team. e concurrently had complete occlusion of the right internal carotid artery with distal reconstitution in its supraclinoid segment from collaterals. Stenting of the region would necessitate inappropriately covering the right vertebral artery which would further compromise intracerebral blood. Surgical intervention was deemed the only safe option and he was thus accepted for cardiothoracic surgery. Standard workup revealed left anterior descending artery stenosis. He underwent coronary artery bypass grafting, left atrial appendectomy and brachiocephalic artery resection with replacement with a interposition graft with 10 mm polytetrafluoroethylene graft. He recovered well. This case demonstrates the multi-disciplinary decision making in a rare cause of embolic stroke.

Enterprise imaging and big data: A review from a medical physics perspective.

In recent years enterprise imaging (EI) solutions have become a core component of healthcare initiatives, while a simultaneous rise in big data has opened up a number of possibilities in how we can analyze and derive insights from large amounts of medical data. Together they afford us a range of opportunities that can transform healthcare in many fields. This paper provides a review of recent developments in EI and big data in the context of medical physics. It summarizes the key aspects of EI and big data in practice, with discussion and consideration of the steps necessary to implement an EI strategy. It examines the benefits that a healthcare service can achieve through the implementation of an EI solution by looking at it through the lenses of: compliance, improving patient care, maximizing revenue, optimizing workflows, and applications of artificial intelligence that support enterprise imaging. It also addresses some of the key challenges in enterprise imaging, with discussion and examples presented for those in systems integration, governance, and data security and privacy.

Antecedents of Suicide Among Active Military, Veteran, and Nonmilitary Residents of the Commonwealth of Virginia: The Role of Intimate Partner Problems.

OBJECTIVE: Intimate partner problems increase suicide risk, particularly among active service members and veterans. Age, marital status and military service status may modify the role of intimate partner problems in suicide. Methods: Participants included 6255 men who died by suicide at 18 years of age and older and who actively, previously, or never served in the military. Reports of intimate partner problems prior to suicide were documented by the Virginia Department of Health. Results: Unmarried active service members, above middle age, were more likely than veterans and individuals without prior military service to have associated reports of intimate partner problems. Conclusion: Life stages and relationship context may influence the role of intimate partner problems as a risk factor for suicide.

Jaw Clonus: A Rhythmic Oscillatory Movement, but Not Tremor.

Background: Jaw clonus is rhythmic, oscillatory contraction of jaw muscles induced by stretch and is caused by lesions of the descending motor neurons in the corticopontine tracts. Phenomenology shown: We illustrate jaw clonus elicited with jaw activation and upon testing of the jaw jerk in a patient with amyotrophic lateral sclerosis. Educational value: This video clearly demonstrates the uncommon sign of jaw clonus, a finding which needs to be distinguished from tremor and should direct the examiner to consider lesions of the corticopontine fibres, including amyotrophic lateral sclerosis.

Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis.

IMPORTANCE: Heritability describes the proportion of variance in the risk of developing a condition that is explained by genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear. OBJECTIVES: To determine the extent of ALS heritability and assess the association of sex with disease transmission. DESIGN, SETTING, AND PARTICIPANTS: A prospective population-based parent-offspring heritability study was conducted from January 1, 2008, to December 31, 2017 to assess ALS heritability, and was the first study to assess heritability in the context of known gene mutations of large effect. A total of 1123 incident cases of ALS, diagnosed according to the El Escorial criteria and recorded on the Irish ALS register, were identified. Ninety-two individuals were excluded (non-Irish parental origin [n = 86] and familial ALS [n = 6]), and 1117 patients were included in the final analysis. MAIN OUTCOMES AND MEASURES: Annual age-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the overall study cohort, for those known to carry the C9orf72 (OMIM 614260) variant, and for those with no known genetic risk. RESULTS: A total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years; 95% CI, 48.8-55.3 years) compared with their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years; P = .008). Lifetime risk of developing ALS in first-degree relatives of individuals with ALS was increased compared with the general population (1.4% [32 of 2234] vs 0.3% [2.6 of 1000]; P < .001). Mean lifetime heritability of ALS for the overall study cohort was 52.3% (95% CI, 42.9%-61.7%) and 36.9% (95% CI, 19.8%-53.9%) for those with no known genetic risk. Heritability estimates were highest in mother-daughter pairings (66.2%; 95% CI, 58.5%-73.9%). CONCLUSIONS AND RELEVANCE: This population-based study confirms that up to 50% of variance in ALS has a genetic basis, and that the presence of the C9orf72 variant is an important determinant of heritability. First-degree relatives of individuals with ALS without a known genetic basis remain at increased risk of developing ALS compared with the general population. A higher heritability estimate in mother-daughter pairings points to a sex-mediated effect that has been previously unrecognized.

Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations.

OBJECTIVES: This study compares the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) within three clinic-based populations from Cuba, Uruguay and Ireland and determines the impact of known ALS-associated genetic variants on phenotypic manifestations within the Cuban population. METHODS: Demographic and clinical information was collected on 115 Cuban, 220 Uruguayan and 1038 Irish patients with ALS attending national specialist clinics through 1996-2017. All Cuban patients and 676 Irish patients underwent next-generation DNA sequencing and were screened for the pathogenic C9orf72 repeat expansion. RESULTS: The mean age of onset was younger in the Cuban (53.0 years, 95% CI 50.4 to 55.6) and Uruguayan (58.2 years, 95% CI 56.5 to 60.0) populations compared with the Irish population (61.6 years, 95% CI 60.9 to 62.4). No differences in survival between populations were observed. 1.7 % (95% CI 0.6 to 4.1) of Cubans with ALS carried the C9orf72 repeat expansion compared with 9.9% (95% CI 7.8 to 12.0) of Irish patients with ALS (p=0.004). Other known variants identified in the Cuban population included ANG (one patient), CHCHD10 (one patient) and DCTN1 (three patients). CONCLUSIONS AND RELEVANCE: This study is the first to describe the clinical characteristics of ALS in Cuban and Uruguayan populations and report differences between the Cuban and Irish genetic signature in terms of known ALS-associated genetic variants. These novel clinical and genetic data add to our understanding of ALS across different and understudied populations.

