UK NEQAS and BSHI guideline: Laboratory testing and clinical interpretation of HLA genotyping results supporting the diagnosis of coeliac disease.

Coeliac disease is a common immune-mediated inflammatory disorder caused by dietary gluten in genetically susceptible individuals. While the diagnosis of coeliac disease is based on serological and histological criteria, HLA-DQ genotyping can be useful, especially in excluding the diagnosis in patients who do not carry the relevant DQ heterodimers: DQA1*05 DQB1*02, DQB1*03:02 or DQA1*02 DQB1*02 (commonly referred to as DQ2.5, DQ8 and DQ2.2, respectively). External quality assessment results for HLA genotyping in coeliac disease have revealed concerning errors in HLA genotyping, reporting and clinical interpretation. In response, these guidelines have been developed as an evidence-based approach to guide laboratories undertaking HLA genotyping for coeliac disease and provide recommendations for reports to standardise and improve the communication of results.

Sonographic features of the uncomplicated postoperative abdomen in dogs treated for pyometra by ovariohysterectomy.

Pyometra is a prevalent disease in intact bitches and the standard treatment is ovariohysterectomy (OHE). Published descriptions of normal sonographic findings after OHE are currently lacking. The aims of this prospective observational study were to describe and compare postoperative abdominal sonographic features for three timepoints following OHE in a group of dogs with pyometra and an uneventful recovery. A total of 22 dogs had sequential focused abdominal ultrasound examinations on days 1, 4-6, and 10-15 postsurgery. Recorded sonographic features for each examination time point and characteristics of the cervical stump and the mesovarium, size, and echogenicity of medial iliac lymph nodes (MILNs), presence of free peritoneal fluid, and pneumoperitoneum. The cervical stump appeared as a heterogenous area with a hypoechoic center surrounded by hyperechogenic tissue in all dogs. The cervical stump transverse-sectional area was larger on day 4-6 compared with day 1 and day 10-15 (P = .0009). Mesovarium ligature reactions were identified as heterogeneous and hyperechoic areas with central and/or edge shadowing in all dogs. The size and echogenicity of MILNs and the mesovarium reactions did not significantly differ among time points. Free peritoneal fluid was detected in 45%, 41%, and 9% and pneumoperitoneum in 95%, 82%, and 14% of dogs at sequential time points. Findings from this sample of dogs with an uneventful recovery following OHE due to pyometra can be used to assist veterinarians in interpreting postoperative abdominal ultrasonographic characteristics in future dogs treated surgically for pyometra.

Minimal reporting guideline for research involving eye tracking (2023 edition).

A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.

Eye tracking: empirical foundations for a minimal reporting guideline.

In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").

Impact of the COVID-19 pandemic on individuals with nystagmus and an exploration of public assumptions about the condition: an electronic questionnaire study.

PURPOSE: Nystagmus is a disorder characterized by uncontrolled, rhythmic oscillations of the eyes. It often causes reduced visual function beyond reduced visual acuity alone. There is a paucity of literature regarding the public understanding of nystagmus, and there are no published data on the impact of the COVID-19 pandemic on people living with the condition. This study explores the self-reported impact of the COVID-19 pandemic on those with nystagmus, and examines both public understanding of how nystagmus affects people who have it and the perceptions of public understanding by those with the condition and their carers. METHODS: A qualitative questionnaire was designed following a stakeholder engagement process. This questionnaire was advertised via social media platforms and charity websites to achieve widespread recruitment. Data were collected between November and December 2020. Participants were divided into two groups based on their response to the question: "Do you, or anyone you know well, have nystagmus?". Questions were posed to participants in a purpose-built, branching survey. The resulting data were analyzed using descriptive and inferential statistical methods. RESULTS: One thousand six hundred forty-five respondents were recruited, of which 849 (51.6%) answered "Yes" to the initial filtering question. Analysis showed that, broadly, public understanding of nystagmus differs from the perception of it by those with nystagmus and their carers, that the COVID-19 pandemic has had a significant impact on those with nystagmus, and that respondents who have met someone with nystagmus, even briefly, tend to have a greater understanding of the impact of the condition. CONCLUSION: This study highlights the lack of public awareness regarding nystagmus and suggests opportunities to increase the awareness of nystagmus without the need for extensive knowledge of the condition. The COVID-19 pandemic has posed additional difficulties for those living with nystagmus, which is likely to be comparable among those with similar ocular disorders.

