What is the role of non-surgical clinicians in the assessment and management of degenerative cervical myelopathy? - insights from the RECODE-DCM peri-operative rehabilitation incubator

Introduction: Evidence on degenerative cervical myelopathy (DCM) has frequently focussed on surgical management, overlooking the role of non-surgical clinicians. Their contributions in the patient journey remain largely underexplored in the literature.Research question: What is the role of non-surgical clinicians in the assessment and management of people with DCM?Material and methods: This narrative review synthesizes knowledge from a comprehensive MEDLINE search and the collective expertise of the RECODE-DCM Peri-Operative Rehabilitation Incubator, an expert working group hosted by Myelopathy.org. Key domains of non-surgical clinician involvement include: 1) early recognition and referral, 2) patient education, 3) pain management, 4) preoperative management, and 5) postoperative rehabilitation.Results: Timely DCM diagnosis depends on first-contact clinicians recognizing hallmark symptoms. In the absence of standardized screening criteria, tools like the modified Japanese Orthopaedic Association score can support early identification. Non-surgical clinicians educate patients with mild or non-myelopathic spinal cord compression to recognize signs of DCM progression, ensuring timely surgical consultation. These clinicians also play a multidisciplinary role in the biopsychosocial management of pain, incorporating pharmacological and non-pharmacological strategies to address nociceptive and neuropathic pain. While predictors of postoperative outcomes, such as disease severity, gait dysfunction and smoking, are known, evidence on preoperative optimization and prehabilitation remains limited. Emerging research highlights the benefits of early postoperative rehabilitation, including cervical range of motion and stabilization exercises, in improving 12-month postoperative outcomes.Discussion and conclusion: Non-surgical clinicians play an integral role in DCM management across the care continuum. A multidisciplinary, patient-centred approach is essential. Postoperative rehabilitation holds promise, but prospective trials are necessary to establish standardization and optimal strategies for clinical delivery.</p

Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF

Previous reports have highlighted that some patients with low von Willebrand factor (VWF) with significant bleeding were diagnosed based on an isolated but persistent reduction in plasma VWF activity levels in the 30 to 50 IU/dL range. These patients had plasma VWF antigen (VWF:Ag) levels >50 IU/dL and thus had qualitative low VWF (low VWF–QL) rather than quantitative low VWF. Although the clinical importance of functional VWF defects in type 2 von Willebrand disease (VWD) is well recognized, the translational implications of mild functional defects in patients with low VWF–QL have not been defined. To address this clinically important question, we combined low VWF data sets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF–QL was common and accounted for ∼50% of our combined low VWF cohort. Importantly, our findings demonstrated that many of these patients with mild isolated functional VWF defects in the 30 to 50 IU/dL range had significant bleeding phenotypes, although their plasma VWF:Ag levels were within the normal range. In addition, we further showed that low VWF–QL is a distinct clinic-pathological entity compared to type 2 VWD. Finally, our studies highlighted that low VWF–QL is predominantly caused by abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.</p

