Direct oral anticoagulants in the treatment of acute venous thromboembolism in patients with obesity: A systematic review with meta-analysis.

BACKGROUND: Direct oral anticoagulants' (DOAC) pharmacokinetics are affected by obesity. Their efficacy and safety in obesity (BMI≥30 kg/m2) and morbid obesity (BMI≥40 kg/m2) are still unclear in the treatment of venous thromboembolism (VTE). OBJECTIVES: To compare the efficacy/safety of DOAC versus vitamin K antagonist (VKA)/low molecular weight heparin (LMWH) for the treatment of VTE in patients with obesity and morbid obesity. The primary efficacy/safety outcomes were VTE recurrence and major bleeding (MB). Clinically relevant non-MB and mortality were also evaluated. METHODS: A systematic literature search (MEDLINE, EMBASE, CENTRAL, Web of Science) identified studies evaluating DOAC in the treatment of VTE in patients with obesity and reporting one of the outcomes. Relative risks (RR) and 95 % confidence intervals (CI) were estimated using the Mantel-Haenszel method. RESULTS: We included 21 studies (50,360pts) of which 16,150 patients had a BMI≥30 kg/m2 and 6443 patients had a BMI≥40 kg/m2. VTE recurrence was similar with DOAC compared to VKA/LMWH in patients with obesity (RR 1.03;95 %CI 0.93-1.15;p = 0.55) and morbid obesity (RR 1.06;95 %CI 0.94-1.19;p = 0.35). DOAC were also associated with a reduction in MB (RR 0.57;95 %CI 0.34-0.94;p = 0.03 and RR 0.71;95 %CI 0.50-1.00;p = 0.05 in patients with obesity and morbid obesity, respectively). Subgroup analyses comparing randomized controlled trials to observational studies showed consistent results. No difference was observed in regards of clinically relevant non-MB and mortality. CONCLUSION: There is no signal for differences in VTE recurrence in patients with obesity and morbid obesity treated with DOAC compared to VKA/LMWH, while DOAC likely reduce the risk of MB compared to VKA/LMWH.

DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis.

Low molecular weight heparins (LMWH) are the standard of care for the treatment of cancer-associated venous thromboembolism (CA-VTE). We performed a systematic review and meta-analysis to compare the effects of direct oral anticoagulants (DOAC) versus LMWH for the treatment of CA-VTE. The primary efficacy and safety outcomes were VTE recurrence and major bleeding (MB). The secondary outcomes were clinically relevant non-MB (CRNMB), all-cause mortality and the net clinical benefit. We searched MEDLINE, EMBASE, CENTRAL and Web of Science (inception-December 2019) and abstracts of relevant conferences (2000-2019) to identify randomized controlled trials comparing DOAC and LMWH for the treatment of CA-VTE. Relative risks (RR) and 95% confidence intervals were estimated (Mantel-Haenszel method, random-effects models). A non-inferiority analysis with a margin of 1.3 for the upper boundary of the RR was conducted for the primary outcomes. From 637 references, we included four publications which encompass three trials (1756 patients). Compared to LMWH, DOAC were associated with a trend for decreased VTE recurrence (RR 0.51; 95%CI 0.25-1.03; p = 0.06; I2 = 51%), whereas MB (RR 1.64; 95%CI 1.00-2.69; p = 0.05; I2 = 0%) and CRNMB (RR 1.83; 95%CI 1.04-3.20; p = 0.03; I2 = 50%) were significantly more frequent with DOAC. Conversely, all-cause mortality (RR 1.06; 95%CI 0.83-1.35; p = 0.64; I2 = 36%) and net clinical benefit (RR 0.74; 95%CI 0.38-1.42; p = 0.36; I2 = 65%) were comparable. DOAC were non-inferior to LMWH in preventing CA-VTE recurrence, but were associated with an increased risk of MB and CRNMB. Further studies are required to confirm these results and inform on the risk/benefit ratio for specific populations.

Tiotropium improves walking endurance in COPD.

