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This ten-year survey of the use of student mental health services offered by the University of North Carolina suggests that increased usage over time has been due to greater availability of staff and a broadening of services offered rather than to an increase of the prevalence of mental illness among the student body. The authors believe that college psychiatry, as one of the earliest examples of the provision of mental health services to a community, can be used as a model for other aspects of public health psychiatry. [ABSTRACT FROM AUTHOR]

Understanding the role of hydrologic variation in structuring aquatic communities is crucial for successful conservation and sustainable management of native freshwater biodiversity. Partitioning beta diversity into the additive components of spatial turnover and nestedness can provide insight into the forces driving variability in fish assemblages across stream flow regimes. We examined stream fish beta diversity across hydrologic and anthropogenic disturbance gradients using long-term (1916-2016) site occurrence records (n = 17,375) encompassing 252 species. We assessed total beta diversity (Sørensen dissimilarity), spatial turnover, and nestedness of fish assemblages in contrasting stream flow regimes across a gradient of decreasing flow stability: groundwater stable (n = 77), groundwater (n = 67), groundwater flashy (n = 175), perennial runoff (n = 141), runoff flashy (n = 255), and intermittent (n = 63) streams. Differences in total beta diversity among the stream flow regimes were driven predominantly (>86 %) by spatial turnover (i.e. species replacement) as opposed to nestedness (i.e. species loss or gain). Total fish beta diversity and spatial turnover were highest in streams with intermediate flow stability (groundwater flashy), while more flow-stable streams (groundwater stable and groundwater) had lower turnover and higher nestedness. Species turnover was also strongly associated with seasonal variation in hydrology across all flow regimes, but these relationships were most evident for assemblages in intermittent streams. Distance-based statistical comparisons showed significant correlations between beta diversity and anthropogenic disturbance variables, including dam density, dam storage volume and water withdrawals in catchments of groundwater stable streams, while hydrologic variables were more strongly correlated with beta diversity in streams with runoff-dominated and flashy flow regimes. The high spatial turnover of species implies that fish conservation actions would benefit from watershed-focused approaches targeting multiple streams with wide spatial distribution, as opposed to simply focusing on preserving sites with the greatest number of species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Pten flox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Pten flox/flox , age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment., (© 2024 Wiley Periodicals LLC.)

The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten ) and non- TMPRSS2-ERG -driven (Hi-Myc +/- mice) PCa. Male mice ( n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc +/- mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc +/- mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.

Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and retinoid X receptor (RXR) agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS-mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced estrogen receptor-positive rat breast model (50% HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists are profoundly effective in prevention and interception of tumors with wild-type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS., (©2023 American Association for Cancer Research.)

We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations., Prevention Relevance: Means to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC., (©2022 American Association for Cancer Research.)

Research Question: Can volatile organic compounds (VOC) be modelled in an IVF clinical setting?, Design: The study performed equilibrium modelling of low concentrations of airborne VOC partitioning from the air phase into the oil cover layer into the water-based culture media and into/onto the embryo (air-oil-water-embryo). The air-phase VOC were modelled based on reported VOC concentrations found in modern assisted reproductive technology (ART) suites, older IVF clinics, and hospitals, as well as at 10 parts per billion (ppb) and 100 ppb for all compounds. The modelling was performed with 23 documented healthcare-specific VOC., Results: Based on the partitioning model, seven compounds (acrolein, formaldehyde, phenol, toluene, acetaldehyde, ethanol and isopropanol) should be of great concern to the embryologist and clinician. Acrolein, formaldehyde, phenol, toluene and acetaldehyde are the VOC with the most potent cytotoxic factor and the highest toxic VOC concentration in media. In addition, ethanol and isopropanol are routinely found in the greatest air-phase concentrations and modelled to have the highest water-based culture concentrations., Conclusions: The results of the equilibrium partitioning modelling of VOC provides a fundamental understanding of how airborne VOC partition from the air phase and negatively influence human IVF outcomes. The results presented here are based on the theoretical model and the values presented have not yet been measured in a laboratory or clinical setting. High air-phase concentrations and toxic concentrations of VOC in culture media are likely indicators of poor clinical outcomes. Based on this model, improved air quality in IVF laboratories reduces the chemical burden imparted on embryos, which supports findings of improved IVF outcomes with reduced air-phase VOC concentrations., (Copyright © 2022. Published by Elsevier Ltd.)

In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Pten flox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Pten flox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc +/ - mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc +/ - mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Pten flox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa., (© 2022 Wiley Periodicals LLC.)

Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice ( n =6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice ( n ≥20) treated with colon carcinogen azoxymethane (AOM) (AOM- Apc min/+ ) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence ( P <0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P <0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P <0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P <0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P <0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1β, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM- Apc min/+ mouse model., Competing Interests: W.S.E-D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix. Dr. El-Deiry has disclosed his relationship with Oncoceutics and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest. Other authors have no potential conflicts of interest., (AJCR Copyright © 2022.)

Objective: To evaluate the reticulorumen pH of beef feedlot steers throughout the feeding period and to assess the association between the respective durations that the reticulorumen pH was ≤ 5.6 (subacute ruminal acidosis) and ≤ 5.2 (acute ruminal acidosis) and liver abscess severity., Animals: 59 feedlot steers (mean body weight, 349.5 kg)., Procedures: On day 0, each steer was orally administered an electronic bolus that monitored the reticulorumen pH every 10 minutes for 150 days. Steers were transitioned from a starter to intermediate ration on day 8 (transition 1) and from the intermediate to finish ration on day 19 (transition 2). The ration carbohydrate and megacalorie contents increased with each transition. During each transition, the lower megacalorie ration was fed at the 8:00 am feeding and the higher megacalorie ration was fed at the 2:00 pm feeding for 3 days before the higher megacalorie ration was fed extensively. Steers were sent to slaughter after 182 days; each carcass was assessed for liver abscesses., Results: The diurnal reticulorumen pH pattern was characterized by a peak at 7:00 am and nadir at 8:00 pm. The mean percentages of time that the reticulorumen pH was ≤ 5.6 and ≤ 5.2 were more than 10-fold greater during transition 1, compared with during transition 2, and were significantly greater for steers with extensive liver abscesses than for steers without extensive liver abscesses., Conclusions and Clinical Relevance: Efforts to minimize the duration that the reticulorumen pH is ≤ 5.6 might mitigate liver abscess formation in feedlot cattle.

Background: There are few effective treatments specifically aimed at basal bladder cancer., Objective: Female F344 rats administered N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) develop large invasive bladder cancers. We determined the efficacy of daily vs weekly dosing of EGFR inhibitors, determined the efficacy of naproxen combined with an EGFR inhibitor, and performed RNA analysis of bladder tumors treated for 5 days with EGFR inhibitors or NO-naproxen to identify pharmacodynamic biomarkers., Methods: Erlotinib (6 mg/Kg BW daily or 21 or 42 mg/Kg BW weekly), lapatinib (25 or 75 mg/Kg BW daily or 263 or 525 mg/Kg BW weekly) and/or naproxen (30 mg/Kg BW daily) were administered to OH-BBN-treated rats beginning 2-12 weeks post OH-BBN. Rats were sacrificed 28 weeks after the final OH-BBN treatment to determine the effects of the EGFR inhibitors + naproxen on bladder weights and tumor development. In a separate study, rats were treated with OH-BBN. When palpable tumors developed, rats were treated with erlotinib, lapatinib, gefitinib, or the NSAID NO-naproxen for 5 days. RNA analysis was performed on the tumors., Results: Daily or weekly dosing of erlotinib or lapatinib and daily dosing of naproxen reduced large tumor formation up to 70%, while combining daily lapatinib and naproxen reduced tumors 100%. RNA Analysis: All EGFR inhibitors strongly reduced cell proliferation and chromosome replication pathways, while NO-naproxen altered the G protein receptor, oxygen homeostasis and immune function pathways., Conclusions: While daily and weekly dosing with EGFR inhibitors and naproxen were effective, combining lapatinib and naproxen yielded no tumors. This might encourage its clinical use in an adjuvant setting with superficial basal tumors, and perhaps even in a more advanced setting. Furthermore, RNA analysis identified specific pathways that might be potential pharmacodynamic biomarkers in clinical trials., Competing Interests: Ronald A. Lubet has no conflict of interest to report. Amit Kumar has no conflict of interest to report. Jennifer T. Fox has no conflict of interest to report. Ming You has no conflict of interest to report. Altaf Mohammed has no conflict of interest to report. M. Margaret Juliana has no conflict of interest to report. Clinton J. Grubbs has no conflict of interest to report., (© 2021 – The authors. Published by IOS Press.)

Dystonias are a group of chronic movement-disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Epidemiology, clinical and experimental animal studies suggest high fructose diets are detrimental to metabolic status and may contribute to tumor development. This due to increased obesity and metabolic syndrome, known risk factors for many types of cancer. We compared tumor development in N-methyl-N-nitrosourea (MNU)-treated rats fed either a high (60%)-fructose diet (HFD) or a standard diet (SD). Female Sprague-Dawley rats at 43 days of age (DOA) were fed a SD or HFD followed by administration of MNU at 50 DOA. Rats were palpated weekly and sacrificed at 190 DOA. MNU-treated rats on HFD exhibited decreased tumor latency and roughly a two-fold increase in tumor multiplicity. RNA-Seq on frozen tumors (SD vs. HFD rats) showed altered expression of approximately 10% of genes (P < 0.05). When examined by Ingenuity Pathway Analysis, multiple highly significant pathways were identified including A) mechanisms of cancer, B) Wnt pathway, C) immune response ( e.g. , "Th1 and Th2 activation" and "antigen presentation") and D) LXR/RXR nuclear receptor. These generalized pathways were indirectly confirmed by alterations of various interrelated disease pathways (epithelial cancers, T cell numbers and apoptosis). In a second study, serum was collected from rats on the HFD or SD pre-MNU and at the time of sacrifice. Metabolomics revealed that the HFD yielded: A) increased levels of fructose, B) increases of various monoglycerols, C) reduced levels of various diacylglycerols and oxygenated inflammatory lipids (9 and 13 HODE and 12,13 DHOME) and D) increased levels of secondary bile acids (hyodeoxycholate and 6-oxolithocholate), which may reflect microbiome changes. These metabolomic changes, which are distinct from those on a high-fat diet, may prove relevant when examining individuals who consume higher levels of fructose.

