Regulation of inositol 5-phosphatase activity by the C2 domain of SHIP1 and SHIP2.

SHIP1, an inositol 5-phosphatase, plays a central role in cellular signaling. As such, it has been implicated in many conditions. Exploiting SHIP1 as a drug target will require structural knowledge and the design of selective small molecules. We have determined apo, and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. The C2 domains of SHIP1 and the related SHIP2 modulate the activity of the phosphatase domain. To understand the mechanism, we performed activity assays, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics on SHIP1 and SHIP2. Our findings demonstrate that the influence of the C2 domain is more pronounced for SHIP2 than SHIP1. We determined 91 structures of SHIP1 with fragments bound, with some near the interface between the two domains. We performed a mass spectrometry screen and determined four structures with covalent fragments. These structures could act as starting points for the development of potent, selective probes.

Comprehensive analysis and assessment of exposure to enteric viruses and bacteria in shellfish.

Shellfish species, including oysters, clams, and mussels, are extensively cultured in coastal waters. Its location is determined by factors such as nutrient availability, water temperature, tidal cycle, and the presence of contaminants such as Escherichia coli and enteric viruses. With the expansion and intensification of human activities at vicinities, the presence of anthropogenic contaminants has increased, threatening shellfish farms and consumer safety give the prevalent consumption of raw shellfish. This literature review aims to provide a comprehensive analysis of the dietary exposure and assess the risk associated with enteric viruses and bacteria detected in shellfish. The predominant bacteria and viruses detected in shellfish are reported, and the potential interrelation is discussed. The main characteristics of each contaminant and shellfish were reviewed for a more comprehensive understanding. To facilitate a direct estimation of exposure, the estimated daily intake (EDI) of bacteria was calculated based on the average levels of E. coli in shellfish, as reported in the literature. The mean daily ingestion of seafood in each of the five continents was considered. Asia exhibited the highest intake of contaminants, with an average of ±5.6 E. coli units/day.kg body weight in cockles. Simulations were conducted using recommended shellfish consumption levels established by state agencies, revealing significantly lower (p < 0.01) EDI for all continents compared to estimations based on recommended levels. This indicates a higher risk associated with healthy shellfish ingestion, potentially leading to increased intoxication incidents with a change in dietary habits. To promote a healthier lifestyle through increased shellfish consumptions, it is imperative to reduce the exposure of shellfish species to bacteria and enteric viruses. The conventional use of E. coli as the sole indicator for consumption safety and water quality in shellfish farms has been deemed insufficient. Instances where shellfish met E. coli limits established by state agencies were often found to be contaminated with human enteric viruses. Therefore, a holistic approach considering the entire production chain is necessary to support the shellfish industry and ensure food safety.

Simplified Synthesis of an Air-Stable Copper-Complexed Josiphos Ligand via Ugi's Amine: Complete Preparation and Analysis from Ferrocene.

Ligands containing ferrocene backbones often feature both planar chirality and asymmetric centers, making them attractive options for asymmetric catalysis. Ugi's amine is a ubiquitous ferrocene-based chiral building block that can be functionalized to form a variety of tunable Josiphos ligands; however, few sources lay out the route from start to finish. Starting from ferrocene, we compile a synthetic route to an air- and moisture-stable copper(I)-Josiphos complex via enantiopure Ugi's amine, providing a potential one-stop shop for the synthesis of a wide range of Josiphos ligands.

Inclusion4EU: Co-Designing a Framework for Inclusive Software Design and Development.

Digital technology is now pervasive, however, not all groups have uniformly benefitted from technological changes and some groups have been left behind or digitally excluded. Comprehensive data from the 2017 Current Population Survey shows that older people and persons with disabilities still lag behind in computer and internet access. Furthermore unique ethical, privacy and safety implications exist for the use of technology for older persons and people with disabilities and careful reflection is required to incorporate these aspects, which are not always part of a traditional software lifecycle. In this paper we present the Inclusion4EU project that aims to co-design a new framework, guidelines and checklists for inclusive software design and development with end-users from excluded categories, academics with expertise in human-computer interaction and industry practitioners from software engineering.

