Aims/Purpose: This study aims to improve bidirectional communication strategies between patients/public, preclinical researchers, and clinical experts to address the lack of effective public and patient involvement (PPI) in preclinical vision research, aiming to refocus research on actual patient needs.Methods: An international team conducted multiple PPI activities, including a critical review on PPI in preclinical ocular research1, World‐café workshops, patient interviews, structured surveys, and round‐table discussions. Dry Eye Disease's wide clinical presentation and impact on daily life were explored. Patient experiences were shared to better understand their needs, increase research value, awareness, and advocacy.Results: Activities highlighted the need for incorporating PPI in ocular research at the preclinical stage. Recurrent themes were identified across patients and researchers. From 20 patient interviews and 50 surveys, 82% responded that they received most information from clinical spaces and were unaware of current research.2 Patients did not know how to become involved in PPI. In a PPI Training Course, 19 preclinical researchers agreed on the need for clearer PPI guidelines and training.Conclusions: PPI activities emphasized DED's severe impact on QoL and the need for new treatments. Round‐table discussions fostered connections and deeper understanding of DED, shifting researchers' focus to unmet patient needs. Further integration of PPI into preclinical research will benefit both researchers and patients. This multimodal PPI approach can benchmark incorporating patient perspectives in preclinical ocular research. Next steps – with patients, create a tool kit for communications skills development for pre‐clinical researchers.References Ames T, Matthews E, Reynolds A et al. How patient/public involvement impacts the research journey – an overview of the visual impairment research field, Open Res Europe 2023, 3: 135. https://doi.org/10.12688/openreseurope.16057.1. Ames T, Matthews E, Reynolds A et al. ARVO. 2024. Dry Eye Disease as a case study to understand the public and patient involvement gap in lab‐based preclinical vision research using interdisciplinary approaches [Poster].

Gellan is an anionic polysaccharide that forms optically clear hydrogels, making it suitable for use in ocular applications. Previous research has demonstrated that gellan fluid gels, when used alongside standard treatments (antibiotics and corticosteroid eye drops), reduce corneal scarring in models of microbial keratitis. This study investigated the potential mechanisms behind the enhanced corneal healing observed with drug-free gellan fluid gels. The impact of varying formulation parameters, such as polymer concentration and applied shear rate, on the physical properties of the fluid gels, including viscosity, stiffness, and lubricity, was examined to optimise gellan fluid gels for use as therapeutic eye drops. Biological analyses were undertaken that highlighted the capacity of gellan fluid gels to provide corneal cells with effective lubrication preventing cell removal on the application of shear. Additionally, gellan fluid gels were shown to sequester TGFβ1, a pro-fibrotic cytokine. Sequestration of the TGFβ1 resulted from electrostatic interactions between the negatively charged gellan and positively charged TGFβ1. As a consequence of this, gellan fluid gels inhibit TGFβ1-induced pro-fibrotic gene expression in corneal fibroblasts, contributing to reduced scarring and improved wound healing. The results suggest that gellan fluid gels, through modulation of physical properties and biological interactions, offer a mechanism for promoting ocular healing and mitigating inflammation-induced scarring, even in the absence of pharmaceutical actives. STATEMENT OF SIGNIFICANCE: This study presents the development of gellan fluid gel eye drops designed to prevent ocular fibrosis after damage. The formulation achieved lubricity comparable to commercial eye drops but with significantly enhanced viscosity and superior capacity to shield cells from damaging shear forces. By optimising gellan concentration and fabrication parameters, the eye drops exhibited reduced ocular friction and improved therapeutic efficacy. Additionally, the fluid gels sequestered TGFβ1, a key fibrosis molecule, with higher gellan concentrations showing enhanced absorption. Importantly, the formulations maintained ease of application through droppers, making them practical for daily use. This work highlights a cost-effective and patient-friendly solution, advancing biomaterial-based therapies for ocular therapies.

