Genetic testing and gene therapy in retinal diseases: Knowledge and perceptions of optometrists in Australia and New Zealand.

With advances in gene-based therapies for heritable retinal diseases, primary eye care clinicians should be informed on ocular genetics topics. This cross-sectional survey evaluated knowledge, attitudes, and concerns regarding genetic testing and gene therapy for retinal diseases among optometrists in Australia and New Zealand. Survey data included practitioner background, attitudes and practices towards genetic testing for monogenic inherited retinal disease (IRDs) and age-related macular degeneration, and knowledge of ocular genetics and gene therapy. Responses were received from 516 optometrists between 1 April and 31 December 2022. Key perceived barriers to accessing genetic testing were lack of clarity on referral pathways (81%), cost (65%), and lack of treatment options if a genetic cause is identified (50%). Almost all respondents (98%) believed that ophthalmologists should initiate genetic testing for IRDs and fewer understood the role of genetic counsellors and clinical geneticists. This study found that optometrists in Australia and New Zealand have a high level of interest in ocular genetics topics. However, knowledge gaps include referral pathways and awareness of genetic testing and gene therapy outcomes. Addressing perceived barriers to access and promoting sharing of knowledge between interdisciplinary networks can set the foundation for genetic education agendas in primary eye care.

The effect of topical decorin on temporal changes to corneal immune cells after epithelial abrasion.

BACKGROUND: Corneal immune cells interact with corneal sensory nerves during both homeostasis and inflammation. This study sought to evaluate temporal changes to corneal immune cell density in a mouse model of epithelial abrasion and nerve injury, and to investigate the immunomodulatory effects of topical decorin, which we have shown previously to promote corneal nerve regeneration. METHODS: Bilateral corneal epithelial abrasions (2 mm) were performed on C57BL/6J mice. Topical decorin or saline eye drops were applied three times daily for 12 h, 24 h, 3 days or 5 days. Optical coherence tomography imaging was performed to measure the abrasion area. The densities of corneal sensory nerves (ß-tubulin III) and immune cells, including dendritic cells (DCs; CD11c+), macrophages (Iba-1+) and neutrophils (NIMP-R14+) were measured. Cx3cr1gfp/gfp mice that spontaneously lack resident corneal intraepithelial DCs were used to investigate the specific contribution of epithelial DCs. Neuropeptide and cytokine gene expression was evaluated using qRT-PCR at 12 h post-injury. RESULTS: In decorin-treated corneas, higher intraepithelial DC densities and lower neutrophil densities were observed at 24 h after injury, compared to saline controls. At 12 h post-injury, topical decorin application was associated with greater re-epithelialisation. At 5 days post-injury, corneal stromal macrophage density in the decorin-treated and contralateral eyes was lower, and nerve density was higher, compared to eyes treated with saline only. Lower expression of transforming growth factor beta (TGF-ß) and higher expression of CSPG4 mRNA was detected in corneas treated with topical decorin. There was no difference in corneal neutrophil density in Cx3cr1gfp/gfp mice treated with or without decorin at 12 h. CONCLUSIONS: Topical decorin regulates immune cell dynamics after corneal injury, by inhibiting neutrophils and recruiting intraepithelial DCs during the acute phase (< 24 h), and inhibiting macrophage density at the study endpoint (5 days). These immunomodulatory effects were associated with faster re-epithelialisation and likely contribute to promoting sensory nerve regeneration. The findings suggest a potential interaction between DCs and neutrophils with topical decorin treatment, as the decorin-induced neutrophil inhibition was absent in Cx3cr1gfp/gfp mice that lack corneal epithelial DCs. TGF-ß and CSPG4 proteoglycan likely regulate decorin-mediated innate immune cell responses and nerve regeneration after injury.

What is the impact of COVID-19 on tissue viability services and pressure ulceration?

