Feasibility and usability of remote monitoring in Alzheimer's disease.

Introduction: Remote monitoring technologies (RMTs) can measure cognitive and functional decline objectively at-home, and offer opportunities to measure passively and continuously, possibly improving sensitivity and reducing participant burden in clinical trials. However, there is skepticism that age and cognitive or functional impairment may render participants unable or unwilling to comply with complex RMT protocols. We therefore assessed the feasibility and usability of a complex RMT protocol in all syndromic stages of Alzheimer's disease and in healthy control participants. Methods: For 8 weeks, participants (N = 229) used two activity trackers, two interactive apps with either daily or weekly cognitive tasks, and optionally a wearable camera. A subset of participants participated in a 4-week sub-study (N = 45) using fixed at-home sensors, a wearable EEG sleep headband and a driving performance device. Feasibility was assessed by evaluating compliance and drop-out rates. Usability was assessed by problem rates (e.g., understanding instructions, discomfort, forgetting to use the RMT or technical problems) as discussed during bi-weekly semi-structured interviews. Results: Most problems were found for the active apps and EEG sleep headband. Problem rates increased and compliance rates decreased with disease severity, but the study remained feasible. Conclusions: This study shows that a highly complex RMT protocol is feasible, even in a mild-to-moderate AD population, encouraging other researchers to use RMTs in their study designs. We recommend evaluating the design of individual devices carefully before finalizing study protocols, considering RMTs which allow for real-time compliance monitoring, and engaging the partners of study participants in the research.

Actigraphy-derived physical activity levels and circadian rhythm parameters in patients with psoriatic arthritis: relationship with disease activity, mood, age and BMI.

Background: Psoriatic arthritis (PsA) is associated with sleep disturbance, depression and a lifetime risk of obesity and cardiovascular disease. To date, there have been no studies investigating the relationship between objectively-measured physical activity (PA) levels and circadian rhythm disturbance with disease activity, daily symptoms and mood in patients with PsA. Objective: This pilot study aimed to investigate the relationship between disease activity, daily symptoms and mood on PA and circadian rhythm in PsA. Design: A prospective cohort study recruiting adults with PsA from rheumatology clinics at a single centre in the UK. Methods: Participants wore an actigraph and recorded their symptoms and mood on a daily basis via a smartphone app for 28 days. Time spent in sedentary, light and moderate-to-vigorous physical activity (MVPA) and parameters reflecting the circadian rhythm of the rest-activity pattern were derived. This included the onset time of the least active 5-h (L5) and most active 10-h (M10) daily consecutive periods and the relative amplitude (RA). The relationship factors between baseline clinical status, daily symptoms, PA and circadian measures were examined using linear mixed effect regression models. Results: Nineteen participants (8/19 female) were included. Participants with active PsA spent 63.87 min (95% CI: 18.5-109.3, p = 0.008) more in inactivity and 30.78 min (95% CI: 0.4-61.1, p = 0.047) less in MVPA per day compared to those in minimal disease activity (MDA). Age, body mass index and disease duration were also associated with PA duration. Participants with worse functional impairment had an M10 onset time 1.94 h (95% CI: 0.05-3.39, p = 0.011) later than those with no reported functional impairment. No differences were detected for L5 onset time or RA. Higher scores for positive mood components such as feeling energetic, cheerful and elated were associated with less time in inactivity and greater time spent in MVPA overall. Conclusion: Our study highlights differences in PA and circadian rest-activity pattern timing based on disease activity, disability and daily mood in PsA. Reduced PA levels in patients with active disease may contribute to the observed increased risk of cardiovascular and metabolic sequelae, with further studies exploring this need.

Wearable Devices for Assessing Function in Alzheimer's Disease: A European Public Involvement Activity About the Features and Preferences of Patients and Caregivers.

