Electronic Properties of Water in Liquid Environment. A Sequential QM/MM Study Using the Free Energy Gradient Method

There is a continuous search for theoretical methods that are able to describe the effects of the liquid environment on molecular systems. Different methods emphasize different aspects, and the treatment of both the local and bulk properties is still a great challenge. In this work, the electronic properties of a water molecule in liquid environment is studied by performing a relaxation of the geometry and electronic distribution using the free energy gradient method. This is made using a series of steps in each of which we run a purely molecular mechanical (MM) Monte Carlo Metropolis simulation of liquid water and subsequently perform a quantum mechanical/molecular mechanical (QM/MM) calculation of the ensemble averages of the charge distribution, atomic forces, and second derivatives. The MP2/aug-cc-pV5Z level is used to describe the electronic properties of the QM water. B3LYP with specially designed basis functions are used for the magnetic properties. Very good agreement is found for the local properties of water, such as geometry, vibrational frequencies, dipole moment, dipole polarizability, chemical shift, and spin-spin coupling constants. The very good performance of the free energy method combined with a QM/MM approach along with the possible limitations are briefly discussed.

Cost-effectiveness of introducing the 10-valent pneumococcal conjugate vaccine into the universal immunisation of infants in Brazil

Background Cost-effectiveness studies have been increasingly part of decision processes for incorporating new vaccines into the Brazilian National Immunisation Program. This study aimed to evaluate the cost-effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) in the universal childhood immunisation programme in Brazil. Methods A decision-tree analytical model based on the ProVac Initiative pneumococcus model was used, following 25 successive cohorts from birth until 5 years of age. Two strategies were compared: (1) status quo and (2) universal childhood immunisation programme with PCV10. Epidemiological and cost estimates for pneumococcal disease were based on National Health Information Systems and literature. A 'top-down' costing approach was employed. Costs are reported in 2004 Brazilian reals. Costs and benefits were discounted at 3%. Results 25 years after implementing the PCV10 immunisation programme, 10 226 deaths, 360 657 disability-adjusted life years (DALYs), 433 808 hospitalisations and 5 117 109 outpatient visits would be avoided. The cost of the immunisation programme would be R$10 674 478 765, and the expected savings on direct medical costs and family costs would be R$1 036 958 639 and R$209 919 404, respectively. This resulted in an incremental cost-effectiveness ratio of R$778 145/death avoided and R$22 066/DALY avoided from the society perspective. Conclusion The PCV10 universal infant immunisation programme is a cost-effective intervention (1-3 GDP per capita/DALY avoided). Owing to the uncertain burden of disease data, as well as unclear long-term vaccine effects, surveillance systems to monitor the long-term effects of this programme will be essential.

The importance of plant life form on spatial associations along a subtropical coastal dune gradient

Questions Does the spatial association between isolated adult trees and understorey plants change along a gradient of sand dunes? Does this association depend on the life form of the understorey plant? Location Coastal sand dunes, southeast Brazil. Methods We recorded the occurrence of understorey plant species in 100 paired 0.25 m2 plots under adult trees and in adjacent treeless sites along an environmental gradient from beach to inland. Occurrence probabilities were modelled as a function of the fixed variables of the presence of a neighbour, distance from the seashore and life form, and a random variable, the block (i.e. the pair of plots). Generalized linear mixed models (GLMM) were fitted in a backward step-wise procedure using Akaike's information criterion (AIC) for model selection. Results The occurrence of understorey plants was affected by the presence of an adult tree neighbour, but the effect varied with the life form of the understorey species. Positive spatial association was found between isolated adult neighbour and young trees, whereas a negative association was found for shrubs. Moreover, a neutral association was found for lianas, whereas for herbs the effect of the presence of an adult neighbour ranged from neutral to negative, depended on the subgroup considered. The strength of the negative association with forbs increased with distance from the seashore. However, for the other life forms, the associational pattern with adult trees did not change along the gradient. Conclusions For most of the understorey life forms there is no evidence that the spatial association between isolated adult trees and understorey plants changes with the distance from the seashore, as predicted by the stress gradient hypothesis, a common hypothesis in the literature about facilitation in plant communities. Furthermore, the positive spatial association between isolated adult trees and young trees identified along the entire gradient studied indicates a positive feedback that explains the transition from open vegetation to forest in subtropical coastal dune environments.

