Sensing Technology to Monitor Behavioral and Psychological Symptoms and to Assess Treatment Response in People With Dementia. A Systematic Review

Background: The prevalence of dementia is expected to rapidly increase in the next decades, warranting innovative solutions improving diagnostics, monitoring and resource utilization to facilitate smart housing and living in the nursing home. This systematic review presents a synthesis of research on sensing technology to assess behavioral and psychological symptoms and to monitor treatment response in people with dementia. Methods: The literature search included medical peer-reviewed English language publications indexed in Embase, Medline, Cochrane library and Web of Sciences, published up to the 5th of April 2019. Keywords included MESH terms and phrases synonymous with “dementia”, “sensor”, “patient”, “monitoring”, “behavior”, and “therapy”. Studies applying both cross sectional and prospective designs, either as randomized controlled trials, cohort studies, and case-control studies were included. The study was registered in PROSPERO 3rd of May 2019. Results: A total of 1,337 potential publications were identified in the search, of which 34 were included in this review after the systematic exclusion process. Studies were classified according to the type of technology used, as (1) wearable sensors, (2) non-wearable motion sensor technologies, and (3) assistive technologies/smart home technologies. Half of the studies investigated how temporarily dense data on motion can be utilized as a proxy for behavior, indicating high validity of using motion data to monitor behavior such as sleep disturbances, agitation and wandering. Further, up to half of the studies represented proof of concept, acceptability and/or feasibility testing. Overall, the technology was regarded as non-intrusive and well accepted. Conclusions: Targeted clinical application of specific technologies is poised to revolutionize precision care in dementia as these technologies may be used both by patients and caregivers, and at a systems level to provide safe and effective care. To highlight awareness of legal regulations, data risk assessment, and patient and public involvement, we propose a necessary framework for sustainable ethical innovation in healthcare technology. The success of this field will depend on interdisciplinary cooperation and the advance in sustainable ethic innovation.publishedVersio

Sensing Technology to Monitor Behavioral and Psychological Symptoms and to Assess Treatment Response in People With Dementia. A Systematic Review

Background: The prevalence of dementia is expected to rapidly increase in the next decades, warranting innovative solutions improving diagnostics, monitoring and resource utilization to facilitate smart housing and living in the nursing home. This systematic review presents a synthesis of research on sensing technology to assess behavioral and psychological symptoms and to monitor treatment response in people with dementia. Methods: The literature search included medical peer-reviewed English language publications indexed in Embase, Medline, Cochrane library and Web of Sciences, published up to the 5th of April 2019. Keywords included MESH terms and phrases synonymous with “dementia”, “sensor”, “patient”, “monitoring”, “behavior”, and “therapy”. Studies applying both cross sectional and prospective designs, either as randomized controlled trials, cohort studies, and case-control studies were included. The study was registered in PROSPERO 3rd of May 2019. Results: A total of 1,337 potential publications were identified in the search, of which 34 were included in this review after the systematic exclusion process. Studies were classified according to the type of technology used, as (1) wearable sensors, (2) non-wearable motion sensor technologies, and (3) assistive technologies/smart home technologies. Half of the studies investigated how temporarily dense data on motion can be utilized as a proxy for behavior, indicating high validity of using motion data to monitor behavior such as sleep disturbances, agitation and wandering. Further, up to half of the studies represented proof of concept, acceptability and/or feasibility testing. Overall, the technology was regarded as non-intrusive and well accepted. Conclusions: Targeted clinical application of specific technologies is poised to revolutionize precision care in dementia as these technologies may be used both by patients and caregivers, and at a systems level to provide safe and effective care. To highlight awareness of legal regulations, data risk assessment, and patient and public involvement, we propose a necessary framework for sustainable ethical innovation in healthcare technology. The success of this field will depend on interdisciplinary cooperation and the advance in sustainable ethic innovation

Measuring coverage and quality of supportive care for inpatient neonatal infections: EN-BIRTH multi-country validation study.

Background: An estimated 7 million episodes of severe newborn infections occur annually worldwide, with half a million newborn deaths, most occurring in low- and middle-income countries. Whilst injectable antibiotics are necessary to treat the infection, supportive care is also crucial in ending preventable mortality and morbidity. This study uses multi-country data to assess gaps in coverage, quality, and documentation of supportive care, considering implications for measurement. Methods: The EN-BIRTH study was conducted in five hospitals in Bangladesh, Nepal, and Tanzania (July 2017-July 2018). Newborns with an admission diagnosis of clinically-defined infection (sepsis, meningitis, and/or pneumonia) were included. Researchers extracted data from inpatient case notes and interviews with women (usually the mothers) as the primary family caretakers after discharge. The interviews were conducted using a structured survey questionnaire. We used descriptive statistics to report coverage of newborn supportive care components such as oxygen use, phototherapy, and appropriate feeding, and we assessed the validity of measurement through survey-reports using a random-effects model to generate pooled estimates. In this study, key supportive care components were assessment and correction of hypoxaemia, hyperbilirubinemia, and hypoglycaemia. Results: Among 1015 neonates who met the inclusion criteria, 89% had an admission clinical diagnosis of sepsis. Major gaps in documentation and care practices related to supportive care varied substantially across the participating hospitals. The pooled sensitivity was low for the survey-reported oxygen use (47%; 95% confidence interval (CI) = 30%-64%) and moderate for phototherapy (60%; 95% CI = 44%-75%). The pooled specificity was high for both the survey-reported oxygen use (85%; 95% CI = 80%-89%) and phototherapy (91%; 95% CI = 82%-97%). Conclusions: The women's reports during the exit survey consistently underestimated the coverage of supportive care components for managing infection. We have observed high variability in the inpatient documents across facilities. A standardised ward register for inpatient small and sick newborn care may capture selected supportive care data. However, tracking the detailed care will require standardised individual-level data sets linked to newborn case notes. We recommend investments in assessing the implementation aspects of a standardised inpatient register in resource-poor settings

Genotypic and functional impact of HIV-1 adaptation to its host population during the North American epidemic.

HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a "consensus-like" founder virus, the median "background" frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were ∼ 2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e.g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were "pre-adapted" to the average host HLA profile was only ∼ 2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins

Genotypic and Functional Impact of HIV-1 Adaptation to Its Host Population during the North American Epidemic

HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979–1989) and 382 modern (2000–2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a “consensus-like” founder virus, the median “background” frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were ~2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e.g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were “pre-adapted” to the average host HLA profile was only ~2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins

Reconstructed ancestral sequences at the root of the inferred Gag and Nef phylogenies, representing the estimated most recent common ancestor (MRCA) of the North American epidemic.

<p>A minimum of ≥50,000 reconstructions of the ancestral sequence at the root of the Gag and Nef phylogenies were performed, and the inferred MRCA was computed as the “grand consensus” of these replicate reconstructions. For each codon, reconstruction confidence (computed as the frequency of each amino acid observed across all reconstructions) is indicated on the y-axis on a scale from 0 (0%) to 1 (100%). Blue letters represent the highest-confidence residue at each position; green letters represent lower-confidence residues. All amino acids observed at >0.01 (>1%) reconstruction frequency are shown. Yellow boxes highlight positions where the highest-confidence (blue) inferred ancestral residue differs from the North American consensus B sequence (displayed in <b><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004295#pgen.1004295.s003" target="_blank">Figure S3</a></b>).</p

Functional implications of Nef diversification during the North American Epidemic.

<p><b>Panel A:</b> Unrooted Maximum-Likelihood phylogenies, drawn on the same distance scale, depicting the inferred ancestor (single black dot), early-historic (red, 1979–1982), mid-historic (green, 1983–1985), late-historic (blue, 1986–1989) and modern (purple: chronic-phase, orange: acute-phase, year 2000+) Nef clonal sequences from unique patients cloned into a GFP-expression vector for functional assessment. <b>Panel B:</b> CD4 downregulation activities of the inferred ancestral Nef sequence (mean±S.E.M. of 8 replicate measurements) and patient-derived Nef clones from various eras (one per patient, representing the mean of triplicate measurements). CD4 downregulation values are normalized to that of HIV subtype B control Nef strain SF2, such that a value of 1 indicates CD4 downregulation activity equal to that of SF2 while values>1 and <1 indicate activities higher or lower than SF2 respectively. Modern Nefs exhibited significantly higher CD4 downregulation activity compared to historic Nefs (Kruskal-Wallis p<0.0001). <b>Panel C:</b> SF2-normalized HLA class I downregulation activities of inferred ancestral (mean±S.E.M. of 8 replicate measurements) and patient-derived Nef sequences (one per patient, mean of triplicate measurements). Modern Nefs exhibited significantly higher HLA downregulation activity compared to historic Nefs (Kruskal-Wallis p<0.0001).</p

Gag residues exhibiting significant diversification over time are biased towards known HLA-associated sites.

<p><b>Panel A:</b> Differences in Shannon entropy (Δentropy) between modern and historic sequences are shown for every Gag codon. Positive y-values indicate higher entropy in modern vs. historic sequences at that codon; negative y-values indicate the opposite. Red bars indicate significant entropy differences (defined as p<0.001, q<0.01); blue colors indicate differences that do not reach this significance threshold. Grey dots designate known HIV sites under selection by HLA (as defined in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004295#pgen.1004295-Carlson1" target="_blank">[43]</a>). Green dots designate sites that display significant evidence of pervasive positive selection (dN/dS>1; posterior probability >0.9). <b>Panel B:</b> Same as panel A, but sorted by decreasing Δentropy rather than codon order. <b>Panel C:</b> Graphical depiction of a 2×2 contingency table stratifying variable (<99% conserved) Gag codons based on their status as HLA-associated (yes vs. no), and whether they exhibited significant Δentropy between modern and historic datasets (p<0.001 [red] vs. not [blue]). Ns are indicated above each bar. <b>Panel D:</b> Graphical depiction of a 2×2 contingency table stratifying variable (<99% conserved) Gag codons based on their status as HLA-associated (yes vs. no) and evidence that they are under significant pervasive positive selection (dN/dS>1; posterior probability >0.9 [green] vs. not [black]). Ns are indicated above each bar.</p

Replicative implications of Gag diversification during the North American Epidemic.

<p><b>Panel A:</b> Unrooted Maximum-Likelihood phylogenies, drawn on the same distance scale, depicting the inferred ancestor (single black dot), early-historic (red, 1979–1982), mid-historic (green, 1983–1985), late-historic (blue, 1986–1989) and modern (purple, 2000+) Gag clonal sequences from unique patients that were used to construct recombinant NL4-3 viruses for functional assessment. <b>Panel B:</b> NL4-3 normalized replication capacities of recombinant viruses containing the Gag sequence of the inferred ancestral sequence (Mean±S.E.M. of 3 replicate measurements) as well as patient-derived Gag clonal sequences (one per patient, representing the mean of ≥2 replicate measurements). An RC of 1 indicates replication equal to that of NL4-3 while RC>1 and <1 indicate RC higher or lower than NL4-3 respectively. Although visually there appears a trend towards lower replication capacity among Gag clones from early historic (1979–1982) era, there no significant differences in RC between any of the groups (Kruskal-Wallis test, p = 0.6).</p