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Development of a lipid-based drug delivery system formulated with a permeation enhancer to increase oral bioavailability of peptides
No full textTherapeutic peptides play a crucial role in a range of treatment areas such as oncology, urology, metabolic and cardiovascular diseases. For these therapies, oral delivery would be highly advantageous, particularly for chronic diseases that require long-term administration. A key challenge associated with oral delivery of peptide drug actives is poor oral bioavailability (BA) due to pre-systemic degradation and low intestinal permeation attributed to their high molecular weight and hydrophilic properties. Two core approaches employed to date to enable oral peptide delivery are i) peptide modification and ii) formulation optimisation. These approaches have had some commercial success, but as oral BA remains low (The overarching goal of this research was to develop a novel prototype drug delivery system capable of increasing oral peptide BA. The underpinning rationale was that hydrophilic peptides subjected to hydrophobic ion pairing (HIP) might have increased lipophilicity and ultimately exhibit higher passive gastrointestinal (GI) transcellular flux. This reversible structural alteration causes a major decrease in aqueous solubility, but also enables solubilisation of the peptide within a self‐emulsifying drug delivery system (SEDDS), offering protection from peptidases and ensuring efficient dispersion within GI luminal fluids. This approach, when co-presented with an intestinal permeation enhancer (PE) was hypothesised to enhance passive GI epithelial permeation.In this thesis, an in vitro screen of novel and established PEs in Caco-2 monolayers identified trehalose 6-monoesters (TEs) with alkyl chain lengths C8 – C16, as lead candidates for inclusion in the DDS. Furthermore, cytotoxicity analysis identified a modest separation between enhancement action and loss in cell viability for these PE candidates. Trehalose laurate (TE12) was found to be the most effective PE in this screen, demonstrating a 13-fold greater Papp of FD4 than sodium caprate. This result was confirmed on rat colonic mucosae with an 8-fold (at 10 mM) increase in Papp of FD4 coupled with moderate reductions in % TEER and tissue functionality preserved, thus justifying its selection for inclusion in the DDS under development.Preliminary HIP development was performed with the model peptide vancomycin and a large panel of potential amphiphilic counterions. This research led to selection of the counterions; sodium docusate, and the novel HIP agent sodium 1-dodecane sulfonate. Following optimisation of the HIP reactions and characterisation of the resultant HIP complexes (HIPs), docusate was selected for HIP with the lead model peptide; leuprolide, resulting in 98.9% precipitation of the peptide and a 3.2-fold increase in LogPOctanol/water. Leuprolide docusate (10 mg/mL) was loaded to a developed SEDDS consisting of 60% Capryol® 90, 30% Kolliphor® EL and 10% Transcutol® HP (% v/v). Characterisation of the dispersed SEDDS revealed formation of a nanoemulsion with dispersed droplets of approximate size and PDI; 64.34 nm and 0.2 respectively. These properties, combined with modest protection of leuprolide by HIP and SEDDS against the action of trypsin, indicate favourable characteristics for GI epithelial absorption.The complete DDS consisting of leuprolide docusate (10 mg/mL) loaded SEDDS, co-delivered with TE12, caused a 4-fold increase in the Papp of leuprolide across Caco-2 monolayers and a 7-fold increase across rat colonic mucosae ex vivo. A mechanistic assessment of the DDS constituents found that the SEDDS caused epithelial perturbation in Caco-2 monolayers, so it was not possible to confirm if there was passive permeation of leuprolide docusate independent from non-specific perturbation. There was a similar trend in isolated rat colonic mucosae, although TE12 as a standalone PE performed best in this study. The combination of HIPs loaded SEDDS and TE12 attenuated the PE effects of TE12 on isolated rat colonic mucosae, which was attributed to an interaction between TE12 and the SEDDS constituents. Furthermore, no loss of colonic tissue viability was observed upon exposure to the DDS or its components, providing preliminary toxicology data for the DDS.Collectively, this study shows the feasibility of HIP as a strategy to hydrophobise ionisable peptides. Solubilisation of the HIPs in SEDDS was a critical step, as low solubility of ion pairs limited their effectiveness. Inclusion of a PE with the HIPs loaded SEDDS improved permeation of leuprolide. In vivo studies are required to determine if this approach can be more effective than traditional PE approaches, which have sub-optimal effectiveness in dynamic in vivo conditions.</p
Quality of health information for women with epilepsy from preconception to postpartum: an evaluation of online resources
