Oral infection drives a distinct population of intestinal resident memory CD8(+) T cells with enhanced protective function.

The intestinal mucosa promotes T cell responses that might be beneficial for effective mucosal vaccines. However, intestinal resident memory T (Trm) cell formation and function are poorly understood. We found that oral infection with Listeria monocytogenes induced a robust intestinal CD8 T cell response and blocking effector T cell migration showed that intestinal Trm cells were critical for secondary protection. Intestinal effector CD8 T cells were predominately composed of memory precursor effector cells (MPECs) that rapidly upregulated CD103, which was needed for T cell accumulation in the intestinal epithelium. CD103 expression, rapid MPEC formation, and maintenance in intestinal tissues were dependent on T cell intrinsic transforming growth factor ß signals. Moreover, intestinal Trm cells generated after intranasal or intravenous infection were less robust and phenotypically distinct from Trm cells generated after oral infection, demonstrating the critical contribution of infection route for directing the generation of protective intestinal Trm cells.

Novel germanene-arsenene and germanene-antimonene lateral heterostructures: interline-dependent electronic and magnetic properties.

Seamlessly stitching two-dimensional (2D) materials may lead to the emergence of novel properties triggered by the interactions at the interface. In this work, a series of 2D lateral heterostructures (LHSs), namely germanene-arsenene (Gem-As8-m) and germanene-antimonene (Gem-Sb8-m), are investigated using first-principles calculations. The results demonstrate a strong interline-dependence of the electronic and magnetic properties. Specifically, the LHS formation along an armchair line preserves the non-magnetic nature of the original materials. However, this is an efficient approach to open the electronic band gap of the germanene monolayer, where band gaps as large as 0.74 and 0.76 eV are induced for Ge2-As6 and Ge2-Sb6 LHSs, respectively. Meanwhile, magnetism may appear in the zigzag-LHSs depending on the chemical composition (m = 3, 4, 5, and 6 for germanene-arsenene and m = 2, 3, 4, 5, and 6 for germanene-antimonene), where total magnetic moments between 0.13 and 0.50 µB are obtained. Herein, magnetic properties are produced mainly by the spin-up state of Ge atoms at the interface, where a small contribution comes from As(Sb) atoms. Spin-resolved band structures show a multivalley profile in both the valence band and the conduction band with a topological insulator-like behavior, where the interface states are derived mainly from the interface Ge-pz state. The results introduce new 2D lateral heterostructures with novel electronic and magnetic properties to allow new functionalities, which could be further explored for optoelectronic and spintronic applications.

Comorbidities of diabetes and hypertension in Vietnam: current burden, trends over time, and correlated factors.

BACKGROUND: Vietnam conducted the national Noncommunicable Disease Risk-Factor Surveillance (STEPs) surveys in the years 2010, 2015, and 2021. This study aims to use STEPs data to assess the burden of comorbidity between diabetes and hypertension, analyze trends over time, and identify factors associated with this comorbidity. METHODS: The study extracted data for the population aged 25-64 years old from three STEPs surveys. Survey weight was used for all estimations of prevalence and 95% CI. Correlated factors with comorbidity were examined by a multivariate logistics model. RESULTS: The prevalence of comorbidity in 2021 was about 3.92% among Vietnamese people aged 25-64. In the last 10 years, this prevalence has increased more than 8 times (from 0.44% to 3.92%). Sub-populations demonstrating the most significant changes included the male population, people living in urban areas, and older people. Significant factors correlated with comorbidity included demographic factors, body mass index (BMI), and clustering of 4 noncommunicable diseases (NCDs) behavioral risk factors (OR = 3.48, p < 0.05). CONCLUSION: The high comorbidity between hypertension and diabetes underscores the imperative for integrated treatment and management approaches in Vietnam. Coordinated care is essential for addressing the complex interplay between these two prevalent conditions.

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A.

Myostatin (MSTN) is a transforming growth factor-ß (TGF-ß) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-ß family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Making Sense of Theories, Models, and Frameworks in Digital Health Behavior Change Design: Qualitative Descriptive Study.

BACKGROUND: Digital health interventions are increasingly being designed to support health behaviors. Although digital health interventions informed by behavioral science theories, models, and frameworks (TMFs) are more likely to be effective than those designed without them, design teams often struggle to use these evidence-informed tools. Until now, little work has been done to clarify the ways in which behavioral science TMFs can add value to digital health design. OBJECTIVE: The aim of this study was to better understand how digital health design leaders select and use TMFs in design practice. The questions that were addressed included how do design leaders perceive the value of TMFs in digital health design, what considerations do design leaders make when selecting and applying TMFs, and what do design leaders think is needed in the future to advance the utility of TMFs in digital health design? METHODS: This study used a qualitative description design to understand the experiences and perspectives of digital health design leaders. The participants were identified through purposive and snowball sampling. Semistructured interviews were conducted via Zoom software. Interviews were audio-recorded and transcribed using Otter.ai software. Furthermore, 3 researchers coded a sample of interview transcripts and confirmed the coding strategy. One researcher completed the qualitative analysis using a codebook thematic analysis approach. RESULTS: Design leaders had mixed opinions on the value of behavioral science TMFs in digital health design. Leaders suggested that TMFs added the most value when viewed as a starting point rather than the final destination for evidence-informed design. Specifically, these tools added value when they acted as a gateway drug to behavioral science, supported health behavior conceptualization, were balanced with expert knowledge and user-centered design principles, were complementary to existing design methods, and supported both individual- and systems-level thinking. Design leaders also felt that there was a considerable nuance in selecting the most value-adding TMFs. Considerations should be made regarding their source, appropriateness, complexity, accessibility, adaptability, evidence base, purpose, influence, audience, fit with team expertise, fit with team culture, and fit with external pressures. Design leaders suggested multiple opportunities to advance the use of TMFs. These included improving TMF reporting, design, and accessibility, as well as improving design teams' capacity to use TMFs appropriately in practice. CONCLUSIONS: When designing a digital health behavior change intervention, using TMFs can help design teams to systematically integrate behavioral insights. The future of digital health behavior change design demands an easier way for designers to integrate evidence-based TMFs into practice.

Honoring the Care Experiences of Chinese Canadian Survivors of Prostate Cancer to Cultivate Cultural Safety and Relationality in Digital Health: Exploratory-Descriptive Qualitative Study.

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed nonskin cancer for Canadian men and has one of the highest 5-year survival rates, straining systems to provide care. Virtual care can be one way to relieve this strain, but survivors' care needs and technology use are influenced by intersecting social and cultural structures. Cultural adaptation has been posited as an effective method to tailor existing interventions to better serve racialized communities, including Chinese men. However, cultural adaptations may inadvertently draw attention away from addressing structural inequities. OBJECTIVE: This study used qualitative methods to (1) explore the perceptions and experiences of Chinese Canadian PCa survivors with follow-up and virtual care, and (2) identify implications for the cultural adaptation of a PCa follow-up care app, the Ned (no evidence of disease) Clinic. METHODS: An axiology of relational accountability and a relational paradigm underpinned our phenomenologically informed exploratory-descriptive qualitative study design. A community-based participatory approach was used, informed by cultural safety and user-centered design principles, to invite Chinese Canadian PCa survivors and their caregivers to share their stories. Data were inductively analyzed to explore their unmet needs, common experiences, and levels of digital literacy. RESULTS: Unmet needs and technology preferences were similar to broader trends within the wider community of PCa survivors. However, participants indicated that they felt uncomfortable, unable to, or ignored when expressing their needs. Responses spoke to a sense of isolation and reflected a reliance on culturally informed coping mechanisms, such as "eating bitterness," and familial assistance to overcome systemic barriers and gaps in care. Moreover, virtual care was viewed as "better than nothing;" it did not change a perceived lack of focus on improving quality of life or care continuity in survivorship care. Systemic changes were identified as likely to be more effective in improving care delivery and well-being rather than the cultural adaptation of Ned for Chinese Canadians. Participants' desires for care reflected accessibility issues that were not culturally specific to Chinese Canadians. CONCLUSIONS: Chinese Canadian survivors are seeking to strengthen their connections in a health care system that provides privacy and accessibility, protects relationality, and promotes transparency, accountability, and responsibility. Designing "trickle-up" adaptations that address structural inequities and emphasize accessibility, relationality, and privacy may be more effective and efficient at improving care than creating cultural adaptations of interventions.

The Complexity of Transferring Remote Monitoring and Virtual Care Technology Between Countries: Lessons From an International Workshop.

