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Purpose: To determine the pattern(s) of onset, variation, and progression of retinopathy in patients with Mucopolysaccharidosis (MPS)., Design: Prospective, longitudinal, observational study., Participants: Between November 2015 and March 2023, individuals with MPS were recruited from Ophthalmology clinics at the Manchester Royal Eye Hospital, United Kingdom., Methods: Participants underwent assessment of visual acuity, corneal clouding, intraocular pressure, along with fundoscopy, ultra-widefield (UWF) colour fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and electroretinography (ERG), where feasible., Main Outcome Measures: Evaluation of findings from clinical examination, retinal imaging, and electroretinogram studies, to ascertain the presence and patterns of retinopathy., Results: Data was collected for 75 patients, including 45 MPS I, 9 MPS II, 13 MPS IVA, and 8 MPS VI, aged 3-58 years. Fundus photography was conducted in 65 patients, FAF in 61, OCT in 58, and electrodiagnostic studies in 36 participants. Retinopathy was defined as signs of retinal disease evident through retinal examination or fundus photography such as depigmentation, bone-spicule pigmentation, vascular tortuosity, retinal pigment epithelium (RPE) mottling/other changes, macular atrophy/puckering/epiretinal membranes, FAF findings such as a central hyperautofluorescent dot, hyperautofluorescent parafoveal ring, hypoautofluorescent lesions around fovea (double bull's eye), areas of hyper/hypoautofluorescence, and extrafoveal changes, OCT imaging features such as central external limiting membrane (ELM) thickening, RPE disturbance, photoreceptor layer loss, parafoveal retinal atrophy, and outer retinal/intrachoroidal cavities, or electroretinogram studies revealing rod-mediated retinopathy or rod-cone dystrophy. Retinopathy was confirmed in 32 patients, including 25 MPS I, 4 MPS II, 1 MPS IVA, and 2 MPS VI. Five participants were first diagnosed with retinopathy with clinical examination, while 31 participants were identified on UWF colour fundus photography supported by FAF and OCT. 21 patients exhibited ERG abnormalities consistent with retinopathy. Fifteen of the total 32 participants described symptoms of nyctalopia. The onset of retinopathy varied substantially, with initial detection between 2 and 53 years of age., Conclusions: MPS patients as young as 2 may develop retinopathy, diagnosed through fundus examination, ophthalmic imaging, or ERG. Emerging treatments, including gene therapy, may prevent or stabilise retinopathy. Phenotypic data and natural history of MPS-related retinopathy are thus of paramount importance., (Copyright © 2024. Published by Elsevier Inc.)

Detecting the use of bisphosphonates (BPs) in equine athletes is of interest to regulators and laboratories due to the threat to welfare issues for the potential to provide analgesic effects and manipulating bone structure. The detection of BPs in biological matrices is challenging due to erratic biological elimination and inconsistent analytical recoveries. Therefore, complementary approaches are needed to provide evidence of their misuse in racehorses. BPs have two sub-classes: nitrogenous and non-nitrogenous. This study investigated plasma elimination following administration of one example from each sub-class, together with changes in endogenous eicosanoid and corticosteroids. Zoledronic acid (ZA) and tiludronic acid (TA) were administered by IV infusion to 8 thoroughbred horses with an 11-month washout period between each administration. Sample preparation for quantification of BPs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) utilised a two-step solid phase extraction (SPE) consisting of polymeric reversed-phase followed by weak anion exchange prior to derivatisation using trimethyl orthoacetate. Endogenous biomarkers were analysed after protein precipitation and SPE with polymeric reversed-phase prior to liquid chromatography-high resolution mass spectrometry (LC-HRMS) using data independent acquisition. The LC-MS/MS analysis showed ZA was undetectable after 8 h post-administration while TA was detected up to the final collection point of 28 days post-administration. The LC-HRMS analysis utilised targeted (i.e., prior inclusion list of compounds) approaches to monitor level changes of eicosanoid and corticosteroid biomarkers. Putative biomarkers were identified and now subject to validation for translation into routine sample analysis for improved retrospectivity to detecting BP misuse in equine plasma., (© 2024 The Author(s). Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Altrenogest is a synthetic progestin that suppresses reproductive behaviours and assists pregnancy maintenance in female horses. Two formulations are available, a 'weekly' intramuscular injection and a daily oral formulation. Altrenogest administration has returned positive swabs for steroids; consequently, using injectable altrenogest in racing mares is prohibited. Oral administration may be permitted in race mares if there is one clear day between dosing and racing. The only pharmacokinetic data available were generated from geldings. Therefore, to assist veterinarians and analysts in determining accurate dosing and detection intervals, pharmacokinetic analysis using mares is required. Blood samples were taken from 10 mares pretreatment to obtain baseline concentrations. Mares were administered altrenogest, either oral (PO; 0.044 mg/kg; daily for 15 days) or intramuscular (IM; 0.3 mg/kg; twice; Days 0 and 7). On the first and last treatment day, blood samples were taken at designated times post dosing. After a 3-week washout, mares received the alternative treatment with sampling repeated. At the initial dose, for IM administration mean (± SD) plasma altrenogest C max was 18.0 ± 6.6 ng/mL at 7.9 ± 3.9 h compared with PO dosing 13.2 ± 5.8 ng/mL at 0.8 ± 0.8 h. Plasma C max on the final day was significantly higher (p = 0.002 [IM]; p = 0.006 [PO]). At 24 h post final oral treatment, mean (± SD) plasma altrenogest was 1.0 ± 0.8 ng/mL and at 48 h were 0.65 ± 0.5 ng/mL. Plasma concentrations well exceeding this may indicate that the one clear day rule or dosage recommendations have not been adhered to., (© 2024 The Author(s). Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Purpose: Mucopolysaccharidoses (MPSs) are a rare group of lysosomal storage disorders characterized by the accumulation of incompletely degraded glycosaminoglycans (GAGs) in multiple organ systems, including the eye. Visual loss occurs in MPS predominantly due to corneal clouding. Despite the success of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) in improving many systemic manifestations of MPS, less is known about their effect on corneal clouding. This study prospectively analyses the effect of both ERT and HSCT on corneal clouding using objective measures over time., Methods: This is a prospective longitudinal observational study. Corneal clouding was assessed in each participant using slitlamp, digital slit-lamp photographs, and an iris camera (Corneal Opacification Measure [COM] and the Pentacam system)., Results: Data were collected for 65 participants: 39 MPS I (Hurler), 5 MPS II (Hunter), 12 MPS IV (Morquio), and 9 MPS VI (Maroteaux-Lamy). Follow-up data are available for 45 participants (29 MPS I, 3 MPS II, 6 MPS IV, and 7 MPS VI)., Conclusions: This study found corneal clouding to be stable in most participants with MPS I, II, IV, and VI over a follow-up period of 5 to 75 months (median of 30 months) when measured with clinical corneal grading systems, graded digital slit-lamp images, and iris camera COMs. For those with Pentacam densitometry measures, there was a progression of corneal clouding, on average, in those with MPS I and MPS VI. There was no apparent difference in progression of corneal clouding between patients who were on ERT, HSCT, or no treatment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The conventional detection of exogenous drugs in equine doping samples has been used for confirmation and subsequent prosecution of participants responsible. In recent years, alternative methods using indirect detection have been investigated due to the expanding number of pharmaceutical agents available with the potential of misuse. The monitoring of endogenous biomarkers such as hydrocortisone (HC) has been studied in equine urine with an international threshold of 1 μg/ml established; however, there is no current threshold for equine plasma. The aim of this research was to investigate plasma concentrations of HC and cortisone (C) in race day samples compared to an administration of Triamcinolone Acetonide (TACA). The reference population (n = 1150) provided HC (6 to 145 ng/ml) and C (0.7 to 13 ng/ml) levels to derive the HC to C ratio (HC/C). Population reference limits (PRLs) were proposed for HC/C values at 0.2 (lower) and 61 (upper). Administration of TACA resulted in down-regulation of HC/C values below the estimated PRLs for up to 96 h post-administration. This indirect detection period was longer than the detection of TACA for 72 h. The use of individual reference limits (IRLs) for HC/C values was investigated to support the Equine Biological Passport (EBP), an intelligence model developed by Racing NSW for longitudinal monitoring of biomarkers., (© 2022 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Purpose: Mucopolysaccharidoses (MPSs) are a heterogeneous group of lysosomal storage disorders. Ocular complications (such as corneal clouding, retinopathy and optic neuropathy) are common. Notably, there is a paucity of data on the effect of genotype and systemic treatments (enzyme replacement therapy or haematopoietic stem cell transplantation) on the ocular phenotype in MPS. We prospectively studied the ocular features of patients with MPSI (Hurler/Hurler-Scheie/Scheie), MPSIV (Morquio) and MPSVI (Maroteaux-Lamy), to evaluate the effect of different therapeutic interventions and to correlate the findings with genetic and biomarker data., Methods: Prospective observational cohort study. Study participants underwent detailed ocular examination including visual acuity; assessment of corneal clouding (Iris camera Corneal Opacification Measure score and Pentacam densitometry) and retinal and optic nerve imaging (optical coherence tomography and wide-field fundus imaging). Data on genotype, biomarkers and delivered therapies (type and length of treatment) were also collected for each patient where available., Results: Overall, 21 patients with MPSI, 4 patients with MPSIV and 3 patients with MPSVI were recruited. Corneal clouding scores were higher in MPSI compared with MPSIV and MPSVI. Retinopathy was evident in patients with MPSI only. Association was observed between corneal clouding and biomarkers in MPSI, MPSIV and MPSVI. However, no clear association was seen between genotype or treatment type and ocular phenotype., Conclusions: The ocular phenotype in MPS is variable, with corneal clouding occurring in MPSI, MPSIV and MPSVI, and retinopathy in MPSI only. There was an association between corneal clouding and efficacy of systemic treatment as measured by biomarkers., Competing Interests: Competing interests: JA reports grants from Biomarin Ltd, during the conduct of the study; personal fees from Biomarin Ltd, personal fees from Inventiva, personal fees from AbbVie, outside the submitted work. TA reports grants from Biomarin, during the conduct of the study. SJ reports personal fees and non-financial support from Biomarin, outside the submitted work. AG reports personal fees from Alexion Pharmaceuticals, non-financial support from Biomarin Pharmaceuticals, non-financial support from Shire Pharmaceuticals, outside the submitted work. PS has nothing to disclose. AJ has nothing to disclose. KS reports grants from Biomarin, during the conduct of the study (research grant awarded to Jane Ashworth and paid to institution)., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Infantile nephropathic cystinosis (INC) is an autosomal recessive lysosomal disorder in which patients develop deposits of cystine crystals in their kidneys and corneas from a young age., Methods: We conducted a retrospective analysis of children with INC seen by ophthalmologists at the Manchester Royal Eye Hospital between 2002 and 2018, to evaluate clinical findings, symptoms and treatment., Results: Twenty-two children diagnosed with INC from age 0 (prenatally) to 11 years were assessed. All evaluable patients had corneal cystine crystal deposits, and 15 had mild to moderate photophobia. Ten patients had other ocular conditions including blepharitis/chalzion (n = 6), swollen optic nerve (n = 3), punctate epitheliopathy (n = 3), corneal scarring (n = 1),and elevated intraocular pressure (n = 2). Confocal imaging identified nerve abnormalities in two patients (enlarged corneal nerve + abnormal-looking tortuous nerves in one patient and beaded nerves in the sub-basal plexus in the other), both of whom had significant crystal deposition in the anterior stroma. Visual acuity was relatively unaffected. All 22 patients were receiving oral cysteamine, and 21 were applying cysteamine eye drops (galenic preparation of 0.55% concentration, compounded by a hospital pharmacy). Recommended application frequency was at least eight times per day in all patients with dosing information available., Conclusions: This case series of patients with INC highlights the consistent pattern of corneal cystine crystal deposition, which is universally present from a young age in this condition, and the high incidence of photophobia even in young children. Corneal manifestations of INC persisted despite frequent administration of the hospital pharmacy-made eye drop preparation. Reasons for this lack of efficacy may include the lag period between diagnosis and first prescription of cysteamine eye drops and the difficulty in maintaining rigorous compliance with this treatment. In addition, the challenge for patients of maintaining optimal storage conditions may adversely affect the stability and efficacy of cysteamine within this preparation., Funding: Editorial assistance was funded by Orphan Europe Ltd.

