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The purpose of this article is to reflect on the online learning offered by Dubai private schools in response to the Covid-19 pandemic. This article considers both positive and negative features of provision, in order to suggest recommendations for future outbreaks. A comprehensive review of literature synthesizes with the results of an online survey. The period of March until July 2020 is referred to as Phase 1 of online learning. Phase 2 covers September and December 2020. The findings show that educators were generally positive toward online learning but have mixed opinions regarding the permanence, opportunities, and approaches of individual schools. Teachers discussed the progression of online learning within their settings and made multiple recommendations for the future including focusing on social–emotional development and well-being, limiting screen time where possible, ensuring Ed-Tech is appropriate for individual needs, and committing to an ongoing evaluation of curriculum adaptation. It was also suggested that schools review their approach to building technological skills, as well as the age in which this area of development is encouraged.

Background Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11–31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.

PURPOSE The purpose of this study was to investigate the most common causes of endogenous feline uveitis in a UK referral population and to investigate associations based on signalment. METHODS Retrospective multicenter cross-sectional study from 2010 to 2019 including cats presented to the Animal Health Trust and the Royal Veterinary College with clinical signs consistent with uveitis. Cats were included in analyzes if they had a full physical examination including an ophthalmic examination, complete blood count, serum biochemistry, and infectious disease testing for at least two diseases unless the diagnosis was found on clinical examination (eg, neoplasia). RESULTS A total of 92 cats were included in the study. The majority of cats presenting with uveitis were male (66.3%). The most common causes of endogenous uveitis were idiopathic uveitis (42/92 45.7%), feline infectious peritonitis (FIP) 15/92 16.3%), and lymphoma (10/92 10.9%). Fisher's exact test showed differences in breed across diagnosis groups (p = .002) with purebred cats being overrepresented in the lymphoma and FIP groups. Kruskal-Wallis test showed differences in median age across diagnosis groups (p

Homocystinuria (HCU) refers to a group of inherited disorders of homocysteine metabolism associated with high blood homocysteine concentration, thromboembolic tendency and neurocognitive symptoms. The most common causes of a high blood homocysteine relate to underlying vitamin B12or folate deficiency which must be excluded first. Thereafter, an inherited metabolic condition can be considered.The most prevalent inherited disorder of homocysteine metabolism is classical HCU caused by deficiency of the pyridoxine-dependent enzyme, cystathione beta-synthase, which converts homocysteine to cystathionine in the transsulphuration pathway. An alternative route for homocysteine metabolism is its remethylation to methionine by the cobalamin-dependent enzyme, methionine synthase, using the folate derivative, methyltetrahydrofolate, as a methyl donor. Remethylation defects are caused by impaired activity of methionine synthase itself, of an enzyme required to generate its methylcobalamin cofactor from dietary vitamin B12, or of the enzyme methyltetrahydrofolate reductase (MTHFR), which generates the methyl donor.The correct diagnosis can be inferred from additional laboratory investigations including a complete blood count and quantitation of methionine and methylmalonic acid. Methionine is high/normal in HCU and low in the remethylation disorders. In the latter, cobalamin defects are readily distinguished from MTHFR by a coexisting macrocytic anaemia and further delineated by presence or absence of methylmalonic acid in urine or plasma.Lowering homocysteine reverses thromboembolic risk. In HCU, this may be achieved with pyridoxine alone or with betaine as an alternative methyl donor. Some patients additionally follow a methionine-restricted diet. Betaine is the primary treatment for MTHFR and cobalamin disorders are managed with high-dose hydroxocobalamin.