Objective:Assess retinal perfusion in sepsis, compared with uncomplicated postoperative care and healthy controls, and assess the effects of reduced perfusion on retinal structure and visual function. Design:We conducted a prospective observational cohort study between March 2018 and December 2022, with follow-up measures collected 3 to 6 months after discharge. Subjects:Twenty-four patients with sepsis were assessed in the intensive care unit (ICU) and 3 to 6 months later, 45 ICU control patients assessed during elective ICU admission after upper gastrointestinal cancer surgery, preoperatively, and 3 to 6 months later, and 15 healthy controls. Testing:Assessments included retinal layer thickness using OCT, retinal perfusion using OCT angiography, and visual function using Humphrey visual field analysis. Organ dysfunction was assessed by Sequential Organ Failure Assessment (SOFA) scoring. Main Outcome Measures:Superficial vascular plexus (SVP) retinal perfusion, OCT retinal ganglion cell layer (GCL) thickness, and mean deviation (MD) on Humphrey visual field testing were evaluated. Results:Superficial vascular plexus retinal perfusion was 37.4% lower in patients with sepsis compared with ICU control patients (P < 0.001) and 59.7% lower than in healthy controls, which returned to normal by final follow-up. Retinal perfusion correlated with the SOFA score (Pearson r = -0.57, P < 0.001) and weakly correlated with C-reactive protein (r = -0.337, P = 0.01) and mean arterial pressure (r = 0.354, P = 0.006). In patients with sepsis and ICU controls, retinal perfusion in the ICU predicted subsequent GCL thickening, with every 1-unit decrease in SVP sum predicting a 1.88 μm increase in GCL thickness at follow-up (P = 0.003), and worsening visual field MD, with every 1-unit decrease in SVP sum predicting a 0.078 decibel lower MD (P = 0.023). Conclusions:Retinal perfusion was impaired in patients with sepsis compared with both healthy controls and patients after major surgery. It was moderately associated with other measures of organ dysfunction assessed by SOFA. Reduced retinal perfusion in both patients with sepsis and patients after major surgery is strongly associated with subsequent GCL thickening and less strongly associated with decreased visual field MD, suggesting reduced retinal perfusion is associated with retinal damage, with consequent visual dysfunction. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

AbstractOptical coherence tomography angiography (OCTA) is widely used for non-invasive retinal vascular imaging, but the OCTA methods used to assess retinal perfusion vary. We evaluated the different methods used to assess retinal perfusion between OCTA studies. MEDLINE and Embase were searched from 2014 to August 2021. We included prospective studies including ≥ 50 participants using OCTA to assess retinal perfusion in either global retinal or systemic disorders. Risk of bias was assessed using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies. Heterogeneity of data was assessed by Q statistics, Chi-square test, and I2 index. Of the 5974 studies identified, 191 studies were included in this evaluation. The selected studies employed seven OCTA devices, six macula volume dimensions, four macula subregions, nine perfusion analyses, and five vessel layer definitions, totalling 197 distinct methods of assessing macula perfusion and over 7000 possible combinations. Meta-analysis was performed on 88 studies reporting vessel density and foveal avascular zone area, showing lower retinal perfusion in patients with diabetes mellitus than in healthy controls, but with high heterogeneity. Heterogeneity was lowest and reported vascular effects strongest in superficial capillary plexus assessments. Systematic review of OCTA studies revealed massive heterogeneity in the methods employed to assess retinal perfusion, supporting calls for standardisation of methodology.

To investigate if retinal thickness has predictive utility in COVID-19 outcomes by evaluating the statistical association between retinal thickness using OCT and of COVID-19-related mortality. Secondary outcomes included associations between retinal thickness and length of stay (LoS) in hospital. In this retrospective cohort study, OCT scans from 230 COVID-19 patients admitted to the Intensive Care Unit (ITU) were compared with age and gender-matched patients with pneumonia from before March 2020. Total retinal, GCL + IPL, and RNFL thicknesses were recorded, and analysed with systemic measures collected at the time of admission and mortality outcomes, using linear regression models, Pearson’s R correlation, and Principal Component Analysis. Retinal thickness was significantly associated with all-time mortality on follow up in the COVID-19 group (p = 0.015), but not 28-day mortality (p = 0.151). Retinal and GCL + IPL layer thicknesses were both significantly associated with LoS in hospital for COVID-19 patients (p = 0.006 for both), but not for patients with pneumonia (p = 0.706 and 0.989 respectively). RNFL thickness was not associated with LoS in either group (COVID-19 p = 0.097, pneumonia p = 0.692). Retinal thickness associated with LoS in hospital and long-term mortality in COVID-19 patients, suggesting that retinal structure could be a surrogate marker for frailty and predictor of disease severity in this group of patients, but not in patients with pneumonia from other causes.

BACKGROUND:Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics. PATIENTS AND METHODS:This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28. FINDINGS:Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection. INTERPRETATION:Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS. TRIAL REGISTRATION:EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.

Wet age-related macular degeneration (wAMD) is a chronic inflammation-associated neurodegenerative disease affecting the posterior part of the eye in the aging population. Aging results in the reduced functionality of cells and tissues, including the cells of the retina. Initiators of a chronic inflammatory and pathologic state in wAMD may be a result of the accumulation of inevitable metabolic injuries associated with the maintenance of tissue homeostasis from a young age to over 50. Apart from this, risk factors like smoking, genetic predisposition, and failure to repair the injuries that occur, alongside attempts to rescue the hypoxic outer retina may also contribute to the pathogenesis. Aging of the immune system (immunosenescence) and a compromised outer blood retinal barrier (BRB) result in the exposure of the privileged milieu of the retina to the systemic immune system, further increasing the severity of the disease. When immune-privileged sites like the retina are under pathological stress, certain age- and disease-related conditions may necessitate assistance from cells distant from the resident ones to help restore the functionality of the tissue. As a necessary part of tissue repair, inflammation is a major response to disease and recruits immune cells to the site of damage. We suspect that the specific reparative inflammatory responses are controlled by an autoantigen-T cell-mediated mechanism, a process that may be hindered in wAMD.

The flavivirus family are responsible for the most abundant arboviral diseases of humans in terms of geographical distribution, morbidity and mortality; at least 2.5 billion people are at risk with, for example, an estimated 100-400 million Dengue infections a year. However, for infections by Dengue, Zika or Yellow Fever virus there are no effective anti-infective drug treatments nor for Dengue or Zika virus a safe effective vaccine and prevention at present focusses on vector (mosquito) control. Whilst symptoms from Dengue, Zika and Yellow Fever virus infection may be mild for some, they are very serious and life threatening for others. For instance, severe Dengue is a leading cause of hospitalisation and death among children and adults in Asian and Latin American countries. Likewise, Zika infection can have catastrophic consequences for pregnant women following the passing of the virus to their foetus with arising miscarriage or birth defects including microcephaly that can be fatal. The aim of the present study was to evaluate the potential of a unique low molecular weight dextran sulphate (LMW-DS) clinical stage drug, ILB ® , to inhibit infection of human cells by four serotypes of Dengue virus (DENV1-4), two strains of Zika virus (African and Asian) and Yellow Fever virus (vaccine strain YF17D) assessed by immunofluorescence of viral particles. ILB ® potently inhibited infection by all the strains of Dengue, Zika and Yellow Fever virus in a concentration-dependent manner with IC 50 for ILB® ranging from 31 to 343 μg/ml. In conclusion, given the safety profile of ILB ® established in a number of Phase I and Phase II clinical trials, these results highlight the potential of ILB ® to treat patients infected with Dengue, Zika or Yellow Fever virus with the opportunity to translate the findings quickly by clinical investigation.

In a previous study, we found that administration of ILB®, a new low molecular weight dextran sulphate, significantly improved mitochondrial functions and energy metabolism, as well as decreased oxidative/nitrosative stress, of brain tissue of rats exposed to severe traumatic brain injury (sTBI), induced by the closed-head weight-drop model of diffused TBI. Using aliquots of deproteinized brain tissue of the same animals of this former study, we here determined the concentrations of 24 amino acids of control rats, untreated sTBI rats (sacrificed at 2 and 7 days post-injury) and sTBI rats receiving a subcutaneous ILB® administration (at the dose levels of 1, 5 and 15 mg/kg b.w.) 30 min post-impact (sacrificed at 2 and 7 days post-injury). Additionally, in a different set of experiments, new groups of control rats, untreated sTBI rats and ILB®-treated rats (administered 30 min after sTBI at the dose levels of 1 or 5 mg/kg b.w.) were studied for their neurocognitive functions (anxiety, locomotor capacities, short- and long-term memory) at 7 days after the induction of sTBI. Compared to untreated sTBI animals, ILB® significantly decreased whole brain glutamate (normalizing the glutamate/glutamine ratio), glycine, serine and γ-aminobutyric acid. Furthermore, ILB® administration restored arginine metabolism (preventing nitrosative stress), levels of amino acids involved in methylation reactions (methionine, L-cystathionine, S-adenosylhomocysteine), and N-acetylaspartate homeostasis. The macroscopic evidences of the beneficial effects on brain metabolism induced by ILB® were the relevant improvement in neurocognitive functions of the group of animals treated with ILB® 5 mg/kg b.w., compared to the marked cognitive decline measured in untreated sTBI animals. These results demonstrate that ILB® administration 30 min after sTBI prevents glutamate excitotoxicity and normalizes levels of amino acids involved in crucial brain metabolic functions. The ameliorations of amino acid metabolism, mitochondrial functions and energy metabolism in ILB®-treated rats exposed to sTBI produced significant improvement in neurocognitive functions, reinforcing the concept that ILB® is a new effective therapeutic tool for the treatment of sTBI, worth being tested in the clinical setting.

Introduction Amyotrophic lateral sclerosis (ALS) is an invariably lethal progressive disease, causing degeneration of neurons and muscle. No current treatment halts or reverses disease advance. This single arm, open label, clinical trial in patients with ALS investigated the safety and tolerability of a novel modified low molecular weight dextran sulphate (LMW-DS, named ILB®) previously proven safe for use in healthy volunteers and shown to exert potent neurotrophic effects in pre-clinical studies. Secondary endpoints relate to efficacy and exploratory biomarkers. Methods Thirteen patients with ALS were treated with 5 weekly subcutaneous injections of ILB®. Safety and efficacy outcome measures were recorded weekly during treatment and at regular intervals for a further 70 days. Functional and laboratory biomarkers were assessed before, during and after treatment. Results No deaths, serious adverse events or participant withdrawals occurred during or after ILB® treatment and no significant drug-related changes in blood safety markers were evident, demonstrating safety and tolerability of the drug in this cohort of patients with ALS. The PK of ILB® in patients with ALS was similar to that seen in healthy controls. The ILB® injection elicited a transient elevation of plasma Hepatocyte Growth Factor, a neurotrophic and myogenic growth factor. Following the ILB® injections patients reported increased vitality, decreased spasticity and increased mobility. The ALSFRS-R rating improved from 36.31 ± 6.66 to 38.77 ± 6.44 and the Norris rating also improved from 70.61 ± 13.91 to 77.85 ± 14.24 by Day 36. The improvement of functions was associated with a decrease in muscle atrophy biomarkers. These therapeutic benefits decreased 3–4 weeks after the last dosage. Conclusions This pilot clinical study demonstrates safety and tolerability of ILB® in patients with ALS. The exploratory biomarker and functional measures must be cautiously interpreted but suggest clinical benefit and have a bearing on the mechanism of action of ILB®. The results support the drug’s potential as the first disease modifying treatment for patients with ALS. Trial registration EudraCT 2017-005065-47.

Background: Acute and chronic neurodegenerative diseases represent an immense socioeconomic burden that drives the need for new disease modifying drugs. Common pathogenic mechanisms in these diseases are evident, suggesting that a platform neuroprotective therapy may offer effective treatments. Here we present evidence for the mode of pharmacological action of a novel neuroprotective low molecular weight dextran sulphate drug called ILB®. The working hypothesis was that ILB® acts via the activation of heparin-binding growth factors (HBGF). Methods: Pre-clinical and clinical (healthy people and patients with ALS) in vitro and in vivo studies evaluated the mode of action of ILB®. In vitro binding studies, functional assays and gene expression analyses were followed by the assessment of the drug effects in an animal model of severe traumatic brain injury (sTBI) using gene expression studies followed by functional analysis. Clinical data, to assess the hypothesized mode of action, are also presented from early phase clinical trials. Results: ILB® lengthened APTT time, acted as a competitive inhibitor for HGF-Glypican-3 binding, effected pulse release of heparin-binding growth factors (HBGF) into the circulation and modulated growth factor signaling pathways. Gene expression analysis demonstrated substantial similarities in the functional dysregulation induced by sTBI and various human neurodegenerative conditions and supported a cascading effect of ILB® on growth factor activation, followed by gene expression changes with profound beneficial effect on molecular and cellular functions affected by these diseases. The transcriptional signature of ILB® relevant to cell survival, inflammation, glutamate signaling, metabolism and synaptogenesis, are consistent with the activation of neuroprotective growth factors as was the ability of ILB® to elevate circulating levels of HGF in animal models and humans. Conclusion: ILB® releases, redistributes and modulates the bioactivity of HBGF that target disease compromised nervous tissues to initiate a cascade of transcriptional, metabolic and immunological effects that control glutamate toxicity, normalize tissue bioenergetics, and resolve inflammation to improve tissue function. This unique mechanism of action mobilizes and modulates naturally occurring tissue repair mechanisms to restore cellular homeostasis and function. The identified pharmacological impact of ILB® supports the potential to treat various acute and chronic neurodegenerative disease, including sTBI and ALS.

