Search

OBJECTIVES: We developed a preliminary agent-based simulation model designed to examine agent-environment interactions that support the development and maintenance of drinking behavior at the population level. METHODS: The model was defined on a 1-dimensional lattice along which agents might move left or right in single steps at each iteration. Agents could exchange information about their drinking with each other. In the second generation of the model, a 'bar' was added to the lattice to attract drinkers. RESULTS: The model showed that changes in drinking status propagated through the agent population as a function of probabilities of conversion, rates of contact, and contact time. There was a critical speed of population mixing beyond which the conversion rate of susceptible nondrinkers was saturated, and the bar both enhanced and buffered the rate of propagation, changing the model dynamics. CONCLUSIONS: The models demonstrate that the basic dynamics underlying social influences on drinking behavior are shaped by contacts between drinkers and focused by characteristics of drinking environments. [ABSTRACT FROM AUTHOR]

This study profiles nursing home residents receiving alcohol and drug treatment, describing their sociodemographic, health, and treatment characteristics. We analyzed 3,662 admission assessments in the Minimum Data Set for people receiving alcohol/drug treatment from June, 1998 through September, 2000. These residents were likely to be male and under age 50. More than half were White and 29 percent were African American. Typically, these residents were not physically or cognitively impaired. However, more than 39 percent had unstable health patterns and almost 21 percent had HIV disease. Thirty-eight percent had a history of mental health conditions, with 24 percent having depression and almost 18 percent having schizophrenia. At least 75 percent received no psychological therapy in the previous 7 days and a majority did not receive antipsychotic, antianxiety, or antidepressant medications. These analyses indicate that most recently admitted residents receiving alcohol/drug treatment did not receive mental health therapy in nursing homes. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac 239 -infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8 + T cells in lymph nodes and reduced expression of BCL-2 in CD4 + T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4 + and CD8 + T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART., (© 2024. The Author(s).)

In recent years, concern has grown about the inappropriate application and interpretation of P values, especially the use of P<0.05 to denote "statistical significance" and the practice of P-hacking to produce results below this threshold and selectively reporting these in publications. Such behavior is said to be a major contributor to the large number of false and non-reproducible discoveries found in academic journals. In response, it has been proposed that the threshold for statistical significance be changed from 0.05 to 0.005. The aim of the current study was to use an evolutionary agent-based model comprised of researchers who test hypotheses and strive to increase their publication rates in order to explore the impact of a 0.005 P value threshold on P-hacking and published false positive rates. Three scenarios were examined, one in which researchers tested a single hypothesis, one in which they tested multiple hypotheses using a P<0.05 threshold, and one in which they tested multiple hypotheses using a P<0.005 threshold. Effects sizes were varied across models and output assessed in terms of researcher effort, number of hypotheses tested and number of publications, and the published false positive rate. The results supported the view that a more stringent P value threshold can serve to reduce the rate of published false positive results. Researchers still engaged in P-hacking with the new threshold, but the effort they expended increased substantially and their overall productivity was reduced, resulting in a decline in the published false positive rate. Compared to other proposed interventions to improve the academic publishing system, changing the P value threshold has the advantage of being relatively easy to implement and could be monitored and enforced with minimal effort by journal editors and peer reviewers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fitzpatrick et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Coronaviruses have been the causative agent of three epidemics and pandemics in the past two decades, including the ongoing COVID-19 pandemic. A broadly-neutralizing coronavirus therapeutic is desirable not only to prevent and treat COVID-19, but also to provide protection for high-risk populations against future emergent coronaviruses. As all coronaviruses use spike proteins on the viral surface to enter the host cells, and these spike proteins share sequence and structural homology, we set out to discover cross-reactive biologic agents targeting the spike protein to block viral entry. Through llama immunization campaigns, we have identified single domain antibodies (VHHs) that are cross-reactive against multiple emergent coronaviruses (SARS-CoV, SARS-CoV-2, and MERS). Importantly, a number of these antibodies show sub-nanomolar potency towards all SARS-like viruses including emergent CoV-2 variants. We identified nine distinct epitopes on the spike protein targeted by these VHHs. Further, by engineering VHHs targeting distinct, conserved epitopes into multi-valent formats, we significantly enhanced their neutralization potencies compared to the corresponding VHH cocktails. We believe this approach is ideally suited to address both emerging SARS-CoV-2 variants during the current pandemic as well as potential future pandemics caused by SARS-like coronaviruses., (© 2023. Springer Nature Limited.)

This is the protocol for a Campbell systematic review. The objectives are as follows: To identify methods used to assess the risk of outcome reporting bias (ORB) in studies included in recent Campbell systematic reviews of intervention effects. The review will answer the following questions: What proportion of recent Campbell reviews included assessment of ORB? How did recent reviews define levels of risk of ORB (what categories, labels, and definitions did they use)? To what extent and how did these reviews use study protocols as sources of data on ORB? To what extent and how did reviews document reasons for judgments about risk of ORB? To what extent and how did reviews assess the inter-rater reliability of ORB ratings? To what extent and how were issues of ORB considered in the review's abstract, plain language summary, and conclusions?, (© 2023 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane glycoprotein that is responsible for the cellular uptake of iron via iron-loaded transferrin (holo-transferrin) binding. It has been hypothesised that the HFE/TFR1 interaction serves as a sensor to the level of iron-loaded transferrin in circulation by means of a competition mechanism between HFE and iron-loaded transferrin association with TFR1. To investigate this, a series of peptides based on the helical binding interface between HFE and TFR1 were generated and shown to significantly interfere with the HFE/TFR1 interaction in an in vitro proximity ligation assay. The helical conformation of one of these peptides, corresponding to the α1 and α2 helices of HFE, was stabilised by the introduction of sidechain lactam "staples", but this did not result in an increase in the ability of the peptide to disrupt the HFE/TFR1 interaction. These peptides inhibitors of the protein-protein interaction between HFE and TFR1 are potentially useful tools for the analysis of the functional role of HFE in the regulation of hepcidin expression.

Background and Aims: Journal metrics assess impact upon the research literature, and are now used to assess individual researchers in hiring and promotion decisions. This study compared the ranking of addiction journals according to eight widely used metrics; assessed the correlations between journal rankings; and assessed changes over time in metric scores., Methods: Data pertaining to the 2020 scores on eight metrics for 43 journals were obtained and the top 20 ranking in each compared and the correlations between rankings assessed. The Impact Factor was employed to assess changes over time., Results: Ignoring the two categorization systems used by some metrics, 31 journals appeared in at least one metric top 20 and 11 in all eight. The top rank in each was occupied by one of three journals. Three-quarters of the correlations between rankings were above 6.0. The number of journals with an Impact Factor rose from 23 in 1997 to 38 in 2020, and the journals added tended to focus on addictions other than alcohol and drugs or have a specific focus., Conclusions and Discussion: The results indicate a concentration of journals at the top of the metrics and moderate to strong agreement between them, but almost three-quarters of journals appeared in at least one metric. The longitudinal data reflect both a broadening and specialization of the addiction field. The study limitations include exclusion of some journals and metrics.

