tbuckley/cabot-search huggingface dataset:
Abstract P071: Metabolic Syndrome Gut Microbial Associations Are Independent Of Country Of Origin: Evidence From African-origin Populations
Authors: Kaavya Adam, Patricia Morrow, Anukriti Sharma, Candice Choo-Kang, Estelle V Lambert, Jacob Plange-Rhule, Kweku Bedu-Addo, Amy Luke, Pascal Bovet, Jack Gilbert, Brian Layden, Lara Dugas
Journal: Circulation (2021)

Introduction: Changes to the overall diversity and relative abundance of the microbiota have been shown to alter not only the functionality of the gut system, in particular with regards to the metabolic rates and levels of pro-inflammatory cytokines, but also the development of disease states such as metabolic syndrome (METS). The purpose of this study was to explore the composition of the gut microbiota diversity, and metabolic outcomes, across three populations: the United States, Ghana and South Africa. Hypothesis: We assessed the hypothesis that differences between the three populations, including variations in diet, would affect the diversity and composition of the microbiome of the participants; these changes would in turn be reflected in the gut-related metabolic outcomes. Methods: Participants(N=560) provided a fecal sample which was analyzed using the analysis of Composition of Microbiome to identify differentially abundant bacterial exact sequence variants (ESVs), and general linearized models (GLM) to test associations between selected ESVs and gut-related metabolic outcomes. Results: Not surprisingly, macronutrient intake was significantly different across the 3 sites (p&lt;0.001), which resulted in differences in the overall microbial diversity (p&lt;0.01) and composition of pro-inflammatory species such as Bacteroides (p&lt;0.01). There were also differences in the relative abundance of ESVs associated with multiple metabolic functional pathways in participants meeting diagnostic criteria for METS. As the number of positive METs criteria increased, there were a significant decline in the proportions of microbiota associated with fatty acid degradation (p = 0.026) and lipid metabolism (p = 0.041). On the other hand, the abundance of organisms participating in the proinflammatory LPS functional pathway were higher in obese participants when compared to age and location matched non-obese participants. Finally, there the difference across countries bacterial diversity was associated with a differential pro-inflammatory LPS abundance (p&lt;0.01). Conclusion: In conclusion, we found that country of origin was significantly associated with bacterial diversity. These differences were associated with alterations in the bacterial functional metabolic and proinflammatory pathways, suggesting a role in cardiovascular health and the development of the METS.
Patient Participation in Clinical Trials of Oncology Drugs and Biologics Preceding Approval by the US Food and Drug Administration
Authors: Nora Hutchinson, Benjamin Carlisle, Adelaide Doussau, Rafia Bosan, Eli Gumnit, Amanda MacPherson, Dean A. Fergusson, Jonathan Kimmelman
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. <h3>Objective</h3> To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. <h3>Design, Setting, and Participants</h3> This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. <h3>Main Outcomes and Measure</h3> The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. <h3>Results</h3> A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). <h3>Conclusions and Relevance</h3> The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.
COVID-19 Pneumonia and ROX index: Time to set a new threshold for patients admitted outside the ICU
Authors: María Laura Vega, Roberto Dongilli, Gustavo Olaizola, Nicolás Colaianni, Mauro Castro Sayat, Lara Pisani, Micaela Romagnoli, Greta Spoladore, Irene Prediletto, Guillermo Montiel, Stefano Nava
Journal: Pulmonology (2021)

High flow nasal cannula (HFNC) is used to treat acute hypoxemic respiratory failure (AHRF) even outside the ICU and the ROX index (pulse oximetry/fraction of inspired oxygen/respiratory rate) may predict HFNC failure. The purpose of this investigation was therefore to verify whether the ROX index is an accurate predictor of HFNC failure for COVID-19 patients treated outside the intensive care unit (ICU) and to evaluate the validity of the previously suggested threshold. Multicenter study. Retrospective observational analysis of prospectively collected data. 3 centres specialized in non-invasive respiratory support (Buenos Aires, Argentina; Bolzano and Treviso, Italy). Patients treated outside the ICU were analysed The variables to calculate the ROX index were collected during the first day of therapy at 2, 6, 12 and 24 hours and then recorded every 24 hours. HFNC failure was defined as escalation of respiratory support to invasive mechanical ventilation (IMV) or death. A total of 35 (29%) patients failed HFNC and required intubation. ROC analysis identified the 12-hour ROX index as the best predictor of intubation with an AUC of 0.7916[CI 95% 0.6905-0.8927] and the best threshold to be 5.99[Specificity 96% Sensitivity 62%]. In the survival analysis, a ROX value <5.99 was associated with an increased risk of failure (p = 0008 log – rank test). The threshold of 4,9 identified by Roca as the best predictor in non-COVID patients, was not able to discriminate between success and failure (p = 0.4 log-rank test) in our patients. ROX index may be useful in guiding the clinicians in their decision to intubate patients, especially in patients with moderate ARF, treated therefore outside the ICU. Indeed, it also demonstrates a different threshold value than reported for non-COVID patients, possibly related to the different mechanisms of hypoxia.
Abstract 17459: Sex Differences in Hypertension Associated With Tobacco and Electronic Cigarette Use
Authors: Mohinder Reddy Vindhyal, Elizabeth Ablah, Hayrettin Okut, Paul M NDUNDA, K James Kallail, Won Choi
Journal: Circulation (2020)

Introduction: Hypertension is one of the leading cardiovascular risk factors, with a prevalence of almost 875 million individuals worldwide. Hypertension prevalence is higher among men than women until after menopause. No studies have determined if there is a relationship between hypertension and the use of electronic cigarettes (E-Cig). This study sought to determine the sex differences in hypertension association with tobacco and E-Cigarette use Methods: National Health Interview Survey Data from years 2014, 2016, 2017 and 2018 were analyzed. Multivariate logistic regression analyses with Fisher’s Scoring iterative algorithm determined the covariate-adjusted and weighted odds ratios of clinical cardiovascular outcomes (i.e. hypertension) and their potential association with use of tobacco or e-cigarettes by sex after controlling for age and body mass index (BMI). Results: A total of 121,705 participants completed the survey and met inclusion criteria of which 66,762 were female users and 54,943 were male users. Female e-cigarette users were 2.23 times more likely (95% CI:1.29 - 3.86, P &lt; 0.05) to report hypertension than those who never used cigarettes or e-cigarettes. Female cigarette smokers were 1.63 times more likely (95% CI: 1.32 – 2.01, P &lt; 0.05), and male cigarette smokers were 1.34 times more likely (95% CI :1.12 -1.60, P &lt; 0.05) to report hypertension than those who never used cigarettes or e-cigarettes. Female and male dual users (of E-Cig and tobacco) had similar odds of 1.40 (95% CI 1.08 -1.83, P &lt; 0.05), and 1.41 (95% CI: 1.13 - 1.77, P &lt; 0.05) to report hypertension than those who never smoked. Discussion: The findings from this study suggest that females reporting current e-cigarette use had the highest odds of reporting hypertension, followed by female tobacco smokers. Both male and female dual users had similar risk of hypertension.
The Autosomal Recessive Cerebellar Ataxias
Authors: Mathieu Anheim, Christine Tranchant, Michel Koenig
Journal: New England Journal of Medicine (2012)

Autosomal recessive cerebellar ataxia must be considered in any child or young adult with a progressive disorder of gait or balance or with hypotonia or excessive clumsiness. This review presents a practical approach to these neurodegenerative diseases.
The microbiome of deep-sea fish reveals new microbial species and a sparsity of antibiotic resistance genes
Authors: Fergus W. J. Collins, Calum J. Walsh, Beatriz Gomez-Sala, Elena Guijarro-García, David Stokes, Klara B. Jakobsdóttir, Kristján Kristjánsson, Finlay Burns, Paul D. Cotter, Mary C. Rea, Colin Hill, R. Paul Ross
Journal: Gut Microbes (2021)

Adaptation to life in the deep-sea can be dramatic, with fish displaying behaviors and appearances unlike those seen in any other aquatic habitat. However, the extent of which adaptations may have developed at a microbial scale is not as clear. Shotgun metagenomic sequencing of the intestinal microbiome of 32 species of deep-sea fish from across the Atlantic Ocean revealed that many of the associated microbes differ extensively from those previously identified in reference databases. 111 individual metagenome-assembled genomes (MAGs) were constructed representing individual microbial species from the microbiomes of these fish, many of which are potentially novel bacterial taxa and provide a window into the microbial diversity in this underexplored environment. These MAGs also demonstrate how these microbes have adapted to deep-sea life by encoding a greater capacity for several cellular processes such as protein folding and DNA replication that can be inhibited by high pressure. Another intriguing feature was the almost complete lack of genes responsible for acquired resistance to known antibiotics in many of the samples. This highlights that deep-sea fish microbiomes may represent one of few animal-associated microbiomes with little influence from human activity. The ability of the microbes in these samples to bioluminesce is lower than expected given predictions that this trait has an important role in their life cycle at these depths. The study highlights the uniqueness, complexity and adaptation of microbial communities living in one of the largest and harshest environments on Earth.
Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of <i>MMP9</i> and <i>ABCG2</i>
Authors: Ying Huang, Shan-He Yu, Wen-Xuan Zhen, Tao Cheng, Dan Wang, Jie-Bo Lin, Yu-Han Wu, Yi-Fan Wang, Yi Chen, Li-Ping Shu, Yi Wang, Xiao-Jian Sun, Yi Zhou, Fan Yang, Chih-Hung Hsu, Peng-Fei Xu
Journal: Theranostics (2021)

Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases.
Abstract 15607: Right Atrial Reservoir Strain Predicts Survival in Patients With Cardiac Amyloidosis
Authors: Peter Huntjens, Kathleen Zhang, Yuko Soyama, Maria Karmpalioti, Daniel Lenihan, John Gorcsan
Journal: Circulation (2020)

Introduction: Myofibril deposition in amyloidosis diffusely may affect cardiac structure and function. Right ventricular involvement has been associated with adverse clinical outcome. However, the utility of right atrial (RA) function assessment by echocardiographic strain imaging is unclear. Hypothesis: We hypothesize that right atrial stain has prognostic value in cardiac amyloidosis. Methods: We studied 121 consecutive patients with cardiac amyloidosis: 18% had transthyretin and 79% had light chain amyloidosis. Cardiac amyloidosis was either confirmed by endocardial biopsy (36%) or by a combination of non-cardiac tissue biopsy and proof of left ventricular hypertrophy (64%). Speckle tracking peak RA reservoir strain was assessed based on 6 segments from the apical 4-chamber view. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic peak longitudinal RA strain was feasible in 109 patients (90%). 60 CA patients died during follow-up period. Peak longitudinal RA strain was reduced in cardiac amyloidosis non-survivors (8.1%) in comparison to survivors (18.3%, p&lt;0.01), showing RA involvement in cardiac amyloidosis. Peak RA strain was significantly associated with survival (using median 12.5%) (p&lt;0.001). Low peak longitudinal RA strain was associated with a 3.3-fold increase in mortality risk (95% confidence interval: 1.83 - 5.96). Conclusions: Reduced peak longitudinal RA strain was significantly associated with survival in patients with cardiac amyloidosis. RA reservoir function assessed by strain appears to be useful as a new means to predict prognosis in cardiac amyloidosis patients and has promise for clinical application.
The Evolution Pathway of Ammonia-Oxidizing Archaea Shaped by Major Geological Events
Authors: Yiyan Yang, Chuanlun Zhang, Timothy M Lenton, Xinmiao Yan, Maoyan Zhu, Mengdi Zhou, Jianchang Tao, Tommy J Phelps, Zhiwei Cao
Journal: Molecular Biology and Evolution (2021)

Abstract Primordial nitrification processes have been studied extensively using geochemical approaches, but the biological origination of nitrification remains unclear. Ammonia-oxidizing archaea (AOA) are widely distributed nitrifiers and implement the rate-limiting step in nitrification. They are hypothesized to have been important players in the global nitrogen cycle in Earth’s early history. We performed systematic phylogenomic and marker gene analyses to elucidate the diversification timeline of AOA evolution. Our results suggested that the AOA ancestor experienced terrestrial geothermal environments at ∼1,165 Ma (1,928–880 Ma), and gradually evolved into mesophilic soil at ∼652 Ma (767–554 Ma) before diversifying into marine settings at ∼509 Ma (629–412 Ma) and later into shallow and deep oceans, respectively. Corroborated by geochemical evidence and modeling, the timing of key diversification nodes can be linked to the global magmatism and glaciation associated with the assembly and breakup of the supercontinent Rodinia, and the later oxygenation of the deep ocean. Results of this integrated study shed light on the geological forces that may have shaped the evolutionary pathways of the AOA, which played an important role in the ancient global nitrogen cycle.
Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study
Authors: Ute Spiekerkoetter, Maria L Couce, Anibh M Das, Corinne de Laet, Carlo Dionisi-Vici, Allan M Lund, Manuel Schiff, Marco Spada, Erik Sparve, Johan Szamosi, Roshni Vara, Mattias Rudebeck
Journal: The Lancet Diabetes & Endocrinology (2021)
Abstract P135: Dietary Sources Of Linoleic Acid (LA) Differ By Race/ethnicity In Adults Participating In The National Health And Nutrition Examination Survey (NHANES) Between 2015-2016
Authors: Shabnam R Momin, Ani Manichaikul, Rasika Mathias, Mackenzie Senn, Mimi Phan, Lindsay M Reynolds, Stephen S Rich, Susan Sergeant, Michael C Seeds, Chaojie Yang, Floyd H Chilton, Alexis C Wood
Journal: Circulation (2021)

