The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) ...collaborate to provide annual updates on cancer occurrence and trends in the United States. This Annual Report highlights survival rates. Data were from the CDC- and NCI-funded population-based cancer registry programs and compiled by NAACCR. Trends in age-standardized incidence and death rates for all cancers combined and for the leading cancer types by sex were estimated by joinpoint analysis and expressed as annual percent change. We used relative survival ratios and adjusted relative risk of death after a diagnosis of cancer (hazard ratios HRs) using Cox regression model to examine changes or differences in survival over time and by sociodemographic factors.
Overall cancer death rates from 2010 to 2014 decreased by 1.8% (95% confidence interval CI = -1.8 to -1.8) per year in men, by 1.4% (95% CI = -1.4 to -1.3) per year in women, and by 1.6% (95% CI = -2.0 to -1.3) per year in children. Death rates decreased for 11 of the 16 most common cancer types in men and for 13 of the 18 most common cancer types in women, including lung, colorectal, female breast, and prostate, whereas death rates increased for liver (men and women), pancreas (men), brain (men), and uterine cancers. In contrast, overall incidence rates from 2009 to 2013 decreased by 2.3% (95% CI = -3.1 to -1.4) per year in men but stabilized in women. For several but not all cancer types, survival statistically significantly improved over time for both early and late-stage diseases. Between 1975 and 1977, and 2006 and 2012, for example, five-year relative survival for distant-stage disease statistically significantly increased from 18.7% (95% CI = 16.9% to 20.6%) to 33.6% (95% CI = 32.2% to 35.0%) for female breast cancer but not for liver cancer (from 1.1%, 95% CI = 0.3% to 2.9%, to 2.3%, 95% CI = 1.6% to 3.2%). Survival varied by race/ethnicity and state. For example, the adjusted relative risk of death for all cancers combined was 33% (HR = 1.33, 95% CI = 1.32 to 1.34) higher in non-Hispanic blacks and 51% (HR = 1.51, 95% CI = 1.46 to 1.56) higher in non-Hispanic American Indian/Alaska Native compared with non-Hispanic whites.
Cancer death rates continue to decrease in the United States. However, progress in reducing death rates and improving survival is limited for several cancer types, underscoring the need for intensified efforts to discover new strategies for prevention, early detection, and treatment and to apply proven preventive measures broadly and equitably.
How do democratic states induce citizens to comply with government directives during times of acute crisis? Focusing on the onset of the Covid‐19 pandemic in France, I argue that the tools states use ...to activate adherence to public health advice have predictable and variable effects on citizens’ willingness to change their routine private behaviours, both because of variation in their levels of restrictiveness but also because of differences in people's political motivations to comply with them. Using data collected in March 2020, I show that people's reports of changes in their behavioural routines are affected by the signals governments send, how they send them and the level of enforcement. I find that a nationally televised speech by President Macron calling for cooperative behaviour and announcing new restrictions elevated people's willingness to comply. Moreover, while co‐partisanship with the incumbent government increased compliance reports before the President's primetime television address, presidential approval boosted reports of compliance after.
We describe NIMBLE, a system for programming statistical algorithms for general model structures within R. NIMBLE is designed to meet three challenges: flexible model specification, a language for ...programming algorithms that can use different models, and a balance between high-level programmability and execution efficiency. For model specification, NIMBLE extends the BUGS language and creates model objects, which can manipulate variables, calculate log probability values, generate simulations, and query the relationships among variables. For algorithm programming, NIMBLE provides functions that operate with model objects using two stages of evaluation. The first stage allows specialization of a function to a particular model and/or nodes, such as creating a Metropolis-Hastings sampler for a particular block of nodes. The second stage allows repeated execution of computations using the results of the first stage. To achieve efficient second-stage computation, NIMBLE compiles models and functions via C++, using the Eigen library for linear algebra, and provides the user with an interface to compiled objects. The NIMBLE language represents a compilable domain-specific language (DSL) embedded within R. This article provides an overview of the design and rationale for NIMBLE along with illustrative examples including importance sampling, Markov chain Monte Carlo (MCMC) and Monte Carlo expectation maximization (MCEM). Supplementary materials for this article are available online.
Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from ...their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo1.1.1pentane motif, which is mainly synthesized by ring-opening ofthe interbridgehead bond of the strained hydrocarbon 1.1.1propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo3.1.1heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from 3.1.1propellane. We found that 3.1.1 propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for mefa-substituted benzene rings for implementation in drug discovery programmes.
Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and ...disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits ethanolamine signaling to recognize and adapt to distinct niches within the host. The bacterial transcription factor EutR promotes ethanolamine metabolism in the intestine, which enables S. Typhimurium to establish infection. Subsequently, EutR directly activates expression of the Salmonella pathogenicity island 2 in the intramacrophage environment, and thus augments intramacrophage survival. Moreover, EutR is critical for robust dissemination during mammalian infection. Our findings reveal that S. Typhimurium co-opts ethanolamine as a signal to coordinate metabolism and then virulence. Because the ability to sense ethanolamine is a conserved trait among pathogenic and commensal bacteria, our work indicates that ethanolamine signaling may be a key step in the localized adaptation of bacteria within their mammalian hosts.
The carbon-to-oxygen ratio (C/O) in a planet provides critical information about its primordial origins and subsequent evolution. A primordial C/O greater than 0.8 causes a carbide-dominated ...interior, as opposed to the silicate-dominated composition found on Earth; the atmosphere can also differ from those in the Solar System. The solar C/O is 0.54 (ref. 3). Here we report an analysis of dayside multi-wavelength photometry of the transiting hot-Jupiter WASP-12b (ref. 6) that reveals C/O ≥ 1 in its atmosphere. The atmosphere is abundant in CO. It is depleted in water vapour and enhanced in methane, each by more than two orders of magnitude compared to a solar-abundance chemical-equilibrium model at the expected temperatures. We also find that the extremely irradiated atmosphere (T > 2,500 K) of WASP-12b lacks a prominent thermal inversion (or stratosphere) and has very efficient day-night energy circulation. The absence of a strong thermal inversion is in stark contrast to theoretical predictions for the most highly irradiated hot-Jupiter atmospheres.
Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis
. Malfunctions within the regulated cell death process, including the clearance of ...dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract
. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component
, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host-pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.
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