Neoadjuvant immunotherapy for resectable non-small-cell lung cancer

Lung cancer is the commonest cause of cancer death worldwide and approximately 85% of cases are non-small-cell cancer (NSCLC). In the decade from 2010 to 2020 there were many new systemic therapies developed and approved for the treatment of advanced NSCLC however no major therapeutic advances in the treatment of surgically resectable disease. Patients with stage II or III NSCLC, despite ostensibly curative surgery, have a survival rate at five years of The five studies included in this PhD encompass the clinical development of neoadjuvant anti-PD-1 immunotherapy with the monoclonal antibody, nivolumab, for resectable NSCLC including the first description of potential biomarkers of response.  In chapter 1, in the first study, I reported the initial results of a 21 patient investigator-initiated clinical trial of neoadjuvant nivolumab for patients with surgically resectable lung cancer. This was the first reported study of neoadjuvant anti-PD-1 for early stage lung cancer, this class of drugs has revolutionized the treatment of advanced lung cancer over the past 10 years. In the study I found that neoadjuvant anti-PD-1 was safe and feasible, that 45% of patients who underwent surgical resection had a major pathologic response after 2 doses of nivolumab, and that tumor mutational burden (TMB) appeared to predict pathologic response, the first descriptions of each of these findings.  Further exploring the potential role of biomarkers in predicting tumor response to PD-1 pathway blockade, chapter 2 exploresthe potential role of circulating tumor DNA (ctDNA) in predicting tumor response to immunotherapy. This study demonstrated for the first time that ctDNA dynamics during the neoadjuvant immunotherapy isa potential predictor of pathologic response in NSCLC and I expanded upon these findings in the phase 3 Check Mate 816 trial.  Chapter 3 constitutes a study of neoadjuvant combination immunotherapy with nivolumab and the anti-CTLA4 antibody, ipilimumab, for patients with resectable NSCLC, a regimen which has been shown survival in advanced NSCLC. Despite promising pathologic responses in this study, neoadjuvant ipilimumab plus nivolumab was also associated with increased toxicity eventually leading to enrolment being halted early.  In chapter 4, building on my original pilot trial of neoadjuvant nivolumabI led the phase 3 trial, Check Mate 816, studying the combination of chemotherapy plus nivolumab compared chemotherapy alone prior to surgery for stage IB to IIIA NSCLC. This study was aimed at showing higher rates of pathologic complete response and improved event-free survival with the combination of chemo-immunotherapy. Ultimately the results were positive for both primary endpoints leading to the regulatory approval of neoadjuvant chemotherapy plus nivolumab as a treatment for NSCLC in the United States and European Union among other jurisdictions. The study also demonstrated that pathologic response is a potential predictor of event-free survival building on my earlier findings that ctDNA clearance during neoadjuvant therapy may portend an improved long term outcome.   Finally, in chapter 5,I reported five year outcomes from my initial trial of neoadjuvant nivolumab showing that patients who experienced a tumor major pathologic response to nivolumab had an excellent long term outcome.  In conclusion, these studies contribute valuable insights into the use of neoadjuvant immunotherapy for NSCLC and have led directly to adoption of neoadjuvant nivolumab plus chemotherapy as a standard therapy in countries worldwide. </p

Defibrillati|on|off

Life is pleasant. Death is peaceful. It’s the transition that’s troublesome.—Isaac AsimovToday, 1 in 5 of us will develop heart failure, a diagnosis that has until recently carried a grave prognosis; however, we now have multiple therapies to improve both morbidity and mortality in this cohort. We know that the use of implantable cardioverter defibrillators (ICDs) can reduce the risk of sudden cardiac death in selected patients with heart failure.2,3 In the early 2000s, results from the ICD trials were met with almost universal enthusiasm, and implantation rates soared; however, decisions on ICD implantation in patients with complex conditions continued to provoke debate in practice. In part, these arguments concerned uncertainties about what we should do when an eligible patient might be exposed to harm. “What goes up, must come down,” said Isaac Newton. Similarly, the implantation and activation of an ICD must be followed by its deactivation. Current decisions on ICD deactivation are usually solely evidence based and do not consider that we know that some patients, often approaching the end of their lives, will not reasonably benefit from any therapy an ICD can deliver.</p

Impact of the Glycan Component of the Biomolecular Corona Formed Around Nanoparticles

Advances in engineering functional structures at the nanoscale have led to the generation of a wide range of nanoparticles (NPs) that have promising therapeutic applications as drug delivery tools. However, when NPs get in contact with a complex biological milieu, they strongly interact with the available biomolecules, mostly glycoproteins, gaining a new layer defined as the “corona”. Recent findings have shown that the glycan component of the corona can affect NPs stability and it is unclear whether it can modulate biological responses through the glycan-binding receptors present in the body. This study developed a new platform to obtain a quantitative and qualitative characterisation of the corona glycosylation and tested its capability to modulate the NP uptake after being exposed to different cell lines. To address this problem, fluorescently labelled 100nm silica NPs were coated with two different biomolecular coronas derived from human plasma, reflective in a diverse glycosylation pattern. The two biomolecular layers of the NPs were characterized in their protein and glycosylated components using a platform recently established in our group with the support of an industrial partner. As the glycans are biologically active molecules, the ones forming the corona were tested to evaluate if they could directly control the NP-corona complexes’ biological fate. Finally, the uptake of the NP-biomolecular coronas in macrophage and hepatocyte cell models was tested, with a focus on the influence of N-glycans and their terminal monosaccharide sialic acid. This research showed that specific glycosylation of the corona could influence the recognition of the nanomaterials, and that differences in the presence of the sialic acid could change the NP-biomolecular corona interaction processes. Overall, these findings may clarify specific nanomaterial behaviours, and give new parameters to predict or functionalise drug carriers for future therapies.</p

Life after stroke and supportive stroke pathways: protocol for a rapid realist review [version 1; peer review: 1 approved]

Background: Ever-growing numbers of individuals are surviving stroke and living with the consequences. Life after stroke is a key pillar in addressing the burden of stroke for the remaining lifespan for those with stroke. No consensus on how to best promote agency and fulfilment in life after stroke or the resources required to achieve this currently exists.Methods: In this realist review protocol we outline the methods we will use to gain an understanding of supporting Life after Stroke through the development of programme theories. These will consist of context-mechanism-outcome configurations (CMOCs) and will acknowledge the resources required. The review will follow the RAMESES five-stage structured methodology to (1) define the scope of the review, and the development of initial programme theories for supporting life after stroke, (2) develop a comprehensive search strategy to identify relevant research, (3) review primary studies and extract data, (4) synthesise evidence (5) refine programme theories iteratively throughout the process using an Expert Panel and reference group, to including stroke researchers, health care professionals working in stroke care, people with lived experience of stroke and carers, and stroke support agencies.Conclusion: This realist review aims to conceptualise supports for Life after Stroke. The CMOCs developed will help explain how generative causation within the life after stroke pathway works. The findings will help inform policy and practice and inform future realist evaluations of Life after Stroke support pathways.</p

Increased risk of admission to neonatal intensive care unit in neonates born to mothers with pregestational diabetes

The purpose of this study was to describe how maternal diabetes impacts admission to the neonatal intensive care unit to support healthcare professionals when counselling patients. The primary outcome was admission rates. A retrospective observational cohort study of 25,238 births was conducted at an Irish tertiary maternity hospital from January 2018 to December 2020. Cases of pregestational and gestational diabetes were examined for neonatal intensive care admission outcomes. R statistical analysis software was used. There were 3905 live neonates born between 34 and 42 weeks to mothers with diabetes (N = 67 type 1 diabetes, N = 60 type 2 diabetes, N = 3712 gestational diabetes, N = 5 mature onset diabetes, excluded N = 61). There was a statistically significant difference in mean gestational age: 37 + 1 (weeks/days) (95% CI 36 + 6–37 + 4), 38 + 1 (95% CI 37 + 5–38 + 3, p = 0.0019), and 39 (95% CI 38 + 6–39 + 1, p ≤ 0.001) in type 1, type 2, and gestational diabetes cohorts. Admission rate was 13.4% with significant differences between the subgroups: 41.8% [95% CI 2.33–4.58, RR 3.32], 31.1% [95% CI 1.55–3.50, RR 3.89], and 12.5% [95% CI 0.12–0.14, RR 0.133] in type 1, type 2, and gestational diabetes cohorts. A higher percentage of mothers with pregestational diabetes (42.9% and 31.5%) were discharged before their infants, versus 21.2% of gestational diabetes.</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

Longitudinal relationship between hip displacement and hip function in children and adolescents with cerebral palsy: a scoping review

Aim: To identify, describe, and synthesize available evidence on the longitudinal relationship between hip displacement and hip function, using the International Classification of Functioning, Disability and Health (ICF) framework, in children and adolescents with cerebral palsy (CP) aged up to 18 years.Method: Five databases were searched systematically from inception to May 2022. Study and sample characteristics, and hip displacement and hip function measures, mapped to the ICF domains, were extracted for narrative synthesis.Results: Twenty-nine studies were included: four longitudinal registry-based studies; 12 prospective studies; 12 retrospective studies; and one randomized controlled trial. Sample size ranged from 11 to 267. Twenty-seven (93%) studies entailed an intervention: surgery (n = 16); rehabilitation (n = 2); nerve block or botulinum neurotoxin A injection (n = 4); and combined surgery and injection (n = 2). Twenty-six studies (90%) reported outcomes at the body structure and function and impairment domain of the ICF; 17 (59%) reported outcomes in the activity domain; and three (10%) included participation measures. The most common hip displacement measure was Reimers' migration percentage (79%).Interpretation: Because of the inclusion of interventions in most studies, and the preponderance of retrospective studies, the relationship between hip displacement and hip function in CP is unclear. More high-quality prospective evidence on the natural history of hip displacement, and its effect on function, is needed to improve population-wide screening of children with CP.</p