Purpose\ud \ud To report surgical and corneal clarity scores (CCSs) of corneo‐limbo‐conjunctival transpositions (CLCTs) in a large number of canine cases.\ud \ud Methods\ud \ud Retrospective review of records that underwent CLCT to repair deep ulcers or perforations between 2002 and 2018. Signalment, concurrent eye disease, additional procedures, pathogenesis, medication, graft orientation, follow‐up, and CCSs were recorded.\ud \ud Results\ud \ud 418 eyes of 399 dogs were included. Brachycephalics were most commonly affected, comprising 325/418 (77.75%) of the eyes. The most commonly affected breeds were Pugs, Shih Tzus, Cavalier King Charles Spaniels, and French Bulldogs, with 116/418 (27.75%), 64/418 (15.31%), 34/418 (8.13%), and 34/418 (8.13%) ulcerated eyes, respectively. Mean age at surgery was 5.5 years (range 59 days‐17.7 years), and median follow‐up time was 100 days (range 3 days‐7.64 years). The most common etiopathogenesis was spontaneous ulceration in 205/418 eyes (49.04%) of which 191 (93.17%) occurred in brachycephalics. Primary keratoconjunctivitis sicca affected 122/418 eyes (29.19%) and injury 39/418 eyes (9.33%). Mean ulcer width was 3.5 mm (0.5‐10 mm). Success rate was 97.13% (406/418 eyes). Failure end points recorded included no menace response, secondary glaucoma, and endophthalmitis. Pre‐existing perforation was found in 101/418 (24.16%) of the eyes and significantly increased failure rate (P < .001). The median CCS was G3 (G0‐G4), which was lower for Pugs (G2). Graft orientation affected CCS, but did not reach statistical significance.\ud \ud Conclusion\ud \ud The high success rate and CCS for CLCT in dogs make it a good technique to treat deep ulcers but a less desirable outcome is anticipated when treating perforations and Pugs.

Background\ud \ud Systemic hypertension (SH) is a potential complication of acute kidney injury (AKI) in dogs.\ud \ud Objective\ud \ud To describe the prevalence of SH and hypertensive retinopathy in dogs with AKI, to investigate the relationship between SH and severity of AKI and to assess possible factors associated with SH.\ud \ud Animals\ud \ud Fifty‐two dogs with AKI.\ud \ud Methods\ud \ud Prospective observational study of dogs presenting to a tertiary referral center that fulfilled the International Renal Interest Society (IRIS) guidelines for the diagnosis of AKI. Systolic blood pressure measurement, urine protein/creatinine ratio (UPCR), urine output, presence of hypertensive retinopathy and fluid overload (FO), survival to discharge and duration of hospitalization were subsequently assessed. The prevalence of SH was calculated and the relationship between SH and recorded factors was examined by nonparametric statistics.\ud \ud Results\ud \ud The prevalence of SH (≥160 mm Hg) on admission or during hospitalization was 75% (39/52) and in 56% (22/39) of cases this was severe (≥180 mm Hg). Sixteen percent (7/43) of dogs had evidence of hypertensive retinopathy and 77% (24/31) dogs had UPCR >0.5. Forty‐two percent (22/52) dogs had FO on admission or during hospitalization. There was no association between SH and IRIS AKI grade, oligo/anuria, survival to discharge, duration of hospitalization or proteinuria. Dogs with FO on presentation were more likely to be hypertensive at admission compared to dogs without FO (P = .02). Dogs that did not survive to discharge were more likely to have FO (P = .007).\ud \ud Conclusions and Clinical Importance\ud \ud Systemic hypertension is common in dogs with AKI. Systemic hypertension might be associated with FO, which itself is associated with nonsurvival. Monitoring for SH and FO is therefore warranted in dogs with AKI.

Protein–RNA interactions regulate all aspects of RNA metabolism and are crucial to the function of catalytic ribonucleoproteins. Until recently, the available technologies to capture RNA-bound proteins have been biased toward poly(A) RNA-binding proteins (RBPs) or involve molecular labeling, limiting their application. With the advent of organic–aqueous phase separation–based methods, we now have technologies that efficiently enrich the complete suite of RBPs and enable quantification of RBP dynamics. These flexible approaches to study RBPs and their bound RNA open up new research avenues for systems-level interrogation of protein–RNA interactions.

