Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

Hyperdominance in Amazonian Forest Carbon Cycling

While Amazonian forests are extraordinarily diverse, the abundance of trees is skewed strongly towards relatively few ‘hyperdominant’ species. In addition to their diversity, Amazonian trees are a key component of the global carbon cycle, assimilating and storing more carbon than any other ecosystem on Earth. Here we ask, using a unique data set of 530 forest plots, if the functions of storing and producing woody carbon are concentrated in a small number of tree species, whether the most abundant species also dominate carbon cycling, and whether dominant species are characterized by specific functional traits. We find that dominance of forest function is even more concentrated in a few species than is dominance of tree abundance, with only ≈1% of Amazon tree species responsible for 50% of carbon storage and productivity. Although those species that contribute most to biomass and productivity are often abundant, species maximum size is also influential, while the identity and ranking of dominant species varies by function and by region

Relative potency of ketamine and S(+)-ketamine in dogs

The aim of this study was to determine the relative potency of racemic ketamine and S(+)-ketamine for the hypnotic effect and to evaluate the clinical anesthesia produced by equianesthetic doses of these two substances in dogs. One hundred and eight dogs were allocated in groups R2, R2.5, R3, R6, R9, R12, S2, S2.5, S3, S6, S9, and S12, to receive by intravenous route 2, 2.5, 3, 6, 9, and 12 mg/kg of ketamine or S(+)-ketamine, respectively. A dose-effect curve was drawn with the dose logarithm and the percentage of dogs that presented hypnosis in each group. The curve was used to obtain a linear regression, to determine the effective doses 100 and the potency relationship. In another experimental phase, eight groups of five dogs received 3, 6, 9 and 12 mg/kg of ketamine or S(+)-ketamine to evaluate the periods of latency, hypnosis, and total recovery. The times in which the dogs reached the sternal position, attempted to stand up for the first time, recovered the standing position, and started to walk were also recorded. The hypnotic dose for ketamine was 9.82 +/- 3.02 (6.86-16.5) mg/kg and for S(+)-ketamine was 7.76 +/- 2.17 (5.86-11.5) mg/kg. The time of hypnosis was longer in R3 and the first attempt to stand up occurred early in R6 when compared with S3 and S6 respectively. When R9 (100% of hypnosis with ketamine) and S6 [100% of hypnosis with S(+)-ketamine] were compared (1:1.5 ratio), the time to sternal position (12 +/- 2.5 and 20.2 +/- 5.6 min respectively) and the total recovery time (45 +/- 5.5 and 60.2 +/- 5.2 min respectively) were significantly shorter with S(+)-ketamine. It was concluded that the potency ratio between ketamine and S(+)-ketamine in dogs is smaller than the one reported in other species, and that the dose obtained after a reduction of 50%, as usually performed in humans, would not be enough to obtain equianesthetic effects in dogs

RNA modulates aggregation of the recombinant mammalian prion protein by direct interaction

Recent studies have proposed that nucleic acids act as potential cofactors for protein aggregation and prionogenesis. By means of sedimentation, transmission electron microscopy, circular dichroism, static and dynamic light scattering, we have studied how RNA can influence the aggregation of the murine recombinant prion protein (rPrP). We find that RNA, independent of its sequence, source and size, modulates rPrP aggregation in a bimodal fashion, affecting both the extent and the rate of rPrP aggregation in a concentration dependent manner. Analogous to RNA-induced liquid-liquid phase transitions observed for other proteins implicated in neurodegenerative diseases, high protein to RNA ratios stimulate rPrP aggregation, while low ratios suppress it. However, the latter scenario also promotes formation of soluble oligomeric aggregates capable of seeding de novo rPrP aggregation. Furthermore, RNA co-aggregates with rPrP and thereby gains partial protection from RNase digestion. Our results also indicate that rPrP interacts with the RNAs with its N-terminus. In summary, this study elucidates the proposed adjuvant role of RNA in prion protein aggregation and propagation, and thus advocates an auxiliary role of the nucleic acids in protein aggregation in general.Manuscript title: Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation</p

Use of gastric balloon manometry for estimation of intra-abdominal pressure in horses