Determining the incidence of familiality in ALS: A study of temporal trends in Ireland from 1994 to 2016.

OBJECTIVE: To assess temporal trends in familial amyotrophic lateral sclerosis (FALS) incidence rates in an Irish population and to determine factors influencing FALS ascertainment. METHODS: Population-based data collected over 23 years, using the Irish amyotrophic lateral sclerosis (ALS) register and DNA biobank, were analyzed and age-standardized rates of FALS and associated familial neuropsychiatric endophenotypes were identified. RESULTS: Between 1994 and 2016, 269 patients with a family history of ALS from 197 unique families were included on the register. Using stringent diagnostic criteria for FALS, the mean age-standardized FALS incidence rate for the study period was 11.1% (95% confidence interval [CI], 8.8-13.4). The FALS incidence rate increased steadily from 5.2% in 1994 to 19.1% in 2016, an annual increase of 0.7% (95% CI, 0.5-0.9, p < 0.0001). Inclusion of the presence of neuropsychiatric endophenotypes within kindreds increased the FALS incidence rate to 30%. The incidence of FALS in newly diagnosed individuals from known families increased significantly with time, accounting for 50% of all FALS diagnoses by 2016. The mean annual rate of recategorization from "sporadic ALS" to "FALS" was 3% (95% CI, 2.6-3.8). CONCLUSIONS: The true population-based rate of FALS is at least 20%. Inclusion of extended endophenotypes within kindreds increases the rate of FALS to 30%. Cross-sectional analysis of clinic-based cohorts and stringent definitions of FALS underestimate the true rate of familial disease. This has implications for genetic counseling and in the recognition of presymptomatic stages of ALS.

The implications of regional and national demographic projections for future GMS costs in Ireland through to 2026.

BACKGROUND: As the health services in Ireland have become more resource-constrained, pressure has increased to reduce public spending on community drug schemes such as General Medical Services (GMS) drug prescribing and to understand current and future trends in prescribing. The GMS scheme covers approximately 37% of the Irish population in 2011 and entitles them, inter alia, to free prescription drugs and appliances. This paper projects the effects of future changes in population, coverage, claims rates and average claims cost on GMS costs in Ireland. METHODS: Data on GMS coverage, claims rates and average cost per claim are drawn from the Primary Care Reimbursement Service (PCRS) and combined with Central Statistics Office (CSO) (Regional and National Population Projections through to 2026). A Monte Carlo Model is used to simulate the effects of demographic change (by region, age, gender, coverage, claims rates and average claims cost) will have on GMS prescribing costs in 2016, 2021 and 2026 under different scenarios. RESULTS: The Population of Ireland is projected to grow by 32% between 2007 and 2026 and by 96% for the over 70s. The Eastern region is estimated to grow by 3% over the lifetime of the projections at the expense of most other regions. The Monte Carlo simulations project that females will be a bigger driver of GMS costs than males. Midlands region will be the most expensive of the eight old health board regions. Those aged 70 and over and children under 11 will be significant drivers of GMS costs with the impending demographic changes. Overall GMS medicines costs are projected to rise to €1.9bn by 2026. CONCLUSIONS: Ireland's population will experience rapid growth over the next decade. Population growth coupled with an aging population will result in an increase in coverage rates, thus the projected increase in overall prescribing costs. Our projections and simulations map the likely evolution of GMS cost, given existing policies and demographic trends. These costs can be contained by government policy initiatives.

The ten essential public health services model as a framework for correctional health care.

Correctional health care is of interest to public health practitioners due to the highly vulnerable social and health characteristics of inmates, ex-offenders, and their communities, as well as the access to health care provided to them through the criminal justice system. The public health model for correctional health care has evolved from one concerned primarily with infectious disease control within the facility to a model of comprehensive health care that additionally recognizes the importance of providing continuity of care as inmates transition into free-living communities. The Ten Essential Public Health Services is proposed as a conceptual framework for a public health approach to correctional health care and is illustrated by application to a health care program for a large jail system in Jacksonville, FL.

Living with an unfixable heart: a qualitative study exploring the experience of living with advanced heart failure.

BACKGROUND: Nurses working with patients with advanced heart failure need knowledge that will help us to help patients cope with their situations of chronic illness. However, our knowledge bank is deficient due to the scarcity of inquiry that takes the affected person's point of view as its central focus. AIM: The aim of this study was to describe patients' experiences of living with advanced heart failure. METHODS: The study sample (N=9) consisted of male (N=6) and female (N=3) patients with advanced (NYHA classes III-IV) heart failure. The design was qualitative and open unstructured interviews were audio-taped and transcribed verbatim during 2006. RESULTS: Four main themes emerged: Living in the Shadow of Fear; Running on Empty; Living a Restricted life; and Battling the System. The experience of living with advanced heart failure was described as a fearful and tired sort of living characterised by escalating impotence and dependence. CONCLUSIONS: The findings suggest that there may be an illogical but enduring ethos of 'cure' pervading health care worker's attitudes to advanced heart failure care. This mindset might be working to hinder the application of additional or alternative therapies, which might better palliate the physical and psychosocial distress of patients.