Remote monitoring of physiology in people living with dementia: an observational cohort study

BACKGROUND: Internet of Things (IoT) technology enables physiological measurements to be recorded at home from people living with dementia and monitored remotely. However, measurements from people with dementia in this context have not been previously studied. We report on the distribution of physiological measurements from 82 people with dementia over approximately 2 years. OBJECTIVE: Our objective was to characterize the physiology of people with dementia when measured in the context of their own homes. We also wanted to explore the possible use of an alerts-based system for detecting health deterioration and discuss the potential applications and limitations of this kind of system. METHODS: We performed a longitudinal community-based cohort study of people with dementia using "Minder," our IoT remote monitoring platform. All people with dementia received a blood pressure machine for systolic and diastolic blood pressure, a pulse oximeter measuring oxygen saturation and heart rate, body weight scales, and a thermometer, and were asked to use each device once a day at any time. Timings, distributions, and abnormalities in measurements were examined, including the rate of significant abnormalities ("alerts") defined by various standardized criteria. We used our own study criteria for alerts and compared them with the National Early Warning Score 2 criteria. RESULTS: A total of 82 people with dementia, with a mean age of 80.4 (SD 7.8) years, recorded 147,203 measurements over 958,000 participant-hours. The median percentage of days when any participant took any measurements (ie, any device) was 56.2% (IQR 33.2%-83.7%, range 2.3%-100%). Reassuringly, engagement of people with dementia with the system did not wane with time, reflected in there being no change in the weekly number of measurements with respect to time (1-sample t-test on slopes of linear fit, P=.45). A total of 45% of people with dementia met criteria for hypertension. People with dementia with α-synuclein-related dementia had lower systolic blood pressure; 30% had clinically significant weight loss. Depending on the criteria used, 3.03%-9.46% of measurements generated alerts, at 0.066-0.233 per day per person with dementia. We also report 4 case studies, highlighting the potential benefits and challenges of remote physiological monitoring in people with dementia. These include case studies of people with dementia developing acute infections and one of a person with dementia developing symptomatic bradycardia while taking donepezil. CONCLUSIONS: We present findings from a study of the physiology of people with dementia recorded remotely on a large scale. People with dementia and their carers showed acceptable compliance throughout, supporting the feasibility of the system. Our findings inform the development of technologies, care pathways, and policies for IoT-based remote monitoring. We show how IoT-based monitoring could improve the management of acute and chronic comorbidities in this clinically vulnerable group. Future randomized trials are required to establish if a system like this has measurable long-term benefits on health and quality of life outcomes

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines

Validation of the psychometric properties of the health-promoting lifestyle profile in a sample of Taiwanese women

PURPOSE: To examine the preliminary psychometric properties of the Chinese health-promoting lifestyle profile II (HPLP II) among Taiwanese women. METHODS: We conducted a secondary analysis of cross-sectional data from 137 middle-aged women in southern Taiwan. HPLP II reliability was estimated with Cronbach's alpha coefficient, and concurrent validity was estimated with Pearson's correlation between the HPLP II, the World Health Organization's abbreviated Quality of Life assessment (WHOQOL-BREF), perceived health, and demographic variables. Confirmatory factor analysis (CFA) evaluated construct validity. RESULTS: Initial CFA using a six-factor measurement model aligned with the original HPLP II, excepting the factor loading of one subsequently excluded item. CFA of the revised 51-item HPLP II yielded a good estimate of fit. Correlations between the revised instrument and the six subscales were acceptable >0.7. The Cronbach's alpha coefficient surpassed 0.7 for the revised instrument and six subscales ranged from 0.71 to 0.91. The relationships between the 51-item instrument, perceived health, WHOQOL-BREF domain scores, and demographic variables were also significantly positive. CONCLUSIONS: The revised HPLP II scale is appropriate to measure the health-promoting lifestyles of Taiwanese women.published_or_final_versionSpringer Open Choice, 21 Feb 201