Handheld Optical Coherence Tomography in a Young Infant With Albinism and Fovea Plana.

ABSTRACT: We present handheld optical coherence tomography (OCT) diagnosis of Grade 4 foveal hypoplasia (fovea plana) in a 28-day-old infant with albinism. Grade 4 foveal hypoplasia is characterized by the absence of the foveal pit, absence of outer segment lengthening, and absence of outer nuclear layer widening. Binocular visual acuity at 58 months follow-up was 1.2 logarithm of the minimal angle of resolution (logMAR). We describe our handheld OCT acquisition protocol and compare the morphological features with a healthy, age-matched control subject.

Can Structural Grading of Foveal Hypoplasia Predict Future Vision in Infantile Nystagmus?: A Longitudinal Study.

PURPOSE: To evaluate structural grading and quantitative segmentation of foveal hypoplasia using handheld OCT, versus preferential looking (PL), as predictors of future vision in preverbal children with infantile nystagmus. DESIGN: Longitudinal cohort study. PARTICIPANTS: Forty-two patients with infantile nystagmus (19 with albinism, 17 with idiopathic infantile nystagmus, and 6 with achromatopsia) were examined. METHODS: Spectral-domain handheld OCT was performed in preverbal children up to 36 months of age. Foveal tomograms were graded using our 6-point grading system for foveal hypoplasia and were segmented for quantitative analysis: photoreceptor length, outer segment (OS) length, and foveal developmental index (FDI; a ratio of inner layers versus total foveal thickness). Patients were followed up until they could perform chart visual acuity (VA) testing. Data were analyzed using linear mixed regression models. Visual acuity predicted by foveal grading was compared with prediction by PL, the current gold standard for visual assessment in infants and young children. MAIN OUTCOME MEASURES: Grade of foveal hypoplasia, quantitative parameters (photoreceptor length, OS length, FDI), and PL VA were obtained in preverbal children for comparison with future chart VA outcomes. RESULTS: We imaged 81 eyes from 42 patients with infantile nystagmus of mean age 19.8 months (range, 0.9-33.4 months; standard deviation [SD], 9.4 months) at the first handheld OCT scan. Mean follow-up was 44.1 months (range, 18.4-63.2 months; SD, 12.0 months). Structural grading was the strongest predictor of future VA (grading: r = 0.80, F = 67.49, P < 0.0001) compared with quantitative measures (FDI: r = 0.74, F = 28.81, P < 0.001; OS length: r = 0.65; F = 7.94, P < 0.008; photoreceptor length: r = 0.65; F = 7.94, P < 0.008). Preferential looking was inferior to VA prediction by foveal grading (PL: r = 0.42, F = 3.12, P < 0.03). CONCLUSIONS: Handheld OCT can predict future VA in infantile nystagmus. Structural grading is a better predictor of future VA than quantitative segmentation and PL testing. Predicting future vision may avert parental anxiety and may optimize childhood development.

POTENTIAL UTILITY OF FOVEAL MORPHOLOGY IN PRETERM INFANTS MEASURED USING HAND-HELD OPTICAL COHERENCE TOMOGRAPHY IN RETINOPATHY OF PREMATURITY SCREENING.

PURPOSE: To investigate dynamic foveal morphology with postmenstrual age, in preterm infants with and without retinopathy of prematurity using hand-held optical coherence tomography, adjusting for gestational age (GA) and birthweight (BW). METHODS: Prospective mixed cross-sectional/longitudinal observational study of 87 participants (23-36 weeks GA; n = 30 with, n = 57 without retinopathy of prematurity) using hand-held optical coherence tomography images (n = 278) acquired between 31 weeks and 44 weeks postmenstrual age excluding treated retinopathy of prematurity. Measurements included foveal width, area, depth, central foveal thickness, maximum slope, and parafoveal retinal thickness at 1,000 µm nasal and temporal to the central fovea. RESULTS: Retinopathy of prematurity was significantly correlated with only foveal width in either GA or BW adjusted statistical models. In contrast, severity of prematurity (GA, BW) correlated with foveal area (P < 0.005), depth (P ≤ 0.001), and slope (P < 0.01), although central foveal thickness (P = 0.007) and parafoveal retinal thickness (P < 0.001) correlated with GA, but not with BW. CONCLUSION: Foveal width is independent of GA and BW with potential in retinopathy of prematurity screening assessment using hand-held optical coherence tomography. Foveal morphology could be graded in prematurity during development, with possible implications for future management of preterm infants.

