Development and evaluation of biomarkers in Huntington’s Disease: furthering our understanding of the disease and preparing for clinical trials

Huntington’s Disease (HD) is a devastating hereditary neurodegenerative disease for which there are currently only symptomatic treatments. Several potentially curative pharmaceutical and genetic therapies are however in varying stages of development and therefore an increasing number of large-scale clinical trials of disease-modifying therapies are imminent. There is consequently a need for biomarkers which are sensitive to beneficial attenuation of disease-related changes. Functional, neuroimaging and biochemical biomarkers have been developed in HD (Andre et al. 2014;Weir et al. 2011). Neuroimaging biomarkers are strong candidates based on their clear relevance to the neuropathology of disease, proven precision and superior sensitivity compared with some standard functional measures (Tabrizi et al. 2011;Tabrizi et al. 2012). Their use in early-stage clinical trials, as surrogate end-points providing initial evidence of biological effect, is becoming increasingly common. Comparison of biomarkers in HD will help to clarify which measures, over varying time intervals, are most sensitive to disease progression. Additionally, the identification of robust fully-automated methods, comparable to manual and semi-automated gold-standards, would facilitate large-scale volumetric analysis. These methods however require validation in observational studies of neurodegenerative disease before they can be applied to sensitive clinical trial data. This thesis will develop and evaluate biomarkers for use in HD; both furthering our understanding of the disease and in preparation for use as end-points in clinical trials. A direct comparison of the sensitivity of diffusion and volumetric imaging biomarkers to HD-related change will be reported for the first time. Several exploratory imaging investigations are also described which enhance current knowledge of the relationship between neuroimaging metrics, brain functioning and behaviour, additionally strengthening the argument for the clinical relevance of neuroimaging measures as surrogate end-points in HD. The thesis will conclude with a comprehensive biomarker evaluation in early-stage HD, along with suggested strategies for selection of primary and secondary trial end-points based on effect sizes and corresponding sample size requirements

Test-Retest Reliability of Diffusion Tensor Imaging in Huntington's Disease.

Diffusion tensor imaging (DTI) has shown microstructural abnormalities in patients with Huntington's Disease (HD) and work is underway to characterise how these abnormalities change with disease progression. Using methods that will be applied in longitudinal research, we sought to establish the reliability of DTI in early HD patients and controls. Test-retest reliability, quantified using the intraclass correlation coefficient (ICC), was assessed using region-of-interest (ROI)-based white matter atlas and voxelwise approaches on repeat scan data from 22 participants (10 early HD, 12 controls). T1 data was used to generate further ROIs for analysis in a reduced sample of 18 participants. The results suggest that fractional anisotropy (FA) and other diffusivity metrics are generally highly reliable, with ICCs indicating considerably lower within-subject compared to between-subject variability in both HD patients and controls. Where ICC was low, particularly for the diffusivity measures in the caudate and putamen, this was partly influenced by outliers. The analysis suggests that the specific DTI methods used here are appropriate for cross-sectional research in HD, and give confidence that they can also be applied longitudinally, although this requires further investigation. An important caveat for DTI studies is that test-retest reliability may not be evenly distributed throughout the brain whereby highly anisotropic white matter regions tended to show lower relative within-subject variability than other white or grey matter regions

Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome

Aim: The objective of the study is to describe management of exomphalos major and investigate the effect of congenital cardiac anomalies. / Methods: A single-center retrospective review (with audit approval) was performed of neonates with exomphalos major (fascial defect ≥ 5cm ± liver herniation) between 2004 and 2014. Demographic and operative data were collected and outcomes compared between infants who had primary or staged closure. Data, median (range), were analyzed appropriately. Results: A total of 22 patients were included, 20 with liver herniation and 1 with pentalogy of Cantrell. Gestational age was 38 (30–40) weeks, birth weight 2.7 (1.4–4.6) kg, and 13 (60%) were male. Two were managed conservatively due to severe comorbidities, 5 underwent primary closure, and 15 had application of Prolene (Ethicon Inc) mesh silo and serial reduction. Five died, including two managed conservatively, none primarily of the exomphalos. Survivors were followed up for 38 months (2–71). Cardiac anomalies were present in 20 (91%) patients: 8 had minor and 12 major anomalies. Twelve (55%) patients had other anomalies. Primary closure was associated with shorter length of stay (13 vs. 85 days, p = 0.02), but infants had similar lengths of intensive care stay, duration of parenteral feeds, and time to full feeds. Infants with cardiac anomalies had shorter times to full closure (28 vs. 62 days, p = 0.03), but other outcomes were similar. / Conclusion: Infants whose defect can be closed primarily have a shorter length of stay, but other outcomes are similar. Infants with more significant abdominovisceral disproportion are managed with staged closure; the presence of major cardiac anomalies does not affect surgical outcome

Occupational respiratory diseases in South Africa results from SORDSA, 1997- 1999

Objectives. To describe the nature and extent of work-related respiratory diseases reported to the national Surveillance of Work-related and Occupational Respiratory Diseases in South Africa (SORDSA) reporting scheme. The causative agents and industrial categories in which they occurred are also characterised.Design. Voluntary monthly reporting of newly diagnosed cases by pulmonologists, occupational medicine practitioners and occupational health nurses.Setting. Medical and occupational health referral centres in the nine provinces of South Africa.Subjects. Cases were workers from non-mining industries or ex-miners, suffering from a newly diagnosed occupational respiratory disease, reported to SORDSA between October 1996 and December 1999.Outcome measures. Frequencies of reported occupational respiratory disease by year, reporting source, province and sex. Frequencies of short- and long-latency diseases by industry and causative agent.Results. There was incomplete reporting coverage of the nine provinces in the first 3 years. Reporting was most comprehensive from Gauteng, KwaZulu-Natal and the Western Cape. Diseases with long latency periods made up 76.2% of the cases. Pneumoconiosis, even in non-mining industries, was the most frequently reported disease, followed by inhalation accidents. Occupational asthma was the fourth most reported disease. Apart from the prominence of pneumoconiosis, the results obtained by . SORDSA are similar to those from a British occupational lung disease surveillance scheme. This study showed that newly diagnosed cases of occupational lung disease occurred in many industries and were caused by a variety of agents.Conclusion. SORDSA has contributed insight into the nature, extent and distribution of occupational respiratory diseases in South Africa. It has also highlighted important causes of occupational respiratory diseases in South Africa, as well as hazardous industries. The data indicate that South Africa has a widespread occupational lung disease problem, and provide a platform for targeted prevention strategies

Effects of acute fatigue on the volitional and magnetically-evoked electromechanical delay of the knee flexors in males and females

Neuromuscular performance capabilities, including those measured by evoked responses, may be adversely affected by fatigue; however, the capability of the neuromuscular system to initiate muscle force rapidly under these circumstances is yet to be established. Sex-differences in the acute responses of neuromuscular performance to exercise stress may be linked to evidence that females are much more vulnerable to ACL injury than males. Optimal functioning of the knee flexors is paramount to the dynamic stabilisation of the knee joint, therefore the aim of this investigation was to examine the effects of acute maximal intensity fatiguing exercise on the voluntary and magnetically-evoked electromechanical delay in the knee flexors of males and females. Knee flexor volitional and magnetically-evoked neuromuscular performance was assessed in seven male and nine females prior to and immediately after: (i) an intervention condition comprising a fatigue trial of 30-seconds maximal static exercise of the knee flexors, (ii) a control condition consisting of no exercise. The results showed that the fatigue intervention was associated with a substantive reduction in volitional peak force (PFV) that was greater in males compared to females (15.0%, 10.2%, respectively, p < 0.01) and impairment to volitional electromechanical delay (EMDV) in females exclusively (19.3%, p < 0.05). Similar improvements in magnetically-evoked electromechanical delay in males and females following fatigue (21%, p < 0.001), however, may suggest a vital facilitatory mechanism to overcome the effects of impaired voluntary capabilities, and a faster neuromuscular response that can be deployed during critical times to protect the joint system

Digital technologies in the public-health response to COVID-19

Digital technologies are being harnessed to support the public-health response to COVID-19 worldwide, including population surveillance, case identification, contact tracing and evaluation of interventions on the basis of mobility data and communication with the public. These rapid responses leverage billions of mobile phones, large online datasets, connected devices, relatively low-cost computing resources and advances in machine learning and natural language processing. This Review aims to capture the breadth of digital innovations for the public-health response to COVID-19 worldwide and their limitations, and barriers to their implementation, including legal, ethical and privacy barriers, as well as organizational and workforce barriers. The future of public health is likely to become increasingly digital, and we review the need for the alignment of international strategies for the regulation, evaluation and use of digital technologies to strengthen pandemic management, and future preparedness for COVID-19 and other infectious diseases

Astrobiological Complexity with Probabilistic Cellular Automata

Search for extraterrestrial life and intelligence constitutes one of the major endeavors in science, but has yet been quantitatively modeled only rarely and in a cursory and superficial fashion. We argue that probabilistic cellular automata (PCA) represent the best quantitative framework for modeling astrobiological history of the Milky Way and its Galactic Habitable Zone. The relevant astrobiological parameters are to be modeled as the elements of the input probability matrix for the PCA kernel. With the underlying simplicity of the cellular automata constructs, this approach enables a quick analysis of large and ambiguous input parameters' space. We perform a simple clustering analysis of typical astrobiological histories and discuss the relevant boundary conditions of practical importance for planning and guiding actual empirical astrobiological and SETI projects. In addition to showing how the present framework is adaptable to more complex situations and updated observational databases from current and near-future space missions, we demonstrate how numerical results could offer a cautious rationale for continuation of practical SETI searches.Comment: 37 pages, 11 figures, 2 tables; added journal reference belo

Tendinopathy—from basic science to treatment

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy