Impact of a Right Ventricular Impedance Sensor on the Cardiovascular Responses to Exercise in Pacemaker Dependent Patients

Background. The evaluation of the heart rate (HR) response to exercise is important for the assessment of the rate response algorithm of sensor-controlled pacemakers. This study examined the effects of a right ventricular impedance sensor driven pacemaker on the cardiovascular responses to incremental exercise in pacemaker dependent patients. Methods. Twelve patients (70.5 ± 9.5 years; 5 Females: 7 Males) implanted with an Inos2+ closed loop stimulation (CLS) pacemaker were compared to 12 healthy age and sex matched controls (70.6 ± 4.8 years). All subjects performed the chronotropic assessment exercise protocol (CAEP). Variables of interest included HR, cardiac output (Q), oxygen uptake (Vo2) and blood pressure (BP). Data were analyzed at rest, throughout exercise and during recovery. Furthermore, patient chronotropic responses were compared to a reference chronotropic response slope for aerobic exercise. Results. There were no differences between groups for HR or Q. response throughout exercise. At peak exercise, V.o2 (mL.kg-1.min-1) was higher for the controls (p < 0.05). The patient chronotropic response slope was comparable to the CAEP reference slope from rest to both the anaerobic threshold (AT) and peak exercise. During recovery, no differences were observed between the groups for any parameters or for the HR decay slopes. Conclusions. Up to the anaerobic threshold, the right ventricular impedance sensor driven pacemaker delivered a pacing rate that contributed to an overall cardiovascular response similar to that observed in healthy age matched subjects

Impact of a right ventricular impedance sensor on the cardiovascular responses to exercise in pacemaker dependent patients

BACKGROUND: The evaluation of the heart rate (HR) response to exercise is important for the assessment of the rate response algorithm of sensor-controlled pacemakers. This study examined the effects of a right ventricular impedance sensor driven pacemaker on the cardiovascular responses to incremental exercise in pacemaker dependent patients. METHODS: Twelve patients (70.5 ± 9.5 years; 5 Females: 7 Males) implanted with an Inos (2+) closed loop stimulation (CLS) pacemaker were compared to 12 healthy age and sex matched controls (70.6 ± 4.8 years). All subjects performed the chronotropic assessment exercise protocol (CAEP). Variables of interest included HR, cardiac output (Q), oxygen uptake (Vo(2)) and blood pressure (BP). Data were analyzed at rest, throughout exercise and during recovery. Furthermore, patient chronotropic responses were compared to a reference chronotropic response slope for aerobic exercise. RESULTS: There were no differences between groups for HR or Q response throughout exercise. At peak exercise, Vo(2) (mL.kg(-1).min(-1)) was higher for the controls (p < 0.05). The patient chronotropic response slope was comparable to the CAEP reference slope from rest to both the anaerobic threshold (AT) and peak exercise. During recovery, no differences were observed between the groups for any parameters or for the HR decay slopes. CONCLUSION: Up to the anaerobic threshold, the right ventricular impedance sensor driven pacemaker delivered a pacing rate that contributed to an overall cardiovascular response similar to that observed in healthy age matched subjects

Metabolic modeling of a mutualistic microbial community

The rate of production of methane in many environments depends upon mutualistic interactions between sulfate-reducing bacteria and methanogens. To enhance our understanding of these relationships, we took advantage of the fully sequenced genomes of Desulfovibrio vulgaris and Methanococcus maripaludis to produce and analyze the first multispecies stoichiometric metabolic model. Model results were compared to data on growth of the co-culture on lactate in the absence of sulfate. The model accurately predicted several ecologically relevant characteristics, including the flux of metabolites and the ratio of D. vulgaris to M. maripaludis cells during growth. In addition, the model and our data suggested that it was possible to eliminate formate as an interspecies electron shuttle, but hydrogen transfer was essential for syntrophic growth. Our work demonstrated that reconstructed metabolic networks and stoichiometric models can serve not only to predict metabolic fluxes and growth phenotypes of single organisms, but also to capture growth parameters and community composition of simple bacterial communities

Preclinical evaluation of a candidate naked plasmid DNA vaccine against SARS-CoV-2

New generation plasmid DNA vaccines may be a safe, fast and simple emergency vaccine platform for preparedness against emerging viral pathogens. Applying platform optimization strategies, we tested the pre-clinical immunogenicity and protective effect of a candidate DNA plasmid vaccine specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The DNA vaccine induced spike-specific binding IgG and neutralizing antibodies in mice, rabbits, and rhesus macaques together with robust Th1 dominant cellular responses in small animals. Intradermal and intramuscular needle-free administration of the DNA vaccine yielded comparable immune responses. In a vaccination-challenge study of rhesus macaques, the vaccine demonstrated protection from viral replication in the lungs following intranasal and intratracheal inoculation with SARS-CoV-2. In conclusion, the candidate plasmid DNA vaccine encoding the SARS-CoV-2 spike protein is immunogenic in different models and confers protection against lung infection in nonhuman primates. Further evaluation of this DNA vaccine candidate in clinical trials is warranted.Peer Reviewe

The enlightenment faith in progress and social science

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Bibliography: leaves 111-120.Not availabl

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR