Personal Assistants for Healthcare Treatment at Home

ABSTRACT This paper describes the research plans in the SuperAssist project, introducing personal assistants in the care of diabetes patients, assisting the patients themselves, the medical specialists looking after the patients' healthcare, and the technical specialists responsible for maintaining the health of the devices involved. The paper discusses the issues of trust and cooperation as the critical success factors within this multi-user multi-agent (MUMA) project and within the future of agent-based healthcare attempting to increase the self-help abilities of individual patients

Detailed Kinetics of the Direct Allo-Response in Human Liver Transplant Recipients: New Insights from an Optimized Assay

Conventional assays for quantification of allo-reactive T-cell precursor frequencies (PF) are relatively insensitive. We present a robust assay for quantification of PF of T-cells with direct donor-specificity, and establish the kinetics of circulating donor-specific T cells after liver transplantation (LTx). B cells from donor splenocytes were differentiated into professional antigen-presenting cells by CD40-engagement (CD40-B cells). CFSE-labelled PBMC from LTx-recipients obtained before and at several time points after LTx, were stimulated with donor-derived or 3rd party CD40-B cells. PF of donor-specific T cells were calculated from CFSE-dilution patterns, and intracellular IFN-γ was determined after re-stimulation with CD40-B cells. Compared to splenocytes, stimulations with CD40-B cells resulted in 3 to 5-fold higher responding T-cell PF. Memory and naïve T-cell subsets responded equally to allogeneic CD40-B cell stimulation. Donor-specific CD4+ and CD8+ T-cell PF ranged from 0.5 to 19% (median: 5.2%). One week after LTx, PF of circulating donor-specific CD4+ and CD8+ T cells increased significantly, while only a minor increase in numbers of T cells reacting to 3rd party allo-antigens was observed. One year after LTx numbers of CD4+ and CD8+ T cells reacting to donor antigens, as well as those reacting to 3rd party allo-antigens, were slightly lower compared to pre-transplant values. Moreover, CD4+ and CD8+ T cells responding to donor-derived, as well as those reacting to 3rd party CD40-B cells, produced less IFN-γ. In conclusion, our alternative approach enables detection of allo-reactive human T cells at high frequencies, and after application we conclude that donor-specific T-cell PF increase immediately after LTx. However, no evidence for a specific loss of circulating T-cells recognizing donor allo-antigens via the direct pathway up to 1 year after LTx was obtained, underscoring the relative insensitiveness of previous assays

FRA2A is a CGG repeat expansion associated with silencing of AFF3

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship

Long-term evolution of human seasonal influenza virus A(H3N2) is associated with an increase in polymerase complex activity

Since the influenza pandemic in 1968, influenza A(H3N2) viruses have become endemic. In this state, H3N2 viruses continuously evolve to overcome immune pressure as a result of prior infection or vaccination, as is evident from the accumulation of mutations in the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). However, phylogenetic studies have also demonstrated ongoing evolution in the influenza A(H3N2) virus RNA polymerase complex genes. The RNA polymerase complex of seasonal influenza A(H3N2) viruses produces mRNA for viral protein synthesis and replicates the negative sense viral RNA genome (vRNA) through a positive sense complementary RNA intermediate (cRNA). Presently, the consequences and selection pressures driving the evolution of the polymerase complex remain largely unknown. Here, we characterize the RNA polymerase complex of seasonal influenza A(H3N2) viruses representative of nearly 50 years of influenza A(H3N2) virus evolution. The H3N2 polymerase complex is a reassortment of human and avian influenza virus genes. We show that since 1968, influenza A(H3N2) viruses have increased the transcriptional activity of the polymerase complex while retaining a close balance between mRNA, vRNA, and cRNA levels. Interestingly, the increased polymerase complex activity did not result in increased replicative ability on differentiated human airway epithelial (HAE) cells. We hypothesize that the evolutionary increase in polymerase complex activity of influenza A(H3N2) viruses may compensate for the reduced HA receptor binding and avidity that is the result of the antigenic evolution of influenza A(H3N2) viruses

