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

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Usage of V2X Applications in Road Tunnels

Featured Application This article provides a general overview of technological aspects and limitations of tunnels with respect to smart technologies such as C-ITS. Many smart city applications work with calculated position and time using the Global Navigation Satellite System (GNSS) signals for enhanced precision. However, there are many places where the availability of GNSS is limited, e.g., road tunnels, which are an essential part of transport infrastructure. Tunnels also require greater attention and greater importance of approaches to ensure the safety and security aspects of traffic. The safety, distribution of information, awareness, and smooth traffic can also be ensured by V2X applications, but the current position is also needed. An experimental analysis of data connection and communication availability was performed in the Blanka tunnel (Prague) and its surroundings. The main objective of the work was to find and clearly describe the tunnel blind spots, with an emphasis on communication between cars and potentially between cars and infrastructure. This article summarizes the evaluation results of the V2X tunnel experimental test, the outputs from the analysis of these blind spots, and it provides a future perspective and suggestions that make tunnels smart by using advanced positioning approaches.Funding Agencies|Technology Agency of the Czech Republic [CK01000163]; Grant Agency of the Czech Technical University in Prague [SGS22/121/OHK2/2T/16]</p

Online Scheduling of Equal-Length Jobs: Randomization and Restarts Help

We consider the following scheduling problem. The input is a set of jobs with equal processing times, where each job is specified by its release time and deadline. The goal is to determine a single-processor, non-preemptive schedule of these jobs that maximizes the number of completed jobs. In the online version, each job arrives at its release time. We give two online algorithms with competitive ratios below 2 and show several lower bounds on the competitive ratios. First, we give a -competitive randomized algorithm. Our algorithm needs only one fair random bit, as it chooses one of two (nearly identical) deterministic algorithms, each with probability . We also show a lower bound of for barely random algorithms, that (with arbitrary probability) choose one of two deterministic algorithms. Next, we give a deterministic -competitive algorithm in the model that allows restarts, and we show that in this model the ratio is optimal. For randomized algorithms with restarts we show a lower bound of

Online scheduling of equal-length jobs: Randomization and restarts help

We consider the following scheduling problem. The input is a set of jobs with equal processing times, where each job is specified by its release time and deadline. The goal is to determine a single-processor, non-preemptive schedule that maximizes the number of completed jobs. In the online version, each job arrives at its release time. We give two online algorithms with competitive ratios below 2 and show several lower bounds on the competitive ratios. First, we give a barely random 5/3-competitive algorithm that uses only one random bit. We also show a lower bound of 3/2 on the competitive ratio of barely random algorithms that randomly choose one of two deterministic algorithms. If the two algorithms are selected with equal probability, we can further improve the bound to 8/5. Second, we give a deterministic 3/2-competitive algorithm in the model that allows restarts, and we show that in this model the ratio 3/2 is optimal. For randomized algorithms with restarts we show a lower bound of 6/5

Improved Online Algorithms for Buffer Management in QoS Switches

We consider the following buffer management problem arising in QoS networks: packets with specified weights and deadlines arrive at a network switch and need to be forwarded so that the total value of forwarded packets is maximized. If a packet is not forwarded before its deadline, it is lost and brings no profit. The main result of the paper is an online 64/3