Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)(1). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%

Breakthrough SARS-CoV-2 infections among patients with cancer following two and three doses of COVID-19 mRNA vaccines: a retrospective observational study from the COVID-19 and Cancer Consortium

BACKGROUND: Breakthrough SARS-CoV-2 infections following vaccination against COVID-19 are of international concern. Patients with cancer have been observed to have worse outcomes associated with COVID-19 during the pandemic. We sought to evaluate the clinical characteristics and outcomes of patients with cancer who developed breakthrough SARS-CoV-2 infections after 2 or 3 doses of mRNA vaccines. METHODS: We evaluated the clinical characteristics of patients with cancer who developed breakthrough infections using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19; NCT04354701). Analysis was restricted to patients with laboratory-confirmed SARS-CoV-2 diagnosed in 2021 or 2022, to allow for a contemporary unvaccinated control population; potential differences were evaluated using a multivariable logistic regression model after inverse probability of treatment weighting to adjust for potential baseline confounding variables. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported. The primary endpoint was 30-day mortality, with key secondary endpoints of hospitalization and ICU and/or mechanical ventilation (ICU/MV). FINDINGS: The analysis included 2486 patients, of which 564 and 385 had received 2 or 3 doses of an mRNA vaccine prior to infection, respectively. Hematologic malignancies and recent receipt of systemic anti-neoplastic therapy were more frequent among vaccinated patients. Vaccination was associated with improved outcomes: in the primary analysis, 2 doses (aOR: 0.62, 95% CI: 0.44-0.88) and 3 doses (aOR: 0.20, 95% CI: 0.11-0.36) were associated with decreased 30-day mortality. There were similar findings for the key secondary endpoints of ICU/MV (aOR: 0.60, 95% CI: 0.45-0.82 and 0.37, 95% CI: 0.24-0.58) and hospitalization (aOR: 0.60, 95% CI: 0.48-0.75 and 0.35, 95% CI: 0.26-0.46) for 2 and 3 doses, respectively. Importantly, Black patients had higher rates of hospitalization (aOR: 1.47, 95% CI: 1.12-1.92), and Hispanic patients presented with higher rates of ICU/MV (aOR: 1.61, 95% CI: 1.06-2.44). INTERPRETATION: Vaccination against COVID-19, especially with additional doses, is a fundamental strategy in the prevention of adverse outcomes including death, among patients with cancer. FUNDING: This study was partly supported by grants from the National Cancer Institute grant number P30 CA068485 to C-YH, YS, SM, JLW; T32-CA236621 and P30-CA046592 to C.R.F; CTSA 2UL1TR001425-05A1 to TMW-D; ACS/FHI Real-World Data Impact Award, P50 MD017341-01, R21 CA242044-01A1, Susan G. Komen Leadership Grant Hunt to MKA. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH)

COVID-19 Severity and Cardiovascular Outcomes in SARS-CoV-2-Infected Patients With Cancer and Cardiovascular Disease

BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all CONCLUSIONS: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701)

The dihydro-beta-agarofuran sesquiterpenoids

Dihydro-Beta-agarofuran sesquiterpenoids are a structurally diverse class of natural products based on tricyclic 5,11-epoxy-5Beta,10alpha-eudesman-4-(14)-ene skeleton. Between January 1990 and June 2006, 462 new dihydro-Beta-agarofuran sesquiterpenoids of 74 structural types have been isolated from about 64 species of Celastraceae, 3 species of Hippocrateaceae and one species of Lamiaceae. The present review covers the chemical and biological activity research of dihydro-Beta-agarofuran sesquiterpenoids in the past 16 years. The chemical research includes structural classification into sesquiterpene polyesters and macrolide sesquiterpene pyridine alkaloids, synthesis of dihydro-Beta-agarofuran as well as extraction, isolation and purification methods. The biological activity research includes activities such as multidrug resistance (MDR) reversal activity, HIV inhibition, cytotoxicity, antitumor activity, antifeedant activity and insecticidal activity with some insights to their modes of actionsNRC publication: Ye

Transfer Among Phonological Tasks in Kindergarten: Essential Instructional Content

The construct of phonological awareness was explored by examining the effects of instructional treatments on the development of specific and generalized phonological skills for kindergarten children. Sixty-six children with low phonological manipulation skills were randomly assigned to 1 of 2 treatments or a control condition: (a) auditory blending and segmenting with limited letter–sound correspondences; (b) a global array of phonological tasks, with letter–sound correspondences; or (c) only letter–sound instruction. Children in both treatments showed improved phonological abilities, which transferred to a reading analog task. Treated children achieved a level of phonological awareness comparable to that of higher skilled children. The combination of blending and segmenting instruction encouraged generalized phonological awareness; however, the ability to blend and segment accounted for more variance in reading analog scores than did other phonological tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved

Teaching Phonological Awareness to Young Children with Learning Disabilities

This study examined the feasibility of teaching phonological manipulation skills to preschool children with disabilities. Forty-seven children, 4-6 years old, enrolled in a special education preschool, were randomly assigned to receive training in one of three categories of phonological tasks (rhyming, blending, and segmenting) or a control group. Results indicated that children were able to make significant progress in each experimental category, but that they demonstrated little or no generalization either within a category (e.g., from one type of blending task to another type of blending task) or between categories (e.g., from blending to segmenting). Although the children\u27s level of cognitive development significantly predicted some learning outcomes, it did not appear to limit the learning of phonological tasks

Role of inflammatory markers in Takayasu arteritis disease monitoring

BACKGROUND: Takayasu arteritis (TA) is an idiopathic large-vessel vasculitis that can result in significant morbidity and mortality secondary to progressive stenosis and occlusion. Monitoring disease progression is crucial to preventing relapse, but is often complicated by the lack of clinical symptoms in the setting of active disease. Although acute phase reactants such as ESR and CRP are generally used as an indicator of inflammation and disease activity, mounting evidence suggests that these markers cannot reliably distinguish active from inactive TA. CASE PRESENTATION: We report a 24-year-old Hispanic female with a 5-year history of TA who presented with stroke-like symptoms and evidence of left MCA occlusion on imaging, despite a history of decreasing inflammatory markers. CTA revealed complete occlusion of the left common carotid artery, left subclavian, and left MCA from their origins. It also revealed a striking compensatory circulation supplying the left anterior circulation as well as the left subclavian as a response to progressive stenosis. CONCLUSION: Monitoring ESR and CRP levels alone may not be a reliable method to evaluate disease progression in patients with TA, and should be taken in context with both patient\u27s clinical picture and the imaging. We recommend that serial imaging be performed regularly in the setting of active disease to monitor progression and allow for immediate therapy in response to evidence of disease advancement, with a relaxation of the imaging interval once the disease is presumed inactive

Role of inflammatory markers in Takayasu arteritis disease monitoring

BACKGROUND: Takayasu arteritis (TA) is an idiopathic large-vessel vasculitis that can result in significant morbidity and mortality secondary to progressive stenosis and occlusion. Monitoring disease progression is crucial to preventing relapse, but is often complicated by the lack of clinical symptoms in the setting of active disease. Although acute phase reactants such as ESR and CRP are generally used as an indicator of inflammation and disease activity, mounting evidence suggests that these markers cannot reliably distinguish active from inactive TA. CASE PRESENTATION: We report a 24-year-old Hispanic female with a 5-year history of TA who presented with stroke-like symptoms and evidence of left MCA occlusion on imaging, despite a history of decreasing inflammatory markers. CTA revealed complete occlusion of the left common carotid artery, left subclavian, and left MCA from their origins. It also revealed a striking compensatory circulation supplying the left anterior circulation as well as the left subclavian as a response to progressive stenosis. CONCLUSION: Monitoring ESR and CRP levels alone may not be a reliable method to evaluate disease progression in patients with TA, and should be taken in context with both patient\u27s clinical picture and the imaging. We recommend that serial imaging be performed regularly in the setting of active disease to monitor progression and allow for immediate therapy in response to evidence of disease advancement, with a relaxation of the imaging interval once the disease is presumed inactive