Background Fabry disease (FD) is a genetic disorder caused by defective α-galactosidase-A enzyme due to mutations in the GLA gene. A reliable diagnosis in classical FD males can be made by measuring the enzyme activity while diagnosing classical FD females and non-classical FD patients requires mutation analysis. Plasma globotriaosylsphingosine (Lyso-Gb3) has progressively gained more importance as a diagnostic biomarker for FD in recent years. Having another biomarker to complement plasma Lyso-Gb3 will increase the diagnostic accuracy in the era of mass screening, and also precision medicine. This study aims to highlight the clinical utility of the total concentration of urinary Lyso-Gb3 plus its analogues in diagnosing FD. Method Random urine samples collected from 42 FD patients and 48 healthy individuals. Lyso-Gb3 and its analogues were enriched by solid phase extraction and analysed by liquid chromatography tandem mass spectrometry. Results The total concentration of Lyso-Gb3 plus its analogues in classical FD male and female patients were 1124.4 ± 181.2 and 308.6 ± 78.6 pmol/mmol creat., respectively. The levels in non-classical FD male and female patients were 229.2 ± 169.4 and 314.4 ± 156.4 pmol/mmol creat., respectively. Urinary Lyso-Gb3 and its analogues were virtually undetectable in healthy volunteers making it 100% specific for FD diagnosis. For FD male and female patients, total concentration of urinary Lyso-Gb3 plus its analogue levels ≥0.25 pmol/mmol creat. yielded a diagnostic sensitivity and specificity of 100% (AUC = 1, p Conclusions Our study findings support that the total concentration of Lyso-Gb3 plus its analogues in urine is specific to FD and may provide extra diagnostic utility for both classical and non-classical FD patients.

Dacryocystitis has been suggested to be a relatively common condition in pet rabbits and is often associated with concurrent disease. The aim of this study was to investigate potential risk factors associated with dacryocystitis in a pet rabbit population.A retrospective review of medical records from all rabbit cases evaluated at a single first opinion/referral UK exotics clinic between 2015 and 2018 was performed.Dacryocystitis was identified in 55 of 821 rabbits (6.70%) examined over the study period. Of those rabbits with dacryocystitis, dental disease was found in 24 rabbits (45%), respiratory disease in 20 rabbits (38%), aural disease in seven rabbits (13%) and concurrent ocular disorders in 15 rabbits (23%). Breed status was found to be a significant risk factor, with Lionhead/Lionhead cross and Dwarf Lop/Dwarf Lop cross rabbits being more likely to have dacryocystitis.These results suggest that a breed predisposition for dacryocystitis may exist, particularly for the popular Lionhead and Dwarf Lop rabbits, and veterinarians should advise clients on this accordingly.

Fusarium&nbsp, graminearum (Fgr) is a devastating filamentous fungal pathogen that causes diseases in cereals, while producing mycotoxins that are toxic for humans and animals, and render grains unusable. Low efficiency in managing Fgr poses a constant need for identifying novel control mechanisms. Evidence that fungal extracellular vesicles (EVs) from pathogenic yeast have a role in human disease led us to question whether this is also true for fungal plant pathogens. We separated EVs from Fgr and performed a proteomic analysis to determine if EVs carry proteins with potential roles in pathogenesis. We revealed that protein effectors, which are crucial for fungal virulence, were detected in EV preparations and some of them did not contain predicted secretion signals. Furthermore, a transcriptomic analysis of corn (Zea&nbsp, mays) plants infected by Fgr revealed that the genes of some of the effectors were highly expressed in vivo, suggesting that the Fgr EVs are a mechanism for the unconventional secretion of effectors and virulence factors. Our results expand the knowledge on fungal EVs in plant pathogenesis and cross-kingdom communication, and may contribute to the discovery of new antifungals.

Objective Domestic Cat Hepadnavirus (DCH) is a novel virus recently identified in the domestic cat. Currently, little is known regarding its clinical significance. The hepadnaviridae family includes the Hepatitis B Virus (HBV). Co-infection of HBV and Hepatitis C in humans increases the risk of uveitis. We aimed to determine whether DCH is present in the United Kingdom (UK) and whether DCH warrants investigation as a potential cause of uveitis in cats. Procedures Clinical records from the Royal Veterinary College (RVC) and the Animal Health Trust (AHT) were reviewed for feline cases diagnosed with endogenous uveitis. A healthy control group was identified from cats presented to the RVC as blood donors. DNA was extracted from stored blood samples using commercially available kits. Polymerase chain reaction assays were performed to confirm the presence of feline DNA and to detect the presence of DCH DNA using previously described protocols. Results Blood samples were available from 65 cats with endogenous uveitis and 43 healthy control cats. Two blood samples from cats with endogenous uveitis tested positive for the presence of DCH DNA. DCH DNA was not detected in the control group. There was no statistically significant difference between the prevalence of DCH between the groups. Conclusions Domestic Cat Hepadnavirus is present in the UK. This study failed to demonstrate a conclusive link between DCH and uveitis in cats, although further studies to investigate an association with other feline diseases are warranted.

