A Mechanistic and Preclinical Assessment of BioRestore Bioactive Glass as a Synthetic Bone Graft Extender and Substitute for Osteoinduction and Spine Fusion.

STUDY DESIGN: Preclinical animal study. OBJECTIVE: Evaluate the osteoinductivity and bone regenerative capacity of BioRestore bioactive glass. SUMMARY OF BACKGROUND DATA: BioRestore is a Food and Drug Administration (FDA)-approved bone void filler that has not yet been evaluated as a bone graft extender or substitute for spine fusion. METHODS: In vitro and in vivo methods were used to compare BioRestore with other biomaterials for the capacity to promote osteodifferentiation and spinal fusion. The materials evaluated (1) absorbable collagen sponge (ACS), (2) allograft, (3) BioRestore, (4) Human Demineralized Bone Matrix (DBM), and (5) MasterGraft. For in vitro studies, rat bone marrow-derived stem cells (BMSC) were cultured on the materials in either standard or osteogenic media (SM, OM), followed by quantification of osteogenic marker genes ( Runx2, Osx, Alpl, Bglap, Spp1 ) and alkaline phosphatase (ALP) activity. Sixty female Fischer rats underwent L4-5 posterolateral fusion (PLF) with placement of 1 of 5 implants: (1) ICBG from syngeneic rats; (2) ICBG+BioRestore; (3) BioRestore alone; (4) ICBG+Allograft; or (5) ICBG+MasterGraft. Spines were harvested 8 weeks postoperatively and evaluated for bone formation and fusion via radiography, blinded manual palpation, microCT, and histology. RESULTS: After culture for 1 week, BioRestore promoted similar expression levels of Runx2 and Osx to cells grown on DBM. At the 2-week timepoint, the relative ALP activity for BioRestore-OM was significantly higher ( P <0.001) than that of ACS-OM and DBM-OM ( P <0.01) and statistically equivalent to cells grown on allograft-OM. In vivo, radiographic and microCT evaluation showed some degree of bridging bone formation in all groups tested, with the exception of BioRestore alone, which did not produce successful fusions. CONCLUSIONS: This study demonstrates the capacity of BioRestore to promote osteoinductivity in vitro. In vivo, BioRestore performed similarly to commercially available bone graft extender materials but was incapable of producing fusion as a bone graft substitute. LEVEL OF EVIDENCE: Level V.

Auxochrome Dimethyl-Dihydroacridine Improves Fluorophores for Prolonged Live-Cell Super-Resolution Imaging.

Superior photostability, minimal phototoxicity, red-shifted absorption/emission wavelengths, high brightness, and an enlarged Stokes shift are essential characteristics of top-tier organic fluorophores, particularly for long-lasting super-resolution imaging in live cells (e.g., via stimulated emission depletion (STED) nanoscopy). However, few existing fluorophores possess all of these properties. In this study, we demonstrate a general approach for simultaneously enhancing these parameters through the introduction of 9,9-dimethyl-9,10-dihydroacridine (DMA) as an electron-donating auxochrome. DMA not only induces red shifts in emission wavelengths but also suppresses photooxidative reactions and prevents the formation of triplet states in DMA-based fluorophores, greatly improving photostability and remarkably minimizing phototoxicity. Moreover, the DMA group enhances the fluorophores' brightness and enlarges the Stokes shift. Importantly, the "universal" benefits of attaching the DMA auxochrome have been exemplified in various fluorophores including rhodamines, difluoride-boron complexes, and coumarin derivatives. The resulting fluorophores successfully enabled the STED imaging of organelles and HaloTag-labeled membrane proteins.

The Irish Trainee Emergency Research Network (ITERN): five years of collaboration.