European Journal of NeuroscienceEarly View COMMENTARYOpen Access A humble neuroanatomist: Martin Berry, PhD (1936–2021) Zubair Ahmed, Corresponding Author Zubair Ahmed z.ahmed.1@bham.ac.uk orcid.org/0000-0001-6267-6442 Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK Correspondence Zubair Ahmed, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Email: z.ahmed.1@bham.ac.ukSearch for more papers by this authorAnn Logan, Ann Logan Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK Division of Biomedical Sciences, University of Warwick, Coventry, UKSearch for more papers by this author Zubair Ahmed, Corresponding Author Zubair Ahmed z.ahmed.1@bham.ac.uk orcid.org/0000-0001-6267-6442 Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK Correspondence Zubair Ahmed, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Email: z.ahmed.1@bham.ac.ukSearch for more papers by this authorAnn Logan, Ann Logan Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK Division of Biomedical Sciences, University of Warwick, Coventry, UKSearch for more papers by this author First published: 01 May 2022 https://doi.org/10.1111/ejn.15681 Edited by: John Foxe AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Martin Berry (Figure 1), Emeritus Professor of Neuroanatomy at the University of Birmingham and a former Chairman of the Department of Anatomy, Kings College London (Guys Campus), died on 30 July 2021 after a valiant fight with cancer. He was 85 years old. The field of Neuroscience has lost a great and humble visionary. FIGURE 1Open in figure viewerPowerPoint Photograph of Professor Martin Berry Martin studied Medicine at the University of Birmingham, but whilst studying, he earned an intercalated BSc degree (1961) followed by a PhD in Neuroanatomy (1964) and eventually graduated with an MBChB in 1967. Having trained as a General Practitioner and spending a brief spell working as one, his love of science overtook him, and he returned to academia in 1969 taking up a post as Lecturer, then Senior Lecturer, then Reader, and in 1982, took up a post as Chair and Head of the Department of Anatomy at Kings College London (Guys Campus). He retired in 2001 but came back to the University of Birmingham as an Emeritus Professor of Neuroanatomy. He continued to teach and took an active part in research right up until when he passed away. Martin was an innovator who was always ahead of the field. His bold and original ideas inspired many scientists across the globe. His early work focused on histogenesis of the cerebral cortex and he showed that the normal six layered cortex was established by inward migration of cells, ultimately constituting to layers V and VI, intermingled with an outward migration of cells destined to form layers II, III and IV (Berry et al., 1964; Berry & Eayrs, 1963). Later, Martin identified the major NG2-expressing glia in the adult CNS as a distinct class of cells, calling them 'synantocytes' ('synanto' meaning 'contact'), since they formed multiple contacts to neurons, astrocytes, oligodendrocytes and myelin (Berry et al., 2002). However, Martin's seminal contributions in the field of CNS axon regeneration is what set him out as a true visionary and inspired many to follow in his stead. For example, it was known that the projection cells of the retina, the retinal ganglion cells (RGC) could regenerate their axons through the environment of a peripheral nerve graft affixed to the cut end of the optic nerve (David & Aguayo, 1981). However, axon regeneration through the native environment of the optic nerve was long considered to be impossible due to the hostile inhibitory nature of the optic nerve. Martin was the first to demonstrate that the RGCs could regenerate their axons through the native environment of the optic nerve after a crush injury, if a small piece of sciatic nerve was implanted into the back of the eye (Berry et al., 1996). This was a revolutionary discovery demonstrating that RGCs could regenerate their axons through the native inhibitory environment of the optic nerve, sparking a renewed enthusiasm in the field of CNS axon regeneration. He continued his work in CNS axon regeneration, even after his retirement in 2001, being the driving force in some of the key observations in the field. These include demonstrating how scar tissue was laid down at a CNS injury site and the important role of TGFβ1 and β2 in CNS scar formation (Logan & Berry, 1993), how RGC axon regeneration promoted by peripheral nerve implants inserted into the back of the eye, stimulated astrocytes in the optic nerve to secrete matrix metalloproteases (MMPs) to facilitate axon regeneration (Ahmed et al., 2005) and how Schwann-cell-derived factors in a peripheral nerve implant promoted RGC axon regeneration through regulated intramembranous proteolysis (RIP) of p75NTR, the main axon growth inhibitory signalling molecule (Ahmed et al., 2006; Logan et al., 2006). In 2011, Martin guided the studies that led to the discovery that caspase-2, always thought of as an initiator caspase, could actually take the function of an executioner caspase and thus kill RGC (Ahmed et al., 2011). After optic nerve crush injury, RGC exclusively activated caspase-2 and a short interfering RNA molecule, designed to resist nucleases degradation, promoted survival of over 98% of RGC within 7 days (Ahmed et al., 2011) with later studies showing neuroprotection of >95% of RGC after 21 days (Vigneswara et al., 2014). Martin was a very charismatic, nonchalant and humble neuroanatomist. He was very well liked and took the time to get to know everyone around him. When he spoke, he did so with authority, knowledge and integrity. Martin was an extremely passionate scientist, an inspirational mentor with an endless inquisitive mind. His scientific curiosity was boundless and he had a remarkable grasp of the 'nitty gritty' of the different pathways involved in axon regeneration. His knowledge was so remarkable that after speaking to him you were left wondering how a person can fathom all of the innuendoes involved and make 'head or tail' of anything. His appetite for neuroscience was infectious, he was always full of big ideas, and his irreproachable style touched the lives of so many friends, students and collaborators. Every person that knew Martin viewed him as a unique individual who was kind, honest, generous, extremely humble and a very thoughtful man. It is fitting, given the focus of his research on the visual system, that he illuminated the field and brought clarity through his discoveries. Martin supported many trainees and faculty members throughout their career and helped them to step up and take charge of their own areas of research by providing a nurturing and evidence-based research environment. Martin lived for research, as demonstrated by his commitment even though he retired at the age of 65. He would still come into the lab every day, perform experiments, analyse data, assimilate information, write papers, teach, mentor and supervise. Despite being retired, he never lost the 'hunger' for the next discovery and was always eager to help. He was an exemplar of perseverance, persistence and perfection. His remarkable knowledge of neuroanatomy, together with his powers of recall and his 'big personality' will be greatly missed by all those who knew him. He has left a significant void, both scientifically and personally, that it will be impossible for anyone to fill. However, we will do our utmost to remember his huge contributions to our lives and appreciate and emulate his wonderful attributes. Martin is survived by his wife, and their two daughters and two sons. He will be dearly missed by those in the College of Medical and Dental Sciences of the University of Birmingham and the entire Neuroscience community. CONFLICT OF INTEREST The authors declare that they have no competing interests. PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/ejn.15681. Open Research PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/ejn.15681. REFERENCES Ahmed, Z., Dent, R. G., Leadbeater, W. E., Smith, C., Berry, M., & Logan, A. (2005). Matrix metalloproteases: Degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons. Molecular and Cellular Neurosciences, 28, 64– 78. CrossrefCASPubMedWeb of Science®Google Scholar Ahmed, Z., Kalinski, H., Berry, M., Almasieh, M., Ashush, H., Slager, N., Brafman, A., Spivak, I., Prasad, N., Mett, I., Shalom, E., Alpert, E., Di Polo, A., Feinsetin, E., & Logan, A. (2011). Ocular neuroprotection by siRNA targeting caspase-2. Cell Death & Disease, 2, e173. CrossrefCASPubMedWeb of Science®Google Scholar Ahmed, Z., Suggate, E. L., Brown, E. R., Dent, R. G., Armstrong, S. J., Barrett, L. B., Berry, M., & Logan, A. (2006). Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro. Brain, 129, 1517– 1533. CrossrefPubMedWeb of Science®Google Scholar Berry, M., Carlile, J., & Hunter, A. (1996). Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. Journal of Neurocytology, 25, 147– 170. CrossrefCASPubMedWeb of Science®Google Scholar Berry, M., & Eayrs, J. T. (1963). Histogenesis of the cerebral cortex. Nature, 197, 984– 985. CrossrefWeb of Science®Google Scholar Berry, M., Hubbard, P., & Butt, M. (2002). Cytology and lineage of NG2-positive glia. Journal of Neurocytology, 31, 457– 467. CrossrefCASPubMedWeb of Science®Google Scholar Berry, M., Rogers, A. W., & Eayrs, J. T. (1964). Pattern of cell migration during cortical histogenesis. Nature, 203, 591– 593. CrossrefCASPubMedWeb of Science®Google Scholar David, S., & Aguayo, A. J. (1981). Axonal elongation into peripheral nervous system "bridges" after central nervous system injury. Science, 214, 931– 933. CrossrefCASPubMedWeb of Science®Google Scholar Logan, A., Ahmed, Z., Baird, A., Gonzalez, A. M., & Berry, M. (2006). Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain, 129, 490– 502. CrossrefPubMedWeb of Science®Google Scholar Logan, A., & Berry, M. (1993). Transforming growth factor-beta 1 and basic fibroblast growth factor in the injured CNS. Trends in Pharmacological Sciences, 14, 337– 342. CrossrefCASPubMedWeb of Science®Google Scholar Vigneswara, V., Akpan, N., Berry, M., Logan, A., Troy, C. M., & Ahmed, Z. (2014). Combined suppression of CASP2 and CASP6 protects retinal ganglion cells from apoptosis and promotes axon regeneration through CNTF-mediated JAK/STAT signalling. Brain, 137, 1656– 1675. CrossrefPubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue FiguresReferencesRelatedInformation