Background Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). Method The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features. Results A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations; 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (VSGP) (70.9%), dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score according to neurological-onset. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, excluding ‘swallowing’ and ‘seizure’. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.43% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.94%), antidepressants (11.76%) and antacids (9.41%). Conclusion The proportion of participants at each age of neurological onset was relatively consistent across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Background Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). Method The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. Results A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for ‘swallowing’ and ‘seizure’. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). Conclusion The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Purpose To assess outcome of phacoemulsification in cats. Methods Records of 71 cats (82 eyes) from five referral centers were reviewed. Groups were divided by cause of cataract (congenital/juvenile [n = 32], traumatic [n = 33], and secondary to uveitis [n = 6]), and group comparisons were performed for the most common complications: postoperative ocular hypertension (POH), uveitis, corneal ulceration, synechia/dyscoria, and posterior capsular opacity (PCO) in three different time periods: immediately postoperatively, at 1‐90 days, and at >90 days. Results Median follow‐up was 198 days (interquartile range 64‐518 days). The overall visual success rate of the cats with a 12‐month follow‐up was 92.6% (25/27 eyes). POH occurred in 35/82 (42.6%) eyes. Immediately postoperatively, uveitis was the most common complication in 28/82 eyes (34.1%) followed by corneal ulceration in 22/82 eyes (26.8%). At 1‐90 days, uveitis in 41/81 eyes (50.6%) remained the most common complication, followed by synechia/dyscoria in 21/81 eyes (25.9%), corneal ulceration in 16/81 eyes (19.7%), and PCO in 15/81 eyes (18.5%). At >90 days, PCO in 17/47 eyes (36.1%), followed by synechia/dyscoria in 16/47 eyes (34%), was the most common complications. The number of eyes with synechia/dyscoria in the trauma group was higher (13/33 [39.3%]) than in the congenital/juvenile group (5/31 [16.1%]) at 1‐90 days (P = .039). No statistical difference was found for the other group comparisons. Three eyes in total were enucleated owing to endophthalmitis, post‐traumatic ocular sarcoma, and secondary glaucoma. Conclusion Uveitis in the short‐term and PCO and synechia/dyscoria in the long‐term were the most common complications following phacoemulsification in cats.

Background: Rates of performed caesarean sections have increased globally [1]. Surgical site infections (SSIs) following a caesarean section pose a threat to the safety of the patient. This study intended to determine the current SSI rate after caesarean sections at one community hospital. The rate of incidence of these infections was compared to benchmark rates from various studies, including a report from the American National Healthcare Safety Network (NHSN). This comparative study provides objective evidence of performance in relation to SSIs. Method: The primary data collection method included a form completed by the obstetrician-gynecologists of the individual patients at the six-week post-partum follow-up visit. Demographic data was collected retrospectively through analysis of medical records. Patients who underwent a caesarean section in the seven-month data collection period (between November 2015 and May 2016) were asked to participate, and consent was obtained. Results: A total of 118 caesarean sections were reviewed and seven SSIs diagnosed. A crude SSI rate was calculated at 5.9%. For further insight, NHSN risk-adjusted SSI rates were calculated. The NHSN risk-adjusted SSI rate was determined at 6.1% for those patients presenting with a risk index level of 0 and at 5.9% for those with a risk index level of 1. Both NHSN risk index levels of 2 and 3 were identified to have an adjusted SSI rate of 0.0%. Conclusion: This study, while limited in scope, does add to the collective literature on SSI rates following caesarean sections. Most significantly, it provides a methodology for other centres interested in determining their own infection rates and could lead to improved practices and better patient outcomes.

Rationale: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. Objectives: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake (VO 2 peak) following rigorous adjustment for other predictors. Methods: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. Measurements and Main Results: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that VO 2 peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. Conclusions: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.

