The critical elements of digital health in diabetes and cardiometabolic care.

Digital innovations provide novel opportunities to individualize a person's care to best match their lifestyle needs and circumstances and to support them as they live their daily lives with diabetes. These innovations also serve to provide actionable data and insights for the care team giving them a "Webb telescope-like" view into their individual self-management journey, allowing them to see what cannot be seen during infrequent and limited office visits, thereby facilitating collaboration and communication to optimize the care plan on a timely basis. Technology advances are enabling diabetes care to transition from episodic, synchronous, primarily in-person care to include synchronous virtual care options and to continuous, on-demand, data-informed, asynchronous digital care better matching the demands of living with a relentless 24/7 chronic condition. In this paper we will discuss the critical elements and considerations in designing and implementing successful diabetes digital health tools in clinical practice.

National implementation trial of BeUpstanding™: an online initiative for workers to sit less and move more.

BACKGROUND: The online BeUpstanding™ program is an eight-week workplace-delivered intervention for desk-based workers to raise awareness of the benefits of sitting less and moving more and build a supportive culture for change. A workplace representative (the "champion") delivers the program, which includes a workshop where teams collectively choose their sit less/move more strategies. A toolkit provides the champion with a step-by-step guide and associated resources to support program uptake, delivery, and evaluation. Here we report on the main findings from the Australian national implementation trial of BeUpstanding. METHODS: Recruitment (12/06/2019 to 30/09/2021) was supported by five policy and practice partners, with desk-based work teams from across Australia targeted. Effectiveness was measured via a single arm, repeated-measures trial. Data were collected via online surveys, toolkit analytics, and telephone calls with champions. The RE-AIM framework guided evaluation, with adoption/reach (number and characteristics); effectiveness (primary: self-reported workplace sitting time); implementation (completion of core components; costs); and, maintenance intentions reported here. Linear mixed models, correcting for cluster, were used for effectiveness, with reach, adoption, implementation, and maintenance outcomes described. RESULTS: Of the 1640 website users who signed-up to BeUpstanding during the recruitment period, 233 were eligible, 198 (85%) provided preliminary consent, and 118 (50.6%) champions consented and started the trial, with 94% (n = 111 champions) completing. Trial participation was from across Australia and across industries, and reached 2,761 staff, with 2,248 participating in the staff survey(s): 65% female; 64% university educated; 17% from a non-English speaking background. The program effectively changed workplace sitting (-38.5 [95%CI -46.0 to -28.7] minutes/8-hour workday) and all outcomes targeted by BeUpstanding (behaviours and culture), with small-to-moderate statistically-significant effects observed. All participating teams (n = 94) completed at least 5/7 core steps; 72.4% completed all seven. Most champions spent $0 (72%) or >$0-$5 (10%) per team member; most (67/70 96%) intended to continue or repeat the program. CONCLUSIONS: BeUpstanding can be adopted and successfully implemented by a range of workplaces, reach a diversity of staff, and be effective at creating a supportive culture for teams of desk-based workers to sit less and move more. Learnings will inform optimisation of the program for longer-term sustainability. TRIAL REGISTRATION: ACTRN12617000682347.

Silicon dioxide particles induce DNA oxidative damage activating the AIM2-mediated PANoptosis in mice cerebellum.

Silicon dioxide (SiO2) particles are novel materials with wide-ranging applications across various fields, posing potential neurotoxic effects. This study investigates the toxicological mechanisms of SiO2 particles of different sizes on murine cerebellar tissue and cells. Six-week-old C57BL/6 mice were orally administered SiO2 particles of three sizes (1 µm, 300 nm, 50 nm) for 21 days to establish an in vivo model, and mice cerebellar astrocytes (C8-D1A cells) were cultured in vitro. Indicators of oxidative stress, DNA damage, and the PANoptosis pathway were detected using methods such as immunofluorescence staining, comet assay, western blotting, and qRT-PCR. The results show that SiO2 particles induce oxidative stress leading to DNA oxidative damage. The aberrant DNA is recognized by AIM2 (absent in melanoma 2), which activates the assembly of the PANoptosome complex, subsequently triggering PANoptosis. Furthermore, the extent of damage is inversely correlated with the size of SiO2 particles. This study elucidates the toxicological mechanism of SiO2 particles causing cerebellar damage via PANoptosis, extending research on PANoptosis in neurotoxicology, and aiding in the formulation of stricter safety standards and protective measures to reduce the potential toxic risk of SiO2 particles to humans.

