Stability of diurnal cortisol measures across days, weeks, and years across middle childhood and early adolescence: Exploring the role of age, pubertal development, and sex.

Effective regulation of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been linked to numerous health outcomes. Within-person variation in diurnal measures of HPA-axis regulation assessed over days, months, and years can range between 50-73% of total variation. In this study of 59 youth (ages 8-13), we quantified the stability of the cortisol awakening response (CAR), the diurnal slope, and tonic cortisol concentrations at waking and bedtime across 8 days (2 sets of 4 consecutive days separated by 3 weeks), 3 weeks, and 3 years. We then compared the stability of these indices across three key developmental factors: age, pubertal status, and sex. Youth provided 4 saliva samples per day (waking, 30 min post-waking, before dinner, and before bedtime) for 4 consecutive days during the 3rd week of an ongoing 8-week daily diary study. Youth repeated this same sampling procedure 3 weeks and 3 years later. Using multi-level modeling, we computed the amount of variance in diurnal HPA-axis regulation that was accounted for by nesting an individual's diurnal cortisol indices within days, weeks, or years. Across days, diurnal slope was the most stable index, whereas waking cortisol and CAR were the least stable. All indices except bedtime cortisol were similarly stable when measured across weeks, and all indices were uniformly stable when measured across 3 years. Boys, younger participants, and youth earlier in their pubertal development at study enrollment exhibited greater HPA-axis stability overall compared with females and older, more physically mature participants. We conclude that important within- and between-subjects questions can be answered about health and human development by studying HPA-axis regulation, and selection of the index of interest should be determined in part by its psychometric characteristics. To this end, we propose a decision tree to guide study design for research in pediatric samples by longitudinal timeframe and sample characteristics

Dietary Supplementation of Hericium erinaceus Increases Mossy Fiber-CA3 Hippocampal Neurotransmission and Recognition Memory in Wild-Type Mice

Hericium erinaceus (Bull.) Pers. is a medicinal mushroom capable of inducing a large number of modulatory effects on human physiology ranging from the strengthening of the immune system to the improvement of cognitive functions. In mice, dietary supplementation with H. erinaceus prevents the impairment of spatial short-term and visual recognition memory in an Alzheimer model. Intriguingly other neurobiological effects have recently been reported like the effect on neurite outgrowth and differentiation in PC12 cells. Until now no investigations have been conducted to assess the impact of this dietary supplementation on brain function in healthy subjects. Therefore, we have faced the problem by considering the effect on cognitive skills and on hippocampal neurotransmission in wild-type mice. In wild-type mice the oral supplementation with H. erinaceus induces, in behaviour test, a significant improvement in the recognition memory and, in hippocampal slices, an increase in spontaneous and evoked excitatory synaptic current in mossy fiber-CA3 synapse. In conclusion, we have produced a series of findings in support of the concept that H. erinaceus induces a boost effect onto neuronal functions also in nonpathological conditions

The LOFAR Two Meter Sky Survey: Deep Fields, I -- Direction-dependent calibration and imaging

The Low Frequency Array (LOFAR) is an ideal instrument to conduct deep extragalactic surveys. It has a large field of view and is sensitive to large-scale and compact emission. It is, however, very challenging to synthesize thermal noise limited maps at full resolution, mainly because of the complexity of the low-frequency sky and the direction dependent effects (phased array beams and ionosphere). In this first paper of a series, we present a new calibration and imaging pipeline that aims at producing high fidelity, high dynamic range images with LOFAR High Band Antenna data, while being computationally efficient and robust against the absorption of unmodeled radio emission. We apply this calibration and imaging strategy to synthesize deep images of the Boötes and Lockman Hole fields at ∼150 MHz, totaling ∼80 and ∼100 h of integration, respectively, and reaching unprecedented noise levels at these low frequencies of .30 and .23 µJy beam−1 in the inner ∼3 deg2 . This approach is also being used to reduce the LOTSS-wide data for the second data release

ATLAS liquid argon calorimeter back end electronics

The Liquid Argon calorimeters play a central role in the ATLAS (A Toroidal LHC Apparatus) experiment. The environment at the Large Hadron Collider (LHC) imposes strong constraints on the detectors readout systems. In order to achieve very high precision measurements, the detector signals are processed at various stages before reaching the Data Acquisition system (DAQ). Signals from the calorimeter cells are received by on-detector Front End Boards (FEB), which sample the incoming pulse every 25ns and digitize it at a trigger rate of up to 75~kHz. Off-detector Read Out Driver (ROD) boards further process the data and send reconstructed quantities to the DAQ while also monitoring the data quality. In this paper, the ATLAS Liquid Argon electronics chain is described first, followed by a detailed description of the off-detector readout system. Finally, the tests performed on the system are summarized

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. METHODS: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. RESULTS: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. CONCLUSIONS: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and ResultsAn lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score >= 1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score >= 1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level >= 190 mg/dL (or from 68% to 50%, considering a more conservative formula). ConclusionsOur study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age. Methods: From the Italian LIPIGEN cohort, we selected 1188 (≥18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation. Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives. Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age

Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study

Background and aims: Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification.Methods: This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH.Results: The DLCN score was applied on a sample of 1377 adults (mean age 42.9 +/- 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3-5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score.Conclusions: Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects