Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations.

Outdoor air pollution is a major contributor to the burden of disease worldwide. Most of the global population resides in places where air pollution levels, because of emissions from industry, power generation, transportation, and domestic burning, considerably exceed the World Health Organization's health-based air-quality guidelines. Outdoor air pollution poses an urgent worldwide public health challenge because it is ubiquitous and has numerous serious adverse human health effects, including cancer. Currently, there is substantial evidence from studies of humans and experimental animals as well as mechanistic evidence to support a causal link between outdoor (ambient) air pollution, and especially particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. It is estimated that hundreds of thousands of lung cancer deaths annually worldwide are attributable to PM air pollution. Epidemiological evidence on outdoor air pollution and the risk of other types of cancer, such as bladder cancer or breast cancer, is more limited. Outdoor air pollution may also be associated with poorer cancer survival, although further research is needed. This report presents an overview of outdoor air pollutants, sources, and global levels, as well as a description of epidemiological evidence linking outdoor air pollution with cancer incidence and mortality. Biological mechanisms of air pollution-derived carcinogenesis are also described. This report concludes by summarizing public health/policy recommendations, including multilevel interventions aimed at individual, community, and regional scales. Specific roles for medical and health care communities with regard to prevention and advocacy and recommendations for further research are also described.

A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle.

A-kinase-anchoring proteins (AKAPs) act as scaffold proteins that anchor the regulatory subunits of the cAMP-dependent protein kinase A (PKA) to coordinate and compartmentalize signaling elements and signals downstream of Gs-coupled G protein-coupled receptors (GPCRs). The beta-2-adrenoceptor (ß2AR), as well as the Gs-coupled EP2 and EP4 receptor subtypes of the E-prostanoid (EP) receptor subfamily, are effective regulators of multiple airway smooth muscle (ASM) cell functions whose dysregulation contributes of asthma pathobiology. Here, we identify specific roles of the AKAPs Ezrin and Gravin, in differentially regulating PKA substrates downstream of the ß2AR, EP2 receptor (EP2R) and EP4 receptor (EP4R). Knockdown of Ezrin, Gravin, or both in primary human ASM cells caused differential phosphorylation of the PKA substrates vasodilator-stimulated phosphoprotein (VASP) and heat shock protein 20 (HSP20). Ezrin knockdown, as well as combined Ezrin + Gravin knockdown significantly reduced the induction of phospho-VASP and phospho-HSP20 by ß2AR, EP2R, and EP4R agonists. Gravin knockdown inhibited the induction of phospho-HSP20 by ß2AR, EP2R, and EP4R agonists. Knockdown of Ezrin, Gravin, or both also attenuated histamine-induced phosphorylation of MLC20. Moreover, knockdown of Ezrin, Gravin or both suppressed the inhibitory effects of Gs-coupled receptor agonists on cell migration in ASM cells. These findings demonstrate the role of AKAPs in regulating Gs-coupled GPCR signaling and function in ASM, and suggest the therapeutic utility of targeting specific AKAP family members in the management of asthma.

Hourly Air Pollutants and Acute Coronary Syndrome Onset in 1.29 Million Patients.

BACKGROUND: Short-term exposure to ambient air pollution has been linked with daily hospitalization and mortality from acute coronary syndrome (ACS); however, the associations of subdaily (hourly) levels of criteria air pollutants with the onset of ACS and its subtypes have rarely been evaluated. METHODS: We conducted a time-stratified case-crossover study among 1 292 880 patients with ACS from 2239 hospitals in 318 Chinese cities between January 1, 2015, and September 30, 2020. Hourly concentrations of fine particulate matter (PM2.5), coarse particulate matter (PM2.5-10), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and ozone (O3) were collected. Hourly onset data of ACS and its subtypes, including ST-segment-elevation myocardial infarction, non-ST-segment-elevation myocardial infarction, and unstable angina, were also obtained. Conditional logistic regressions combined with polynomial distributed lag models were applied. RESULTS: Acute exposures to PM2.5, NO2, SO2, and CO were each associated with the onset of ACS and its subtypes. These associations were strongest in the concurrent hour of exposure and were attenuated thereafter, with the weakest effects observed after 15 to 29 hours. There were no apparent thresholds in the concentration-response curves. An interquartile range increase in concentrations of PM2.5 (36.0 µg/m3), NO2 (29.0 µg/m3), SO2 (9.0 µg/m3), and CO (0.6 mg/m3) over the 0 to 24 hours before onset was significantly associated with 1.32%, 3.89%, 0.67%, and 1.55% higher risks of ACS onset, respectively. For a given pollutant, the associations were comparable in magnitude across different subtypes of ACS. NO2 showed the strongest associations with all 3 subtypes, followed by PM2.5, CO, and SO2. Greater magnitude of associations was observed among patients older than 65 years and in the cold season. Null associations of exposure to either PM2.5-10 or O3 with ACS onset were observed. CONCLUSIONS: The results suggest that transient exposure to the air pollutants PM2.5, NO2, SO2, or CO, but not PM2.5-10 or O3, may trigger the onset of ACS, even at concentrations below the World Health Organization air quality guidelines.

