Reduced healthcare access contributes to delay of care in endometrial cancer.

OBJECTIVE: We aimed to characterize delays to care in patients with endometrioid endometrial cancer and the role healthcare access plays in these delays. METHODS: A chart review was performed of patients with endometrioid endometrial cancer who presented with postmenopausal bleeding at a diverse, urban medical center between 2006 and 2018. The time from symptom onset to treatment was abstracted from the medical record. This interval was subdivided to assess for delay to presentation, delay to diagnosis, and delay to treatment. RESULTS: We identified 484 patients who met the inclusion criteria. The median time from symptom onset to treatment was 4 months with an interquartile range of 2 to 8 months. Most patients had stage I disease at diagnosis (88.6%). There was no significant difference in race/ethnicity or disease stage at time of diagnosis between different groups. Patients who had not seen a primary care physician or general obstetrician-gynecologist in the year before symptom onset were more likely to have significantly delayed care (27.7% vs 14.3%, p = 0.02) and extrauterine disease (20.2% vs 4.9%, p < 0.01) compared to those with established care. Black and Hispanic patients were more likely to experience significant delays from initial biopsy to diagnosis. CONCLUSIONS: Delays exist in the evaluation of endometrial cancer. This delay is most pronounced in patients without an established outpatient primary care provider or obstetrician-gynecologist.

Lung Cancer Screening Penetration in an Urban Underserved County.

PURPOSE: To compare residential geography, sex, socioeconomic status (SES), and race/ethnicity of patients screened at Montefiore's Lung Cancer Screening Program with those of patients diagnosed with lung cancer, assessing whether screening efforts are appropriately focused. METHODS: This retrospective cohort study involved patients within a multisite urban medical center undergoing lung cancer screening or diagnosed with lung cancer from January 1, 2015 to December 31, 2019. Inclusion criteria were residence within the Bronx, NY and age between 55 and 80 years. Institutional review board approval was obtained. Data were analyzed using the Wilcoxon two-sample t test and χ2. RESULTS: The cohorts comprised 1568 (50.3%) women and 1551 (49.7%) men (mean age 65.6 ± 6.16). The Southeast Bronx had the most diagnosed lung cancers (29.96%) and screenings (31.22%). Sex did not significantly differ (p = 0.053). Cancer and screening cohorts were from impoverished neighborhoods with mean SES of - 3.11 ± 2.78 and - 3.44 ± 2.80 (p < 0.01). The lower tier SES neighborhoods demonstrated more patients in the screening cohort than cancer cohort (p = 0.01). Both cohorts included a majority of Hispanic patients, although race/ethnicity differed significantly (p = 0.01). Lower SES neighborhoods showed no significant difference in race/ethnicity between cancer and screening cohorts (p = 0.262). CONCLUSION: Though statistically significant differences were found between cohorts, likely due to sample size, few clinically meaningful differences were found, implying our lung cancer screening program was effective in reaching the desired population. Demographics-based programs should be considered in global efforts to screen vulnerable populations.

Predictive Value of CT Biomarkers in Lung Transplantation Survival: Preliminary Investigation in a Diverse, Underserved, Urban Population.

INTRODUCTION: Survival following lung transplant is low. With limited donor lung availability, predicting post-transplant survival is key. We investigated the predictive value of pre-transplant CT biomarkers on survival. METHODS: In this single-center retrospective cohort study of adults in a diverse, underserved, urban lung transplant program (11/8/2017-5/20/2022), chest CTs were analyzed using TeraRecon to assess musculature, fat, and bone. Erector spinae and pectoralis muscle area and attenuation were analyzed. Sarcopenia thresholds were 34.3 (women) and 38.5 (men) Hounsfield Units (HU). Visceral and subcutaneous fat area and HU, and vertebral body HU were measured. Demographics and pre-transplant metrics were recorded. Survival analyses included Kaplan-Meier and Cox proportional hazard. RESULTS: The study cohort comprised 131 patients, 50 women, mean age 60.82 (SD 10.15) years, and mean follow-up 1.78 (SD 1.23) years. Twenty-nine percent were White. Mortality was 32.1%. Kaplan-Meier curves did not follow the proportional hazard assumption for sex, so analysis was stratified. Pre-transplant EMR metrics did not predict survival. Women without sarcopenia at erector spinae or pectoralis had 100% survival (p = 0.007). Sarcopenia did not predict survival in men and muscle area did not predict survival in either sex. Men with higher visceral fat area and HU had decreased survival (p = 0.02). Higher vertebral body density predicted improved survival in men (p = 0.026) and women (p = 0.045). CONCLUSION: Pre-transplantation CT biomarkers had predictive value in lung transplant survival and varied by sex. The absence of sarcopenia in women, lower visceral fat attenuation and area in men, and higher vertebral body density in both sexes predicted survival in our diverse, urban population.

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion.

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

Epidemiology, Risk Factors and Outcomes of Pneumomediastinum in Patients with Coronavirus Disease 2019: A Case-Control Study.

Background: Since the beginning of the ongoing Coronavirus Disease 2019 (COVID-19) pandemic, pneumomediastinum has been reported in patients with COVID-19 pneumonia and acute respiratory distress syndrome. It has been suggested that pneumomediastinum may portend a worse outcome in such patients although no investigation has established this association definitively. Research Question: We hypothesized that the finding of pneumomediastinum in the setting of COVID-19 disease may be associated with a worse clinical outcome. The purpose of this study was to determine if the presence of pneumomediastinum was predictive of increased mortality in patients with COVID-19. Study Design and Methods: A retrospective case-control study utilizing clinical data and imaging for COVID-19 patients seen at our institution from 3/7/2020 to 5/20/2020 was performed. 87 COVID-19 positive patients with pneumomediastinum were compared to 87 COVID-19 positive patients without pneumomediastinum and to a historical group of patients with pneumomediastinum during the same time frame in 2019. Results: The incidence of pneumomediastinum was increased more than 6-fold during the COVID-19 pandemic compared to 2019 (P = <.001). 1.5% of all COVID-19 patients and 11% of mechanically ventilated COVID-19 patients at our institution developed pneumomediastinum. Patients who developed pneumomediastinum had a significantly higher PEEP and lower P/F ratio than those who did not (P = .002 and .033, respectively). Pneumomediastinum was not found to be associated with increased mortality (P = .16, confidence interval [CI]: 0.89-2.09, 1.37). The presence of concurrent pneumothorax at the time of pneumomediastinum diagnosis was associated with increased mortality (P = .013 CI: 1.15-3.17, 1.91). Conclusion: Pneumomediastinum is not independently associated with a worse clinical prognosis in COVID-19 positive patients. The presence of concurrent pneumothorax was associated with increased mortality.

Using Routine Chest Computed Tomography to Diagnose Pulmonary Embolism.

OBJECTIVE: This study investigated the use of routine contrast-enhanced chest computed tomography (CT) to diagnose unsuspected pulmonary embolism (PE). METHODS: All adult routine contrast-enhanced chest CTs performed at Montefiore in 2018 were included. Pulmonary artery enhancement was measured by placing regions of interest in the pulmonary vasculature. Adequate enhancement was defined as 200 Hounsfield units (HU) or greater. Presence or absence of PE was noted. Descriptive statistics and logistic regression analysis were performed. RESULTS: A total of 3164 CTs were evaluated (55.8% women; mean age, 63.2 years). Main pulmonary enhancement was highly correlated with peripheral enhancement. Of all cases, 28.7% (907 of 3164) reached the 200 HU threshold. Greater enhancement was associated with female sex, older age, outpatients, and contrast amount administered. Pulmonary embolism-positive cases comprised 1.8% (58 of 3164) of total cases. Furthermore, 39.7% (23 of 58) of PE-positive cases reached the 200 HU threshold. CONCLUSIONS: Over one quarter of routine contrast-enhanced chest CT scans met the 200 HU threshold indicative of adequate pulmonary artery enhancement, including nearly half of the 2% of examinations positive for PE.

