"You are just left to get on with it": qualitative study of patient and carer experiences of the transition to secondary progressive multiple sclerosis

Objectives Although the transition to secondary progressive multiple sclerosis (SPMS) is known to be a period of uncertainty for clinicians, who may find progressive disease challenging to objectively identify, little research has explored the experiences of patients and carers specifically during this transition period. Our objective was to explore what patients and their carers understand about their disease stage and describe their experiences and perspectives on the transition to SPMS. Design Semistructured qualitative interviews and subsequent validation focus groups were analysed using inductive thematic analysis. Setting South East Wales, UK. Participants 20 patients with MS and 13 carers were interviewed. Eight patients and two carers participated in focus groups. Results Four main themes around disease progression were identified. ‘Realisation’ describes how patients came to understand they had SPMS while ‘reaction’ describes their response to this realisation. The ‘realities’ of living with SPMS, including dealing with the healthcare system during this period, were described along with ‘future challenges’ envisaged by patients and carers. Conclusions Awareness that the transition to SPMS has occurred, and subsequent emotional reactions and coping strategies, varied widely between patients and their carers. The process of diagnosing the transition was often not transparent and some individuals wanted information to help them understand what the transition to SPMS meant for them

The role of the Cucumber mosaic virus 2b protein in viral movement and symptom induction

The Cucumber mosaic virus (CMV) 2b protein is a counter-defense factor and symptom determinant. Conserved domains in the 2b protein sequence were mutated in the 2b gene of strain Fny-CMV. The effects of these mutations were assessed by infection of Nicotiana tabacum, N. benthamiana, and Arabidopsis thaliana (ecotype Col-0) with mutant viruses and by expression of mutant 2b transgenes in A. thaliana. We confirmed that two nuclear localization signals were required for symptom induction and found that the N-terminal domain was essential for symptom induction. The C-terminal domain and two serine residues within a putative phosphorylation domain modulated symptom severity. Further infection studies were conducted using Fny-CMVΔ2b, a mutant that cannot express the 2b protein and that induces no symptoms in N. tabacum, N. benthamiana, or A. thaliana ecotype Col-0. Surprisingly, in plants of A. thaliana ecotype C24, Fny-CMVΔ2b induced severe symptoms similar to those induced by the wild-type virus. However, C24 plants infected with the mutant virus recovered from disease while those infected with the wild-type virus did not. Expression of 2b transgenes from either Fny-CMV or from LS-CMV (a mild strain) in Col-0 plants enhanced systemic movement of Fny-CMVΔ2b and permitted symptom induction by Fny-CMVΔ2b. Taken together, the results indicate that the 2b protein itself is an important symptom determinant in certain hosts. However, they also suggest that the protein may somehow synergize symptom induction by other CMV-encoded factors

NHS Health Check Programme rapid evidence synthesis

Background: The NHS Health Check programme is the largest current prevention initiative in England. Since its introduction in 2009 a growing literature has been published evaluating the first eight years of the programme. These have been summarised in reports published by Public Health England but, to date, no synthesis has been performed. There is, therefore, a need for an independent, comprehensive, rapid evidence synthesis to identify what has been learnt about the NHS Health Check programme so far. Aims and Objectives: To provide a rapid synthesis of the published research evidence on NHS Health Checks, specifically addressing the six research questions posed by Public Health England: 1. Who is and who is not having an NHS Health Check? 2. What are the factors that increase take-up among the population and sub-groups? 3. Why do people not take up an offer of an NHS Health Check? 4. How is primary care managing people identified as being at risk of cardiovascular disease or with abnormal risk factor results? 5. What are patients’ experiences of having an NHS Health Check? 6. What is the effect of the NHS Health Check on disease detection, changing behaviours, referrals to local risk management services, reductions in individual risk factor prevalence, reducing cardiovascular disease risk and on statin and antihypertensive prescribing? Design: A systematic review with descriptive synthesis of quantitative data and thematic synthesis of qualitative data. Data sources: Medline, PubMed, Embase, Health Management Information Consortium (HMIC), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Global Health, PsycInfo, Web of Science, the Cochrane Library, NHS Evidence, Google Scholar, Google, OpenGrey, Clinical Trials.gov, the ISRCTN registry, and article reference lists. Study selection: Studies identified by the searches were selected for inclusion in the review by two reviewers in a two-step process. First, studies relevant to the NHS Health Check were identified. These were then screened against predefined inclusion and exclusion criteria for each of the six research questions. Data extraction: At least two researchers assessed eligibility, extracted data, and assessed the quality of the included studies. Key findings: Coverage varies substantially across regions and in different settings. Multiple definitions used interchangeably make comparisons difficult. It is consistently higher in older people, females and more deprived populations but this may reflect targeting. Outreach services in the community can reach particular socio-demographic groups but better descriptions and robust evaluations are needed. There is a lack of national level studies reporting the characteristics of those who take-up the invitation to an NHS Health Check. Regional studies report uptake between 27% and 53%, similar to national reported uptake (48.3%). Older people, women in younger age groups and men in older age groups, and those from least deprived areas are more likely to take up invitations. Promising methods to increase uptake are modifications to the invitation (3-4% increase), and text message invites or reminders (up to 9% increase). There is a lack of quantitative evidence for the effect of community settings on uptake but qualitative evidence highlights their convenience and the value of community ambassadors. People do not take up the offer of an NHS Health Check due to lack of awareness or knowledge, competing priorities, misunderstanding the purpose, an aversion to preventive medicine, difficulty getting an appointment with a GP, and concerns about privacy and confidentiality of pharmacies. Amongst attendees there are high levels of satisfaction (over 80%). Some reported attendance had acted as a wake-up call and precipitant for lifestyle changes. Others were left with feelings of unmet expectations, were confused about or unable to remember their risk scores, and found lifestyle advice too simplistic and un-personalised. There are wide variations in the process, delivery and content of NHS Health Checks across the country, in part due to different local implementation. Regardless of region or setting those delivering NHS Health Checks reported challenges with workload, IT, funding, and training. Amongst general practice professionals there were concerns about inequality of uptake and doubts about the evidence underpinning the programme and the cost-effectiveness. NHS Health Checks are associated with small increases in disease detection. There is very little data on behaviour change or referrals to lifestyle services. NHS Health Checks are associated with a 3-4% increase in prescribing of statins