International deployment of remote monitoring and virtual care (RMVC) technologies would efficiently harness their positive impact on outcomes. Since Canada and the United Kingdom have similar populations, health care systems, and digital health landscapes, transferring digital health innovations between them should be relatively straightforward. Yet examples of successful attempts are scarce. In a workshop, we identified 6 differences that may complicate RMVC transfer between Canada and the United Kingdom and provided recommendations for addressing them. These key differences include (1) minority groups, (2) physical geography, (3) clinical pathways, (4) value propositions, (5) governmental priorities and support for digital innovation, and (6) regulatory pathways. We detail 4 broad recommendations to plan for sustainability, including the need to formally consider how highlighted country-specific recommendations may impact RMVC and contingency planning to overcome challenges; the need to map which pathways are available as an innovator to support cross-country transfer; the need to report on and apply learnings from regulatory barriers and facilitators so that everyone may benefit; and the need to explore existing guidance to successfully transfer digital health solutions while developing further guidance (eg, extending the nonadoption, abandonment, scale-up, spread, sustainability framework for cross-country transfer). Finally, we present an ecosystem readiness checklist. Considering these recommendations will contribute to successful international deployment and an increased positive impact of RMVC technologies. Future directions should consider characterizing additional complexities associated with global transfer.

Fusarium solani PQF9 Isolated from Podocarpus pilgeri Growing in Vietnam as a New Producer of Paclitaxel.

Endophytic fungi are known as an alternative promising source of anticancer drug, paclitaxel, however fungi inhabiting in medicinal plant Podocarpus pilgeri and their paclitaxel production have not been reported to date. In the present study, a total of 15 culturable fungi classified into 5 genera, were successfully recovered from P. pilgeri collected in Vietnam. Screening fungal dichloromethane extracts for anticancer activity revealed that only PQF9 extract displayed potent inhibitory effects on A549 and MCF7 cancer cell lines with IC50 values of 33.9 ± 2.3 µg/mL and 43.5 ± 1.7 µg/mL, respectively. Through PCR-based molecular screening, the isolate PQF9 was found to possess 3 key genes involved in paclitaxel biosynthesis. Importantly, high-performance liquid chromatography quantification showed that fungal isolate PQF9 was able to produce 18.2 µg/L paclitaxel. The paclitaxel-producing fungus was identified as Fusarium solani PQF9 based on morphological and molecular phylogenetic analysis. Intensive investigations by chromatographic methods and spectroscopic analyses confirmed the presence of paclitaxel along with tyrosol and uracil. The pure paclitaxel had an IC50 value of 80.8 ± 9.4 and 67.9 ± 7.0 nM by using cell viability assay on A549 lung and MCF7 breast cancer cells. In addition, tyrosol exhibited strong antioxidant activity by scavenging 2, 2-diphenyl-picrylhydrazyl (DPPH) (IC50 5.1 ± 0.2 mM) and hydroxyl radical (IC50 3.6 ± 0.1 mM). In contrast, no biological activity was observed for uracil. Thus, the paclitaxel-producing fungus F. solani PQF9 could serve as a new material for large-scale production and deciphering paclitaxel biosynthesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01119-z.

Highly sensitive detection of EGFR L858R mutation at the mRNA level.

The missense mutation EGFR L858R implies increased sensitivity to EGFR tyrosine kinase inhibitor (TKIs) therapy, despite a significant non-response rate. Currently, detection of EGFR L858R mutation is mostly DNA based, therefore, the allele-specific expression level of the mutated gene and its clinical relevance is hidden. Based on the extendable blocking probes and hot-start protocol for reverse transcription, we have developed and validated a novel one-step realtime RT-PCR assay that enables detection of EGFR L858R mutation at the mRNA level. This RNA-based assay was able to detect the EGFR L858R mutation in a 10,000-fold excess of its wildtype counterpart, indicating an analytical sensitivity of 0.01%. In comparison to the reference DNA-based assay, the RNA-based assay further detected the EGFR L858R mutation in significantly additional formalin-fixed paraffin-embedded (FFPE) samples (19.2% vs 15.0%). Interestingly, our data showed that the relative mRNA levels of EGFR L858R mutation varied greatly in tumor tissues (∼4 logs); and the circulating mRNA of EGFR L858R mutation was detectable in plasma of NSCLC patients. This novel RNA-based PCR assay provides a simple and ultrasensitive tool for detection of EGFR L858R mutation at the mRNA level as a new class of biomarkers.