Prone Chest Radiographs: Distinguishing Features and Identification of Support Devices.

PURPOSE: Prone position is known to improve acute lung injury, and chest radiographs are often necessary to monitor disease and confirm support device placement. However, there is a paucity of literature regarding radiographs obtained in this position. We evaluated prone radiographs for distinguishing features and ability to identify support devices. METHODS: Pairs of prone and supine radiographs obtained during the COVID-19 pandemic were assessed retrospectively. IRB approval and waiver of informed consent were obtained. Radiographs were assessed for imaging adequacy, distinguishing features, and support device identification (endotracheal tube, enteric tube, or central line). Radiographs were reviewed by ≥ 2 cardiothoracic radiologists. RESULTS: Radiographs from 81 patients (63yo ± 13, 30% women) were reviewed. Prone and supine radiographs were comparable for imaging the lung bases (81% vs. 90%, p = 0.35) and apices (93% vs. 94%, p = 1); prone radiographs more frequently had significant rotation (36% vs. 19%, p = 0.021). To identify prone technique, scapula tip located beyond the rib border was 89% sensitive (95%CI 80-95%) and 85% specific (76-92%), and a fundal stomach bubble was 44% sensitive (33-56%) and 90% specific (81-96%). For women, displaced breast shadow was 46% sensitive (26-67%) and 92% specific (73-99%). Prone and supine radiographs each identified > 99% of support devices. Prone exams trended toward increased rate of malpositioned device (12% vs. 6%, p = 0.07). CONCLUSION: Scapula position reliably distinguishes prone from supine position; fundal stomach bubble or displaced breast shadow is specific for prone position. Prone radiographs reliably identify line and tube position, which is particularly important as prone patients appear at increased risk for malpositioned devices.

Detecting, quantifying, and discriminating the mechanism of mosaic chromosomal aneuploidies using MAD-seq.

Current approaches to detect and characterize mosaic chromosomal aneuploidy are limited by sensitivity, efficiency, cost, or the need to culture cells. We describe the mosaic aneuploidy detection by massively parallel sequencing (MAD-seq) capture assay and the MADSEQ analytical approach that allow low (<10%) levels of mosaicism for chromosomal aneuploidy or regional loss of heterozygosity to be detected, assigned to a meiotic or mitotic origin, and quantified as a proportion of the cells in the sample. We show results from a multi-ethnic MAD-seq (meMAD-seq) capture design that works equally well in populations of diverse racial and ethnic origins and how the MADSEQ analytical approach can be applied to exome or whole-genome sequencing data, revealing previously unrecognized aneuploidy or copy number neutral loss of heterozygosity in samples studied by the 1000 Genomes Project, cell lines from public repositories, and one of the Illumina Platinum Genomes samples. We have made the meMAD-seq capture design and MADSEQ analytical software open for unrestricted use, with the goal that they can be applied in clinical samples to allow new insights into the unrecognized prevalence of mosaic chromosomal aneuploidy in humans and its phenotypic associations.

The Utility of 18FDG PET/CT Versus Bone Scan for Identification of Bone Metastases in a Pediatric Sarcoma Population and a Review of the Literature.

BACKGROUND: Outcome of patients with osteosarcoma (OS) and Ewing sarcoma (EWS) is dependent on presence of metastases. Imaging guidelines for OS and EWS include radiographs, computed tomography (CT), and magnetic resonance imaging for primary tumor evaluation and CT chest and bone scintigraphy (BS) for metastatic detection. 18Fluorodeoxyglucose (18FDG) positron emission tomography (PET)/CT has become more common for disease evaluation, yet there is no consensus for its use in this population. OBJECTIVE: We aimed to compare identification of osseous metastases using BS versus 18FDG PET/CT in our patient population. We hypothesized that 18FDG PET/CT is more likely to detect osseous metastases both at diagnosis and relapse. MATERIALS AND METHODS: We performed retrospective chart reviews of pediatric sarcoma patients treated at our institution from 2008 to 2019. Paired BS and 18FDG PET/CT scans were reviewed. Review of the literature was also performed. RESULTS: Thirty-three patients had paired BS and 18FDG PET/CT during diagnosis or treatment. Fifteen patients had distant osseous metastases. In the OS cohort, 8/16 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 75% on BS. Thirty-one bony lesions were seen on imaging in OS patients; 100% of these were identified on 18FDG PET/CT but only 29% on BS. In the EWS cohort, 6/15 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 50% on BS. Eighteen bony lesions were seen on imaging in EWS patients; 94% of these were identified on 18FDG PET/CT, but only 28% on BS. CONCLUSION: For patients in our institution with OS or EWS, osseous metastases were more likely detected using 18FDG PET/CT.

Safety and efficacy of image-guided retrocalcaneal bursa corticosteroid injection for the treatment of retrocalcaneal bursitis.

OBJECTIVE: To determine the safety and efficacy of image-guided retrocalcaneal bursa corticosteroid injection for retrocalcaneal bursitis. MATERIALS AND METHODS: After IRB approval, all fluoroscopically guided and ultrasound-guided retrocalcaneal bursa injections (2013-2019) were retrospectively evaluated. Pre-procedure US and radiographs were scored by 2 blinded radiologists in consensus for Achilles tendinosis and retrocalcaneal bursitis (0-3 scale), Achilles enthesopathy (present/absent), and Haglund deformity (present/absent). Pre- and post-procedure pain scores (0-10 scale) evaluated short-term response at 1-4 weeks: excellent (7-10 point decline), good (4-6 point decline), fair (1-3 point decline), or no response. Paired t-test determined significance of short-term improvement. Kaplan-Meier method analyzed time to progression to surgery or complication at 6-month minimum follow-up. Logistic regression analysis evaluated for association between demographic and imaging variables and negative outcome. RESULTS: Two hundred eighteen injections (181 female; mean 54.5 years) performed under ultrasonographic (157, 72%) or fluoroscopic (61, 28%) guidance were evaluated for complication and long-term outcomes. Injections with short-term follow-up (n = 62) yielded excellent or good response in 62.9% (p < 0.00001). Thirty patients (14%) had subsequent elective Achilles surgery. Bursal Doppler flow was associated with progression to surgery (p = 0.00042). No differences were identified in outcomes between US and fluoroscopic-guidance cohorts. Four Achilles ruptures (1.8%) were identified 15-59 days post-injection, each with immediately preceding acute injury. CONCLUSION: Image-guided retrocalcaneal bursa corticosteroid injection yields significant short-term decrease in pain score in majority (63%) of patients. Subsequent Achilles tendon rupture rate was 1.8%. Bursa Doppler flow was significantly correlated with progression to surgery and may represent a negative prognostic indicator.

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence.

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC50; 2) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to taxol or DDM; 3) reduced propensity for senescence induction relative to DDM; 4) superior long-term activity in cancer cells versus taxol or DDM; and 5) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a DDM congener with broad range anticancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anticancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and taxane-resistant cancer cell models, diminished risk of chemotherapy-mediated senescence, and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to ß-tubulin that could account for the improved anticancer activity. These findings support continued preclinical development of discodermolide, particularly in the chemorefractory setting.

Lower-extremity Arterial Thrombosis Associated with COVID-19 Is Characterized by Greater Thrombus Burden and Increased Rate of Amputation and Death.

Background During the peak of the coronavirus disease 2019 (COVID-19) pandemic, the authors noted an increase in positive lower-extremity CT angiography examinations in patients who presented with leg ischemia. The goal of this study was to determine whether lower-extremity arterial thrombosis was associated with COVID-19 and whether it was characterized by greater severity in these patients. Materials and Methods In this retrospective propensity score-matched study approved by the institutional review board, 16 patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and who underwent CT angiography of the lower extremities and 32 patients who tested negative for SARS-CoV-2 observed from January to April 2018, January to April 2019, and January to April 2020 were compared using three scoring systems: two systems including all vessels, with weighting in one system given to more proximal vessels and with weighting in the other system given to more distal vessels, and a third system in which only the common iliac through popliteal arteries were considered. Correlation with presenting symptoms and outcomes was computed. Fisher exact tests were used to compare patients who tested positive for COVID-19 with patients who tested negative for COVID-19 regarding the presence of clots and presenting symptoms. A Mantel-Haenszel test was used to associate outcome of death and/or amputation with COVID-19 adjusted according to history of peripheral vascular disease (PVD). Results Sixteen patients with confirmed COVID-19 (70 years ± 14 [standard deviation]; seven women) who underwent CT angiography and 32 propensity score-matched control patients (71 years ± 15; 16 women) were included. All patients with COVID-19 (100%, 95% confidence interval [CI]: 79%, 100%) had at least one thrombus, and only 69% of control patients (95% CI: 50%, 84%) had thrombi (P = .02). Ninety-four percent of patients with COVID-19 (95% CI: 70%, 99.8%) had proximal thrombi compared with 47% of control patients (95% CI: 29%, 65%) (P < .001). The mean thrombus score using any of the three scoring systems yielded greater scores in patients with COVID-19 (P < .001). Adjusted for history of PVD, death or limb amputation was more common in patients with COVID-19 (odds ratio = 25; 95% CI: 4.3, 147; P < .001). Patients with COVID-19 who presented with symptoms of leg ischemia only were more likely to avoid amputation or death than patients who also presented with pulmonary or systemic symptoms (P = .001). Conclusion Coronavirus disease 2019 is associated with lower-extremity arterial thrombosis characterized by a greater clot burden and a more dire prognosis. © RSNA, 2020.

Low molecular weight serum cell-free DNA concentration is associated with clinicopathologic indices of poor prognosis in women with uterine cancer.

BACKGROUND: Serum cell-free DNA (cfDNA) holds promise as a non-invasive cancer biomarker. The objective of this study was to evaluate the association of cfDNA concentration with clinicopathologic variables of poor prognosis and overall survival among women with uterine cancer compared to benign cancer-free controls. METHODS: cfDNA was extracted from the serum of 91 women with multiple uterine cancer histologies and 22 post-menopausal controls without cancer. Low molecular weight (LMW) cfDNA was separated from contaminating genomic high molecular weight cfDNA using paramagnetic bead purification and its concentration was measured using fluorometric quantification. Clinicopathologic data was abstracted from the electronic medical record. The association between serum cfDNA concentration, clinicopathologic variables, and overall survival was assessed using linear regression modelling, Cox proportional hazards modelling, and the Kaplan-Meier method. RESULTS: Median total serum cfDNA concentration for the cohort was 69.2 ng/mL (IQR 37.4, 132.3) and median LMW cfDNA concentration was 23.8 ng/mL (IQR 14.9, 44.4). There were no significant differences in total serum cfDNA concentration with any clinicopathologic variables. However, LMW cfDNA concentration was significantly higher in serum of women with cancer (25.8 ng/mL IQR 16.0, 49.6) compared to benign controls (15.5 ng/mL IQR 9.3, 25.8 ng/mL) (p < 0.01). It is also significantly higher among women with early stage cancer than benign controls (p < 0.01). There were also significant associations between LMW cfDNA concentration and stage of cancer (p = 0.01) and histology (p = 0.02). Patients with leiomyosarcoma and carcinosarcoma had higher cfDNA concentrations than those with endometrioid cancer. Over a median follow-up of 51.9 months, 75th percentile for overall survival for women with cancer was 24.0 months. Higher LMW cfDNA concentrations is associated with lower survival among women with cancer (p < 0.01). CONCLUSIONS: Serum LMW cfDNA concentration is associated with overall survival in women with uterine cancer, and it is higher among women with uterine cancer compared to those of controls.

The contribution of de novo coding mutations to autism spectrum disorder.

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

Measuring shared variants in cohorts of discordant siblings with applications to autism.

We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS (P value ∼ 0.00001). Fathers in multiplex families have marginally greater similarity (P value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender.

The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis.

Sporadic colon cancer accounts for approximately 80% of colorectal cancer (CRC) with high incidence in Western societies strongly linked to long-term dietary patterns. A unique mouse model for sporadic CRC results from feeding a purified rodent Western-style diet (NWD1) recapitulating intake for the mouse of common nutrient risk factors each at its level consumed in higher risk Western populations. This causes sporadic large and small intestinal tumors in wild-type mice at an incidence and frequency similar to that in humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts and decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumor development. Here we establish that NWD1 transcriptionally reprograms Lgr5hi cells, and that nutrients are interactive in reprogramming. Furthermore, the DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, paralleled by reduced accumulation of relevant somatic mutations detected by single-cell exome sequencing. In compensation, NWD1 also reprograms Bmi1+ cells to function and persist as stem-like cells in mucosal homeostasis and tumor development. The data establish the key role of the nutrient environment in defining the contribution of two different stem cell populations to both mucosal homeostasis and tumorigenesis. This raises important questions regarding impact of variable human diets on which and how stem cell populations function in the human mucosa and give rise to tumors. Moreover, major differences reported in turnover of human and mouse crypt base stem cells may be linked to their very different nutrient exposures.

Adjustment for covariates using summary statistics of genome-wide association studies.

Linear regression is a standard approach to identify genetic variants associated with continuous traits in genome-wide association studies (GWAS). In a standard epidemiology study, linear regression is often performed with adjustment for covariates to estimate the independent effect of a predictor variable or to improve statistical power by reducing residual variability. However, it is problematic to adjust for heritable covariates in genetic association analysis. Here, we propose a new method that utilizes summary statistics of the covariate from additional samples for reducing the residual variability and hence improves statistical power. Our simulation study showed that the proposed methodology can maintain a good control of Type I error and can achieve much higher power than a simple linear regression. The method is illustrated by an application to the GWAS results from the Genetic Investigation of Anthropometric Traits consortium.

Multi-modal neuroimaging of dual-task walking: Structural MRI and fNIRS analysis reveals prefrontal grey matter volume moderation of brain activation in older adults.

It has been well established over the last two decades that walking is not merely an automatic, motoric activity; it also utilizes executive function circuits, which play an increasingly important role in walking for older people and those with mobility and cognitive deficits. Dual-task walking, such as walking while performing a cognitive task, is a necessary skill for everyday functioning, and has been shown to activate prefrontal lobe areas in healthy older people. Another well-established point in healthy aging is the loss of grey matter, and in particular loss of frontal lobe grey matter volume. However, the relationship between increased frontal lobe activity during dual-task walking and loss of frontal grey matter in healthy aging remains unknown. In the current study, we combined oxygenated hemoglobin (HbO2) data from functional near-infrared spectroscopy (fNIRS), taken during dual-task walking, with structural MRI volumetrics in a cohort of healthy older subjects to identify this relationship. We studied fifty-five relatively healthy, older participants (≥65 years) during two separate sessions: fNIRS to measure HbO2 changes between single-task (i.e., normal walking) and dual-task walking-while-talking, and high-resolution, structural MRI to measure frontal lobe grey matter volumes. Linear mixed effects modeling was utilized to determine the moderation effect of grey matter volume on the change in prefrontal oxygenated hemoglobin between the two walking tasks, while controlling for covariates including task performance. We found a highly significant interaction effect between frontal grey matter volume and task on HbO2 levels (p < 0.0001). Specifically, increased HbO2 levels during dual-task compared to single-task walking were associated with reduced frontal grey matter volume. Regional analysis identified bilateral superior and rostral middle gyri as the primary areas driving these results. The findings provide support for the concept of neural inefficiency: in the absence of behavioral gains, grey matter loss in relatively healthy, older individuals leads to over-activation of frontal lobe during a cognitively demanding walking task with established clinical and predictive utility.