Reasons for performing study: Standing laparoscopic procedures, facilitated by abdominal insufflation with carbon dioxide, are being employed to an increasingly greater extent in horses. However, a sustained increase in abdominal pressure may be life-threatening. A practical method for intra-abdominal pressure (IAP) assessment is imperative. Although indirect methods for estimating IAP have been extensively studied in man, little work has been performed in veterinary medicine.Objectives: To investigate the utility of gastric manometry for purposes of evaluating IAP in horses.Methods: Gastric pressure (P(ga)) was estimated by balloon manometry in 8 healthy, mature horses, before and during a 30 min passive pneumoperitoneum induced by right paralumbar puncture. The balloon manometer was positioned within the gastric lumen and inflated using 2 separate volumes of air: 10 and 50 ml. P(ga) Gastric pressure was determined at baseline (0) and 5, 15 and 30 min after induction of passive pneumoperitoneum. Intra-abdominal pressure was measured directly by right paralumbar puncture using an 8 gauge needle at baseline and immediately following establishment of passive pneumoperitoneum.Results: Baseline IAP values were negative and increased (P <= 0.05) during development of passive pneumoperitoneum. However, recorded P(ga) measurements for both inflation volumes were positive before (baseline) and during the course of the passive pneumoperitoneum. Measured P(ga) values did not correlate with IAP at any time.Conclusions and potential relevance: Our results suggest that the indirect method used in human patients for estimating IAP by P(ga) is not applicable for horses.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Immunohistochemistry analysis to confirm cases of cutaneous pythiosis in horses diagnosed by means of clinic characterization and histopathologic evaluation

Twelve granulomatous lesions in the thoracic and pelvic limbs of horses from pantaneira breed were evaluated. It was performed suggestive diagnostic of cutaneous pythiosis according to the clinic characteristics of the lesions and histopathological exams using hematoxylin and eosin (HE) and Grocott's methenamine silver (GMS) stains. The confirmation of the diagnoses was performed by the labelled streptavidin biotin (LSAB) method (immunohistochemistry). Extensive focal pyogranulomatous dermatitis associated with pseudo hyphae characteristic of Pythium insidiosum (subcutaneous pythiosis) was the histopathological diagnosis for all 12 horses used in this study. It was confirmed in 100% of the cases by the positive result to Pythium insidiosum in the immunohistochemistry exam, characterized by the visualization of branched and septated structures. It was observed 100% of parity between the techniques. We can conclude that clinical characterization of the granulomatous lesions with pythiosis aspects in horses associated with histopathology suggestive of equine pythiosis constitute a reliable method of diagnostic that can be confirmed by immunohistochemistry technique

Effect of passive pneumoperitoneum on oesophageal pressure, cardiovascular parameters and blood gas analysis in horses

P>Reasons for performing study:Standing surgical procedures are being employed to an ever-greater extent in horses. Pneumoperitoneum during abdominal surgery might adversely affect the work of breathing.Objectives:To determine whether development of pneumoperitoneum during abdominal surgery adversely influences the work of breathing.Methods:Eight healthy mature horses were equipped with carotid artery and thoracic vena cava catheters and an intraluminal manometry system. The following measurements were obtained before and at +5, +10, +15 and +30 min following establishment of pneumoperitoneum by paralumbar puncture using an 8 gauge needle: vital signs, oesophageal pressure, gastric pressure, arterial and central venous blood pressures, and arterial and mixed venous blood gas analyses.Results:Significant changes in oesophageal pressure, central venous pressure and results of arterial and mixed venous blood gas analysis were not detected. Arterial diastolic and mean pressures and rectal temperature increased slightly (P < 0.05).Conclusions:Passive pneumoperitoneum did not adversely affect breathing mechanics or haemodynamic variables under experimental conditions. Changes in arterial pressure could have occurred as a response to the passive pneumoperitoneum or be related to handling stress. Subtle variations in rectal temperature were not clinically relevant and likely resulted from stress associated with restraint.Potential relevance:It is unlikely that mature horses will develop signs of respiratory difficulty as a result of the development of passive pneumoperitoneum during standing laparoscopy.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES