De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations.

Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly 'pure' HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.

The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia.

BACKGROUND: Adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by pathogenic biallelic variants in AP4B1, AP4M1, AP4E1, and AP4S1. OBJECTIVE: The aim was to explore blood markers of neuroaxonal damage in AP-4-HSP. METHODS: Plasma neurofilament light chain (pNfL) and glial fibrillary acidic protein (GFAP) levels were measured in samples from patients and age- and sex-matched controls (NfL: n = 46 vs. n = 46; GFAP: n = 14 vs. n = 21) using single-molecule array assays. Patients' phenotypes were systematically assessed using the AP-4-HSP natural history study questionnaires, the Spastic Paraplegia Rating Scale, and the SPATAX disability score. RESULTS: pNfL levels increased in AP-4-HSP patients, allowing differentiation from controls (Mann-Whitney U test: P = 3.0e-10; area under the curve = 0.87 with a 95% confidence interval of 0.80-0.94). Phenotypic cluster analyses revealed a subgroup of individuals with severe generalized-onset seizures and developmental stagnation, who showed differentially higher pNfL levels (Mann-Whitney U test between two identified clusters: P = 2.5e-6). Plasma GFAP levels were unchanged in patients with AP-4-HSP. CONCLUSIONS: pNfL is a potential disease marker in AP-4-HSP and can help differentiate between phenotypic subgroups. © 2023 International Parkinson and Movement Disorder Society.

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

BACKGROUND: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype. OBJECTIVE: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST. METHODS: This study used a systematic cross-sectional analysis of clinical and molecular features. RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

Play, Learn, and Teach Outdoors-Network (PLaTO-Net): terminology, taxonomy, and ontology.

BACKGROUND: A recent dialogue in the field of play, learn, and teach outdoors (referred to as "PLaTO" hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the field evolves and diversifies in its approaches, contents, and contexts over time and in different countries, cultures, and settings. Within this paper, we report the systematic and iterative processes undertaken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). METHODS: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and definitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then finalized based on the feedback received from 50 international PLaTO member participants who responded to ≥ 3 rounds of the consultation survey and dialogue. Finally, efforts to share and disseminate project outcomes were made through different online platforms. RESULTS: This paper presents the final definitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontology model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The final terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). CONCLUSIONS: This project contributes to advancing PLaTO-based research and facilitating intersectoral and interdisciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO's synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO.

Systematic translation and adaptation of the FOCUS program, a USA-based supportive intervention for persons with cancer and their family caregivers, for use in six European countries.

PURPOSE: Having advanced cancer presents many challenges for patients and family caregivers. The FOCUS program is a psychoeducational nurse-led intervention, developed in the USA, to support dyads of patients with cancer and their family caregivers to live with the illness. The program includes a conversation manual and information resources for dyads. We aimed to develop a version of the program for dyads facing advanced cancer in six European countries. METHOD: The Participatory and Iterative Process Framework for Language Adaptation (PIPFLA) was used to guide the translation of the program to the local contexts of Belgium, Denmark, Ireland, Italy, the Netherlands, and the UK. In several rounds, potential program users (e.g., nurses, clinicians, patients, family caregivers) and researchers from all six countries reviewed program materials and advised on adaptations. RESULTS: The PIPFLA process resulted in one European version of the program in different languages (FOCUS +). The FOCUS + conversation manual is uniform across all countries. The main adaptations included additional attention to both family caregiver and patient needs; more emphasis on self-management, advance care planning, and shared responsibilities; discussing the dyad's outlook rather than optimism; addressing the role of nurses as educational rather than therapeutic; and more suggestions to refer dyads to health care professionals for specific care needs. The information resources for dyads were adapted to fit with local contexts. CONCLUSION: The PIPFLA methodology is an efficient and effective framework to thoroughly translate and culturally adapt a complex USA-based program for use in six European countries in collaboration with end users.

Evaluation of the safety of tranexamic acid use in pediatric patients undergoing spinal fusion surgery: a retrospective comparative cohort study.

