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Objective: In this study, we examined whether self-reported prostate cancer screening rates differed by ethnicity. Methods: We used 2014 and 2018 data from the Behavioral Risk Factor Surveillance System (BRFSS) to determine if self-reported screening rates differed by ethnicity and year, while we controlled for geographic, demographic, and health factors. We also investigated factors that may influence screening rates. Results: Self-reported screening rates decreased between 2014 and 2018, both overall and by each ethnicity. Blacks had significantly higher odds of reporting a PSA test than Whites (OR = 1.13 ± 0.01 in 2014; 1.14 ± 0.01 in 2018); all other group had lower odds than Whites. By ethnicity, only Blacks and Native Hawaiians/Pacific Islanders had higher odds of being asked the questions than Whites; all other groups had lower odds. Overall screening rates were positively correlated with prostate cancer incidence rates by state but not for any racial group individually. Conclusions: Self-reported PSA test rates are declining, are associated with PSA test knowledge, are less likely in non-black minorities, and may be influenced by healthcare discussions and state-level incidence rates

Studies of the observed record of global warming suggest that the Earth’s climate sensitivity is at the lower end of the range produced by the CMIP6 Earth System Models (Jimenez and Mauritsen, 2019; Nijsse et al., 2020; Tokarska et al., 2020). However, studies based on top-of-the-atmosphere fluxes often suggest the opposite (Brown et al., 2017; Sherwood et al., 2020).Earthshine estimates (Goode et al., 2021) and satellite measurements of the planetary albedo from CERES (Loeb et al., 2018) both indicate that the Earth has darkened significantly over the past two decades. Planetary darkening is also simulated in CMIP6 historical simulations , but the models with the highest climate sensitivities tend to fit the observed decline in planetary albedo much better. Observed planetary darkening therefore favours higher climate sensitivities, but constraints based on ground-based global warming records favour lower climate senstivities.We explore this apparent paradox by calculating the contributions to changes in global warming that arise from diagnosable changes in planetary albedo and effective global emissivity, in both models and observational records. Differences between low and high sensitivity models are found to be predominantly due to the rate at which the modelled planetary albedo declines, which can in principle be due to a combination of forcing and feedbacks. However, planetary darkening in higher sensitivity models is primarily due to reductions in cloud cover, which results in a positive SW cloud feedback.By contrast, the planetary darkening seen in the CERES satellite record is driven not by reductions in cloud cover, but instead by the darkening of clouds, and to a lesser extent by the darkening of clear skies. This suggest that darkening in CERES is driven by reductions in aerosols, which leads to reductions in negative aerosol forcing. Planetary darkening in CERES therefore seems to be due primarily to changes in aerosol forcing.Our proposed resolution to ‘The paradox of the darkening planet and the Earth’s climate sensitivity’ is therefore that climate sensitivity is indeed towards the lower end of the CMIP6 model range (as suggested by observed records of global warming), and that higher sensitivity models get the rate of planetary darkening ‘right’ but by the wrong mechanism (i.e. as a cloud forcing rather than as an aerosol feedback). We will back this up by comparing the spatial patterns of planetary albedo change from models and the CERES satellite data, and finish by discussing possible implications for the time-varying aerosol precursor fields that are used to drive the CMIP6 simulations.

We analyse a large number of Earth System Models (ESMs) and find that there is some evidence that the temperatures of extreme events are rising faster than local background rises in mean summer temperatures. We find this to be true for almost all land regions when analysing the SSP585 scenario and for the decades from now until the end of the 21st Century. We find strong correlations between the level of acceleration and upward trends in sensible heat fluxes. In the few tropical regions where there is less correlation, we instead find a link to background latent plus sensible heat, which acts as a proxy for overall available energy. We then study extreme acceleration in the contemporary period, in both ESMs and ERA5 data. We find in these circumstances particularly strong evidence of faster warming of extreme events, but only for selected regions. We suggest this is a consequence of highly regional effects such as aerosols. Our analysis hints that as atmospheric composition changes move towards alteration by greenhouse gases only, there will be a more general globally-applicable occurrence of high-temperature extremes, with their mean increase more than the more general background warming levels.