This paper explores and reviews the relevant literature and examines the impact that the first wave of the COVID-19 pandemic has had on the tissue viability service (TVS) and the incidence of pressure ulcers (PUs) in a large UK teaching hospital NHS trust. A comparison has been undertaken of referral data to the TVS during two time periods-Oct-Dec 2019 and April-June 2020. Data show that the PU rate per 1000 beds increased from a pre-pandemic level of around 1 to over 2.7 in the first month of the pandemic, with an increase in device and prone position-related PUs, particularly in the expanded critical care patient population. Even though the bed occupancy decreased, the proportion of ungradable PUs increased, but there was little change in the number of Category 1 and 2 PUs.

The neuroregenerative effects of topical decorin on the injured mouse cornea.

BACKGROUND: The cornea is innervated with a rich supply of sensory nerves that play important roles in ocular surface health. Any injury or pathology of the corneal nerves increases the risk of dry eye disease and infection. This study aims to evaluate the therapeutic potential of topical decorin to improve corneal nerve regeneration in a mouse model of sterile epithelial abrasion injury. METHODS: Bilateral central corneal epithelial abrasions (2-mm, Alger Brush) were performed on young C57BL/6 J mice to remove the corneal sensory nerves. Decorin, or vehicle, was applied topically, three times per day for 1 week or every 2 h for 6 h. Spectral-domain optical coherence tomography was performed to measure the abrasion area and corneal thickness. Wholemount immunofluorescence staining was used to assess sensory nerve regeneration (ß-tubulin III) and immune cell density (CD45, Iba1, CD11c). To investigate the specific role of dendritic cells (DCs), Cx3cr1gfp/gfp mice, which spontaneously lack resident corneal epithelial DCs, were also investigated. The effect of prophylactic topical administration of recombinant human decorin (applied prior to the abrasion) was also investigated. Nerve tracing (NeuronJ software) was performed to compare recovery of basal nerve axons and superficial nerve terminals in the central and peripheral cornea. RESULTS: At 6 h after injury, topical decorin application was associated with greater intraepithelial DC recruitment but no change in re-epithelialisation or corneal thickness, compared to the vehicle control. One week after injury, sub-basal nerve plexus and superficial nerve terminal density were significantly higher in the central cornea in the decorin-treated eyes. The density of corneal stromal macrophages in the decorin-treated eyes and their contralateral eyes was significantly lower compared to saline-treated corneas. No significant improvement in corneal nerve regeneration was observed in Cx3cr1gfp/gfp mice treated with decorin. CONCLUSIONS: Decorin promotes corneal epithelial nerve regeneration after injury. The neuroregenerative effect of topical decorin was associated with a higher corneal DC density during the acute phase, and fewer macrophages at the study endpoint. The corneal neuroregenerative effects of decorin were absent in mice lacking intraepithelial DCs. Together, these findings support a role for decorin in DC-mediated neuroregeneration following corneal abrasion injury.

Effects of antiemetic doses of dexamethasone on plasma mediators of inflammation resolution and pain after surgery in women.

