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Here, we report a pathomimetic Leaky Gut Chip that recapitulates increased epithelial permeability and intestinal inflammation to assess probiotic intervention as live biotherapeutics. We leveraged a mechanodynamic human gut-on-a-chip (Gut Chip) that recreates three-dimensional epithelial layers in a controlled oxygen gradient and biomechanical cues, where the addition of a cocktail of pro-inflammatory cytokines, TNF-α and IL-1β, reproducibly induced impaired epithelial barrier followed by intestinal inflammation. This inflamed leaky epithelium was not recovered for up to 3 days, although the cytokine treatment ceased. However, when probiotic bacteria, either Lactobacillus rhamnosus GG or a multi-species mixture (VSL#3), were respectively administered on the leaky epithelium, bacterial cells colonized mucosal surface and significantly improved barrier function, enhanced the localization of tight junction proteins such as ZO-1 and occludin, and elevated mucus production. In addition, inflammatory markers, including p65, pSTAT3, and MYD88, that were highly expressed in the germ-free control were significantly reduced when probiotic bacteria were co-cultured in a Leaky Gut Chip. Probiotic treatment also significantly reduced the production of secretory pro-inflammatory cytokines. Hence, our pathomimetic Leaky Gut Chip may offer a translational strategy to dissect the therapeutic mechanism of live biotherapeutic products and validate their clinical potential by incorporating patient-derived organoids.

We document the central role of collateral in the pricing of tri-party repos. Markets are competitive for repos with safe collateral but are severely segmented for repos with risky collateral, such as equities and low-grade corporate bonds. Fund families are the sole contributors to the segmentation, and collateral concentration is the main determinant in the substantial variation in repo pricing, both across and within segments. The segmented structure points to Fidelity as a systemically important player and the markets potential fragility. Facing market segmentation, dealers optimize financing costs by allocating their collateral across fund families.

The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

Telepresence robots are being increasingly used in long-term care (LTC) homes for virtual visits between families and residents. This study investigated the impacts and experiences of residents and their families using a telepresence robot (Double 3) for 4 to 12 months during the COVID-19 pandemic. A total of 51 participants were recruited through purposive sampling, including 9 residents, 15 family members, and 27 staff from 4 LTC homes in British Columbia, Canada. Conversational interviews were conducted with residents and family members. Focus groups and one-to-one interviews were held with frontline staff. Thematic analysis was performed, with five themes identified: (1) Stay connected, (2) Regain autonomy, (3) Relieve caregiver burden, (4) Environmental and technical issues, and (5) Scheduling concerns. In conclusion, telepresence robots helped maintain social connections between residents and families, despite the COVID-19 restrictions.

Although there is a growing literature on the use of telepresence robots in institutional dementia care settings, limited research focused on the perspectives of frontline staff members who deliver dementia care. Our objective was to understand staff perspectives on using telepresence robots to support residents with dementia and their families. Guided by the Consolidated Framework for Implementation Research, we conducted four focus groups and 11 semi-structured interviews across four long-term care (LTC) homes and one hospital in Canada. We included 22 interdisciplinary staff members (e.g., registered nurses, social workers, occupational therapists, recreational therapists) to understand their experiences with telepresence robots. Thematic analysis identified three key themes: 1) Staff Training and Support; 2) Robot Features; 3) Environmental dynamics for Implementation. Our results underscore the imperative of structural support at micro-, meso- and macro-levels for staff in dementia care settings to effectively implement technology. This study contributes to future research and practice by elucidating factors facilitating staff involvement in technology research, integrating staff voices into technology implementation planning, and devising strategies to provide structural support to staff, care teams, and care homes.

The rapid development of artificial intelligence (AI) in medicine has resulted in an increased number of applications deployed in clinical trials. AI tools have been developed with goals of improving diagnostic accuracy, workflow efficiency through automation, and discovery of novel features in clinical data. There is subsequent concern on the role of AI in replacing existing tasks traditionally entrusted to physicians. This has implications for medical trainees who may make decisions based on the perception of how disruptive AI may be to their future career. This commentary discusses current barriers to AI adoption to moderate concerns of the role of AI in the clinical setting, particularly as a standalone tool that replaces physicians. Technical limitations of AI include generalizability of performance and deficits in existing infrastructure to accommodate data, both of which are less obvious in pilot studies, where high performance is achieved in a controlled data processing environment. Economic limitations include rigorous regulatory requirements to deploy medical devices safely, particularly if AI is to replace human decision-making. Ethical guidelines are also required in the event of dysfunction to identify responsibility of the developer of the tool, health care authority, and patient. The consequences are apparent when identifying the scope of existing AI tools, most of which aim to be physician assisting rather than a physician replacement. The combination of the limitations will delay the onset of ubiquitous AI tools that perform standalone clinical tasks. The role of the physician likely remains paramount to clinical decision-making in the near future.

We propose a market-wide liquidity measure by exploiting the connection between the amount of arbitrage capital in the market and observed \"noise\" in U.S. Treasury bonds—the shortage of arbitrage capital allows yields to deviate more freely from the curve, resulting in more noise in prices. Our noise measure captures episodes of liquidity crises of different origins across the financial market, providing information beyond existing liquidity proxies. Moreover, as a priced risk factor, it helps to explain cross-sectional returns on hedge funds and currency carry trades, both known to be sensitive to the general liquidity conditions of the market.

