Comparison of bleeding and ischemic events with apixaban vs. rivaroxaban in triple antithrombotic therapy regimens.

OBJECTIVE: To compare the risk of readmissions for major bleeding within one year between apixaban and rivaroxaban as a component of triple antithrombotic therapy. METHODS: This study was a multicenter, retrospective cohort study conducted at two academic medical centers in the Western New York and New York City region between July 1, 2011 and September 25, 2019. Adult patients were included if they were diagnosed with atrial fibrillation or venous thromboembolism and discharged on new triple antithrombotic therapy. The primary outcome compared the rates of 1-year readmission for major bleeding between apixaban and rivaroxaban groups. Secondary outcomes included rate of ischemic outcomes. Time to event analysis was determined with a Kaplan-Meier plot and Cox proportional hazard ratios (HR). RESULTS: A total of 378 patients were included in the study, 212 in the apixaban group and 166 in the rivaroxaban group. Within 1 year, readmission for major bleeding events occurred in six (2.8%) patients in the apixaban group and four (2.4%) patients in the rivaroxaban group ( P  = 1.000). After adjustment, the major bleeding event rate was not statistically significantly different between apixaban and rivaroxaban [adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.12-3.77; P  = 0.6624]. Higher albumin levels were identified to be protective against major bleeding related readmission events (aHR 0.18, 95% CI 0.05-0.63; P  = 0.0072). The ischemic outcome occurred in seven (3.3%) patients in the apixaban group and three (1.8%) in the rivaroxaban group ( P  = 0.7368). CONCLUSION: Use of apixaban or rivaroxaban in a triple antithrombotic regimen was not associated with bleeding or ischemic outcomes.

Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV1 (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV1 and FVC. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.

Investigating associations of omega-3 fatty acids, lung function decline, and airway obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have anti-inflammatory properties and may benefit lung health. Objectives: Investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in adults of diverse races/ethnicities from general population cohorts. Methods: Complementary study designs: (1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV 1 and FVC measures in the National Heart, Lung, and Blood Institute Pooled Cohorts Study, and (2) two-sample Mendelian Randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid concentrations were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for docosahexaenoic acid (DHA). One standard deviation higher DHA was associated with an attenuation of 1.8 mL/year for FEV 1 (95% confidence interval [CI] 1.3-2.2) and 2.4 mL/year for FVC (95% CI 1.9-3.0). One standard deviation higher DHA was also associated with a 9% lower incidence of spirometry-defined airway obstruction (95% CI 0.86-0.97). DHA associations persisted across sexes, smoking histories, and Black, white and Hispanic participants, with the largest magnitude associations in former smokers and Hispanics. The MR study showed positive associations of genetically predicted omega-3 fatty acids with FEV 1 and FVC, with statistically significant findings across multiple MR methods. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher circulating omega-3 fatty acids, especially DHA, on lung health.

Nontraditional Risk Factors for Progression Through Chronic Kidney Disease Risk Categories: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: There may be nontraditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine nontraditional risk factors for incident CKD and its progression. METHODS: We used the generally healthy population (n = 4382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which is an observational longitudinal study. Nontraditional risk factors included forced vital capacity, inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-1996 and repeated every 5 years for 20 years: No CKD, low risk, moderate risk, high risk, and very high risk. RESULTS: At baseline, 84.8% had no CKD (eGFR ≥60 mL/min/1.73 m2 and UACR <10 mg/g), 10.3% were in the low risk (eGFR ≥60 and UACR 10-29), and 4.9% had CKD (eGFR <60 and/or UACR ≥ 30). Nontraditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and low and moderate risk into CKD were inverse for forced vital capacity and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors. CONCLUSION: Several nontraditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs. METHODS: We retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors. RESULTS: Among patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes. CONCLUSIONS: Routine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

Calcium Intake Is Inversely Related to Risk of Obesity among American Young Adults over a 30-Year Follow-Up.

BACKGROUND: Calcium (Ca) is an essential nutrient that may play an important role in weight maintenance through its involvement in energy or lipid metabolism. However, little is known about the long-term associations of Ca intake with obesity risk. OBJECTIVES: We aimed to prospectively examine the association between cumulative Ca intake and the incidence of obesity among American young adults over 30 y of follow-up. METHODS: Participants were from the CARDIA (Coronary Artery Risk Development in Young Adults) study. A total of 4097 of 5115 black and white individuals aged 18-30 y at baseline in 1985-1986 were included in the current analysis. Dietary and supplemental Ca intake was assessed by the validated interview-based CARDIA diet history at baseline and exam years 7 and 20. Incident cases of obesity were identified when BMI was ≥30 kg/m2 for the first time since baseline. A survival analysis was performed using Cox proportional hazards regression models to estimate the HRs and corresponding 95% CIs for obesity incidence during follow-up. RESULTS: During a 30-y follow-up (mean ± SD: 20 ± 10 y), 1675 participants developed obesity. Cumulative total Ca intake (dietary plus supplemental Ca) was inversely associated with incidence of obesity in multivariable-adjusted analysis [quintile (Q)5 (highest intake) compared with Q1 (lowest intake): HR: 0.68; 95% CI: 0.56, 0.82; P-trend < 0.01]. This inverse association persisted among Ca supplement users (Q5 compared with Q1: HR: 0.53; 95% CI: 0.40, 0.70; P-trend < 0.01), but was not seen among nonusers. CONCLUSIONS: Following a cohort of Americans from young adulthood to midlife, an inverse association between calcium intake and obesity incidence was observed. Further studies are needed to confirm our findings.

Magnesium intake was inversely associated with hostility among American young adults.

Hostility is a complex personality trait associated with many cardiovascular risk factor phenotypes. Although magnesium intake has been related to mood and cardio-metabolic disease, its relation with hostility remains unclear. We hypothesize that high total magnesium intake is associated with lower levels of hostility because of its putative antidepressant mechanisms. To test the hypothesis, we prospectively analyzed data in 4,716 young adults aged 18-30 years at baseline (1985-1986) from four U.S. cities over five years of follow-up using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Magnesium intake was estimated from a dietary history questionnaire plus supplements at baseline. Levels of hostility were assessed using the Cook-Medley scale at baseline and year 5 (1990-1991). Generalized estimating equations were applied to estimate the association of magnesium intake with hostility as repeated measures at the two time-points (baseline and year 5). General linear model was used to determine the association between magnesium intake and change in hostility over 5 years. After adjustment for socio-demographic and major lifestyle factors, a significant inverse association was observed between magnesium intake and hostility level over 5 years of follow-up. Beta coefficients (95% CI) across higher quintiles of magnesium intake were 0 (reference), -1.28 (-1.92, -0.65), -1.45 (-2.09, -0.81), -1.41 (-2.08, -0.75) and -2.16 (-2.85, -1.47), respectively (Plinear-trend<.01). The inverse association was independent of socio-demographic and major lifestyle factors, supplement use, and depression status at year 5. This prospective study provides evidence that in young adults, high magnesium intake was inversely associated with hostility level independent of socio-demographic and major lifestyle factors.

Residential proximity to greenhouse crops and pesticide exposure (via acetylcholinesterase activity) assessed from childhood through adolescence.