Background: Past research has shown how fires, heat and hot substances are important causes of health loss globally. Detailed estimates of the morbidity and mortality from these injuries could help drive preventative measures and improved access to care., Methods: We used the Global Burden of Disease 2017 framework to produce three main results. First, we produced results on incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years from 1990 to 2017 for 195 countries and territories. Second, we analysed these results to measure mortality-to-incidence ratios by location. Third, we reported the measures above in terms of the cause of fire, heat and hot substances and the types of bodily injuries that result., Results: Globally, there were 8 991 468 (7 481 218 to 10 740 897) new fire, heat and hot substance injuries in 2017 with 120 632 (101 630 to 129 383) deaths. At the global level, the age-standardised mortality caused by fire, heat and hot substances significantly declined from 1990 to 2017, but regionally there was variability in age-standardised incidence with some regions experiencing an increase (eg, Southern Latin America) and others experiencing a significant decrease (eg, High-income North America)., Conclusions: The incidence and mortality of injuries that result from fire, heat and hot substances affect every region of the world but are most concentrated in middle and lower income areas. More resources should be invested in measuring these injuries as well as in improving infrastructure, advancing safety measures and ensuring access to care., Competing Interests: Competing interests: Dr. Spencer James reports grants from Sanofi Pasteur, outside the submitted work. All other authors have nothing to disclose. Dr. Carl Abelardo T Antonio reports grants and personal fees from Johnson & Johnson (Philippines), Inc., outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Falls in older aged adults are an important public health problem. Insight into differences in fall-related injury rates between countries can serve as important input for identifying and evaluating prevention strategies. The objectives of this study were to compare Global Burden of Disease (GBD) 2017 estimates on incidence, mortality and disability-adjusted life years (DALYs) due to fall-related injury in older adults across 22 countries in the Western European region and to examine changes over a 28-year period., Methods: We performed a secondary database descriptive study using the GBD 2017 results on age-standardised fall-related injury in older adults aged 70 years and older in 22 countries from 1990 to 2017., Results: In 2017, in the Western European region, 13 840 per 100 000 (uncertainty interval (UI) 11 837-16 113) older adults sought medical treatment for fall-related injury, ranging from 7594 per 100 000 (UI 6326-9032) in Greece to 19 796 per 100 000 (UI 15 536-24 233) in Norway. Since 1990, fall-related injury DALY rates showed little change for the whole region, but patterns varied widely between countries. Some countries (eg, Belgium and Netherlands) have lost their favourable positions due to an increasing fall-related injury burden of disease since 1990., Conclusions: From 1990 to 2017, there was considerable variation in fall-related injury incidence, mortality, DALY rates and its composites in the 22 countries in the Western European region. It may be useful to assess which fall prevention measures have been taken in countries that showed continuous low or decreasing incidence, death and DALY rates despite ageing of the population., Competing Interests: Competing interests: Dr. Briggs reports grants from Australian National Health and Medical Research Council, outside the submitted work. Professor Cooper reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. Dr. Haro reports personal fees from Lundbeck and from Roche, and that the institution for which they work provides scientific work for Eli Lilly and Co. Dr. James reports grants from Sanofi Pasteur, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Vietnam has been one of the fastest-growing world economies in the past decade. The burden of injuries can be affected by economic growth given the increased exposure to causes of injury as well as decreased morbidity and mortality of those that experience injury. It is of interest to evaluate the trends in injury burden that occurred alongside Vietnam's economic growth in the past decade., Methods: Results from Global Burden of Disease 2017 were obtained and reviewed. Estimates of incidence, cause-specific mortality, years lived with disability, years of life lost, disability-adjusted life years were analysed and reported for 30 causes of injury in Vietnam from 2007 to 2017., Results: Between 2007 and 2017, the age-standardised incidence rate of all injuries increased by 14.6% (11.5%-18.2%), while the age-standardised mortality rate decreased by 11.6% (3.0%-20.2%). Interpersonal violence experienced the largest increase in age-standardised incidence (28.3% (17.6%-40.1%)), while exposure to forces of nature had the largest decrease in age-standardised mortality (47.1% (37.9%-54.6%)). The five leading causes of injury in both 2007 and 2017 were road injuries, falls, exposure to mechanical forces, interpersonal violence and other unintentional injuries, all of which increased in incidence from 2007 to 2017. Injury burden varied markedly by age and sex., Conclusions: The rapid expansions of economic growth in Vietnam as well as improvements in the Sociodemographic Index have occurred alongside dynamic patterns in injury burden. These results should be used to develop and implement prevention and treatment programme., Competing Interests: Competing interests: SLJ works on a grant on influenza and RSV hospitalisations, which is funded by Sanofi Pasteur., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: The global burden of road injuries is known to follow complex geographical, temporal and demographic patterns. While health loss from road injuries is a major topic of global importance, there has been no recent comprehensive assessment that includes estimates for every age group, sex and country over recent years., Methods: We used results from the Global Burden of Disease (GBD) 2017 study to report incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years for all locations in the GBD 2017 hierarchy from 1990 to 2017 for road injuries. Second, we measured mortality-to-incidence ratios by location. Third, we assessed the distribution of the natures of injury (eg, traumatic brain injury) that result from each road injury., Results: Globally, 1 243 068 (95% uncertainty interval 1 191 889 to 1 276 940) people died from road injuries in 2017 out of 54 192 330 (47 381 583 to 61 645 891) new cases of road injuries. Age-standardised incidence rates of road injuries increased between 1990 and 2017, while mortality rates decreased. Regionally, age-standardised mortality rates decreased in all but two regions, South Asia and Southern Latin America, where rates did not change significantly. Nine of 21 GBD regions experienced significant increases in age-standardised incidence rates, while 10 experienced significant decreases and two experienced no significant change., Conclusions: While road injury mortality has improved in recent decades, there are worsening rates of incidence and significant geographical heterogeneity. These findings indicate that more research is needed to better understand how road injuries can be prevented., Competing Interests: Competing interests: SLJ reports grants from Sanofi Pasteur outside the submitted work. TRM reports a contract to evaluate AB InBev Foundation’s efforts to, among other things, reduce impaired driving in 6 cities using GBD road safety data in calculating baseline harm., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria., Methods: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced., Results: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes., Conclusions: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future., Competing Interests: Competing interests: Dr. James reports grants from Sanofi Pasteur, outside the submitted work. Dr. Driscoll reports grants from World Health Organisation, during the conduct of the study. Dr Shariful Islam is funded by a Fellowship from National Heart Foundation of Australia and Institute for Physical Activity and Nutrition, Deakin University. Dr. Ivers reports grants from National Health and Medical Research Council of Australia, during the conduct of the study. Dr. Jozwiak reports personal fees from TEVA, personal fees from ALAB, personal fees from BOEHRINGER INGELHEIM, personal fees from SYNEXUS, non-financial support from SERVIER, non-financial support from MICROLIFE, non-financial support from MEDICOVER, outside the submitted work. Walter Mendoza is currently Program Analyst Population and Development at the Peru Country Office of the United Nations Population Fund-UNFPA, which does not necessarily endorses this study. Dr. Rakovac reports grants from World Health Organization, during the conduct of the study. Dr. Sheikh reports grants from Health Data Research UK, outside the submitted work. Dr. Singh reports personal fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Spherix, Practice Point communications, the National Institutes of Health and the American College of Rheumatology, personal fees from Speaker’s bureau of Simply Speaking. Dr. Singh owns stock options in Amarin pharmaceuticals and Viking pharmaceuticals. Dr. Singh serves on the steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arms-length funding from 12 pharmaceutical companies. Dr. Singh serves on the FDA Arthritis Advisory Committee. Dr. Singh is a member of the Veterans Affairs Rheumatology Field Advisory Committee. Dr. Singh is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis, outside the submitted work. Dr. Stein reports personal fees from Lundbeck and Sun, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Falls can lead to severe health loss including death. Past research has shown that falls are an important cause of death and disability worldwide. The Global Burden of Disease Study 2017 (GBD 2017) provides a comprehensive assessment of morbidity and mortality from falls., Methods: Estimates for mortality, years of life lost (YLLs), incidence, prevalence, years lived with disability (YLDs) and disability-adjusted life years (DALYs) were produced for 195 countries and territories from 1990 to 2017 for all ages using the GBD 2017 framework. Distributions of the bodily injury (eg, hip fracture) were estimated using hospital records., Results: Globally, the age-standardised incidence of falls was 2238 (1990-2532) per 100 000 in 2017, representing a decline of 3.7% (7.4 to 0.3) from 1990 to 2017. Age-standardised prevalence was 5186 (4622-5849) per 100 000 in 2017, representing a decline of 6.5% (7.6 to 5.4) from 1990 to 2017. Age-standardised mortality rate was 9.2 (8.5-9.8) per 100 000 which equated to 695 771 (644 927-741 720) deaths in 2017. Globally, falls resulted in 16 688 088 (15 101 897-17 636 830) YLLs, 19 252 699 (13 725 429-26 140 433) YLDs and 35 940 787 (30 185 695-42 903 289) DALYs across all ages. The most common injury sustained by fall victims is fracture of patella, tibia or fibula, or ankle. Globally, age-specific YLD rates increased with age., Conclusions: This study shows that the burden of falls is substantial. Investing in further research, fall prevention strategies and access to care is critical., Competing Interests: Competing interests: SJ reports grants from Sanofi Pasteur outside the submitted work; AB reports personal fees from World Health Organization outside the submitted work; CC reports personal fees from Amgen, personal fees from Danone, personal fees from Eli Lilly, personal fees from GlaxoSmithKline, personal fees from Kyowa Kirin, personal fees from Medtronic, personal fees from Merck, personal fees from Nestle, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from Servier, personal fees from Shire, personal fees from Takeda, and personal fees from UCB outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries., Methods: We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs)., Findings: In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505)., Interpretation: Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care., Competing Interests: Competing interests: Dr. James reports grants from Sanofi Pasteur, outside the submitted work. Dr. Driscoll reports grants from World Health Organization, during the conduct of the study. Dr. Ivers reports grants from National Health and Medical Research Council of Australia, during the conduct of the study. Dr. Jozwiak reports personal fees from TEVA, personal fees from ALAB, personal fees from BOEHRINGER INGELHEIM, personal fees from SYNEXUS, non-financial support from SERVIER, non-financial support from MICROLIFE, non-financial support from MEDICOVER, outside the submitted work. Dr. Rakovac reports grants from World Health Organization, during the conduct of the study. Dr Shariful Islam is funded by National Heart Foundation of Australia and Institute for Physical Activity and Nutrition, Deakin University. Dr. Sheikh reports grants from Health Data Research UK, outside the submitted work. Dr. Singh reports personal fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Spherix, Practice Point communications, the National Institutes of Health and the American College of Rheumatology, and Speaker’s bureau of Simply Speaking, owns stock options in Amarin pharmaceuticals and Viking pharmaceuticals, serves on the steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arm’s length funding from 12 pharmaceutical companies, serves on the FDA Arthritis Advisory Committee, is a member of the Veterans Affairs Rheumatology Field Advisory Committee, and is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis, outside the submitted work. Dr. Stein reports personal fees from Lundbeck, personal fees from Sun, outside the submitted work. Dr. Degenhardt reports grants from Indivior, Seqirus, Reckitt Benckiser, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: As global rates of mortality decrease, rates of non-fatal injury have increased, particularly in low Socio-demographic Index (SDI) nations. We hypothesised this global pattern of non-fatal injury would be demonstrated in regard to bony hand and wrist trauma over the 27-year study period., Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 was used to estimate prevalence, age-standardised incidence and years lived with disability for hand trauma in 195 countries from 1990 to 2017. Individual injuries included hand and wrist fractures, thumb amputations and non-thumb digit amputations., Results: The global incidence of hand trauma has only modestly decreased since 1990. In 2017, the age-standardised incidence of hand and wrist fractures was 179 per 100 000 (95% uncertainty interval (UI) 146 to 217), whereas the less common injuries of thumb and non-thumb digit amputation were 24 (95% UI 17 to 34) and 56 (95% UI 43 to 74) per 100 000, respectively. Rates of injury vary greatly by region, and improvements have not been equally distributed. The highest burden of hand trauma is currently reported in high SDI countries. However, low-middle and middle SDI countries have increasing rates of hand trauma by as much at 25%., Conclusions: Certain regions are noted to have high rates of hand trauma over the study period. Low-middle and middle SDI countries, however, have demonstrated increasing rates of fracture and amputation over the last 27 years. This trend is concerning as access to quality and subspecialised surgical hand care is often limiting in these resource-limited regions., Competing Interests: Competing interests: Dr. Jozwiak reports personal fees from TEVA, personal fees from ALAB, personal fees from BOEHRINGER INGELHEIM, personal fees from SYNEXUS, non-financial support from SERVIER, non-financial support from MICROLIFE, and non-financial support from MEDICOVER, outside the submitted work. Dr. James reports grants from Sanofi Pasteur, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates., Methods: Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm-the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate., Results: For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced., Conclusions: The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum., Competing Interests: Competing interests: Dr. Carl Abelardo T Antonio reports personal fees from Johnson & Johnson (Philippines), Inc., outside the submitted work. Dr. Jasvinder Singh reports personal fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Spherix, the National Institutes of Health and the American College of Rheumatology, stock options in Amarin pharmaceuticals and Viking pharmaceuticals, participating in the steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arm’s length funding from 12 pharmaceutical companies, including Amgen, Janssen, Novartis, Roche, UCB Group, Ardea/Astra Zeneca, Bristol Myers Squibb, Celgene, EliLilly, Horizon Pharma, Pfizer, and Centrexion. Dr. Josep Maria Haro reports personal fees from Roche and Lundbeck, and that the institute for which they work provides services to Eli Lilly and Co., outside the submitted work. Dr. Mete Saylan is an employee of Bayer AG, outside the submitted work. Dr Sheikh Mohammed Shariful Islam is funded by National Heart Foundation of Australia and supported by a senior research fellowship from Deakin University, outside the submitted work. Dr. Spencer James reports grants from Sanofi Pasteur, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: To date, the burden of injury in Mexico has not been comprehensively assessed using recent advances in population health research, including those in the Global Burden of Disease Study 2017 (GBD 2017)., Methods: We used GBD 2017 for burden of unintentional injury estimates, including transport injuries, for Mexico and each state in Mexico from 1990 to 2017. We examined subnational variation, age patterns, sex differences and time trends for all injury burden metrics., Results: Unintentional injury deaths in Mexico decreased from 45 363 deaths (44 662 to 46 038) in 1990 to 42 702 (41 439 to 43 745) in 2017, while age-standardised mortality rates decreased from 65.2 (64.4 to 66.1) in 1990 to 35.1 (34.1 to 36.0) per 100 000 in 2017. In terms of non-fatal outcomes, there were 3 120 211 (2 879 993 to 3 377 945) new injury cases in 1990, which increased to 5 234 214 (4 812 615 to 5 701 669) new cases of injury in 2017. We estimated 2 761 957 (2 676 267 to 2 859 777) disability-adjusted life years (DALYs) due to injuries in Mexico in 1990 compared with 2 376 952 (2 224 588 to 2 551 004) DALYs in 2017. We found subnational variation in health loss across Mexico's states, including concentrated burden in Tabasco, Chihuahua and Zacatecas., Conclusions: In Mexico, from 1990 to 2017, mortality due to unintentional injuries has decreased, while non-fatal incident cases have increased. However, unintentional injuries continue to cause considerable mortality and morbidity, with patterns that vary by state, age, sex and year. Future research should focus on targeted interventions to decrease injury burden in high-risk populations., Competing Interests: Competing interests: SLJ works in an influenza/RSV grant that is funded by Sanofi Pasteur., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: The Global Burden of Disease Study (GBD) has historically produced estimates of causes of injury such as falls but not the resulting types of injuries that occur. The objective of this study was to estimate the global incidence, prevalence and years lived with disability (YLDs) due to facial fractures and to estimate the leading injurious causes of facial fracture., Methods: We obtained results from GBD 2017. First, the study estimated the incidence from each injury cause (eg, falls), and then the proportion of each cause that would result in facial fracture being the most disabling injury. Incidence, prevalence and YLDs of facial fractures are then calculated across causes., Results: Globally, in 2017, there were 7 538 663 (95% uncertainty interval 6 116 489 to 9 493 113) new cases, 1 819 732 (1 609 419 to 2 091 618) prevalent cases, and 117 402 (73 266 to 169 689) YLDs due to facial fractures. In terms of age-standardised incidence, prevalence and YLDs, the global rates were 98 (80 to 123) per 100 000, 23 (20 to 27) per 100 000, and 2 (1 to 2) per 100 000, respectively. Facial fractures were most concentrated in Central Europe. Falls were the predominant cause in most regions., Conclusions: Facial fractures are predominantly caused by falls and occur worldwide. Healthcare systems and public health agencies should investigate methods of all injury prevention. It is important for healthcare systems in every part of the world to ensure access to treatment resources., Competing Interests: Competing interests: SLJ works on a grant for influenza and respiratory syncytial disease that is funded by Sanofi Pasteur. This work does not relate to facial fracture burden., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Nepal is a low-income country undergoing rapid political, economic and social development. To date, there has been little evidence published on the burden of injuries during this period of transition., Methods: The Global Burden of Disease Study (GBD) is a comprehensive measurement of population health outcomes in terms of morbidity and mortality. We analysed the GBD 2017 estimates for deaths, years of life lost, years lived with disability, incidence and disability-adjusted life years (DALYs) from injuries to ascertain the burden of injuries in Nepal from 1990 to 2017., Results: There were 16 831 (95% uncertainty interval 13 323 to 20 579) deaths caused by injuries (9.21% of all-cause deaths (7.45% to 11.25%)) in 2017 while the proportion of deaths from injuries was 6.31% in 1990. Overall, the injury-specific age-standardised mortality rate declined from 88.91 (71.54 to 105.31) per 100 000 in 1990 to 70.25 (56.75 to 85.11) per 100 000 in 2017. In 2017, 4.11% (2.47% to 6.10%) of all deaths in Nepal were attributed to transport injuries, 3.54% (2.86% to 4.08%) were attributed to unintentional injuries and 1.55% (1.16% to 1.85%) were attributed to self-harm and interpersonal violence. From 1990 to 2017, road injuries, falls and self-harm all rose in rank for all causes of death., Conclusions: The increase in injury-related deaths and DALYs in Nepal between 1990 and 2017 indicates the need for further research and prevention interventions. Injuries remain an important public health burden in Nepal with the magnitude and trend of burden varying over time by cause-specific, sex and age group. Findings from this study may be used by the federal, provincial and local governments in Nepal to prioritise injury prevention as a public health agenda and as evidence for country-specific interventions., Competing Interests: Competing interests: SLJ reports grants from Sanofi Pasteur outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