The primary objective of this study was to evaluate the effects of a 3-week treatment with tiotropium on walking capacity in chronic obstructive pulmonary disease (COPD). After familiarisation with study procedures, 36 patients were randomised to receive tiotropium 18 µg once daily or a matching placebo in a double-blind, parallel-group study. Pre- (trough) and 2-h post-dose pulmonary function was measured. An endurance shuttle walk was then completed. The same procedures were repeated after 3 weeks of treatment. Ventilatory parameters were monitored during exercise. At 3 weeks, tiotropium significantly improved walking endurance time in comparison with placebo, with a mean±sd between-group difference of 128±141 s (p=0.017). At 3 weeks, trough values for forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were significantly improved with tiotropium in comparison with placebo. The post-dose response to tiotropium was statistically superior to placebo after the first dose and after 3 weeks of treatment for FEV(1), FVC and inspiratory capacity. Ventilation and tidal volume at the end of walking were significantly improved with tiotropium. 3 weeks of tiotropium resulted in a greater walking endurance in patients with COPD. Improvements in FEV(1), maximal ventilation and tidal volume may contribute to this enhanced exercise capacity.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis.

BACKGROUND: The role of biomarkers such as B-type natriuretic peptides (BNP and NT-proBNP) and troponins in risk stratification of acute pulmonary embolism (APE) is still debated. A meta-analysis was performed to assess the association between raised natriuretic peptide levels, alone or in conjunction with troponins, and all-cause and APE-related mortality, serious adverse events and echographic right ventricular dysfunction. METHODS: MEDLINE and EMBASE databases were searched and conference abstracts were hand searched up to February 2008. Studies were included if a 2x2 table could be constructed based on natriuretic peptide results and at least one of the outcomes. RESULTS: Twenty-three studies were included (1127 patients). Raised natriuretic peptide levels were significantly associated with all-cause mortality (odds ratio (OR) 6.2; 95% confidence interval (CI) 3.0 to 12.7), APE-related mortality (OR 5.0; 95% CI 2.2 to 11.5) and serious adverse events (OR 6.7; 95% CI 3.9 to 11.6), with homogeneity across studies. Among patients with raised natriuretic peptide levels, increased serum troponins were associated with a further increase in the risk of adverse outcomes. Analysis of the accuracy of natriuretic peptides in detecting right ventricular dysfunction was limited by heterogeneity across studies. BNP appeared to have better sensitivity and specificity than NT-proBNP in detecting right ventricular dysfunction. CONCLUSIONS: Raised levels of B-type natriuretic peptides identified a subset of patients with APE at higher risk of adverse outcomes. Among patients with raised natriuretic peptide levels, increased troponins were found to be an independent prognostic marker. The results of this meta-analysis may have important clinical implications in the management of APE.

Changes in exercise haemodynamics during treatment in pulmonary arterial hypertension.

Improvement in exercise capacity may not be associated with significant changes in resting pulmonary haemodynamics. The present prospective study documented the relationships between improvement in 6-min walking distance (6MWD) and changes in resting and exercise pulmonary haemodynamics after treatment in patients with idiopathic pulmonary arterial hypertension (IPAH). A total of 42 IPAH patients underwent supine submaximal exercise haemodynamic assessments at baseline and after 5+/-2 months of therapy. The 6MWD, the corresponding chronotropic response (peak minus resting heart rate), and resting and exercise haemodynamic variables were analysed. The isoflow was defined as the lowest of the pre- and post-treatment peak cardiac index (CI). The extrapolated isoflow mean pulmonary artery pressure ((pa)) was used to characterise changes in (pa)-CI regression lines following treatment. Patients were given bosentan (n = 28), epoprostenol (n = 12) or both. The 6MWD increased significantly, from 399+/-88 to 442+/-86 m. On univariate analysis, changes in 6MWD correlated with changes in isoflow (pa), chronotropic response, resting haemodynamics (CI, pulmonary vascular resistance and mixed venous oxygen saturation) and exercise haemodynamics (peak CI). On multivariate analysis, only changes in isoflow (pa) and chronotropic response were independently associated with changes in 6MWD. Improvement in exercise tolerance with chronic therapy is independently related to improvement in pulmonary haemodynamics measured in exercise but not in resting conditions.

Identity crisis in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) shares many hallmarks with cancer. Cancer cells acquire their hallmarks by a pathological Darwinian evolution process built on the so-called cancer cell "identity crisis." Here we demonstrate that PAH shares the most striking features of the cancer identity crisis: the ectopic expression of normally silent tissue-specific genes.

Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysis of the management outcome studies.