BACKGROUND: Pediatric spinal fusion may be associated with significant intraoperative blood loss, leading to complications from transfusion, hypoperfusion and coagulopathy. One emerging strategy to mediate these risks is by utilization of the anti-fibrinolytic agent tranexamic acid (TXA). However, concerns regarding potential adverse reactions, specifically postoperative seizures and thrombotic events, still exist. To assess these risks, we examined the perioperative morbidity of TXA use in a large national database. METHODS: Retrospective data from pediatric patients (age 18 years or younger), discharged between January 2013 to December 2015, who underwent primary or revision posterior spinal fusions, was collected from the Premier Perspective database (Premier, Charlotte, NC). Patients were stratified by TXA use and records were assessed for complications of new onset seizures, strokes, pulmonary embolisms (PE) or deep vein thromboses (DVT) occurring during the perioperative period. RESULTS: In this cohort of 2,633 pediatric patients undergoing posterior spinal fusions, most often to treat adolescent idiopathic scoliosis, 15% received TXA. Overall, adverse events were rare in this patient population. The incidence of seizure, stoke, PE, or DVT in the control group was 0.54% (95% CI, 0.31% to 0.94%) and not significantly different from the TXA group. There was no significant difference in the incidence of DVTs, and no incidences of stroke in either group. There were no new-onset seizures or PEs in patients who received TXA. CONCLUSIONS: The use of TXA was not associated with an increased risk of adverse events including seizure, stroke, PE, and DVT. Our findings support the safety of TXA use in pediatric patients undergoing spinal fusion surgery.

Effectiveness of a nurse-delivered (FOCUS+) and a web-based (iFOCUS) psychoeducational intervention for people with advanced cancer and their family caregivers (DIAdIC): study protocol for an international randomized controlled trial.

BACKGROUND: Worldwide, millions of people with advanced cancer and their family caregivers are experiencing physical and psychological distress. Psychosocial support and education can reduce distress and prevent avoidable healthcare resource use. To date, we lack knowledge from large-scale studies on which interventions generate positive outcomes for people with cancer and their informal caregivers' quality of life. This protocol describes the DIAdIC study that will evaluate the effectiveness of two psychosocial and educational interventions aimed at improving patient-family caregiver dyads' emotional functioning and self-efficacy. METHODS: We will conduct an international multicenter three-arm randomized controlled trial in Belgium, Denmark, Ireland, Italy, The Netherlands, and the United Kingdom. In each country, 156 dyads (936 in total) of people with advanced cancer and their family caregiver will be randomized to one of the study arms: 1) a nurse-led face-to-face intervention (FOCUS+), 2) a web-based intervention (iFOCUS) or 3) a control group (care as usual). The two interventions offer tailored psychoeducational support for patient-family caregiver dyads. The nurse-led face-to-face intervention consists of two home visits and one online video session and the web-based intervention is completed independently by the patient-family caregiver dyad in four online sessions. The interventions are based on the FOCUS intervention, developed in the USA, that addresses five core components: family involvement, optimistic outlook, coping effectiveness, uncertainty reduction, and symptom management. The FOCUS intervention will be adapted to the European context. The primary outcomes are emotional functioning and self-efficacy of the patient and the family caregiver, respectively. The secondary outcomes are quality of life, benefits of illness, coping, dyadic communication, and ways of giving support of the patient and family caregiver. DISCUSSION: DIAdIC aims to develop cost-effective interventions that integrate principles of early palliative care into standard care. The cross-country setup in six European countries allows for comparison of effectiveness of the interventions in different healthcare systems across Europe. By focusing on empowerment of the person with cancer and their family caregiver, the results of this RCT can contribute to the search for cost-effective novel interventions that can relieve constraints on professional healthcare. TRIAL REGISTRATION: Registration on ClinicalTrials.gov on 12/11/2020, identifier NCT04626349 . DATE AND VERSION IDENTIFIER: 20211209_DIAdIC_Protocol_Article.

A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments.