In both estrogen receptor/progesterone receptor-positive (ER + /PR + ) human breast cancer and in ER + /PR + cancers in the methylnitrosourea (MNU)-induced rat model, short-term modulation of proliferation in early cancers predicts preventive/therapeutic efficacy. We determined the effects of known effective/ineffective chemopreventive agents on proliferative index (PI) in both rat mammary epithelium and small cancers. Female Sprague-Dawley rats were treated with MNU at 50 days of age. Five days later, the rats were treated with the individual compounds for a period of 14 days. At that time, normal mammary tissue from the inguinal gland area was surgically removed. After removal, the rats remained on the agents for an additional 5 months. This cancer prevention study confirmed our prior results of striking efficacy with tamoxifen, vorozole, Targretin, and gefitinib, and no efficacy with metformin, naproxen, and Lipitor. Employing a separate group of rats, the effects of short-term (7 days) drug exposure on small palpable cancers were examined. The PI in both small mammary cancers and in normal epithelium from control rats was >12%. In agreement with the cancer multiplicity data, tamoxifen, vorozole, gefitinib, and Targretin all strongly inhibited proliferation (>65%; P < 0.025) in the normal mammary epithelium. The ineffective agents metformin, naproxen, and Lipitor minimally affected PI. In the small cancers, tamoxifen, vorozole, and Targretin all reduced the PI, while metformin and Lipitor failed to do so. Thus, short-term changes in the PI in either normal mammary epithelium or small cancers correlated with long-term preventive efficacy in the MNU-induced rat model., (©2019 American Association for Cancer Research.)

