Nearly one-third of patients with high-grade serous ovarian cancer (HGSC) do not respond to initial treatment with platinum-based therapy. Genomic and clinical characterization of these patients may ...lead to potential alternative therapies. Here, the objective is to classify non-responders into subsets using clinical and molecular features. Using patients from The Cancer Genome Atlas (TCGA) dataset with platinum-resistant or platinum-refractory HGSC, we performed a genome-wide unsupervised cluster analysis that integrated clinical data, gene copy number variations, gene somatic mutations, and DNA promoter methylation. Pathway enrichment analysis was performed for each cluster to identify the targetable processes. Following the unsupervised cluster analysis, three distinct clusters of non-responders emerged. Cluster 1 had overrepresentation of the stage IV disease and suboptimal debulking, under-expression of miRNAs and mRNAs, hypomethylated DNA, "loss of function"
mutations, and the overexpression of genes in the
pathway. Cluster 2 had low miRNA expression, generalized hypermethylation,
mutations, and significant activation of the HIF-1 signaling pathway. Cluster 3 had more optimally cytoreduced stage III patients, overexpression of miRNAs, mixed methylation patterns, and "gain of function"
mutations. However, the survival for all clusters was similar. Integration of genomic and clinical data from patients that do not respond to chemotherapy has identified different subgroups or clusters. Pathway analysis further identified the potential alternative therapeutic targets for each cluster.
To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants.
Preterm infants in the discovery cohort were enrolled ...through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis.
Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 × 10(-5)) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P = 2.9 × 10(-7)).
Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.
Lorcaserin, a selective serotonin 2C receptor agonist, is an effective pharmacologic weight-loss therapy that improves several cardiovascular risk factors. The long-term clinical cardiovascular and ...metabolic safety and efficacy in patients with elevated cardiovascular risk are unknown.
CAMELLIA-TIMI 61 (NCT02019264) is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the safety and efficacy of lorcaserin with regard to major adverse cardiovascular events and progression to diabetes in overweight or obese patients at high cardiovascular risk. Overweight or obese patients either with established cardiovascular disease or with diabetes and at least 1 other cardiovascular risk factor were randomized in a 1:1 ratio to lorcaserin 10 mg twice daily or matching placebo. The primary safety objective is to assess for noninferiority of lorcaserin for the composite end point of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular event MACE) (with noninferiority defined as the upper bound of a 1-sided 97.5% CI excluding a hazard ratio of 1.4) compared with placebo assessed at an interim analysis with 460 adjudicated events. The efficacy objectives, assessed at study completion, will evaluate the superiority of lorcaserin for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+) and the key secondary end point of conversion to diabetes. Recruitment began in January 2014 and was completed in November 2015 resulting in a total population of 12,000 patients. The trial is planned to continue until at least 1,401 adjudicated MACE+ events are accrued and the median treatment duration exceeds 2.5 years.
CAMELLIA-TIMI 61 is investigating the safety and efficacy of lorcaserin for MACEs and conversion to diabetes in overweight or obese patients with established cardiovascular disease or multiple cardiovascular risk factors.
A global test of ecoregions Smith, Jeffrey R; Letten, Andrew D; Ke, Po-Ju ...
Nature ecology & evolution,
12/2018, Letnik:
2, Številka:
12
Journal Article
Recenzirano
A foundational paradigm in biological and Earth sciences is that our planet is divided into distinct ecoregions and biomes demarking unique assemblages of species. This notion has profoundly ...influenced scientific research and environmental policy. Given recent advances in technology and data availability, however, we are now poised to ask whether ecoregions meaningfully delimit biological communities. Using over 200 million observations of plants, animals and fungi we show compelling evidence that ecoregions delineate terrestrial biodiversity patterns. We achieve this by testing two competing hypotheses: the sharp-transition hypothesis, positing that ecoregion borders divide differentiated biotic communities; and the gradual-transition hypothesis, proposing instead that species turnover is continuous and largely independent of ecoregion borders. We find strong support for the sharp-transition hypothesis across all taxa, although adherence to ecoregion boundaries varies across taxa. Although plant and vertebrate species are tightly linked to sharp ecoregion boundaries, arthropods and fungi show weaker affiliations to this set of ecoregion borders. Our results highlight the essential value of ecological data for setting conservation priorities and reinforce the importance of protecting habitats across as many ecoregions as possible. Specifically, we conclude that ecoregion-based conservation planning can guide investments that simultaneously protect species-, community- and ecosystem-level biodiversity, key for securing Earth's life support systems into the future.