No full textBackground: Many women with epilepsy (WWE) navigate complex decisions regarding their reproductive health. The internet can provide specific educational resources for WWE from preconception to postpartum. This study reviewed the type and quality of online resources targeting WWE from preconception to postpartum.Methods: A systematic search of Google, YouTube, GooglePlay Store, and Spotify was conducted online using four search terms: "women and epilepsy," "epilepsy in women," "preconception to postpartum and women with epilepsy," and "epilepsy and pregnancy." The HONcode and DISCERN tools were used to measure the reliability and overall quality of the resources. Additional study-specific questions were included to assess each resource's audience relevancy.Results: A total of 240 initial search results were identified. Of these, 43 resources were included for quality assessment. These resources comprised of 26 websites (22 %), 13 videos (33 %), 4 podcasts (10 %), and no Applications. The average quality score for these 43 resources was 47.97 (SD = 13.67), out of a maximum of 75, which is rated as 'fair.' Out of the 26 websites, 12 % were HONCode certified. The average readability/listenability, language, sensitivity, accessibility, value, and consistency of information was high (from a scale of 1 to 5, the scores ranged from M = 3.90, SD = 1.13 to M = 4.27, SD = 0.930).Conclusion: Online resources for WWE are deemed usable, however improvements could be made to enhance their overall quality. This paper provides a list of reviewed resources to support in the delivery of reliable information for women with epilepsy.</p
Uncovering the hidden implications of water scarcity for maternal health: a photovoice study in rural Malawi (Thyolo district)
No full textIntroduction: Access to clean water is essential for health, but in rural Malawi, water scarcity significantly threatens the health of postpartum women and their babies. Water is critical not only for hydration but also for hygiene, preventing infections, and promoting overall health, particularly during the postpartum period. Despite women's central role in water management within their households, they are seldom included in discussions about water access and management at the community level or within formal governance structures, where decisions are often made without their input. As climate change exacerbates water scarcity, addressing these challenges becomes increasingly urgent for maternal and child health.Goal & methods: This study aimed to create space for postpartum women to document and share their experiences with water scarcity and its implications through participatory photography. Eight women from rural communities in Thyolo District, Southern Malawi, were trained in photography and ethics. They captured images reflecting the challenges they faced with water access and maternal health. Through gallery walks and group discussions, photovoice allowed women to share the stories behind their images, providing deeper insight into the emotional, social and health implications of water insecurity. A phenomenological analysis was conducted to interpret the photographs and narratives.Results: The women's photographs and stories highlighted the multifaceted impact of water scarcity on health. They depicted not only the physical toll of water collection but also the emotional stress and heightened risk of infection due to inadequate sanitation. Through photovoice, the women conveyed a powerful narrative of vulnerability, resilience and frustration, revealing issues that are often invisible in traditional health research.Conclusion: Photovoice proved to be an effective tool for amplifying the voices of marginalized postpartum women, enabling them to highlight the urgent need for clean water access. This approach not only raised awareness of water-related health issues but also provided valuable insights into the lived realities of women in rural Malawi. As climate change continues to intensify water scarcity, these findings underscore the need for sustainable, community-driven solutions. The study offers a model for inclusive research on global health challenges, particularly in vulnerable communities.</p
I don’t mind my information going to the Moon, but I don’t want any letters from Mars: a qualitative exploration of the challenges with secondary use of health data in Ireland
No full textBackground: Secondary use of health data is important for public and individual health due to its potential to drive research and healthcare improvement; however, there are challenges to be managed from a socio-ethical, legal and technological perspective. The aim of this qualitative study was to explore knowledge, experiences and perspectives of key stakeholders towards secondary use of health data in Ireland, with a specific focus on the challenges with secondary use.Methods: The study employed a qualitative cross-sectional approach in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines. Thirty-five people participated in the study, with seven participants in each of the five focus groups: academics and researchers; healthcare professionals; data controllers, ethics and privacy experts; industry group; and patients and public. Two thirds of the sample were female, and over half of participants were between 35 and 54 years of age. Participants were recruited through purposive and snowballing method. Data was collected through focus group discussions, transcribed and analysed thematically.Results: The participants across all study groups were supportive of secondary use of health data; however, significant challenges were identified. The four main categories of challenges were related to (1) health data use, (2) ethics, (3) health data ecosystem and (4) social inequalities. Specifically, insufficient collection and low quality of health data, alongside issues regarding access, linking and sharing are a significant barrier to effective secondary use. This is further complicated by complex ethical approval processes and requirements around data protection. The fragmented national Information Technology (IT) and data infrastructure and limited resources further hamper secondary use, and concerns about low health literacy among the public and negative experiences with the healthcare system influence patients' willingness to share data for secondary use.Conclusions: This study identified the multi-layered and intersecting challenges in the Irish health data ecosystem around secondary use, and highlighted the need for structural improvements, reform of ethical processes, integration of disadvantaged communities, and education and awareness-raising among the public. A careful consideration of these challenges on a national level is required to enable effective secondary use of health data.</p
Antibiotic-eluting scaffolds with responsive dual-release kinetics facilitate bone healing and eliminate <i>S. </i><i>aureus </i>infection
No full textOsteomyelitis (OM) is a progressive, inflammatory infection of bone caused predominately by Staphylococcus aureus. Herein, we engineered an antibiotic-eluting collagen-hydroxyapatite scaffold capable of eliminating infection and facilitating bone healing. An iterative freeze-drying and chemical crosslinking approach was leveraged to modify antibiotic release kinetics, resulting in a layered dual-release system whereby an initial rapid release of antibiotic to clear infection was followed by a sustained controlled release to prevent reoccurrence of infection. We observed that the presence of microbial collagenase accelerated antibiotic release from the crosslinked layer of the scaffold, indicating that the material is responsive to microbial activity. As exemplar drugs, vancomycin and gentamicin-eluting scaffolds were demonstrated to be bactericidal, and supported osteogenesis in vitro. In a pilot murine model of OM, vancomycin-eluting scaffolds were observed to reduce S. aureus infection within the tibia. Finally, in a rabbit model of chronic OM, gentamicin-eluting scaffolds both facilitated radial bone defect healing and eliminated S. aureus infection. These results show that antibiotic-eluting collagen-hydroxyapatite scaffolds are a one-stage therapy for OM, which when implanted into infected bone defects simultaneously eradicate infection and facilitate bone tissue healing.</p
Both the extended neck position and insertion of a supraglottic airway device increases the height of the cricothyroid membrane in females. A prospective observational study
No full textBackground: Emergency Front of Neck access (eFONA) via cricothyroidotomy using a size 6 internal diameter tracheal tube is recommended by the Difficult Airway Society in the event of a 'can't intubate, can't oxygenate' (CICO) scenario in adults. There is a lack of clear guidance on whether to retain or remove a previously inserted supraglottic airway device (SAD) before eFONA. We aimed to study the effect of both neck extension and insertion of an SAD on sagittal cricothyroid membrane (CTM) height.Methods: We recruited 40 adult female patients attending for minor gynaecological surgery under general anaesthesia and suitable for an SAD. Sagittal ultrasound images of the CTM were obtained in the neutral and extended neck position, both before and after insertion of the i-gel® (160 images). The CTM height was measured from the images by a blinded assessor and the data analysed to determine the magnitude of change in CTM height and its relevance for cricothyroidotomy.Results: There was a significant difference in the height of the CTM between the groups (PConclusions: Both neck extension and the insertion of an i-gel® increased the sagittal height of the CTM. This suggests there may be benefit to retaining or re-inserting an SAD during eFONA.</p
Primary site influences the ability of magnetic resonance imaging to assess cartilage invasion in advanced laryngeal cancer