Background: Alzheimer's Disease (AD) impairs the ability to carry out daily activities, reduces independence and quality of life and increases caregiver burden. Our understanding of functional decline has traditionally relied on reports by family and caregivers, which are subjective and vulnerable to recall bias. The Internet of Things (IoT) and wearable sensor technologies promise to provide objective, affordable, and reliable means for monitoring and understanding function. However, human factors for its acceptance are relatively unexplored. Objective: The Public Involvement (PI) activity presented in this paper aims to capture the preferences, priorities and concerns of people with AD and their caregivers for using monitoring wearables. Their feedback will drive device selection for clinical research, starting with the study of the RADAR-AD project. Method: The PI activity involved the Patient Advisory Board (PAB) of the RADAR-AD project, comprised of people with dementia across Europe and their caregivers (11 and 10, respectively). A set of four devices that optimally represent various combinations of aspects and features from the variety of currently available wearables (e.g., weight, size, comfort, battery life, screen types, water-resistance, and metrics) was presented and experienced hands-on. Afterwards, sets of cards were used to rate and rank devices and features and freely discuss preferences. Results: Overall, the PAB was willing to accept and incorporate devices into their daily lives. For the presented devices, the aspects most important to them included comfort, convenience and affordability. For devices in general, the features they prioritized were appearance/style, battery life and water resistance, followed by price, having an emergency button and a screen with metrics. The metrics valuable to them included activity levels and heart rate, followed by respiration rate, sleep quality and distance. Some concerns were the potential complexity, forgetting to charge the device, the potential stigma and data privacy. Conclusions: The PI activity explored the preferences, priorities and concerns of the PAB, a group of people with dementia and caregivers across Europe, regarding devices for monitoring function and decline, after a hands-on experience and explanation. They highlighted some expected aspects, metrics and features (e.g., comfort and convenience), but also some less expected (e.g., screen with metrics).

Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.

BACKGROUND: Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. METHODS: This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure. RESULTS: First results are expected to be disseminated in 2022. CONCLUSION: Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.

Distemper, extinction, and vaccination of the Amur tiger.

Canine distemper virus (CDV) has recently emerged as an extinction threat for the endangered Amur tiger (Panthera tigris altaica). CDV is vaccine-preventable, and control strategies could require vaccination of domestic dogs and/or wildlife populations. However, vaccination of endangered wildlife remains controversial, which has led to a focus on interventions in domestic dogs, often assumed to be the source of infection. Effective decision making requires an understanding of the true reservoir dynamics, which poses substantial challenges in remote areas with diverse host communities. We carried out serological, demographic, and phylogenetic studies of dog and wildlife populations in the Russian Far East to show that a number of wildlife species are more important than dogs, both in maintaining CDV and as sources of infection for tigers. Critically, therefore, because CDV circulates among multiple wildlife sources, dog vaccination alone would not be effective at protecting tigers. We show, however, that low-coverage vaccination of tigers themselves is feasible and would produce substantive reductions in extinction risks. Vaccination of endangered wildlife provides a valuable component of conservation strategies for endangered species.

Selecting Remote Measurement Technologies to Optimize Assessment of Function in Early Alzheimer's Disease: A Case Study.

Despite the importance of function in early Alzheimer's disease (AD), current measures are outdated and insensitive. Moreover, COVID-19 has heighted the need for remote assessment in older people, who are at higher risk of being infection and are particularly advised to use social distancing measures, yet the importance of diagnosis and treatment of dementia remains unchanged. The emergence of remote measurement technologies (RMTs) allows for more precise and objective measures of function. However, RMT selection is a critical challenge. Therefore, this case study outlines the processes through which we identified relevant functional domains, engaged with stakeholder groups to understand participants' perspectives and worked with technical experts to select relevant RMTs to examine function. After an extensive literature review to select functional domains relevant to AD biomarkers, quality of life, rate of disease progression and loss of independence, functional domains were ranked and grouped by the empirical evidence for each. For all functional domains, we amalgamated feedback from a patient advisory board. The results were prioritized into: highly relevant, relevant, neutral, and less relevant. This prioritized list of functional domains was then passed onto a group of experts in the use of RMTs in clinical and epidemiological studies to complete the selection process, which consisted of: (i) identifying relevant functional domains and RMTs; (ii) synthesizing proposals into final RMT selection, and (iii) verifying the quality of these decisions. Highly relevant functional domains were, "difficulties at work," "spatial navigation and memory," and "planning skills and memory required for task completion." All functional domains were successfully allocated commercially available RMTs that make remote measurement of function feasible. This case study provides a set of prioritized functional domains sensitive to the early stages of AD and a set of RMTs capable of targeting them. RMTs have huge potential to transform the way we assess function in AD-monitoring for change and stability continuously within the home environment, rather than during infrequent clinic visits. Our decomposition of RMT and functional domain selection into identify, synthesize, and verify activities, provides a pragmatic structure with potential to be adapted for use in future RMT selection processes.

Evaluating the Feasibility of Frequent Cognitive Assessment Using the Mezurio Smartphone App: Observational and Interview Study in Adults With Elevated Dementia Risk.