BACKGROUND: Dexamethasone is commonly given as an antiemetic during surgical procedures. It has immunosuppressive effects and can affect key enzymes involved in the synthesis of specialised lipid mediators of inflammation resolution (SPM) that direct inflammation resolution and have anti-nociceptive actions. This study examined the effect of dexamethasone on plasma SPM, and the relationship between SPM and perceived pain in women undergoing surgery. METHODS: Plasma SPM were measured in samples obtained from two double-blind controlled interventions. The first, included 51 women mean age 53 ± 1.5 years, undergoing breast surgery allocated to either intravenous saline, or dexamethasone (4 mg or 8 mg) after induction of anaesthesia. The second study included 31 women of mean age 44 ± 0.5 years undergoing laparoscopic gynecological surgery that were allocated to either saline, or dexamethasone (4 mg). SPM (18-HEPE, 17-HDHA, RvE2, RvD1 17R-RvD1 and RvD2) were measured in plasma collected prior to induction of anaesthesia and at 24 h, and 6 weeks post-surgery. Pain was assessed using a verbal analogue scale at discharge from the post-anaesthesia recovery unit. The data from each study was combined to examine the effect of dexamethasone on plasma SPM. The relationship between pain score and SPM was examined using ordinal logistic regression. RESULTS: The SPM 18-HEPE, 17-HDHA, RvE2, RvD1 17R-RvD1 and RvD2 were detectable in all plasma samples. There was no significant difference in any SPM due to dexamethasone over the duration of the study. There was a fall in 17-HDHA between baseline and 24 h in both the dexamethasone and saline groups (P = 0.003) but no change in the downstream SPM (RvD1, 17R-RvD1 and RvD2) or 18-HEPE and RvE2. Pain score was negatively related to levels of RvE2 measured prior to induction of anaesthesia (rho = -0.2991, P = 0.006) and positively related to BMI (rho = 0.279, P = 0.011). In ordinal logistic regression the odds ratio for RvE2 was 0.931 (CI 0.880, 0.986; P = 0.014); after adjusting for the effect of BMI indicating that an increase in RvE2 of 1 pg/ml would result in a 6.9 % fall in pain score. Allocation to a dexamethasone group did not influence the pain score or the relationship between RvE2 and pain score. CONCLUSION: Dexamethasone administered as an anti-emetic does not affect plasma SPM levels. An elevated RvE2 level prior to surgery is predictive of a lower perceived pain score post-anaesthesia.

Longevity of Preserved Germplasm: The Temperature Dependency of Aging Reactions in Glassy Matrices of Dried Fern Spores.

This study explores the temperature dependency of the aging rate in dry cells over a broad temperature range encompassing the fluid to solid transition (Tg) and well below. Spores from diverse species of eight families of ferns were stored at temperatures ranging from +45�C to approximately -176�C (vapor phase above liquid nitrogen), and viability was monitored periodically for up to 4,300 d (∼12 years). Accompanying measurements using differential scanning calorimetry (DSC) provide insights into structural changes that occur, such as Tg between +45 and -20�C (depending on moisture), and triacylglycerol (TAG) crystallization between -5 and -35�C (depending on species). We detected aging even at cryogenic temperatures, which we consider analogous to unscheduled degradation of pharmaceuticals stored well below Tg caused by a shift in the nature of molecular motions that dominate chemical reactivity. We occasionally observed faster aging of spores stored at -18�C (conventional freezer) compared with 5�C (refrigerator), and linked this with mobility and crystallization within TAGs, which probably influences molecular motion of dried cytoplasm in a narrow temperature range. Temperature dependency of longevity was remarkably similar among diverse fern spores, despite widely disparate aging rates; this provides a powerful tool to predict deterioration of germplasm preserved in the solid state. Future work will increase our understanding of molecular organization and composition contributing to differences in longevity.

The kinetics of ageing in dry-stored seeds: a comparison of viability loss and RNA degradation in unique legacy seed collections.

BACKGROUND AND AIMS: Determining seed longevity by identifying chemical changes that precede, and may be linked to, seed mortality, is an important but difficult task. The standard assessment, germination proportion, reveals seed longevity by showing that germination proportion declines, but cannot be used to predict when germination will be significantly compromised. Assessment of molecular integrity, such as RNA integrity, may be more informative about changes in seed health that precede viability loss, and has been shown to be useful in soybean. METHODS: A collection of seeds stored at 5 °C and 35-50 % relative humidity for 1-30 years was used to test how germination proportion and RNA integrity are affected by storage time. Similarly, a collection of seeds stored at temperatures from -12 to +32 °C for 59 years was used to manipulate ageing rate. RNA integrity was calculated using total RNA extracted from one to five seeds per sample, analysed on an Agilent Bioanalyzer. RESULTS: Decreased RNA integrity was usually observed before viability loss. Correlation of RNA integrity with storage time or storage temperature was negative and significant for most species tested. Exceptions were watermelon, for which germination proportion and storage time were poorly correlated, and tomato, which showed electropherogram anomalies that affected RNA integrity number calculation. Temperature dependencies of ageing reactions were not significantly different across species or mode of detection. The overall correlation between germination proportion and RNA integrity, across all experiments, was positive and significant. CONCLUSIONS: Changes in RNA integrity when ageing is asymptomatic can be used to predict onset of viability decline. RNA integrity appears to be a metric of seed ageing that is broadly applicable across species. Time and molecular mobility of the substrate affect both the progress of seed ageing and loss of RNA integrity.