Use of passive diffusion sampling method for defining NO2 concentrations gradient in São Paulo, Brazil

Abstract Background Air pollution in São Paulo is constantly being measured by the State of Sao Paulo Environmental Agency, however there is no information on the variation between places with different traffic densities. This study was intended to identify a gradient of exposure to traffic-related air pollution within different areas in São Paulo to provide information for future epidemiological studies. Methods We measured NO2 using Palmes' diffusion tubes in 36 sites on streets chosen to be representative of different road types and traffic densities in São Paulo in two one-week periods (July and August 2000). In each study period, two tubes were installed in each site, and two additional tubes were installed in 10 control sites. Results Average NO2 concentrations were related to traffic density, observed on the spot, to number of vehicles counted, and to traffic density strata defined by the city Traffic Engineering Company (CET). Average NO2concentrations were 63μg/m3 and 49μg/m3 in the first and second periods, respectively. Dividing the sites by the observed traffic density, we found: heavy traffic (n = 17): 64μg/m3 (95% CI: 59μg/m3 – 68μg/m3); local traffic (n = 16): 48μg/m3 (95% CI: 44μg/m3 – 52μg/m3) (p < 0.001). Conclusion The differences in NO2 levels between heavy and local traffic sites are large enough to suggest the use of a more refined classification of exposure in epidemiological studies in the city. Number of vehicles counted, traffic density observed on the spot and traffic density strata defined by the CET might be used as a proxy for traffic exposure in São Paulo when more accurate measurements are not available.

New Methods in Organocatalysis

In the following chapters new methods in organocatalysis are described. The design of new catalysts is explored starting from the synthesis and the study of ion tagged prolines to their applications and recycle, then moving to the synthesis of new bicyclic diarylprolinol silyl ethers and their use in organocatalytic transformations. The study of new organocatalytic reaction is also investigated, in particular bifunctional thioureas are employed to catalyse the conjugate addition of nitro compounds to 3-yilidene oxindoles in sequential and domino reactions. Finally, preliminary results on photochemical organocatalytic atom transfer radical addition to alkenes are discussed in the last chapter.

High gradient magnetic separation (HGMS) of erythrocytes infected with plasmodium falciparum

This thesis was undertaken to explore possible applications of high gradient magnetic separation (HGMS) for the separation of RBCs infected with Plasmodium falciparum, with the dual aim of establishing a novel and superior method for isolating late-stage infected cells, and of obtaining synchronized cell cultures.rnThe presented work presents protocols for HGMS of parasitized RBCs that fulfil these aims. Late-stage parasitized cell can be isolated essentially devoid of contamination with non-infected and ring-stage infected cells. Such an easy method for a highly quantitative and qualitative purification has not yet been reported. Synchronous cultures can be obtained both following depletion of late-stage infected cells, and following isolation of the latter. The quality of synchronization cultures matches that of sorbitol lysis, the current standard method for malaria culture synchronization. An advantage of HGMS is the avoidance of osmotic stress for RBCs. The new methods further have the appeal of high reproducibility, cost-effectiveness, and simple protocol.rnIt should be possible to take the methods beyond Plasmodium infected RBCs. Most magnetic separation techniques in the sector of biomedical research employ columns with a hydrophilic polymer-coated matrix. Our procedure employs an optimized buffer system. Polymer coating becomes unnecessary and uncoated columns are available at a fraction of the cost.

Geophysical Analysis of Seasonal Montandon Gravel Ridge Water Table Fluctuation and Moisture Gradient Variation due to Storm Events

The purpose of this research project is to continue exploring the Montandon Long-Term Hydrologic Research Site(LTHR) by using multiple geophysical methods to obtain more accurate and precise information regarding subsurface hydrologic properties of a local gravel ridge,which are important to both the health of surrounding ecosystems and local agriculture. Through using non-invasive geophysical methods such as seismic refraction, Direct Current resistivity and ground penetrating radar (GPR) instead of invasive methods such as boreholedrilling which displace sediment and may alter water flow, data collection is less likely to bias the data itself. In addition to imaging the gravel ridge subsurface, another important researchpurpose is to observe how both water table elevation and the moisture gradient (moisture content of the unsaturated zone) change over a seasonal time period and directly after storm events. The combination of three types of data collection allows the strengths of each method combine together and provide a relatively strongly supported conclusions compared to previous research. Precipitation and geophysical data suggest that an overall increase in precipitation during the summer months causes a sharp decrease in subsurface resistivity within the unsaturated zone. GPR velocity data indicate significant immediate increase in moisture content within the shallow vadose zone (< 1m), suggesting that rain water was infiltrating into the shallow subsurface. Furthermore, the combination of resistivity and GPR results suggest that the decreased resistivity within the shallow layers is due to increased ion content within groundwater. This is unexpected as rainwater is assumed to have a DC resistivity value of 3.33*105 ohm-m. These results may suggest that ions within the sediment must beincorporated into the infiltrating water.