More parasitic myositis cases in humans in Australia, and the definition of genetic markers for the causative agents as a basis for molecular diagnosis

Since 1998, there have been six reported human cases of myositis in Australia, attributable to infection with the nematode Haycocknema perplexum. However, an unequivocal diagnosis of H. perplexum infection and associated disease has been seriously compromised by a lack of molecular markers for this nematode. Here, we report new cases of disseminated myositis in two male patients from the states of Queensland and Tasmania in Australia, respectively; genetically characterize the causative agent from each case; and, also establish a PCR-based sequencing approach as a tool to support the diagnosis of future cases and to underpin epidemiological studies

Visually identified Tau 18F-MK6240 PET patterns in symptomatic Alzheimer\u27s disease

Background: In Alzheimer\u27s disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. Objective: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. Methods : Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. Results: Visual rating resulted in 59.6 % classified as Typical, 17.9 % as MTL-sparing, 9.9 % LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen\u27s kappa values of 0.89 and 0.86 respectively). Tracer retention in a hook -like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High crtical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. Conclusion: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition

Exposure to unhealthy product advertising: Spatial proximity analysis to schools and socio-economic inequalities in daily exposure measured using Scottish Children's individual-level GPS data

This study aimed to understand socio-spatial inequalities in the placement of unhealthy commodity advertisements at transportation stops within the Central Belt of Scotland and to measure advertisement exposure using children's individual-level mobility data. We found that children who resided within more deprived areas had greater contact with the transport network and also greater exposure to unhealthy food and drink product advertising, compared to those living in less deprived areas. Individual-level mobility data provide evidence that city- or country-wide restrictions to advertising on the transport network might be required to reduce inequalities in children's exposure to unhealthy commodity advertising

A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota

Objective; Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22). Design A randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry. Results; Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects. Conclusion; Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure. Trial registration number; ISRCTN18662143

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI

To improve understanding of Alzheimer’s disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p \u3c 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses

D'Annunzio sulla scena lirica: libretto o "Poema"?

Australia Direct Action climate change policy relies on purchasing greenhouse gas abatement from projects undertaking approved abatement activities. Management of soil organic carbon (SOC) in agricultural soils is an approved activity, based on the expectation that land use change can deliver significant changes in SOC. However, there are concerns that climate, topography and soil texture will limit changes in SOC stocks. This work analyses data from 1482 sites surveyed across the major agricultural regions of Eastern Australia to determine the relative importance of land use vs. other drivers of SOC. Variation in land use explained only 1.4% of the total variation in SOC, with aridity and soil texture the main regulators of SOC stock under different land uses. Results suggest the greatest potential for increasing SOC stocks in Eastern Australian agricultural regions lies in converting from cropping to pasture on heavy textured soils in the humid regions

Response inhibition and serotonin in autism:a functional MRI study using acute tryptophan depletion

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target