TGF-ß-induced IOP elevations are mediated by RhoA in the early but not the late fibrotic phase of open angle glaucoma.

Purpose: Elevations in intraocular pressure (IOP) are associated with the development of glaucoma and loss of sight. High transforming growth factor-ß (TGF-ß) 1 levels in the eye's anterior chamber can lead to dysfunctional contractions through RhoA signaling in trabecular meshwork (TM) cells and IOP spikes. Sustained high TGF-ß levels leads to TM fibrosis and sustained increases in IOP. We investigated whether inhibiting RhoA, using a siRNA-mediated RhoA (siRhoA), controls IOP by altering TM expression of fibrosis and contractility-related proteins in a rodent model of glaucoma. Methods: TGF-ß was injected intracamerally twice a week into adult Sprague Dawley rats, and IOP was recorded with tonometry. Animals were euthanized on day 7 and 35 with TM expression of fibrosis and contractility-related proteins, as well as survival of retinal ganglion cells (RGCs) assessed with immunohistochemistry. siRNA against RhoA or enhanced green fluorescent protein (EGFP) was also injected intracamerally into select animals. Successful RhoA knockdown was determined with quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, and the effects of the knockdown on the parameters above analyzed. Results: TGF-ß caused increased TM contractile proteins and IOP spikes by day 7, sustained increases in IOP from day 15, and TM fibrosis at day 35. siRhoA abolished the transient 7 day IOP rise but not the later sustained IOP increase (due to fibrosis). At 35 days, TGF-ß-related RGC loss was not prevented with siRhoA treatment. Conclusions: We conclude that RhoA signaling mediates the early IOP rise induced by TM cellular changes associated with contractility but not the sustained IOP elevation caused by TM fibrosis. Thus, RhoA therapies offer a clinically relevant opportunity for IOP management, likely through the modulation of TM contractility, but appear to be ineffective in the amelioration of fibrosis.

Volatile emission in dry seeds as a way to probe chemical reactions during initial asymptomatic deterioration.

The nature and kinetics of reactions in dry seeds determines how long the seeds survive. We used gas chromatography to assay volatile organic compounds (VOCs) emitted from seeds of three unrelated species as a means to non-invasively probe chemical changes during very dry, dry, and humid storage (seeds were dried to 5.5, 33, and 75% relative humidity at room temperature). VOCs emitted from seeds stored in humid conditions reflected fermentation-type reactions, with methanol and ethanol being predominant in Lactuca sativa and Carum carvi, and acetaldehyde and acetone being predominant in Eruca vesicaria. Dried C. carvi seeds continued to emit fermentation-type products, although at slower rates than the seeds stored in humid conditions. In contrast, drying caused a switch in VOC emission in L. sativa and E. vesicaria seeds towards higher emission of pentane and hexanal, molecules considered to be byproducts from the peroxidation of polyunsaturated fatty acids. Longevity correlated best with the rate of fermentation-type reactions and appeared unrelated to the rate of lipid peroxidation. Emission of VOCs decreased when seed species were mixed together, indicating that seeds adsorbed VOCs. Adsorption of VOCs did not appear to damage seeds, as longevity was not affected in seed mixtures. Collectively, the study shows similarity among species in the types of reactions that occur in dry seeds, but high diversity in the substrates, and hence the byproducts, of the reactions. Moreover, the study suggests that the most abundant VOCs arise from degradation of storage reserves within seed cells, and that these reactions and their byproducts are not, in themselves, damaging.

