17 research outputs found

    Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism

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    Neuroticism is a relatively stable personality trait characterized by negative emotionality (for example, worry and guilt)1; heritability estimated from twin studies ranges from 30 to 50%2, and SNP-based heritability ranges from 6 to 15%3,4,5,6. Increased neuroticism is associated with poorer mental and physical health7,8, translating to high economic burden9. Genome-wide association studies (GWAS) of neuroticism have identified up to 11 associated genetic loci3,4. Here we report 116 significant independent loci from a GWAS of neuroticism in 329,821 UK Biobank participants; 15 of these loci replicated at P < 0.00045 in an unrelated cohort (N = 122,867). Genetic signals were enriched in neuronal genesis and differentiation pathways, and substantial genetic correlations were found between neuroticism and depressive symptoms (rg = 0.82, standard error (s.e.) = 0.03), major depressive disorder (MDD; rg = 0.69, s.e. = 0.07) and subjective well-being (rg = –0.68, s.e. = 0.03) alongside other mental health traits. These discoveries significantly advance understanding of neuroticism and its association with MDD

    Genetic contributions to two special factors of neuroticism are associated with affluence, higher intelligence, better health, and longer life

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    Higher scores on the personality trait of neuroticism, the tendency to experience negative emotions, are associated with worse mental and physical health. Studies examining links between neuroticism and health typically operationalize neuroticism by summing the items from a neuroticism scale. However, neuroticism is made up of multiple heterogeneous facets, each contributing to the effect of neuroticism as a whole. A recent study showed that a 12-item neuroticism scale described one broad trait of general neuroticism and two special factors, one characterizing the extent to which people worry and feel vulnerable, and the other characterizing the extent to which people are anxious and tense. This study also found that, although individuals who were higher on general neuroticism lived shorter lives, individuals whose neuroticism was characterized by worry and vulnerability lived longer lives. Here, we examine the genetic contributions to the two special factors of neuroticism—anxiety/tension and worry/vulnerability—and how they contrast with that of general neuroticism. First, we show that, whereas the polygenic load for neuroticism is associated with the genetic risk of coronary artery disease, lower intelligence, lower socioeconomic status (SES), and poorer self-rated health, the genetic variants associated with high levels of anxiety/tension, and high levels of worry/vulnerability are associated with genetic variants linked to higher SES, higher intelligence, better self-rated health, and longer life. Second, we identify genetic variants that are uniquely associated with these protective aspects of neuroticism. Finally, we show that different neurological pathways are linked to each of these neuroticism phenotypes.</p

    Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

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    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (P = 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association

    Genetic prediction of male pattern baldness

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    Male pattern baldness can have substantial psychosocial effects, and it has been phenotypically linked to adverse health outcomes such as prostate cancer and cardiovascular disease. We explored the genetic architecture of the trait using data from over 52,000 male participants of UK Biobank, aged 40-69 years. We identified over 250 independent genetic loci associated with severe hair loss (P<5x10-8). By splitting the cohort into a discovery sample of 40,000 and target sample of 12,000, we developed a prediction algorithm based entirely on common genetic variants that discriminated (AUC = 0.78, sensitivity = 0.74, specificity = 0.69, PPV = 59%, NPV = 82%) those with no hair loss from those with severe hair loss. The results of this study might help identify those at greatest risk of hair loss, and also potential genetic targets for intervention

    Double-Carbapenem Therapy for Carbapenemase-Producing Klebsiella pneumoniae▿

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    The limited treatment options available for carbapenemase-producing Klebsiella pneumoniae (KPC) have made it a formidable pathogen. Previously we have shown the enhanced activity of pharmacodynamically optimized doripenem against KPC. Capitalizing on KPC's increased affinity for ertapenem, we evaluated the efficacy of a combination of ertapenem and doripenem in both an in vitro chemostat and an in vivo murine thigh infection model. Overall, the combination of doripenem plus ertapenem demonstrated enhanced efficacy over either agent alone

    In Vivo Efficacy of Simulated Human Dosing Regimens of Prolonged-Infusion Doripenem against Carbapenemase- Producing Klebsiella pneumoniae▿

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    Carbapenemase-producing Klebsiella pneumoniae (KPC) bacteria are rapidly becoming one of the most detrimental drug-resistant Gram-negative pathogens. Doripenem is the newest FDA-approved carbapenem that has the greatest in vitro potency against a wide range of Gram-negative organisms, including multidrug-resistant organisms. Previous work in an animal model has shown efficacy against Pseudomonas aeruginosa with MICs above the current breakpoints of susceptibility. The purpose of this study is to evaluate the efficacy of 1-g and 2-g dose prolonged infusions of doripenem against KPC isolates in both an immunocompetent and neutropenic murine thigh model. Seven clinical KPC isolates (broth microdilution [BMD] MIC range, 4 to 32 μg/ml; Etest MIC range, 3 to >32 μg/ml) were used. After infection, groups of mice were administered doripenem doses previously shown to simulate the exposures observed in humans after the administration of 1 or 2 g every 8 h as a 4-h infusion. In immunocompromised mice, 1- and 2-g doses of doripenem achieved bacteriostasis against isolates with MICs up to and including 8 μg/ml and 16 μg/ml, respectively. In immunocompetent animals, statistically significant reductions in the number of CFU were observed with overall decreases of approximately 1 log (P < 0.05). While carbapenemase-producing Klebsiella pneumoniae continues to decrease our meager supply of active agents, the ability of doripenem to produce CFU reductions in the presence of white blood cells (WBCs) using humanized exposures suggests the potential utility of this agent in combination against this increasingly problematic pathogen

    In Vivo Efficacy of 1- and 2-Gram Human Simulated Prolonged Infusions of Doripenem against Pseudomonas aeruginosa▿

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    Doripenem is a new carbapenem antimicrobial with activity against a range of gram-negative organisms, including Pseudomonas aeruginosa. Previous animal studies have shown efficacy of a 500-mg dose of doripenem given as a 4-h infusion against P. aeruginosa with MICs of ≤4 μg/ml. The purpose of this study is to evaluate the efficacy of 1- and 2-g-dose prolonged infusions of doripenem against a wide range of P. aeruginosa isolates in the neutropenic murine thigh model. Eighteen clinical P. aeruginosa isolates (MIC range, 2 to 32 μg/ml) were used; 15 of these were multidrug resistant. After infection, groups of mice were administered doripenem doses designed to simulate the free time above the MIC (fT>MIC) observed in humans given 1 or 2 g of doripenem every 8 h as a 4-h infusion. Efficacy correlated well with published fT>MIC bactericidal targets of 40%. After 24 h, 1- and 2-g doses achieved approximately ≥2 log decreases in CFU against isolates with MICs of ≤8 and 16 μg/ml, respectively (fT>MIC range, 52.5 to 95%). Results with organisms with higher MICs, where fT>MIC was 0%, were variable, including both increases and decreases in CFU. Compared with 1-g doses, statistically greater efficacy was noted for 2-g doses against three of the eight isolates with MICs of ≥16 μg/ml. While MIC distributions of P. aeruginosa at present necessitate increased exposures for only the most-resistant isolates, the ability of increased doses to achieve pharmacodynamic targets and the efficacy observed when these targets were attained could prove useful when these resistant isolates are encountered

    Clinical Pharmacodynamics of Cefepime in Patients Infected with Pseudomonas aeruginosa▿

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    We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [fT > MIC], the ratio of the minimum concentration of free drug to the MIC [fCmin/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 μg/ml, resulting in median fT > MIC, fCmin/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an fT > MIC of ≤60% (77.8% failed cefepime therapy when fT > MIC was ≤60%, whereas 36.2% failed cefepime therapy when fT > MIC was >60%; P = 0.013). A similar fT > MIC target of ≤63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with fT > MIC values of ≤60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% fT > MIC will minimize the possibility of a poor microbiological response

    In Vivo Comparison of CXA-101 (FR264205) with and without Tazobactam versus Piperacillin-Tazobactam Using Human Simulated Exposures against Phenotypically Diverse Gram-Negative Organisms

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    CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam
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