IMPORTANCE: In response to calls to reduce unnecessary diagnostic testing with computed tomographic pulmonary angiography (CTPA) for suspected pulmonary embolism (PE), there have been growing efforts ...to create and implement decision rules for PE testing. It is unclear if the use of advanced imaging tests for PE has diminished over time. OBJECTIVE: To assess the use of advanced imaging tests, including chest computed tomography (CT) (ie, all chest CT except for CTPA), CTPA, and ventilation-perfusion (V/Q) scan, for PE from 2004 to 2016. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of adults by age group (18-64 years and ≥65 years) enrolled in 7 US integrated and mixed-model health care systems. Joinpoint regression analysis was used to identify years with statistically significant changes in imaging rates and to calculate average annual percentage change (growth) from 2004 to 2007, 2008 to 2011, and 2012 to 2016. Analyses were conducted between June 11, 2019, and March 18, 2020. MAIN OUTCOMES AND MEASURES: Rates of chest CT, CTPA, and V/Q scan by year and age, as well as annual change in rates over time. RESULTS: Overall, 3.6 to 4.8 million enrollees were included each year of the study, for a total of 52 343 517 person-years of follow-up data. Adults aged 18 to 64 years accounted for 42 223 712 person-years (80.7%) and those 65 years or older accounted for 10 119 805 person-years (19.3%). Female enrollees accounted for 27 712 571 person-years (52.9%). From 2004 and 2016, chest CT use increased by 66.3% (average annual growth, 4.4% per year), CTPA use increased by 450.0% (average annual growth, 16.3% per year), and V/Q scan use decreased by 47.1% (decreasing by 4.9% per year). The use of CTPA increased most rapidly from 2004 to 2006 (44.6% in those aged 18-64 years and 43.9% in those ≥65 years), with ongoing rapid growth from 2006 to 2010 (annual growth, 19.8% in those aged 18-64 years and 18.3% in those ≥65 years) and persistent but slower growth in the most recent years (annual growth, 4.3% in those aged 18-64 years and 3.0% in those ≥65 years from 2010 to 2016). The use of V/Q scanning decreased steadily since 2004. CONCLUSIONS AND RELEVANCE: From 2004 to 2016, rates of chest CT and CTPA for suspected PE continued to increase among adults but at a slower pace in more contemporary years. Efforts to combat overuse have not been completely successful as reflected by ongoing growth, rather than decline, of chest CT use. Whether the observed imaging use was appropriate or was associated with improved patient outcomes is unknown.
Tobacco smoking and cannabis use are independently associated with depression, and evidence suggests that people who use both tobacco and cannabis (co-consumers) are more likely to report mental ...health problems, greater nicotine dependence and alcohol misuse than those who use either product exclusively. We examined prevalence of cannabis use and depressive symptoms among Canadian adults who smoke cigarettes and tested whether co-consumers of cannabis and tobacco were more likely to report depressive symptoms than cigarette-only smokers; we also tested whether cigarette-only smokers and co-consumers differed on cigarette dependence measures, motivation to quit smoking and risky alcohol use by the presence or absence of depressive symptoms.
We analyzed cross-sectional data from adult (age ≥ 18 yr) current (≥ monthly) cigarette smokers from the Canadian arm of the 2020 International Tobacco Control Policy Evaluation Project Four Country Smoking and Vaping Survey. Canadian respondents were recruited from Leger's online probability panel across all 10 provinces. We estimated weighted percentages for depressive symptoms and cannabis use among all respondents and tested whether co-consumers (≥ monthly use of cannabis and cigarettes) were more likely to report depressive symptoms than cigarette-only smokers. Weighted multivariable regression models were used to identify differences between co-consumers and cigarette-only smokers with and without depressive symptoms.
A total of 2843 current smokers were included in the study. The prevalence of past-year, past-30-day and daily cannabis use was 44.0%, 33.2% and 16.1%, respectively (30.4% reported using cannabis at least monthly). Among all respondents, 30.0% screened positive for depressive symptoms, with co-consumers being more likely to report depressive symptoms (36.5%) than those who did not report current cannabis use (27.4%,
< 0.001). Depressive symptoms were associated with planning to quit smoking (
= 0.01), having made multiple attempts to quit smoking (
< 0.001), the perception of being very addicted to cigarettes (
< 0.001) and strong urges to smoke (
= 0.001), whereas cannabis use was not (all
≥ 0.05). Cannabis use was associated with high-risk alcohol consumption (
< 0.001), whereas depressive symptoms were not (
= 0.1).
Co-consumers were more likely to report depressive symptoms and high-risk alcohol consumption; however, only depression, and not cannabis use, was associated with greater motivation to quit smoking and greater perceived dependence on cigarettes. A deeper understanding of how cannabis, alcohol use and depression interact among people who smoke cigarettes is needed, as well as how these factors affect cessation activity over time.
The neuromuscular blocking drugs rocuronium and vecuronium are often used during general anesthesia. These drugs temporarily paralyze the patient and thus both facilitate placement of an endotracheal ...tube and prevent any patient movement during surgery. Reversal of neuromuscular blockade is necessary at the end of surgery to avoid postoperative weakness and adverse respiratory events in the recovery room. Neostigmine, the traditional reversal agent, may not completely restore muscle strength. Sugammadex is a reversal agent that is more effective and quicker acting than neostigmine. In adults, sugammadex administration has rarely been associated with bradycardia and cardiac arrest. In healthy children, the bradycardia that occurs after sugammadex administration is benign and does not require intervention. There is 1 case report of a 10- to 15-second bradycardic arrest after sugammadex administration to a 10-year-old child with heart disease. The present case report describes an 8-month-old child with complex congenital heart disease who experienced a 10-minute bradycardic arrest after the administration of sugammadex. Pediatric anesthesiologists should be aware that sugammadex administration to children with heart disease may cause hemodynamically significant bradycardia.
The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the ‘Pubmed Era’. Recent neuroimaging studies ...have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer's disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer's Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (
N
=
234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (
N
=
50) or without (
N
=
89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical–radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2.
Despite the high cannabis use rates among sexual minority (SM) individuals, less research has examined factors related to cannabis use among SM (vs. heterosexual) individuals, especially in places ...with legal medical cannabis retail markets and high structural stigma, like Oklahoma.
Data were from a survey of Oklahoma adults, including 3020 females (18.6% SM) and 2279 males (10.1% SM). Bivariate analyses examined associations of sexual identity with cannabis-related factors (i.e., perceived harm, positive attitudes, marketing exposure, depressive symptoms, anxiety symptoms) and cannabis use and use severity (i.e., past 30-day use, daily/near-daily use, cannabis use disorder CUD symptoms). Logistic regression examined associations of sexual identity and cannabis-related factors with cannabis use and use severity among females and males, separately.
SM (vs. heterosexual) females reported greater odds of past 30-day cannabis use and daily/near-daily use, lower harm perceptions, greater marketing exposure, and higher rates of depressive/anxiety symptoms. Lower harm perceptions and greater marketing exposure were associated with greater odds of past 30-day use, whereas marketing exposure was associated with greater odds of daily/near-daily use. SM (vs. heterosexual) males reported greater odds of daily/near-daily use and higher rates of depressive/anxiety symptoms.
SM (vs. heterosexual) females reported higher rates of cannabis use, whereas SM (vs. heterosexual) females and males reported higher rates of daily/near-daily cannabis use. Potential targets for cannabis-related health campaigns aimed at reducing use differences include correcting misinterpretations of harm that may emanate from cannabis marketing efforts among females and addressing depressive symptoms among males.
Toward the future goal of creating a lung surgery system featuring multiple tentacle-like robots, we present a new folding concept for continuum robots that enables them to squeeze through openings ...smaller than the robot's nominal diameter (e.g., the narrow space between adjacent ribs). This is facilitated by making the disks along the robot's backbone foldable. We also demonstrate that such a robot can feature not only straight, but also curved tendon routing paths, thereby achieving a diverse family of conformations. We find that the foldable robot performs comparably, from a kinematic perspective, to an identical non-folding continuum robot at varying deployment lengths. This work paves the way for future applications with a continuum robot that can fold and fit through smaller openings, with the potential to reduce invasiveness during surgical tasks.
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