Comparing pneumococcal conjugate vaccine schedules based on 3 and 2 primary doses: systematic review and meta-analysis

Background Pneumococcal conjugate vaccines (PCV) were first licensed for use with 3 primary doses in infancy and a booster dose. The evidence for the effects of different schedules was examined in this systematic review and meta-analysis. Methods We searched 12 databases and trial registers up to March 2010. We selected randomised controlled trials (RCTs), cohort and case–control studies making direct comparisons between PCV schedules with (2p) or (3p) primary doses, with (+1) or without (+0) a booster dose. We extracted data on clinical, nasopharyngeal carriage and immunological outcomes and used meta-analysis to combine results where appropriate. Results Seropositivity levels (antibody concentration ≥0.35 μg/ml) following 3p and 2p PCV schedules were high for most serotypes (5 RCTs). Differences between schedules were generally small and tended to favour 3p schedules, particularly for serotypes 6B and 23F; between-study heterogeneity was high. Seropositivity levels following 3p+1 and 2p+1 schedules were similar but small differences favouring 3p+1 schedules were seen for serotypes 6B and 23F. We did not identify any RCTs reporting clinical outcomes for these comparisons. In 2 RCTs there was weak evidence of a reduction in carriage of S. pneumoniae serotypes included in the vaccine when 3p+0 schedules were compared to 2p+0 at 6 months of age. Conclusions Most data about the relative effects of different PCV schedules relate to immunological outcomes. Both 3p and 2p schedules result in high levels of seropositivity. The clinical relevance of differences in immunological outcomes between schedules is not known. There is an absence of clinical outcome data from RCTs with direct comparisons of any 2p with any 3p PCV schedule.

Squared Extrapolation Methods (SQUAREM): A New Class of Simple and Efficient Numerical Schemes for Accelerating the Convergence of the EM Algorithm

We derive a new class of iterative schemes for accelerating the convergence of the EM algorithm, by exploiting the connection between fixed point iterations and extrapolation methods. First, we present a general formulation of one-step iterative schemes, which are obtained by cycling with the extrapolation methods. We, then square the one-step schemes to obtain the new class of methods, which we call SQUAREM. Squaring a one-step iterative scheme is simply applying it twice within each cycle of the extrapolation method. Here we focus on the first order or rank-one extrapolation methods for two reasons, (1) simplicity, and (2) computational efficiency. In particular, we study two first order extrapolation methods, the reduced rank extrapolation (RRE1) and minimal polynomial extrapolation (MPE1). The convergence of the new schemes, both one-step and squared, is non-monotonic with respect to the residual norm. The first order one-step and SQUAREM schemes are linearly convergent, like the EM algorithm but they have a faster rate of convergence. We demonstrate, through five different examples, the effectiveness of the first order SQUAREM schemes, SqRRE1 and SqMPE1, in accelerating the EM algorithm. The SQUAREM schemes are also shown to be vastly superior to their one-step counterparts, RRE1 and MPE1, in terms of computational efficiency. The proposed extrapolation schemes can fail due to the numerical problems of stagnation and near breakdown. We have developed a new hybrid iterative scheme that combines the RRE1 and MPE1 schemes in such a manner that it overcomes both stagnation and near breakdown. The squared first order hybrid scheme, SqHyb1, emerges as the iterative scheme of choice based on our numerical experiments. It combines the fast convergence of the SqMPE1, while avoiding near breakdowns, with the stability of SqRRE1, while avoiding stagnations. The SQUAREM methods can be incorporated very easily into an existing EM algorithm. They only require the basic EM step for their implementation and do not require any other auxiliary quantities such as the complete data log likelihood, and its gradient or hessian. They are an attractive option in problems with a very large number of parameters, and in problems where the statistical model is complex, the EM algorithm is slow and each EM step is computationally demanding.