Extracellular vesicles (EVs) are nano-sized compartments involved in cell communication and macromolecule transport that are well characterized in mammalian organisms. Fungal EVs transport virulence-related cargo and modulate the host immune response, but most work has been focused on human yeast pathogens. Additionally, the study of EVs from filamentous fungi has been hindered by the lack of protein markers and efficient isolation methods. In this study we performed the isolation and proteomic characterization of EVs from the filamentous cotton pathogen Fusarium oxysporum f. sp. vasinfectum (Fov). EVs were recovered from two different growth media, Czapek Dox and Saboraud's dextrose broth, and purified by size-exclusion chromatography. Our results show that the EV proteome changes depending on the growth medium but EV production remains constant. EVs contained proteins involved in polyketide synthesis, cell wall modifications, proteases and potential effectors. These results support a role in modulation of host-pathogen interactions for Fov EVs.

Background There is a lack of evidence-based guidelines on perioperative insulin administration and fasting time in diabetic dogs. The aim of this study was to compare two protocols with respect to intraoperative changes in blood glucose (BG) concentrations compared to preoperative values. Methods Thirty-two dogs were included. Dogs of group AM (n = 15) underwent anaesthesia in the morning after 12 hours fasting and received half their usual insulin dose, while dogs of group PM (n = 17) had surgery in the afternoon after 6 hours fasting and received their usual insulin dose; BG was measured before premedication (baseline), after anaesthetic induction, every 30 minutes throughout surgery, at extubation and after anaesthetic recovery. The occurrence of intraoperative complications was recorded. Results There were no differences between groups in perioperative changes in BG over time, and in the proportion of dogs experiencing complications. Common complications were hypotension (53 per cent of dogs in either groups), hyperglycaemia (67 and 65 per cent in groups AM and PM) and hyperkalaemia (20 and 11 per cent in groups AM and PM). Conclusions Either protocols may be used in diabetic dogs undergoing anaesthesia. The occurrence of hyperkalaemia in the study population supports routine intraoperative monitoring of blood potassium concentration.

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (Almsflin/flin;Adipo-Cre+/-) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Introduction Alstrom syndrome (ALMS) is an ultra-rare metabolic disorder caused by biallelic loss-of-function in the Alms1 gene which encodes a ubiquitously expressed centrosomal protein of the primary cilium. Although ALMS is characterised by several metabolic and hormonal dysfunctions that can lead to an increased risk of developing osteoporosis and bone fracture, an increased BMD have been observed. The aim of this study was to characterise the anthropometric, clinical, genetic and densitometric features of bone health in a large adult UK cohort of subjects with ALMS. Methods Twenty-three patients with ALMS and 23 age-matched male control subjects were recruited. Lumbar spine (LS) and total hip (TH) bone mineral density (BMD) were evaluated by DXA in all subjects. A CT scan to assess the spinal bone architecture was performed in ALMS patients with raised lumbar density. Blood analysis for biochemical parameters and thyroid and sex hormones was performed in all ALMS patients. Results LS Z-score levels were higher than +2 SD in 35% of all ALMS study participants, of whom 75% were men and 25% were women. TH Z-scores were higher than +1 SD 13% of patients and all of them have higher than expected lumbar Z-score. An extremely high BMD was found in two of the oldest patients (LS Z-score +10.8 and +15.3 SD). Conclusion ALMS patients tend to have high levels of BMD that increase with age, in particular of the trabecular bones. Although obesity and lifelong IR can be responsible for the increase in BMD, at least in part, of a possible signalling role of Alms1 protein as a bone-forming factor is plausible.

Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

Key Clinical Message A rhomboid blepharoplasty can be used to achieve functional and cosmetic eyelid reconstruction at the medial canthus in the horse. Combination of a rhomboid blepharoplasty with cryotherapy is a treatment option for eyelid ocular squamous cell carcinomas.