Essentials Computed tomographic pulmonary angiography (CTPA) is used to exclude pulmonary embolism. This meta-analysis explores the occurrence of venous thromboembolic events (VTE) after a CTPA. Occurrence of VTE after a negative CTPA is ˜8% in study subgroups with a prevalence of PE ≥ 40%. CTPA may be insufficient to safely rule out VTE as a stand-alone diagnostic test for this subgroup. SUMMARY: Background Outcome studies have reported the safety of computed tomographic pulmonary angiography (CTPA) as a stand-alone imaging technique to rule out pulmonary embolism (PE). Whether this can be applied to all clinical probabilities remains controversial. Objectives We performed a meta-analysis to determine the proportion of patients with venous thromboembolic events (VTE) despite a negative CTPA according to pretest PE prevalence. Methods We searched MEDLINE, EMBASE and the Cochrane Library (January 1990 to May 2017) for outcome studies recruiting patients with suspected PE using CTPA as a diagnostic strategy. The primary outcome was the cumulative occurrence of VTE at 3 months following a negative CTPA. Results Twenty-two different studies were identified. VTE was confirmed in 2.4% of patients (95% CI, 1.3-3.8%) either at the time of the index event or in the 3 months follow-up. Subgroup analyses suggested that the cumulative occurrence of VTE was related to pretest prevalence of PE, as VTE occurred in 1.8% (95% CI, 0.5-3.7%), 1.4% (95% CI, 0.7-2.3%), 1.0% (95% CI, 0.5-1.8%) and 8.1% (95% CI, 3.5-14.5%) of subgroups of patients with a PE prevalence < 20%, 20-29%, 30-39% and ≥ 40%, respectively. This was further confirmed using meta-regression analysis. Conclusions The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand-alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.

Chronic hypocalcemia of vitamin D deficiency leads to lower intracellular calcium concentrations in rat hepatocytes.

Several lines of evidence indicate that calcium deficiency is associated with cellular defects in many tissues and organs. Owing to the large in vivo gradient between ionized extra- and intracellular Ca2+ concentrations ([Ca2+]i), it is generally recognized that the prevailing circulating Ca2+ does not significantly affect resting cytosolic Ca2+. To probe the consequences of hypocalcemia on [Ca2+]i, a model of chronic hypocalcemia secondary to vitamin D (D) deficiency was used. Hepatocytes were isolated from livers of hypocalcemic D-deficient, of normocalcemic D3-repleted, or of normal control rats presenting serum Ca2+ of 0.78 +/- 0.02, 1.24 +/- 0.03, or 1.25 +/- 0.01 mM, respectively (P < 0.0001). [Ca2+]i was measured in cell couplets using the fluorescent probe Fura-2. Hepatocytes of normocalcemic D3-repleted and of normal controls exhibited similar [Ca2+]i of 227 +/- 10 and 242 +/- 9 nM, respectively (NS), whereas those of hypocalcemic rats had significantly lower resting [Ca2+]i (172 +/- 10 nM; P < 0.0003). Stimulation of hepatocytes with the alpha 1-adrenoreceptor agonist phenylephrine illicited increases in cytosolic Ca2+ leading to similar [Ca2+]i and phosphorylase a (a Ca(2+)-dependent enzyme) activity in all groups but in contrast to normocalcemia, low extracellular Ca2+ was often accompanied by a rapid decay in the sustained phase of the [Ca2+]i response. When stimulated with the powerful hepatic mitogen epidermal growth factor (EGF), hepatocytes isolated from hypocalcemic rat livers responded with a blunted maximal [Ca2+]i of 237.6 +/- 18.7 compared with 605.2 +/- 89.9 nM (P < 0.0001) for their normal counterparts, while the EGF-mediated DNA synthesis response was reduced by 50% by the hypocalcemic condition (P < 0.03). Further studies on the possible mechanisms involved in the perturbed [Ca2+]i homeostasis associated with chronic hypocalcemia revealed the presence of an unchanged plasma membrane Ca2+ ATPase but of a significant decrease in agonist-stimulated Ca2+ entry as indicated using Mn2+ as surrogate ion (P < 0.03). Our data, thus indicate that, in rat hepatocytes, the in vivo calcium status significantly affects resting [Ca2+]i, and from this we raise the hypothesis that this lower than normal [Ca2+]i may be linked, in calcium disorders, to inappropriate cell responses mediated through the calcium signaling pathway as illustrated by the response to phenylephrine and EGF.

The secondary structure of salt-extracted ribosomal proteins from Escherichia coli as studied by circular dichroic spectroscopy.

Ribosomal proteins from Escherichia coli MRE600 have been obtained by a new, mild purification procedure. This involves extraction of the subunits with salt followed by chromatographic fractionation in the presence of salt. The use of urea or other denaturing agents and conditions is avoided. A survey of the secondary structure of the 30 S and 50 S proteins, as observed by circular dichroic spectroscopy, is presented. The spectra have been analysed by a new procedure which uses a library of 16 circular dichroic spectra of proteins with a known three-dimensional structure. This method provides a more reliable analysis, especially of the contribution from beta-sheet. The results show that most of the 30 S proteins have a high alpha-helix content, whereas the 50 S proteins are more diverse. The latter group shows a larger contribution from beta-sheet. The data presented here are compared with those already published for a number of proteins which were, with one exception, prepared in the presence of urea. In most cases we find higher alpha-helix and beta-sheet values for the salt-extracted proteins than for the corresponding urea-treated proteins. In those cases, however, where special care was taken to renature the urea-treated proteins agreement is found to within the expected experimental error. The results show that salt-extracted ribosomal proteins have a well-defined secondary structure with a relatively small contribution from unordered structure.

[Diagnosis and classification of pulmonary arterial hypertension]. / Diagnostic et classification des hypertensions artérielles pulmonaires.

The clinical classification of types of pulmonary hypertension has made it possible to better standardize the approach to the diagnosis and treatment of patients, to perform clinical studies among homogeneous patients, and to discover common laboratory abnormalities that may serve as markers or help elucidate mechanisms of disease. Pulmonary arterial hypertension groups together different diseases that affect the small-caliber pulmonary arteries and lead to a progressive increase in pulmonary arterial resistance and right heart failure. A specific diagnosis of pulmonary arterial hypertension is generally based on a detailed and methodical clinical evaluation. Pulmonary biopsy is rarely indicated. Work-up in a center specialized in the management of this disease is frequently appropriate when the cause of the hypertension is not clear or when a specific treatment is envisaged.

Oxidation of ethanol at rest and during prolonged exercise in men.

The purpose of this study was to measure the oxidation of ethanol at rest and during prolonged moderate exercise with use of 13C labeling. Five healthy young males (22.4 +/- 2.7 yr; maximal O2 uptake = 56 +/- 6.6 ml.kg-1.min-1) performed three exercises (68.4 +/- 6.7% maximal O2 uptake; 90 min) on a cycle ergometer with ingestion of 0.4 (trial A) and 0.8 (trial B) g/kg body wt of [13C]ethanol (diluted in 770 +/- 72 ml of water) or water only (trial C). The subjects were also studied during a 90-min rest period after the ingestion of 0.8 g/kg body wt of [13C]ethanol (trial D). At rest, over the 90-min observation period, only 2.1 +/- 0.3 g of the 61.6 +/- 5.7 g of ethanol ingested were oxidized, providing 11.1 +/- 1.9% of the total energy expenditure. Over the 90 min of exercise, the amounts of ethanol oxidized were similar in trials A (9.5 +/- 2.0 g) and B (8.5 +/- 2.5 g). The contribution of ethanol represented 5.2 +/- 1.0% of the total energy expenditure, which is much lower than that previously reported for exogenous carbohydrates (8-18%) or medium-chain free fatty acids (7-14%). The small contribution of ethanol to energy metabolism did not significantly modify endogenous substrate oxidation.

Toward an in vivo neurochemical profile: quantification of 18 metabolites in short-echo-time (1)H NMR spectra of the rat brain.

Localized in vivo (1)H NMR spectroscopy was performed with 2-ms echo time in the rat brain at 9.4 T. Frequency domain analysis with LCModel showed that the in vivo spectra can be explained by 18 metabolite model solution spectra and a highly structured background, which was attributed to resonances with fivefold shorter in vivo T(1) than metabolites. The high spectral resolution (full width at half maximum approximately 0.025 ppm) and sensitivity (signal-to-noise ratio approximately 45 from a 63-microL volume, 512 scans) was used for the simultaneous measurement of the concentrations of metabolites previously difficult to quantify in (1)H spectra. The strongly represented signals of N-acetylaspartate, glutamate, taurine, myo-inositol, creatine, phosphocreatine, glutamine, and lactate were quantified with Cramér-Rao lower bounds below 4%. Choline groups, phosphorylethanolamine, glucose, glutathione, gamma-aminobutyric acid, N-acetylaspartylglutamate, and alanine were below 13%, whereas aspartate and scyllo-inositol were below 22%. Intra-assay variation was assessed from a time series of 3-min spectra, and the coefficient of variation was similar to the calculated Cramér-Rao lower bounds. Interassay variation was determined from 31 pooled spectra, and the coefficient of variation for total creatine was 7%. Tissue concentrations were found to be in very good agreement with neurochemical data from the literature.

Three-dimensional reconstruction from electron micrographs of disordered specimens. I. Method.

A method is presented for three-dimensional reconstruction from electron micrographs of a specimen containing a disordered collection of identical objects with unknown orientations. All the data from all the images are simultaneously used to obtain an approximately maximum likelihood estimate of the three-dimensional electron density, which is represented as a truncated expansion in a complete orthonormal set of basis functions. Anomalous objects can nevertheless be detected and eliminated. The method remains under statistical control, and a hypothesis test is used to choose the lowest resolution reconstruction that is consistent with the data. Error propagation is quantitatively traced from the micrograph to the reconstructed electron density. Random orientation is not necessary, and prior knowledge of preferred orientation can be used to advantage. Similarly, symmetry in the object is not necessary, but it can be imposed and exploited, if appropriate. Evidence is presented that useful reconstructions can be obtained with only one or two extra tilts from highly disordered specimens, even if the objects are asymmetric. The companion paper discusses in detail the implementation and verification of the method.

Three-dimensional reconstruction from electron micrographs of disordered specimens. II. Implementation and results.

The computational procedures to implement the method described in the companion paper for three-dimensional reconstruction from projections of a disordered collection of single particles are presented. Computer simulations are used to demonstrate the way the method functions, and practical aspects are discussed in detail. Examples are given of how different symmetries can be exploited by imposing selection rules on the model equations. Applications to negatively stained 50S ribosomes and to cryo-electron micrographs of thin vitrified layers of unstained and unsupported tomato bushy stunt and Semliki Forest viruses are described, and the resulting reconstructions are presented.

Direct analysis of continuous relaxation spectra.

The dynamic response of a complex biological or chemical system to a perturbation must often be described by an integral over an effectively continuous relaxation spectrum. Because of its well known instability to experimental error, the direct estimation of the spectrum is generally considered unfeasible. However, we show that good estimates can be obtained by constraining the spectrum to be the smoothest one that is consistent with the data. Also constraining the spectrum to be non-negative, if there is a priori knowledge of this, can further increase its accuracy. The method is completely automatic in that no initial estimates or assumptions about the functional form of the spectrum are necessary. Therefore models can be tested more rigorously and objectively since the functional form that they predict for the spectrum need not be assumed at the outset of the analysis as with parameter-fitting procedures. The method is illustrated on simulated data on the photodissociation of CO from heme proteins at low temperatures. The nonuniqueness of the solutions is discussed.

Stopped-flow solution scattering using synchrotron radiation: apparatus, data collection and data analysis.

We have constructed an experimental system, under remote control, for stopped-flow X-ray scattering using synchrotron radiation. It has been used, in conjunction with an annular detector and its associated electronics, to obtain good scattering curves, with time-slices as short as 200 ms, in a new study of the dissociation of the enzyme complex aspartate transcarbamylase. The data have been analysed by new statistical methods, and they agree well with the results from parallel chemical quench experiments. For studying dissociation reactions, stopped-flow X-ray scattering is a quite practical method, which need not use very much more material than conventional stopped-flow experiments.

[Study of a cancer aggregate in a metallurgy plant: practical implications for public health]. / Etude d'un agrégat de cancer dans une enterprise de métallurgie: implications pratiques pour la santé publique.

We present the strategy used to determine whether there was an excess of laryngeal cancer at a primary metal factory in Montreal. The study period extended from 1968 to 1987. Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) were computed for different cancer sites. The number of person-years at risk was estimated (N = 10,860 person-years). This method permitted a summary evaluation of the situation. Statistically significant excesses were not observed for laryngeal cancer or any other site of cancer: SMRs and SIRs were elevated for certain cancers, particularly cancers of the larynx and cancers of the central nervous system (CNS). No association was observed with potential carcinogens in the workplace. However, all three CNS cancer cases were crane operators. Following this investigation, we recommended an industrial hygiene evaluation of the workplace.