TDP-43 Identified from a Genome Wide RNAi Screen for SOD1 Regulators

Amyotrophic Lateral Sclerosis (ALS) is a late-onset, progressive neurodegenerative disease affecting motor neurons in the brain stem and spinal cord leading to loss of voluntary muscular function and ultimately, death due to respiratory failure. A subset of ALS cases are familial and associated with mutations in superoxide dismutase 1 (SOD1) that destabilize the protein and predispose it to aggregation. In spite of the fact that sporadic and familial forms of ALS share many common patho-physiological features, the mechanistic relationship between SOD1-associated and sporadic forms of the disease if any, is not well understood. To better understand any molecular connections, a cell-based protein folding assay was employed to screen a whole genome RNAi library for genes that regulate levels of soluble SOD1. Statistically significant hits that modulate SOD1 levels, when analyzed by pathway analysis revealed a highly ranked network containing TAR DNA binging protein (TDP-43), a major component of aggregates characteristic of sporadic ALS. Biochemical experiments confirmed the action of TDP-43 on SOD1. These results highlight an unexpected relationship between TDP-43 and SOD1 which may have implications in disease pathogenesis

Interpretation of In Vitro Concentration-Response Data for Risk Assessment and Regulatory Decision-making: Report from the 2022 IWGT Quantitative Analysis Expert Working Group Meeting.

Quantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non-animal approaches can be human-relevant alternatives. There is an urgent need to build confidence in non-animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established. To address this issue, an Expert Working Group (EWG) of the 8th International Workshop on Genotoxicity Testing (IWGT) evaluated the utility of quantitative in vitro genotoxicity concentration-response data for risk assessment. The EWG first evaluated available in vitro methodologies and then examined the variability and maximal response of in vitro tests to estimate biologically relevant values for the critical effect sizes considered adverse or unacceptable. Next, the EWG reviewed the approaches and computational models employed to provide human-relevant dose context to in vitro data. Lastly, the EWG evaluated risk assessment applications for which in vitro data are ready for use and applications where further work is required. The EWG concluded that in vitro genotoxicity concentration-response data can be interpreted in a risk assessment context. However, prior to routine use in regulatory settings, further research will be required to address the remaining uncertainties and limitations. This article is protected by copyright. All rights reserved

Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α

<p>Abstract</p> <p>Background</p> <p>Hepatocyte nuclear factor 4α (HNF4α), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response. In order to obtain a genomic view of HNF4α in this context, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokine stimulation in a model of HNF4α knock-down in HepG2 cells.</p> <p>Results</p> <p>The expression of over five thousand genes in HepG2 cells is significantly changed with the dramatic reduction of HNF4α concentration compared to the cells with native levels of HNF4α. Over two thirds (71%) of genes that exhibit differential expression in response to cytokine treatment also reveal differential expression in response to HNF4α knock-down. In addition, we found that a number of HNF4α target genes may be indirectly mediated by an ETS-domain transcription factor ELK1, a nuclear target of mitogen-activated protein kinase (MAPK).</p> <p>Conclusion</p> <p>The results indicate that HNF4α has an extensive impact on the regulation of a large number of the liver-specific genes. HNF4α may play a role in regulating the cytokine-induced inflammatory response. This study presents a novel function for HNF4α, acting not only as a global player in many cellular processes, but also as one of the components of inflammatory response in the liver.</p

Two-Particle-Self-Consistent Approach for the Hubbard Model

Even at weak to intermediate coupling, the Hubbard model poses a formidable challenge. In two dimensions in particular, standard methods such as the Random Phase Approximation are no longer valid since they predict a finite temperature antiferromagnetic phase transition prohibited by the Mermin-Wagner theorem. The Two-Particle-Self-Consistent (TPSC) approach satisfies that theorem as well as particle conservation, the Pauli principle, the local moment and local charge sum rules. The self-energy formula does not assume a Migdal theorem. There is consistency between one- and two-particle quantities. Internal accuracy checks allow one to test the limits of validity of TPSC. Here I present a pedagogical review of TPSC along with a short summary of existing results and two case studies: a) the opening of a pseudogap in two dimensions when the correlation length is larger than the thermal de Broglie wavelength, and b) the conditions for the appearance of d-wave superconductivity in the two-dimensional Hubbard model.Comment: Chapter in "Theoretical methods for Strongly Correlated Systems", Edited by A. Avella and F. Mancini, Springer Verlag, (2011) 55 pages. Misprint in Eq.(23) corrected (thanks D. Bergeron