Pulsed electromagnetic fields after arthroscopic treatment for osteochondral defects of the talus: double-blind randomized controlled multicenter trial

Background. Osteochondral talar defects usually affect athletic patients. The primary surgical treatment consists of arthroscopic debridement and microfracturing. Although this is mostly successful, early sport resumption is difficult to achieve, and it can take up to one year to obtain clinical improvement. Pulsed electromagnetic fields (PEMFs) may be effective for talar defects after arthroscopic treatment by promoting tissue healing, suppressing inflammation, and relieving pain. We hypothesize that PEMF-treatment compared to sham-treatment after arthroscopy will lead to earlier resumption of sports, and aim at 25% increase in patients that resume sports. Methods/Design. A prospective, double-blind, randomized, placebo-controlled trial (RCT) will be conducted in five centers throughout the Netherlands and Belgium. 68 patients will be randomized to either active PEMF-treatment or sham-treatment for 60 days, four hours daily. They will be followed-up for one year. The combined primary outcome measures are (a) the percentage of patients that resume and maintain sports, and (b) the time to resumption of sports, defined by the Ankle Activity Score. Secondary outcome measures include resumption of work, subjective and objective scoring systems (American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale, Foot Ankle Outcome Score, Numeric Rating Scales of pain and satisfaction, EuroQol-5D), and computed tomography. Time to resumption of sports will be analyzed using Kaplan-Meier curves and log-rank tests. Discussion. This trial will provide level-1 evidence on the effectiveness of PEMFs in the management of osteochondral ankle lesions after arthroscopy. Trial registration. Netherlands Trial Register (NTR1636)

Determinants of epidemic size and the impacts of lulls in seasonal influenza virus circulation

During the COVID-19 pandemic, levels of seasonal influenza virus circulation were unprecedentedly low, leading to concerns that a lack of exposure to influenza viruses, combined with waning antibody titres, could result in larger and/or more severe post-pandemic seasonal influenza epidemics. However, in most countries the first post-pandemic influenza season was not unusually large and/or severe. Here, based on an analysis of historical influenza virus epidemic patterns from 2002 to 2019, we show that historic lulls in influenza virus circulation had relatively minor impacts on subsequent epidemic size and that epidemic size was more substantially impacted by season-specific effects unrelated to the magnitude of circulation in prior seasons. From measurements of antibody levels from serum samples collected each year from 2017 to 2021, we show that the rate of waning of antibody titres against influenza virus during the pandemic was smaller than assumed in predictive models. Taken together, these results partially explain why the re-emergence of seasonal influenza virus epidemics was less dramatic than anticipated and suggest that influenza virus epidemic dynamics are not currently amenable to multi-season prediction

Potential impacts of prolonged absence of influenza virus circulation on subsequent epidemics