The surfaces of most materials in aqueous systems are charged due to the ionization of surface functional groups. When these surfaces interact, the surface charge, electrostatic potential, and pH will vary as a function of separation distance, and this process is termed the charge-regulation effect. Charge regulation is a controlling factor in the adhesion and transport of colloids and microorganisms in aqueous systems, and its modeling requires representation of the pH-charge response of the surfaces, typically provided as the equilibrium constants ( K ) and site densities ( N ) of the dominant surface functional groups. Existing methods for obtaining these parameters demonstrate shortcomings when applied to many natural and man-made materials, such as weathered materials, materials with undefined or complex surface structures, and permeable materials, and for materials that do not provide the requisite high surface area in suspension due to small sample sizes. This hinders inclusion of the charge-regulation effect in colloid and microbial transport studies, and most studies of colloidal and microbial surface interactions use simplifying assumptions; a key example is the routine use of the constant potential assumption in DLVO modeling. Here we present a robust method that overcomes these issues and provides a rapid means to characterize charge-regulated surfaces using zeta potential data, without requiring a priori knowledge of the material composition. Applying a combined charge-regulation and Gouy-Chapman model, K and N values are obtained that accurately represent the electrostatic response of a charge-regulated surface. This method is demonstrated using activated carbon, aluminum oxide, iron (hydr)oxide, feldspar, and silica sand. The resulting K and N values are then used to show the variations in surface charge, electrostatic potential, and pH that can occur as these charge-regulated surfaces interact. This method provides a readily applied experimental approach for characterizing charge-regulated surfaces, with the overall goal to promote the inclusion of charge-regulated interactions into adhesion and transport studies with natural and undefined materials.

Aquatic organisms have adapted over evolutionary time-scales to hydrologic variability represented by the natural flow regime of rivers and streams in their unimpaired state. Rapid landscape change coupled with growing human demand for water have altered natural flow regimes of many rivers and streams on a global scale. Climate non-stationarity is expected to further intensify hydrologic variability, placing increased pressure on aquatic communities. Using a machine learning approach and georeferenced species occurrence data, we modeled and mapped spatial patterns of hydrologic disturbance for streams in Arkansas, Missouri, and eastern Oklahoma. Random forest (RF) models trained on fish community data, hydrologic, and landscape metrics for gaged streams in the National Hydrography (NHDPlusV2) database were used to predict a hydrologic disturbance index (HDI) for ungaged streams. The HDI is part of the USGS Geospatial Attributes of Gages for Evaluating Streamflow (GAGESII) database and is a composite index of watershed-scale disturbance from anthropogenic stressors. Fish presence/absence data had similar overall model prediction accuracy (77%; 95% CI: 0.74, 0.80) as flow variables (76%; CI: 0.73, 0.80). Including topographic variables increased the RF prediction accuracy of both the fish (90%; CI: 0.88, 0.92) and flow models (86%; CI: 0.84, 0.89). Spatial patterns of hydrologic disturbance suggest distinct ecohydrological regions exist where conservation actions may be focused. Streams with low HDI were predominately located in the Ozark Highlands, Boston Mountains, and Ouachita Mountains. Correlation analysis of HDI by flow regime showed groundwater stable streams had the lowest disturbance frequency, with over 50% of stream reaches with low HDI located in forested land cover. HDI was highest for big rivers, intermittent runoff streams and streams in areas of agricultural land use. Our results show long-term georeferenced biological data can provide a valuable resource for predictive modeling of hydrologic disturbance for ungaged rivers and streams., (Copyright © 2019. Published by Elsevier B.V.)