γδ T cells exhibit multifunctional and protective memory in intestinal tissues.

The study of T cell memory and the target of vaccine design have focused on memory subsumed by T cells bearing the αß T cell receptor. Alternatively, γδ T cells are thought to provide rapid immunity, particularly at mucosal borders. Here, we have shown that a distinct subset of mucosal γδ T cells mounts an immune response to oral Listeria monocytogenes (Lm) infection and leads to the development of multifunctional memory T cells capable of simultaneously producing interferon-γ and interleukin-17A in the murine intestinal mucosa. Challenge infection with oral Lm, but not oral Salmonella or intravenous Lm, induced rapid expansion of memory γδ T cells, suggesting contextual specificity to the priming pathogen. Importantly, memory γδ T cells were able to provide enhanced protection against infection. These findings illustrate that γδ T cells play a role with hallmarks of adaptive immunity in the intestinal mucosa.

The Future of Virtual Care for Older Ethnic Adults Beyond the COVID-19 Pandemic.

The COVID-19 pandemic has fundamentally changed how Canadians access health care. Although it is undeniable that the rapid adoption of virtual care has played a critical role in reducing viral transmission, the gap in equitable access to virtual care remains pervasive for Canada's aging and ethnocultural minority communities. Existing virtual care solutions are designed for the English-speaking, health-literate, and tech-savvy patient population, excluding older ethnic adults who often do not see themselves reflected in these identities. In acknowledging the permanency of virtual care brought on by the pandemic, we have a collective responsibility to co-design new models that serve our older ethnic patients who have been historically marginalized by the status quo. Building on existing foundations of caregiving within ethnocultural minority communities, one viable strategy to realize culturally equitable virtual care may be to engage the highly motivated and skilled family caregivers of older ethnic adults as partners in the technology-mediated management of their chronic disease. The time is now to build a model of shared virtual care that embraces Canada's diverse cultures, while also providing its older ethnic adults with access to health innovations in partnership with equally invested family caregivers who have their health at heart.

The Value of Technology to Support Dyadic Caregiving for Individuals Living With Heart Failure: Qualitative Descriptive Study.

BACKGROUND: The demand for health services to meet the chronic health needs of the aging population is significant and remains unmet because of the limited supply of clinical resources. Specifically, in managing heart failure (HF), digital health sought to address this gap during the COVID-19 pandemic but highlighted an access issue for those who could not use technology-mediated health care services without the support of their informal caregivers (ICs). The complexity of managing HF symptoms and recurrent exacerbations requires many patients to comanage their illness with their ICs in a care dyad, working together to optimize patient outcomes and health-related quality of life. However, most HF programs have missed the opportunity to consider the dyadic perspective despite interdependencies on HF outcomes. OBJECTIVE: This study aims to characterize the value of technology in supporting caregiving for individuals living with HF. METHODS: Motivated by an observed unique pattern of engagement in patients enrolled in our Medly HF management program at the Peter Munk Cardiac Centre in Toronto, Canada, we conducted 20 semistructured interviews with a convenience sample of ICs. All interviews were analyzed using the iterative refinement of a codeveloped codebook. The team maintained reflexivity journals to reflect the impact of their positionality on their coding. Themes were first derived deductively using HF typologies (patient-oriented dyads, caregiver-oriented dyads, and collaboratively oriented dyads) and then inductively refined and recategorized based on concepts from the van Houtven et al framework. RESULTS: We believe that there is a need to formally and intentionally expand HF technologies to include dyadic needs and goals. We suggest defining 3 opportunities in which value can be added to technological design. First, identify how technology may be leveraged to increase psychological bandwidth by reducing uncertainty and providing peace of mind. We found that actionable feedback was highly desired by both partners. Second, develop technology that can serve as a member of the dyad's support system. In our experience, automated prompts for patients to take measurements can mimic the support typically provided by ICs and ease their workload. Third, consider how technology can mitigate the dyad's clinical knowledge requirements and learning curve. Our approach includes real-time actionable feedback paired with a human-in-the-loop, nurse-led model of care. CONCLUSIONS: Our findings identified a need to focus on improving the dyadic experience as a whole by building IC functionality into digital health self-management interventions. Through a shared model of care that supports the role of the patient in their own HF management, includes ICs to expand and enhance the patient's capacity to care, and acknowledges the need of ICs to care for themselves, we anticipate improved outcomes for both partners.

