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472

The increasing prevalence of tattoos provoked safety concerns with respect to particle distribution and effects inside the human body. We used skin and lymphatic tissues from human corpses to address local biokinetics by means of synchrotron X-ray fluorescence (XRF) techniques at both the micro (μ) and nano (ν) scale. Additional advanced mass spectrometry-based methodology enabled to demonstrate simultaneous transport of organic pigments, heavy metals and titanium dioxide from skin to regional lymph nodes. Among these compounds, organic pigments displayed the broadest size range with smallest species preferentially reaching the lymph nodes. Using synchrotron μ-FTIR analysis we were also able to detect ultrastructural changes of the tissue adjacent to tattoo particles through altered amide I α-helix to β-sheet protein ratios and elevated lipid contents. Altogether we report strong evidence for both migration and long-term deposition of toxic elements and tattoo pigments as well as for conformational alterations of biomolecules that likely contribute to cutaneous inflammation and other adversities upon tattooing.

Concepts: Oxygen, Lymph node, Lymphatic system, Skin, Tissue, Titanium dioxide, Heavy metal music, Tattoo

404

Objectives To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes.Design Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome.Data sources PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references.Eligibility criteria for selecting studies Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded.Results The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83, 95% confidence interval 0.83 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men.Conclusion Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded.

Concepts: Pregnancy, Epidemiology, Medical statistics, Evidence-based medicine, Systematic review, Randomized controlled trial, Relative risk, Obstetrics

390

To describe the average primary care physician consultation length in economically developed and low-income/middle-income countries, and to examine the relationship between consultation length and organisational-level economic, and health outcomes.

Concepts: Medicine, Economics, Social sciences, Primary care physician

387

This study investigates change over time in the level of hiring discrimination in US labor markets. We perform a meta-analysis of every available field experiment of hiring discrimination against African Americans or Latinos (n = 28). Together, these studies represent 55,842 applications submitted for 26,326 positions. We focus on trends since 1989 (n = 24 studies), when field experiments became more common and improved methodologically. Since 1989, whites receive on average 36% more callbacks than African Americans, and 24% more callbacks than Latinos. We observe no change in the level of hiring discrimination against African Americans over the past 25 years, although we find modest evidence of a decline in discrimination against Latinos. Accounting for applicant education, applicant gender, study method, occupational groups, and local labor market conditions does little to alter this result. Contrary to claims of declining discrimination in American society, our estimates suggest that levels of discrimination remain largely unchanged, at least at the point of hire.

Concepts: Experimental design, Evaluation methods, Experiment, Employment, Race, African American, Racism, Racial segregation

374

To determine the association of hospital nursing skill mix with patient mortality, patient ratings of their care and indicators of quality of care.

Concepts: Patient, Hospital, Cross-sectional study, Physician, The Association

364

Most mammalian species produce facial expressions. Historically, animal facial expressions have been considered inflexible and involuntary displays of emotional states rather than active attempts to communicate with others. In the current study, we aimed to test whether domestic dog facial expressions are subject to audience effects and/ or changes in response to an arousing stimulus (e.g. food) alone. We presented dogs with an experimental situation in which a human demonstrator was either attending to them or turned away, and varied whether she presented food or not. Dogs produced significantly more facial movements when the human was attentive than when she was not. The food, however, as a non-social but arousing stimulus, did not affect the dogs' behaviour. The current study is therefore evidence that dogs are sensitive to the human’s attentional state when producing facial expressions, suggesting that facial expressions are not just inflexible and involuntary displays of emotional states, but rather potentially active attempts to communicate with others.

Concepts: Psychology, Dog, Apex predator, Dog health, Carnivora, Gray Wolf

362

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

Concepts: Renal failure, Statistics, Myocardial infarction, Atherosclerosis, Hypertension, Cardiovascular disease, Low-density lipoprotein, Cardiovascular diseases

359

In the third trimester of pregnancy, the human fetus has the capacity to process perceptual information [1-3]. With advances in 4D ultrasound technology, detailed assessment of fetal behavior [4] is now possible. Furthermore, modeling of intrauterine conditions has indicated a substantially greater luminance within the uterus than previously thought [5]. Consequently, light conveying perceptual content could be projected through the uterine wall and perceived by the fetus, dependent on how light interfaces with maternal tissue. We do know that human infants at birth show a preference to engage with a top-heavy, face-like stimulus when contrasted with all other forms of stimuli [6, 7]. However, the viability of performing such an experiment based on visual stimuli projected through the uterine wall with fetal participants is not currently known. We examined fetal head turns to visually presented upright and inverted face-like stimuli. Here we show that the fetus in the third trimester of pregnancy is more likely to engage with upright configural stimuli when contrasted to inverted visual stimuli, in a manner similar to results with newborn participants. The current study suggests that postnatal experience is not required for this preference. In addition, we describe a new method whereby it is possible to deliver specific visual stimuli to the fetus. This new technique provides an important new pathway for the assessment of prenatal visual perceptual capacities.

Concepts: Pregnancy, Childbirth, Infant, Embryo, Fetus, Uterus, Abortion, 3D ultrasound

358

Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged ≥50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be ≥50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000-300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5-3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.

Concepts: Medical statistics, United States, Industrial Revolution, Osteoarthritis, Body mass index, United Kingdom, Gerontology, Life expectancy

357

The CRISPR-associated endonuclease Cas9 binds to a guide RNA and cleaves double-stranded DNA with a sequence complementary to the RNA guide. The Cas9-RNA system has been harnessed for numerous applications, such as genome editing. Here we use high-speed atomic force microscopy (HS-AFM) to visualize the real-space and real-time dynamics of CRISPR-Cas9 in action. HS-AFM movies indicate that, whereas apo-Cas9 adopts unexpected flexible conformations, Cas9-RNA forms a stable bilobed structure and interrogates target sites on the DNA by three-dimensional diffusion. These movies also provide real-time visualization of the Cas9-mediated DNA cleavage process. Notably, the Cas9 HNH nuclease domain fluctuates upon DNA binding, and subsequently adopts an active conformation, where the HNH active site is docked at the cleavage site in the target DNA. Collectively, our HS-AFM data extend our understanding of the action mechanism of CRISPR-Cas9.

Concepts: DNA, Gene, Genetics, Biology, Virus, Genome, RNA, Endonuclease