A statistical measure for the skewness of X chromosome inactivation based on family trios.

BACKGROUND: X chromosome inactivation (XCI) is an important gene regulation mechanism in females to equalize the expression levels of X chromosome between two sexes. Generally, one of two X chromosomes in females is randomly chosen to be inactivated. Nonrandom XCI (XCI skewing) is also observed in females, which has been reported to play an important role in many X-linked diseases. However, there is no statistical measure available for the degree of the XCI skewing based on family data in population genetics. RESULTS: In this article, we propose a statistical approach to measure the degree of the XCI skewing based on family trios, which is represented by a ratio of two genotypic relative risks in females. The point estimate of the ratio is obtained from the maximum likelihood estimates of two genotypic relative risks. When parental genotypes are missing in some family trios, the expectation-conditional-maximization algorithm is adopted to obtain the corresponding maximum likelihood estimates. Further, the confidence interval of the ratio is derived based on the likelihood ratio test. Simulation results show that the likelihood-based confidence interval has an accurate coverage probability under the situations considered. Also, we apply our proposed method to the rheumatoid arthritis data from USA for its practical use, and find out that a locus, rs2238907, may undergo the XCI skewing against the at-risk allele. But this needs to be further confirmed by molecular genetics. CONCLUSIONS: The proposed statistical measure for the skewness of XCI is applicable to complete family trio data or family trio data with some paternal genotypes missing. The likelihood-based confidence interval has an accurate coverage probability under the situations considered. Therefore, our proposed statistical measure is generally recommended in practice for discovering the potential loci which undergo the XCI skewing.

Study protocol for a two-center test of a nurse-implemented chronotherapeutic restoring bundle in critically ill children: RESTORE Resilience (R2).

Often, pediatric intensive care environments are not conducive to healing the sick. Critically ill children experience disruptions in their circadian rhythms, which can contribute to delayed recovery and poor outcomes. We aim to test the hypothesis that children managed via RESTORE Resilience (R2), a nurse-implemented chronotherapeutic bundle, will experience restorative circadian rhythms compared to children receiving usual care. In this two-phased, prospective cohort study, two separate pediatric intensive care units in the United Sates will enroll a total of 20 baseline subjects followed by 40 intervention subjects, 6 months to less than 18 years of age, requiring invasive mechanical ventilation. During the intervention phase, we will implement the R2 bundle, which includes: (1) a focused effort to replicate the child's pre-hospitalization daily routine, (2) cycled day-night lighting and sound modulation, (3) minimal yet effective sedation (RESTORE), (4) nighttime fasting with bolus enteral daytime feedings, (5) early progressive mobility (PICU Up!), (6) continuity in nursing care, and (7) parent diaries. Our primary outcome is circadian activity ratio post-extubation. We hypothesize that children receiving R2 will experience restored circadian rhythms as evidenced by decreased nighttime activity while in the PICU. Our exploratory outcomes include salivary melatonin levels; electroencephalogram (EEG) slow-wave activity; R2 feasibility, adherence, and system barriers; levels of patient comfort; exposure to sedative medications; time to physiological stability; and parent perception of being well cared for. This paper describes the design, rationale, and implementation of R2. CLINICALTRIALSGOV IDENTIFIER: NCT04695392.

Quantitative assessment of left ventricular mechanical dyssynchrony using cine cardiovascular magnetic resonance imaging: Inter-study reproducibility.

OBJECTIVES: To determine the inter-study reproducibility of left ventricular (LV) mechanical dyssynchrony measures based on standard cardiovascular magnetic resonance (CMR) cine images. DESIGN: Steady-state free precession (SSFP) LV short-axis stacks and three long-axes were acquired on the same day at three time points. Circumferential strain systolic dyssynchrony indexes (SDI), area-SDI as well as circumferential and radial uniformity ratio estimates (CURE and RURE, respectively) were derived from CMR myocardial feature-tracking (CMR-FT) based on the tracking of three SSFP short-axis planes. Furthermore, 4D-LV-analysis based on SSFP short-axis stacks and longitudinal planes was performed to quantify 4D-volume-SDI. SETTING: A single-centre London teaching hospital. PARTICIPANTS: 16 healthy volunteers. MAIN OUTCOME MEASURES: Inter-study reproducibility between the repeated exams. RESULTS: CURE and RURE as well as 4D-volume-SDI showed good inter-study reproducibility (coefficient of variation [CoV] 6.4%-12.9%). Circumferential strain and area-SDI showed higher variability between the repeated measurements (CoV 24.9%-37.5%). Uniformity ratio estimates showed the lowest inter-study variability (CoV 6.4%-8.5%). CONCLUSIONS: Derivation of LV mechanical dyssynchrony measures from standard cine images is feasible using CMR-FT and 4D-LV-analysis tools. Uniformity ratio estimates and 4D-volume-SDI showed good inter-study reproducibility. Their clinical value should next be explored in patients who potentially benefit from cardiac resynchronization therapy.