BackgroundIn 2009, the China National Tobacco Company (CNTC) began their Premiumization Strategy, designed to encourage smokers to trade up to more expensive brands, mainly by promoting the concept that higher class cigarettes are better quality and less harmful. This study is the first evaluation of the strategy’s impact on: (1) prevalence of premium brand cigarettes (PBC), mid-priced brand cigarettes (MBC) and discount brand cigarettes (DBC) over 9 years, from 3 years pre-strategy (2006) to 6 years post-strategy (2015); and (2) changes in reasons for choosing PBCs, MBCs and DBCs.MethodsA representative cohort of adult Chinese smokers (n=9047) in seven cities who participated in five waves of the International Tobacco Control (ITC) China Survey: pre-implementation (Wave 1 (2006; n=3452), Wave 2 (2007–2008; n=3586)); mid-implementation (Wave 3 (2009; n=4172)); and post-implementation (Wave 4 (2011–2012; n=4070), Wave 5 (2013–2015; n=2775)). Generalised estimating equations were conducted to examine changes in prevalence of PBCs, MBCs and DBCs, and reasons for brand choice from pre-implementation to post-implementation.ResultsFrom pre-implementation to post-implementation, there was an increase in prevalence of PBCs (5.4% to 23.2%, p<0.001) and MBCs (40.0% to 50.4%, p<0.001), and a decrease in DBCs (54.6% to 26.5%, p<0.001). There was an increase in smokers who chose their current brand because they believed it to be less harmful, both for MBC smokers (+13.0%, p=0.001) and PBC smokers (+9.0%, p=0.06). There was an increase for smokers in all brand classes for choosing their current brand because they were ‘higher in quality’ and because of affordable price, but the greatest increase was among PBC smokers (+18.6%, p<0.001 and +34.9%, p<0.001, respectively).ConclusionsOur findings demonstrate that the rising trend in Chinese smokers’ choice of ‘less harmful’, ‘higher quality’ and ‘affordable’ cigarettes, particularly PBCs, is likely due to CNTC’s aggressive marketing strategies. Strong tobacco control policies that prohibit CNTC’s marketing activities are critical in order to dispel erroneous beliefs that sustain continued smoking in China, where the global tobacco epidemic is exerting its greatest toll.

Objective As people living with dementia move into long-term care (LTC), their care partners face a difficult role change from primary caregiver to visitor, losing a significant degree of control and direct care involvement. The COVID-19 pandemic exacerbated these challenges with health risks, changing care home protocols, and government policies. To help address these challenges, this study aimed to investigate the experiences of care partners who used telepresence robots to maintain contact with and care for their loved ones during the pandemic. Methods This study was guided by the Collaborative Action Research (CAR) approach. Along with interdisciplinary researchers and trainees, our team included patient and family partners as co-researchers throughout the project. We conducted semi-structured interviews with 20 care partners who used the robots in five urban Canadian LTC homes between May 2021 and August 2023. Results Thematic analysis identified four key themes characterizing their experiences using the robot: (a) decreases care partner burden, (b) facilitates care partner–staff relationship, (c) creates relational autonomy, and (d) expands the scope of what is possible. Conclusion The results of the study suggest that telepresence robots can play a useful role in enhancing the caregiving experience for informal care partners in multifaceted ways. Care partners reported positive benefits of having the robot assist their virtual visits. However, further research is needed to determine the sustainability of robot implementation among diverse geographic regions and care home compositions.

Melittin is a cytolytic peptide component of bee venom which rapidly integrates into lipid bilayers and forms pores resulting in osmotic lysis. While the therapeutic utility of free melittin is limited by its cytotoxicity, incorporation of melittin into the lipid shell of a perfluorocarbon nanoparticle has been shown to reduce its toxicity in vivo. Our group has previously demonstrated that perfluorocarbon nanoparticles containing melittin at concentrations <10 µM inhibit HIV infectivity in vitro. In the current study, we assessed the impact of blank and melittin-containing perfluorocarbon nanoparticles on sperm motility and the viability of both sperm and vaginal epithelial cells. We found that free melittin was toxic to sperm and vaginal epithelium at concentrations greater than 2 µM (p<0.001). However, melittin nanoparticles were not cytotoxic to sperm (p = 0.42) or vaginal epithelium (p = 0.48) at an equivalent melittin concentration of 10 µM. Thus, nanoparticle formulation of melittin reduced melittin cytotoxicity fivefold and prevented melittin toxicity at concentrations previously shown to inhibit HIV infectivity. Melittin nanoparticles were toxic to vaginal epithelium at equivalent melittin concentrations ≥20 µM (p<0.001) and were toxic to sperm at equivalent melittin concentrations ≥40 µM (p<0.001). Sperm cytotoxicity was enhanced by targeting of the nanoparticles to the sperm surface antigen sperm adhesion molecule 1. While further testing is needed to determine the extent of cytotoxicity in a more physiologically relevant model system, these results suggest that melittin-containing nanoparticles could form the basis of a virucide that is not toxic to sperm and vaginal epithelium. This virucide would be beneficial for HIV serodiscordant couples seeking to achieve natural pregnancy.