Universal Child Mental Health Screening for Parents: a Systematic Review of the Evidence.

Childhood represents a critical window for the emergence and treatment of mental health disorders, yet many are not being identified, or are identified too late to receive adequate intervention. This systematic review (Prospero registration: CRD42022299560) aimed to determine the effectiveness and acceptability of parent reported universal mental health screening (UMHS) to improve the early identification of children at-risk of mental health difficulties, and to identify barriers and enablers that may influence parental engagement. Six databases were searched in February 2022 for peer-reviewed, primary research. Studies conducted in targeted populations, evaluating psychometric properties, or focused on screening non-psychological problems were excluded. Ten studies examined parent reported (n = 3,464 parents) UMHS for children from birth to 18 years, suggesting an overall scarcity of research. Findings are presented in a table of study characteristics and a narrative summary of acceptability, effectiveness, barriers, and enablers. Quantitative findings indicated that parents generally support and accept UMHS. Research assessing effectiveness was limited, although two studies indicated increased referrals and referral adherence following positive screens. Confidentiality and stigma were commonly identified barriers. Quality assessment using the Mixed Methods Appraisal Tool indicated that studies varied in quality, meeting four to seven of the seven quality criteria. Understanding and addressing parent attitudes to UMHS across settings is necessary for the successful implementation of screening and improvement of child mental health outcomes. More high-quality research studies, including randomized controlled trials are therefore needed to examine the acceptability and effectiveness of UMHS for parents and their children.

Self-harm in adolescence and risk of crash: a 13-year cohort study of novice drivers in New South Wales, Australia.

INTRODUCTION: Self-harm and suicide are leading causes of morbidity and death for young people, worldwide. Previous research has identified self-harm is a risk factor for vehicle crashes, however, there is a lack of long-term crash data post licensing that investigates this relationship. We aimed to determine whether adolescent self-harm persists as crash risk factor in adulthood. METHODS: We followed 20 806 newly licensed adolescent and young adult drivers in the DRIVE prospective cohort for 13 years to examine whether self-harm was a risk factor for vehicle crashes. The association between self-harm and crash was analysed using cumulative incidence curves investigating time to first crash and quantified using negative binominal regression models adjusted for driver demographics and conventional crash risk factors. RESULTS: Adolescents who reported self-harm at baseline were at increased risk of crashes 13 years later than those reporting no self-harm (relative risk (RR) 1.29: 95% CI 1.14 to 1.47). This risk remained after controlling for driver experience, demographic characteristics and known risk factors for crashes, including alcohol use and risk taking behaviour (RR 1.23: 95% CI 1.08 to 1.39). Sensation seeking had an additive effect on the association between self-harm and single-vehicle crashes (relative excess risk due to interaction 0.87: 95% CI 0.07 to 1.67), but not for other types of crashes. DISCUSSION: Our findings add to the growing body of evidence that self-harm during adolescence predicts a range of poorer health outcomes, including motor vehicle crash risks that warrant further investigation and consideration in road safety interventions. Complex interventions addressing self-harm in adolescence, as well as road safety and substance use, are critical for preventing health harming behaviours across the life course.

Acculturation and risk of traffic crashes in young Asian-born Australian drivers.

The study examines changes over time in crash risk differences between young Australian drivers born in Asia and those born in Australia.Data from the 2003 baseline survey of the DRIVE cohort of 20 806 young drivers aged 17-24 years were linked to police, hospital and death data up until 2016. The association between country of birth and crash was investigated using flexible parametric survival models adjusted for confounders.Six months after baseline, the crash risk in Asian-born drivers was less than half that of their Australian-born counterparts (mean HR, MHR 0.41; 95% CI 0.29 to 0.57), only to increase steadily over time to resemble that of Australian-born drivers 13 years later (MHR 0.94; 95% CI 0.66 to 1.36).This is likely to be associated with acculturation and the adoption by young Asian-born Australian drivers of driving behaviour patterns akin to those born locally. This needs to be considered in future road safety campaigns.

SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

Micro-fusion inhibition tests: quantifying antibody neutralization of virus-mediated cell-cell fusion.

Although enveloped viruses canonically mediate particle entry through virus-cell fusion, certain viruses can spread by cell-cell fusion, brought about by receptor engagement and triggering of membrane-bound, viral-encoded fusion proteins on the surface of cells. The formation of pathogenic syncytia or multinucleated cells is seen in vivo, but their contribution to viral pathogenesis is poorly understood. For the negative-strand paramyxoviruses respiratory syncytial virus (RSV) and Nipah virus (NiV), cell-cell spread is highly efficient because their oligomeric fusion protein complexes are active at neutral pH. The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has also been reported to induce syncytia formation in infected cells, with the spike protein initiating cell-cell fusion. Whilst it is well established that fusion protein-specific antibodies can block particle attachment and/or entry into the cell (canonical virus neutralization), their capacity to inhibit cell-cell fusion and the consequences of this neutralization for the control of infection are not well characterized, in part because of the lack of specific tools to assay and quantify this activity. Using an adapted bimolecular fluorescence complementation assay, based on a split GFP-Renilla luciferase reporter, we have established a micro-fusion inhibition test (mFIT) that allows the identification and quantification of these neutralizing antibodies. This assay has been optimized for high-throughput use and its applicability has been demonstrated by screening monoclonal antibody (mAb)-mediated inhibition of RSV and NiV fusion and, separately, the development of fusion-inhibitory antibodies following NiV vaccine immunization in pigs. In light of the recent emergence of coronavirus disease 2019 (COVID-19), a similar assay was developed for SARS-CoV-2 and used to screen mAbs and convalescent patient plasma for fusion-inhibitory antibodies. Using mFITs to assess antibody responses following natural infection or vaccination is favourable, as this assay can be performed entirely at low biocontainment, without the need for live virus. In addition, the repertoire of antibodies that inhibit cell-cell fusion may be different to those that inhibit particle entry, shedding light on the mechanisms underpinning antibody-mediated neutralization of viral spread.

Prevalence and Epidemiology of Non-O157 Escherichia coli Serogroups O26, O103, O111, and O145 and Shiga Toxin Gene Carriage in Scottish Cattle, 2014-2015.

Cattle are a reservoir for Shiga toxin-producing Escherichia coli (STEC), zoonotic pathogens that cause serious clinical disease. Scotland has a higher incidence of STEC infection in the human population than the European average. The aim of this study was to investigate the prevalence and epidemiology of non-O157 serogroups O26, O103, O111, and O145 and Shiga toxin gene carriage in Scottish cattle. Fecal samples (n = 2783) were collected from 110 herds in 2014 and 2015 and screened by real-time PCR. Herd-level prevalence (95% confidence interval [CI]) for O103, O26, and O145 was estimated as 0.71 (0.62, 0.79), 0.43 (0.34, 0.52), and 0.23 (0.16, 0.32), respectively. Only two herds were positive for O111. Shiga toxin prevalence was high in both herds and pats, particularly for stx2 (herd level: 0.99; 95% CI: 0.94, 1.0). O26 bacterial strains were isolated from 36 herds on culture. Fifteen herds yielded O26 stx-positive isolates that additionally harbored the intimin gene; six of these herds shed highly pathogenic stx2-positive strains. Multiple serogroups were detected in herds and pats, with only 25 herds negative for all serogroups. Despite overlap in detection, regional and seasonal effects were observed. Higher herd prevalence for O26, O103, and stx1 occurred in the South West, and this region was significant for stx2 at the pat level (P = 0.015). Significant seasonal variation was observed for O145 prevalence, with the highest prevalence in autumn (P = 0.032). Negative herds were associated with Central Scotland and winter. Herds positive for all serogroups were associated with autumn and larger herd size and were not housed at sampling.IMPORTANCE Cattle are reservoirs for Shiga toxin-producing Escherichia coli (STEC), bacteria shed in animal feces. Humans are infected through consumption of contaminated food or water and by direct contact, resulting in serious disease and kidney failure in the most vulnerable. The contribution of non-O157 serogroups to STEC illness was underestimated for many years due to the lack of specific tests. Recently, non-O157 human cases have increased, with O26 STEC of particular note. It is therefore vital to investigate the level and composition of non-O157 in the cattle reservoir and to compare them historically and by the clinical situation. In this study, we found cattle prevalence high for toxin, as well as for O103 and O26 serogroups. Pathogenic O26 STEC were isolated from 14% of study herds, with toxin subtypes similar to those seen in Scottish clinical cases. This study highlights the current risk to public health from non-O157 STEC in Scottish cattle.