To characterize the immune cells present in different forms of feline anterior uveitis.Eyes were obtained from 49 cats diagnosed with chronic idiopathic lymphoplasmacytic anterior uveitis, 7 cats with feline infectious peritonitis (FIP), and 9 cats euthanized for nonocular disease.HE sections were scored on the level of infiltrate in the anterior uvea. Immunohistochemistry was performed for FoxP3, CD3, and IL-17A, and positive cells were quantified in multiple images of each sample. A generalized estimating equation tested for an association between the level of inflammation and the prevalence of these cell types.Cells stained positive for IL-17A in idiopathic uveitis but not in FIP samples. We found significantly fewer FoxP3Idiopathic, but not FIP-associated, uveitis appears to have Th17 cell involvement. The numbers of FoxP3

Amniotic membrane is widely used in the treatment of ocular surface disorders in human and veterinary patients. Preservation and storage of amnion has proven challenging, prompting the development of new preservation techniques. Omnigen®, a novel low-temperature vacuum-dehydrated amnion, is reported to possess enhanced structural properties and biochemical stability in vitro, but its clinical use in veterinary patients is not well-described. This study aims to document and describe the varied use of Omnigen for the surgical treatment of corneal ulceration in cats and dogs. A total of 45 patients (46 eyes) were recruited from the clinical record system of the Royal Veterinary College (London) between January 2016 and December 2017. Brachycephalic breeds were over-represented (37/45; 82.2%). Omnigen was used as a standalone graft in 5/46 (10.9%) eyes, as a supplementary graft in 29/46 (63.0%) eyes and as a patch in 12/46 (26.1%) eyes. Graft failure occurred in 10/46 eyes (21.7%). At final examination 43/46 eyes (93.5%) had healed and 31/33 eyes (93.9%) were visual. This study demonstrates the successful use of Omnigen for the surgical treatment of corneal ulceration in cats and dogs. Further studies are needed to clarify its properties and benefits in the clinical field.

Background Pigmentary keratitis (PK) is commonly recognised in Pugs, but its aetiology is not completely understood. The aim of this study was to determine the prevalence and associated features of PK in Pugs in the United Kingdom (UK). Results A total of 210 Pugs (420 eyes) were recruited from 12 UK dog shows and social events. The median age of Pugs recruited was 2.50 years (range 0.25–16.25 years). Pigmentary keratitis was detected in 369/420 (87.8%) eyes and in at least one eye 193/210 (91.9%) Pugs, of which 17/193 (8.8%) were affected unilaterally and 176/193 (91.2%) bilaterally. Pigmentary keratitis was typically mild to moderate (46.3 and 49.9% of eyes, respectively). Detection of PK was significantly associated with increased age (P = 0.002) and the presence of medial entropion of the lower eyelid (MELE) (P = 0.001). Severity of PK was significantly associated with the grade of MELE (P P = 0.036) that warrants further study. Conclusions This study estimated a high disease prevalence of PK in UK Pugs, and demonstrated significant associations with age and the presence of MELE. These associations, which have not been previously reported, offer an insight into the underlying pathophysiology of this condition in Pugs. The results encourage further population research, such as prospective longitudinal studies. These findings also support the development of clinical and breeding strategies based on the reduction of MELE and, possibly, limbal pigment.

Background: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. Methods: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. Results: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. Conclusion: This study describes the natural history of classic galactosemia based on the hitherto largest data set. The initial GalNet meeting to discuss the registry was financially supported by a grant to M.E.R-G. from The Netherlands Organisation for Scientific Research (NWO). Development, implementation and maintenance were supported by grants from the Dutch Galactosemia Research foundation, European Galactosemia Society and Metakids grants to M.E. R-G. Data entry for 6 of the 7 participating Dutch centers was done by the coordinating center and was financially supported by a Stofwisselkracht grant to M.E.R-G. in 2016. Analysis and interpretation of data was financially supported by Stofwisselkracht and Metakids grants to M.E.R-G. (2017 and 2018). The Irish data entry was supported by a national Health Research Board (HRB) grant to E.P.T. The British inherited Metabolic Disease Group supported access to the registry in the UK. M.G. was supported by a grant from the Batzebär foundation of the University Hospital Bern, and one from the Galaktosämie Schweiz patient organization for the set-up of the registry and data entry for all patients of Switzerland. The Spanish Galactosemia foundation financially supported data entry for Spanish patients. SI