PURPOSE: Intravitreal bevacizumab is increasingly used to treat severe retinopathy of prematurity (ROP), but it enters the bloodstream, and there is concern that it may alter development of other organs. Previously we reported short-term outcomes of 61 infants enrolled in a dose de-escalation study, and we report the late recurrences and additional treatments. DESIGN: Masked, multicenter, dose de-escalation study. PARTICIPANTS: A total of 61 premature infants with type 1 ROP. METHODS: If type 1 ROP was bilateral at enrollment, then the study eye was randomly selected. In the study eye, bevacizumab intravitreal injections were given at de-escalating doses of 0.25 mg, 0.125 mg, 0.063 mg, or 0.031 mg; if needed, fellow eyes received 1 dose level higher: 0.625 mg, 0.25 mg, 0.125 mg, or 0.063 mg, respectively. After 4 weeks, additional treatment was at the discretion of the investigator. MAIN OUTCOME MEASURES: Early and late ROP recurrences, additional treatments, and structural outcomes after 6 months. RESULTS: Of 61 study eyes, 25 (41%; 95% confidence interval [CI], 29%-54%) received additional treatment: 3 (5%; 95% CI, 1%-14%) for early failure (within 4 weeks), 11 (18%; 95% CI, 9%-30%) for late recurrence of ROP (after 4 weeks), and 11 (18%; 95% CI, 9%-30%) for persistent avascular retina. Re-treatment for early failure or late recurrence occurred in 2 of 11 eyes (18%; 95% CI, 2%-52%) treated with 0.25 mg, 4 of 16 eyes (25%; 95% CI, 7%-52%) treated with 0.125 mg, 8 of 24 eyes (33%; 95% CI, 16%-55%) treated with 0.063 mg, and 0 (0%; 95% CI, 0%-31%) of 10 eyes treated with 0.031 mg. By 6 months corrected age, 56 of 61 study eyes had regression of ROP with normal posterior poles, 1 study eye had developed a Stage 5 retinal detachment, and 4 infants had died of preexisting medical conditions. CONCLUSIONS: Retinal structural outcomes are very good after low-dose bevacizumab treatment for ROP, although many eyes received additional treatment.

Intracranial hypertension: a current review.

PURPOSE OF REVIEW: To provide a current review of recent publications with regards to intracranial hypertension. RECENT FINDINGS: Attempts were made to provide pediatric data; however, the recent completion of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) has provided a wealth of data with regards to adult intracranial hypertension.The pediatric incidence of intracranial hypertension ranges between 0.63 and 0.71 per 100 000 children. A majority of pediatric cases responded to acetazolamide, with resolution of headache averaging 3.8 weeks. Most patients require less than 1 year of treatment with male sex, older age at diagnosis, primary intracranial hypertension, and lack of headache being predictors of good response. Fluorescein angiography has the highest accuracy in distinguishing true papilledema from pseudopapilledema. The IIHTT found Frisen grade of papilledema was within 1 grade in 92.8% of patients. Monitoring of potassium levels is not required and aplastic anemia was not seen in patients taking acetazolamide. SUMMARY: Although the newer pediatric studies report incidence rates in pediatric intracranial hypertension are lower than seen in adults, intracranial hypertension is still a concern in pediatrics. There has been a wealth of information with regards to symptomatology, treatment, and outcomes from the IIHTT that will hopefully assist with management in the pediatric population.

PSORS2 is due to mutations in CARD14.

Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.

Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.

Peripheral retinal finding on fluorescein angiography in neuronal ceroid lipofuscinosis type 2 (CLN2).

Classically, peripheral vascular changes in the retina in patients with neuronal ceroid lipofuscinosis type 2 (CLN2) are described as vascular attenuation seen in the late stages of disease on the Weill Connell Ophthalmic Severity Score (WCOSS) staging system. We describe isolated, mild, peripheral vasculitis with peripheral arteriolar dropout identified by fluorescein angiography in patients with a WCOSS grade of stage 2. We believe this vasculitis represents an early vasodegenerative phase of disease that leads to the vascular attenuation seen in later stages of the disease.

Yearly Occurrence and Seasonality of Neuro-ophthalmic Manifestations of Pediatric Lyme Disease.

PURPOSE: To review the neuro-ophthalmic manifestations of Lyme disease at a central Ohio pediatric tertiary care center. METHODS: A retrospective chart review of patients diagnosed as having Lyme disease from September 2015 to September 2020 was completed. Demographic information, diagnosis dates, and manifestations of Lyme disease were recorded. Patients were excluded for age older than 18 years or lack of corroborated Lyme disease diagnosis. Descriptive statistics were performed. RESULTS: Of the 212 cases of pediatric Lyme disease reviewed, 50 patients had neuroborreliosis. The data showed an increase in Lyme disease and neuroborreliosis cases from 2018 to 2020, with a preponderance of diagnoses in the summer months. Twenty-four patients had meningitis, and 6 of these patients (25%) were diagnosed as having bilateral optic disc edema that was clinically consistent with intracranial hypertension. CONCLUSIONS: Papilledema in the setting of Lyme meningitis may be more common than previously reported in central Ohio. If Lyme disease meningitis is suspected, an opening pressure should be recorded at the time of lumbar puncture and, if elevated, an ophthalmologic evaluation for optic nerve edema is indicated. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XXX-XXX.].

Secondary Intracranial Hypertension in Pediatric Lyme Meningitis.

Lyme disease is the most common vector-borne disease in the United States and has been associated with secondary intracranial hypertension. We reviewed 11 pediatric patients with Lyme-associated secondary intracranial hypertension. All patients presented with headache, ten had papilledema, 7 with a rash, and 5 with a cranial nerve palsy. All patients were treated with acetazolamide, and 3 received combination therapy with furosemide. Three patients were considered to have fulminant intracranial hypertension because of the severity in their presenting courses. Two of the fulminant intracranial hypertension patients were treated with a temporary lumbar drain in addition to medications, whereas 1 fulminant intracranial hypertension patient was treated exclusively with medical therapy alone. The addition of a lumbar drain decreased the time to resolution of papilledema compared to medical management alone. Final visual acuity was 20/20 in each eye of all patients, suggesting that a titrated approach to therapy depending on the severity of presentation can result in good visual outcomes in these cases. Additionally, symptoms can recur after medication wean, so patients should be monitored closely with any discontinuation of intracranial pressure lowering medications.

Age-related hearing loss associated with differences in the neural correlates of feature binding in visual working memory.

The underlying neural mechanisms underpinning the association between age-related hearing loss (ARHL) and dementia remain unclear. A limitation has been the lack of functional neuroimaging studies in ARHL cohorts to help clarify this relationship. In the present study, we investigated the neural correlates of feature binding in visual working memory with ARHL (controls = 14, mild HL = 21, and moderate or greater HL = 23). Participants completed a visual change detection task assessing feature binding while their neural activity was synchronously recorded via high-density electroencephalography. There was no difference in accuracy scores for ARHL groups compared to controls. There was increased electrophysiological activity in those with ARHL, particularly in components indexing the earlier stages of visual cognitive processing. This activity was more pronounced with more severe ARHL and was associated with maintained feature binding. Source space (sLORETA) analyses indicated greater activity in networks modulated by frontoparietal and temporal regions. Our results demonstrate there may be increased involvement of neurocognitive control networks to maintain lower-order neurocognitive processing disrupted by ARHL.

A self-management psychoeducational eHealth program to support and empower people with advanced cancer and their family caregivers: Development using the scrum methodology.

