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BACKGROUND: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. OBJECTIVES: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). METHODS: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). RESULTS: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

INTRODUCTION: Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described. METHODS: This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022). RESULTS: Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1-2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%). CONCLUSIONS: These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745.

Abstract Aims LMNA‐related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM‐DCM trial evaluated a potential disease‐modifying therapy for LMNA‐related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM‐DCM to descriptively characterize the phenotype and progression of LMNA‐related DCM in a contemporary cohort of patients using common heart failure (HF) measures. Methods REALM‐DCM enrolled patients with stable LMNA‐related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. Results Between 2018 and 2022, 77 patients took part in REALM‐DCM. The median patient age was 53 years (range: 23–72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ‐OS) score and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentration at baseline were 42% (23–62), 403 m (173–481), 67 (18–97) and 866 pg/mL (57–5248), respectively. LVEF, 6MWT distance and KCCQ‐OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ‐OS score: 43 vs. 70), whereas NT‐proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow‐up was 73 weeks (range: 0.4–218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ‐OS and NT‐proBNP values during follow‐up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF‐related hospitalization or urgent care visit) or all‐cause death; six had NYHA Class II and four had NYHA Class III at baseline. All‐cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. Conclusions Findings confirm the significant morbidity and mortality associated with LMNA‐related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ‐OS score and NT‐proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA‐related DCM. NCT03439514.

Abstract Aims Recognition of transthyretin amyloid cardiomyopathy is increasing due to advances in cardiac imaging and diagnostic strategies, but questions remain regarding disease frequency and characteristics. We examined the prevalence and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy of unascertained aetiology. Methods and results TTRACK was a multicentre, non‐interventional, cross‐sectional epidemiologic study funded by Pfizer and conducted in 20 hospitals and medical centres in 11 countries (NCT03842163). Eligible patients were aged ≥50 years, had hypertrophic cardiomyopathy (maximal end‐diastolic left ventricular wall thickness ≥15 mm on echocardiogram) without an identified genetic or alternative origin at study enrolment, and underwent 99mTechnetium bone scintigraphy, with or without single photon emission computed tomography (SPECT). Cardiac‐versus‐bone uptake on scans was visually scored from 0 to 3 (Perugini scoring). Patients with grades 1–3 underwent monoclonal protein and laboratory testing and transthyretin (TTR) gene sequencing. Of 766 eligible patients, 691 (90.2%) had scintigraphy alone and 75 (9.8%) scintigraphy plus SPECT. Two hundred and eight patients (27.2%) had grade 2 or 3 cardiac uptake on scintigraphy; 144 (18.8%) had grade 2 or 3 cardiac uptake and no evidence of plasma cell dyscrasia and were diagnosed with transthyretin amyloid cardiomyopathy. Of patients with transthyretin amyloid cardiomyopathy, 11 (7.6%) had a pathogenic TTR gene variant and 34 (23.8%), 74 (51.7%), and 35 (24.5%) had New York Heart Association class I, II, and III/IV heart failure (HF) symptoms, respectively. Clinical and laboratory diagnostic characteristics were observed in ≥90% of patients with transthyretin amyloid cardiomyopathy. The characteristics most strongly associated with transthyretin amyloid cardiomyopathy on multivariable analysis were carpal tunnel syndrome (odds ratio [OR] 54.3; P

Abstract Background Sepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT. Methods We developed a CKRT “module” in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2–25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0–30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa. Results Assuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100–150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function. Conclusions Our new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.

Abstract Objective The aim of this study is to describe the pre‐ and post‐operative developmental and intellectual functions in a cohort of patients who underwent surgery for drug‐resistant epilepsy (DRE) before the age of 5 years. Method We retrospectively reviewed the medical records and neurodevelopmental assessments of a cohort of 80 surgically treated pediatric patients with DRE. We included patients if they had at least one pre‐ and one post‐surgical neuropsychological assessments; 27 met the inclusion criteria. We evaluated Developmental Quotient (DQ) and Intelligence Quotient (IQ) before and after surgery. We identified two groups based on psychological evaluation outcome: Group 1, with stable or improved developmental and intellectual functions, and Group 2, experiencing developmental and intellectual loss. Results The mean age at seizure onset was 1.2 ± 1.0 years, and the mean age at surgery was 2.9 ± 1.2 years. At the last follow‐up (mean 4 years, SD ± 2), 19/27 (70%) patients were seizure‐ and drug‐free; 18/27 patients (67%) fit in Group 1, and 9/27 (33%) fit in Group 2. The mean age at surgery was 2.6 years (SD ± 1.1; range 1.2–5.1) in Group 1 and 3.4 years in Group 2 (SD ± 1.1; range 1.6–5.0). Group 1 had a lower pre‐operative DQ/IQ total score than Group 2 (median DQ/IQ respectively 82 vs 108, p = 0.05). Between pre‐ and post‐assessments, we found that in Group 1, Performance scores improved (82.7 vs 102, p = 0.001), while in Group 2, the Total and Verbal scores worsened (respectively 108 vs 75, p = 0.008, and 100 vs 76, p = 0.021). Significance Our study's results emphasize the positive impact of surgery before the age of 5 years on developmental and intellectual outcomes. Despite limitations such as a small sample size, lack of a control group, and diverse etiologies, our findings support the crucial role of early intervention in preserving or enhancing developmental and intellectual functions in young patients with DRE. Plain Language Summary This retrospective study, conducted at the Bambino Gesù Children Hospital in Italy, reports neuropsychological and developmental and/or cognitive data for children undergoing early epilepsy surgery (before the age of 5). It found that children with lower developmental or cognitive profiles gained the highest scores on post‐operative neuropsychological evaluations. This study provides information on the potential benefits of early surgery in shortening the duration of epilepsy, preventing or arresting deterioration, and enhancing plasticity and recovery.

Interpreting and enacting curriculum in any school is a complex undertaking, even more so in special school contexts where teachers must develop and enact appropriate curriculum modifications and accommodations for small groups of students and individual students. In special education contexts, educational modifications are changes teachers make based on a standardised curriculum, in order to be able to support the individual learning of students with intellectual and other profound disabilities, in terms of personalising learning for each student. These modifications are derived from teachers' curriculum (re)interpretations. Conversely, educational accommodations are the adjustments that teachers make in how they deliver the interpreted curriculum through individual learning episodes without changing the existent learning foci. This article presents a theorisation of how some special school educators interpret and reinterpret standardised curriculum to support the individual learning needs of students with moderate to profound disabilities through operationalising a theoretical framework of personalised learning. Operationalising personalised learning in special school contexts is theorised to be a collaged hermeneutical circle, where special education teachers work to (re)interpret curriculum, alongside the individual learning needs evidenced through teacher assessments and observations, and from student individual education plans. Within special school contexts, teachers approach the Australian Curriculum text as collaborative teams and engage in dialogue and planning about the curriculum to be taught and assessed. Thus, they aim to ensure that their students engage with the appropriate curriculum and have opportunities for learning on the same basis as students without their specific needs (i.e. students without disability). Unlike teachers in mainstream schooling contexts, teachers in special schools must (re)interpret curriculum that has not been explicitly developed for the unique learning needs of students with profound disability.

This article reports on the findings of a qualitative case study exploring the auditory skill "deficits" of a twice-exceptional male student who had multiple exceptionalities, including deficits in auditory processing skills, which contributed to learning issues and social connection difficulties in unique ways. Auditory skill deficits are an under-researched area in the field of gifted education, yet these are requisite skills necessary for learning in school. For this case study, auditory deficits were related to phonological processing, auditory sequential memory, lowered auditory recall abilities, and weaknesses in auditory analysis skills. The role that these auditory skill deficits played in the educational experiences of this young person is explored. Findings suggest that the presentation and impact of auditory processing deficits is very individual.