BACKGROUND: By enabling frequent, sensitive, and economic remote assessment, smartphones will facilitate the detection of early cognitive decline at scale. Previous studies have sustained participant engagement with remote cognitive assessment over a week; extending this to a period of 1 month clearly provides a greater opportunity for measurement. However, as study durations are increased, the need to understand how participant burden and scientific value might be optimally balanced also increases. OBJECTIVE: This study explored the little but often approach to assessment employed by the Mezurio app when prompting participants to interact every day for over a month. Specifically, this study aimed to understand whether this extended duration of remote study is feasible, and which factors promote sustained participant engagement over such periods. METHODS: A total of 35 adults (aged 40-59 years) with no diagnosis of cognitive impairment were prompted to interact with the Mezurio smartphone app platform for up to 36 days, completing short, daily episodic memory tasks in addition to optional executive function and language tests. A subset (n=20) of participants completed semistructured interviews focused on their experience of using the app. RESULTS: Participants complied with 80% of the daily learning tasks scheduled for subsequent tests of episodic memory, with 88% of participants still actively engaged by the final task. A thematic analysis of the participants' experiences highlighted schedule flexibility, a clear user interface, and performance feedback as important considerations for engagement with remote digital assessment. CONCLUSIONS: Despite the extended study duration, participants demonstrated high compliance with the schedule of daily learning tasks and were extremely positive about their experiences. Long durations of remote digital interaction are therefore definitely feasible but only when careful attention is paid to the design of the users' experience.

The True Colours Remote Symptom Monitoring System: A Decade of Evolution.

The True Colours remote mood monitoring system was developed over a decade ago by researchers, psychiatrists, and software engineers at the University of Oxford to allow patients to report on a range of symptoms via text messages, Web interfaces, or mobile phone apps. The system has evolved to encompass a wide range of measures, including psychiatric symptoms, quality of life, and medication. Patients are prompted to provide data according to an agreed personal schedule: weekly, daily, or at specific times during the day. The system has been applied across a number of different populations, for the reporting of mood, anxiety, substance use, eating and personality disorders, psychosis, self-harm, and inflammatory bowel disease, and it has shown good compliance. Over the past decade, there have been over 36,000 registered True Colours patients and participants in the United Kingdom, with more than 20 deployments of the system supporting clinical service and research delivery. The system has been adopted for routine clinical care in mental health services, supporting more than 3000 adult patients in secondary care, and 27,263 adolescent patients are currently registered within Oxfordshire and Buckinghamshire. The system has also proven to be an invaluable scientific resource as a platform for research into mood instability and as an electronic outcome measure in randomized controlled trials. This paper aimed to report on the existing applications of the system, setting out lessons learned, and to discuss the implications for tailored symptom monitoring, as well as the barriers to implementation at a larger scale.

Gallery Game: Smartphone-based assessment of long-term memory in adults at risk of Alzheimer's disease.

Introduction: Gallery Game, deployed within the Mezurio smartphone app, targets the processes of episodic memory hypothesized to be first vulnerable to neurofibrillary tau-related degeneration in Alzheimer's Disease, prioritizing both perirhinal and entorhinal cortex/hippocampal demands.Methods: Thirty-five healthy adults (aged 40-59 years), biased toward those at elevated familial risk of dementia, completed daily Gallery Game tasks for a month. Assessments consisted of cross-modal paired-associate learning, with subsequent tests of recognition and free recall following delays ranging from one to 13 days.Results: Retention intervals of at least three days were needed to evidence significant forgetting at both recognition and paired-associate recall test. The association between Gallery Game outcomes and established in-clinic memory assessments were small but numerically in the anticipated direction. In addition, there was preliminary support for utilizing the perirhinal-dependent pattern of semantic false alarms during object recognition as a marker of early impairment.Conclusions: These results support the need for tests of longer-term memory to sensitively record behavioral differences in adults with no diagnosis of cognitive impairment. Aggregate behavioral outcomes promote Gallery Game's utility as a digital assessment of episodic memory, aligning with established theoretical models of object memory and showing small yet uniform associations with existing in-clinic tests. Initial support for the discriminatory value of perirhinal-targeted outcomes justifies ongoing large-sample validation against traditional biomarkers of Alzheimer's disease.

Large-scale roll out of electronic longitudinal mood-monitoring for research in affective disorders: Report from the UK bipolar disorder research network.

BACKGROUND: Electronic longitudinal mood monitoring has been shown to be acceptable to patients with affective disorders within clinical settings, but its use in large-scale research has not yet been established. METHODS: Using both postal and email invitations, we invited 4080 past research participants with affective disorders who were recruited into the Bipolar Disorder Research Network (BDRN) over a 10 year period to participate in online weekly mood monitoring. In addition, since January 2015 we have invited all newly recruited BDRN research participants to participate in mood monitoring at the point they were recruited into BDRN. RESULTS: Online mood monitoring uptake among past participants was 20%, and among new participants to date was 46% with participants recruited over the last year most likely to register (61%). More than 90% mood monitoring participants engaged for at least one month, with mean engagement period greater than one year (58 weeks) and maximum engagement for longer than three years (165 weeks). There were no significant differences in the proportion of past and new BDRN participants providing data for at least 4 weeks (91%, 92% respectively), 3 months (78%, 82%), 6 months (65%, 54%) or one year (51%, 44%). LIMITATIONS: Our experiences with recruiting participants for electronic prospective mood monitoring may not necessarily generalise fully to research situations that are very different from those we describe. CONCLUSIONS: Large-scale electronic longitudinal mood monitoring in affective disorders for research purposes is feasible with uptake highest among newly recruited participants.

Daily and weekly mood ratings using a remote capture method in high-risk offspring of bipolar parents: Compliance and symptom monitoring.

OBJECTIVES: To determine the compliance and clinical utility of weekly and daily electronic mood symptom monitoring in adolescents and young adults at risk for mood disorder. METHODS: Fifty emerging adult offspring of bipolar parents were recruited from the Flourish Canadian high-risk offspring cohort study along with 108 university student controls. Participants were assessed by KSADS/SADS-L semi-structured interviews and used a remote capture method to complete weekly and daily mood symptom ratings using validated scales for 90 consecutive days. Hazard models and generalized estimating equations were used to determine differences in summary scores and regularity of ratings. RESULTS: Seventy-eight and 77% of high-risk offspring and 97% and 93% of controls completed the first 30 days of weekly and daily ratings, respectively. There were no differences in drop-out rates between groups over 90 days (weekly P = 0.2149; daily P = 0.9792). There were no differences in mean summary scores or regularity of weekly anxiety, depressive or hypomanic symptom ratings between high-risk offspring and control groups. However, high-risk offspring compared to controls had daily ratings indicating lower positive affect, higher negative affect and lower self-esteem (P = 0.0317). High-risk offspring with remitted mood disorder compared to those without had more irregularity in weekly anxiety and depressive symptom ratings and daily ratings of lower positive affect, higher negative affect, and higher shame and self-doubt (P = 0.0365). CONCLUSIONS: Findings support that high-resolution electronic mood tracking may be a feasible and clinically useful approach in monitoring emerging psychopathology in young people at high-risk offspring of mood disorder onset or recurrence.

Digital technologies for the assessment of cognition: a clinical review.

Dementia is the most widespread form of neurodegenerative disorder and is associated with an immense societal and personal cost. Prevalence of this disorder is projected to triple worldwide by 2050 leading to an urgent need to make advances in the efficiency of both its care and therapy research. Digital technologies are a rapidly advancing field that provide a previously unavailable opportunity to alleviate challenges faced by clinicians and researchers working in this area. This clinical review aimed to summarise currently available evidence on digital technologies that can be used to monitor cognition. We identified a range of pervasive digital systems, such as smartphones, smartwatches and smart homes, to assess and assist elderly demented, prodromal and preclinical populations. Generally, the studies reported good level of agreement between the digital measures and the constructs they aimed to measure. However, most of the systems are still only in the initial stages of development with limited data on acceptability in patients. Although it is clear that the use of digital technology to monitor and support the cognitive domains affected by dementia is a promising area of development, additional research validating the efficacy, utility and cost-effectiveness of these systems in patient populations is needed.

Psychoeducation and online mood tracking for patients with bipolar disorder: A randomised controlled trial.

BACKGROUND: Psychoeducation is an effective adjunct to medications in bipolar disorder (BD). Brief psychoeducational approaches have been shown to improve early identification of relapse. However, the optimal method of delivery of psychoeducation remains uncertain. Here, our objective was to compare a short therapist-facilitated vs. self-directed psychoeducational intervention for BD. METHODS: BD outpatients who were receiving medication-based treatment were randomly assigned to 5 psychoeducation sessions administered by a therapist (Facilitated Integrated Mood Management; FIMM; n=60), or self-administered psychoeducation (Manualized Integrated Mood Management; MIMM; n=61). Follow-up was based on patients' weekly responses to an electronic mood monitoring programme over 12 months. RESULTS: Over follow-up, there were no group differences in weekly self-rated depression symptoms or relapse/readmission rates. However, knowledge of BD (assessed with the Oxford Bipolar Knowledge questionnaire (OBQ)) was greater in the FIMM than the MIMM group at 3 months. Greater illness knowledge at 3 months was related to a higher proportion of weeks well over 12 months. LIMITATIONS: Features of the trial may have reduced the sensitivity to our psychoeducation approach, including that BD participants had been previously engaged in self-monitoring. CONCLUSIONS: Improved OBQ score, while accelerated by a short course of therapist-administered psychoeducation (FIMM), was seen after both treatments. It was associated with better outcome assessed as weeks well. When developing and testing a new psychosocial intervention, studies should consider proximal outcomes (e.g., acquired knowledge) and their short-term impact on illness course in bipolar disorder.