Improving data driven decision making through integration of environmental sensing technologies

Coastal and estuarine zones contain vital and increasingly exploited resources. Traditional uses in these areas (transport, fishing, tourism) now sit alongside more recent activities (mineral extraction, wind farms). However, protecting the resource base upon which these marine-related economic and social activities depend requires access to reliable and timely data. This requires both acquisition of background (baseline) data and monitoring impacts of resource exploitation on aquatic processes and the environment. Management decisions must be based on analysis of collected data to reduce negative impacts while supporting resource-efficient, environmentally sustainable uses. Multi-modal sensing and data fusion offer attractive possibilities for providing such data in a resource efficient and robust manner. In this paper, we report the results of integrating multiple sensing technologies, including autonomous multi-parameter aquatic sensors with visual sensing systems. By focussing on salinity measurements, water level and freshwater influx into an estuarine system; we demonstrate the potential of modelling and data mining techniques in allowing deployment of fewer sensors, with greater network robustness. Using the estuary of the River Liffey in Dublin, Ireland, as an example, we present the outputs and benefits resulting from fusion of multi-modal sensing technologies to predict and understand freshwater input into estuarine systems and discuss the potential of multi-modal datasets for informed management decisions

Spectroscopic and Electrochemical Properties of (\u3cem\u3eμ\u3c/em\u3e-Oxo)diiron(III) Complexes Related to Diiron-Oxo Proteins. Structure of [Fe\u3csub\u3e2\u3c/sub\u3eO(TPA)\u3csub\u3e2\u3c/sub\u3e(MoO)\u3csub\u3e4\u3c/sub\u3e)](ClO\u3csub\u3e4\u3c/sub\u3e)\u3csub\u3e2\u3c/sub\u3e

A series of (μ-oxo)diiron(III) complexes of tris(2-pyridylmethy1)amine (TPA), [Fe2O(TPA)2(L)] (C1O4)2, were synthesized and characterized where L represents the bridging tetraoxo anion ligands sulfate, phosphate, arsenate, vanadate, and molybdate. These tetraoxo anion complexes are the first (μ-oxo)diiron(III) complexes that reproduce the protein-tetraoxo anion stoichiometry found in purple acid phosphatases (PAPs). [Fe2O(TPA)2( MoO4)] (C104)2- CH3N (9) crystallizes in the monoclinic space group P21/n (a = 12.74(1) Å, b = 24.69(2) Å, c = 13.733(8) Å, β = 103.41 (7)°, and Z = 4) and consists of two distinct six-coordinate Fe(II1) centers bridged by oxo and molybdate. 9 represents the first (μ-oxo)diiron(III) complex with a single bridging molybdate to be structurally characterized. These new complexes together with previously reported (μ-oxo)diiron(III) TPA complexes constitute a series with a wide range of Fe-μ-0-Fe angles and bridging anion basicities which affect their electronic absorption, resonance Raman, and electrochemical properties. A linear correlation between the Raman vs(FeO-Fe) mode and the energy of the long-wavelength visible absorption band provides a method in which UV-vis spectroscopy can be used to estimate the Fe-O-Fe angle. The electrochemical properties of these complexes show the expected dependence on charge and basicity and thus serve as a basis on which to interpret the redox properties of diiron-xo proteins, particularly uteroferrin, the purple acid phosphatase from porcine uterus. Comparison of the electrochemical properties of the phosphate, arsenate ,and molybdate complexes in the (μ-oxo)diiron(III) TPA series with those of corresponding complexes of uteroferrin suggests that both phosphate and arsenate bridge the diiron core in uteroferrin, while molybdate must bind only to the redox inactive Fe(II1) center. The mixed-valent forms of several of these complexes exhibit EPR signals with gaav \u3c 2, like those observed for the mixed-valent diiron enzymes but with smaller g anisotropies