Telemedicine use among patients with metastatic breast cancer during the COVID-19 pandemic: Differences by race, age, and region.

PURPOSE: Our objective was to describe differences in telemedicine use among women with metastatic breast cancer (mBC) by race, age, and geographic region. METHODS: This was a retrospective cohort study of women with recurrent or de novo mBC treated in US community cancer practices that initiated a new line of therapy between March 2020 and February 2021. Multivariable modified Poisson regression models were used to calculate adjusted rate ratios (RR) and robust 95% confidence intervals (CI) associated with telemedicine visits within 90 days of therapy initiation. RESULTS: Overall, among 3412 women with mBC, 751 (22%) patients had telemedicine visits following therapy initiation, with lower risks observed among older women (<50 years: 24%; 50-64 years: 22%; 65-74 years: 21%; ≥75 years: 20%). Greater telemedicine use was observed among Asian women (35%) compared to White (21%), Black (18%), and Hispanic (21%) women. Fewer telemedicine visits occurred in Southern (12%) and Midwestern (17%) states versus Northeastern (37%) or Western (36%) states. In multivariable models, women ages ≥75 years had significantly lower risks of telemedicine visits (RR = 0.76, 95% CI 0.62-0.95) compared to ages <50 years. Compared to patients in Northeastern states, women in Midwestern (RR = 0.46, 95% CI 0.37-0.57) and Southern (RR = 0.31, 95% CI 0.26-0.37) states had significantly lower risks of telemedicine visits; but not women in Western states (RR = 0.96, 95% CI 0.83-1.12). No statistically significant differences in telemedicine use were found between racial groups in overall multivariable models. CONCLUSIONS: In this study of community cancer practices, older mBC patients and those living in Southern and Midwestern states were less likely to have telemedicine visits. Preferences for communication and delivery of care may have implications for measurement of exposures and endpoints in pharmacoepidemiologic studies of cancer patients.

MALDI Mass Spectrometry Imaging and Semi-Quantification of Topically Delivered Lactic Acid.

BACKGROUND: Lactic acid is a common active ingredient in many topical skincare products; however, measuring its delivery into the skin is challenging due to the presence of a large level of endogenous lactic acid. In this study, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to quantitatively and qualitatively measure the delivery of lactic acid into the skin from a range of topical skincare products. MATERIALS AND METHODS: Porcine skin samples were treated with various skincare products containing lactic acid. After 24 h, skin samples were sectioned and treated via H&E staining or prepared for MALDI-MSI using chemical derivatization. Samples were then analyzed by MALDI-MSI imaging to obtain lactic acid distribution in the entire skin section. RESULTS: Due to the high level of endogenous lactic acid in the skin, a "triple isotope" of lactic acid (L-Lactic acid-13 C3 ), was needed to provide full resolution from the skin's background signal with MALDI-MSI. With this approach, the topically delivered lactic acid could be quantitatively and qualitatively analyzed from a variety of skincare products. CONCLUSIONS: The combination of L-Lactic acid-13 C3 and MALDI-MSI was successfully used to quantitatively and qualitatively measure the topical delivery of lactic acid from a variety of skincare products. This approach could be used in future work to better understand the mode of action of lactic acid as an active ingredient in skincare products.

Incorrect analysis in "Effects of the application of a food processing-based classification system in obese women: A randomized controlled pilot study" has resulted in incorrect conclusions of demonstrated effects where no such effects have been demonstrated.

