Early plasma ferritin concentrations are not associated with time to red cell transfusions in extremely and very preterm neonates: a prospective single-site observational study

Objective: To assess the relationship between plasma ferritin concentrations and (1) antenatal factors and (2) requirement for red cell transfusionStudy design: This single-site prospective study recruited infants in the first week of life who were born Results: Plasma ferritin concentrations were not significantly associated with birth weight or gestational age in this cohort of extremely/very preterm neonates (n=114: n=26, Conclusions: Plasma ferritin concentrations in very/extremely preterm neonates are variable and associated with the intrauterine environment. Ferritin concentration was not predictive of time to transfusion in this cohort and was not significantly different at smaller birth weight or earlier gestation. This is important for considerations of iron storage in very preterm neonates and its developmental consequences.</p

Acute effects of psilocybin on attention and executive functioning in healthy volunteers: a systematic review and multilevel meta-analysis

Rationale: Psilocybin shows promise for treating neuropsychiatric disorders. However, insight into its acute effects on cognition is lacking. Given the significant role of executive functions in daily life and treatment efficacy, it is crucial to evaluate how psilocybin influences these cognitive domains.Objectives: This meta-analysis aims to quantify the acute effects of psilocybin on executive functions and attention, while examining how dosage, timing of administration, cognitive domain, and task characteristics moderate these effects.Methods: A systematic review and multilevel meta-analysis were conducted on empirical studies assessing psilocybin's acute effects on working memory, conflict monitoring, response inhibition, cognitive flexibility, and attention. Effect sizes for reaction time (RT) and accuracy (ACC) were calculated, exploring the effects of timing (on-peak defined as 90-180 min post-administration), dosage, cognitive function categories, and task sensitivity to executive functions as potential moderators.Results: Thirteen studies (42 effect sizes) were included. In the acute phase, psilocybin increased RTs (Hedges' g = 1.13, 95% CI [0.57, 1.7]) and did not affect ACC (Hedges' g = -0.45, 95% CI [-0.93, 0.034]). Effects on RT were dose dependent. Significant between-study heterogeneity was found for both RT and ACC. Task sensitivity to executive functions moderated RT effects. Publication bias was evident, but the overall effect remained significant after adjustment for this.Conclusions: Our meta-analysis shows that psilocybin impairs executive functions and results in a slowing down of RT. We discuss potential neurochemical mechanisms underlying the observed effects as well as implications for the safe use of psilocybin in clinical and experimental contexts.</p

Redefining cancer care: the importance of primary care cancer research in Ireland

Cancer represents a significant public health challenge in Ireland. As of 2022, nearly a third of all deaths were attributed to invasive malignancies [1]. Moreover, one in every two people in Ireland will develop invasive cancer (excluding non-melanoma skin cancer) in their lifetime [2]. Forecasts also indicate a potential doubling of cancer diagnoses between 2010 and 2040, primarily due to an ageing population [3].Despite these stark statistics, the past three decades have seen Ireland make significant advancements in cancer care, guided by three successive national cancer strategies [1]. These have contributed to reduced mortality rates for the most prevalent cancers and an increase in 5-year age-standardised cancer survival rates from 42 to 65% over a twenty-year period [4]. Despite these achievements, Ireland’s age-standardised incidence and mortality rates remain amongst the highest within the OECD (Organisation for Economic Co-Operation and Development) [5]. This indicates a need for continued innovation in our approach to cancer control.</p

Key considerations for a prostate cancer mRNA vaccine

Prostate cancer has the second highest cancer mortality rate in the UK in males. Early prostate cancer is typically asymptomatic, with diagnosis at a locally advanced or metastatic stage. In addition, the inherent heterogeneity of prostate cancer tumours differs significantly in terms of genetic, molecular, and histological features. The successful treatment of prostate cancer is therefore exceedingly challenging. Immunotherapies, particularly therapeutic vaccines, have been widely used in preclinical and clinical studies to treat various cancers. Sipuleucel-T was the first cancer vaccine approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), ushering in a new era of immunotherapy. In this review, the latest immunotherapy strategies for prostate cancer are considered with key tumour-associated antigens (TAA) and tumour-specific antigens (TSA) highlighted. The key components of mRNA vaccines include in vitro transcription, stability, and immunogenicity. Finally, strategies to circumvent in vivo mRNA degradation and approaches to optimise in vitro transcription (IVT) process are also discussed.</p