Usual Primary Care Provider Characteristics of a Patient-Centered Medical Home and Mental Health Service Use

BACKGROUND: The benefits of the patient-centered medical home (PCMH) over and above that of a usual source of medical care have yet to be determined, particularly for adults with mental health disorders. OBJECTIVE: To examine qualities of a usual provider that align with PCMH goals of access, comprehensiveness, and patient-centered care, and to determine whether PCMH qualities in a usual provider are associated with the use of mental health services (MHS). DESIGN: Using national data from the Medical Expenditure Panel Survey, we conducted a lagged cross-sectional study of MHS use subsequent to participant reports of psychological distress and usual provider and practice characteristics. PARTICIPANTS: A total of 2,358 adults, aged 18–64 years, met the criteria for serious psychological distress and reported on their usual provider and practice characteristics. MAIN MEASURES: We defined “usual provider” as a primary care provider/practice, and “PCMH provider” as a usual provider that delivered accessible, comprehensive, patient-centered care as determined by patient self-reporting. The dependent variable, MHS, included self-reported mental health visits to a primary care provider or mental health specialist, counseling, and psychiatric medication treatment over a period of 1 year. RESULTS: Participants with a usual provider were significantly more likely than those with no usual provider to have experienced a primary care mental health visit (marginal effect [ME] = 8.5, 95 % CI = 3.2–13.8) and to have received psychiatric medication (ME = 15.5, 95 % CI = 9.4–21.5). Participants with a PCMH were additionally more likely than those with no usual provider to visit a mental health specialist (ME = 7.6, 95 % CI = 0.7–14.4) and receive mental health counseling (ME = 8.5, 95 % CI = 1.5–15.6). Among those who reported having had any type of mental health visit, participants with a PCMH were more likely to have received mental health counseling than those with only a usual provider (ME = 10.0, 95 % CI = 1.0–19.0). CONCLUSIONS: Access to a usual provider is associated with increased receipt of needed MHS. Patients who have a usual provider with PCMH qualities are more likely to receive mental health counseling

Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation

Background: Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings: To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. Conclusion: The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines. This model may both facilitate understanding of the events involved in neuroinflammation and aid in the development of neuroprotective therapies for the treatment of MS and other neurodegenerative diseases

Transmembrane potential induced on the internal organelle by a time-varying magnetic field: a model study

<p>Abstract</p> <p>Background</p> <p>When a cell is exposed to a time-varying magnetic field, this leads to an induced voltage on the cytoplasmic membrane, as well as on the membranes of the internal organelles, such as mitochondria. These potential changes in the organelles could have a significant impact on their functionality. However, a quantitative analysis on the magnetically-induced membrane potential on the internal organelles has not been performed.</p> <p>Methods</p> <p>Using a two-shell model, we provided the first analytical solution for the transmembrane potential in the organelle membrane induced by a time-varying magnetic field. We then analyzed factors that impact on the polarization of the organelle, including the frequency of the magnetic field, the presence of the outer cytoplasmic membrane, and electrical and geometrical parameters of the cytoplasmic membrane and the organelle membrane.</p> <p>Results</p> <p>The amount of polarization in the organelle was less than its counterpart in the cytoplasmic membrane. This was largely due to the presence of the cell membrane, which "shielded" the internal organelle from excessive polarization by the field. Organelle polarization was largely dependent on the frequency of the magnetic field, and its polarization was not significant under the low frequency band used for transcranial magnetic stimulation (TMS). Both the properties of the cytoplasmic and the organelle membranes affect the polarization of the internal organelle in a frequency-dependent manner.</p> <p>Conclusions</p> <p>The work provided a theoretical framework and insights into factors affecting mitochondrial function under time-varying magnetic stimulation, and provided evidence that TMS does not affect normal mitochondrial functionality by altering its membrane potential.</p