Preliminary Findings of a Dedicated Ocular Myasthenia Gravis Rating Scale: The OMGRate.

There is a pressing need for a robust rating scale for ocular myasthenia gravis (OMG). Rating scales for myasthenia gravis (MG) research have a predominant focus on generalised disease. We present results of the first dedicated rating scale for OMG: the ocular myasthenia gravis rating scale (OMGRate). The OMGRate was developed through an international collaboration between neuromuscular and neuro-ophthalmology experts in OMG. It comprises two components: a physician- examination (OMGRate-e) and a patient questionnaire (OMGRate-q).. The OMGRate was prospectively validated in patients attending a neuro-ophthalmology clinic from April 2017 to October 2018. External validity and reliability of OMGRate were evaluated using validated MG rating scales: the Myasthenia Gravis Composite (MGC), the Myasthenia Gravis Quality of Life (MG-QOL), and the ocular component from the Myasthenia Gravis Impairment Index questionnaire (MGII). Two hundred and eleven assessments were completed in 104 patients (67 males, mean age 55 y, range 18-86 y). There was very good external validity of the OMGRate: good correlation between OMGRate-e and MGC (r = 0.64, 95% confidence intervals [CI] 0.54-0.74, p < .0001); excellent correlation between OMGRate-q and MGII (r = 0.85, 95% CI 0.78-0.91, p < .0001) and good correlation between OMGRate and MG-QOL (r = 0.68, 95% CI 0.60-0.77, p < .0001). A higher correlation of OMGRate and MG-QOL compared with MGC and MG-QOL (r = 0.47, 95% CI 0.34-0.59, p < .0001) suggests that OMGRate is better able to capture significant QOL information in patients with OMG. It had excellent reliability with an intraclass correlation coefficient of 0.83 (95% CI 0.67-0.92). Feedback from examiners and patients indicated that the OMGRate was easy to use. In conclusion, OMGRate is an easy-to-use, valid and reliable rating scale for monitoring the severity of OMG.

Factors associated with common and atypical chromosome abnormalities after positive combined first-trimester screening in Chinese women: a retrospective cohort study.

BACKGROUND: When cell-free DNA (cfDNA) testing is used as a secondary screening tool following combined first-trimester screening (cFTS), cFTS is used to estimate the prior risk for chromosome abnormalities. This study aimed to assess the factors that are associated with common and atypical abnormalities following cFTS, including cFTS risk, advanced maternal age, increased nuchal translucency (NT) ≥3.5 mm, and abnormal levels of serum markers. METHODS: We reviewed a historical cohort of 1855 Chinese women carrying singleton pregnancies with a positive cFTS [at a threshold of 1:250 for trisomy (T) 21 or 1:180 for T18] in one public hospital over a five-year period. All chromosome abnormalities were confirmed by invasive prenatal diagnosis (IPD) with karyotyping, with or without array comparative genomic hybridization. Using multivariable binary logistic regression analysis, we determined the parameters that were associated with common and atypical abnormalities. RESULTS: Overall, the prevalence of common and atypical abnormalities was 6.2 and 1.2%, respectively, and the prevalence increased with the risk of T21 by cFTS. In pregnancies with a risk of T21 > 1 in 100, a high risk of both T21 and T18, an increased NT, or a pregnancy-associated plasma A (PAPP-A) level <  0.2 multiple of medians (MoM), the prevalence of common abnormalities was 12.2, 64.7, 25.5 and 33.8%, respectively, while that of atypical abnormalities was 1.6, 3.9, 4.2, and 7.4%, respectively. In the multivariable binary logistic regression analysis, out of these four factors, only two (increased NT and PAPP_A <  0.2 MoM) were significant predictors of common and atypical abnormalities, respectively. Of all positive cFTS pregnancies, 50.4% did not have any of these four factors, and the prevalence of common and atypical abnormalities was 1.1 and 0.6%, respectively. There were three atypical abnormalities, all of which were mosaicism, and they were detected among women with IPD alone. The ages of these women were ≥ 35 years. All three pregnancies were continued after proper counseling. After giving birth, only one child had mild abnormalities, while the other two were phenotypically normal. CONCLUSIONS: Our study identified factors associated with common and atypical abnormalities after cFTS. These factors can be used to estimate the prior risk for these abnormalities to help with post-cFTS counseling in terms of choosing between cfDNA testing and IPD.