The iCanCope pain self-management application for adolescents with juvenile idiopathic arthritis: a pilot randomized controlled trial.

OBJECTIVES: To evaluate the feasibility and preliminary effectiveness of iCanCope with Pain (iCanCope), a smartphone-based pain self-management program, in adolescents with JIA. iCanCope featured symptom tracking, goal-setting, pain coping skills and social support. METHODS: A two-arm pilot randomized controlled trial was used to evaluate the iCanCope app compared with a version with symptom tracking only. Primary (feasibility) outcomes were: participant accrual/attrition rates, success of app deployment, acceptability and adherence. Secondary (preliminary effectiveness) outcomes were: pain intensity, pain-related activity limitations and health-related quality of life. Outcomes were assessed at baseline and 8 weeks. Adherence was defined as the proportion of completed symptom reports: 'low' (≤24%); 'low-moderate' (25-49%); 'high-moderate' (50-75%); or 'high' (76-100%). Linear mixed models were applied for preliminary effectiveness analyses as per intention-to-treat. RESULTS: Adolescents (N = 60) were recruited from three paediatric rheumatology centres. Rates of accrual and attrition were 82 and 13%, respectively. Both apps were deployed with high success (over 85%) and were rated as highly acceptable. Adherence was similar for both groups, with most participants demonstrating moderate-to-high adherence. Both groups exhibited a clinically meaningful reduction in pain intensity (≥1 point) that did not statistically differ between groups. There were no significant changes in activity limitations or health-related quality of life. CONCLUSION: The iCanCope pilot randomized controlled trial was feasible to implement in a paediatric rheumatology setting. Both apps were deployed successfully, with high acceptability, and were associated with moderate-to-high adherence. Preliminary reductions in pain intensity warrant a future trial to evaluate effectiveness of iCanCope in improving health outcomes in adolescents with JIA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02764346.

Optimal protection against Salmonella infection requires noncirculating memory.

While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity. Using a YFP-IFN-γ reporter system, we identified Th1 cells in the liver of immunized mice that displayed markers of tissue residence, including P2X7, ARTC2, LFA-1, and CD101. Adoptive transfer of liver memory cells after ARTC2 blockade increased protection against highly virulent bacteria. Taken together, these data demonstrate that noncirculating memory Th1 cells are a vital component of immunity to Salmonella infection and should be the focus of vaccine strategies.

The Need for Ethnoracial Equity in Artificial Intelligence for Diabetes Management: Review and Recommendations.

There is clear evidence to suggest that diabetes does not affect all populations equally. Among adults living with diabetes, those from ethnoracial minority communities-foreign-born, immigrant, refugee, and culturally marginalized-are at increased risk of poor health outcomes. Artificial intelligence (AI) is actively being researched as a means of improving diabetes management and care; however, several factors may predispose AI to ethnoracial bias. To better understand whether diabetes AI interventions are being designed in an ethnoracially equitable manner, we conducted a secondary analysis of 141 articles included in a 2018 review by Contreras and Vehi entitled "Artificial Intelligence for Diabetes Management and Decision Support: Literature Review." Two members of our research team independently reviewed each article and selected those reporting ethnoracial data for further analysis. Only 10 articles (7.1%) were ultimately selected for secondary analysis in our case study. Of the 131 excluded articles, 118 (90.1%) failed to mention participants' ethnic or racial backgrounds. The included articles reported ethnoracial data under various categories, including race (n=6), ethnicity (n=2), race/ethnicity (n=3), and percentage of Caucasian participants (n=1). Among articles specifically reporting race, the average distribution was 69.5% White, 17.1% Black, and 3.7% Asian. Only 2 articles reported inclusion of Native American participants. Given the clear ethnic and racial differences in diabetes biomarkers, prevalence, and outcomes, the inclusion of ethnoracial training data is likely to improve the accuracy of predictive models. Such considerations are imperative in AI-based tools, which are predisposed to negative biases due to their black-box nature and proneness to distributional shift. Based on our findings, we propose a short questionnaire to assess ethnoracial equity in research describing AI-based diabetes interventions. At this unprecedented time in history, AI can either mitigate or exacerbate disparities in health care. Future accounts of the infancy of diabetes AI must reflect our early and decisive action to confront ethnoracial inequities before they are coded into our systems and perpetuate the very biases we aim to eliminate. If we take deliberate and meaningful steps now toward training our algorithms to be ethnoracially inclusive, we can architect innovations in diabetes care that are bound by the diverse fabric of our society.

Evaluation of the expression levels of BRAFV600E mRNA in primary tumors of thyroid cancer using an ultrasensitive mutation assay.

BACKGROUND: The BRAFV600E gene encodes for the mutant BRAFV600E protein, which triggers downstream oncogenic signaling in thyroid cancer. Since most currently available methods have focused on detecting BRAFV600E mutations in tumor DNA, there is limited information about the level of BRAFV600E mRNA in primary tumors of thyroid cancer, and the diagnostic relevance of these RNA mutations is not known. METHODS: Sixty-two patients with thyroid cancer and non-malignant thyroid disease were included in the study. Armed with an ultrasensitive technique for mRNA-based mutation analysis based on a two step RT-qPCR method, we analysed the expression levels of the mutated BRAFV600E mRNA in formalin-fixed paraffin-embedded samples of thyroid tissues. Sanger sequencing for detection of BRAFV600E DNA was performed in parallel for comparison and normalization of BRAFV600E mRNA expression levels. RESULTS: The mRNA-based mutation detection assay enables detection of the BRAFV600E mRNA transcripts in a 10,000-fold excess of wildtype BRAF counterparts. While BRAFV600E mutations could be detected by Sanger sequencing in 13 out of 32 malignant thyroid cancer FFPE tissue samples, the mRNA-based assay detected mutations in additionally 5 cases, improving the detection rate from 40.6 to 56.3%. Furthermore, we observed a surprisingly large, 3-log variability, in the expression level of the BRAFV600E mRNA in FFPE samples of thyroid cancer tissue. CONCLUSIONS: The expression levels of BRAFV600E mRNA was characterized in the primary tumors of thyroid cancer using an ultrasensitive mRNA-based mutation assay. Our data inspires further studies on the prognostic and diagnostic relevance of the BRAFV600E mRNA levels as a molecular biomarker for the diagnosis and monitoring of various genetic and malignant diseases.

A novel incompatibility group X3 plasmid carrying blaNDM-1 encodes a small RNA that regulates host fucose metabolism and biofilm formation.

The emergence of New Delhi metallo-beta-lactamase (NDM-1) has become a major health threat to clinical managements of gram-negative bacteria infections. A novel incompatibility group X3 plasmid (IncX3) pNDM-HN380 carrying blaNDM-1 has recently been found to epidemiologically link with multiple geographical areas in China. In this paper, we studied the metabolic responses of host bacteria E. coli J53 upon introduction of pNDM-HN380. A reduction of bacterial motility was observed in J53/pNDM-HN380. We profiled the RNA repertoires of the transconjugants and found a downregulation of genes involved in flagella and chemotaxis metabolic pathways at logarithmic (log) phase. We also identified a novel intragenic region (IGR) small RNA plas2. The plasmid-transcribed sRNA IGR plas2 was further characterized as a regulator of fucRwhich controls the fucose metabolism. By knockdown of IGR plas2 using an antisense decoy, we managed to inhibit the formation of bacterial biofilm of the host. Our study demonstrated a potential way of utilizing plasmid-transcribed sRNA against infectious bacteria.

Evaluation of Digital Technologies Tailored to Support Young People's Self-Management of Musculoskeletal Pain: Mixed Methods Study.