Purpose: To determine whether the ocular phenotype in patients with mucopolysaccharidosis type I (MPSI) Hurler is affected by the efficacy of previous haemopoietic stem cell transplantation (HSCT)., Design: A retrospective cohort study of patients with MPSI who had undergone treatment with HSCT., Methods: Ocular phenotype was documented for each patient and compared to levels of biomarkers representing efficacy of previous transplantation., Main Outcome Measures: Assessment of visual acuity (VA), severity of corneal clouding and the presence of optic neuropathy or retinopathy. Biomarker assessment included dermatan sulphate/chondroitin sulphate (DS/CS) ratio and iduronidase enzyme level., Results: Severe corneal clouding was significantly greater in patients with lower iduronidase levels (p = 0.023) and raised DS/CS ratio (R 2  = 0.28 p = 0.043). Better VA was related to a higher iduronidase levels (R 2  = 0.15, p = 0.004) and lower DS/CS ratio (R 2  = 0.38, p = 0.001)., Conclusion: Improved ocular phenotypes in MPSI are associated with markers signifying efficacy of prior transplant. Early and effective HSCT may result in a better visual prognosis and reduction in ocular complications for patients with MPSI., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The association between abusive head trauma and retinal hemorrhages is well documented. As such, ophthalmic review in suspected nonaccidental injury has become routine. However, there is a paucity of reports focusing on ocular trauma and retinal detachment presenting as unilateral findings in nonaccidental injury and in the absence of other signs of physical abuse. This report identifies 2 suspected cases of nonaccidental injury in infants presenting to a tertiary care center with retinal detachment presumed secondary to severe unilateral direct ocular trauma. The fellow eye was normal in both cases. Findings were inconsistent with the reported histories from parents., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Gold-modified TiO 2 (Au-TiO 2 ) photocatalysts were utilised for the degradation of estrone (E1), a major endocrine disrupting chemical in water and wastewater. Au-TiO 2 catalysts were synthesised by a deposition-precipitation method with gold loadings of 0-8% (wt%). The Au-TiO 2 nanocomposite exhibited superior activity compared to P25 TiO 2 under UVA (λ=365nm), cool white (λ>420nm) and green (λ=523nm) light emitting diodes (LEDs), for treating 1mgl -1 of E1. The 4wt% Au loading was found to produce the best photocatalytic activity with a rate constant of 2.44±0.36h -1 , compared to 0.06±0.01h -1 for P25 TiO 2 , under visible light. In total 4 by-products were identified, one from negative ionization mode (m/z=269) and three from positive ionization mode (m/z=287) during photocatalysis, which were also degraded with time by Au-TiO 2 . For different water matrices, the photodegradation rate of E1 decreased in the order: ultrapure water>synthetic wastewater≈wastewater effluent from membrane bio-reactor. Overall, 4wt% Au-TiO 2 demonstrated superior performance compared to P25 TiO 2 in water and wastewater., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Biochar and functionalized biochar (fBC-1 and fBC-2) were prepared and applied to remove antibiotic chloramphenicol from deionized water, lake water and synthetic wastewater. Results showed that chloramphenicol removal on biochar was pH dependent and maximum sorption occurred at pH4.0-4.5. The sorption data of chloramphenicol fitted better with the Langmuir isotherm model than the Freundlich isotherm model with the maximum Langmuir sorption capacity of 233μMg -1 using fBC-2. Chloramphenicol sorption on fBC-2 followed the trend: deionized water>lake water>synthetic wastewater. The presence of humic acid decreased the sorption distribution coefficient (K d ) while the presence of low ionic strength and soil in solution increased K d value significantly. The mechanism of sorption on fBC mainly involved electron-donor-acceptor (EDA) interactions at pH<2.0; formation of charge assisted hydrogen bond (CAHB) and hydrogen bonds in addition to EDA in the pH4.0-4.5; and CAHB and EDA interactions at pH>7.0. Additionally, solvent and thermal regeneration of fBC-2 for repeatable applications showed excellent sorption of chloramphenicol under the same condition, due to the creation of a molecular imprinting effect in fBC-2. Consequently, fBC-2 can be applied with excellent reusability properties to remove chloramphenicol and other similar organic contaminants., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This article reviews different photodegradation technologies used for the removal of four endocrine disrupting chemicals (EDCs): estrone (E1), 17β-estradiol (E2), estriol (E3) and 17α-ethinylestradiol (EE2). The degradation efficiency is greater under UV than visible light; and increases with light intensity up to when mass transfer becomes the rate limiting step. Substantial rates are observed in the environmentally relevant range of pH7-8, though higher rates are obtained for pH above the pKa (~10.4) of the EDCs. The effects of dissolved organic matter (DOM) on EDC photodegradation are complex with both positive and negative impacts being reported. TiO2 remains the best catalyst due to its superior activity, chemical and photo stability, cheap commercial availability, capacity to function at ambient conditions and low toxicity. The optimum TiO2 loading is 0.05-1gl(-1), while higher loadings have negative impact on EDC removal. The suspended catalysts prove to be more efficient in photocatalysis compared to the immobilised catalysts, while the latter are considered more suitable for commercial scale applications. Photodegradation mostly follows 1st or pseudo 1st order kinetics. Photodegradation typically eradicates or moderates estrogenic activity, though some intermediates are found to exhibit higher estrogenicity than the parent EDCs; the persistence of estrogenic activity is mainly attributed to the presence of the phenolic moiety in intermediates., (Copyright © 2016 Elsevier B.V. All rights reserved.)