Retinal development in albinism: a prospective study using optical coherence tomography in infants and young children.

BACKGROUND: Retinal development normally involves migration of the inner retinal layers away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the photoreceptors over time. This process is arrested prematurely in albinism. However, because retinal development continues at least until the age of 4 years, when development arrests in albinism is uncertain. In this study we outlined the time course of retinal development in children with albinism. METHODS: We studied 44 children with a diagnosis of albinism and 223 control participants. All participants were aged between 0 and 6 years. We obtained 219 mixed cross-sectional and longitudinal optical coherence tomography examinations in the albinism group and compared them with 558 control examinations. Retinal layer segmentation was performed with ImageJ software. Generalised linear mixed regression modelling was used to analyse group differences in retinal development. FINDINGS: In the albinism group, inner retinal layer migration from the fovea was delayed and arrested prematurely, resulting in a significantly thicker central macular thickness than in the control group (p<0·0001). Whereas the central macular thickness increased with age in the control group, in the albinism group it initially decreased with age as a result of continuing regression of the inner retinal layers (p=0·041). The perifoveal retinal thickness was significantly decreased in albinism from a reduction of both inner (p<0·0001) and outer (p<0·0001) retinal layer thicknesses. There was evidence that the photoreceptor layers across the fovea were elongating in albinism, albeit at a reduced rate, compared with the control group. This difference was most apparent for the foveal photoreceptor inner segment (p=0·001). INTERPRETATION: Our findings show that perturbations exist in several aspects of retinal development including the migration and differentiation of the neuronal cells within the retina. We showed continuing regression of the inner retinal layers and elongation of the photoreceptor layers suggesting residual plasticity of the developing albino retina. This finding is important because treatment at the earliest stages of the condition might normalise retinal development and optimise vision. FUNDING: UK Medical Research Council (grant number MR/J004189/1), Ulverscroft Foundation, National Eye Research Centre, Nystagmus Network UK.

Optic Nerve Head Development in Healthy Infants and Children Using Handheld Spectral-Domain Optical Coherence Tomography.

PURPOSE: To determine feasibility of optic nerve head (ONH) imaging and to characterize ONH development in full-term infants without sedation using handheld spectral-domain optical coherence tomography (SD OCT). DESIGN: Prospective cross-sectional study. PARTICIPANTS: Three hundred fifty-two children aged between 1 day and 13 years. METHODS: All participants were imaged using handheld SD OCT without sedation during a single scan session. The percentage of successful scans was calculated. Interexaminer reproducibility and differences between right and left eyes were assessed using intraclass correlation coefficients (ICCs). Images were analyzed using ImageJ software. The developmental trajectories over time for ONH parameters were calculated using fractional polynomial modelling. MAIN OUTCOME MEASURES: Disc and cup diameter (expressed as distance in micrometers and visual angle in degrees), cup depth, Bruch's membrane opening-minimum rim width (BMO-MRW), retinal thickness, and retinal nerve fiber layer (RNFL; 1700 µm and 6° from the disc center). RESULTS: On average, 70% of participants were imaged successfully. Interexaminer reliability was excellent (ICC, >0.89) for diametric and retinal thickness parameters. Right and left eyes were similar for diametric measurements (ICC, >0.79), but more variable for nasal BMO-MRW, RNFL, and retinal thickness. The mean disc and cup diameter increase by 30% and 40%, respectively, between birth and 13 years of age when expressed as a distance measure, but remained constant (at 5°-5.5° and 2°, respectively) when expressed as a visual angle with reference to the eye nodal point. The peripapillary temporal RNFL demonstrated a marked initial decrease of nearly 35% between birth and approximately 18 months of age. This was followed by a slow increase up to 12 years of age when measured at 1700 µm from the disc center, although there was little change when measured at 6° from the disc center. CONCLUSIONS: We demonstrated feasibility of handheld SD OCT imaging of the ONH in full-term infants and children without anaesthesia or sedation. This is the first in vivo handheld SD OCT study to describe the development of ONH parameters during the critical early years of visual maturation. Our results provide a normative database for use in routine practice and further studies of ONH pathologic features.

An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.

Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.

Monitoring of chimerism following allogeneic haematopoietic stem cell transplantation (HSCT): technical recommendations for the use of short tandem repeat (STR) based techniques, on behalf of the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping Chimerism Working Group.

