Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Molecular interactions of a model bile salt and porcine bile with (1,3:1,4)-β-glucans and arabinoxylans probed by 13C NMR and SAXS

Two main classes of interaction between soluble dietary fibres (SDFs), such as (1,3:1,4)-β-d-glucan (βG) and arabinoxylan (AX) and bile salt (BS) or diluted porcine bile, were identified by C NMR and small angle X-ray scattering (SAXS). Small chemical shift differences of BS NMR resonances were consistent with effective local concentration or dilution of BS micelles mostly by βG, suggesting dynamic interactions; whilst the reduced line widths/intensities observed were mostly caused by wheat AX and the highest molecular size and concentrations of βG. SAXS showed evidence of changes in βG but not AX in the presence of BS micelles, at >13 nm length scale consistent with molecular level interactions. Thus intermolecular interactions between SDF and BS depend on both SDF source and its molecular weight and may occur alone or in combination

Divergent Fe and S mineralization pathways during the oxidative transformation of greigite, Fe₃S₄

The iron sulfide mineral greigite, Fe3S4, has previously been identified in the surface layers of the intertidal zone of a partially remediated acid sulfate soil wetland, representing an end-member in an iron sulfide mineralization pathway distinct from that of pyrite. The persistence of greigite is important for the stability of the remediated landscape, but the response of greigite to periods of oxygenation (for example, during a neap tide) is poorly understood. In this study, we employ X-ray absorption spectroscopy to identify the Fe and S speciation and mineralogy resulting from the oxidative disintegration of synthetic greigite under physiochemical solution conditions consistent with a partially remediated acid sulfate soil wetland. Results indicate divergent Fe and S mineralization pathways culminating in elemental sulfur and iron (hyr)oxide minerals. No sulfate-containing minerals were identified, and under all conditions tested, residual greigite remains. The oxidation products, and the presence of sulfur reducing bacteria, provide the right chemical environment for the reformation of greigite during the sub-oxic conditions of the rest of the tidal cycle. This likely explains the persistence of greigite in the intertidal zone, and implies that the oxidation of greigite is not detrimental to the long term stability of the acid sulfate soil remediation process

High-amylose wheat and maize starches have distinctly different granule organization and annealing behaviour: a key role for chain mobility

For regular starches, gelatinization occurs over a relatively narrow temperature range in excess water; however, high-amylose starches typically gelatinise over an extended temperature range by a process that is less understood. The present study compared granule organisation of high-amylose starches from wheat (HAWS) and maize (HAMS), and investigated the role of granule organization in determining the gelatinization heterogeneity and different responses to annealing. During gelatinization (starch/water = 1:2), the melting peaks of double helices and amylose-lipid complexes are merged in HAMS, whereas the peaks are separated for HAWS. It is hypothesized that the glucan chains in HAWS are relatively more mobile (i.e., fewer inter-chain interactions), compared to HAMS. Due to this mobility, hot water leaches amylose more readily from HAWS than from HAMS at similar levels of apparent amylose content. After two-step annealing, T (gelatinization onset temperature) of HAWS increased from 58 to 84 °C, while T of HAMS only increased from 70 to 82 °C. For HAWS, annealing apparently extended double helical lengths and made semi-crystalline lamellae more heterogeneous, but reduced double helix content. For HAMS with more organised granular structure, annealing has a relatively limited effect on lamellar layers and chain conformation. The study demonstrates that HAMS and HAWS have distinctly different granule organisation and behaviours during hydrothermal processing and that HAWS, with more mobile chains, has the potential to form thermostable molecular order. The molecular basis for these differences is proposed to be the greater proportion of very long chains/branches in HAWS than HAMS

Morphology-Mediated Photoresponsive and Fluorescence Behaviors of Azobenzene-Containing Block Copolymers

We investigated the relationship between the self-assembled morphology of poly­(<i>tert</i>-butyl acrylate)-<i>block</i>-poly­(6-[4-(4′-methoxyphenylazo)­phenoxy]­hexyl methacrylate) (P<i>t</i>BA-<i>b</i>-PAzoMA) block copolymers and their photoresponsive and fluorescence behaviors. The morphology of P<i>t</i>BA-<i>b</i>-PAzoMA copolymers was manipulated by dissolving them in mixed dimethylformamide (DMF)/hexanol solvents. When P<i>t</i>BA-<i>b</i>-PAzoMA was dissolved in DMF-rich (neutral) solvents, a favorable interaction between the DMF molecules and both blocks resulted in a random-coiled conformation. The unconfined morphology facilitated the formation of both nonassociated and head-to-head organized azobenzene mesogens, which promoted fluorescence emission. When hexanol, a P<i>t</i>BA-selective solvent, was added to DMF, the solvency of P<i>t</i>BA-<i>b</i>-PAzoMA worsened, leading to its assembly into micelles, with PAzoMA in the micelle core. The confinement of azobenzene moieties in the micelle core hindered their <i>trans</i>-to-<i>cis</i> photoisomerization, thereby considerably decreasing the kinetics of photoisomerization and the population of <i>cis</i> isomers. Additionally, a nanoconfined geometry resulted in compactly packed chromophores, causing fluorescence loss. When P<i>t</i>BA-<i>b</i>-PAzoMA was exposed to UV light, the increased number of <i>cis</i> isomers hampered the closely packed mesogens, resulting in a substantial enhancement of fluorescence emission. When the mole fraction of the PAzoMA block was increased, P<i>t</i>BA-<i>b</i>-PAzoMA formed clusters, causing the slow kinetics of photoisomerization and fluorescence quenching

Assessment of starch branching and lamellar structure in rice flours

Apparent amylose content is used to describe milled rice flour composition. This spectrophotometric method is often the only direct measurement of starch structure in routine quality analysis. However, starch exhibits 6 levels of structure. The (supra)molecular starch structure in rice flours was measured: average degree of branching by 1H NMR spectroscopy and semi-crystalline lamellar structure by small angle X-ray scattering (SAXS). The suitability of these methods in routine quality analysis for breeding programs or the food industry was assessed in terms of precision and accuracy. Determination of apparent amylose content exhibits high precision (ca 5 % error) but low accuracy. Determination of average degree of branching exhibits a similar precision but good accuracy. Sample preparation (dissolution) is the first source of error in 1H NMR spectroscopy and presumably also in spectrophotometry. Within narrow ranges of apparent amylose content (less than 2.5 % absolute difference) differences in average degree of branching and lamellar structure could be observed. The difference between chemical structures of different amyloses/amylopectins within a given sample is not negligible. This opens a way to explore how finer details of molecular and supramolecular starch structure can play a role in understanding rice quality