Cardiorenal Outcomes Among Patients With Atrial Fibrillation Treated With Oral Anticoagulants.

RATIONALE & OBJECTIVE: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kidney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diagnosis of nonvalvular AF during 2011-2018. EXPOSURE: Initiation of DOAC or VKA treatment. OUTCOME: Primary outcomes were CKD progression (composite of >30% estimated glomerular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism. ANALYTICAL APPROACH: Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estimation of per-protocol effects. RESULTS: We included 32,699 patients (56% initiated DOAC) who were observed for a median of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60mL/min/1.73m2. The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.98) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.89) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation. LIMITATIONS: Missing information on time in therapeutic range and treatment dosages. CONCLUSIONS: Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death.

Nutritional inter-dependencies and a carbazole-dioxygenase are key elements of a bacterial consortium relying on a Sphingomonas for the degradation of the fungicide thiabendazole.

Thiabendazole (TBZ), is a persistent fungicide/anthelminthic and a serious environmental threat. We previously enriched a TBZ-degrading bacterial consortium and provided first evidence for a Sphingomonas involvement in TBZ transformation. Here, using a multi-omic approach combined with DNA-stable isotope probing (SIP) we verified the key degrading role of Sphingomonas and identify potential microbial interactions governing consortium functioning. SIP and amplicon sequencing analysis of the heavy and light DNA fraction of cultures grown on 13 C-labelled versus 12 C-TBZ showed that 66% of the 13 C-labelled TBZ was assimilated by Sphingomonas. Metagenomic analysis retrieved 18 metagenome-assembled genomes with the dominant belonging to Sphingomonas, Sinobacteriaceae, Bradyrhizobium, Filimonas and Hydrogenophaga. Meta-transcriptomics/-proteomics and non-target mass spectrometry suggested TBZ transformation by Sphingomonas via initial cleavage by a carbazole dioxygenase (car) to thiazole-4-carboxamidine (terminal compound) and catechol or a cleaved benzyl ring derivative, further transformed through an ortho-cleavage (cat) pathway. Microbial co-occurrence and gene expression networks suggested strong interactions between Sphingomonas and a Hydrogenophaga. The latter activated its cobalamin biosynthetic pathway and Sphingomonas its cobalamin salvage pathway to satisfy its B12 auxotrophy. Our findings indicate microbial interactions aligning with the 'black queen hypothesis' where Sphingomonas (detoxifier, B12 recipient) and Hydrogenophaga (B12 producer, enjoying detoxification) act as both helpers and beneficiaries.

Stopping renin-angiotensin system inhibitors after hyperkalemia and risk of adverse outcomes.

BACKGROUND: Stopping renin-angiotensin system inhibitors (RASi) after an episode of hyperkalemia is common but may involve therapeutic compromises, in that the cessation of RASi deprives patients of their beneficial cardiovascular effects. METHODS AND RESULTS: Observational study from the Stockholm Creatinine Measurements (SCREAM) project including patients initiating RASi in routine care and surviving a first-detected episode of hyperkalemia (potassium >5.0 mmol/L). We used target trial emulation techniques based on cloning, censoring and weighting to compare stopping vs. continuing RASi within 6 months after hyperkalemia. Outcomes were 3-year risks of mortality, major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction and stroke hospitalization) and recurrent hyperkalemia. Of 5669 new users of RASi who developed hyperkalemia (median age 72 years, 44% women), 1425 (25%) stopped RASi therapy within 6 months. Compared with continuing RASi, stopping therapy was associated with a higher 3-year risk of death (absolute risk difference 10.8%; HR 1.49, 95% CI 1.34-1.64) and MACE (risk difference 4.7%; HR 1.29, 1.14-1.45), but a lower risk of recurrent hyperkalemia (risk difference -9.5%; HR 0.76, 0.69-0.84). Results were consistent for events following potassium of >5.0 or >5.5 mmol/L, after censoring when the treatment decision was changed, across prespecified subgroups, and after adjusting for albuminuria. CONCLUSION: These findings suggest that stopping RASi after hyperkalemia may be associated with a lower risk of recurrence of hyperkalemia, but higher risk of death and cardiovascular events.

Nitrogen use efficiency, rhizosphere bacterial community, and root metabolome reprogramming due to maize seed treatment with microbial biostimulants.