In their 2023 Nutrition and Health paper "Effects of the application of a food processing-based classification system in obese women: A randomized controlled pilot study", Giacomello et al. investigated the effects of an educational intervention based on the Dietary Guidelines for the Brazilian Population among obese women. The authors concluded that the intervention significantly improved weight loss, quality of life, components of metabolic syndrome, and pain. However, we believe the statistical analysis employed in the study was flawed. The authors used within-group changes to draw conclusions, which is known as a difference in nominal significance error. This error has the potential to inflate Type I error rates substantially. To address this issue, we re-analyzed the data obtained from the authors. We focused on body mass and hip circumference and replicated the incorrectly chosen within-group analyses, which remained significant. However, to properly evaluate the intervention's effectiveness, it is essential to compare the differences between the groups directly. Therefore, we calculated change scores for each participant and used independent samples t-tests and linear mixed models to compare between-group differences. Both methods yielded similar non-significant p-values, indicating that there is no significant effect of treatment on body mass or hip circumference. The original paper's conclusions regarding the effectiveness of the intervention are not supported by the proper statistical analysis. The data should be re-analyzed using appropriate between-group comparisons, and the corrected results should be published, or the incorrect results and original paper should be retracted.

Ambient Particulate Air Pollution and Daily Mortality in 652 Cities.

BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias. METHODS: We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 µm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 µm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived. RESULTS: On average, an increase of 10 µg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations. CONCLUSIONS: Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.).

Holistic approach to visualize and quantify collagen organization at macro, micro, and nano-scale.

BACKGROUND: There is scarcity of imaging and image processing techniques for accurate discrimination and quantitation of the dermal extracellular matrix (ECM), primarily collagen. The aim of this study was to develop and demonstrate a holistic imaging and image processing approach to visualize and quantify collagen remodeling at the macro-, micro- and nano-scale using histochemical imaging, Reflectance Confocal Microscopy (RCM), and Atomic Force Microscopy (AFM), respectively. MATERIAL AND METHODS: For proof-of-concept, a commercial anti-aging product known to induce collagen neo-synthesis and re-organization was tested ex vivo on human skin biopsies from two aged females. RESULTS: Relative to untreated skin, collagen fibers (RCM) and fibrils (AFM) were longer and aligned after treatment. The content of collagen and elastin (histochemical imaging and ELISA) statistically improved after treatment. CONCLUSION: Based on our findings, we can conclude: (1) AFM, RCM, and histochemical imaging can accurately discriminate collagen from other ECM components in the skin and (2) the image processing methods can enable quantitation and hence capture small improvements in collagen remodeling after treatment (commercial cosmetic product with collagen organizer technology as proof-of-concept). The reported holistic imaging approach has direct clinical implications for scientists and dermatologists to make quick, real-time, and accurate decisions in skin research and diagnostics.

Ambient and household PM2.5 pollution and adverse perinatal outcomes: A meta-regression and analysis of attributable global burden for 204 countries and territories.

BACKGROUND: Particulate matter <2.5 micrometer (PM2.5) is associated with adverse perinatal outcomes, but the impact on disease burden mediated by this pathway has not previously been included in the Global Burden of Disease (GBD), Mortality, Injuries, and Risk Factors studies. We estimated the global burden of low birth weight (LBW) and preterm birth (PTB) and impacts on reduced birth weight and gestational age (GA), attributable to ambient and household PM2.5 pollution in 2019. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science for peer-reviewed articles in English. Study quality was assessed using 2 tools: (1) Agency for Healthcare Research and Quality checklist; and (2) National Institute of Environmental Health Sciences (NIEHS) risk of bias questions. We conducted a meta-regression (MR) to quantify the risk of PM2.5 on birth weight and GA. The MR, based on a systematic review (SR) of articles published through April 4, 2021, and resulting uncertainty intervals (UIs) accounted for unexplained between-study heterogeneity. Separate nonlinear relationships relating exposure to risk were generated for each outcome and applied in the burden estimation. The MR included 44, 40, and 40 birth weight, LBW, and PTB studies, respectively. Majority of the studies were of retrospective cohort design and primarily from North America, Europe, and Australia. A few recent studies were from China, India, sub-Saharan Africa, and South America. Pooled estimates indicated 22 grams (95% UI: 12, 32) lower birth weight, 11% greater risk of LBW (1.11, 95% UI: 1.07, 1.16), and 12% greater risk of PTB (1.12, 95% UI: 1.06, 1.19), per 10 µg/m3 increment in ambient PM2.5. We estimated a global population-weighted mean lowering of 89 grams (95% UI: 88, 89) of birth weight and 3.4 weeks (95% UI: 3.4, 3.4) of GA in 2019, attributable to total PM2.5. Globally, an estimated 15.6% (95% UI: 15.6, 15.7) of all LBW and 35.7% (95% UI: 35.6, 35.9) of all PTB infants were attributable to total PM2.5, equivalent to 2,761,720 (95% UI: 2,746,713 to 2,776,722) and 5,870,103 (95% UI: 5,848,046 to 5,892,166) infants in 2019, respectively. About one-third of the total PM2.5 burden for LBW and PTB could be attributable to ambient exposure, with household air pollution (HAP) dominating in low-income countries. The findings should be viewed in light of some limitations such as heterogeneity between studies including size, exposure levels, exposure assessment method, and adjustment for confounding. Furthermore, studies did not separate the direct effect of PM2.5 on birth weight from that mediated through GA. As a consequence, the pooled risk estimates in the MR and likewise the global burden may have been underestimated. CONCLUSIONS: Ambient and household PM2.5 were associated with reduced birth weight and GA, which are, in turn, associated with neonatal and infant mortality, particularly in low- and middle-income countries.