Signal transducer and activator of transcription 3 (STAT3) plays a key role in the transformation of normal cells to cancerous cells. Although inhibitors of STAT3 have been shown to suppress the growth of multiple cancer types in vitro and in vivo, such agents are of particular interest for the prevention of breast cancer, which affects over 200,000 women and claims more than 40,000 lives in the United States each year. In the present study, we employed the MMTV/Neu transgenic mouse model, which develops estrogen receptor (ER)‑negative, Neu‑overexpressing tumors, and the Sprague‑Dawley (SD) rat model, which develops ER‑positive tumors upon exposure to the carcinogen 7,12‑dimethylbenz[a]anthracene (DMBA), to test the efficacy of the STAT3 inhibitor GLG‑302 in the prevention of mammary cancer. Orally administered GLG‑302 and its trizma salt derivative reduced mammary cancer incidence, multiplicity, and tumor weights in female MMTV/Neu mice, and GLG‑302 reduced tumor multiplicity and weights in female DMBA‑treated rats. Consistent with the mechanism of action of STAT3 inhibitors, the reductions in mammary tumors were correlated with decreases in STAT3 phosphorylation and cell proliferation. These data suggest that GLG‑302 is a novel agent with potential for prevention of mammary cancer and support the further development of STAT3 inhibitors for this cause.