Sustainable production and pharmaceutical applications of ß-glucan from microbial sources.

ß-glucans are a large class of complex polysaccharides found in abundant sources. Our dietary sources of ß-glucans are cereals that include oats and barley, and non-cereal sources can consist of mushrooms, microalgae, bacteria, and seaweeds. There is substantial clinical interest in ß-glucans; as they can be used for a variety of diseases including cancer and cardiovascular conditions. Suitable sources of ß-glucans for biopharmaceutical applications include bacteria, microalgae, mycelium, and yeast. Environmental factors including culture medium can influence the biomass and ultimately ß-glucan content. Therefore, cultivation conditions for the above organisms can be controlled for sustainable enhanced production of ß-glucans. This review discusses the various sources of ß-glucans and their cultivation conditions that may be optimised to exploit sustainable production. Finally, this article discusses the immune-modulatory potential of ß-glucans from these sources.

Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides.

Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson's Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide-containing compound, USP30inh. Activity-based protein profiling mass spectrometry confirmed target engagement, high selectivity, and potency of USP30inh for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. In vitro characterization of USP30inh enzyme kinetics inferred slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen-deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with USP30inh, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that USP30inh binds to this thumb-palm cleft, which guides the ubiquitin C terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.

Polysaccharides-Naturally Occurring Immune Modulators.

The prevention of disease and infection requires immune systems that operate effectively. This is accomplished by the elimination of infections and abnormal cells. Immune or biological therapy treats disease by either stimulating or inhibiting the immune system, dependent upon the circumstances. In plants, animals, and microbes, polysaccharides are abundant biomacromolecules. Due to the intricacy of their structure, polysaccharides may interact with and impact the immune response; hence, they play a crucial role in the treatment of several human illnesses. There is an urgent need for the identification of natural biomolecules that may prevent infection and treat chronic disease. This article addresses some of the naturally occurring polysaccharides of known therapeutic potential that have already been identified. This article also discusses extraction methods and immunological modulatory capabilities.

Predictive Coding and Internal Error Correction in Speech Production.

Speech production involves the careful orchestration of sophisticated systems, yet overt speech errors rarely occur under naturalistic conditions. The present functional magnetic resonance imaging study sought neural evidence for internal error detection and correction by leveraging a tongue twister paradigm that induces the potential for speech errors while excluding any overt errors from analysis. Previous work using the same paradigm in the context of silently articulated and imagined speech production tasks has demonstrated forward predictive signals in auditory cortex during speech and presented suggestive evidence of internal error correction in left posterior middle temporal gyrus (pMTG) on the basis that this area tended toward showing a stronger response when potential speech errors are biased toward nonwords compared to words (Okada et al., 2018). The present study built on this prior work by attempting to replicate the forward prediction and lexicality effects in nearly twice as many participants but introduced novel stimuli designed to further tax internal error correction and detection mechanisms by biasing speech errors toward taboo words. The forward prediction effect was replicated. While no evidence was found for a significant difference in brain response as a function of lexical status of the potential speech error, biasing potential errors toward taboo words elicited significantly greater response in left pMTG than biasing errors toward (neutral) words. Other brain areas showed preferential response for taboo words as well but responded below baseline and were less likely to reflect language processing as indicated by a decoding analysis, implicating left pMTG in internal error correction.

Pulsed ultraviolet (PUV) disinfection of artificially contaminated seawater seeded with high levels of pathogen disease indicators as an alternative for the shellfish industry depuration systems.

The increase in pathogen levels in seawater threatens the safety of entire aquatic ecosystems. Foodborne pathogens can potentially accumulate in shellfish, especially in filter feeders such as bivalves, requiring an efficient depuration process before consumption. Alternative approaches to promote a cost-efficient purge at depuration plants are urgently needed. A small prototype pulsed ultraviolet (PUV) light recirculation system was designed, and its depuration potential was tested in a seawater matrix artificially contaminated with high levels of microbial pathogens Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Bacillus cereus and Candida albicans. The analysis of treatment parameters including voltage, number of pulses and duration of treatment was performed to ensure the highest reduction in contaminant levels. Optimal PUV disinfection was attained at 60 pulses/min at 1 kV for 10 min (a UV output of 12.9 J/cm2). All reductions were statistically significant, and the greatest was observed for S. aureus (5.63 log10), followed by C. albicans (5.15 log10), S. typhimurium (5 log10), B. cereus (4.59 log10) and E. coli (4.55 log10). PUV treatment disrupted the pathogen DNA with the result that S. aureus, C. albicans and S. typhimurium were not detectable by PCR. Regulations were reviewed to address the applicability of PUV treatment as a promising alternative to assist in the reduction of microbial pathogens at depuration plants due to its high efficiency, short treatment period, high UV dose and recirculation system as currently employed in shellfish depuration plants.

Treatment with levosimendan in an experimental model of early ventilator-induced diaphragmatic dysfunction.

Introduction: Mechanical ventilation (MV) is a life-saving approach in critically ill patients. However, it may affect the diaphragmatic structure and function, beyond the lungs. Levosimendan is a calcium sensitizer widely used in clinics to improve cardiac contractility in acute heart failure patients. In vitro studies have demonstrated that levosimendan increased force-generating capacity of the diaphragm in chronic obstructive pulmonary disease patients. Thus the aim of this study was to evaluate the effects of levosimendan administration in an animal model of ventilator-induced diaphragmatic dysfunction (VIDD) on muscle contraction and diaphragm muscle cell viability. Methods: Sprague-Dawley rats underwent prolonged MV (5 hours). VIDD+Levo group received a starting bolus of levosimendan immediately after intratracheal intubation and then an intravenous infusion of levosimendan throughout the study. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis and Western blot analysis. Healthy rats were used as the control. Results: Levosimendan treatment maintained an adequate mean arterial pressure during the entire experimental protocol, preserved levels of autophagy-related proteins (LC3BI and LC3BII) and the muscular cell diameter demonstrated by histological analysis. Levosimendan did not affect the diaphragmatic contraction or the levels of proteins involved in the protein degradation (atrogin). Conclusions: Our data suggest that levosimendan preserves muscular cell structure (cross-sectional area) and muscle autophagy after 5 hours of MV in a rat model of VIDD. However, levosimendan did not improve diaphragm contractile efficiency.

Soil-transmitted helminth surveillance in Benin: A mixed-methods analysis of factors influencing non-participation in longitudinal surveillance activities.

BACKGROUND: Despite the significant success of deworming programs in reducing morbidity due to soil-transmitted helminth (STH) infections globally, efforts to achieve elimination of STH as a public health problem or to potentially interrupt transmission will require improving and intensifying surveillance. However, non-participation in surveillance threatens the ability of programs to adequately monitor program status and limited research has been conducted to investigate drivers of non-participation in stool-based surveillance. METHODOLOGY/PRINCIPAL FINDINGS: This mixed-methods exploratory sequential study took place in Comé, Benin in association with the DeWorm3 Project. Six focus group discussions were conducted with individuals invited to participate in annual DeWorm3 stool surveillance. Thematic analysis was used to identify facilitators and barriers to participation and inform the quantitative analysis. A mixed-effects logistic regression model was built using baseline DeWorm3 survey data to identify factors associated with non-participation. Qualitative and quantitative findings were merged for interpretation. Among the 7,039 individuals invited to participate in baseline stool surveillance, the refusal rate was 8.1%. Qualitative themes included: community members weighing community-level benefits against individual-level risks, circulating rumors about misuse of stool samples, interpersonal communication with field agents, and cultural norms around handling adult feces. The quantitative analysis demonstrated that adults were significantly less likely to provide a stool sample than school-aged children (OR:0.69, 95%CI: 0.55-0.88), a finding that converged with the qualitative results. Individuals from areas in the highest quartile of population density were more likely to refuse to participate (OR:1.71, 95%CI:1.16-2.52). Several variables linked to community-affinity aligned with qualitative results; residing mainly in the community (OR:0.36, 95%CI:0.20-0.66) and having lived in the community for more than 10 years (OR:0.82, 95%CI:0.54-1.25) decreased likelihood of refusal. CONCLUSIONS/SIGNIFICANCE: Optimizing STH surveillance will require that programs reimagine STH surveillance activities to address community concerns and ensure that no subpopulations are inadvertently excluded from surveillance data.