In 2018, a group of Irish emergency medicine (EM) trainees recognised their common interest in collaborative research and the difficulties that trainees can encounter when trying to broaden their research capacity, prompting the beginning of the Irish Trainee Emergency Research Network (ITERN) journey. Trainee-led collaboratives have been shown to be feasible and have the potential to deliver impactful research projects, generating an evidence base that may not have been possible without collaboration. This article describes the successes and achievement of ITERN and describes the processes and challenges that a trainee-led research network can encounter. The authors believe that trainee-led collaboratives can deliver powerful and impactful research for patients and broaden the research capacity of individuals, hospitals, and groups of healthcare professionals.

Randomised trial of stable chest pain investigation: 3-year clinical and quality of life results from CE-MARC 2.

AIMS: Guidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures. METHODS: CE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded. RESULTS: 1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains. CONCLUSION: Despite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT01664858).

Attitudes and knowledge of emergency doctors towards end-of-life care in the emergency department: a national survey.

BACKGROUND: Emergency departments (EDs) are seeing an increase in patients requiring end-of-life (EOL) care. There is paucity of data of attitudes and knowledge of physicians providing EOL care in the ED both internationally and in Ireland. OBJECTIVE: The aim of this project was to assess the attitudes and knowledge of ED physicians towards EOL care. METHODS: This was a cross-sectional electronic survey of ED physicians working in Irish EDs and was facilitated through the Irish Trainee Emergency Research Network over a 6-week period. The questionnaire covered the following domains: demographic data, awareness of EOL Care, views and attitudes towards EOL care. RESULTS: Of a potential 679 respondents, 441 responses were received, of which 311 (response rate of 44.8%) had fully completed the survey across 23 participant sites. Majority of the respondents were under the age of 35 (62%), were male (58%) and at Senior House Officer level (36%). In terms of awareness, 32% (98) of respondents were not aware of palliative care services in their hospitals while only 29% (91) were aware of national EOL guidance. Fifty-five percent (172) reported commencing EOL care in the ED, however 75.5% (234) respondents reported their knowledge of EOL care to be limited or non-existent. Only 30.2% respondents felt comfortable commencing EOL care in the ED without speciality team input. There appears to be a lack of clarity on the roles and responsibilities of emergency medicine nurses and doctors in the care of the dying patient in ED with only 31.2% (95) being clear on this role. Significant differences were observed associated with clinical experience and physician grade. CONCLUSION: This study has highlighted a lack of awareness and knowledge of EOL care particularly amongst less experienced emergency medicine doctors. Formalized training and education programs in the provision of EOL care in the ED will improve comfort levels and knowledge amongst the emergency medicine doctors and improve the quality of care provided.

Three birds one stone: an enzyme-activatable theragnostic agent for fluorescence diagnosis, photodynamic and inhibitor therapies.

AX11890, an inhibitor of overexpressed enzyme, KIAA1363, in some breast cancers, was conjugated with a benzo[a]phenothiazinium photosensitizer to develop a tumor micro-environment-responsive photosensitizer NBS-L-AX. In normal cells, the special geometry of NBS-L-AX causes the fluorescence and photodynamic therapeutic (PDT) effect of NBS-L to be quenched. In cancer cells, when allowed to interact with the enzyme KIAA1363, the geometry of NBS-L-AX changes such that it becomes fluorescent and photodynamically active. Thus, the material of NBS-L-AX serves as an activated imaging and PDT treatment agent for breast cancers. In addition, NBS-L-AX also shows a selective inhibition effect against breast cancer cells.

Cardiovascular imaging techniques for the assessment of coronary artery disease.

Coronary artery disease continues to be the leading cause of morbidity and mortality worldwide. Recent clinical trials have not demonstrated any mortality benefit of percutaneous coronary intervention compared to medical management alone in the treatment of stable angina. While invasive coronary angiography remains the gold standard for diagnosing coronary artery disease, it comes with significant risks, including myocardial infarction, stroke and death. There have been significant advances in imaging techniques to diagnose coronary artery disease in haemodynamically stable patients. The latest National Institute for Health and Care Excellence and European College of Cardiology guidelines emphasise the importance of using these imaging techniques first to inform diagnosis. This review discusses these guidelines and imaging techniques, alongside their benefits and drawbacks.

Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model.

STUDY DESIGN: This was a preclinical study. OBJECTIVE: Evaluate sex-dependent differences in the bone healing response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat posterolateral spinal fusion model. SUMMARY OF BACKGROUND DATA: Minimal and conflicting data exist concerning potential sex-dependent differences in rhBMP-2-mediated bone regeneration in the context of spinal fusion. MATERIALS AND METHODS: Forty-eight female and male Sprague-Dawley rats (N=24/group), underwent L4-L5 posterolateral fusion with bilateral placement of an absorbable collagen sponge, each loaded with 5 µg of bone morphogenetic protein-2 (10 µg/animal). At eight weeks postoperative, 10 specimens of each sex were tested in flexion-extension with quantification of range of motion and stiffness. The remaining specimens were evaluated for new bone growth and successful fusion via radiography, blinded manual palpation and microcomputed tomography (microCT). Laboratory microCT quantified bone microarchitecture, and synchrotron microCT examined bone microstructure at the 1 µm level. RESULTS: Manual palpation scores differed significantly between sexes, with mean fusion scores of 2.4±0.4 in females versus 3.1±0.6 in males ( P <0.001). Biomechanical stiffness did not differ between sexes, but range of motion was significantly greater and more variable for females versus males (3.7±5.6° vs. 0.27±0.15°, P <0.005, respectively). Laboratory microCT showed significantly smaller volumes of fusion masses in females versus males (262±87 vs. 732±238 mm 3 , respectively, P <0.001) but significantly higher bone volume fraction (0.27±0.08 vs. 0.12±0.05, respectively, P <0.001). Mean trabecular thickness was not different, but trabecular number was significantly greater in females (3.1±0.5 vs. 1.5±0.4 mm -1 , respectively, P <0.001). Synchrotron microCT showed fine bone structures developing in both sexes at the eight-week time point. CONCLUSIONS: This study demonstrates sex-dependent differences in bone regeneration induced by rhBMP-2. Further investigation is needed to uncover the extent of and mechanisms underlying these sex differences, particularly at different doses of rhBMP-2.

National Emergency Resuscitation Airway Audit (NERAA): a pilot multicentre analysis of emergency intubations in Irish emergency departments.

BACKGROUND: There is paucity of literature on why and how patients are intubated, and by whom, in Irish Emergency Departments (EDs). The aim of this pilot study was to characterise emergency airway management (EAM) of critically unwell patients presenting to Irish EDs. METHODS: A multisite prospective pilot study was undertaken from February 10 to May 10, 2020. This project was facilitated through the Irish Trainee Emergency Research Network (ITERN). All patients over 16 years of age requiring EAM were included. Eleven EDs participated in the project. Data recorded included patients' demographics, indication for intubation, technique of airway management, medications used to facilitate intubation, level of training and specialty of the intubating clinician, number of attempts, success/complications rates and variation across centres. RESULTS: Over a 3-month period, 118 patients underwent 131 intubation attempts across 11 EDs. The median age was 57 years (IQR: 40-70). Medical indications were reported in 83% of patients compared to 17% for trauma. Of the 118 patients intubated, Emergency Medicine (EM) doctors performed 54% of initial intubations, while anaesthesiology/intensive care medicine (ICM) doctors performed 46%. The majority (90%) of intubating clinicians were at registrar level. Emergency intubation check lists, video laryngoscopy and bougie were used in 55, 53 and 64% of first attempts, respectively. The first pass success rate was 89%. Intubation complications occurred in 19% of patients. EM doctors undertook a greater proportion of intubations in EDs with > 50,000 attendance (65%) compared to EDs with < 50,000 attendances (16%) (p < 0.000). CONCLUSION: This is the first study to describe EAM in Irish EDs, and demonstrates comparable first pass success and complication rates to international studies. This study highlights the need for continuous EAM surveillance and could provide a vector for developing national standards for EAM and EAM training in Irish EDs.