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تربية طفل متمرد : دليل يحفظ العقل لإيقاف السلوك السيئ
يوفر هذا الكتاب، سواء أظهر طفلك أنماطا متكررة من السلوك المندفع الغيرالملائم، لا أكثر، أم استوفى معايير التشخيص لاضطراب العناد الشارد، أساليب داعمة ومنورة، تم اختبارها، لتوجيهك وطفلك في الاتجاه الصحيح، وستتعلم كيفية منح طفلك الأساس والدعم اللذين يحتاجهما ليدرك إشارات التواصل الاجتماعي بدقة أكبر، ويمتلك السيطرة على اندفاعاته، فضلا عن تعزيز العلاقة بينكما، وتوفير الإمكانية لطفلك لتحقيق كل ما تعلم بقدرته على إنجازه.
BOOK
Genetic architecture of laterality defects revealed by whole exome sequencing
Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.
Journal Article
Phonetic neutralization in Palestinian Arabic vowel shortening, with implications for lexical organization
This study acoustically compares lexically short vowels in Palestinian Arabic to vowels that are underlyingly long, but have undergone closed syllable shortening, a phonological process affecting certain CV:CC sequences (as in /faːq-ʃ/ → faqʃ ‘woke-negative’; /ӡaːb-l-ak/ → ӡablak ‘brought to you’). In a study of word pairs produced by 74 speakers, the two vowel types were found to be indistinguishable in duration. Speakers differ as to the contexts in which they apply shortening: some shorten before the negative suffix /-ʃ/, but not the dative suffix /-l/, likely due to paradigm leveling. The results are compared to earlier studies finding incomplete neutralization in Arabic vowel epenthesis, to identify factors that affect completeness of neutralization. It appears that orthography is not an important factor, but that morphologized or lexicalized processes produce more complete neutralization. It is proposed that allomorphs produced by more fossilized processes are more weakly linked in the mental lexicon, and that incomplete neutralization of vowel quantity in particular would require linkage through the abstract CV word pattern.
Journal Article
A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea
Study Objectives
To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA).
Methods
E2006-A001-113 (Study 113; NCT04647383) was a double-blind, two-period crossover, placebo-controlled study in adults (ages ≥ 45 to ≤ 90 years, n = 33) with moderate (apnea-hypopnea index [AHI] score ≥ 15 to < 30 events/h, n = 13) or severe (AHI ≥ 30 events/h, n = 20) OSA. Participants were randomized to lemborexant 10 mg (LEM10) or placebo (PBO) for two treatment periods of 8 nights with a ≥ 14-day washout period. AHI and peripheral oxygen saturation were evaluated after treatment on Day 1 (after a single dose) and Day 8 (after multiple doses).
Results
No significant differences in AHI were observed after single and multiple doses of LEM10 compared with PBO in participants with moderate to severe OSA (least-squares mean: single-dose LEM10, 41.7; PBO, 44.8; multiple-dose LEM10, 44.9; PBO, 45.7). In addition, there were no significant differences between treatments in peripheral oxygen saturation (least-squares mean: single-dose LEM10, 93.0; PBO, 93.1; multiple-dose LEM10, 93.1; PBO, 93.4). Further, there were no significant differences between treatments in percentage of total sleep time with peripheral oxygen saturation < 90%, < 85%, or < 80%. No significant differences were observed between treatments when AHI and peripheral oxygen saturation outcomes were analyzed by OSA severity. Altogether, 6/33 (18.2%) participants receiving LEM10, vs 3/33 (9.1%) PBO, reported treatment-emergent adverse events, mostly mild in severity.
Conclusions
LEM10 demonstrated respiratory safety and was well tolerated with single-dose and multiple-dose administration in participants with moderate to severe OSA. This suggests that LEM may be a treatment option for patients with OSA and comorbid insomnia.
Clinical Trial Registration
Registry: ClinicalTrials.gov; Name: A Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Participants With Moderate to Severe Obstructive Sleep Apnea and in Adult and Elderly Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease; URL:
https://clinicaltrials.gov/ct2/show/NCT04647383
; Identifier: NCT04647383.
Journal Article
Public Health Response to Multistate Salmonella Typhimurium Outbreak Associated with Prepackaged Chicken Salad, United States, 2018
Quantifying the effect of public health actions on population health is essential when justifying sustained public health investment. Using modeling, we conservatively estimated that rapid response to a multistate foodborne outbreak of Salmonella Typhimurium in the United States in 2018 potentially averted 94 reported cases and $633,181 in medical costs and productivity losses.