Early Recognition of Raised Intracranial Pressure in Craniosynostosis Using Optical Coherence Tomography.

OBJECTIVE: Craniosynostosis can be associated with raised intracranial pressure (ICP), which can pose deleterious effects on the brain and vision if untreated. Estimating ICP in children is challenging, whilst gold standard direct intracranial measurement of ICP is invasive and carries risk. This systematic review aims to evaluate the role of optical coherence tomography (OCT), a noninvasive imaging technique, for detecting raised ICP in children with craniosynostosis. METHODS: The authors conducted a systematic review of the literature published from inception until 19 August, 2019 in the Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, and EMBASE. Eligible studies evaluated the role of OCT in detecting raised ICP in children aged 0 to 16 years with craniosynostosis. Main outcome measures were sensitivity and specificity of OCT parameters for raised ICP. Quality assessment was performed using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. RESULTS: Out of 318 records identified, data meeting the inclusion criteria were obtained from 3 studies. The quality of 2 studies was poor whilst 1 was fair. Optical coherence tomography demonstrated higher sensitivity and specificity for detecting raised ICP compared to fundus examination, clinical history, radiological testing, and visual field testing. CONCLUSIONS: This systematic review demonstrated a lack of quality evidence for OCT as a screening tool for children with craniosynostosis. Further research is required to clarify the strength of OCT in this role and to determine which OCT parameters are most appropriate.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.

Abnormal retinal development associated with FRMD7 mutations.

Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder, often associated with FRMD7 mutations. As the appearance of the retina is reported to be normal based on conventional fundus photography, IIN is postulated to arise from abnormal cortical development. To determine whether the afferent visual system is involved in FRMD7 mutations, we performed in situ hybridization studies in human embryonic and fetal stages (35 days post-ovulation to 9 weeks post-conception). We show a dynamic retinal expression pattern of FRMD7 during development. We observe expression within the outer neuroblastic layer, then in the inner neuroblastic layer and at 9 weeks post-conception a bilaminar expression pattern. Expression was also noted within the developing optic stalk and optic disk. We identified a large cohort of IIN patients (n = 100), and performed sequence analysis which revealed 45 patients with FRMD7 mutations. Patients with FRMD7 mutations underwent detailed retinal imaging studies using ultrahigh-resolution optical coherence tomography. The tomograms were compared with a control cohort (n = 60). The foveal pit was significantly shallower in FRMD7 patients (P < 0.0001). The optic nerve head morphology was abnormal with significantly decreased optic disk area, retinal nerve fiber layer thickness, cup area and cup depth in FRMD7 patients (P < 0.0001). This study shows for the first time that abnormal afferent system development is associated with FRMD7 mutations and could be an important etiological factor in the development of nystagmus.

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.

The Development of a Nystagmus-Specific Quality-of-Life Questionnaire.

