Huntington Disease: The Complexities of Making and Disclosing a Clinical Diagnosis After Premanifest Genetic Testing

The management of patients and families affected by Huntington disease (HD) is complicated by several factors, both practical and ethical. It can be difficult to determine the onset of clinically manifest HD (mHD). In addition, it can be challenging to decide when to disclose the diagnosis to the affected individual. Firstly, the features of HD, an incurable, inherited, neurocognitive disorder that often manifests in young adulthood, influence how the person presents and accepts a diagnosis. Secondly, a positive genetic test for HD may result in a genetic diagnosis, sometimes years before the development of clinical features and the diagnosis of mHD. Thirdly, observational studies of unaffected gene expansion carriers documented HD manifestations up to 10 years before the typical presentation for diagnosis. These developments may permit earlier genetic diagnosis and information regarding the patient’s likely status with respect to the development of clinical disease. Making the genetic diagnosis of HD and providing information regarding disease status, earlier rather than later, respects the person’s right to know and preserves honesty in the doctor/patient relationship. Conversely, delaying the diagnosis respects the right not to know, avoids potential discrimination, and permits the person to live a “normal” life for longer, in the context of a disease without cure. This discussion has implications for other inherited and neurocognitive disorders

Derivation and Analysis of Dynamic Handwriting Features as Clinical Markers of Parkinson’s Disease

Parkinson’s Disease (PD) is a complex neurodegenerative disorder that is challenging to diagnose. Recent research has demonstrated predictive value in the analysis of dynamic handwriting features for detecting PD, however, consensus on clinically-useful features is yet to be reached. Here we explore and evaluate secondary kinematic handwriting features hypothesized to be diagnostically relevant to Parkinson’s Disease using a publicly-available Spiral Drawing Test PD dataset. Univariate and multivariate analysis was performed on derived features. Classification outcome was determined using logistic regression models with 10-fold cross validation. Feature correlation was based on model specificity and sensitivity. Variations in grip angle, instantaneous acceleration and pressure indices were found to have high predictive potential as clinical markers of PD, with combined classification accuracy of above 90%. Our results show that the significance of secondary handwriting features and recommend the feature expansion step for hypothesis generation, comparative evaluation of test types and improved classification accuracy

Single- and double-scattering production of four muons in ultraperipheral PbPb collisions at the Large Hadron Collider

We discuss production of two $\mu^+\mu^-$ pairs in ultraperipheral ultrarelativistic heavy ion collisions at the LHC. We take into account electromagnetic (two-photon) double-scattering production and for a first time direct $\gamma\gamma$ production of four muons in one scattering. We study the unexplored process $\gamma \gamma \to \mu^+\mu^-\mu^+\mu^-$. We present predictions for total and differential cross sections. Measurable nuclear cross sections are obtained and corresponding differential distributions and counting rates are presented.Comment: 13 pages, 11 figures, 1 tabl

Radiologists' perspectives about evidence-based medicine and their clinical practice: a semistructured interview study

Objectives: To describe radiologist’s attitudes and perspectives on evidence-based medicine (EBM) and their practice. Design: Face-to-face semistructured interviews, thematic analysis. Setting: 24 institutions across six Australian states and New Zealand. Transcripts were imported into HyperRESEARCH software and thematically analysed. Participants: 25 radiologists. Results: Six themes were identified: legitimising decisions (validated justification, prioritising patient preferences, reinforcing protocols), optimising outcomes (ensuring patient safety, maximising efficiency), availability of access (requiring immediacy, inadequacy of evidence, time constraints, proximity of peer networks, grasping information dispersion), overriding pragmatism ( perceptibly applicability, preserving the art of medicine, technical demands), limited confidence (conceptual obscurity, reputation-based trust, demands constant practice, suspicion and cynicism), and competing powers (hierarchical conflict, prevailing commercial interests). Conclusions: Radiologists believe EBM can support clinical decision-making for optimal patient outcomes and service efficiency but feel limited in their capacities to assimilate and apply EBM in practice. Improving access to evidence, providing ongoing education and training supplemented with practical tools for appraising evidence; and developing evidence-based guidelines and protocols may enhance feasibility and promote the confidence and skills among radiologists in applying EBM in radiology practice for better patient care

Delusions in frontotemporal lobar degeneration

We assessed the significance and nature of delusions in frontotemporal lobar degeneration (FTLD), an important cause of young-onset dementia with prominent neuropsychiatric features that remain incompletely characterised. The case notes of all patients meeting diagnostic criteria for FTLD attending a tertiary level cognitive disorders clinic over a three year period were retrospectively reviewed and eight patients with a history of delusions were identified. All patients underwent detailed clinical and neuropsychological evaluation and brain MRI. The diagnosis was confirmed pathologically in two cases. The estimated prevalence of delusions was 14 %. Delusions were an early, prominent and persistent feature. They were phenomenologically diverse; however paranoid and somatic delusions were prominent. Behavioural variant FTLD was the most frequently associated clinical subtype and cerebral atrophy was bilateral or predominantly right-sided in most cases. We conclude that delusions may be a clinical issue in FTLD, and this should be explored further in future work

Experiences of using the Theoretical Domains Framework across diverse clinical environments: a qualitative study

