Comparing the cost-effectiveness of two- and three-dose schedules of human papillomavirus vaccination: a transmission-dynamic modelling study.

BACKGROUND: Recent evidence suggests that two doses of HPV vaccines may be as protective as three doses in the short-term. We estimated the incremental cost-effectiveness of two- and three-dose schedules of girls-only and girls & boys HPV vaccination programmes in Canada. METHODS: We used HPV-ADVISE, an individual-based transmission-dynamic model of multi-type HPV infection and diseases (anogenital warts, and cancers of the cervix, vulva, vagina, anus, penis and oropharynx). We conducted the analysis from the health payer perspective, with a 70-year time horizon and 3% discount rate, and performed extensive sensitivity analyses, including duration of vaccine protection and vaccine cost. FINDINGS: Assuming 80% coverage and a vaccine cost per dose of $85, two-dose girls-only vaccination (vs. no vaccination) produced cost/quality-adjusted life-year (QALY)-gained varying between$7900-24,300. The incremental cost-effectiveness ratio of giving the third dose to girls (vs. two doses) was below $40,000/QALY-gained when: (i) three doses provide longer protection than two doses and (ii) two-dose protection was shorter than 30 years. Vaccinating boys (with two or three doses) was not cost-effective (vs. girls-only vaccination) under most scenarios investigated. INTERPRETATION: Two-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls

Coronary Obstruction Following Transcatheter Aortic Valve Implantation for Degenerative Bioprosthetic Surgical Valves: a Systematic Literature Review

ABSTRACTBackgroundVery few data exist on coronary obstruction following transcatheter aortic valve implantation (TAVI) for degenerative bioprosthetic valves (valve-in-valve [ViV]). The present trial evaluated, through a systematic review of the literature, the clinical characteristics, management and clinical outcomes of patients with coronary obstruction after ViV-TAVI.MethodsStudies published between 2002 and 2013 evaluating coronary obstruction as a complication of ViV-TAVI were identified using a systematic electronic search. Data on the clinical and procedural characteristics, management of the complication, and clinical outcomes were analyzed.ResultsA total of four publications describing seven patients were identified. Most patients (71%) were women, with mean age of 82±5 years, and STS-PROM score of 9.4±2.6%. Mean left coronary artery (LCA) ostium height and aortic root width were 8.8±1.5mm and 28.0±5.0mm, respectively. Most patients had stented bioprosthetic valves with externally mounted leaflets or stentless aortic bioprosthesis, and the LCA was involved in all patients. Percutaneous coronary intervention (PCI) was attempted in all patients and was successful in four (57%). In-hospital mortality was 42.9% (three cases), all of them after failed PCI.ConclusionsCoronary obstruction following ViV-TAVI occurred more frequently in women with stented bioprosthetic valves with externally mounted leaflets or with stentless bioprosthesis. The LCA was involved in all cases and PCI was successful in 60% of them. Continued efforts may help identify the factors associated with this complication so that appropriate prevention measures may be implemented

Early childhood development of visual texture segregation in full-term and preterm children

AbstractTo date, very little is known about the normal development trajectory of visual texture segregation, or how it is affected by preterm birth. The goal of this study was to characterize the development of visual texture segregation using texture segregation visual evoked potentials (tsVEPs) in children born full-term and children born preterm without major neurological impairment. Forty-five full-term and 43 preterm children were tested at either 12, 24 or 36months of age (corrected age for prematurity at 12 and 24months old). VEPs were obtained using two lower-level stimuli defined by orientation (oriVEP) and two higher-level stimuli defined by texture (texVEP). TsVEP was obtained by dividing by two the subtraction of oriVEP from texVEP. Results show a clear maturation of the processes underlying visual texture segregation in the full-term group, with a significant N2 latency reduction between 12 and 36months of age for all conditions. Significant N2 amplitude reduction was observed for oriVEP between 12 and 24months, as well as for texVEP between 12 and 24months, and 12 and 36months. Comparison between full-term and preterm children indicated significantly lower N2 amplitude for the preterm group at 12months for oriVEP and texVEP. These differences were no longer apparent at 24months of age, suggesting that children born preterm catch up with their full-term counterparts somewhere between 12 and 24months of age. Our results appear to reflect a maturational delay in preterm children in both lower-level and higher-level visual processing during, at least, early childhood

Impact of Low Flow on the Outcome of High-Risk Patients Undergoing Transcatheter Aortic Valve Replacement