PURPOSE: To develop a nystagmus-specific quality-of-life (QOL) questionnaire derived from patient concerns based on eudaimonic aspects of well-being. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 206 participants with nystagmus for factor analysis phase and an additional 42 participants with nystagmus for construct validity phase. METHODS: Questionnaire items were written on the basis of the 6 domains of everyday living affected by nystagmus that were elicited by previous semistructured interviews conducted with 21 people with nystagmus. After consultation with 8 nystagmus experts, 37 items were administered to 206 people with nystagmus. Factor analysis was used to identify latent factors among the items and identify items to propose new nystagmus QOL scales. Cronbach's alpha was used to assess the internal reliability of the new scales. To assess for discriminate and concurrent validity between the new nystagmus scales and an existing vision-related QOL tool, the Visual Function Questionnaire-25 (VFQ-25) was administered to 42 additional participants. MAIN OUTCOME MEASURES: Questionnaire response scores on nystagmus-specific QOL items. RESULTS: The factor analysis revealed the retention of 29 items to form a measure comprising 2 distinct subscales reflecting "personal and social" and "physical and environmental" functioning as relating to nystagmus-specific QOL. The Cronbach's alpha coefficients for the "personal and social" functioning scale and "physical and environmental" functioning were 0.95 and 0.93, respectively. Tests for validity of the measure, consistent with a priori predictions, when compared with the VFQ-25, revealed the "physical and environmental" subscale showed concurrent validity (0.88), whereas the "personal and social" subscale was demonstrated to have discriminative validity (0.81). CONCLUSIONS: We have developed a 29-item, nystagmus-specific QOL questionnaire (NYS-29) based on eudaimonic aspects of well-being with subscales that address not only physical functioning but also psycho-social issues. The NYS-29 is grounded in the perspectives and concerns of those who have nystagmus and can be used to determine the impact of nystagmus on daily living in terms of both physical and psychosocial aspects.

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.

High-Resolution Imaging of the Optic Nerve and Retina in Optic Nerve Hypoplasia.

PURPOSE: To investigate the optic nerve and macular morphology in patients with optic nerve hypoplasia (ONH) using spectral-domain optical coherence tomography (SD OCT). DESIGN: Prospective, cross-sectional, observational study. SUBJECTS: A total of 16 participants with ONH (10 female and 6 male; mean age, 17.2 years; 6 bilateral involvement) and 32 gender-, age-, ethnicity-, and refraction-matched healthy controls. METHODS: High-resolution SD OCT (Copernicus [Optopol Technology S.A., Zawiercie, Poland], 3 µm resolution) and handheld SD OCT (Bioptigen Inc [Research Triangle Park, NC], 2.6 µm resolution) devices were used to acquire horizontal scans through the center of the optic disc and macula. MAIN OUTCOME MEASURES: Horizontal optic disc/cup and rim diameters, cup depth, peripapillary retinal nerve fiber layer (RNFL), and thickness of individual retinal layers in participants with ONH and in controls. RESULTS: Patients with ONH had significantly smaller discs (P < 0.03 and P < 0.001 compared with unaffected eye and healthy controls, respectively), horizontal cup diameter (P < 0.02 for both), and cup depth (P < 0.02 and P < 0.01, respectively). In the macula, significantly thinner RNFL (nasally), ganglion cell layer (GCL) (nasally and temporally), inner plexiform layer (IPL) (nasally), outer nuclear layer (ONL) (nasally), and inner segment (centrally and temporally) were found in patients with ONH compared with the control group (P < 0.05 for all comparisons). Continuation of significantly thicker GCL, IPL, and outer plexiform layer in the central retinal area (i.e., foveal hypoplasia) was found in more than 80% of patients with ONH. Clinically unaffected fellow eyes of patients with ONH showed mild features of underdevelopment. Visual acuity and presence of septo-optic dysplasia were associated with changes in GCL and IPL. Sensitivity and specificity for the detection of ONH based on disc and retinal optical coherence tomography (OCT) parameters were >80%. CONCLUSIONS: Our study provides evidence of retinal changes in ONH. In addition to thinning of retina layers mainly involving the RNFL and GCL, signs reminiscent of foveal hypoplasia were observed in patients with ONH. Optic nerve and foveal parameters measured using OCT showed high sensitivity and specificity for detecting ONH, demonstrating their useful for clinical diagnosis.

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

A randomized controlled trial comparing soft contact lens and rigid gas-permeable lens wearing in infantile nystagmus.

