In vitro models to evaluate ingestible devices:present status and current trends

Orally ingestible medical devices offer significant opportunity in the diagnosis and treatment of gastrointestinal conditions. Their development necessitates the use of models that simulate the gastrointestinal environment on both a macro and micro scale. An evolution in scientific technology has enabled a wide range of in vitro, ex vivo and in vivo models to be developed that replicate the gastrointestinal tract. This review describes the landscape of the existing range of in vitro tools that are available to characterize ingestible devices. Models are presented with details on their benefits and limitations with regards to the evaluation of ingestible devices and examples of their use in the evaluation of such devices is presented where available. The multitude of models available provides a suite of tools that can be used in the evaluation of ingestible devices that should be selected on the functionality of the device and the mechanism of its function

Community research report

University College Cork introduced its first Community-based Participatory Research (CBPR) module in 2016. The module was funded and supported by Horizon2020 funding, specifically the EnRRICH project (Enhancing Responsible Research and Innovation through Curricula in Higher Education). The module is a 5-credit module for PhD students from all disciplines in the early stages of their PhD at University College Cork. Following two fruitful partnerships in the areas of social justice / equality, community family support services and older persons, there was a keen interested to explore partnerships in markedly different areas such as environmental sustainability. A dialogue ensued with CEF where the opportunity and feasibility to collaborate on the CBPR module was explored

Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects

YesBackgorund Prior data suggest pre-diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple-negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. Method NOD/SCID mice were implanted with HER2+ MDA-MB-231/LN/2-4/H2N, trastuzumab-resistant HER2+ HCC1954 or a TNBC patient-derived xenograft (PDX). A daily low-dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA-MB-231/LN/2-4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre-treatment aspirin, 3 weeks post-resection, HCC1954/TNBC animals received standard-of-care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. Results Aspirin delayed time to metastasis in MDA-MB-231/LN/2-4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre-treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co-culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF-C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. Conclusion Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo-preventative agent in the HER2+ or TNBC setting.Funding is acknowledged from the Irish Cancer Society Collaborative Cancer Research Centre under BREAST- PREDICT grant CCRC13GAL (www.breas tpred ict.com). I.S.M, E.M and A.T.B, are members of the EurOPDX Consortium, and receive funding from the European Union's Horizon 2020 research and innovation programme, grant agreement no. #731105 (EurOPDX Research Infrastructure, www.europ dx.eu)

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Formulation of an antibacterial topical cream containing bioengineered honey that generates reactive oxygen species

SurgihoneyRO™ (SHRO) is a bioengineered medicinal honey proven to eradicate multi-drug resistant strains of bacteria by delivering a controlled dose of reactive oxygen species (ROS). The urgent need for novel antimicrobial therapies capable of tackling pathogens that have developed resitance to existing antimicrobial medicines, such as antibiotics, makes SHRO a highly desirable biomaterial. However, its application is currently limited in the medical field due to undesirable material properties. This study aims to formulate the honey into a clinically viable topical cream whilst maintaining antimicrobial efficacy. SHRO droplets were emulsified to protect the active until activation in-situ. Xanthan gum (XG) and fumed silica (FS) thickener systems were explored, with both formulations able to inhibit the growth of S. aureus in-vitro. However, FS formulations exhibited significantly higher hydrogen peroxide release over a period of 7 days and resulted in larger zones of inhibition (42%) than XG formulations. Selection of the optimum FS formulation was made based on evaluation of the material characteristics by means of rheology and texture analysis. In place of the sticky and highly viscous initial SHRO product, desirable material characteristics for a topical product were achieved, including thixotropic shear-thinning behaviour and significantly lower cohesiveness (15.3–22.4 N) than standard SHRO formulations (79.9 N). Furthermore, the product exhibited a low contact angle on porcine skin, indicating that these formulations would spread favourably on the skin surface, demonstrate a favourable sensory perception and be retained on the skin, making for a more clinically effective product. This work is the first report of an engineered cream system to controllably deliver ROS to a wound site and demonstrate its ability of eradicating clinically relevant bacteria in vitro.</p

Formulation of an antibacterial topical cream containing bioengineered honey that generates reactive oxygen species

SurgihoneyRO™ (SHRO) is a bioengineered medicinal honey proven to eradicate multi-drug resistant strains of bacteria by delivering a controlled dose of reactive oxygen species (ROS). The urgent need for novel antimicrobial therapies capable of tackling pathogens that have developed resitance to existing antimicrobial medicines, such as antibiotics, makes SHRO a highly desirable biomaterial. However, its application is currently limited in the medical field due to undesirable material properties. This study aims to formulate the honey into a clinically viable topical cream whilst maintaining antimicrobial efficacy. SHRO droplets were emulsified to protect the active until activation in-situ. Xanthan gum (XG) and fumed silica (FS) thickener systems were explored, with both formulations able to inhibit the growth of S. aureus in-vitro. However, FS formulations exhibited significantly higher hydrogen peroxide release over a period of 7 days and resulted in larger zones of inhibition (42%) than XG formulations. Selection of the optimum FS formulation was made based on evaluation of the material characteristics by means of rheology and texture analysis. In place of the sticky and highly viscous initial SHRO product, desirable material characteristics for a topical product were achieved, including thixotropic shear-thinning behaviour and significantly lower cohesiveness (15.3–22.4 N) than standard SHRO formulations (79.9 N). Furthermore, the product exhibited a low contact angle on porcine skin, indicating that these formulations would spread favourably on the skin surface, demonstrate a favourable sensory perception and be retained on the skin, making for a more clinically effective product. This work is the first report of an engineered cream system to controllably deliver ROS to a wound site and demonstrate its ability of eradicating clinically relevant bacteria in vitro.</p

Correction: Schütt et al. Simulating the hydrodynamic conditions of the human ascending colon: a digital twin of the dynamic colon model. Pharmaceutics 2022, 14, 184

In the original publication [1], there was a mistake in Figure 6 when published. The experimental data points in the upper diagram were missing. The corrected Figure 6 appears below