Cancer chemopreventive agents inhibit the formation of precursor lesions and/or the progression of these lesions to late stage disease. This approach to disease control has the potential to reduce the physical and financial costs of cancer in society. Several drugs that have been approved by the FDA for other diseases and have been extensively evaluated for their safety and pharmacokinetic/pharmacodynamic characteristics have the potential to be repurposed for use as cancer chemopreventive agents. These agents often mechanistically inhibit signaling molecules that play key roles in the carcinogenic process. The safety profile of agents is a primary concern when considering the administration of drugs for chemoprevention, as the drugs will be given chronically to high-risk, asymptomatic individuals. To decrease drug toxicity while retaining efficacy, several approaches are currently being explored. In this short review, we describe studies that use preclinical in vivo models to assess efficacy of alternative drug dosing strategies and routes of drug administration on chemopreventive drug efficacy. In vivo drug dosing strategies that reduce toxicity while retaining efficacy will pave the way for future cancer prevention clinical trials., (Published by Oxford University Press on behalf of the Society of Toxicology 2019.)

A simple method to modify hydroxyapatite and pectin into an efficient zinc sorbent was investigated. Process and formulation modifications enabled the formation of a flower-like hydroxyapatite/pectin hybrid material. The hybrid material was characterized with scanning electron microscopy, elemental analysis, and zeta potential tests. Sorption data were analyzed with different kinetic and isotherm models. The results showed that the pseudo-second order kinetic model and two-staged isotherm curves with Langmuir at the first stage and a Freundlich model the at second stage could best describe the zinc sorption on the hybrid. The maximum experimental sorption capacity was 330.4 mg Zn 2+ per gram of sorbent, which was obtained with an initial concentration of 260 mg L -1 Zn 2+ at pH 5.0. pH monitoring and Zeta potential tests suggested surface complexation and electrostatic attraction were fundamental in the zinc sorption process., Competing Interests: The authors declare no conflicts of interest within this work., (This journal is © The Royal Society of Chemistry.)

Little is known about the role of surface water in the propagation of antibiotic resistance (AR), or the relationship between AR and water quality declines. While healthcare and agricultural sectors are considered the main contributors to AR dissemination, few studies have been conducted in their absence. Using linear models and Bayesian kriging, we evaluate AR among Escherichia coli water isolates collected bimonthly from the Chobe River in Northern Botswana ( n = 1997, n = 414 water samples; July 2011-May 2012) in relation to water quality dynamics ( E. coli , fecal coliform, and total suspended solids), land use, season, and AR in wildlife and humans within this system. No commercial agricultural or large medical facilities exist within this region. Here, we identify widespread AR in surface water, with land use and season significant predicators of AR levels. Mean AR was significantly higher in the wet season than the dry season ( p = 0.003), and highest in the urban landscape (2.15, SD = 0.098) than the protected landscape (1.39, SD = 0.051). In-water E. coli concentrations were significantly positively associated with mean AR in the wet season ( p < 0.001) but not in the dry season ( p = 0.110), with TSS negatively associated with mean AR across seasons ( p = 0.016 and p = 0.029), identifying temporal and spatial relationships between water quality variables and AR. Importantly, when human, water, and wildlife isolates were examined, similar AR profiles were identified ( p < 0.001). Our results suggest that direct human inputs are sufficient for extensive dispersal of AR into the environment, with landscape features, season, and water quality variables influencing AR dynamics. Focused and expensive efforts to minimize pollution from agricultural sources, while important, may only provide incremental benefits to the management of AR across complex landscapes. Controlling direct human AR inputs into the environment remains a critical and pressing challenge.

Delivering effective, efficient and extraordinary healthcare to all requires full access to care. Health insurance, either private or government, is essential to that access, which is why Beaumont Health is urging President Donald Trump and members of Congress to tread carefully as they consider changes in the Affordable Care Act.