Seed inoculation with beneficial microorganisms has gained importance as it has been proven to show biostimulant activity in plants, especially in terms of abiotic/biotic stress tolerance and plant growth promotion, representing a sustainable way to ensure yield stability under low input sustainable agriculture. Nevertheless, limited knowledge is available concerning the molecular and physiological processes underlying the root-inoculant symbiosis or plant response at the root system level. Our work aimed to integrate the interrelationship between agronomic traits, rhizosphere microbial population and metabolic processes in roots, following seed treatment with either arbuscular mycorrhizal fungi (AMF) or Plant Growth-Promoting Rhizobacteria (PGPR). To this aim, maize was grown under open field conditions with either optimal or reduced nitrogen availability. Both seed treatments increased nitrogen uptake efficiency under reduced nitrogen supply revealed some microbial community changes among treatments at root microbiome level and limited yield increases, while significant changes could be observed at metabolome level. Amino acid, lipid, flavone, lignan, and phenylpropanoid concentrations were mostly modulated. Integrative analysis of multi-omics datasets (Multiple Co-Inertia Analysis) highlighted a strong correlation between the metagenomics and the untargeted metabolomics datasets, suggesting a coordinate modulation of root physiological traits.

Comprehensive comparison of stroke risk score performance: a systematic review and meta-analysis among 6 267 728 patients with atrial fibrillation.

AIMS: Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations and updates, assess their methodological quality, and calculate pooled estimates of the predictive performance. METHODS AND RESULTS: We searched PubMed and Web of Science for studies developing, validating, or updating risk scores for IS in AF patients. Methodological quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). To assess discrimination, pooled c-statistics were calculated using random-effects meta-analysis. We identified 19 scores, which were validated and updated once or more in 70 and 40 studies, respectively, including 329 validations and 76 updates-nearly all on the CHA2DS2-VASc and CHADS2. Pooled c-statistics were calculated among 6 267 728 patients and 359 373 events of IS. For the CHA2DS2-VASc and CHADS2, pooled c-statistics were 0.644 [95% confidence interval (CI) 0.635-0.653] and 0.658 (0.644-0.672), respectively. Better discriminatory abilities were found in the newer risk scores, with the modified-CHADS2 demonstrating the best discrimination [c-statistic 0.715 (0.674-0.754)]. Updates were found for the CHA2DS2-VASc and CHADS2 only, showing improved discrimination. Calibration was reasonable but available for only 17 studies. The PROBAST indicated a risk of methodological bias in all studies. CONCLUSION: Nineteen risk scores and 76 updates are available to predict IS in patients with AF. The guideline-endorsed CHA2DS2-VASc shows inferior discriminative abilities compared with newer scores. Additional external validations and data on calibration are required before considering the newer scores in clinical practice. CLINICAL TRIAL REGISTRATION: ID CRD4202161247 (PROSPERO).

Validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function.

AIMS: The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function. METHODS AND RESULTS: Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30-60 mL/min/1.73 m2), and advanced CKD (eGFR <30 mL/min/1.73 m2). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS2 score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration. CONCLUSION: In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients.

Gas exchange, vine performance and modulation of secondary metabolism in Vitis vinifera L. cv Barbera following long-term nitrogen deficit.

MAIN CONCLUSION: A reprogramming of secondary metabolism to acclimate to nitrogen deficiency was seen in grapevine eliciting an accumulation of strigolactones and jasmonate. This response links with photosynthetic compensation and enhanced ripening. In addition to the metabolism directly related to nitrogen assimilation, long-term nitrogen depletion may affect plant secondary metabolism, in turn affecting grapevine performance. In this work, the effect of nitrogen deficit was investigated in V. vinifera cv. Barbera potted vines following three years of deprivation, using a combination of morpho-physiological assessments and mass spectrometry-based untargeted metabolomics. Plants grown under nitrogen limitation showed reduced growth and even more curtailed yields, lowered SPAD values, and a quite preserved leaf gas exchange, compared to plants grown under non-limiting nitrogen availability. Ripening was decidedly accelerated, and berry composition improved in terms of higher sugar and phenolic contents under nitrogen-limiting conditions. Metabolomics showed the broad involvement of secondary metabolism in acclimation to nitrogen deficiency, including a distinctive modulation of the phytohormone profile. Several nitrogen-containing metabolites were down accumulated under nitrogen-limiting conditions, including alkaloids, glucosinolates, hypoxanthine, and inosine. On the other hand, phenylpropanoids showed an accumulation trend. Concerning the recruitment of hormones, nitrogen deprivation elicited an accumulation of strigolactones and jasmonate. Noteworthy, both strigolactones and jasmonates have been previously related to increased photosynthetic efficiency under abiotic stress. Furthermore, the severe reduction of lateral shoot development we recorded in N-deprived vines is consistent with the accumulation of strigolactones. Overall, our results suggest that nitrogen deprivation induced a rather broad metabolic reprogramming, mainly including secondary metabolism and hormones profile, reflected in the modulation of photosynthetic performance, canopy growth, and possibly fruit quality.

