IMPORTANCE: There is limited information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing and infection among pediatric patients across the United States. OBJECTIVE: To ...describe testing for SARS-CoV-2 and the epidemiology of infected patients. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted using electronic health record data from 135 794 patients younger than 25 years who were tested for SARS-CoV-2 from January 1 through September 8, 2020. Data were from PEDSnet, a network of 7 US pediatric health systems, comprising 6.5 million patients primarily from 11 states. Data analysis was performed from September 8 to 24, 2020. EXPOSURE: Testing for SARS-CoV-2. MAIN OUTCOMES AND MEASURES: SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) illness. RESULTS: A total of 135 794 pediatric patients (53% male; mean SD age, 8.8 6.7 years; 3% Asian patients, 15% Black patients, 11% Hispanic patients, and 59% White patients; 290 per 10 000 population range, 155-395 per 10 000 population across health systems) were tested for SARS-CoV-2, and 5374 (4%) were infected with the virus (12 per 10 000 population range, 7-16 per 10 000 population). Compared with White patients, those of Black, Hispanic, and Asian race/ethnicity had lower rates of testing (Black: odds ratio OR, 0.70 95% CI, 0.68-0.72; Hispanic: OR, 0.65 95% CI, 0.63-0.67; Asian: OR, 0.60 95% CI, 0.57-0.63); however, they were significantly more likely to have positive test results (Black: OR, 2.66 95% CI, 2.43-2.90; Hispanic: OR, 3.75 95% CI, 3.39-4.15; Asian: OR, 2.04 95% CI, 1.69-2.48). Older age (5-11 years: OR, 1.25 95% CI, 1.13-1.38; 12-17 years: OR, 1.92 95% CI, 1.73-2.12; 18-24 years: OR, 3.51 95% CI, 3.11-3.97), public payer (OR, 1.43 95% CI, 1.31-1.57), outpatient testing (OR, 2.13 1.86-2.44), and emergency department testing (OR, 3.16 95% CI, 2.72-3.67) were also associated with increased risk of infection. In univariate analyses, nonmalignant chronic disease was associated with lower likelihood of testing, and preexisting respiratory conditions were associated with lower risk of positive test results (standardized ratio SR, 0.78 95% CI, 0.73-0.84). However, several other diagnosis groups were associated with a higher risk of positive test results: malignant disorders (SR, 1.54 95% CI, 1.19-1.93), cardiac disorders (SR, 1.18 95% CI, 1.05-1.32), endocrinologic disorders (SR, 1.52 95% CI, 1.31-1.75), gastrointestinal disorders (SR, 2.00 95% CI, 1.04-1.38), genetic disorders (SR, 1.19 95% CI, 1.00-1.40), hematologic disorders (SR, 1.26 95% CI, 1.06-1.47), musculoskeletal disorders (SR, 1.18 95% CI, 1.07-1.30), mental health disorders (SR, 1.20 95% CI, 1.10-1.30), and metabolic disorders (SR, 1.42 95% CI, 1.24-1.61). Among the 5374 patients with positive test results, 359 (7%) were hospitalized for respiratory, hypotensive, or COVID-19–specific illness. Of these, 99 (28%) required intensive care unit services, and 33 (9%) required mechanical ventilation. The case fatality rate was 0.2% (8 of 5374). The number of patients with a diagnosis of Kawasaki disease in early 2020 was 40% lower (259 vs 433 and 430) than in 2018 or 2019. CONCLUSIONS AND RELEVANCE: In this large cohort study of US pediatric patients, SARS-CoV-2 infection rates were low, and clinical manifestations were typically mild. Black, Hispanic, and Asian race/ethnicity; adolescence and young adulthood; and nonrespiratory chronic medical conditions were associated with identified infection. Kawasaki disease diagnosis is not an effective proxy for multisystem inflammatory syndrome of childhood.