Raman Spectroscopy (RS) and machine learning are explored for the rapid, real-time, sensitive application of neurological diagnostics through the human eye. Biochemical information is obtained of fatty porcine tissue and flat-mounted porcine retinal samples using an in-house built, portable RS system. RS and FUNDUS imaging have been combined with a phantom eye model to obtain spectra under eye-safe parameters in an in-vivo environment, identifying high wavenumber bands. This system has the potential to detect acute, biochemical changes indicative of neurodegenerative disorders such as Traumatic Brain Injury for early and accurate diagnoses, crucial for neurological recovery.

Assess the relationship between photoreceptor degeneration and visual function after retinal reattachment surgery (RRS) in a prospective cohort. Patients with rhegmatogenous retinal detachment (RRD) were reviewed before and 6 months after vitreoretinal surgery. Optical coherence tomographical thickness of the outer nuclear layer (ONL), outer retinal segment (ORS), retinal pigmented epithelium to ellipsoid zone (RPE-EZ) and external limiting membrane to EZ (ELM-EZ) were recorded 6 months post-operatively. These were compared to best corrected visual acuity (BCVA) and retinal sensitivity (Humphrey visual field). Thirteen macula-off and 8 macula-on RRD patients were included. The mean ONL thickness was higher after macula-on RRD compared to macula-off RRD (97.70 ± 3.62 μm vs. 73.10 ± 4.98 μm). In all RRD eyes, every 1 μm decrease in ONL thickness correlated with a 0.052 dB decrease and in retinal sensitivity and every 1 μm decrease in ORS thickness was associated with a 0.062 dB reduction in retinal sensitivity. ORS, ELM-EZ and RPE-EZ thickness did not correlate with BCVA post-RRS. There was greater ONL and ORS thinning following macula-off compared to macula-on RRD. Correlations between ONL and ORS thinning with decreased retinal sensitivity may be explained by RRD-induced photoreceptor death.