Machine learning interatomic potentials have emerged as a powerful tool for bypassing the spatio-temporal limitations of ab initio simulations, but major challenges remain in their efficient parameterization. We present AL4GAP, an active learning software workflow for generating multi-composition Gaussian approximation potentials (GAP) for arbitrary molten salt mixtures. The workflow capabilities includes: (1) setting up user-defined combinatorial chemical spaces of charge neutral mixtures of arbitrary molten mixtures spanning 11 cations (Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba and two heavy species, Nd and Th) and 4 anions (F, Cl, Br and I), (2) configurational sampling using low-cost empirical parameterizations, (3) ensemble active learning for down-selecting configurational samples for single point density functional theory calculations at the level of strongly constrained and appropriately normed (SCAN) exchange-correlation functional, and (4) Bayesian optimization for hyperparameter tuning of two-body and many-body GAP models. We apply the workflow to showcase high throughput generation of five independent GAP models for multi-composition binary-mixture melts, each of increasing complexity with respect to charge valency and electronic structure, namely: LiCl-KCl, NaCl-CaCl2, KCl-NdCl3, CaCl2-NdCl3 and KCl-ThCl4. Our results indicate that GAP models, can accurately predict structure for diverse molten salt mixture with DFT-SCAN accuracy, capturing the intermediate range ordering characteristic of the multi-valent cationic melts.

The discovery of a near-proportionality between cumulative anthropogenic carbon dioxide emissions and global warming since pre-industrial times is arguably the most important policy-relevant simplification of climate change science in the last 25 years. Unfortunately, the latest CMIP6 Earth System Models continue to diagnose a wide range of carbon budgets for each level of global warming. In this paper we present emergent constraints on the carbon budget as a function of global warming, which combine the available CMIP6 Earth System Model historical simulations and future projections with observational estimates of global warming and anthropogenic CO2 emissions to the present day. We derive estimates for cumulative carbon budgets for the Paris targets of 1.5oC and 2oC of global warming of 812 +/- 121 PgC and 1048 +/- 167 PgC, which are significantly larger than the ensemble mean values from the CMIP6 models of 727 +/- 181 PgC and 911 +/- 247 PgC. Our approach produces estimates of the remaining carbon budgets for 1.5oC and 2.0oC within the uncertainty bounds of values given in the IPCC WG1 6th Assessment report, without requiring individual assumptions about the likely range of a number of climate and carbon cycle sensitivity factors, or implicit assumptions about changes in non-CO2 forcing factors. We infer a reduced mean specific carbon budget in the future (473+/-80 PgC/oC beyond 1.2oC of global warming) compared to the past (553+/82 PgC/oC ), primarily due to the decline in cooling atmospheric aerosols. However, the linearity between future cumulative emissions and future global warming is found to be maintained at least until 4oC of global warming, and is consistent with an effective Transient Climate Response to Emissions (TCRE) of 2.1 oC per trillion tonnes of carbon (likely range of 1.8 to 2.6 oC/1000PgC), from now onwards.

The negative ecological impacts of invasive species are well documented, although their effects are often more pronounced on islands than on the mainland. This is because many island species exhibit high degrees of endemism, have small geographic distributions, are rare, and exhibit low genetic diversity, which reduces their ability to respond to new emerging threats. One of the world’s most notorious invasive species is the cane toad (Rhinella marina), which is a voracious predator that is native to the neo-tropics but was intentionally introduced in the early 20th century to many warm regions and islands to control crop pests. Cane toads produce two kinds of toxins in neck glands that are often lethal to non-adapted predators in the invasive range. Although well-studied in Australia, their ecological impacts on many islands have received much less attention. Australia is the sixth largest country on Earth, so the effects of cane toads on small island nations may differ considerably from there. Here, we discuss the potential ecological impacts of cane toads in the Philippines and on other island nations. Cane toads were introduced onto the largest Philippine island, Luzon, in 1930 and have since spread over all but a few of the 7641 islands that make up the country. We speculate that, unlike most biological invasions with predators or herbivores where the ecological effects are strictly ‘top-down’, cane toads, by virtue of their biology and ecology, may have even more serious effects on island fauna because they exhibit both ‘top-down’ and ‘bottom-up’ effects.

Background The etiology of brain cancer is poorly understood. The only confirmed environmental risk factor is exposure to ionizing radiation. Because nuclear reactors emit ionizing radiation, we examined brain cancer incidence rates in the USA in relation to the presence of nuclear reactors per state. Methods Data on brain cancer incidence rates per state for Whites by sex for three age groups (all ages, 50 and older, and under 50) were obtained from cancer registries. The location, number, and type of nuclear reactor, i.e., power or research reactor, was obtained from public sources. We examined the association between these variables using multivariate linear regression and ANOVA. Results Brain cancer incidence rates were not associated with the number of nuclear power reactors. Conversely, incidence rates per state increased with the number of nuclear research reactors. This was significant for both sexes combined and for males in the ‘all ages’ category (β = 0.08, p = 0.0319 and β = 0.12, p = 0.0277, respectively), and for both sexes combined in the’50 and older’ category (β = 0.18, p = 0.0163). Brain cancer incidence rates for counties with research reactors were significantly higher than the corresponding rates for their states overall (p = 0.0140). These findings were not explicable by known confounders. Conclusions Brain cancer incidence rates are positively associated with the number of nuclear research reactors per state. These findings merit further exploration and suggest new opportunities for research in brain cancer epidemiology.

Unraveling the liquid structure of multi-component molten salts is challenging due to the difficulty in conducting and interpreting high temperature diffraction experiments. Motivated by this challenge, we developed composition-transferable Gaussian Approximation Potentials (GAP) for molten LiCl-KCl. A DFT-SCAN accurate GAP is active learned from only ~1100 training configurations drawn from 10 unique mixture compositions enriched with metadynamics. The GAP-computed structures show strong agreement across HEXRD experiments, including for a eutectic not explicitly included in model training, thereby opening the possibility for composition discovery.

Background A well-designed cancer control plan is an important tool for a nation, state, or community to address the burden of cancer. Furthermore, it provides the opportunity to devise and implement measurable objectives. However, there has been little to no assessment of the success rates of such objectives. Methods I compared the success rate of objectives between US states’ current plan and most recent past plan to determine the proportion of success in the United States overall. I also tested possible reasons for low success rates. Results The mean success rate was 20% for stringent successes (only exact matches between plans) and 28% for loose successes (exact and similar matches between plans). The magnitude of change in percentage between the baseline and target for loose objectives significantly predicted success (P = .0347). Higher change resulted in lower success. However, neither the number of objectives nor the level of overlap significantly predicted success rate. Nor was population size, region, or rural–urban status significantly related to success rate. The most successful states had high proportions of objectives that were measurable and a high number of overlapping objectives. Conclusion I found that objective success rates were low for cancer control plans. To improve success rates, I suggest that future cancer control plans ensure each objective has a measurable baseline and realistically attainable target.

Introduction We recently showed that the prevalence of Parkinson’s Disease (PD) in U.S. states is positively associated with the quantity of acid rain. Acid rain could play an etiologic role in PD by mobilizing metals, e.g., lead, from watersheds and pipes into drinking water. We assessed the correlation of PD with lead service lines, the underground pipes that connect homes to municipal water sources, which are a major aqueous source of lead. Methods We used multiple regression techniques to examine PD prevalence rates by state relative to the number of lead service lines. We included known or suspected aqueous risk factors, e.g., the Acid Precipitation Index (a measure of acid rain) and well water use. Results Age-, race-, and sex-adjusted prevalence rates for PD were significantly and positively correlated with the log number of lead service lines (p = 0.0004). The effect of lead service lines remained significant after adjusting for the effects of acid rain and well water use (p = 0.0019). Conclusion These findings are consistent with a role for lead in the etiology of PD. Studies of lead service line exposure in relation to PD at the individual level are warranted.

