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\"Lake Charles: 1908-1926 Along the cool sequester'd vale of life, They kept the noiseless tenor of their way. September 23, 1996 KLM Flight 287 rolled to a seamless stop on the tarmac, and settled on its wheels under the translucent Moscow sky. A contingent of American heart surgeons and support staff blinked and stretched. Their leader was famous for dozing off as soon as the wheels were up on any flight of length, and more than one of his retinue had mimicked that feat on this last leg of their journey from Houston via Amsterdam. This was not the first sojourn to Russia for their Chief - that had been back in 1958, when the country had another name and quite another polity. Many other visits had followed, accompanied by accolades and fetes, mostly with a Cold War political undertone he neither shared nor acknowledged. By nature he was fond of reflecting on change and history, and he did not miss the significance of returning to this place, the both of them now so different, in a position to alter the life path of a man who, himself, was responsible for much of this country's metamorphosis. The President of Russia, Boris Yeltsin, was suffering from congestive heart failure and severe coronary artery disease. The situation was grave; he was not expected to live without open-heart surgery - coronary bypass - but it was not clear that he could survive the procedure itself. The leading Russian heart surgeons and cardiologists had asked this Houston team to come to Moscow to assess the risks and provide recommendations as to how to proceed. In the geopolitically-charged climate of the immediate post-Cold War period, bringing in a coterie of Americans as consultants on the medical care of the most powerful man in Russia provoked all manner of responses on both sides of the Atlantic. The world's major news organizations focused on the story, covering every aspect. This fuss was of little consequence to the team from Texas, however. They were there to do a job, and their very presence in the Russian capital was as much of a validation as any that they were the most qualified group in the world for the task\"-- Provided by publisher.

Vaccination complacency occurs when perceived risks of vaccine-preventable diseases are sufficiently low so that vaccination is no longer perceived as a necessary precaution. Disease outbreaks can once again increase perceptions of risk, thereby decrease vaccine complacency, and in turn decrease vaccine hesitancy. It is not well understood, however, how change in perceived risk translates into change in vaccine hesitancy. We advance the concept of vaccine propensity, which relates a change in willingness to vaccinate with a change in perceived risk of infection-holding fixed other considerations such as vaccine confidence and convenience. We used an original survey instrument that presents 7 vaccine-preventable \"new\" diseases to gather demographically diverse sample data from the United States in 2018 (N = 2,411). Our survey was conducted online between January 25, 2018, and February 2, 2018, and was structured in 3 parts. First, we collected information concerning the places participants live and visit in a typical week. Second, participants were presented with one of 7 hypothetical disease outbreaks and asked how they would respond. Third, we collected sociodemographic information. The survey was designed to match population parameters in the US on 5 major dimensions: age, sex, income, race, and census region. We also were able to closely match education. The aggregate demographic details for study participants were a mean age of 43.80 years, 47% male and 53% female, 38.5% with a college degree, and 24% nonwhite. We found an overall change of at least 30% in proportion willing to vaccinate as risk of infection increases. When considering morbidity information, the proportion willing to vaccinate went from 0.476 (0.449-0.503) at 0 local cases of disease to 0.871 (0.852-0.888) at 100 local cases (upper and lower 95% confidence intervals). When considering mortality information, the proportion went from 0.526 (0.494-0.557) at 0 local cases of disease to 0.916 (0.897-0.931) at 100 local cases. In addition, we ffound that the risk of mortality invokes a larger proportion willing to vaccinate than mere morbidity (P = 0.0002), that older populations are more willing than younger (P<0.0001), that the highest income bracket (>$90,000) is more willing than all others (P = 0.0001), that men are more willing than women (P = 0.0011), and that the proportion willing to vaccinate is related to both ideology and the level of risk (P = 0.004). Limitations of this study include that it does not consider how other factors (such as social influence) interact with local case counts in people's vaccine decision-making, it cannot determine whether different degrees of severity in morbidity or mortality failed to be statistically significant because of survey design or because participants use heuristically driven decision-making that glosses over degrees, and the study does not capture the part of the US that is not online. In this study, we found that different degrees of risk (in terms of local cases of disease) correspond with different proportions of populations willing to vaccinate. We also identified several sociodemographic aspects of vaccine propensity. Understanding how vaccine propensity is affected by sociodemographic factors is invaluable for predicting where outbreaks are more likely to occur and their expected size, even with the resulting cascade of changing vaccination rates and the respective feedback on potential outbreaks.

This study examines use of an expandable bovine pericardial prosthetic valve inserted with a catheter system for valvular aortic stenosis. Outcomes were noninferior to those of surgical aortic-valve replacement, but the risk of stroke, aortic regurgitation, and vascular complications was substantial. After the appearance of symptoms, aortic stenosis is associated with a high rate of death if left untreated. 1 – 10 Although surgical aortic-valve replacement improves symptoms and survival, 11 – 15 observational studies have identified various subgroups of patients (i.e., those with an advanced age and those with poor left ventricular function or other coexisting disorders) who are at increased risk for operative complications or death. 16 – 21 In such patients, a less invasive treatment may be a desirable alternative. Transcatheter aortic-valve replacement treats aortic stenosis by displacing and functionally replacing the native valve with a bioprosthetic valve delivered on a catheter through the . . .

Background Computational methods of predicting protein stability changes upon missense mutations are invaluable tools in high-throughput studies involving a large number of protein variants. However, they are limited by a wide variation in accuracy and difficulty of assessing prediction uncertainty. Using a popular computational tool, FoldX, we develop a statistical framework that quantifies the uncertainty of predicted changes in protein stability. Results We show that multiple linear regression models can be used to quantify the uncertainty associated with FoldX prediction for individual mutations. Comparing the performance among models with varying degrees of complexity, we find that the model precision improves significantly when we utilize molecular dynamics simulation as part of the FoldX workflow. Based on the model that incorporates information from molecular dynamics, biochemical properties, as well as FoldX energy terms, we can generally expect upper bounds on the uncertainty of folding stability predictions of ± 2.9 kcal/mol and ± 3.5 kcal/mol for binding stability predictions. The uncertainty for individual mutations varies; our model estimates it using FoldX energy terms, biochemical properties of the mutated residue, as well as the variability among snapshots from molecular dynamics simulation. Conclusions Using a linear regression framework, we construct models to predict the uncertainty associated with FoldX prediction of stability changes upon mutation. This technique is straightforward and can be extended to other computational methods as well.

The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that mortality at 1 year, 2 years, and 3 years is much the same with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) for high-risk patients with aortic stenosis. We report here the 5-year outcomes. We did this randomised controlled trial at 25 hospitals, in Canada (two), Germany (one), and the USA (23). We used a computer-generated randomisation sequence to randomly assign high-risk patients with severe aortic stenosis to either SAVR or TAVR with a balloon-expandable bovine pericardial tissue valve by either a transfemoral or transapical approach. Patients and their treating physicians were not masked to treatment allocation. The primary outcome of the trial was all-cause mortality in the intention-to-treat population at 1 year, we present here predefined outcomes at 5 years. The study is registered with ClinicalTrials.gov, number NCT00530894. We screened 3105 patients, of whom 699 were enrolled (348 assigned to TAVR, 351 assigned to SAVR). Overall mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 11·7%. At 5 years, risk of death was 67·8% in the TAVR group compared with 62·4% in the SAVR group (hazard ratio 1·04, 95% CI 0·86–1·24; p=0·76). We recorded no structural valve deterioration requiring surgical valve replacement in either group. Moderate or severe aortic regurgitation occurred in 40 (14%) of 280 patients in the TAVR group and two (1%) of 228 in the SAVR group (p<0·0001), and was associated with increased 5-year risk of mortality in the TAVR group (72·4% for moderate or severe aortic regurgitation vs 56·6% for those with mild aortic regurgitation or less; p=0·003). Our findings show that TAVR as an alternative to surgery for patients with high surgical risk results in similar clinical outcomes. Edwards Lifesciences.

Early public health strategies to prevent the spread of COVID-19 in the United States relied on non-pharmaceutical interventions (NPIs) as vaccines and therapeutic treatments were not yet available. Implementation of NPIs, primarily social distancing and mask wearing, varied widely between communities within the US due to variable government mandates, as well as differences in attitudes and opinions. To understand the interplay of trust, risk perception, behavioral intention, and disease burden, we developed a survey instrument to study attitudes concerning COVID-19 and pandemic behavioral change in three states: Idaho, Texas, and Vermont. We designed our survey ( n = 1034) to detect whether these relationships were significantly different in rural populations. The best fitting structural equation models show that trust indirectly affects protective pandemic behaviors via health and economic risk perception. We explore two different variations of this social cognitive model: the first assumes behavioral intention affects future disease burden while the second assumes that observed disease burden affects behavioral intention. In our models we include several exogenous variables to control for demographic and geographic effects. Notably, political ideology is the only exogenous variable which significantly affects all aspects of the social cognitive model (trust, risk perception, and behavioral intention). While there is a direct negative effect associated with rurality on disease burden, likely due to the protective effect of low population density in the early pandemic waves, we found a marginally significant, positive, indirect effect of rurality on disease burden via decreased trust ( p = 0.095). This trust deficit creates additional vulnerabilities to COVID-19 in rural communities which also have reduced healthcare capacity. Increasing trust by methods such as in-group messaging could potentially remove some of the disparities inferred by our models and increase NPI effectiveness.