This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.phpBACKGROUND: The Theoretical Domains Framework (TDF) is an integrative framework developed from a synthesis of psychological theories as a vehicle to help apply theoretical approaches to interventions aimed at behavior change. PURPOSE: This study explores experiences of TDF use by professionals from multiple disciplines across diverse clinical settings. METHODS: Mixed methods were used to examine experiences, attitudes, and perspectives of health professionals in using the TDF in health care implementation projects. Individual interviews were conducted with ten health care professionals from six disciplines who used the TDF in implementation projects. Deductive content and thematic analysis were used. RESULTS: Three main themes and associated subthemes were identified including: 1) reasons for use of the TDF (increased confidence, broader perspective, and theoretical underpinnings); 2) challenges using the TDF (time and resources, operationalization of the TDF) and; 3) future use of the TDF. CONCLUSION: The TDF provided a useful, flexible framework for a diverse group of health professionals working across different clinical settings for the assessment of barriers and targeting resources to influence behavior change for implementation projects. The development of practical tools and training or support is likely to aid the utility of TDF

Targeted, High-Resolution RNA Sequencing of Non-coding Genomic Regions Associated With Neuropsychiatric Functions

The human brain is one of the last frontiers of biomedical research. Genome-wide association studies (GWAS) have succeeded in identifying thousands of haplotype blocks associated with a range of neuropsychiatric traits, including disorders such as schizophrenia, Alzheimer’s and Parkinson’s disease. However, the majority of single nucleotide polymorphisms (SNPs) that mark these haplotype blocks fall within non-coding regions of the genome, hindering their functional validation. While some of these GWAS loci may contain cis-acting regulatory DNA elements such as enhancers, we hypothesized that many are also transcribed into non-coding RNAs that are missing from publicly available transcriptome annotations. Here, we use targeted RNA capture (‘RNA CaptureSeq’) in combination with nanopore long-read cDNA sequencing to transcriptionally profile 1,023 haplotype blocks across the genome containing non-coding GWAS SNPs associated with neuropsychiatric traits, using post-mortem human brain tissue from three neurologically healthy donors. We find that the majority (62%) of targeted haplotype blocks, including 13% of intergenic blocks, are transcribed into novel, multi-exonic RNAs, most of which are not yet recorded in GENCODE annotations. We validated our findings with short-read RNA-seq, providing orthogonal confirmation of novel splice junctions and enabling a quantitative assessment of the long-read assemblies. Many novel transcripts are supported by independent evidence of transcription including cap analysis of gene expression (CAGE) data and epigenetic marks, and some show signs of potential functional roles. We present these transcriptomes as a preliminary atlas of non-coding transcription in human brain that can be used to connect neurological phenotypes with gene expression

C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in ‘non-expansion’ patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5–17% of patients (21–41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine ‘expansion-positive’ patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an ‘intermediate’ allele with a mean size of only ~65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of ‘non-expansion’ FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ~65 repeats may be sufficient to cause disease.Carol Dobson-Stone, Marianne Hallupp, Clement T. Loy, Elizabeth M. Thompson, Eric Haan, Carolyn M. Sue, Peter K. Panegyres, Cristina Razquin, Manuel Seijo-Martínez, Ramon Rene, Jordi Gascon, Jaume Campdelacreu, Birgit Schmoll, Alexander E. Volk, William S. Brooks, Peter R. Schofield, Pau Pastor, John B. J. Kwo

Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Zunt JR, Kassebaum NJ, Blake N, et al. Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology. 2018;17(12):1061-1082.Background Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes. Methods The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilus influenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and daims data was used to estimate meningitis incidence via a Bayesian meta-regression tool. Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitis were applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education. Findings Global meningitis deaths decreased by 21.0% from 1990 to 2016, from 403 012 (95% uncertainty interval [UI] 319426-458 514) to 318 400 (265 218-408 705). Incident cases globally increased from 2.50 million (95% UI 2.19-2.91) in 1990 to 2.82 million (2.46-3.31) in 2016. Meningitis mortality and incidence were dosely related to SDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzae type b was the most common cause of incident meningitis in 1990, at 780 070 cases (95% UI 613 585-978 219) globally, but decreased the most (-494%) to become the least common cause in 2016, with 397 297 cases (291076-533 662). Meningococcus was the leading cause of meningitis mortality in 1990 (192833 deaths [95% UI 153 358-221 503] globally), whereas other meningitis was the leading cause for both deaths (136 423 [112 682-178 022]) and incident cases (1.25 million [1.06-1.49]) in 2016. Pneumococcus caused the largest number of YLDs (634458 [444 787-839 749]) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1.48 million (1.04-1.96) YLDs were due to meningitis compared with 21.87 million (18.20-28.28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes. Interpretation Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world. Copyright (C) The Author(s). Published by Elsevier Ltd

The Many Facets of Unawareness in Huntington Disease

Background: Unawareness or diminished awareness is present when a patient's perception of obvious disease manifestations and impact differ from that of observers such as clinicians or family members.Methods: We examined studies that specifically investigate unawareness in Huntington disease (HD).Results: Unawareness of motor, cognitive, behavioral, and functional aspects of HD has been documented throughout the disease course. This can occur at motor and cognitive onset but is more pronounced as the disease progresses.Discussion: We discuss the implications for diagnosis, symptom report at presentation, timing of diagnosis, acceptance of symptomatic care strategies, and reporting in clinical trials. Assessments of work place competency, discrimination, driving, and the particular challenges of isolated patients without caregivers are described. Engaging with a person who is unaware of their disease or its impact presents a number of conflicts, including maintaining the right to autonomy, privacy, confidentiality, and independence while recognizing concerns for the wellbeing of the vulnerable person with HD and their caregiver when the unaware person refuses assistance. Unawareness is seen increasingly as neurologically based due to the impairment of functional networks, predominantly in nondominant frontostriatal pathways.</p