This work resulted from a workshop (Towards an integrated assessment of the environmental risks posed by non-native species, GMOs and wildlife diseases) held as part of the UK Population Biology Network (UKPopNet) and funded by the Natural Environment Research Council (Agreement R8-H12-01) and English Nature. Its development was stimulated by the workshop on ‘Frameworks used in Invasion Science’ hosted by the DSI-NRF Centre of Excellence for Invasion Biology that was supported by the National Research Foundation of South Africa and Stellenbosch University. Emerging microparasite (e.g. viruses, bacteria, protozoa and fungi) epidemics and the introduction of non-native pests and weeds are major biosecurity threats worldwide. The likelihood of these threats is often estimated from probabilities of their entry, establishment, spread and ease of prevention. If ecosystems are considered equivalent to hosts, then compartment disease models should provide a useful framework for understanding the processes that underpin non-native species invasions. To enable greater cross-fertilisation between these two disciplines, the Epidemiological Framework for Biological Invasions (EFBI) is developed that classifies ecosystems in relation to their invasion status: Susceptible, Exposed, Infectious and Resistant. These states are linked by transitions relating to transmission, latency and recovery. This viewpoint differs markedly from the species-centric approaches often applied to non-native species. It allows generalisations from epidemiology, such as the force of infection, the basic reproductive ratio R0, super-spreaders, herd immunity, cordon sanitaire and ring vaccination, to be discussed in the novel context of non-native species and helps identify important gaps in the study of biological invasions. The EFBI approach highlights several limitations inherent in current approaches to the study of biological invasions including: (i) the variance in non-native abundance across ecosystems is rarely reported; (ii) field data rarely (if ever) distinguish source from sink ecosystems; (iii) estimates of the susceptibility of ecosystems to invasion seldom account for differences in exposure to non-native species; and (iv) assessments of ecosystem susceptibility often confuse the processes that underpin patterns of spread within -and between- ecosystems. Using the invasion of lakes as a model, the EFBI approach is shown to present a new biosecurity perspective that takes account of ecosystem status and complements demographic models to deliver clearer insights into the dynamics of biological invasions at the landscape scale. It will help to identify whether management of the susceptibility of ecosystems, of the number of vectors, or of the diversity of pathways (for movement between ecosystems) is the best way of limiting or reversing the population growth of a non-native species. The framework can be adapted to incorporate increasing levels of complexity and realism and to provide insights into how to monitor, map and manage biological invasions more effectively. Publisher PDF

COVID-19 is a global pandemic with uncertain death rates. We examined county-level population morality rates (per 100,000) and case fatality rates by US region and rural-urban classification, while controlling for demographic, socioeconomic, and hospital variables. We found that population mortality rates and case fatality rates were significantly different across region, rural-urban classification, and their interaction. All significant comparisons had p &lt, 0.001. Northeast counties had the highest population mortality rates (27.4) but had similar case fatality rates (5.9%) compared to other regions except the Southeast, which had significantly lower rates (4.1%). Population mortality rates were highest in urban counties but conversely, case fatality rates were highest in rural counties. Death rates in the Northeast were driven by urban areas (e.g., small, East Coast states), while case fatality rates tended to be highest in the most rural counties for all regions, especially the Southwest. However, on further inspection, high case fatality rate percentages in the Southwest, as well as in overall US counties, were driven by a low case number. This makes it hard to distinguish genuinely higher mortality or an artifact of a small sample size. In summary, coronavirus deaths are not homogenous across the United States but instead vary by region and population and highlight the importance of fine-scale analysis.

Purpose Weekend surgery carries higher mortality than weekday surgery, with complications most commonly arising within the first 48 hours. There is a reduced ability to identify complications at the weekend, with early signs going undetected in the absence of thorough early patient review, particularly in the elderly with multiple co-morbidities. Weekend working practices vary amongst UK hospitals and specialties. The weekend effect has been a prominent feature in the literature over the past decade. The purpose of this paper is to identify the number of patients undergoing weekend surgery who receive a Day 1 post-operative review and improve this outcome by implementing an effective change. Design/methodology/approach It was observed that not all patients undergoing surgery on a Friday or Saturday at the authors’ District General Hospital were receiving Day 1 post-operative review by a clinician. A retrospective audit was carried out to identify percentage of patients reviewed on post-operative Day 1 at the weekend. A change in handover practice was implemented before re-audit. Findings In Phase 1, 54 per cent of patients received Day 1 post-operative reviews at the weekend against a set standard of 100 per cent. A simple change to handover practice was implemented to improve patient safety in the immediate post-operative period resulting in 96 per cent of patients reviewed on Day 1 post-operatively at re-audit. Originality/value This study confirms that simple changes in handover practices can produce effective and translatable improvements to weekend working. This further contributes to the body of literature that acknowledges the existence of a weekend effect, but aims to evolve weekend working practices to accommodate improvement within current staffing and resource availability by maximising efficiency and communication.