Antibiotic-eluting scaffolds with responsive dual-release kinetics facilitate bone healing and eliminate <i>S. </i><i>aureus </i>infection

Osteomyelitis (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

Evaluation of the Role of Glycans of the Biomolecular Corona and Development of Well-Characterised Glyco-Nanoparticles for Biomedical Applications

Nanoparticles (NPs) have gained great attention in medicine thanks to their advantageous properties that make them excellent candidates for application in modern medicine. In particular, the NP surface can be tailored and modified with targeting moieties to increase the localisation in diseased areas. Despite these advantages, several drawbacks are decreasing the implementation of clinical trials and there is a need to tackle several issues.Upon intravenous injection, NPs encounter biological barriers resulting in macrophage uptake and liver accumulation and low circulation half-time. Additionally, their surface is dramatically altered by the adsorption of biomolecules with high affinity towards the NP surface, which can dramatically affect the NPs’ biodistribution and accumulation, thus their therapeutic efficacy. In the last decades, several studies have been focused on the correlation between the NP physico-chemical properties, corona formation and biological outcome, and it has become a regulatory burden as this phenomenon is too complex to be studied and it has too many variables. As the protein corona is formed by glycosylated plasma proteins, it is possible to speculate that these glycans become part of the corona. Additionally, glycans modulate several biological processes, including protein clearance and inflammation. Several studies have focused on the development of NPs with longer circulation half-time. A typical approach is the surface functionalisation with stealth polymers, such as PEG. However, increasing studies have shown that PEG can lead to complement activation, pseudo-allergies and to the development of anti-PEG antibodies. Therefore, there is the need to develop biocompatible polymers.In this thesis, I have carried out a deep corona characterisation using citrate gold NPs, where I have identified the glycan types on the corona proteins and I have shown with different techniques that these glycans are biologically accessible and capable of interacting with specific receptors. I have also evaluated whether glycans can be used as biomolecules to increase the NP circulation half-life by attenuating the protein corona formation, and increase the nanomaterial biocompatibility by masking PEG and modulate the immunological response. I have developed a novel platform for characterisation.</p

TLR/NLRP3 inflammasome signaling pathways as a main target in frailty, cachexia and sarcopenia

Mobility disability is a common condition affecting older adults, making walking and the performance of activities of daily living difficult. Frailty, cachexia and sarcopenia are related conditions that occur with advancing age and are characterized by a decline in muscle mass, strength, and functionality that negatively impacts health. Chronic low-grade inflammation is a significant factor in the onset and progression of these conditions. The toll-like receptors (TLRs) and the NLRP3 inflammasome are the pathways of signaling that regulate inflammation. These pathways can potentially be targeted therapeutically for frailty, cachexia and sarcopenia as research has shown that dysregulation of the TLR/NLRP3 inflammasome signaling pathways is linked to these conditions. Activation of TLRs with pathogen-associated molecular patterns (PAMPs or DAMPs) results in chronic inflammation and tissue damage by releasing pro-inflammatory cytokines. Additionally, NLRP3 inflammasome activation enhances the inflammatory response by promoting the production and release of interleukins (ILs), thus exacerbating the underlying inflammatory mechanisms. These pathways are activated in the advancement of disease in frail and sarcopenic individuals. Targeting these pathways may offer therapeutic options to reduce frailty, improve musculoskeletal resilience and prevent or reverse cachexia-associated muscle wasting. Modulating TLR/NLRP3 inflammasome pathways may also hold promise in slowing down the progression of sarcopenia, preserving muscle mass and enhancing overall functional ability in elderly people. The aim of this review is to investigate the signaling pathways of the TLR/NLRP3 inflammasome as a main target in frailty, cachexia and sarcopenia.</p

Tuning star polymer architecture to tailor secondary structures and mechanical properties of diblock polypeptide hydrogels for direct ink writing