OBJECTIVE: To perform the first randomized controlled trial comparing soft contact lens (SCL) with rigid gas-permeable lens (RGPL) wearing in infantile nystagmus (IN), using spectacle wear as a baseline. DESIGN: Randomized, controlled cross-over trial with an intention-to-treat design. PARTICIPANTS AND CONTROLS: A total of 24 participants with IN (12 idiopathic, 12 with albinism). METHODS: Participants were randomized into 1 of 2 treatment arms receiving the following sequence of treatments (2-3 weeks for each treatment): (A) spectacles, SCL, RGPL, and spectacle wear; or (B) spectacles, RGPL, SCL, and spectacle wear. MAIN OUTCOME MEASURES: The main outcome measure was mean intensity of nystagmus at the null region viewing at 1.2 m. Secondary outcome measures included the same measure at 0.4 m viewing and across the horizontal meridian (measured over a ±30° range at 3° intervals) for distance and near. The nystagmus foveation characteristics were similarly assessed over ±30° and at the null region at 1.2 m and 0.4 m viewing. Visual outcome measures included best-corrected visual acuity (BCVA) at 4 m and 0.4 m, gaze-dependent visual acuity (GDVA) (i.e., visual acuity when maintaining gaze angles over a ±30° range at 10° intervals) at 4 m, and reading performance at 0.4 m derived from the Radner reading chart. RESULTS: There were no significant differences between SCL and RGPL wearing for any nystagmus characteristics or compared with spectacle wearing. The BCVA, reading acuity, and critical print size were significantly worse for SCL wearing compared with RGPL and baseline spectacle wear (P<0.05), although mean differences were less than 1 logarithm of the minimum angle of resolution (logMAR) line. CONCLUSIONS: Nystagmus was not significantly different during SCL and RGPL wearing in IN, and contact lens wearing does not significantly reduce nystagmus compared with baseline spectacle wearing. The wearing of SCL leads to a small but statistically significant deterioration in visual function compared with both RGPL and spectacle wearing at baseline, although mean effect sizes were not clinically relevant.

Using mobile technology to support lower-salt food choices for people with cardiovascular disease: protocol for the SaltSwitch randomized controlled trial.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of early death worldwide, responsible for an estimated 29% of all global deaths. Reducing salt intake lowers blood pressure and risk of secondary cardiac events. However, identifying low salt foods can be challenging. SaltSwitch is a simple smartphone application (app) that enables shoppers to scan the barcode of packaged foods and receive an immediate, interpretive, traffic light nutrition label on the screen, along with suggestions for healthier lower-salt alternatives. A growing body of evidence suggests mobile technologies can support healthy behaviour change. However, robust evidence for the impact of smartphone interventions is lacking. This manuscript outlines the rationale and methods for a randomized controlled trial designed to determine the effectiveness of SaltSwitch in supporting people with CVD to make lower-salt food choices. DESIGN/METHODS: A 6-week, two-arm, parallel, randomized controlled trial is being undertaken in New Zealand (2 weeks baseline and 4 weeks intervention). Three hundred adults aged 40 years and older with CVD and their main household shoppers are recruited from research lists, cardiac rehabilitation clinics, and communities in Auckland. Participants are randomized to receive either the SaltSwitch smartphone app or no intervention (control). Randomisation is stratified by ethnicity and age. The primary outcome is the salt content of household food purchases. Secondary outcomes are the saturated fat and energy content of household food purchases, household food expenditure, use and acceptability of the SaltSwitch app by shoppers, and urinary sodium and blood pressure of participants with CVD. Ambulatory blood pressure and potential longer-term impact (12 weeks) of SaltSwitch will be assessed in sub-studies (n ~ 40 and n ~ 20, respectively). Household purchases of salt and other nutrients will be assessed using till receipt data electronically linked with branded food composition data. DISCUSSION: The results of the SaltSwitch trial will determine the effectiveness, use and acceptability of a smartphone application to support lower salt food choices and secondary prevention of CVD. TRIAL REGISTRATION: ACTRN12614000206628. Registered 30 March 2014.