Young adults experiencing first-episode psychosis have historically been difficult to retain in mental health treatment. Communities across the United States are implementing Coordinated Specialty Care to improve outcomes for individuals experiencing first-episode psychosis. This mixed-methods research study examined the relationship between program services and treatment retention, operationalized as the likelihood of remaining in the program for 9 months or more. In the adjusted analysis, male gender and participation in home-based cognitive behavioral therapy were associated with an increased likelihood of remaining in treatment. The key informant interview findings suggest the shared decision-making process and the breadth, flexibility, and focus on functional recovery of the home-based cognitive behavioral therapy intervention may have positively influenced treatment retention. These findings suggest the use of shared decision-making and improved access to home-based cognitive behavioral therapy for first-episode psychosis patients may improve outcomes for this vulnerable population.

IN THE PAST 45 years, no-one has ventured further from the Earth's surface than the average height of the International Space Station's orbit (about 400km), which critics have characterised as being 'stuck in low-Earth orbit'. Well-publicised announcements on Mars colonisation from SpaceX CEO Elon Musk suggest that NewSpace entrepreneurs are ready to pick up the space travel baton, but to some this is still science-fiction. Space policy expert and professor emeritus of political science at George Washington University, John Logsdon, says: "Elon Musk's suggestion of a million-person city on Mars is almost pure fantasy. Why would that many people want to immigrate to a hostile environment? What would be the basis for a Martian economy to sustain them? Would they eat more than potatoes? Would there be good wine to drink?"

Communication between healthcare professionals is a key aspect in patient safety especially when dealing with patients with musculoskeletal trauma. The change of junior doctors’ working patterns within the last decade and a multidisciplinary approach has resulted in more healthcare professionals being involved in any one patient’s care. A robust handover and communication tool is essential in ensuring patients’ safety and to allow efficient service coordination. We compared the use of a simple traditional template-based handover system with an electronic interactive database developed using Microsoft Excel specifically designed as a handover tool and to coordinate acute trauma referrals to the orthopaedic department in our hospital. We compared the adequacy and accessibility of patient details and clinical information as well as assessing these systems as tools to facilitate coordination of patients with trauma. Data from both handover systems were collected prospectively over the period of 12 weeks and analysed for the degree of missing information based on the General Medical Council and British Medical Association guidelines for safe handover. A questionnaire was also handed to members of the multidisciplinary team to assess their impression of each handover system on coordination and management of the trauma service. Our study showed a significant reduction in missing information in the electronic database handover system in multiple domains (p

Why do some conflict zones exhibit more violence against civilians than others? In answering this question, the literature has emphasized ethnic fractionalization, territorial control and strategic incentives, while overlooking the consequences of armed conflict itself. This oversight is partly due to the methodological hurdles of finding an appropriate counterfactual for observed battle events. In this chapter, we aim to test empirically the effect of instances of armed clashes between rebels and the government in civil wars on violence against civilians. Battles between belligerents may create conditions that lead to surges in civilian killings as combatants seek to consolidate civilian control or inflict punishment against populations residing near areas of contestation. Since there is no relevant counterfactual for these battles, we utilize road networks to help build a synthetic risk-set of plausible locations for conflict. Road networks are crucial for the logistical operations of a civil war and are thus the main conduit for conflict diffusion. As such, the majority of battles should take place in the proximity of road networks; by simulating events in the same geographic area, we are able to better approximate locations where battles hypothetically could have occurred but did not. We test this simulation approach using a case study of the Democratic Republic of the Congo (1998–2000) and model the causal effect of battles using a spatially disaggregated framework. This work contributes both substantively and methodologically to the literature on micro-foundations of civil war and reactive violence in two main ways: (1) It offers a tentative framework for crafting synthetic counterfactuals with event data. (2) It proposes an empirical test for explaining the variation of violence against civilians as a result of battle events.

Although the etiology of Parkinson’s disease (PD) is unknown, potentially informative clues lie in its geographic distribution. PD prevalence rates within the U.S. are significantly higher in the Midwest and Northeast, a pattern that resembles the geographic distribution of acid precipitation (“acid rain”). Using linear and multivariable regression, we examined state-wide data on PD prevalence in relation to environmental factors including total precipitation, the acidity of precipitation, the use of well water, and industrial releases of sulfuric acid. In multivariate analyses, age-, race-, and gender-adjusted prevalence rates for PD were inversely correlated with well water use and positively correlated with industrial releases of sulfuric acid and with the quantity of acid precipitation (p &lt, 0.0001). To our knowledge, this is the first report of an association between PD and acid rain. Because acid rain is known to leach metals from soils and pipes into drinking water, acid rain’s association with PD prevalence adds support for a role for metals in the etiology of PD.

For children of the 1960s, rocketry was simple. The sleek red Thunderbird 3 tripped into space without the tiresome dropping of stages, returned in its entirety to an island launch pad and refuelled for another mission. So how close are we to Gerry Andersοn's vision of the reusable rocket?.

The 21st century has seen a significant increase in space activity, driven by private sector entities using space for commercial enterprises. This increased use of space is not without cost to the delicate space environment. The threat posed by human-made debris in low Earth orbit (LEO) is now widely recognised as presenting a danger to current levels of space activity, and a more sustainable approach is sought by private and public sector actors. This article will evaluate sustainability in LEO and whether the consensus regarding orbital debris is matched by legislative or governmental action. More broadly, however, it will be contended that notions of space sustainability have largely been restricted to LEO. This article will seek to move the sustainability debate beyond LEO, by highlighting the potential risks to delicate space environments that arise from human activity in both exploring and settling other celestial bodies. The article will attempt to reframe the discussion on sustainability, advocating legal and policy solutions that need to guide future space activity to ensure that humanity avoids replicating the problems now found in LEO.

The cross-sectional and planar analysis of current generation 3D device structures can be analyzed using a single Focused Ion Beam (FIB) mill. This is achieved using a diagonal milling technique that exposes a multilayer planar surface as well as the cross-section. this provides image data allowing for an efficient method to monitor the fabrication process and find device design errors. This process saves tremendous sample-to-data time, decreasing it from days to hours while still providing precise defect and structure data.

Motivation The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2). Time period and grain BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates. Software format .csv and .SQL., Global Ecology and Biogeography, 27 (7), ISSN:1466-822X, ISSN:1466-8238

Herein we report for the first time the biological fate of poly[(oligoethylene glycol) acrylate] (POEGA) star polymers synthesised via a versatile arm-first reversible addition-fragmentation chain transfer (RAFT) polymerisation approach. The biopharmaceutical behaviour of three different molecular weight (49, 64 and 94kDa) POEGA stars was evaluated in rats and nude mice bearing human MDA MB-231 tumours after intravenous administration. The 94kDa star polymer exhibited a longer plasma exposure time than the 49kDa or 64kDa star polymer; an observation attributable to differences in the rates of both polymer biodegradation and urinary excretion. Tumour biodistribution also correlated with molecular weight and was greatest for the longest circulating 94kDa star. Different patterns of liver and spleen biodistribution were observed between mice and rats for the different sized polymers. The polymers were also well-tolerated in vivo and in vitro at therapeutic concentrations. From the Clinical Editor Advances in nanotechnology has enabled scientists to produce nanoparticle as drug carriers in cancer therapeutics. In this article, the authors studied the biological fate of poly[(oligoethylene glycol) acrylate] (POEGA) star polymers of different size, after intravenous injections. This would allow the subsequent comparison to other drug delivery systems for better drug delivery.

Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules.Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes.The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma.The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.

3D printing (Additive manufacturing) is emerging as a popular technology in tie space industry where it increases the potential to reduce spacecraft mass and cut launch costs. But will it ever be possible to print the rockets themselves. The company responsible for the early adoption of this technology is aerospace giant Lockheed Martin which, far from being in it for the novelty, is "streamlining satellite production with 3D titanium printing to lower cycle times and reduce cost". The company currently uses 3D printers in two main ways: for prototyping parts,using polymers, and for printing "flightready parts" in titanium, aluminium and Inconel.

Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors.

The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.

The author stated that In the mid-20th century, Detroit was an icon of the motor industry and the backbone of America's blue-collar aspirations. Today, the legendary manufacturing plants lie in ruins and the city is a shadow of its former self.