BACKGROUND: Off-target drift of pesticides from farms increases the risk of pesticide exposure of people living nearby. Cholinesterase inhibitors (i.e. organophosphates and carbamates) are frequently used in agriculture and inhibit acetylcholinesterase (AChE) activity. Greenhouse agriculture is an important production method, but it is unknown how far pesticide drift from greenhouses can extend and expose people living nearby. METHODS: This study included 1156 observations from 3 exams (2008, Apr, 2016 and Jul-Oct 2016) of 623 children aged 4-to-17 years living in agricultural communities in Ecuador. AChE, a physiological marker of cholinesterase inhibitor exposure, was measured in blood. Geographic positioning of greenhouses and homes were obtained using GPS receivers and satellite imagery. Distances between homes and the nearest greenhouse edge, and areas of greenhouse crops within various buffer zones around homes were calculated. Repeated-measures regression adjusted for hemoglobin and other covariates estimated change in AChE relative to distance from greenhouses. RESULTS: The pooled mean (SD) of AChE activity was 3.58 U/mL (0.60). The median (25th-75th %tile) residential distance to crops was 334 m (123, 648) and crop area within 500 m of homes (non-zero values only) was 18,482 m2 (7115, 61,841). Residential proximity to greenhouse crops was associated with lower AChE activity among children living within 275 m of crops (AChE difference per 100 m of proximity [95% CI] = -0.10 U/mL [-0.20, -0.006]). Lower AChE activity was associated with greater crop area within 500 m of homes (AChE difference per 1000 m2 [95% CI] = -0.026 U/mL [-0.040, -0.012]) and especially within 150 m (-0.037 U/mL [-0.065, -0.007]). CONCLUSIONS: Residential proximity to floricultural greenhouses, especially within 275 m, was associated with lower AChE activity among children, reflecting greater cholinesterase inhibitor exposure from pesticide drift. Analyses of residential proximity and crop areas near homes yielded complementary findings. Mitigation of off-target drift of pesticides from crops onto nearby homes is recommended.

Evaluating the use of the heart age tool in community pharmacies: a 4-week cluster-randomized controlled trial.

BACKGROUND: Joint British Societies have developed a tool that utilizes information on cardiovascular disease (CVD) risk factors to estimate an individual's 'heart age'. We studied if using heart age as an add-on to conventional risk communication could enhance the motivation for adapting to a healthier lifestyle resulting in improved whole-blood cholesterol and omega-3 status after 4 weeks. METHODS: A total of 48 community pharmacies were cluster-randomized to use heart age+conventional risk communication (intervention) or only conventional risk communication (control) in 378 subjects after CVD risk-factor assessment. Dried blood spots were obtained with a 4-week interval to assay whole-blood cholesterol and omega-3 fatty acids. We also explored pharmacy-staff's (n=27) perceived utility of the heart age tool. RESULTS: Subjects in the intervention pharmacies (n=137) had mean heart age 64 years and chorological age 60 years. In these, cholesterol decreased by median (interquartile range) -0.10 (-0.40, 0.35) mmol/l. Cholesterol decreased by -0.20 (-0.70, 0.30) mmol/l (P difference =0.24) in subjects in the control pharmacies (n=120) with mean chronological age 60 years. We observed increased concentrations of omega-3 fatty acids after 4 weeks, non-differentially between groups. Pharmacy-staff (n=27) agreed that heart age was a good way to communicate CVD risk, and most (n=25) agreed that it appeared to motivate individuals to reduce elevated CVD risk factors. CONCLUSIONS: The heart age tool was considered a convenient and motivating communication tool by pharmacy-staff. Nevertheless, communicating CVD risk as heart age was not more effective than conventional risk communication alone in reducing whole-blood cholesterol levels and improving omega-3 status.

A longitudinal study of pre-pregnancy antioxidant levels and subsequent perinatal outcomes in black and white women: The CARDIA Study.

BACKGROUND: Although protective associations between dietary antioxidants and pregnancy outcomes have been reported, randomized controlled trials of supplementation have been almost uniformly negative. A possible explanation is that supplementation during pregnancy may be too late to have a beneficial effect. Therefore, we examined the relationship between antioxidant levels prior to pregnancy and birth outcomes. METHODS AND FINDINGS: Serum carotenoids and tocopherols were assayed in fasting specimens at 1985-86 (baseline) and 1992-1993 (year 7) from 1,215 participants in Coronary Artery Risk Development in Young Adults (CARDIA) study. An interviewer-administered quantitative food-frequency questionnaire assessed dietary intake of antioxidants. Pregnancy outcome was self-reported at exams every 2 to 5 years. Linear and logistic regression modeling was used to assess relationships of low birthweight (LBW; <2,500 g), continuous infant birthweight, preterm birth (PTB; <37 weeks) and length of gestation with antioxidant levels adjusted for confounders, as well as interactions with age and race. RESULTS: In adjusted models, lycopene was associated with higher odds of LBW (adjusted odds ratio for top quartile, 2.15, 95% confidence interval 1.14, 3.92) and shorter gestational age (adjusted beta coefficient -0.50 weeks). Dietary intake of antioxidants was associated with lower birthweight, while supplement use of vitamin C was associated with higher gestational age (0.41 weeks, 0.01, 0.81). CONCLUSIONS: Higher preconception antioxidant levels are not associated with better birth outcomes.

Faecal analyses and alimentary tracers reveal the foraging ecology of two sympatric bats.

We used three complementary methods to assess the diet of two insectivorous bat species: one an obligate aerial hunter, Miniopterus natalensis, and the other Myotis tricolor whose morphology and taxonomic affiliation to other trawling bats suggests it may be a trawler (capturing insects from the water surface with its feet and tail). We used visual inspection, stable isotope values and fatty acid profiles of insect fragments in bat faeces sampled across five sites to determine the contribution of aquatic and terrestrial arthropods to the diets of the two species. The niche widths of M. tricolor were generally wider than those of Miniopterus natalensis but with much overlap, both taking aquatic and terrestrial insects, albeit in different proportions. The diet of M. tricolor had high proportions of fatty acids (20:5ω3 and 22:6ω3) that are only obtainable from aquatic insects. Furthermore, the diet of M. tricolor had higher proportions of water striders (Gerridae) and whirligig beetles (Gyrinidae), insects obtainable via trawling, than Miniopterus natalensis. These results suggest both species are flexible in their consumption of prey but that M. tricolor may use both aerial hawking and trawling, or at least gleaning, to take insects from water surfaces. The resultant spatial segregation may sufficiently differentiate the niches of the two species, allowing them to co-exist. Furthermore, our results emphasize that using a combination of methods to analyse diets of cryptic animals yields greater insights into animal foraging ecology than any of them on their own.

Revefenacin for the treatment of chronic obstructive pulmonary disease.

Introduction: Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by irreversible or incompletely reversible airflow limitation. Long-acting bronchodilators, including ß2 agonists (LABA) and muscarinic antagonists (LAMA), serve as the standard of care for maintenance therapy in COPD. Individualizing therapy to optimize selection of delivery device has the potential to improve medication adherence and clinical outcomes among COPD patients.Areas covered: Revefenacin (Yupelri) is the only LAMA approved for once-daily administration via standard jet nebulizer for the maintenance therapy in patients with COPD. Revefenacin has a unique biphenyl carbamate tertiary amine structure, differing from the quaternary amine structure of previously approved LAMAs. Here we summarize the available clinical data for this new agent and discuss its potential place in the treatment of COPD.Expert opinion: Based on available clinical trial data, revefenacin appears to be an effective and safe option for long-term maintenance therapy of COPD. Revefenacin offers a once-daily option for LAMA therapy for patients who prefer or require nebulized drug delivery. The availability of this agent can allow patients to combine nebulized therapies that could improve clinical outcomes in appropriately selected patients with COPD.

Effects of seafood consumption and toenail mercury and selenium levels on cognitive function among American adults: 25 y of follow up.

OBJECTIVES: The aim of this study was to examine the longitudinal association between seafood and intake of long-chain ω-3 polyunsaturated fatty acids (LCω-3 PUFA) and cognitive function and to explore the possible effect modifications owing to mercury (Hg) and selenium (Se) levels. METHODS: Participants (N = 3231) from the CARDIA (Coronary Artery Risk Development in Young Adults) study underwent baseline examination and were reexamined in eight follow-up visits. Diet was assessed at baseline and in exam years 7 and 20. Toenail Hg and Se were measured at exam year 2. Cognitive function was measured at exam year 25 using three tests: Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and the Stroop test. The general linear regression model was used to examine cumulative average intakes of LCω-3 PUFA and seafood in relation to the cognitive test scores; and to explore the possible effect modifications caused by Hg and Se. RESULTS: LCω-3 PUFA intake was significantly associated with better performance in the DSST test (quintile 5 versus quintile 1; mean difference = 1.74; 95% confidence interval, 0.19-3.29; Ptrend, 0.048]), but not in the RAVLT and Stroop tests. Similar results were observed for intakes of eicosapentaenoic acid, docosahexaenoic acid, and non-fried seafood. The observed associations were more pronounced in participants with body mass index ≥25 kg/m2, but not significantly modified by toenail Hg or Se. CONCLUSION: This longitudinal study supported the hypothesis that LCω-3 PUFA or non-fried seafood intake is associated with better cognitive performance in psychomotor speed among US adults, especially those who are overweight or obese.