Increasingly, youth experiencing mental health crises present to acute care medical hospitals and "board" on medical units due to inpatient psychiatric bed shortages. We conducted a retrospective ...cohort study of children experiencing mental health boarding at a US children's hospital from October 2020 to September 2022. We examined associations between patients' characteristics and their disposition and outcomes. Our cohort included 1891 boarding hospitalizations: 53.9% transferred to an inpatient psychiatric hospital and 46.1% discharged home. Characteristics associated with not being transferred to an inpatient psychiatric hospital included age <13 years (adjusted odds ratio aOR 0.6; 95% confidence interval CI: 0.4-0.7), disruptive or aggressive behavior (aOR 0.6; 95% CI: 0.4-0.8), psychosis (aOR 0.5; 95% CI: 0.3-0.8), COVID-19 infection (aOR 0.3; 95% CI: 0.2-0.6), or a complex chronic medical condition (aOR 0.8; 95% CI: 0.6-1.0). Our findings suggest that certain populations of children experiencing mental health boarding face disparate access to inpatient psychiatric care.
The primary objective of this trade study report is to explore the potential of using Active Flow Control (AFC) for achieving lighter and mechanically simpler high-lift systems for transonic ...commercial transport aircraft. This assessment was conducted in four steps. First, based on the Common Research Model (CRM) outer mold line (OML) definition, two high-lift concepts were developed. One concept, representative of current production-type commercial transonic transports, features leading edge slats and slotted trailing edge flaps with Fowler motion. The other CRM-based design relies on drooped leading edges and simply hinged trailing edge flaps for high-lift generation. The relative high-lift performance of these two high-lift CRM variants is established using Computational Fluid Dynamics (CFD) solutions to the Reynolds-Averaged Navier-Stokes (RANS) equations for steady flow. These CFD assessments identify the high-lift performance that needs to be recovered through AFC to have the CRM variant with the lighter and mechanically simpler high-lift system match the performance of the conventional high-lift system. Conceptual design integration studies for the AFC-enhanced high-lift systems were conducted with a NASA Environmentally Responsible Aircraft (ERA) reference configuration, the so-called ERA-0003 concept. These design trades identify AFC performance targets that need to be met to produce economically feasible ERA-0003-like concepts with lighter and mechanically simpler high-lift designs that match the performance of conventional high-lift systems. Finally, technical challenges are identified associated with the application of AFC-enabled highlift systems to modern transonic commercial transports for future technology maturation efforts.
High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on ...the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools.
Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival.
Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection point in precision medicine. This study suggests that the use of personalized ctDNA biomarkers in gynecologic cancers can identify the presence of residual tumor while also more dynamically predicting response to treatment relative to currently used serum and imaging studies. Of particular interest, ctDNA was an independent predictor of survival in patients with ovarian and endometrial cancers. Earlier recognition of disease persistence and/or recurrence and the ability to stratify into better and worse outcome groups through ctDNA surveillance may open the window for improved survival and quality and life in these cancers.
Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca(2+) signalling in ...cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) cycling and neurohumoral stimulation leading to hypertrophy is unknown.
In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca(2+) concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca(2+)-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure.
The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca(2+) cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.
Genome-wide association studies (GWASs) have identified numerous loci that influence risk for psychiatric diseases. Genetically engineered mice are often used to characterize genes implicated by ...GWASs. These studies are based on the assumption that observed genotype-phenotype relationships will generalize to humans, implying that the results would at least generalize to other inbred mouse strains. Given current concerns about reproducibility, we sought to directly test this assumption. We produced F1 crosses between male C57BL/6J mice heterozygous for null alleles of Cacna1c and Tcf7l2 and wild-type females from 30 inbred laboratory strains. We found extremely strong interactions with genetic background that sometimes supported diametrically opposing conclusions. These results do not negate the invaluable contributions of mouse genetics to biomedical science, but they do show that genotype-phenotype relationships cannot be reliably inferred by studying a single genetic background, and thus constitute a major challenge to the status quo.
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•Cacna1c and Tcf7l2 null allele effects were strongly influenced by genetic background•Some interactions with genetic background supported opposite conclusions•Genetic background modulated mutant phenotypes more strongly than sex•These results do not negate the contributions of mutant mice to biomedical research
Sittig et al. demonstrate low generalizability of mouse null allele phenotypes across a panel of F1 genetic backgrounds, which suggests that the use of single strains is a barrier to robust characterization of genotype-phenotype relationships.
Endometrial cancer is the most common gynecologic malignancy, and its incidence and associated mortality are increasing. Despite the immediate need to detect these cancers at an earlier stage, there ...is no effective screening methodology or protocol for endometrial cancer. The comprehensive, genomics-based analysis of endometrial cancer by The Cancer Genome Atlas (TCGA) revealed many of the molecular defects that define this cancer. Based on these cancer genome results, and in a prospective study, we hypothesized that the use of ultra-deep, targeted gene sequencing could detect somatic mutations in uterine lavage fluid obtained from women undergoing hysteroscopy as a means of molecular screening and diagnosis.
Uterine lavage and paired blood samples were collected and analyzed from 107 consecutive patients who were undergoing hysteroscopy and curettage for diagnostic evaluation from this single-institution study. The lavage fluid was separated into cellular and acellular fractions by centrifugation. Cellular and cell-free DNA (cfDNA) were isolated from each lavage. Two targeted next-generation sequencing (NGS) gene panels, one composed of 56 genes and the other of 12 genes, were used for ultra-deep sequencing. To rule out potential NGS-based errors, orthogonal mutation validation was performed using digital PCR and Sanger sequencing. Seven patients were diagnosed with endometrial cancer based on classic histopathologic analysis. Six of these patients had stage IA cancer, and one of these cancers was only detectable as a microscopic focus within a polyp. All seven patients were found to have significant cancer-associated gene mutations in both cell pellet and cfDNA fractions. In the four patients in whom adequate tumor sample was available, all tumor mutations above a specific allele fraction were present in the uterine lavage DNA samples. Mutations originally only detected in lavage fluid fractions were later confirmed to be present in tumor but at allele fractions significantly less than 1%. Of the remaining 95 patients diagnosed with benign or non-cancer pathology, 44 had no significant cancer mutations detected. Intriguingly, 51 patients without histopathologic evidence of cancer had relatively high allele fraction (1.0%-30.4%), cancer-associated mutations. Participants with detected driver and potential driver mutations were significantly older (mean age mutated = 57.96, 95% confidence interval CI: 3.30-∞, mean age no mutations = 50.35; p-value = 0.002; Benjamini-Hochberg BH adjusted p-value = 0.015) and more likely to be post-menopausal (p-value = 0.004; BH-adjusted p-value = 0.015) than those without these mutations. No associations were detected between mutation status and race/ethnicity, body mass index, diabetes, parity, and smoking status. Long-term follow-up was not presently available in this prospective study for those women without histopathologic evidence of cancer.
Using ultra-deep NGS, we identified somatic mutations in DNA extracted both from cell pellets and a never previously reported cfDNA fraction from the uterine lavage. Using our targeted sequencing approach, endometrial driver mutations were identified in all seven women who received a cancer diagnosis based on classic histopathology of tissue curettage obtained at the time of hysteroscopy. In addition, relatively high allele fraction driver mutations were identified in the lavage fluid of approximately half of the women without a cancer diagnosis. Increasing age and post-menopausal status were associated with the presence of these cancer-associated mutations, suggesting the prevalent existence of a premalignant landscape in women without clinical evidence of cancer. Given that a uterine lavage can be easily and quickly performed even outside of the operating room and in a physician's office-based setting, our findings suggest the future possibility of this approach for screening women for the earliest stages of endometrial cancer. However, our findings suggest that further insight into development of cancer or its interruption are needed before translation to the clinic.
Background & Aims The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently ...activated in liver CSCs is NF-κB signaling. Methods We evaluated the CSCs-depleting potential of NF-κB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of side population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting. Results HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-κB inhibition. The treatment also led to a selective CSC-depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-κB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF-κB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-κB inhibition. Conclusions These results demonstrate that blocking NF-κB can specifically target CSC populations and suggest a potential for combined inhibition of NF-κB and HDAC signaling for treatment of liver cancer patients with poor prognosis.
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