No full textObjective: Accurate staging of advanced laryngeal cancer is important, as treatment can vary significantly between larynx preservation and total laryngectomy. The purpose of this study was to evaluate the accuracy of magnetic resonance imaging (MRI) in assessing features of T4a disease in locally advanced laryngeal cancer and determine if primary site played a role in the accuracy of MRI in this setting.Methods: A retrospective cohort study of patients undergoing a total laryngectomy in a tertiary referral center for head and neck cancer over a 10-year time period was carried out. Patients met inclusion criteria if they underwent a primary total laryngectomy for squamous cell carcinoma (SCC) of the larynx during the study period. Data collected included basic demographic data, primary tumor subsite, and clinical and pathological staging. The predictive ability of MRI on outer thyroid cortex invasion, extralaryngeal extension, and overall T4a stage was analyzed with receiver operating characteristics analysis. Analysis was compared to histological data on outer thyroid cortex invasion, extralaryngeal extension, and histological T4a stage.Results: A total of 112 patients met inclusion criteria. The mean age of the cohort was 65.1. Glottic primary subsite was associated with a statistically significant elevated risk for histological outer cortex erosion (p = 0.006), but MRI demonstrated worse sensitivity in detecting this outer cortex invasion in glottic primaries (p = 0.002).Conclusion: Glottic primaries tumors display an increased likelihood of thyroid cartilage invasion, however, MRI demonstrates a poorer sensitivity for detecting these features.Level of evidence: 3 Laryngoscope, 135:723-728, 2025.</p
Enhancing the quality of surgical care through improved patient handover processes
No full textSurgical handover remains a high-risk process with no gold standard for practice despite 20 years of available guidance. Variability in practice is common, and poorly performed handover poses significant, yet avoidable, risk to patients. Research in this domain is underfunded with widely heterogenous methodology, meaning that the evidence base for better handover is deficient. In this correspondence, recommendations are made to address these shortcomings, including standardised operating procedures supported by electronic health records to enable staff training and audit. Prioritisation of the sickest patients at the handover outset and two-way, verbal communication, including a “read-back” to confirm that information is both transmitted and received. Rigorous evaluation of handover interventions before use, and discontinuation of practices that add no value. Lastly, a core outcome set for surgical handover is urgently needed to improve the comparability of studies. By clearly defining best practices and demonstrating the impact of interventions on patient outcomes, surgeons will be more inclined to adopt meaningful improvements in handover processes.</p
Mechanical circulatory support for infarct-related cardiogenic shock: a systematic review, pairwise and network meta-analysis
No full textAims: Mortality from cardiogenic shock complicating acute myocardial infarction (AMI-CS) remains high, despite the increasing mechanical circulatory support (MCS) use in clinical practice.Methods and results: We undertook a systematic review and meta-analysis of trials assessing MCS in adults with AMI-CS. We searched Medline, EMBASE, CENTRAL, Web of Science, and Scopus from inception to May 2024. We evaluated the effect of each intervention on early mortality using a random-effects network meta-analysis of odds ratios (ORs). Safety outcomes included stroke, bleeding, and sepsis. Fourteen trials randomizing 1858 patients were included: intra-aortic balloon pump (IABP) vs. medical therapy (four trials, n = 748 patients), veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) vs. No VA-ECMO (four trials, n = 568 patients), percutaneous ventricular assist device (pVAD) vs. No pVAD (six trials, n = 542 patients). No MCS device showed a significant effect on early mortality vs. initial medical therapy {IABP (OR 0.87, 95% CI 0.66-1.15), VA-ECMO (OR 0.91, 95% CI 0.65-1.27), pVAD (OR 0.80, 95% CI 0.56-1.14), and P (inconsistency) = 0.76}. VA-ECMO and pVAD were associated with increased major bleeding [OR 2.81 (95% CI 1.68-4.71) and OR 5.13 (95% CI 1.87-14.04), respectively]. Higher rates of stroke and sepsis were noted with pVAD. No significant safety concerns were identified with IABP.Conclusion: The mortality benefit of MCS devices in AMI-CS remains uncertain. Using such devices may be associated with increased risks, including major bleeding, stroke, and sepsis. Current evidence does not support the routine use of MCS devices in the management of AMI-CS.</p
The Way Home
No full textThe Way Home was created to gently support children who have experienced traumatic loss, offering comfort and clarity through storytelling. This book aims to validate children’s emotional experiences, open safe conversations, and help caring adults respond to children’s questions with compassion and honesty. It is recommended to read this book together and allow time for questions or quiet reflection. Children’s understanding of loss changes as they grow, so revisiting this story may help in different ways over time.</p