Analysis of short tandem repeats (STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme.

Complications of Reduced Intensity Conditioning HSCT for XIAP Deficiency (Alloimmune Cytopenias and HLH) Successfully Managed With Donor Lymphocyte Infusion.

X-linked inhibitor of apoptosis protein deficiency is a rare illness and although stem cell transplant is curative, full intensity conditioning is associated with high mortality rates. We describe a child with unusual complications associated with residual host lymphocytes following reduced intensity stem cell transplant. Recipient derived, donor directed, antigranulocyte antibodies led to life-threatening and prolonged neutropenia and residual recipient lymphocytes reestablished hemophagocytic lymphohistiocytosis after withdrawal of immune suppression despite high levels of whole blood chimerism. Hemophagocytic lymphohistiocytosis was abolished following specific improvement in donor T-cell chimerism after donor lymphocyte infusions, and alloimmune cytopenias were no longer evident.

Macular morphology in patients with optic nerve head drusen and optic disc edema.

PURPOSE: In this study we investigated macular morphology, including individual retinal layers, in patients with optic nerve head drusen (ONHD) and optic disc edema (ODE) compared with healthy participants, using high-resolution spectral domain optical coherence tomography (OCT). DESIGN: Prospective, cross-sectional, observational study. PARTICIPANTS: A total of 67 patients with ONHD, 36 patients with ODE, and 57 healthy participants. METHODS: High-resolution spectral domain OCT (Copernicus [OPTOPOL Technology S.A., Zawiercie, Poland] 3-µm resolution, 7 × 7 × 2-mm volumetric scans) was used to image macula morphology. Average retinal nerve fiber layer (RNFL) thickness was measured using a semiautomated method with manual correction of the internal limiting membrane, RNFL, and retinal pigment epithelium (RPE). Retinal and RNFL thicknesses were measured and analyzed in 3 circular zones (Early Treatment Diabetic Retinopathy Study protocol). Individual retinal layers at the macula were quantified by analyzing tomograms using ImageJ (http://rsbweb.nih.gov/ij/; Accessed June 1, 2013). MAIN OUTCOME MEASURES: Average retinal and individual retinal layer thickness in patients with ODE or ONHD, and healthy controls. RESULTS: Patients with ONHD had thicker retinae in the inner annulus compared with patients with ODE and controls (significant in the temporal segment compared with those with ODE [P = 0.013] and in the superior segment compared with controls [P = 0.05]). Patients with ONHD had a significantly thinner inner plexiform layer (IPL) (P = 0.02), nerve fiber layer (P = 0.05), and RPE (P = 0.0001), and thicker ganglion cell layer (P = 0.003) and outer plexiform layer (OPL) (P < 0.001) compared with controls. Patients with ODE demonstrated the thickest retina and RNFL in the outer annulus (significant in the inferior segment compared with controls, P = 0.02 for both) with significant thickening in the IPL (P = 0.004), OPL (P < 0.003), and outer segment layer (P ≤ 0.02), and severe ganglion cell loss (P = 0.004) and RPE (P = 0.0001) thinning compared with healthy volunteers. CONCLUSIONS: Our study shows that optic nerve diseases are associated with selective changes in different retinal layers in patients with ODE and ONHD. These findings may be of diagnostic value and could be taken into consideration in assessing patients and studying the pathogenesis of these conditions.

Two unusual cases of haemoglobin Bart's hydrops fetalis due to uniparental disomy or non-paternity.

The authors present 2 unusual cases of haemoglobin (Hb) Bart's hydrops fetalis and highlight the problem of a screening system for α-thalassaemia which focuses on maternal and paternal mean corpuscular volume (MCV) alone. Normal paternal MCV may not preclude fetal Hb Bart's disease because of the rare occurrence of maternal uniparental disomy or non-paternity. During a mid-trimester anomaly scan, with fetal cardiomegaly or hydrops in a woman with low MCV but normal paternal MCV, obstetricians should remain alert for fetal Hb Bart's disease. This is very important and relevant for national screening systems in South-East Asia, where a routine mid-trimester scan may not be available. A routine mid-trimester anomaly scan should therefore be implemented and in high prevalence areas, sonographers should be sensitive to the cardio-thoracic ratio even if screening shows that pregnancy is unlikely to be at risk.