BACKGROUND: During the first two years of the COVID-19 pandemic, the circulation of seasonal influenza viruses was unprecedentedly low. This led to concerns that the lack of immune stimulation to influenza viruses combined with waning antibody titres could lead to increased susceptibility to influenza in subsequent seasons, resulting in larger and more severe epidemics. METHODS: We analyzed historical influenza virus epidemiological data from 2003-2019 to assess the historical frequency of near-absence of seasonal influenza virus circulation and its impact on the size and severity of subsequent epidemics. Additionally, we measured haemagglutination inhibition-based antibody titres against seasonal influenza viruses using longitudinal serum samples from 165 healthy adults, collected before and during the COVID-19 pandemic, and estimated how antibody titres against seasonal influenza waned during the first two years of the pandemic. FINDINGS: Low country-level prevalence of influenza virus (sub)types over one or more years occurred frequently before the COVID-19 pandemic and had relatively small impacts on subsequent epidemic size and severity. Additionally, antibody titres against seasonal influenza viruses waned negligibly during the first two years of the pandemic. INTERPRETATION: The commonly held notion that lulls in influenza virus circulation, as observed during the COVID-19 pandemic, will lead to larger and/or more severe subsequent epidemics might not be fully warranted, and it is likely that post-lull seasons will be similar in size and severity to pre-lull seasons. FUNDING: European Research Council, Netherlands Organization for Scientific Research, Royal Dutch Academy of Sciences, Public Health Service of Amsterdam. RESEARCH IN CONTEXT: Evidence before this study: During the first years of the COVID-19 pandemic, the incidence of seasonal influenza was unusually low, leading to widespread concerns of exceptionally large and/or severe influenza epidemics in the coming years. We searched PubMed and Google Scholar using a combination of search terms (i.e., "seasonal influenza", "SARS-CoV-2", "COVID-19", "low incidence", "waning rates", "immune protection") and critically considered published articles and preprints that studied or reviewed the low incidence of seasonal influenza viruses since the start of the COVID-19 pandemic and its potential impact on future seasonal influenza epidemics. We found a substantial body of work describing how influenza virus circulation was reduced during the COVID-19 pandemic, and a number of studies projecting the size of future epidemics, each positing that post-pandemic epidemics are likely to be larger than those observed pre-pandemic. However, it remains unclear to what extent the assumed relationship between accumulated susceptibility and subsequent epidemic size holds, and it remains unknown to what extent antibody levels have waned during the COVID-19 pandemic. Both are potentially crucial for accurate prediction of post-pandemic epidemic sizes.Added value of this study: We find that the relationship between epidemic size and severity and the magnitude of circulation in the preceding season(s) is decidedly more complex than assumed, with the magnitude of influenza circulation in preceding seasons having only limited effects on subsequent epidemic size and severity. Rather, epidemic size and severity are dominated by season-specific effects unrelated to the magnitude of circulation in the preceding season(s). Similarly, we find that antibody levels waned only modestly during the COVID-19 pandemic.Implications of all the available evidence: The lack of changes observed in the patterns of measured antibody titres against seasonal influenza viruses in adults and nearly two decades of epidemiological data suggest that post-pandemic epidemic sizes will likely be similar to those observed pre-pandemic, and challenge the commonly held notion that the widespread concern that the near-absence of seasonal influenza virus circulation during the COVID-19 pandemic, or potential future lulls, are likely to result in larger influenza epidemics in subsequent years

The usability of interacting with the virtual and the real in COMRIS

COMRIS (Cohabited Mixed Reality Information spaces) is a research project that aims to create a wearable assistant that provides contex-sensitive information about interesting persons and events to conference and workshop Visitors. Virtual and augmented reality applications generally require users to switch from one reality to another or to emerge themselves into a heavyweight VR environment. In Comris the two worlds are intimately linked and extended into each other without the need to switch or emerge. In the physical world, the most tangible part of the Comris system is a small wearable and personal device the parrot that speaks in the user's ear and provides a few buttons to fine-tune messaging defaults to the circumstances and to respond to messages. The parrot also houses an active badge that keeps track of the whereabouts of its 'wearer' relative to beacons distributed around the conference premises. Conference visitors also have a number of information kiosks at their disposal to enter and adjust their interest profiles and to consult the conference schedule and their personal agenda. In the virtual world, agents represent and attempt to match the possible (events and persons) and the actual interests (from the interest profile) of the users. A process 'competition for attention' selects the interests on the basis of the user's context and guards the user from information overload. Interests are subsequently translated into natural language and presented to the user as spoken messages. After presenting an overview of Comris, this paper focuses on usability evaluation which deserves special attention because Cornris users remain engaged in their regular working and social relations while receiving assistance and distraction from the virtual world. The paper describes the general approach and the plans concerning usability evaluation in the Comris project and discusses the preliminary results from the first experiment