Background: Linoleic acid (LA), a primary polyunsaturated fatty acid, is a nutritional quandary as has been associated with diabetes and cardiovascular disease (CVD) protection but may have negative effects in inflammation and cancer. Objective: To determine whether the relative contributions of nine food sources (dairy, eggs, select fats and oils, fish, fruit, grains, meat, nuts, and desserts) to overall LA intake differ by race / ethnicity in the adult US population. Methods: We included all non-pregnant, non-lactating adults (&lt; 20 years, ~50% female) with plausible dietary data (average daily caloric intake ≥600 kcals/day and ≤6000 kcals/day; N=3,884). The percentage of LA calories attributable from each of the nine food groups was calculated. Linear regression models, incorporating survey weights, examined differences by race/ethnicity and included age, gender, income level, highest level of education and daily caloric intake as covariates, with a post-hoc Tukey test applied to group comparison. Significance was set at Bonferroni corrected P≤.006. Results: Across the population as a whole, 7.14% of the overall caloric intake was attributable to LA. Grains contributed to the highest percentage of LA intake (29%) followed by meat (18%), with fish contributing the least (4%). Significant differences in the relative contribution of almost all food sources to overall LA were found across race/ethnic groups (all except dairy; Table 1). Fruits and Grains showed the greatest number of differences by race/ethnicity, with NHBs reporting the greatest intake contribution of fruit to LA intake (14.8%) and MAs the lowest (9.6%; P&lt;.001 for the difference; Table 1). This pattern was reversed when looking at the contribution of grains to overall LA intake (25.9% vs 41.2% respective; P&lt;.001; Table 1). Conclusions: Our findings suggest that the foods contributing to overall LA intake differ across race/ethnic groups. Interventions designed to alter LA intake may benefit from tailoring to a population’s ethnic/race distribution.
Abstract P142: Metabolically Healthy Obesity In A Young Adult Population Provided By A Primary Healthcare Center In Brazil (LAPARC Study)
Authors: Beatriz D Marinho, Tomás de Souza Mello, Rafael B Azevedo, Daniella Barbalho, Clara Muguet, Natalia Ushijima, Flávia Libório, Rodrigo Borges, Ludmilla F Aragão, Ana Cristina Fernandes, Elizabeth Muxfeldt
Journal: Circulation (2021)

Background: Obesity is increasing in younger populations, and is associated with a high cardiovascular (CV) risk, however, it is not clear whether metabolically healthy obesity (MHO) may have a lower CV risk or if it is just an earlier stage of the disease. Objective: To evaluate the prevalence and CV risk factors associated with MHO in a young adult population provided by a Primary Healthcare Center in a large urban area of Brazil. Methods: A cross-sectional population study for CV risk assessment in adults aged 20-50 years old provided by a Primary Healthcare Center in Rio de Janeiro, Brazil. Demographic, anthropometric data and CV risk factors were recorded. All underwent office blood pressure (OBP) measurements, laboratory evaluation (lipid and glycemic profile). Obesity was defined as a BMI ≥ 30 kg/m2 and MHO are those who have less than 3 of the following criteria: hypertension, diabetes, total cholesterol ≥ 200 mg/dL, HDL&lt;40 mg/dL (men) and 50 mg/dL (women), triglycerides&gt;150 mg/dL and increased waist circumference. Results: A total of 632 individuals were evaluated (60% female; mean age 37 ± 9 years). The prevalence of obesity was 25% (161 of 632 individuals), of which 73% (117 of 161 individuals) were classified as MHO. Obese individuals are older, with a higher prevalence of physical inactivity (51% vs 41%, p=0.03), hypertension (44% vs 19%, p&lt;0.001), dyslipidemia (50% vs 36%, p=0.002) and diabetes (7% vs 2%, p=0.001) with higher systolic OBP. MHO compared to unhealthy ones are significantly younger and smoke less. Despite being obese, they have lower BMI (33.6 vs 35.2 kg/m2, p=0.02) and abdominal circumference (102 vs 110 cm, p=0.03), with lower diastolic BP. Conclusions: MHO was more prevalent in this young adult population and seems to have a lower CV risk, however it is not clear whether these younger and less obese individuals are only at an earlier stage of the disease. Perhaps the CV diseases onset is postponed for a few years. Even so, these individuals should not be excluded from public health policies as a form of primary prevention.