The role of phone-based triage nurses in supporting older adults with multimorbidity to digitally self-manage - Findings from the ProACT proof-of-concept study.

Background: Achieving patient-centred care necessitates supporting individuals to have more involvement in the self-management of their care. Digital health technologies are widely recognised as a solution to empower more effective self-management. However, given the complexity of multiple chronic condition (multimorbidity) management, coupled with changes that occur as part of the normal ageing process, human support alongside digital self-management is often necessary for older people with multimorbidity (PwM) to sustain successful self-management. Methods: The aim of the study was to explore the role played by a clinical, nurse-led telephone triage service in responding to alerts generated by older adults using a digital health platform, ProACT, to self-manage multiple chronic conditions over a period of 1 year. Semi-structured interviews with participants with multimorbidity were carried out across four time points during the trial, while interviews and focus groups were conducted with triage nurses at the end of the trial. Thematic analysis was conducted on the resulting transcripts. Results: Themes found in the data include the work of triage nurses; the benefits of triage support; tensions such as anxiety due to patient monitoring; and the relationship between triage nurses and participants. Discussion: This work contributes to an understanding of how older adults with multimorbidity and triage nurses collaborate in multiple chronic disease self-management. Findings are discussed within the context of Hudon et al.'s patient-centred care framework and indicate that patient-centred care was achieved, with both PwM and triage participants reporting positive experiences, relationships and several benefits of the triage support alongside digital self-management.

Women Trust Their OBGYNs to Provide Preexposure Prophylaxis: An Opportunity for HIV Prevention.

Objective: The objective of this study was to understand how women perceive the role of their Obstetrician and Gynecologist (OBGYN) in screening for and providing preexposure prophylaxis (PrEP) for HIV prevention. Methods: We recruited women ages 18-45 years receiving obstetric or gynecological care at an academic medical center in the Bronx, NY. Thirty participants were enrolled: 10 seeking care for family planning, 10 seeking prenatal care, and 10 seeking care for a sexually transmitted infection. We screened participants for HIV acquisition risk using a PrEP screening tool. We conducted face-to-face, semi-structured interviews, which were audio-recorded, transcribed, and entered into Dedoose for analysis of themes using a grounded theory approach. Results: Sixty percent of the participants were Latinx and 33% African American. Seventy percent had one or more risk factors for HIV acquisition based on the PrEP screening tool, indicating they would benefit from a PrEP discussion. Three main themes emerged from the analysis of interview data. Participants viewed OBGYNs as experts in sexual and reproductive healthcare and believed they were experts in PrEP. Participants were concerned about "PrEP stigma", being judged by their clinicians as being sexually promiscuous if they expressed a need for PrEP. Lastly, when participants trusted their OBGYN, that trust became a facilitator for women to consider PrEP and offset stigma as a barrier to identifying patients who are candidates for PrEP. Conclusion: Women established in care with an OBGYN are enthusiastic about having access to PrEP services incorporated into their sexual and reproductive healthcare. A universal approach to HIV prevention would avert stigma surrounding HIV care and prevention.

Use of next generation sequencing and bioinformatics for profiling freshwater eukaryotic microalgae in a novel peatland integrated multi-trophic aquaculture (IMTA) system: Case study from the Republic of Ireland.