Background: eHealth programs could be a flexible and scalable resource to support and empower people with advanced cancer and their family caregivers. A face-to-face intervention that has demonstrated effectiveness is the "FOCUS" program, developed and tested in the USA. Recently the FOCUS program was translated and adapted to the European context as part of an international study in six European countries, resulting in the "FOCUS+" program. FOCUS+ served as the basis for development of the web-based iFOCUS program. Objective: We aim to (1) describe the development process of the iFOCUS program, (2) outline the challenges we encountered and how they were overcome, and (3) present findings regarding the acceptability and usability of iFOCUS. Methods: We used the four phased agile Scrum methodology to develop iFOCUS and applied set timeframes of rapid program development and evaluation (sprints). Five teams were involved in the development i.e. a core development group, a web development team, an international consortium, audio-visual experts, and potential end-users. Results: Development followed seven steps, integrated across the four phases of Scrum: (1) concept design, (2) development of mock-ups, (3) Feedback from the international consortium, (4) technical development of iFOCUS, (5) creating versions for the six participating countries, (6) preliminary testing of iFOCUS and (7) implementing the final version in a randomized controlled trial. User testing included 42 participants (twenty patient-family caregiver dyads and two bereaved family caregivers) who reviewed the iFOCUS program. Users found the iFOCUS program to be acceptable and usable. Feedback mainly focused on text size and fonts. Minor changes to the content, tailoring, and program flow were required. During development we encountered program specific and general challenges. Using the Scrum methodology facilitated iterative development to address these issues. For some challenges, such as tailoring, we had to make pragmatic choices due to time and resource limitations. Conclusions/discussion: The development of a tailored, self-managed psychoeducational eHealth program for people with advanced cancer and their family caregivers is an intense process and requires pragmatic choices. By keeping the emphasis on the target population during development, no specific remarks pertaining to advanced cancer were identified. Some challenges we encountered are common to eHealth development, others were related to program specific requirements. Using the Scrum methodology allows teams to efficiently collaborate during program development and increases the flexibility of the development process. Interpersonal contact between research staff and potential end-users is recommended during and after the development of eHealth programs.

Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial.

Importance: Controlling myopia progression is of interest worldwide. Low-dose atropine eye drops have slowed progression in children in East Asia. Objective: To compare atropine, 0.01%, eye drops with placebo for slowing myopia progression in US children. Design, Setting, and Participants: This was a randomized placebo-controlled, double-masked, clinical trial conducted from June 2018 to September 2022. Children aged 5 to 12 years were recruited from 12 community- and institution-based practices in the US. Participating children had low to moderate bilateral myopia (-1.00 diopters [D] to -6.00 D spherical equivalent refractive error [SER]). Intervention: Eligible children were randomly assigned 2:1 to 1 eye drop of atropine, 0.01%, nightly or 1 drop of placebo. Treatment was for 24 months followed by 6 months of observation. Main Outcome and Measures: Automated cycloplegic refraction was performed by masked examiners. The primary outcome was change in SER (mean of both eyes) from baseline to 24 months (receiving treatment); other outcomes included change in SER from baseline to 30 months (not receiving treatment) and change in axial length at both time points. Differences were calculated as atropine minus placebo. Results: A total of 187 children (mean [SD] age, 10.1 [1.8] years; age range, 5.1-12.9 years; 101 female [54%]; 34 Black [18%], 20 East Asian [11%], 30 Hispanic or Latino [16%], 11 multiracial [6%], 6 West/South Asian [3%], 86 White [46%]) were included in the study. A total of 125 children (67%) received atropine, 0.01%, and 62 children (33%) received placebo. Follow-up was completed at 24 months by 119 of 125 children (95%) in the atropine group and 58 of 62 children (94%) in the placebo group. At 30 months, follow-up was completed by 118 of 125 children (94%) in the atropine group and 57 of 62 children (92%) in the placebo group. At the 24-month primary outcome visit, the adjusted mean (95% CI) change in SER from baseline was -0.82 (-0.96 to -0.68) D and -0.80 (-0.98 to -0.62) D in the atropine and placebo groups, respectively (adjusted difference = -0.02 D; 95% CI, -0.19 to +0.15 D; P = .83). At 30 months (6 months not receiving treatment), the adjusted difference in mean SER change from baseline was -0.04 D (95% CI, -0.25 to +0.17 D). Adjusted mean (95% CI) changes in axial length from baseline to 24 months were 0.44 (0.39-0.50) mm and 0.45 (0.37-0.52) mm in the atropine and placebo groups, respectively (adjusted difference = -0.002 mm; 95% CI, -0.106 to 0.102 mm). Adjusted difference in mean axial elongation from baseline to 30 months was +0.009 mm (95% CI, -0.115 to 0.134 mm). Conclusions and Relevance: In this randomized clinical trial of school-aged children in the US with low to moderate myopia, atropine, 0.01%, eye drops administered nightly when compared with placebo did not slow myopia progression or axial elongation. These results do not support use of atropine, 0.01%, eye drops to slow myopia progression or axial elongation in US children. Trial Registration: ClinicalTrials.gov Identifier: NCT03334253.

Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.