Comparing Haemophilus influenzae type b conjugate vaccine schedules: a systematic review and meta-analysis of vaccine trials

BACKGROUND The optimal schedule and the need for a booster dose are unclear for Haemophilus influenzae type b (Hib) conjugate vaccines. We systematically reviewed relative effects of Hib vaccine schedules. METHODS We searched 21 databases to May 2010 or June 2012 and selected randomized controlled trials or quasi-randomized controlled trials that compared different Hib schedules (3 primary doses with no booster dose [3p+0], 3p+1 and 2p+1) or different intervals in primary schedules and between primary and booster schedules. Outcomes were clinical efficacy, nasopharyngeal carriage and immunological response. Results were combined in random-effects meta-analysis. RESULTS Twenty trials from 15 countries were included; 16 used vaccines conjugated to tetanus toxoid (polyribosylribitol phosphate conjugated to tetanus toxoid). No trials assessed clinical or carriage outcomes. Twenty trials examined immunological outcomes and found few relevant differences. Comparing polyribosylribitol phosphate conjugated to tetanus toxoid 3p+0 with 2p+0, there was no difference in seropositivity at the 1.0 μg/mL threshold by 6 months after the last primary dose (combined risk difference -0.02; 95% confidence interval: -0.10, 0.06). Only small differences were seen between schedules starting at different ages, with different intervals between primary doses, or with different intervals between primary and booster doses. Individuals receiving a booster were more likely to be seropositive than those at the same age who did not. CONCLUSIONS There is no clear evidence from trials that any 2p+1, 3p+0 or 3p+1 schedule of Hib conjugate vaccine is likely to provide better protection against Hib disease than other schedules. Until more data become available, scheduling is likely to be determined by epidemiological and programmatic considerations in individual settings.

Clinical outcomes of patients with low-flow, low-gradient, severe aortic stenosis and either preserved or reduced ejection fraction undergoing transcatheter aortic valve implantation

AIMS Our aim was to evaluate the invasive haemodynamic indices of high-risk symptomatic patients presenting with 'paradoxical' low-flow, low-gradient, severe aortic stenosis (AS) (PLF-LG) and low-flow, low-gradient severe AS (LEF-LG) and to compare clinical outcomes following transcatheter aortic valve implantation (TAVI) among these challenging AS subgroups. METHODS AND RESULTS Of 534 symptomatic patients undergoing TAVI, 385 had a full pre-procedural right and left heart catheterization. A total of 208 patients had high-gradient severe AS [HGAS; mean gradient (MG) ≥40 mmHg], 85 had PLF-LG [MG ≤ 40 mmHg, indexed aortic valve area [iAVA] ≤0.6 cm(2) m(-2), stroke volume index ≤35 mL/m(2), ejection fraction (EF) ≥50%], and 61 had LEF-LG (MG ≤ 40 mmHg, iAVA ≤0.6 cm(2) m(-2), EF ≤40%). Compared with HGAS, PLF-LG and LEF-LG had higher systemic vascular resistances (HGAS: 1912 ± 654 vs. PLF-LG 2006 ± 586 vs. LEF-LG 2216 ± 765 dyne s m(-5), P = 0.007) but lower valvulo-arterial impedances (HGAS: 7.8 ± 2.7 vs. PLF-LG 6.9 ± 1.9 vs. LEF-LG 7.7 ± 2.5 mmHg mL(-1) m(-2), P = 0.027). At 30 days, no differences in cardiac death (6.5 vs. 4.9 vs. 6.6%, P = 0.90) or death (8.4 vs. 6.1 vs. 6.6%, P = 0.88) were observed among HGAS, PLF-LG, and LEF-LG groups, respectively. At 1 year, New York Heart Association functional improvement occurred in most surviving patients (HGAS: 69.2% vs. PLF-LG 71.7% vs. LEF-LG 89.3%, P = 0.09) and no significant differences in overall mortality were observed (17.6 vs. 20.5 vs. 24.5%, P = 0.67). Compared with HGAS, LEF-LG had a higher 1 year cardiac mortality (adjusted hazard ratio 2.45, 95% confidence interval 1.04-5.75, P = 0.04). CONCLUSION TAVI in PLF-LG or LEF-LG patients is associated with overall mortality rates comparable with HGAS patients and all groups profit symptomatically to a similar extent.

Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent β--emitters: in vitro and in vivo study of a 44Sc-DOTA-folate conjugate

In recent years, implementation of 68Ga-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of 44Sc (half-life = 3.97 h, average β+ energy [Eβ+av] = 632 keV) as a valuable alternative to 68Ga (half-life = 68 min, Eβ+av = 830 keV) for imaging and dosimetry before 177Lu-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced 44Sc and its in vitro and in vivo comparison with the 177Lu-labeled pendant. Methods: 44Sc was produced via the 44Ca(p,n)44Sc nuclear reaction at a cyclotron (17.6 ± 1.8 MeV, 50 μA, 30 min) using an enriched 44Ca target (10 mg 44CaCO3, 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95°C within 10 min. The stability of 44Sc-cm09 was tested in human plasma. 44Sc-cm09 was investigated in vitro using folate receptor–positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice Results: Under the given irradiation conditions, 44Sc was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of 44Sc from 44Ca targets allowed formulation of up to 300 MBq of 44Sc in a volume of 200–400 μL of ammonium acetate/HCl solution (1 M, pH 3.5–4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, 44Sc-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor–specific binding to KB tumor cells. PET/CT images of mice injected with 44Sc-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with 44Sc and 177Lu revealed almost identical pharmacokinetics. Conclusion: This study presents a high-yield production and efficient separation method of 44Sc at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of 44Sc for PET imaging. Thus, 44Sc is a valid alternative to 68Ga for imaging and dosimetry before 177Lu-radionuclide tumor therapy.

Identification of the Causative Bacteria in Musculoskeletal Infections Using 16s rDNA - Denaturing Gradient Gel Electrophoresis Analysis

Musculoskeletal infections are infections of the bone and surrounding tissues. They are currently diagnosed based on culture analysis, which is the gold standard for pathogen identification. However, these clinical laboratory methods are frequently inadequate for the identification of the causative agents, because a large percentage (25-50%) of confirmed musculoskeletal infections are false negatives in which no pathogen is identified in culture. My data supports these results. The goal of this project was to use PCR amplification of a portion of the 16S rRNA gene to test an alternative approach for the identification of these pathogens and to assess the diversity of the bacteria involved. The advantages of this alternative method are that it should increase sample sensitivity and the speed of detection. In addition, bacteria that are non-culturable or in low abundance can be detected using this molecular technique. However, a complication of this approach is that the majority of musculoskeletal infections are polymicrobial, which prohibits direct identification from the infected tissue by DNA sequencing of the initial 16S rDNA amplification products. One way to solve this problem is to use denaturing gradient gel electrophoresis (DGGE) to separate the PCR products before DNA sequencing. Denaturing gradient gel electrophoresis (DGGE) separates DNA molecules based on their melting point, which is determined by their DNA sequence. This analytical technique allows a mixture of PCR products of the same length that electrophoreses through agarose gels as one band, to be separated into different bands and then used for DNA sequence analysis. In this way, the DGGE allows for the identification of individual bacterial species in polymicrobial-infected tissue, which is critical for improving clinical outcomes. By combining the 16S rDNA amplification and the DGGE techniques together, an alternative approach for identification has been used. The 16S rRNA gene PCR-DGGE method includes several critical steps: DNA extraction from tissue biopsies, amplification of the bacterial DNA, PCR product separation by DGGE, amplification of the gel-extracted DNA, and DNA sequencing and analysis. Each step of the method was optimized to increase its sensitivity and for rapid detection of the bacteria present in human tissue samples. The limit of detection for the DNA extraction from tissue was at least 20 Staphylococcus aureus cells and the limit of detection for PCR was at least 0.05 pg of template DNA. The conditions for DGGE electrophoreses were optimized by using a double gradient of acrylamide (6 – 10%) and denaturant (30-70%), which increased the separation between distinct PCR products. The use of GelRed (Biotium) improved the DNA visualization in the DGGE gel. To recover the DNA from the DGGE gels the gel slices were excised, shredded in a bead beater, and the DNA was allowed to diffuse into sterile water overnight. The use of primers containing specific linkers allowed the entire amplified PCR product to be sequenced and then analyzed. The optimized 16S rRNA gene PCR-DGGE method was used to analyze 50 tissue biopsy samples chosen randomly from our collection. The results were compared to those of the Memorial Hermann Hospital Clinical Microbiology Laboratory for the same samples. The molecular method was congruent for 10 of the 17 (59%) culture negative tissue samples. In 7 of the 17 (41%) culture negative the molecular method identified a bacterium. The molecular method was congruent with the culture identification for 7 of the 33 (21%) positive cultured tissue samples. However, in 8 of the 33 (24%) the molecular method identified more organisms. In 13 of the 15 (87%) polymicrobial cultured tissue samples the molecular method identified at least one organism that was also identified by culture techniques. Overall, the DGGE analysis of 16S rDNA is an effective method to identify bacteria not identified by culture analysis.