Adjuvant ß-Lactam Therapy Combined with Vancomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: Does ß-Lactam Class Matter?

We analyzed the impact of vancomycin (VAN) combined with adjuvant ß-lactam therapy (Combo) on persistent (≥5 days) methicillin-resistant Staphylococcus aureus bacteremia versus VAN alone by using pooled data from two previously published observational studies (n = 156). Combo was inversely associated with persistent bacteremia (adjusted odds ratio, 0.460; 95% confidence interval, 0.229 to 0.923). Acute kidney injury was more common with Combo than with VAN (18.9% and 7.6%, respectively; P = 0.062).

New approaches to cope with possible harms of low-dose environmental chemicals.

Low-dose environmental chemicals including endocrine-disrupting chemicals can disturb endocrine, nervous and immune systems. Traditional chemical-focused approaches, strict regulation and avoidance of exposure sources, can help protect humans from individual or several chemicals in the high-dose range, but their value in the low-dose range is questionable. First, exposure sources to problematic environmental chemicals are omnipresent, and many common pollutants present no safe level. In this situation, the value of any effort focusing on individual chemicals is very limited. Second, critical methodological issues, including the huge number of environmental chemicals, biological complexity of mixtures and non-linearity, make it difficult for risk assessment-based regulation to provide reliable permissible levels of individual chemicals. Third, the largest exposure source is already internal; human adipose tissue contains the most complex chemical mixtures. Thus, in the low-dose range, a paradigm shift is required from a chemical-focused to a human-focused approach for health protection. Two key questions are (1) how to control toxicokinetics of chemical mixtures to decrease their burden in critical organs and (2) how to mitigate early harmful effects of chemical mixtures at cellular levels. Many lifestyles can be evaluated for these purposes. Although both the chemical-focused and human-focused approaches are needed to protect humans, the human-focused holistic approach must be the primary measure in the low-dose range of environmental chemicals.

Mechanisms of cnidocyte development in the moon jellyfish Aurelia.

Stinging cells called cnidocytes are a defining trait of the cnidarians (sea anemones, corals, jellyfish, and their relatives). In hydrozoan cnidarians such as Hydra, cnidocytes develop from interstitial stem cells set aside in the ectoderm. It is less clear how cnidocytes develop outside the Hydrozoa, as other cnidarians appear to lack interstitial stem cells. We addressed this question by studying cnidogenesis in the moon jellyfish (Aurelia) through the visualization of minicollagen-a protein associated with cnidocyte development-as well as transmission electron microscopy. We discovered that developing cnidoblasts are rare or absent in feeding structures rich in mature cnidocytes, such as tentacles and lappets. Using transmission electron microscopy, we determined that the progenitors of cnidocytes have traits consistent with epitheliomuscular cells. Our data suggests a dynamic where cnidocytes develop at high concentrations in the epithelium of more proximal regions, and subsequently migrate to more distal regions where they exhibit high usage and turnover. Similar to some anthozoans, cnidocytes in Aurelia do not appear to be generated by interstitial stem cells; instead, epitheliomuscular cells appear to be the progenitor cell type. This observation polarizes the evolution of cnidogenesis, and raises the question of how interstitial stem cells came to regulate cnidogenesis in hydrozoans.

The genome of the jellyfish Aurelia and the evolution of animal complexity.