Based on the early results of the Placement of Aortic Transcatheter Valves (PARTNER) trial, transcatheter aortic valve replacement (TAVR) is an accepted treatment for patients with severe aortic stenosis who are not suitable for surgery. However, little information is available about the late clinical outcomes in such patients. We did this randomised controlled trial at 21 experienced valve centres in Canada, Germany, and the USA. We enrolled patients with severe symptomatic inoperable aortic stenosis and randomly assigned (1:1) them to transfemoral TAVR or to standard treatment, which often included balloon aortic valvuloplasty. Patients and their treating physicians were not masked to treatment allocation. The randomisation was done centrally, and sites learned of the assignment only after a patient had been screened, consented, and entered into the database. The primary outcome of the trial was all-cause mortality at 1 year in the intention-to-treat population, here we present the prespecified findings after 5 years. This study is registered with ClinicalTrials.gov, number NCT00530894. We screened 3015 patients, of whom 358 were enrolled (mean age 83 years, Society of Thoracic Surgeons Predicted Risk of Mortality 11·7%, 54% female). 179 were assigned to TAVR treatment and 179 were assigned to standard treatment. 20 patients crossed over from the standard treatment group and ten withdrew from study, leaving only six patients at 5 years, of whom five had aortic valve replacement treatment outside of the study. The risk of all-cause mortality at 5 years was 71·8% in the TAVR group versus 93·6% in the standard treatment group (hazard ratio 0·50, 95% CI 0·39–0·65; p<0·0001). At 5 years, 42 (86%) of 49 survivors in the TAVR group had New York Heart Association class 1 or 2 symptoms compared with three (60%) of five in the standard treatment group. Echocardiography after TAVR showed durable haemodynamic benefit (aortic valve area 1·52 cm2 at 5 years, mean gradient 10·6 mm Hg at 5 years), with no evidence of structural valve deterioration. TAVR is more beneficial than standard treatment for treatment of inoperable aortic stenosis. TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement to improve their survival and functional status. Appropriate selection of patients will help to maximise the benefit of TAVR and reduce mortality from severe comorbidities. Edwards Lifesciences.

Changes in developmental gene regulatory networks enable evolved changes in morphology. These changes can be in cis regulatory elements that act in an allele-specific manner, or changes to the overall trans regulatory environment that interacts with cis regulatory sequences. Here we address several questions about the evolution of gene expression accompanying a convergently evolved constructive morphological trait, increases in tooth number in two independently derived freshwater populations of threespine stickleback fish (Gasterosteus aculeatus). Are convergently evolved cis and/or trans changes in gene expression associated with convergently evolved morphological evolution? Do cis or trans regulatory changes contribute more to gene expression changes accompanying an evolved morphological gain trait? Transcriptome data from dental tissue of ancestral low-toothed and two independently derived high-toothed stickleback populations revealed significantly shared gene expression changes that have convergently evolved in the two high-toothed populations. Comparing cis and trans regulatory changes using phased gene expression data from F1 hybrids, we found that trans regulatory changes were predominant and more likely to be shared among both high-toothed populations. In contrast, while cis regulatory changes have evolved in both high-toothed populations, overall these changes were distinct and not shared among high-toothed populations. Together these data suggest that a convergently evolved trait can occur through genetically distinct regulatory changes that converge on similar trans regulatory environments.

The larval tobacco hornworm, Manduca sexta , has been used in a laboratory setting for physiological studies and for pathogen virulence studies. This moth offers a much larger size than the commonly used wax moth ( Galleria mellonella ), and it can thus be used for a greater variety of assays, such as repeated sampling of the same individual, growth measurements, and tissue sampling. Yet their occasional use in research has led to a minimally documented set of rearing methods. To facilitate further adoption of this insect model, we expanded on previously reported protocols and developed our own rearing methods, which we report here. Our protocol requires little specialized equipment, with a cost less than $100/month for the feeding and maintenance of a laboratory colony of about five hundred larvae of differing instar phases. The low cost generalized equipment and supplies, and the simplification of the standardized protocols allows for an easy entry point for rearing tobacco hornworm populations. We also describe a few methods that are relevant to the uses of these organisms as infection models.