Mesenchymal stromal cell-mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma.

BACKGROUND AIMS: Glaucoma is a leading cause of irreversible blindness involving loss of retinal ganglion cells (RGC). Mesenchymal stromal cells (MSC) have shown promise as a paracrine-mediated therapy for compromised neurons. It is, however, unknown whether dental pulp stem cells (DPSC) are effective as a cellular therapy in glaucoma and how their hypothesized influence compares with other more widely researched MSC sources. The present study aimed to compare the efficacy of adipose-derived stem cells, bone marrow-derived MSC (BMSC) and DPSC in preventing the loss of RGC and visual function when transplanted into the vitreous of glaucomatous rodent eyes. METHODS: Thirty-five days after raised intraocular pressure (IOP) and intravitreal stem cell transplantation, Brn3a(+) RGC numbers, retinal nerve fibre layer thickness (RNFL) and RGC function were evaluated by immunohistochemistry, optical coherence tomography and electroretinography, respectively. RESULTS: Control glaucomatous eyes that were sham-treated with heat-killed DPSC had a significant loss of RGC numbers, RNFL thickness and function compared with intact eyes. BMSC and, to a greater extent, DPSC provided significant protection from RGC loss and RNFL thinning and preserved RGC function. DISCUSSION: The study supports the use of DPSC as a neuroprotective cellular therapy in retinal degenerative disease such as glaucoma.

Factors affecting stress tolerance in recalcitrant embryonic axes from seeds of four Quercus (Fagaceae) species native to the USA or China.

BACKGROUND AND AIMS: Quercus species are often considered 'foundation' components of several temperate and/or subtropical forest ecosystems. However, the populations of some species are declining and there is considerable urgency to develop ex situ conservation strategies. In this study, the storage physiology of seeds within Quercus was explored in order to determine factors that affect survival during cryopreservation and to provide a quantitative assessment of seed recalcitrance to support future studies of this complex trait. METHODS: Water relations and survival of excised axes in response to water loss and cryo-exposure were compared for four Quercus species from subtropical China (Q. franchetii, Q. schottkyana) and temperate USA (Q. gambelii, Q. rubra). KEY RESULTS: Seed tissues initially had high water contents and water potentials. Desiccation tolerance of the embryonic axis was not correlated with the post-shedding rainfall patterns where the samples originated. Instead, higher desiccation tolerance was observed in samples growing in areas with colder winters. Survival following cryo-exposure correlated with desiccation tolerance. Among species, plumule tissues were more sensitive than radicles to excision, desiccation and cryo-exposure, and this led to a higher proportion of abnormally developing embryos during recovery following stress. CONCLUSIONS: Quercus species adapted to arid and semi-humid climates still produce recalcitrant seeds. The ability to avoid freezing rather than drought may be a more important selection factor to increase desiccation tolerance. Cryopreservation of recalcitrant germplasm from temperate species is currently feasible, whilst additional protective treatments are needed for ex situ conservation of Quercus from tropical and subtropical areas.

Age and strength influences on lingual tactile acuity.

Sensory function during the oral processing of liquids is thought to play a key role in informing the tailoring of swallowing motor behaviours to the flow characteristics of the bolus. In addition to taste receptors, the mouth and tongue house trigeminal nerve receptors that support the sensory detection of bolus size, shape (stereognosis), mass, temperature and movement. Recent studies suggest that healthy adults lose tongue strength with advancing age. However, little is known about changes in the sensory function of the tongue attributable to age, or associated with reductions in strength. In this study, we explored lingual tactile acuity in healthy young and older adults, and measured the relationship between tactile acuity and measures of tongue strength. The results showed an age-related reduction in lingual tactile acuity that was not explained by variations in tongue strength. PRACTICAL APPLICATIONS: Sensory motor interactions are a topic of interest in understanding the processing activities that take place in the mouth during eating and swallowing. In this paper, we explore a test of sensory acuity in the mouth, in which the tongue is used to "read" embossed letters on Teflon strips. Our questions were to determine whether sensory acuity for this task declines with age, or with age-related reductions in tongue strength. We determined that older people perform this task with less accuracy, suggesting some changes in oral sensory function with age. However, these changes were not related to tongue strength. The findings suggest that strength does not play a major role in the kind of sensory discrimination task tested in this study.

Topical Decorin Reduces Corneal Inflammation and Imparts Neuroprotection in a Mouse Model of Benzalkonium Chloride-induced Corneal Neuropathy.

Purpose: We evaluated the neuroprotective and immunomodulatory effects of topical decorin in a murine model of benzalkonium chloride (BAK)-induced corneal neuropathy. Methods: Topical BAK (0.1%) was administered daily to both eyes of female C57BL/6J mice (n = 14) for 7 days. One group of mice received topical decorin (1.07 mg/mL) eye drops to one eye and saline (0.9%) to the contralateral eye; the other group received saline eye drops to both eyes. All eye drops were given three times daily over the experimental period. A control group (n = 8) received daily topical saline only, instead of BAK. Optical coherence tomography imaging was performed before (at day 0) and after (day 7) treatment to evaluate the central corneal thickness. Whole-mount immunofluorescence staining was performed to evaluate the density of corneal intraepithelial nerves and immune cells. Results: BAK-exposed eyes showed corneal epithelial thinning, infiltration of inflammatory macrophages and neutrophils, and a lower density of intraepithelial nerves. No change to the corneal stromal thickness or dendritic cell density was observed. After BAK exposure, decorin-treated eyes had a lower density of macrophages and less neutrophil infiltration and a higher nerve density than the saline-treated group. Contralateral eyes from the decorin-treated animals showed fewer macrophages and neutrophils relative to saline-treated animals. A negative correlation was found between corneal nerve density and macrophage or neutrophil density. Conclusions: Topical decorin provides neuroprotective and anti-inflammatory effects in a chemical model of BAK-induced corneal neuropathy. The attenuation of corneal inflammation by decorin may contribute to decreasing corneal nerve degeneration induced by BAK.

Experimental drugs for the treatment of idiopathic intracranial hypertension (IIH): shedding light on phase I and II trials.

INTRODUCTION: Idiopathic intracranial hypertension is a neurological condition characterized by a raised intracranial pressure and papilledema that causes debilitating headaches. While the extent of the pathophysiology is being discovered, the condition is emerging as a systemic metabolic disease distinct to people living with obesity alone. Idiopathic intracranial hypertension is becoming more common and therefore establishing licensed therapeutics is a key priority. AREA COVERED: The translation of preclinical work in idiopathic intracranial hypertension is evident by the two early phase trials evaluating 11-ß-hydroxysteroid dehydrogenase inhibitor, AZD4017, and a glucagon like peptide-1 receptor agonist, Exenatide. This review summarizes these two early phase trials evaluating targeted medicines for the treatment of intracranial pressure. The modulation of these two distinct mechanisms have potential for therapeutic intervention in people living with idiopathic intracranial hypertension. EXPERT OPINION: The clinical trial landscape in idiopathic intracranial hypertension is a challenge due to the rarity of the disease and the lack of agreed meaningful trial outcomes. Further preclinical work to fully understand the pathogenesis is required to enable personalized targeted drug treatment.

Common microRNA regulated pathways in Alzheimer's and Parkinson's disease.

MicroRNAs (miRNAs) are small non-coding RNAs involved in gene regulation. Recently, miRNA dysregulation has been found in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The diagnosis of Alzheimer's and Parkinson's is currently challenging, mainly occurring when pathology is already present, and although treatments are available for both diseases, the role of treatment is primarily to prevent or delay the progress of the diseases instead of fully overcoming the diseases. Therefore, the challenge in the near future will be to determine effective drugs to tackle the dysregulated biological pathways in neurodegenerative diseases. In the present study, we describe the dysregulation of miRNAs in blood of Alzheimer's and Parkinson's patients with the aim to identify common mechanisms between the 2 pathologies and potentially to identify common therapeutic targets which can stop or delay the progression of two most frequent neuropathologies. Two independent systematic reviews, bioinformatic analysis, and experiment validation were performed to identify whether AD and PD share common pathways. A total of 15 common miRNAs were found in the literature and 13 common KEGG pathways. Among the common miRNAs, two were selected for validation in a small cohort of AD and PD patients. Let-7f-5p and miR-29b-3p showed to be good predictors in blood of PD patients.

Non-adherence and non-persistence to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy: a systematic review and meta-analysis.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections play a key role in treating a range of macular diseases. The effectiveness of these therapies is dependent on patients' adherence (the extent to which a patient takes their medicines as per agreed recommendations from the healthcare provider) and persistence (continuation of the treatment for the prescribed duration) to their prescribed treatment regimens. The aim of this systematic review was to demonstrate the need for further investigation into the prevalence of, and factors contributing to, patient-led non-adherence and non-persistence, thus facilitating improved clinical outcomes. METHODS: Systematic searches were conducted in Google Scholar, Web of Science, PubMed, MEDLINE, and the Cochrane Library. Studies in English conducted before February 2023 that reported the level of, and/or barriers to, non-adherence or non-persistence to intravitreal anti-VEGF ocular disease therapy were included. Duplicate papers, literature reviews, expert opinion articles, case studies, and case series were excluded following screening by two independent authors. RESULTS: Data from a total of 409,215 patients across 52 studies were analysed. Treatment regimens included pro re nata, monthly and treat-and-extend protocols; study durations ranged from 4 months to 8 years. Of the 52 studies, 22 included a breakdown of reasons for patient non-adherence/non-persistence. Patient-led non-adherence varied between 17.5 and 35.0% depending on the definition used. Overall pooled prevalence of patient-led treatment non-persistence was 30.0% (P = 0.000). Reasons for non-adherence/non-persistence included dissatisfaction with treatment results (29.9%), financial burden (19%), older age/comorbidities (15.5%), difficulty booking appointments (8.5%), travel distance/social isolation (7.9%), lack of time (5.8%), satisfaction with the perceived improvement in their condition (4.4%), fear of injection (4.0%), loss of motivation (4.0%), apathy towards eyesight (2.5%), dissatisfaction with facilities 2.3%, and discomfort/pain (0.3%). Three studies found non-adherence rates between 51.6 and 68.8% during the COVID-19 pandemic, in part due to fear of exposure to COVID-19 and difficulties travelling during lockdown. DISCUSSION: Results suggest high levels of patient-led non-adherence/non-persistence to anti-VEGF therapy, mostly due to dissatisfaction with treatment results, a combination of comorbidities, loss of motivation and the burden of travel. This study provides key information on prevalence and factors contributing to non-adherence/non-persistence in anti-VEGF treatment for macular diseases, aiding identification of at-risk individuals to improve real-world visual outcomes. Improvements in the literature can be achieved by establishing uniform definitions and standard timescales for what constitutes non-adherence/non-persistence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020216205.

Staphylococcus aureus infections in kidney transplantation: a matched case controlled study.