Impact of Climatic Conditions on the Resveratrol Concentration in Blend of Vitis vinifera L. cvs. Barbera and Croatina Grape Wines.

The aim of this work was to investigate the effect of meteorological conditions on resveratrol concentration of red wines produced in Piacenza viticultural region (Italy). In this regard, six representative estates producing Colli Piacentini Gutturnio DOC (a blend of V. vinifera L. cvs. Barbera and Croatina) vintage wines were analysed for trans- and cis-resveratrol over an 8-year period (1998-2005). Grapes were taken from the same vineyard in each estate by using the same enological practices over the entire investigated period. The meteorological conditions corresponding to the production areas were recorded, and bioclimatic indices were calculated as well. Overall, cis-resveratrol concentration was negatively correlated to Huglin index and August mean temperature, whilst positive correlation coefficients were found when considering the Selianinov index and the rainfall of September.

Identification of markers of sensory quality in ground coffee: an untargeted metabolomics approach.

INTRODUCTION: In the last years, consumers increased the demand for high-quality and healthy beverages, including coffee. To date, among the techniques potentially available to determine the overall quality of coffee beverages, metabolomics is emerging as a valuable tool. OBJECTIVE: In this study, 47 ground coffee samples were selected during the 2018 Edition of the "International coffee tasting" (ICT) in order to provide discrimination based on both chemical and sensory profiles. In particular, 20 samples received a gold medal ("high quality" group), while lower sensory scores characterized 27 samples (without medal). METHODS: Untargeted metabolomics based on ultra-high pressure liquid chromatography coupled with quadrupole-time-of-flight (UHPLC-QTOF) and head space-gas chromatography coupled with mass spectrometry platforms followed by multivariate statistical approaches (i.e., both supervised and unsupervised) were used to provide new insight into the searching of potential markers of sensory quality. RESULTS: Several compounds were identified, including polyphenols, alkaloids, diazines, and Maillard reaction products. Also, the headspace/GC-MS highlighted the most important volatile compounds. Polyphenols were scarcely correlated to the sensory parameters, whilst the OPLS-DA models built using typical coffee metabolites and volatile/Maillard compounds possessed prediction values > 0.7. The "high quality" group showed specific metabolomic signatures, thus corroborating the results from the sensory analysis. Overall, methyl pentanoate (ROC value = 0.78), 2-furfurylthiol (ROC value = 0.75), and L-Homoserine (ROC value = 0.74) established the higher number of significant (p < 0.05) correlations with the sensory parameters. CONCLUSION: Although ad-hoc studies are advisable to further confirm the proposed markers, this study demonstrates the suitability of untargeted metabolomics for evaluating coffee quality and the potential correlations with the sensory attributes.

Short- and long-term outcomes after incident pneumonia in adults with chronic kidney disease: a time-dependent analysis from the Stockholm CREAtinine Measurement project.

BACKGROUND: Little is known about the health sequelae of pneumonia in persons with chronic kidney disease (CKD). METHODS: We studied adults with CKD in Stockholm during 2006-11, who not previously been diagnosed with lower respiratory tract infections. We used multivariable-adjusted Cox regression with pneumonia as a time-varying exposure to estimate hazard ratios (HRs) [95% confidence intervals (CIs)] for the events of death, major adverse cardiovascular events (MACEs), acute kidney injury (AKI), CKD progression or hospitalization for urinary tract infections (UTIs)/sepsis. Cataract and knee/joint replacement served as negative control outcomes. RESULTS: We identified 71 931 adults (mean age 79 years, 59% women), of whom 8379 (12%) were diagnosed with pneumonia during follow-up; incident pneumonia was associated with 10 times higher adjusted mortality risk during the first 90 days [HR = 10.0, 95% confidence interval (CI) 9.5-10.5] and double the mortality beyond 90 days from pneumonia diagnosis (HR = 2.0; 95% CI 1.9-2.1). Incident pneumonia was similarly associated with higher adjusted risk of MACE (<90 days: HR = 12.6; 95% CI 12.0-13.3; ≥90 days: HR = 1.5; 95% CI 1.4-1.6). The adjusted risk of CKD progression and UTI/sepsis hospitalization was highest within 90 days from pneumonia but remained elevated thereafter. For AKI, the association with incident pneumonia was only seen within 90 days. Neither cataract nor knee/joint replacement was related to pneumonia. CONCLUSIONS: Incident pneumonia was associated with increased risks of MACE, CKD progression, severe UTI/sepsis and death, with risks highest soon after pneumonia diagnosis but extending beyond 90 days. Our findings highlight the susceptibility for adverse outcomes of CKD patients following pneumonia diagnosis, and may inform clinical decisions regarding vaccination strategies.