Correction: Ambient and household PM2.5 pollution and adverse perinatal outcomes: A meta-regression and analysis of attributable global burden for 204 countries and territories.

[This corrects the article DOI: 10.1371/journal.pmed.1003718.].

The Art of M. Michael Cohen, Jr.

This article describes Dr. M. Michael Cohen, Jr.'s passion for art and music. His two sons share family memories and photos. Dr. Cohen developed a keen interest in the visual arts, collecting lithographs, enjoying many art exhibits, and conducting original research on Picasso's art. His interest in faces formed a central connection between his professional life and his artistic interest. His love of music began as a young boy. Classical music and opera were the soundtrack to his creative pursuits. He enjoyed sharing music with his family immensely, especially opera performances.

Mid- to Late-Life Inflammation and Risk of Cardiac Dysfunction, HFpEF and HFrEF in Late Life.

BACKGROUND: Epidemiologic data supporting the association of accumulated inflammation from mid- to late life with late-life risk of cardiac dysfunction and heart failure (HF) is limited. METHODS AND RESULTS: Among 4011 participants in the Atherosclerosis Risk in Communities study who were free of prevalent cardiovascular disease at study Visit 5, accumulated inflammation was defined as time-averaged high-sensitivity c-reactive protein (hsCRP) over 3 visits spanning 1990 to 2013. Associations with left ventricular (LV) function at Visit 5 and with incident adjudicated HF post Visit 5 were assessed using linear and Cox regression, adjusting for demographics and comorbidities. Higher accumulated hsCRP was associated with greater LV mass index, lower e', higher E/e', and higher adjusting for demographics (all P ≤0.01), but only with higher pulmonary artery systolic pressure after adjustment for comorbidities (P = 0.024). At 5.3 ± 1.2 year follow-up, higher accumulated hsCRP was associated with greater risk of incident HF (HR 1.31 [95% CI 1.18-1.47], P < 0.001), HFrEF (1.26 [1.05-1.52], P = 0.01), and HFpEF (1.30 [1.11-1.53], P = 0.001) in demographic-adjusted models, but not after adjustment for comorbidities (all P > 0.10). Only Visit 5 hsCRP remained associated with incident HF (1.12 [1.02-1.24], P = 0.02) after full adjustment. CONCLUSIONS: Greater accumulated inflammation is associated with worse LV function and heightened HF risk in late-life. These relationships are attenuated after adjusting for HF risk factors.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Reversible Photoswitching in Poly(2-oxazoline) Nanoreactors.

This contribution reports light responsive catalytic nanoreactors based on poly(2-oxazoline) diblock copolymers. The hydrophobic block of the copolymer is a random copolymer consisting of a spiropyran functionalized 2-oxazoline (SPOx) and 2-(but-3-yn-1-yl)-4,5-dihydrooxazole (ButynOx), while the hydrophilic block is based on 2-methyl-2-oxazoline (MeOx). The block copolymer is terminated with tris(2-aminoethyl) amine (TREN) that serves as catalyst in a Knoevenagel condensation. Four block copolymers with different ButynOx/SPOx and hydrophilic/hydrophobic ratios are synthesized and self-assembled through solvent exchange. Micelles and vesicles of various sizes are observed by TEM, which undergo morphological and size changes in response to irradiation with UV light. We hypothesize that these transformations in the nanostructures are caused by increases in the hydrophilicity of the hydrophobic block when spiropyran (SP) isomerizes to merocyanine (MC) in the presence of UV light. The reversible transition from micellar to vesicular nanoreactors resulted in increased reaction kinetics through improved substrate accessibility to the catalytic site, or termination of the catalytic reaction due to polymer precipitation. These nanoreactors present a promising platform towards photoregulating reaction outcomes based on changes in nanostructure morphology.

