There is a paucity of data on incidence, prevalence and mortality associated with non-cystic fibrosis bronchiectasis.Using the Clinical Practice Research Datalink for participants registered between ...January 1, 2004 and December 31, 2013, we determined incidence, prevalence and mortality associated with bronchiectasis in the UK and investigated changes over time.The incidence and point prevalence of bronchiectasis increased yearly during the study period. Across all age groups, the incidence in women increased from 21.2 per 100 000 person-years in 2004 to 35.2 per 100 000 person-years in 2013 and in men from 18.2 per 100 000 person-years in 2004 to 26.9 per 100 000 person-years in 2013. The point prevalence in women increased from 350.5 per 100 000 in 2004 to 566.1 per 100 000 in 2013 and in men from 301.2 per 100 000 in 2004 to 485.5 per 100 000 in 2013. Comparing morality rates in women and men with bronchiectasis in England and Wales (n=11 862) with mortality rates in the general population from Office of National Statistics data showed that in women the age-adjusted mortality rate for the bronchiectasis population was 1437.7 per 100 000 and for the general population 635.9 per 100 000 (comparative mortality figure of 2.26). In men, the age-adjusted mortality rate for the bronchiectasis population was 1914.6 per 100 000 and for the general population 895.2 per 100 000 (comparative mortality figure of 2.14).Bronchiectasis is surprisingly common and is increasing in incidence and prevalence in the UK, particularly in older age groups. Bronchiectasis is associated with a markedly increased mortality.
Vaccines, when available, will likely become our best tool to control the COVID-19 pandemic. Even in the most optimistic scenarios, vaccine shortages will likely occur. Using an age-stratified ...mathematical model paired with optimization algorithms, we determined optimal vaccine allocation for four different metrics (deaths, symptomatic infections, and maximum non-ICU and ICU hospitalizations) under many scenarios. We find that a vaccine with effectiveness ≥50% would be enough to substantially mitigate the ongoing pandemic, provided that a high percentage of the population is optimally vaccinated. When minimizing deaths, we find that for low vaccine effectiveness, irrespective of vaccination coverage, it is optimal to allocate vaccine to high-risk (older) age groups first. In contrast, for higher vaccine effectiveness, there is a switch to allocate vaccine to high-transmission (younger) age groups first for high vaccination coverage. While there are other societal and ethical considerations, this work can provide an evidence-based rationale for vaccine prioritization.
The goal congruity perspective provides a theoretical framework to understand how motivational processes influence and are influenced by social roles. In particular, we invoke this framework to ...understand communal goal processes as proximal motivators of decisions to engage in science, technology, engineering, and mathematics (STEM). STEM fields are not perceived as affording communal opportunities to work with or help others, and understanding these perceived goal affordances can inform knowledge about differences between (a) STEM and other career pathways and (b) women’s and men’s choices. We review the patterning of gender disparities in STEM that leads to a focus on communal goal congruity (Part I), provide evidence for the foundational logic of the perspective (Part II), and explore the implications for research and policy (Part III). Understanding and transmitting the opportunities for communal goal pursuit within STEM can reap widespread benefits for broadening and deepening participation.
Scientists are trained to evaluate and interpret evidence without bias or subjectivity. Thus, growing evidence revealing a gender bias against women—or favoring men—within science, technology, ...engineering, and mathematics (STEM) settings is provocative and raises questions about the extent to which gender bias may contribute to women’s underrepresentation within STEM fields. To the extent that research illustrating gender bias in STEM is viewed as convincing, the culture of science can begin to address the bias. However, are men and women equally receptive to this type of experimental evidence? This question was tested with three randomized, double-blind experiments—two involving samples from the general public (n= 205 and 303, respectively) and one involving a sample of university STEM and non-STEM faculty (n= 205). In all experiments, participants read an actual journal abstract reporting gender bias in a STEM context (or an altered abstract reporting no gender bias in experiment 3) and evaluated the overall quality of the research. Results across experiments showed that men evaluate the gender-bias research less favorably than women, and, of concern, this gender difference was especially prominent among STEM faculty (experiment 2). These results suggest a relative reluctance among men, especially faculty men within STEM, to accept evidence of gender biases in STEM. This finding is problematic because broadening the participation of underrepresented people in STEM, including women, necessarily requires a widespread willingness (particularly by those in the majority) to acknowledge that bias exists before transformation is possible.
Efficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is "Crabtree positive", displaying a rapid metabolic switch from the ...assimilation of alternative carbon sources to sugars. Following exposure to sugars, this switch is mediated by the transcriptional repression of genes (carbon catabolite repression) and the turnover (catabolite inactivation) of enzymes involved in the assimilation of alternative carbon sources. The pathogenic yeast Candida albicans is Crabtree negative. It has retained carbon catabolite repression mechanisms, but has undergone posttranscriptional rewiring such that gluconeogenic and glyoxylate cycle enzymes are not subject to ubiquitin-mediated catabolite inactivation. Consequently, when glucose becomes available, C. albicans can continue to assimilate alternative carbon sources alongside the glucose. We show that this metabolic flexibility promotes host colonization and virulence. The glyoxylate cycle enzyme isocitrate lyase (CaIcl1) was rendered sensitive to ubiquitin-mediated catabolite inactivation in C. albicans by addition of a ubiquitination site. This mutation, which inhibits lactate assimilation in the presence of glucose, reduces the ability of C. albicans cells to withstand macrophage killing, colonize the gastrointestinal tract and cause systemic infections in mice. Interestingly, most S. cerevisiae clinical isolates we examined (67%) have acquired the ability to assimilate lactate in the presence of glucose (i.e. they have become Crabtree negative). These S. cerevisiae strains are more resistant to macrophage killing than Crabtree positive clinical isolates. Moreover, Crabtree negative S. cerevisiae mutants that lack Gid8, a key component of the Glucose-Induced Degradation complex, are more resistant to macrophage killing and display increased virulence in immunocompromised mice. Thus, while Crabtree positivity might impart a fitness advantage for yeasts in environmental niches, the more flexible carbon assimilation strategies offered by Crabtree negativity enhance the ability of yeasts to colonize and infect the mammalian host.
Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the ...incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection.
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe.
Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval CI, 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups.
A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).
Structural MRI allows unparalleled in vivo study of the anatomy of the developing human brain. For more than two decades 1, MRI research has revealed many new aspects of this multifaceted maturation ...process, significantly augmenting scientific knowledge gathered from postmortem studies. Postnatal brain development is notably protracted and involves considerable changes in cerebral cortical 2–4, subcortical 5, and cerebellar 6, 7 structures, as well as significant architectural changes in white matter fiber tracts 8–11 (see 12). Although much work has described isolated features of neuroanatomical development, it remains a critical challenge to characterize the multidimensional nature of brain anatomy, capturing different phases of development among individuals. Capitalizing on key advances in multisite, multimodal MRI, and using cross-validated nonlinear modeling, we demonstrate that developmental brain phase can be assessed with much greater precision than has been possible using other biological measures, accounting for more than 92% of the variance in age. Further, our composite metric of morphology, diffusivity, and signal intensity shows that the average difference in phase among children of the same age is only about 1 year, revealing for the first time a latent phenotype in the human brain for which maturation timing is tightly controlled.
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► Multimodal neuroanatomical measures predict child age with greater than 92% accuracy ► Morphology, diffusivity, and signal intensity capture brain maturity equally well ► Reveals a phenotype that varies by only about a year for most same-aged individuals ► Suggests timing of brain maturation is more tightly controlled than previously known
Fungal cells change shape in response to environmental stimuli, and these morphogenic transitions drive pathogenesis and niche adaptation. For example, dimorphic fungi switch between yeast and hyphae ...in response to changing temperature. The basidiomycete Cryptococcus neoformans undergoes an unusual morphogenetic transition in the host lung from haploid yeast to large, highly polyploid cells termed Titan cells. Titan cells influence fungal interaction with host cells, including through increased drug resistance, altered cell size, and altered Pathogen Associated Molecular Pattern exposure. Despite the important role these cells play in pathogenesis, understanding the environmental stimuli that drive the morphological transition, and the molecular mechanisms underlying their unique biology, has been hampered by the lack of a reproducible in vitro induction system. Here we demonstrate reproducible in vitro Titan cell induction in response to environmental stimuli consistent with the host lung. In vitro Titan cells exhibit all the properties of in vivo generated Titan cells, the current gold standard, including altered capsule, cell wall, size, high mother cell ploidy, and aneuploid progeny. We identify the bacterial peptidoglycan subunit Muramyl Dipeptide as a serum compound associated with shift in cell size and ploidy, and demonstrate the capacity of bronchial lavage fluid and bacterial co-culture to induce Titanisation. Additionally, we demonstrate the capacity of our assay to identify established (cAMP/PKA) and previously undescribed (USV101) regulators of Titanisation in vitro. Finally, we investigate the Titanisation capacity of clinical isolates and their impact on disease outcome. Together, these findings provide new insight into the environmental stimuli and molecular mechanisms underlying the yeast-to-Titan transition and establish an essential in vitro model for the future characterization of this important morphotype.
The university participant pool is a key resource for behavioral research, and data quality is believed to vary over the course of the academic semester. This crowdsourced project examined time of ...semester variation in 10 known effects, 10 individual differences, and 3 data quality indicators over the course of the academic semester in 20 participant pools (N=2696) and with an online sample (N=737). Weak time of semester effects were observed on data quality indicators, participant sex, and a few individual differences—conscientiousness, mood, and stress. However, there was little evidence for time of semester qualifying experimental or correlational effects. The generality of this evidence is unknown because only a subset of the tested effects demonstrated evidence for the original result in the whole sample. Mean characteristics of pool samples change slightly during the semester, but these data suggest that those changes are mostly irrelevant for detecting effects.
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