Hydrogel three-dimensional (3D) printing has emerged as a highly valuable fabrication tool for applications ranging from electronics and biomedicine. While conventional hydrogels such as gelatin, alginate, and hyaluronic acid satisfy biocompatibility requirements, they distinctly lack reproducibility in terms of mechanical properties and 3D printability. Aiming to offer a high-performance alternative, here we present a range of amphiphilic star-shaped diblock copolypeptides of l-glutamate and l-leucine residues with different topologies. Hydrophobic side chains of the l-leucine polymer block drive conformational self-assembly in water, spontaneously forming hydrogels with tunable mechanical properties, through variation of star topology. Their amenable shear-thinning and self-recovery properties render them suitable as hydrogel inks for direct ink writing. Well-defined 3D-printed structures can be readily generated and rapidly photo-cross-linked using visible light (405 nm) after methacrylamide functionalization, while hydrogel inks demonstrate good biocompatibility with top-seeded and encapsulated MC3T3 cells.</p

Risk-stratification tools for emergency department patients with syncope: a systematic review and meta-analysis of direct evidence for SAEM GRACE

Objectives: Approximately 10% of patients with syncope have serious or life-threatening causes that may not be apparent during the initial emergency department (ED) assessment. Consequently, researchers have developed clinical decision rules (CDRs) to predict adverse outcomes and risk stratify ED syncope patients. This systematic review and meta-analysis (SRMA) aims to cohere and synthesize the best current evidence regarding the methodological quality and predictive accuracy of CDRs for developing an evidence-based ED syncope management guideline.Methods: We conducted a systematic literature search according to the patient-intervention-control-outcome question: In patients 16 years of age or older who present to the ED with syncope for whom no underlying serious/life-threatening condition was found during the index ED visit (population), are risk stratification tools (intervention), better than unstructured clinical judgment (i.e., usual care; comparison), for providing accurate prognosis and aiding disposition decision for outcomes within 30 days (outcome)? Two reviewers independently assessed articles for inclusion and methodological quality. We performed statistical analysis using Meta-DiSc. We used GRADEPro GDT software to determine the certainty of the evidence and create a summary of the findings (SoF) tables.Results: Of 2047 publications obtained through the search strategy, 31 comprising 13 CDRs met the inclusion criteria. There were 13 derivation studies (17,578 participants) and 24 validation studies (14,845 participants). Only three CDRs were validated in more than two studies. The San Francisco Syncope Rule (SFSR) was validated in 12 studies: positive likelihood ratio (LR+) 1.15-4.70 and negative likelihood ratio (LR-) 0.03-0.64. The Canadian Syncope Risk Score (CSRS) was validated in five studies: LR+ 1.15-2.58 and LR- 0.05-0.50. The Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk score was validated in five studies: LR+ 1.16-3.32 and LR- 0.14-0.46.Conclusions: Most CDRs for ED adult syncope management have low-quality evidence for routine clinical practice use. Only three CDRs (SFSR, CSRS, OESIL) are validated by more than two studies, with significant overlap in operating characteristics.</p

Developing and piloting a peer quality improvement coaching protocol for front-line healthcare staff

Background: Improving the quality of patient care remains a global necessity. Despite system and professional benefits, current evidence indicates that the spread of improvement principles among front-line healthcare workers remains poor. While education and training alone are unlikely to result in consistent improvement practice, coaching can play a critical role in sustainable, evidence-based improvement implementation. Peer quality improvement coaching (PQIC) places the power and agency in the shared relationship between coach and coachee to shape coachee quality improvement (QI) outcomes. Study objective was to develop and pilot an evidence-based protocol for implementation and evaluation of a PQIC for front-line staff engaged in small to intermediate improvement efforts.Methods: We conducted a multistage case-study design and implementation process. First, a systematised literature review identified themes about the theory and practice of QI coaching (QIC). Second, these themes guided the development of a PQIC protocol. Finally, the protocol was piloted and evaluated among staff in a single-centre tertiary maternity hospital. PQIC effectiveness was assessed using evaluation tools identified in the literature.Results: Effectiveness; strategies and models; moderating factors and methods for evaluation of QIC emerged from the literature. Together with Bloom's taxonomy and Kirkpatrick's educational model, these themes informed the development of this PQIC protocol. It was piloted in three steps: education, coaching and evaluation. A survey revealed that the participants in the education step achieved excellent scores. Following the coaching journey, the coached multidisciplinary team leaders completed their improvement initiatives and demonstrated increased QI knowledge and skills measured by the 'IHI improvement advisor self-assessment tool' and 'IHI assessment scale for collaboratives'.Conclusion: Built on established education, peer coaching and QI concepts, this evidence-based PQIC protocol adds to international evidence on how to support front-line healthcare workers in their improvement efforts. Future research needs to assess protocol effectiveness across different settings.</p