Journal Article
Edematous severe acute malnutrition is characterized by hypomethylation of DNA
Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.
The edematous form of severe acute childhood malnutrition (ESAM) presents with more severe multi-organ dysfunction than non-edematous SAM (NESAM). Here the authors assess genome-wide DNA methylation in buccal cells of SAM children and find that ESAM is characterized by hypomethylation at genes associated with disorders of nutrition and metabolism, including fatty liver and diabetes.
Journal Article
Multi-scale kinetics of a field-directed colloidal phase transition
Polarizable colloids are expected to form crystalline equilibrium phases when exposed to a steady, uniform field. However, when colloids become localized this field-induced phase transition arrests and the suspension persists indefinitely as a kinetically trapped, percolated structure. We anneal such gels formed from magneto-rheological fluids by toggling the field strength at varied frequencies. This processing allows the arrested structure to relax periodically to equilibrium—colloid-rich, cylindrical columns. Two distinct growth regimes are observed: one in which particle domains ripen through diffusive relaxation of the gel, and the other where the system-spanning structure collapses and columnar domains coalesce apparently through field-driven interactions. There is a stark boundary as a function of magnetic field strength and toggle frequency distinguishing the two regimes. These results demonstrate how kinetic barriers to a colloidal phase transition are subverted through measured, periodic variation of driving forces. Such directed assembly may be harnessed to create unique materials from dispersions of colloids.
Journal Article
Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension
Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 ( SYNE1 ), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1 , we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future.
Journal Article
Effect of hepatic impairment on pharmacokinetics, safety, and tolerability of lemborexant
Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open‐label, parallel‐group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child–Pugh class A) or moderate (Child–Pugh class B) HI and healthy age‐, sex‐, and body mass index (BMI)‐matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax] and area under the curve extrapolated to infinity [AUC0‐inf]) increased by ~58% (Cmax) and ~25% (AUC0‐inf) in subjects with mild HI and ~22% (Cmax) and ~54% (AUC0‐inf) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060–0.065). All treatment‐emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups. Lemborexant is a dual orexin receptor antagonist approved for the treatment of adults with insomnia. The effect of mild hepatic impairment (HI) on lemborexant (LEM) exposure was small; therefore, a dose adjustment is not warranted in patients with mild HI. However, moderate HI increased overall LEM exposure, thereby warranting a maximum dose recommendation of no more than 5 mg once‐nightly in patients with moderate HI. Lemborexant has not been studied in subjects with severe HI and is not recommended for use in such patients.
Journal Article
Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant
The primary aim of this study was to examine the effect of severe renal impairment (SRI) on the pharmacokinetics of lemborexant, a dual orexin receptor antagonist indicated for the treatment of insomnia. A phase 1 multicenter, single‐dose, open‐label, parallel‐group study was conducted in subjects with SRI not requiring dialysis (estimated glomerular filtration rate 15–29 ml/min/1.73 m2; n = 8) compared with demographically matched healthy subjects with normal renal function (n = 8). Plasma levels of lemborexant and its metabolites were measured over 240 h following a single oral 10‐mg dose administered in the morning. Relative to subjects with normal renal function, lemborexant maximum plasma concentration (Cmax) was similar, whereas area under the plasma concentration–time curve from zero to time of last quantifiable concentration (AUC(0‐t)) and AUC from zero to infinity (AUC(0‐inf)) were about 1.5‐fold higher in subjects with SRI. The geometric mean ratios (90% confidence interval) were 104.8 (77.4–142.0), 150.5 (113.2–200.3), and 149.8 (113.1–198.6) for Cmax, AUC(0‐t), and AUC(0‐inf), respectively. In both groups, the median lemborexant time to Cmax (tmax) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax was reduced ~20% and exposure (AUC(0‐t) and AUC(0‐inf)) was ~1.4‐ to 1.5‐fold higher in subjects with SRI versus healthy subjects; tmax was delayed ~1.5–2 h for M4 and M10. All treatment‐emergent adverse events were mild or moderate. Lemborexant pharmacokinetics were not sufficiently altered to warrant a dose adjustment for subjects with renal impairment. Lemborexant is a dual orexin receptor antagonist approved for the treatment of adults with insomnia. Lemborexant tmax and Cmax were not altered in subjects with severe renal impairment compared with healthy subjects, but exposure (AUC) was increased approximately 1.5‐fold. Lemborexant has a favorable safety profile and dosing is initiated at 5 mg, which can be increased based on efficacy and tolerability. Thus, these results support the use of lemborexant in subjects with mild to severe renal impairment without dosing adjustment.
Journal Article