The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.

Mycobacterium tuberculosis (Mtb) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb. These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a pore-forming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb-infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasome-associated pathomechanisms may foster the development of novel host-directed therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis.

Implementation Evaluation of a Parks- and Faith-Based Multilevel Intervention to Promote Physical Activity Among Latinos.

BACKGROUND: Latinos in the United States face multiple barriers to engaging in physical activity (PA). We implemented a faith-based multilevel intervention to promote PA in parks for Latino adults, which was partially adapted to a virtual platform during the COVID-19 pandemic, and evaluated it using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. METHODS: We conducted in-depth semistructured interviews (83% in Spanish) with 24 intervention participants (75% women) participating in a cluster randomized controlled trial in 2019-2022 that linked 6 churches (3 intervention, 3 control) with parks in East Los Angeles, CA. The intervention included in-person, park-based fitness classes, which were adapted to Facebook during the pandemic; PA motivational text messages; and other activities. Interviews assessed Reach (participation), Effectiveness (perceived impacts), Implementation (participation barriers/facilitators), and Maintenance (plans for sustaining PA), as well as perceived pandemic impacts. RESULTS: About 80% of interviewees participated in ≥1 park class and 67% in ≥1 virtual class (Reach). Interviewees perceived positive intervention impacts across multiple health and well-being domains (Effectiveness) despite perceived negative pandemic impacts; several facilitators to participation (personal, social, program) and few barriers (personal, virtual, environmental; Implementation); and plans for maintaining PA (eg, revisiting intervention text messages and video recordings; Maintenance). CONCLUSIONS: Findings support the utility of Reach, Effectiveness, Adoption, Implementation, and Maintenance to understand the broad impacts of a faith-based PA intervention. Findings point to the adaptability and robustness of the intervention during a public health crisis. Overall, findings may help inform the translation of the intervention to other communities to advance health equity.

Coaching the coaches: exploring the effectiveness of the 'Move Well Be strong' youth injury prevention programme for grassroot coaches and PE teachers.

INTRODUCTION: Coaches play a major role in developing movement in their performers, especially at grassroots levels. However, there are significant knowledge gaps amongst grassroots coaches and physical education (PE) teachers regarding movement competency and injury prevention programs. This study aimed to explore the effectiveness of knowledge gain, adoption and implementation following a youth injury prevention workshop for grassroots coaches and PE teachers. METHODS: 56 grassroots coaches and PE teachers completed a validated questionnaire exploring use, knowledge, attitude towards and confidence to deliver youth movement competency training before and after an online workshop. Bayesian Wilcoxon signed-rank tests were used to assess the knowledge, attitude, and confidence to deliver an injury prevention programme following the workshop. For all the Bayesian inference tests run, the Bayesian factor (BF10) was interpreted using the evidence categories ranging from extreme evidence (BF10 > 100) to anecdotical evidence (BF10 < 1). RESULTS: Post-workshop there was a 34% increase in respondents indicating that they had greater knowledge of injury prevention issues (55% pre-workshop vs 89% post-workshop) with statistically positive and moderate effects (BF10 > 100 [extreme evidence]). There was also a 25% increase in respondents indicating that they had a more sympathetic attitude towards injury prevention (67% sympathetic pre-workshop vs 93% sympathetic post-workshop) with statistically moderate effects (BF10 = 87.4 [very strong evidence]). A 19% increase in attendees' confidence to deliver an injury prevention programme was observed (69% high pre-workshop vs. 89% high post-workshop) with statistically moderate effects (BF10 = 85.9 [very strong evidence]). 100% of participants indicated an intent to adopt the injury prevention programme. CONCLUSIONS: An online workshop increased knowledge and confidence in grassroots coaches and PE teachers to deliver a youth injury prevention programme. Knowledge gained from training and upskilling created a positive attitude and confidence to deliver movement competency into coaching. Appropriate resources need to be developed and delivered in an accessible way to grassroots coaches and PE teachers via workshops and should be included in governing body coaching awards or as continuing professional development for youth coaches and PE teachers.