We present the genome of the moon jellyfish Aurelia, a genome from a cnidarian with a medusa life stage. Our analyses suggest that gene gain and loss in Aurelia is comparable to what has been found in its morphologically simpler relatives-the anthozoan corals and sea anemones. RNA sequencing analysis does not support the hypothesis that taxonomically restricted (orphan) genes play an oversized role in the development of the medusa stage. Instead, genes broadly conserved across animals and eukaryotes play comparable roles throughout the life cycle. All life stages of Aurelia are significantly enriched in the expression of genes that are hypothesized to interact in protein networks found in bilaterian animals. Collectively, our results suggest that increased life cycle complexity in Aurelia does not correlate with an increased number of genes. This leads to two possible evolutionary scenarios: either medusozoans evolved their complex medusa life stage (with concomitant shifts into new ecological niches) primarily by re-working genetic pathways already present in the last common ancestor of cnidarians, or the earliest cnidarians had a medusa life stage, which was subsequently lost in the anthozoans. While we favour the earlier hypothesis, the latter is consistent with growing evidence that many of the earliest animals were more physically complex than previously hypothesized.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

BACKGROUND: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. METHODS: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. RESULTS: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). CONCLUSIONS: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Intake of niacin, folate, vitamin B-6, and vitamin B-12 through young adulthood and cognitive function in midlife: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Background: Epidemiologic evidence regarding niacin, folate, vitamin B-6, and vitamin B-12 intake in relation to cognitive function is limited, especially in midlife.Objective: We hypothesize that higher intake of these B vitamins in young adulthood is associated with better cognition later in life.Design: This study comprised a community-based multicenter cohort of black and white men and women aged 18-30 y in 1985-1986 (year 0, i.e., baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3136). We examined participants' CARDIA diet history at years 0, 7, and 20 to assess nutrient intake, including dietary and supplemental B vitamins. We measured cognitive function at year 25 (mean ± SD age: 50 ± 4 y) through the use of the Rey Auditory Verbal Learning Test (RAVLT) for verbal memory, the Digit Symbol Substitution Test (DSST) for psychomotor speed, and a modified Stroop interference test for executive function. Higher RAVLT and DSST scores and a lower Stroop score indicated better cognitive function. We used multivariable-adjusted linear regressions to estimate mean differences in cognitive scores and 95% CIs.Results: Comparing the highest quintile with the lowest (quintile 5 compared with quintile 1), cumulative total intake of niacin was significantly associated with 3.92 more digits on the DSST (95% CI: 2.28, 5.55; P-trend < 0.01) and 1.89 points lower interference score on the Stroop test (95% CI: -3.10, -0.68; P-trend = 0.05). Total folate was associated with 2.56 more digits on the DSST (95% CI: 0.82, 4.31; P-trend = 0.01). We also found that higher intakes of vitamin B-6 (quartile 5 compared with quartile 1: 2.62; 95% CI: 0.97, 4.28; P-trend = 0.02) and vitamin B-12 (quartile 5 compared with quartile 1: 2.08; 95% CI: 0.52, 3.65; P-trend = 0.02) resulted in better psychomotor speed measured by DSST scores.Conclusion: Higher intake of B vitamins throughout young adulthood was associated with better cognitive function in midlife.

Invited Commentary: Can Estimation of Sodium Intake Be Improved by Borrowing Information From Other Variables?

Estimation of dietary sodium intake is problematic. The most accurate measure is average sodium excretion from multiple 24-hour urine collections, but such an approach is impractical. Using data from the Women's Health Initiative, Prentice et al. (Am J Epidemiol. 2017;186(9):1035-1043) assessed the relationship of calibrated estimates of sodium and potassium excretion with cardiovascular outcomes. The calibrated estimates were a function of self-reported sodium-to-potassium ratio from a food frequency questionnaire, age, body mass index, race, supplement use, smoking status, educational level, income, and aspirin use. In general, associations with outcomes using the calibrated estimates were in the expected direction: direct for the sodium-to-potassium ratio and sodium intake and indirect for potassium. The unexpected associations were an increased risk of hemorrhagic stroke with lower sodium-to-potassium ratio and sodium intake and increased risk with higher potassium intake, along with a null relationship of sodium intake with ischemic stroke. Overall, our assessment is that the authors have improved the estimation of mean dietary sodium and potassium intakes. However, more work is needed to show that calibrated estimates actually improve estimation of future clinical events. If this methodological issue can be successfully addressed, their approach has the potential to improve estimation of dietary sodium and potassium intakes in observational studies.