Comparison of Next-Generation Sequencing Technologies for Comprehensive Assessment of Full-Length Hepatitis C Viral Genomes.

Affordable next-generation sequencing (NGS) technologies for hepatitis C virus (HCV) may potentially identify both viral genotype and resistance genetic motifs in the era of directly acting antiviral (DAA) therapies. This study compared the ability of high-throughput NGS methods to generate full-length, deep, HCV sequence data sets and evaluated their utility for diagnostics and clinical assessment. NGS methods using (i) unselected HCV RNA (metagenomics), (ii) preenrichment of HCV RNA by probe capture, and (iii) HCV preamplification by PCR implemented in four United Kingdom centers were compared. Metrics of sequence coverage and depth, quasispecies diversity, and detection of DAA resistance-associated variants (RAVs), mixed HCV genotypes, and other coinfections were compared using a panel of samples with different viral loads, genotypes, and mixed HCV genotypes/subtypes [geno(sub)types]. Each NGS method generated near-complete genome sequences from more than 90% of samples. Enrichment methods and PCR preamplification generated greater sequence depth and were more effective for samples with low viral loads. All NGS methodologies accurately identified mixed HCV genotype infections. Consensus sequences generated by different NGS methods were generally concordant, and majority RAVs were consistently detected. However, methods differed in their ability to detect minor populations of RAVs. Metagenomic methods identified human pegivirus coinfections. NGS provided a rapid, inexpensive method for generating whole HCV genomes to define infecting genotypes, RAVs, comprehensive viral strain analysis, and quasispecies diversity. Enrichment methods are particularly suited for high-throughput analysis while providing the genotype and information on potential DAA resistance.

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

Genetic complementation of hepatitis C virus nonstructural protein functions associated with replication exhibits requirements that differ from those for virion assembly.

UNLABELLED: Within the polyprotein encoded by hepatitis C virus (HCV), the minimum components required for viral RNA replication lie in the NS3-5B region, while virion assembly requires expression of all virus components. Here, we have employed complementation systems to examine the role that HCV polyprotein precursors play in RNA replication and virion assembly. In a trans-complementation assay, an HCV NS3-5A polyprotein precursor was required to facilitate efficient complementation of a replication-defective mutation in NS5A. However, this requirement for precursor expression was partially alleviated when a second functional copy of NS5A was expressed from an additional upstream cistron within the RNA to be rescued. In contrast, rescue of a virion assembly mutation in NS5A was more limited but exhibited little or no requirement for expression of functional NS5A as a precursor, even when produced in the context of a second replicating helper RNA. Furthermore, expression of NS5A alone from an additional cistron within a replicon construct gave greater rescue of virion assembly in cis than in trans. Combined with the findings of confocal microscope analysis examining the extent to which the two copies of NS5A from the various expression systems colocalize, the results point to NS3-5A playing a role in facilitating the integration of nonstructural (NS) proteins into viral membrane-associated foci, with this representing an early stage in the steps leading to replication complex formation. The data further imply that HCV employs a minor virion assembly pathway that is independent of replication. IMPORTANCE: In hepatitis C virus-infected cells, replication is generally considered an absolute prerequisite for virus particle formation. Here we investigated the role that the viral protein NS5A has in both replication and particle assembly using complementation assays and microscopy. We found that efficient rescue of replication required NS5A to be expressed as part of a larger polyprotein, and this correlated with detection of NS5A at sites where replication occurred. In contrast, rescue of particle assembly did not require expression of NS5A within the context of a polyprotein. Interestingly, although only partial restoration of particle assembly was possible by complementation, that proportion that could be rescued benefitted from expressing NS5A from the same RNA being packaged. Collectively, these findings provide new insight into aspects of polyprotein function. They also support the existence of a minor virion assembly pathway that bypasses replication.

On the importance of intellectual property rights for e-science and the integrated health record.

An integrated health record (IHR) that enables clinical data to be shared at a national level has profound implications for medical research. Data that have been useful primarily within a single clinic will instead be free to move rapidly around a national network infrastructure. This raises challenges for technologists, clinical practice, and for the governance of these data. This article considers one specific issue that is currently poorly understood: how intellectual property (IP) relates to the sharing of medical data for research on large-scale electronic networks. Based on an understanding of current practices, this article presents recommendations for the governance of IP in an integrated health record.