Mood regulation in euthymic patients with a history of antidepressant-induced mania.

INTRODUCTION: The use of antidepressants in bipolar disorder (BD) remains contentious, in part due to the risk of antidepressant-induced mania (AIM). However, there is no information on the architecture of mood regulation in patients who have experienced AIM. We compared the architecture of mood regulation in euthymic patients with and without a history of AIM. METHODS: Eighty-four euthymic participants were included. Participants rated their mood, anxiety and energy levels daily using an electronic (e-) visual analog scale, for a mean (SD) of 280.8(151.4) days. We analyzed their multivariate time series by computing each variable's auto-correlation, inter-variable cross-correlation, and composite multiscale entropy of mood, anxiety, and energy. Then, we compared the data features of participants with a history of AIM and those without AIM, using analysis of covariance, controlling for age, sex, and current treatment. RESULTS: Based on 18,103 daily observations, participants with AIM showed significantly stronger day-to-day auto-correlation and cross-correlation for mood, anxiety, and energy than those without AIM. The highest cross-correlation in participants with AIM was between mood and energy within the same day (median (IQR), 0.58 (0.27)). The strongest negative cross-correlation in participants with AIM was between mood and anxiety series within the same day (median (IQR), -0.52 (0.34)). CONCLUSION: Patients with a history of AIM have a different underlying mood architecture compared to those without AIM. Their mood, anxiety and energy stay the same from day-to-day; and their anxiety is negatively correlated with their mood.

EIF2AK2 protein targeted activation of AIM2-mediated PANoptosis promotes sepsis-induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) frequently occurs as a complication of sepsis. PANoptosis refers to a type of inflammatory programmed cell death that exhibits key characteristics of apoptosis, necroptosis, and pyroptosis. Here, we evaluated the role of absent in melanoma 2 (AIM2) and eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) in septic AKI. METHODS: A septic AKI model was created through cecal ligation and puncture (CLP), while an in vitro model was developed using lipopolysaccharide (LPS)-stimulated HK2 cells. Hematoxylin and eosin (HE), Periodic acid-Schiff (PAS), and TUNEL staining were conducted to assess kidney injury in mice. Levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected by kits. Gene expression was detected utilizing RT-qPCR, and Western blot was used to test protein levels. Immunofluorescence was employed to measure EIF2AK2 and AIM2 expression in mouse kidney tissue. Lactate dehydrogenase (LDH) activity assay was conducted to evaluate cytotoxicity. Co-immunoprecipitation (Co-IP) was performed to verify the binding relationship between EIF2AK2 and AIM2. RESULTS: AIM2 expression was increased in the renal tissue of mice subjected to CLP. Activation of the inflammasome and PANoptosis were observed in the renal tissue of CLP mice. AIM2 depletion attenuated PANoptosis in LPS-treated HK-2 cells. Additionally, EIF2AK2 could directly target AIM2, leading to a positive regulation of AIM2 expression. Notably, EIF2AK2 induced PANoptosis through upregulating AIM2 in HK-2 cells stimulated by LPS. CONCLUSIONS: Our results revealed the important role of EIF2AK2-induced AIM2 upregulation in the activation of PANoptosis during septic AKI.

Renal tissue from CLP mice exhibited an increase in AIM2 expression.Renal tissue from CLP mice demonstrated inflammasome activation and PANoptosis.AIM2 silencing reduced PANoptosis in LPS-treated HK-2 cells.EIF2AK2 directly targeted AIM2 and positively regulated its expression.EIF2AK2 promoted PANoptosis via AIM2 in LPS-triggered HK-2 cells.