Diagnostic yield of head CT in pediatric emergency department patients with acute psychosis or hallucinations.

BACKGROUND: Children presenting to the emergency department with acute psychosis or hallucinations sometimes undergo a head CT to evaluate for a causative lesion. The diagnostic yield of head CT in this scenario has not been reported. OBJECTIVE: To determine the yield for head CT in children with acute psychosis or hallucinations. MATERIALS AND METHODS: We retrospectively searched the radiology report database over a 7.5-year period for head CT reports for pediatric emergency department patients using the following keywords: hallucination, psychosis, psychotic or "hearing voices." All reports were categorized as normal or abnormal, and we reviewed and categorized the abnormal cases. We calculated the 95% confidence interval for abnormal CTs using the method of Clopper and Pearson. RESULTS: We identified 397 pediatric emergency department head CTs. We excluded one non-diagnostic exam. We excluded 34 additional cases (which were all normal) because of clinical indications that might have independently triggered a head CT. Of the remaining 362 cases, 12 reports described abnormalities or variants and we reviewed them individually. Based on consensus review, four were normal, four had congenital malformations, three had encephalomalacia versus demyelination and one demonstrated cortical atrophy. There were no cases with actionable findings such as mass, hemorrhage, infection or hydrocephalus. The 95% confidence interval for a CT demonstrating causative findings was calculated at 0-0.82%. CONCLUSION: In the absence of concerning factors such as focal neurological deficits, evidence of central nervous system infection, trauma or headache, routine screening head CT might not be warranted in children presenting with acute psychosis or hallucinations.

Ventricular Arterial Coupling: A Novel Echocardiographic Risk Factor for Disease Progression in Pediatric Dilated Cardiomyopathy.

In adult heart failure (HF) patients, a higher ventricular arterial (VA) coupling ratio measured non-invasively is associated with worse HF prognosis and response to treatment. There are no data regarding the relationship of VA coupling to outcome in pediatric dilated cardiomyopathy (DCM) patients. We investigated the association of VA coupling ratio with worse outcome (mechanical circulatory support, transplant, or death) in 48 children with DCM and 97 age-gender matched controls. Mean age at presentation was 9 ± 7 years; DCM patients had a higher arterial elastance (3.8 ± 1.7 vs 2.7 ± 0.7 respectively p = 0.001), a lower LV elastance (1.1 ± 0.65 vs 4.5 ± 1.4, respectively p = 0.001) and higher VA coupling ratio (5.0 ± 3.9 vs 0.34 ± 0.14, respectively p = 0.001). Outcome events occurred in 27/48 (56%) patients. Patients with an outcome event had a higher NYHA class (p = 0.001), lower LV elastance (0.8 ± 0.47 vs 1.6 ± 0.57, respectively p = 0.001), higher arterial elastance (4.5 ± 1.8 vs 2.9 ± 1.1, respectively p = 0.002), and a higher VA coupling ratio (7.1 ± 3.8 vs 2.2 ± 1.5, respectively p = 0.001) compared to those without. In a multivariate CART analysis, VA coupling was the top and only discriminator of poor outcome. In conclusion, a higher VA coupling ratio is associated with worse outcome in pediatric patients with DCM. VA coupling is promising as a bedside analysis tool that may provide insight into the mechanisms of HF in pediatric DCM and identify potential targets for therapy.