Most coronaviruses infect animals including bats, birds and mammals, which act as hosts and reservoirs for the viruses, but the viruses can sometimes move host species and infect humans. Coronoviruses were first identified as human pathogens in the 1960s and now there are seven types known to infect humans. Whilst four of these types cause mild-to-moderate respiratory disease, the other three may cause more severe and possibly even fatal disease in vulnerable individuals particularly, with the most recent SARS-CoV-2 pandemic being associated with severe acute respiratory syndrome (SARS) in many infected people. The aim of the present study was to evaluate the potential of a unique low molecular weight dextran sulphate (LMW-DS) clinical stage drug, ILB ® , to inhibit infection of human cells by the NL63 coronavirus assessed by immunofluorescence of viral particles, and also to see if the drug directly blocked the interaction of the SARS-CoV-2 viral spike protein with the ACE2 receptor. Furthermore, we evaluated if ILB ® could modulate the downstream consequences of viral infection including the reactive cytokine release from human microglia induced by various SARS-CoV-2 variant spike proteins. We demonstrated that ILB ® blocked ACE2:spike protein interaction and inhibited coronaviral infection. ILB ® also attenuated the omicron-induced release of pro-inflammatory cytokines, including TNFα, from human microglia, indicating control of post-viral neuroinflammation. In conclusion, given the safety profile of ILB ® established in a number of Phase I and Phase II clinical trials, these results highlight the potential of ILB ® to treat patients infected with coronaviruses to both limit infectivity and attenuate the progression to severe disease. There is now an opportunity to translate these findings quickly by the clinical investigation of drug efficacy.

The treatment of spinal cord injury (SCI) is a complex challenge in regenerative medicine, complicated by the low intrinsic capacity of CNS neurons to regenerate their axons and the heterogeneity in size, shape and extent of human injuries. For example, some contusion injuries do not compromise the dura mater and in such cases implantation of preformed scaffolds or drug delivery systems may cause further damage. Injectable in situ thermosensitive scaffolds are therefore a less invasive alternative. In this study, we report the development of a novel, flowable, thermosensitive, injectable drug delivery system comprising bovine collagen (BC) and fibrinogen (FB) that forms a solid BC/FB gel (Gel) immediately upon exposure to physiological conditions and can be used to deliver reparative drugs, such as the naturally occurring anti-inflammatory, anti-scarring agent Decorin, into adult rat spinal cord lesion sites. In dorsal column lesions of adult rats treated with the Gel + Decorin, cavitation was completely suppressed and instead lesion sites became filled with injury-responsive cells and extracellular matrix materials, including collagen and laminin. Decorin increased the intrinsic potential of dorsal root ganglion neurons (DRGN) by increasing their expression of regeneration associated genes (RAGs), enhanced local axon regeneration/sprouting, as evidenced both histologically and by improved electrophysiological, locomotor and sensory function recovery. These results suggest that this drug formulated, injectable hydrogel has the potential to be further studied and translated into the clinic.

Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB®. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients’ clinical conditions, indicating a response to ILB® treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes.

To assess the stability of retinal structure and blood flow measures over time and in different clinical settings using portable optical coherence tomography angiography (OCTA) as a potential biomarker of central perfusion in critical illness, 18 oesophagectomy patients completed retinal structure and blood flow measurements by portable OCT and OCTA in the eye clinic and intensive therapy unit (ITU) across three timepoints: (1) pre-operation in a clinic setting; (2) 24–48 h post-operation during ITU admission; and (3) seven days post-operation, if the patient was still admitted. Blood flow and macular structural measures were stable between the examination settings, with no consistent variation between pre- and post-operation scans, while retinal nerve fibre layer thickness increased in the post-operative scans (+2.31 µm, p = 0.001). Foveal avascular zone (FAZ) measurements were the most stable, with an intraclass correlation coefficient of up to 0.92 for right eye FAZ area. Blood flow and structural measures were lower in left eyes than right eyes. Retinal blood flow assessed in patients before and during an ITU stay using portable OCTA showed no systematic differences between the clinical settings. The stability of retinal blood flow measures suggests the potential for portable OCTA to provide clinically useful measures in ITU patients.