Development of integrated multi-trophic aquaculture (IMTA) systems constitutes a step change in the sustainable production of freshwater fish to meet emerging needs for high-protein foods globally. Recently, there has been a paradigm shift away from harvesting peat as a fuel towards the development of wettable peatland innovation (termed 'paludiculture'), such as aquaculture. Such eco-innovations support carbon sequestration and align with a balanced environmental approach to protecting biodiversity. This novel peatland-based IMTA process in the Irish midlands relies upon natural microalgae for waste treatment, recirculation and water quality where there is no use of pesticides or antibiotics. This novel IMTA system is powered with a wind turbine and the process has 'organic status'; moreover, it does not discharge aquaculture effluent to receiving water. However, there is a significant lack of understanding as to diversity of microalgae in this 'paludiculture'-based IMTA processes. This constitutes the first case study to use conventional microscopy combined with next-generation sequencing and bioinformatics to profile microalgae occurring in this novel IMTA system from pooled samples over a 12 month period in 2020. Conventional microscopy combined with classic identification revealed twenty genera of algae; with Chlorophyta and Charophyta being the most common present. However, algal DNA isolation, 16 s sequencing and bioinformatics revealed a combined total of 982 species from 341 genera across nine phyla from the same IMTA system, which emphasized a significant underestimation in the number and diversity of beneficial or potentially harmful algae in the IMTA-microbiome. These new methods also yield rich data that can be used by digital technologies to transform future monitoring and performance of the IMTA system for sustainability. The findings of this study align with many sustainability development goals of the United Nations including no poverty, zero hunger, good health and well-being, responsible consumption and production, climate change, and life below water.

Hyaluronic Acid: A Review of the Drug Delivery Capabilities of This Naturally Occurring Polysaccharide.

The inclusion of physiologically active molecules into a naturally occurring polymer matrix can improve the degradation, absorption, and release profile of the drug, thus boosting the therapeutic impact and potentially even reducing the frequency of administration. The human body produces significant amounts of polysaccharide hyaluronic acid, which boasts exceptional biocompatibility, biodegradability, and one-of-a-kind physicochemical features. In this review, we will examine the clinical trials currently utilizing hyaluronic acid and address the bright future of this versatile polymer, as well as summarize the numerous applications of hyaluronic acid in drug delivery and immunomodulation.

"Being able to do whatever you wanna do as a woman is important:" a qualitative exploration of contraception as a frame of reference for HIV prevention with PrEP.

BACKGROUND: Use of HIV PrEP (pre-exposure prophylaxis) is a strategic tool in the effort to end the HIV epidemic. 20% of new HIV infections in the US are among cis-gender women, yet they comprise only 5% of all PrEP users. Black women disproportionately bear the burden of new HIV acquisition and accounted for almost 60% of new HIV diagnoses among women in 2018. Increasing understanding and uptake of PrEP among women at risk of HIV acquisition in alignment with their reproductive values and preferences is key to increasing PrEP uptake and decreasing HIV burden in this population. OBJECTIVE: This study examines how experiences with contraception among women of color shape their perceptions and preferences regarding HIV PrEP to inform counseling that aligns with their reproductive values. METHODS: Women aged 18-45 who self-identified as Black or Latina were recruited at an academic medical center in the Bronx from June 2018 to July 2019. We enrolled 30 participants seeking family planning care (10), prenatal care (10), or care for sexually transmitted infections (10). Participants completed a brief written survey assessing their risk of HIV acquisition. Semi-structured, face-to-face interviews were then audio-recorded, transcribed, and entered into Dedoose. Grounded theory and constant comparison approaches were used to analyze the data. RESULTS: Twenty-one participants (70%) screened positive for HIV acquisition risk. Four had received information on PrEP from a medical provider prior to the interview. Three themes emerged from the qualitative analysis: (1) Similar to oral contraception, women conceptualized PrEP as a "daily pill" to support their reproductive health; (2) Women perceived PrEP as a tool to support autonomy and pleasure in their sexual health; (3) Like birth control, women desired multiple delivery options for HIV prophylaxis. CONCLUSIONS: Contraception may serve as a frame of reference when counseling about PrEP among cis-women at risk of acquiring HIV. Our study suggests that this approach re-contextualizes counseling on PrEP within a sex-positive framework that prioritizes pleasure, safety, and autonomy as integral to sexual and reproductive wellness. Consideration of historically marginalized women's experiences with contraception and reproductive values may facilitate their use of PrEP.

