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The subgenual anterior cingulate cortex (sgACC) is a critical site for understanding the neural correlates of affect and emotion. While the activity of the sgACC is functionally homogenous, it is comprised of multiple Brodmann Areas (BAs) that possess different cytoarchitectures. In some sgACC BAs, Layer 5 is sublaminated into L5a and L5b which has implications for its projection targets. To understand how the transcriptional profile differs between the BAs, layers, and sublayers of human sgACC, we collected layer strips using laser capture microdissection followed by RNA sequencing. We found no significant differences in transcript expression in these specific cortical layers between BAs within the sgACC. In contrast, we identified striking differences between Layers 3 and 5a or 5b that were concordant across sgACC BAs. We found that sublayers 5a and 5b were transcriptionally similar. Pathway analyses of L3 and L5 revealed overlapping biological processes related to synaptic function. However, L3 was enriched for pathways related to cell-to-cell junction and dendritic spines whereas L5 was enriched for pathways related to brain development and presynaptic function, indicating potential functional differences across layers. Our study provides important insight into normative transcriptional features of the sgACC.
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Giro del Cíngulo , Transcriptoma , Humanos , Giro del Cíngulo/fisiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Adulto Joven , Captura por Microdisección con LáserRESUMEN
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).
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Ritmo Circadiano , Proyectos de Investigación , Humanos , Animales , Ratones , Ritmo Circadiano/genética , Perfilación de la Expresión Génica , Transcriptoma , Tamaño de la MuestraRESUMEN
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.
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Cabeza Humeral , Fracturas del Hombro , Adolescente , Placas Óseas , Tornillos Óseos , Fijación Interna de Fracturas , Humanos , Cabeza Humeral/diagnóstico por imagen , Cabeza Humeral/cirugía , Estudios Retrospectivos , Fracturas del Hombro/diagnóstico por imagen , Fracturas del Hombro/cirugía , Resultado del TratamientoRESUMEN
Causal mediation analysis provides a systematic approach to explore the causal role of one or more mediators in the association between exposure and outcome. In omics or imaging data analysis, mediators are often high-dimensional, which brings new statistical challenges. Existing methods either violate causal assumptions or fail in interpretable variable selection. Additionally, mediators are often highly correlated, presenting difficulties in selecting and prioritizing top mediators. To address these issues, we develop a framework using Partial Sum Statistic and Sample Splitting Strategy, namely PS5, for high-dimensional causal mediation analysis. The method provides a powerful global mediation test satisfying causal assumptions, followed by an algorithm to select and prioritize active mediators with quantification of individual mediation contributions. We demonstrate its accurate type I error control, superior statistical power, reduced bias in mediation effect estimation, and accurate mediator selection using extensive simulations of varying levels of effect size, signal sparsity, and mediator correlations. Finally, we apply PS5 to an imaging genetics dataset of chronic obstructive pulmonary disease (COPD) patients ( N =8,897) in the COPDGene study to examine the causal mediation role of lung images ( p =5,810) in the associations between polygenic risk score and lung function and between smoking exposure and lung function, respectively. Both causal mediation analyses successfully estimate the global indirect effect and detect mediating image regions. Collectively, we find a region in the lower lobe of the right lung with a strong and concordant mediation effect for both genetic and environmental exposures. This suggests that targeted treatment toward this region might mitigate the severity of COPD due to genetic and smoking effects.
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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.
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Trastornos Relacionados con Cocaína , Cocaína , Síndrome de Abstinencia a Sustancias , Masculino , Animales , Ratas , Sueño REM , Cocaína/farmacología , Neuronas/fisiología , Núcleo Accumbens , Sueño , Recurrencia , AutoadministraciónRESUMEN
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 (χ2â=â3.8898; Pâ<â.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 (Pâ=â0.005). 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.
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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.