BACKGROUND: Digital technologies connect young people with health services and resources that support their self-care. The lack of accessible, reliable digital resources tailored to young people with persistent musculoskeletal pain is a significant gap in the health services in Australia. Recognizing the intense resourcing required to develop and implement effective electronic health (eHealth) interventions, the adaptation of extant, proven digital technologies may improve access to pain care with cost and time efficiencies. OBJECTIVE: This study aimed to test the acceptability and need for adaptation of extant digital technologies, the painHEALTH website and the iCanCope with Pain app, for use by young Australians with musculoskeletal pain. METHODS: A 3-phased, mixed methods evaluation was undertaken from May 2019 to August 2019 in Australia. Young people aged 15 to 25 years with musculoskeletal pain for >3 months were recruited. Phases were sequential: (1) phase 1, participant testing (3 groups, each of n=5) of co-designed website prototypes compared with a control website (painHEALTH), with user tasks mapped to eHealth quality and engagement criteria; (2) phase 2, participants' week-long use of the iCanCope with Pain app with engagement data captured using a real-time analytic platform (daily check-ins for pain, interference, sleep, mood, physical activity, and energy levels; goal setting; and accessing resources); and (3) phase 3, semistructured interviews were conducted to gain insights into participants' experiences of using these digital technologies. RESULTS: Fifteen young people (12/15, 80% female; mean age 20.5 [SD 3.3] years; range 15-25 years) participated in all 3 phases. The phase 1 aggregated group data informed the recommendations used to guide 3 rapid cycles of prototype iteration. Adaptations included optimizing navigation, improving usability (functionality), and enhancing content to promote user engagement and acceptability. In phase 2, all participants checked in, with the highest frequency of full check-ins attributed to pain intensity (183/183, 100.0%), pain interference (175/183, 95.6%), and mood (152/183, 83.1%), respectively. Individual variability was evident for monitoring progress with the highest frequency of history views for pain intensity (51/183, 32.3%), followed by pain interference (24/183, 15.2%). For the goals set feature, 87% (13/15) of participants set a total of 42 goals covering 5 areas, most frequently for activity (35/42, 83%). For phase 3, metasynthesis of qualitative data highlighted that these digital tools were perceived as youth-focused and acceptable. A total of 4 metathemes emerged: (1) importance of user-centered design to leverage user engagement; (2) website design (features) promoting user acceptability and engagement; (3) app functionality supporting self-management; and (4) the role of wider promotion, health professional digital prescriptions, and strategies to ensure longer-term engagement. CONCLUSIONS: Leveraging extant digital tools, with appropriate user-informed adaptations, can help to build capacity tailored to support young people's self-management of musculoskeletal pain.

The development of bioresorbable composite polymeric implants with high mechanical strength.

Implants for the treatment of tissue defects should mimic the mechanical properties of the native tissue of interest and should be resorbable as well as biocompatible. In this work, we developed a scaffold from variants of poly(glycolic) acid which were braided and coated with an elastomer of poly(glycolide-co-caprolactone) and crosslinked. The coating of the scaffold with the elastomer led to higher mechanical strength in terms of compression, expansion and elasticity compared to braids without the elastomer coating. These composite scaffolds were found to have expansion properties similar to metallic stents, utilizing materials which are typically much weaker than metal. We optimized the mechanical properties of the implant by tuning the elastomer branching structure, crosslink density, and molecular weight. The scaffolds were shown to be highly resorbable following implantation in a porcine femoral artery. Biocompatibility was studied in vivo in an ovine model by implanting the scaffolds into femoral arteries. The scaffolds were able to support an expanded open lumen over 12 months in vivo and also fully resorbed by 18 months in the ovine model.

Dual Immunization with SseB/Flagellin Provides Enhanced Protection against Salmonella Infection Mediated by Circulating Memory Cells.

The development of a subunit Salmonella vaccine has been hindered by the absence of detailed information about antigenic targets of protective Salmonella-specific T and B cells. Recent studies have identified SseB as a modestly protective Ag in susceptible C57BL/6 mice, but the mechanism of protective immunity remains undefined. In this article, we report that simply combining Salmonella SseB with flagellin substantially enhances protective immunity, allowing immunized C57BL/6 mice to survive for up to 30 d following challenge with virulent bacteria. Surprisingly, the enhancing effect of flagellin did not require flagellin Ag targeting during secondary responses or recognition of flagellin by TLR5. Although coimmunization with flagellin did not affect SseB-specific Ab responses, it modestly boosted CD4 responses. In addition, protective immunity was effectively transferred in circulation to parabionts of immunized mice, demonstrating that tissue-resident memory is not required for vaccine-induced protection. Finally, protective immunity required host expression of IFN-γR but was independent of induced NO synthase expression. Taken together, these data indicate that Salmonella flagellin has unique adjuvant properties that improve SseB-mediated protective immunity provided by circulating memory.