BACKGROUND: Data are lacking on the risk factors and outcomes of Staphylococcus aureus infections in kidney transplant recipients. METHODS: Kidney recipients with S. aureus infections (n = 20) were retrospectively identified and compared to age- and transplant-type-matched (1:2) non-S. aureus-infected controls (n = 40). Risk factors for S. aureus infections were identified by conditional logistic regression analysis. RESULTS: Methicillin-resistant S. aureus (MRSA) was the cause of 32.1% of infections. Localizations of the infections were as follows: skin 42.9%, intra-abdominal 35.7%, blood stream 7.1%, and pulmonary 10.7%. The infections developed at a median time of 29 days (range 0-358 days) after transplantation. By univariate analysis, variables significantly associated with infection were steroid administration 4 weeks prior to infection (odds ratio (OR) 4.2, 95% confidence interval (95% CI) 1.1-15.8; p = 0.03) and the presence of a central venous catheter 7 days prior to infection (OR 5.6, 95% CI 1.1-27.8; p = 0.03). By multivariate analysis, subjects with steroid treatment during the previous 4 weeks had a 6.13-times higher risk of developing S. aureus infection (95% CI 1.5-25.7; p = 0.01), and the risk of infection decreased by a factor of 0.65 for every 1-y increase in age (95% CI 0.44-0.97; p = 0.03); these results were adjusted for matched criteria. Post-infection outcomes (cases vs controls) included graft loss (10% vs 0%; p = 0.11) and 12-month mortality (0% vs 2.5%; p = 0.99). CONCLUSIONS: Younger age and steroid treatment were significant independent risk factors associated with S. aureus infections after kidney transplantation. Graft and patient survival were not affected, but the study was not powered for these outcomes.

Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation.

In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4+ T cells, can be inhibitory to corneal re-innervation. Finally, this review considers the bidirectional interactions between corneal immune cells and corneal nerves, and how leveraging this interaction could represent a potential therapeutic approach for corneal neuropathy.

Emerging therapies and their delivery for treating age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of blindness in the Western world and is characterised in its latter stages by retinal cell death and neovascularisation and earlier stages with the loss of parainflammatory homeostasis. Patients with neovascular AMD (nAMD) are treated with frequent intraocular injections of anti-vascular endothelial growth factor (VEGF) therapies, which are not only unpopular with patients but carry risks of sight-threatening complications. A minority of patients are unresponsive with no alternative treatment available, and some patients who respond initially eventually develop a tolerance to treatment. New therapeutics with improved delivery methods and sustainability of clinical effects are required, in particular for non-neovascular AMD (90% of cases and no current approved treatments). There are age-related and disease-related changes that occur which can affect ocular drug delivery. Here, we review the latest emerging therapies for AMD, their delivery routes and implications for translating to clinical practice. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Triazole-derivatized near-infrared cyanine dyes enable local functional fluorescent imaging of ocular inflammation.

Near-infrared (NIR) chemical fluorophores are promising tools for in-vivo imaging in real time but often succumb to rapid photodegradation. Indocyanine green (ICG) is the only NIR dye with regulatory approval for ocular imaging in humans; however, ICG, when employed for applications such as labelling immune cells, has limited sensitivity and does not allow precise detection of specific inflammatory events, for example leukocyte recruitment during uveitic flare-ups. We investigated the potential use of photostable novel triazole NIR cyanine (TNC) dyes for detecting and characterising activated T-cell activity within the eye. Three TNC dyes were evaluated for ocular cytotoxicity in-vitro using a MTT assay and optimised concentrations for intraocular detection within ex-vivo porcine eyes after topical application or intracameral injections of the dyes. TNC labelled T-cell tracking experiments and mechanistic studies were also performed in-vitro. TNC-1 and TNC-2 dyes exhibited greater fluorescence intensity than ICG at 10 µM, whereas TNC-3 was only detectable at 100 µM within the porcine eye. TNC dyes did not demonstrate any ocular cell toxicity at working concentrations of 10 µM. CD4+T-cells labelled with TNC-1 or TNC-2 were detected within the porcine eye, with TNC-1 being brighter than TNC-2. Detection of TNC-1 and TNC-2 into CD4+T-cells was prevented by prior incubation with dynole 34-2 (50 µM), suggesting active uptake of these dyes via dynamin-dependent processes. The present study provides evidence that TNC dyes are suitable to detect activated CD4+T-cells within the eye with potential as a diagnostic marker for ocular inflammatory diseases.