ObjectivesThis study sought to assess the impact of baseline left ventricular (LV) outflow, LV ejection fraction (LVEF), and transvalvular gradient on outcomes following transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis (AS).BackgroundLow flow (i.e., reduced stroke volume index [SVi]) can occur with both reduced and preserved LVEF. Low flow is often associated with low gradient despite severe stenosis and with worse outcomes following surgical aortic valve replacement. However, there are few data about the impact of low flow on outcomes following TAVR.MethodsWe retrospectively analyzed the clinical, Doppler-echocardiographic, and outcome data prospectively collected in 639 patients who underwent TAVR for symptomatic severe AS in 2 Canadian centers.ResultsIn this cohort, 334 (52.3%) patients had a low flow (SVi <35 ml/m2) and these patients had increased 30-day mortality (11.4 vs. 5.9%, p = 0.01), 2-year all-cause mortality (35.3 vs. 30.9%, p = 0.005), and 2-year cardiovascular mortality (25.7 vs. 16.8%, p = 0.01) compared with patients with normal flow. Reduced flow was an independent predictor of 30-day mortality (odds ratio: 1.94, p = 0.026), cumulative all-cause mortality (hazard ratio: 1.27 per 10 ml/m² SVi decrease, p = 0.016), and cumulative cardiovascular mortality (hazard ratio: 1.29 per 10 ml/m² decrease, p = 0.04). Despite significant association in univariable analyses, low LVEF and low mean gradient were not found to be independent predictors of outcomes in multivariable analyses.ConclusionsLow flow but not low LVEF or low gradient is an independent predictor of early and late mortality following TAVR in high-risk patients with severe AS. SVi should be integrated in the risk stratification process of these patients

Incidence, predictive factors and haemodynamic consequences of acute stent recoil following transcatheter aortic valve implantation with a balloon-expandable valve

Aims: The elastic behaviour (acute recoil) of a valve prosthesis stent following transcatheter aortic valve implantation (TAVI) is unknown. This study sought to determine the occurrence, severity, predictive factors and haemodynamic consequences of acute recoil following TAVI. Methods and results : A prospective angiographic analysis of the stent frame dimensions in 111 consecutive patients who underwent TAVI with a balloon-expandable valve (36 Edwards SAPIEN; 75 SAPIEN XT) was performed. Acute recoil was defined as the difference between minimal lumen diameter (MLD) at full balloon expansion and immediately after balloon deflation. MLD during balloon inflation was significantly larger than MLD after balloon deflation (23.40±2.31 mm vs. 22.29±2.21 mm, p<0.001), which represented an absolute and percent decrease in stent dimension of 1.10±0.40 mm and 4.70±1.76%, respectively. In the multivariate analysis, the predictors of larger recoil were a higher prosthesis/annulus ratio (r²=0.0624, p=0.015) and the SAPIEN XT prosthesis (r²=0.1276, p=0.001). No significant changes in haemodynamic performance were observed at discharge and follow-up in patients with larger recoil. Conclusions : TAVI with a balloon-expandable valve was systematically associated with a certain degree of valve stent recoil after balloon deflation. A higher degree of valve oversizing and the SAPIEN XT prosthesis predicted a larger degree of stent recoil

Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss

The Src substrate associated in mitosis of 68 kDa (Sam68) is a KH-type RNA binding protein that has been shown to regulate several aspects of RNA metabolism; however, its physiologic role has remained elusive. Herein we report the generation of Sam68-null mice by homologous recombination. Aged Sam68(−/−) mice preserved their bone mass, in sharp contrast with 12-month-old wild-type littermates in which bone mass was decreased up to approximately 75%. In fact, the bone volume of the 12-month-old Sam68(−/−) mice was virtually indistinguishable from that of 4-month-old wild-type or Sam68(−/−) mice. Sam68(−/−) bone marrow stromal cells had a differentiation advantage for the osteogenic pathway. Moreover, the knockdown of Sam68 using short hairpin RNA in the embryonic mesenchymal multipotential progenitor C3H10T1/2 cells resulted in more pronounced expression of the mature osteoblast marker osteocalcin when differentiation was induced with bone morphogenetic protein-2. Cultures of mouse embryo fibroblasts generated from Sam68(+/+) and Sam68(−/−) littermates were induced to differentiate into adipocytes with culture medium containing pioglitazone and the Sam68(−/−) mouse embryo fibroblasts shown to have impaired adipocyte differentiation. Furthermore, in vivo it was shown that sections of bone from 12-month-old Sam68(−/−) mice had few marrow adipocytes compared with their age-matched wild-type littermate controls, which exhibited fatty bone marrow. Our findings identify endogenous Sam68 as a positive regulator of adipocyte differentiation and a negative regulator of osteoblast differentiation, which is consistent with Sam68 being a modulator of bone marrow mesenchymal cell differentiation, and hence bone metabolism, in aged mice

Correlating Global Gene Regulation to Angiogenesis in the Developing Chick Extra-Embryonic Vascular System

International audienceBACKGROUND: Formation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis. METHOLOGY/PRINCIPAL FINDINGS: We accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21-66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process. CONCLUSIONS/SIGNIFICANCE: Our study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

SignificanceThere is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population