Experimental design and power calculation in omics circadian rhythmicity detection using the cosinor model.

Circadian clocks are 24-h endogenous oscillators in physiological and behavioral processes. Though recent transcriptomic studies have been successful in revealing the circadian rhythmicity in gene expression, the power calculation for omics circadian analysis have not been fully explored. In this paper, we develop a statistical method, namely CircaPower, to perform power calculation for circadian pattern detection. Our theoretical framework is determined by three key factors in circadian gene detection: sample size, intrinsic effect size and sampling design. Via simulations, we systematically investigate the impact of these key factors on circadian power calculation. We not only demonstrate that CircaPower is fast and accurate, but also show its underlying cosinor model is robust against variety of violations of model assumptions. In real applications, we demonstrate the performance of CircaPower using mouse pan-tissue data and human post-mortem brain data, and illustrate how to perform circadian power calculation using mouse skeleton muscle RNA-Seq pilot as case study. Our method CircaPower has been implemented in an R package, which is made publicly available on GitHub ( https://github.com/circaPower/circaPower).

Rapid Eye Movement Sleep Engages Melanin-Concentrating Hormone Neurons to Reduce Cocaine Seeking.

BACKGROUND: Persistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders. METHODS: We trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features. To test for causal relationships, we then used behavioral, chemogenetic, or optogenetic methods to selectively increase rapid eye movement sleep (REMS) and measured behavioral and electrophysiological outcomes to probe for cellular and circuit mechanisms underlying REMS-mediated regulation of cocaine seeking. RESULTS: A selective set of REMS features was preferentially associated with the intensity of cue-induced cocaine seeking after drug withdrawal. Moreover, selectively increasing REMS time and continuity by environmental warming attenuated a withdrawal time-dependent intensification of cocaine seeking, or incubation of cocaine craving, suggesting that REMS may benefit withdrawal. Warming increased the activity of lateral hypothalamic melanin-concentrating hormone (MCH) neurons selectively during prolonged REMS episodes and counteracted cocaine-induced synaptic accumulation of calcium-permeable AMPA receptors in the nucleus accumbens-a critical substrate for incubation. Finally, the warming effects were partly mimicked by chemogenetic or optogenetic stimulations of MCH neurons during sleep, or intra-accumbens infusions of MCH peptide during the rat's inactive phase. CONCLUSIONS: REMS may encode individual vulnerability to relapse, and MCH neuron activities can be selectively targeted during REMS to reduce drug relapse.

Preoperative measurement of the thickness of the center of the humeral head predicts screw cutout after locked plating of proximal humeral fractures.

HYPOTHESIS AND BACKGROUND: Preoperative computed tomography (CT) scans can be used to measure the thickness of the center of the humeral head to identify patients at a higher risk of screw cutout after open reduction-internal fixation. METHODS: At an academic medical center, we performed a retrospective review of all patients aged ≥ 18 years who had sustained a proximal humeral fracture that was treated with open reduction-internal fixation between January 1, 2005, and December 31, 2014, and who underwent preoperative shoulder CT. Ninety-four patients were included. Patient charts were reviewed to obtain demographic data, and radiographs were reviewed to assess screw cutout. A standardized method was devised to measure the thickness of the center of the humeral head. RESULTS: Screw cutout developed in 17 patients (17.7%). The mean humeral head thickness was significantly smaller on the axial (18 mm vs. 21 mm, P = .0031), coronal (18 mm vs. 21 mm, P = .0084), and sagittal (18 mm vs. 21 mm, P = .0033) sections in the patients who experienced screw cutout. When the smallest of the 3 measurements for each patient was analyzed, the risk of cutout was markedly greater when the humeral head thickness was <20 mm (25% vs. 6%). In addition, when the humeral head thickness was >25 mm, the risk of cutout was reduced to 0%. A low-energy injury was associated with a lower risk of cutout whereas age, sex, and fracture classification were not independent predictors of cutout on multivariate logistic regression. CONCLUSIONS: In a patient with a proximal humeral fracture in whom a preoperative CT scan is available, calculating the thickness of the center of the humeral head may provide valuable information to both the surgeon and the patient for preoperative planning and counseling. A smaller thickness of the center of the humeral head on preoperative CT is predictive of screw cutout following locked plating of proximal humeral fractures. A measurement of >25 mm in any one plane is highly protective against cutout; however, extreme caution and consideration of supplemental fixation methods should be taken when the measurements in all planes are <15 mm. This information may be helpful in counseling patients regarding the possibility of postoperative screw cutout.

Rethinking strategies for blood transfusion in hip fracture patients.

OBJECTIVES: Most patients can tolerate a hemoglobin (Hgb) > 8 g per deciliter. In some cases, however, transfusion will delay physical therapy and hospital discharge. This study aims to review Hgb and transfusion data for a large volume of recent hip fracture patients in order to identify new opportunities for decreasing the length of hospital stay. Our hypotheses are that in some cases, earlier transfusion of more blood will be associated with shorter hospital stays, and that Hgb levels consistently decrease for more than 3 days postoperatively. DESIGN: Retrospective chart review. SETTING: Two academic medical centers with Geriatric Fracture Programs. PATIENTS: Data was collected from patients 50 years and older with hip fractures April 2015 and October 2017. INTERVENTION: Operative stabilization of the hip fractures according to standard of care for the fracture type and patient characteristics. Transfusion according to established standards. MAIN OUTCOME MEASUREMENTS: Electronic records were retrospectively reviewed for demographic information, Hgb levels, and transfusion events. RESULTS: One thousand fifteen patients with femoral neck or intertrochanteric hip fractures were identified. Eight hundred sixty met the inclusion criteria. The average length of hospital stay was 6.7 days. The mean patient age was 82 years. The average American Society of Anesthesiologists score was 2.9. The average Hgb level consistently decreased for 5 days postoperatively before beginning to increase on day 6. There was poor consistency between intraoperative Hgb levels and preoperative or postoperative Hgb levels. Three hundred sixty-eight (42.8%) patients were transfused an average of 1.9 (range 1-6) units. One hundred five patients required a transfusion on postoperative day (POD) 1: 72 received only 1 unit of blood: 36 (50%) of the 72 required a second transfusion in the following days, compared to 9 of 33 (27%) who received 2 units on POD 1 (χ2 = 3.8898; P < .05). Patients who received transfusions on POD 3 or later had an average length of stay >2.5 days longer than those who received a transfusion earlier (P = 0.005). CONCLUSIONS: Our findings do not support earlier transfusion of more blood. Although in some cases, there is an association between earlier transfusion of more blood and shorter hospital stay, routine transfusion of more blood would incur higher transfusion risks in some patients who would not otherwise meet criteria for transfusion. After hip fracture surgery, the Hgb usually decreases for 5 days and does not begin to increase until POD 6. This information will provide utility in the population health management of hip fracture patients. LEVEL OF EVIDENCE: Level III, Retrospective Cohort Study.

The trauma severity model: An ensemble machine learning approach to risk prediction.

Statistical theory indicates that a flexible model can attain a lower generalization error than an inflexible model, provided that the setting is appropriate. This is highly relevant for mortality risk prediction with trauma patients, as researchers have focused exclusively on the use of generalized linear models for trauma risk prediction, and generalized linear models may be too inflexible to capture the potentially complex relationships in trauma data. To improve trauma risk prediction, we propose a machine learning model, the Trauma Severity Model (TSM). In order to validate TSM's performance, this study compares TSM to three established risk prediction models: the Bayesian Logistic Injury Severity Score, the Harborview Assessment for Risk of Mortality, and the Trauma Mortality Prediction Model. Our results indicate that TSM has superior predictive performance on National Trauma Data Bank data and on Nationwide Readmission Database data.