First-line immune checkpoint inhibitor use in cisplatin-eligible patients with advanced urothelial carcinoma: a secular trend analysis.

Aim: Standard first-line treatment of advanced urothelial cell carcinoma involves cisplatin-based chemotherapy, with carboplatin or immune checkpoint inhibitor therapy (ICI) reserved for cisplatin-ineligible individuals. Methods: Using a large de-identified electronic health record-derived database of patients with advanced urothelial cell carcinoma in the USA, we examined trends in utilization of first-line systemic therapies in cisplatin-eligible patients from 1 January 2015 to 31 March 2018. Results: Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (ptrend <0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (ptrend = 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68). Conclusion: Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.

mTORC1 is required for expression of LRPPRC and cytochrome-c oxidase but not HIF-1α in Leigh syndrome French Canadian type patient fibroblasts.

Leigh syndrome French Canadian type (LSFC) is a mitochondrial disease caused by mutations in the leucine-rich pentatricopeptide repeat-containing (LRPPRC) gene leading to a reduction of cytochrome-c oxidase (COX) expression reaching 50% in skin fibroblasts. We have shown that under basal conditions, LSFC and control cells display similar ATP levels. We hypothesized that this occurs through upregulation of mechanistic target of rapamycin (mTOR)-mediated metabolic reprogramming. Our results showed that compared with controls, LSFC cells exhibited an upregulation of the mTOR complex 1 (mTORC1)/p70 ribosomal S6 kinase pathway and higher levels of hypoxia-inducible factor 1α (HIF-1α) and its downstream target pyruvate dehydrogenase kinase 1 (PDHK1), a regulator of mitochondrial pyruvate dehydrogenase 1 (PDH1). Consistent with these signaling alterations, LSFC cells displayed a 40-61% increase in [U-13C6]glucose contribution to pyruvate, lactate, and alanine formation, as well as higher levels of the phosphorylated and inactive form of PDH1-α. Interestingly, inhibition of mTOR with rapamycin did not alter HIF-1α or PDHK1 protein levels in LSFC fibroblasts. However, this treatment increased PDH1-α phosphorylation in control and LSFC cells and reduced ATP levels in control cells. Rapamycin also decreased LRPPRC expression by 41 and 11% in LSFC and control cells, respectively, and selectively reduced COX subunit IV expression in LSFC fibroblasts. Taken together, our data demonstrate the importance of mTORC1, independent of the HIF-1α/PDHK1 axis, in maintaining LRPPRC and COX expression in LSFC cells.

Trends in Checkpoint Inhibitor Therapy for Advanced Urothelial Cell Carcinoma at the End of Life: Insights from Real-World Practice.

Several immune checkpoint inhibitor therapies (CPIs) have been approved to treat metastatic urothelial cell carcinoma (mUC). Because of the favorable toxicity profile of CPI compared with chemotherapy, oncologists may have a low threshold to prescribe CPI to patients near the end of life. We evaluated trends in initiation of end-of-life systemic therapy in 1,637 individuals in the Flatiron Health Database who were diagnosed with mUC between 2015 and 2017 and who died. Rates of systemic therapy initiation in the last 30 and 60 days of life were 17.0% and 29.8%, respectively. The quarterly proportion of patients who initiated CPI within 60 days of death increased from 1.0% to 23% during the study period (p trend < .001). After CPI approval, end-of-life CPI initiation significantly increased among patients with poor performance status (p trend = .020) and did not significantly change among individuals with good performance status. The quarterly proportion of patients who initiated any systemic therapy at the end of life doubled (17.4% to 34.8%) during the study period, largely explained by increased CPI use. These findings suggest a dramatic rise in CPI use at the end of life in patients with mUC, a finding that may have important guideline and policy implications.

Unsupervised low-dimensional vector representations for words, phrases and text that are transparent, scalable, and produce similarity metrics that are not redundant with neural embeddings.

Neural embeddings are a popular set of methods for representing words, phrases or text as a low dimensional vector (typically 50-500 dimensions). However, it is difficult to interpret these dimensions in a meaningful manner, and creating neural embeddings requires extensive training and tuning of multiple parameters and hyperparameters. We present here a simple unsupervised method for representing words, phrases or text as a low dimensional vector, in which the meaning and relative importance of dimensions is transparent to inspection. We have created a near-comprehensive vector representation of words, and selected bigrams, trigrams and abbreviations, using the set of titles and abstracts in PubMed as a corpus. This vector is used to create several novel implicit word-word and text-text similarity metrics. The implicit word-word similarity metrics correlate well with human judgement of word pair similarity and relatedness, and outperform or equal all other reported methods on a variety of biomedical benchmarks, including several implementations of neural embeddings trained on PubMed corpora. Our implicit word-word metrics capture different aspects of word-word relatedness than word2vec-based metrics and are only partially correlated (rho = 0.5-0.8 depending on task and corpus). The vector representations of words, bigrams, trigrams, abbreviations, and PubMed title + abstracts are all publicly available from http://arrowsmith.psych.uic.edu/arrowsmith_uic/word_similarity_metrics.html for release under CC-BY-NC license. Several public web query interfaces are also available at the same site, including one which allows the user to specify a given word and view its most closely related terms according to direct co-occurrence as well as different implicit similarity metrics.

Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015.

BACKGROUND: Exposure to ambient air pollution increases morbidity and mortality, and is a leading contributor to global disease burden. We explored spatial and temporal trends in mortality and burden of disease attributable to ambient air pollution from 1990 to 2015 at global, regional, and country levels. METHODS: We estimated global population-weighted mean concentrations of particle mass with aerodynamic diameter less than 2·5 µm (PM2·5) and ozone at an approximate 11 km × 11 km resolution with satellite-based estimates, chemical transport models, and ground-level measurements. Using integrated exposure-response functions for each cause of death, we estimated the relative risk of mortality from ischaemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infections from epidemiological studies using non-linear exposure-response functions spanning the global range of exposure. FINDINGS: Ambient PM2·5 was the fifth-ranking mortality risk factor in 2015. Exposure to PM2·5 caused 4·2 million (95% uncertainty interval [UI] 3·7 million to 4·8 million) deaths and 103·1 million (90·8 million 115·1 million) disability-adjusted life-years (DALYs) in 2015, representing 7·6% of total global deaths and 4·2% of global DALYs, 59% of these in east and south Asia. Deaths attributable to ambient PM2·5 increased from 3·5 million (95% UI 3·0 million to 4·0 million) in 1990 to 4·2 million (3·7 million to 4·8 million) in 2015. Exposure to ozone caused an additional 254 000 (95% UI 97 000-422 000) deaths and a loss of 4·1 million (1·6 million to 6·8 million) DALYs from chronic obstructive pulmonary disease in 2015. INTERPRETATION: Ambient air pollution contributed substantially to the global burden of disease in 2015, which increased over the past 25 years, due to population ageing, changes in non-communicable disease rates, and increasing air pollution in low-income and middle-income countries. Modest reductions in burden will occur in the most polluted countries unless PM2·5 values are decreased substantially, but there is potential for substantial health benefits from exposure reduction. FUNDING: Bill & Melinda Gates Foundation and Health Effects Institute.

Shell Cross-Linked Micelles as Nanoreactors for Enantioselective Three-Step Tandem Catalysis.

Functionalized amphiphilic poly(2-oxazoline)-based triblock copolymers that assemble into shell cross-linked micelles (SCMs) are described. These micelles permit the site isolation of three incompatible catalysts through compartmentalization, thereby enabling three-step non-orthogonal tandem processes in one pot. In particular, the acid-catalyzed ketal hydrolysis to prochiral ketones proceeded in the hydrophilic corona, followed by the Rh-catalyzed asymmetric transfer hydrogenation to enantio-enriched alcohols in the cross-linked shell, and nucleophilic base-catalyzed acylation in the hydrophobic core. The catalysts are positioned in close proximity on a single micelle support to take advantage of the intramicellar substrate diffusion, yet they are sufficiently spaced apart from each other in physically distinct microenvironments. These compartmentalized micelles are substrate selective and, on a basic level, mimic compartmentalized catalytic architectures found in nature.