PrEP (pre-exposure prophylaxis) is a medicine taken daily by people at risk of getting HIV from sex or injection drug use. Although PrEP is a safe and effective medication for women, the use of PrEP remains exceedingly low among cis-gender women at risk of HIV in the US. This study examines how experiences with contraception among women of color, who disproportionately bear the burden of HIV acquisition, shape their perceptions and preferences regarding PrEP. We interviewed 30 women who self-identified as Black or Latina at an academic medical center in the Bronx. Similar to oral contraception, women in this study conceptualized PrEP as a "daily pill" to support their reproductive health. This report details how women's experiences with contraception may serve as the foundation to re-contextualize conversations on PrEP within a sex-positive framework that prioritizes pleasure, safety, and autonomy as integral to sexual and reproductive wellness.

Immunomodulatory activity of ß-glucan polysaccharides isolated from different species of mushroom - A potential treatment for inflammatory lung conditions.

Acute respiratory distress syndrome (ARDS) is the most common form of acute severe hypoxemic respiratory failure in the critically ill with a hospital mortality of 40%. Alveolar inflammation is one of the hallmarks for this disease. ß-Glucans are polysaccharides isolated from a variety of natural sources including mushrooms, with documented immune modulating properties. To investigate the immunomodulatory activity of ß-glucans and their potential as a treatment for ARDS, we isolated and measured glucan-rich polysaccharides from seven species of mushrooms. We used three models of in-vitro injury in THP-1 macrophages, Peripheral blood mononuclear cells (CD14+) (PMBCs) isolated from healthy volunteers and lung epithelial cell lines. We observed variance between ß-glucan content in extracts isolated from seven mushroom species. The extracts with the highest ß-glucan content found was Lentinus edodes which contained 70% w/w and Hypsizygus tessellatus which contained 80% w/w with low levels of α-glucan. The extracts had the ability to induce secretion of up to 4000 pg/mL of the inflammatory cytokine IL-6, and up to 5000 pg/mL and 500 pg/mL of the anti-inflammatory cytokines IL-22 and IL-10, respectively, at a concentration of 1 mg/mL in THP-1 macrophages. In the presence of cytokine injury, IL-8 was reduced from 15,000 pg/mL to as low as 10,000 pg/mL in THP-1 macrophages. After insult with LPS, phagocytosis dropped from 70-90% to as low 10% in CD14+ PBMCs. After LPS insult CCL8 relative gene expression was reduced, and IL-10 relative gene expression increased from 50 to 250-fold in THP-1 macrophages. In lung epithelial cells, both A549 and BEAS-2B after IL-1ß insult, IL-8 levels dropped from 10,000 pg/mL to as low as 6000 pg/mL. TNF-α levels dropped 10-fold from 100 pg/mL to just below 10 pg/mL. These results demonstrate the therapeutic potential of ß-glucans in inflammatory lung conditions. Findings also advance bio-based research that connects green innovation with One Health applications for the betterment of society.

A Digital Platform to Support Self-management of Multiple Chronic Conditions (ProACT): Findings in Relation to Engagement During a One-Year Proof-of-Concept Trial.

BACKGROUND: Populations globally are ageing, resulting in higher incidence rates of chronic diseases. Digital health platforms, designed to support those with chronic conditions to self-manage at home, offer a promising solution to help people monitor their conditions and lifestyle, maintain good health, and reduce unscheduled clinical visits. However, despite high prevalence rates of multimorbidity or multiple chronic conditions, most platforms tend to focus on a single disease. A further challenge is that despite the importance of users actively engaging with such systems, little research has explored engagement. OBJECTIVE: The objectives of this study are to design and develop a digital health platform, ProACT, for facilitating older adults self-managing multimorbidity, with support from their care network, and evaluate end user engagement and experiences with this platform through a 12-month trial. METHODS: The ProACT digital health platform is presented in this paper. The platform was evaluated in a year-long proof-of-concept action research trial with 120 older persons with multimorbidity in Ireland and Belgium. Alongside the technology, participants had access to a clinical triage service responding to symptom alerts and a technical helpdesk. Interactions with the platform during the trial were logged to determine engagement. Semistructured interviews were conducted with participants and analyzed using inductive thematic analysis, whereas usability and user burden were examined using validated questionnaires. RESULTS: This paper presents the ProACT platform and its components, along with findings on engagement with the platform and its usability. Of the 120 participants who participated, 24 (20%) withdrew before the end of the study, whereas 3 (2.5%) died. The remaining 93 participants actively used the platform until the end of the trial, on average, taking 2 or 3 health readings daily over the course of the trial in Ireland and Belgium, respectively. The participants reported ProACT to be usable and of low burden. Findings from interviews revealed that participants experienced multiple benefits as a result of using ProACT, including improved self-management, health, and well-being and support from the triage service. For those who withdrew, barriers to engagement were poor health and frustration when technology, in particular sensing devices, did not work as expected. CONCLUSIONS: This is the first study to present findings from a longitudinal study of older adults using digital health technology to self-manage multimorbidity. Our findings show that older adults sustained engagement with the technology and found it usable. Potential reasons for these results include a strong focus on user-centered design and engagement throughout the project lifecycle, resulting in a platform that meets user needs, as well as the integration of behavior change techniques and personal analytics into the platform. The provision of triage and technical support services alongside the platform during the trial were also important facilitators of engagement. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/22125.

A Digital Health Platform for Integrated and Proactive Patient-Centered Multimorbidity Self-management and Care (ProACT): Protocol for an Action Research Proof-of-Concept Trial.

BACKGROUND: Multimorbidity is defined as the presence of two or more chronic diseases and associated comorbidities. There is a need to improve best practices around the provision of well-coordinated, person-centered care for persons with multimorbidities. Present health systems across the European Union (EU) focus on supporting a single-disease framework of care; the primary challenge is to create a patient-centric, integrated care ecosystem to understand and manage multimorbidity. ProACT is a large-scale project funded by the European Commission under the Horizon 2020 programme, that involved the design, development, and evaluation of a digital health platform to improve and advance home-based integrated care, and supported self-management, for older adults (aged ≥65 years) living with multimorbidity. OBJECTIVE: This paper describes the trial implementation protocol of a proof-of-concept digital health platform (ProACT) in 2 EU member states (Ireland and Belgium) to support older persons with multimorbidities self-managing at home, supported by their care network (CN). METHODS: Research was conducted across 2 EU member states, Ireland and Belgium. A 12-month action research trial design, divided into 3 evaluation cycles and lasting 3 months each, with a reflective redesign and development phase of 1 month after cycles 1 and 2 was conducted. Participants were 120 (60/120, 50% in Ireland and 60/120, 50% in Belgium) older persons with multimorbidities diagnosed with two or more of the following chronic conditions: diabetes, chronic obstructive pulmonary disease, chronic heart failure, and cardiovascular diseases. With permission from persons with multimorbidities, members of their CN were invited to participate in the study. Persons with multimorbidities were provided with ProACT technologies (tablet, devices, or sensors) to support them in self-managing their conditions. CN members also received access to an app to remotely support their persons with multimorbidity. Qualitative and quantitative feedback and evaluation data from persons with multimorbidity and CN participants were collected across four time points: baseline (T1), at the end of each 3-month action research cycle (T2 and T3), and in a final posttrial interview (T4). Thematic analysis was used to analyze the qualitative interview data. Quantitative data were analyzed via platform use statistics (to assess engagement) and standardized questionnaires (using descriptive and inferential statistics). This study is approved by the ethics committees of Ireland and Belgium. RESULTS: The trial implementation phase for this 44-month (2016-2019) funded study was April 2018 to June 2019. The trial outcomes are at various stages of publication since 2021. CONCLUSIONS: ProACT aims to co-design and develop a digital intervention with persons with multimorbidities and their CN, incorporating clinical guidelines with the state of the art in human-computer interaction, behavioral science, health psychology, and data analytic methods to deliver a digital health platform to advance self-management of multimorbidity at home, as part of a proactive, integrated model of supported person-centered care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/22125.