Evaluating the implementation of weekly rifapentine-isoniazid (3HP) for tuberculosis prevention among people living with HIV in Uganda: A qualitative evaluation of the 3HP Options Trial.

Three months of isoniazid-rifapentine (3HP) is being scaled up for tuberculosis (TB) preventive treatment (TPT) among people living with HIV (PLHIV) in high-burden settings. More evidence is needed to identify factors influencing successful 3HP delivery. We conducted a qualitative assessment of 3HP delivery nested within the 3HP Options Trial, which compared three optimized strategies for delivering 3HP: facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), and patient choice between facilitated DOT and facilitated SAT at the Mulago HIV/AIDS clinic in Kampala, Uganda. We conducted 72 in-depth interviews among PLHIV purposively selected to investigate factors influencing 3HP acceptance and completion. We conducted ten key informant interviews with healthcare providers (HCPs) involved in 3HP delivery to identify facilitators and barriers at the clinic level. We used post-trial 3HP delivery data to assess sustainability. We conducted an inductive thematic analysis and aligned the emergent themes with the RE-AIM framework dimensions to report implementation outcomes. Understanding the need for TPT, once-weekly dosing, shorter duration, and perceived 3HP safety enhanced acceptance overall. Treatment monitoring by HCPs and reduced risk of HIV status disclosure enabled DOT acceptance. Dosing autonomy enabled SAT acceptance. Switching between DOT and SAT as required enabled acceptance for patient choice. Dosing reminders, reimbursement for clinical visits, and social support enabled 3HP completion; pill burden, side effects, and COVID-19-related treatment restrictions hindered completion. All HCPs were trained and participated in 3HP delivery with high fidelity. Training, care integration, and collaboration among HCPs enabled, whereas initial concerns about 3HP safety among HCPs delayed 3HP adoption and implementation. SAT was maintained post-trial; DOT was discontinued due to inadequate ongoing financial support beyond the study period. Facilitated delivery strategies made 3HP treatment convenient for PLHIV and were feasible and implemented with high fidelity by HCPs. However, the costs of 3HP facilitation may limit wider scale-up.

Deletion of absent in melanoma-2 (AIM2) drives bone marrow adipogenesis and impairs bone microarchitecture.

Absent in melanoma (AIM) 2, a gene induced by interferon, acts as a cytosolic sensor for double-stranded (ds) DNA. It forms the AIM2 inflammasome, producing interleukin (IL)-1ß and IL-18. Our previous study demonstrated that mice lacking AIM2 exhibit spontaneous obesity, insulin resistance, and inflammation in adipose tissue. In this study, we aimed to explore the impact of AIM2 gene deletion on the bone marrow microenvironment and bone morphology in adult and aged mice. Utilizing micro-computed tomography (micro-CT), we discovered that female mice lacking AIM2 showed an increase in the total cross-sectional area at 5 months of age, accompanied by an increase in cortical thickness in the mid-diaphysis of the femur at both 5 and 15 months of age. At 15 months, the cortical bone mineral density (BMD) significantly decreased in AIM2 null females compared to wildtype (WT) mice. Trabecular bone volume and BMD at the distal metaphysis of the femur and the lumbar vertebra-4 were also significantly decreased in AIM2 null females. Histological examination of femurs from aged mice demonstrated increased bone marrow adiposity in AIM2 null mice, accompanied by a significant increase in CD45 - /CD31 - /Sca1 + /Pdgfa + adipogenic progenitor cells and a decrease in the ratio of CD45 - /CD31 - /Sca1 - /Pdgfa + osteogenic progenitor cells, as determined by flow cytometry of bone marrow cells. RNAseq analysis of the bone marrow revealed a significant increase in interferon-stimulated genes with Ifi202b as the top-upregulated gene in AIM2 null mice. Our findings suggest that AIM2 deficiency affects bone health by promoting adipogenesis in the bone marrow and inducing a pro-inflammatory environment, thereby contributing to decreased bone mineral density.