Pulmonary veins to left atrium cycle length gradient predicts procedural and clinical outcomes of persistent atrial fibrillation ablation.

BACKGROUND Rapid pulmonary vein (PV) activity has been shown to maintain paroxysmal atrial fibrillation (AF). We evaluated in persistent AF the cycle length (CL) gradient between PVs and the left atrium (LA) in an attempt to identify the subset of patients where PVs play an important role. METHODS AND RESULTS Ninety-seven consecutive patients undergoing first ablation for persistent AF were studied. For each PV, the CL of the fastest activation was assessed over 1 minute (PVfast) using Lasso recordings. The PV to LA CL gradient was quantified by the ratio of PVfast to LA appendage (LAA) AF CL. Stepwise ablation terminated AF in 73 patients (75%). In the AF termination group, the PVfast CL was much shorter than the LAA CL resulting in lower PVfast/LAA ratios compared with the nontermination group (71±10% versus 92±7%; P<0.001). Within the termination group, PVfast/LAA ratios were notably lower if AF terminated after PV isolation or limited adjunctive substrate ablation compared with patients who required moderate or extensive ablation (63±6% versus 75±8%; P<0.001). PVfast/LAA ratio <69% predicted AF termination after PV isolation or limited substrate ablation with 74% positive predictive value and 95% negative predictive value. After a mean follow-up of 29±17 months, freedom from arrhythmia recurrence off-antiarrhythmic drugs was achieved in most patients with PVfast/LAA ratios <69% as opposed to the remaining population (80% versus 43%; P<0.001). CONCLUSIONS The PV to LA CL gradient may identify the subset of patients in whom persistent AF is likely to terminate after PV isolation or limited substrate ablation and better long-term outcomes are achieved.

Impact of mitral regurgitation on clinical outcomes of patients with low-ejection fraction, low-gradient severe aortic stenosis undergoing transcatheter aortic valve implantation.

BACKGROUND Up to 1 in 6 patients undergoing transcatheter aortic valve implantation (TAVI) present with low-ejection fraction, low-gradient (LEF-LG) severe aortic stenosis and concomitant relevant mitral regurgitation (MR) is present in 30% to 55% of these patients. The effect of MR on clinical outcomes of LEF-LG patients undergoing TAVI is unknown. METHODS AND RESULTS Of 606 consecutive patients undergoing TAVI, 113 (18.7%) patients with LEF-LG severe aortic stenosis (mean gradient ≤40 mm Hg, aortic valve area <1.0 cm(2), left ventricular ejection fraction <50%) were analyzed. LEF-LG patients were dichotomized into ≤mild MR (n=52) and ≥moderate MR (n=61). Primary end point was all-cause mortality at 1 year. No differences in mortality were observed at 30 days (P=0.76). At 1 year, LEF-LG patients with ≥moderate MR had an adjusted 3-fold higher rate of all-cause mortality (11.5% versus 38.1%; adjusted hazard ratio, 3.27 [95% confidence interval, 1.31-8.15]; P=0.011), as compared with LEF-LG patients with ≤mild MR. Mortality was mainly driven by cardiac death (adjusted hazard ratio, 4.62; P=0.005). As compared with LEF-LG patients with ≥moderate MR assigned to medical therapy, LEF-LG patients with ≥moderate MR undergoing TAVI had significantly lower all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.019-0.75) at 1 year. CONCLUSIONS Moderate or severe MR is a strong independent predictor of late mortality in LEF-LG patients undergoing TAVI. However, LEF-LG patients assigned to medical therapy have a dismal prognosis independent of MR severity suggesting that TAVI should not be withheld from symptomatic patients with LEF-LG severe aortic stenosis even in the presence of moderate or severe MR.