Complete Genome Sequence of the N2-Fixing Broad Host Range Endophyte Klebsiella pneumoniae 342 and Virulence Predictions Verified in Mice

We report here the sequencing and analysis of the genome of the nitrogen-fixing endophyte, Klebsiella pneumoniae 342. Although K. pneumoniae 342 is a member of the enteric bacteria, it serves as a model for studies of endophytic, plant-bacterial associations due to its efficient colonization of plant tissues (including maize and wheat, two of the most important crops in the world), while maintaining a mutualistic relationship that encompasses supplying organic nitrogen to the host plant. Genomic analysis examined K. pneumoniae 342 for the presence of previously identified genes from other bacteria involved in colonization of, or growth in, plants. From this set, approximately one-third were identified in K. pneumoniae 342, suggesting additional factors most likely contribute to its endophytic lifestyle. Comparative genome analyses were used to provide new insights into this question. Results included the identification of metabolic pathways and other features devoted to processing plant-derived cellulosic and aromatic compounds, and a robust complement of transport genes (15.4%), one of the highest percentages in bacterial genomes sequenced. Although virulence and antibiotic resistance genes were predicted, experiments conducted using mouse models showed pathogenicity to be attenuated in this strain. Comparative genomic analyses with the presumed human pathogen K. pneumoniae MGH78578 revealed that MGH78578 apparently cannot fix nitrogen, and the distribution of genes essential to surface attachment, secretion, transport, and regulation and signaling varied between each genome, which may indicate critical divergences between the strains that influence their preferred host ranges and lifestyles (endophytic plant associations for K. pneumoniae 342 and presumably human pathogenesis for MGH78578). Little genome information is available concerning endophytic bacteria. The K. pneumoniae 342 genome will drive new research into this less-understood, but important category of bacterial-plant host relationships, which could ultimately enhance growth and nutrition of important agricultural crops and development of plant-derived products and biofuels

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

J-PLUS: The Javalambre Photometric Local Universe Survey

The Javalambre Photometric Local Universe Survey (J-PLUS) is an ongoing 12-band photometric optical survey, observing thousands of square degrees of the Northern Hemisphere from the dedicated JAST/T80 telescope at the Observatorio Astrofisico de Javalambre (OAJ). The T80Cam is a camera with a field of view of 2 deg(2) mounted on a telescope with a diameter of 83 cm, and is equipped with a unique system of filters spanning the entire optical range (3500-10 000 angstrom). This filter system is a combination of broad-, medium-, and narrow-band filters, optimally designed to extract the rest-frame spectral features (the 3700-4000 angstrom Balmer break region, H delta, Ca H+K, the G band, and the Mg b and Ca triplets) that are key to characterizing stellar types and delivering a low-resolution photospectrum for each pixel of the observed sky. With a typical depth of AB similar to 21.25 mag per band, this filter set thus allows for an unbiased and accurate characterization of the stellar population in our Galaxy, it provides an unprecedented 2D photospectral information for all resolved galaxies in the local Universe, as well as accurate photo-z estimates (at the delta z/(1 + z) similar to 0.005-0.03 precision level) for moderately bright (up to r similar to 20 mag) extragalactic sources. While some narrow-band filters are designed for the study of particular emission features ([O II]/lambda 3727, H alpha/lambda 6563) up to z < 0.017, they also provide well-defined windows for the analysis of other emission lines at higher redshifts. As a result, J-PLUS has the potential to contribute to a wide range of fields in Astrophysics, both in the nearby Universe (Milky Way structure, globular clusters, 2D IFU-like studies, stellar populations of nearby and moderate-redshift galaxies, clusters of galaxies) and at high redshifts (emission-line galaxies at z approximate to 0.77, 2.2, and 4.4, quasi-stellar objects, etc.). With this paper, we release the first similar to 1000 deg(2) of J-PLUS data, containing about 4.3 million stars and 3.0 million galaxies at r < 21 mag. With a goal of 8500 deg(2) for the total J-PLUS footprint, these numbers are expected to rise to about 35 million stars and 24 million galaxies by the end of the survey

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

The association between passive and active tobacco smoke exposure and child weight status among Spanish children.

OBJECTIVE: To assess the impact of passive and active tobacco smoke exposure, both pre- and postnatally, on child body mass index (BMI) and overweight. METHODS: Pregnant women were enrolled into the Spanish INMA prospective birth cohort during 1997 to 2008. Tobacco smoke exposure was assessed by questionnaire and corroborated by pre- and postnatal cotinine measurements. Children were followed up until 4 years in newer subcohorts (N = 1866) and until 14 years in one older subcohort (N = 427). Child age- and sex-specific BMI Z-scores were calculated, and generalized estimating equations were used to model their relationship with repeated measures of tobacco smoke exposure. RESULTS: Associations between prenatal passive exposure to tobacco smoke (adjusted beta = 0.15, 95% CI: 0.05-0.25) and active maternal smoking (adjusted beta = 0.20, 95% CI: 0.08-0.33) and child zBMI up to 4 years were observed. Stronger associations were observed in the older subcohort between both prenatal and child passive smoke exposure and zBMI up to 14 years. CONCLUSIONS: Evidence for an effect of both passive and maternal active smoking on child postnatal growth has been provided. Although residual confounding cannot be completely ruled out, associations were robust to adjustment for a range of lifestyle factors

Synthesis and biological evaluation of organoruthenium complexes with azole antifungal agents : first crystal structure of a tioconazole metal complex

Nine organoruthenium complexes with azole antifungal agents (L) clotrimazole (ctz), tioconazole (tcz), and miconazole (mcz) with the general formulas [(eta(6)-p-cymene)-RuCl2(L)], [(eta(6)-p-cymene)RuCl(L)(2)]Cl, and [(eta(6)-p-cymene)-Ru(L)(3)](PF6)(2) were prepared and characterized by NMR, HRMS, IR, UV-vis, and X-ray crystallography. Herein, we report the first crystal structure of a tioconazole metal complex as well as the structure of the tioconazole ligand itself and the bis-clotrimazole complex as a hexafluorophosphate salt. The complexes possess a pseudooctahedral geometry typical for organoruthenium(II) compounds where half of the coordination sites are occupied by the pi-bonded arene ligand p-cymene while the remaining sites are occupied by either the chlorido ligands and/or the azole ligands. The stability of the compounds in dmso solution was studied by NMR spectroscopy. The biological activity of all nine complexes and the ruthenium precursor against the fungus Culvularia lunata was evaluated. The complexes showed antifungal activity at low millimolar concentrations, where the activity decreased with the increasing number of ligands. However at 0.5 mM concentrations all tris-azole complexes statistically significantly reduced the radial growth rate, and also at 0.01 mM concentrations the monoazole complexes showed statistically significant effects. Mcz and its complexes were also tested against the human parasite Schistosoma mansoni and revealed schistocidal activity at 10-100 mu g/mL in vitr