Background: Registration of research studies is designed to lock investigators into a data collection and analysis plan before a study starts and thereby limit their ability to engage in flexible data analysis and selective outcome reporting. Studies of registered clinical trials show that one- to two-thirds are registered after the study has started and that non-adherence to important design and analytic features, such as reporting data pertaining to all primary outcomes, remains high. Less is known about the effects of registration on research transparency and integrity outside of clinical trials. To address this gap in knowledge, the current study examined the effects of registration on the reporting of research findings in a sample of behavioral health trials published in BMC Public Health., Methods: Registered trials published in the BMC Public Health section "Health Behavior, Health Promotion and Society" between 2011 and 2015 were included in the study. For each trial, we reviewed associated online submissions from 13 different registration sites. For those determined to have been prospectively registered, we used the trial registry, MEDLINE (Pubmed), PsychINFO, Web of Science and e-mails to investigators to identify subsequent publications from the study that reported results pertaining to primary outcomes. The two investigators then independently reviewed the outcome publication(s) and compared the primary outcomes reported in these to the registered primary outcomes., Results: The final analytic sample comprised 136 locatable, registered trials with an identifiable start date. Sixty-eight of the 136 were prospectively registered. Among these prospectively registered trials, only 16 published manuscripts reported outcomes and methods that were concordant with their registrations., Conclusions: Retrospective submission of protocols for publication and retrospective registration remain common in public health research, and adherence to prespecified outcomes is rare. In its current form, registration of behavioral and health promotion trials is likely to have minimal effect on preventing selective outcome reporting in publications, and the pervasiveness of vague and incomplete registry entries means that registries will have limited utility in terms of facilitating replication studies., (© 2022. The Author(s).)

The anaphylatoxin C5a is core effector of complement activation. C5a exerts potent proinflammatory and immunomodulatory actions through interacting with its C5a receptors, C5aR1 and C5aR2, modulating multiple signaling and functional activities of immune cells. Native C5a contains a large N -linked glycosylation site at Asn 64 , which accounts for up to 25% of its m.w. To date, the vast majority of published studies examining C5a are performed using Escherichia coli -generated recombinant C5a, which is readily available from numerous commercial suppliers, but lacks this glycosylation moiety. However, a plasma-purified "native" form of C5a is also commercially available. The different size and glycosylation of these two C5a versions could have functional implications. Therefore, the current study aimed to compare recombinant human C5a to purified plasma-derived human C5a in driving the signaling and functional activities of human primary macrophages. We found that both versions of C5a displayed similar potencies at triggering C5aR1- and C5aR2-mediated cell signaling, but elicited distinct functional responses in primary human monocyte-derived macrophages. Multiple commercial sources of recombinant C5a, but not the plasma-purified or a synthetic C5a version, induced human monocyte-derived macrophages to produce IL-6 and IL-10 in a C5a receptor-independent manner, which was driven through Syk and NF-κB signaling and apparently not due to endotoxin contamination. Our results, therefore, offer caution against the sole use of recombinant human C5a, particularly in functional/cytokine assays conducted in human primary immune cells, and suggest studies using recombinant human C5a should be paired with C5aR1 inhibitors or purified/synthetic human C5a to confirm relevant findings., (Copyright © 2021 by The American Association of Immunologists, Inc.)

The complement C5a receptor 1 (C5aR1) has been studied as a potential therapeutic target for autoimmune and inflammatory diseases, with several drug candidates identified. Understanding the pharmacokinetics and pharmacodynamics of a drug candidate is a crucial preclinical step that allows for a greater understanding of a compound's in vivo biodistribution and target engagement to assist in clinical dose selection and dosing frequency. However, few in vivo pharmacodynamic methods have been described for C5a inhibitors. In this study, we, therefore, developed a complete in vivo pharmacodynamic assay in mice and applied this method to the peptide-based C5aR1 antagonists PMX53 and JPE-1375. Intravenous administration of recombinant mouse C5a induced rapid neutrophil mobilization and plasma TNF elevation over a 60 min period. By using C5a receptor-deficient mice, we demonstrated that this response was driven primarily through C5aR1. We next identified using this model that both PMX53 and JPE-1375 have similar in vivo working doses that can inhibit C5aR1-mediated neutrophilia and cytokine production in a dose as low as 1 mg/kg following intravenous injection. However, the in vivo active duration for PMX53 lasted for up to 6 h, significantly longer than that for JPE-1375 (<2 h). Pharmacokinetic analysis demonstrated rapid plasma distribution and elimination of both compounds, although PMX53 had a longer half-life, which allowed for the development of an accurate pharmacokinetic/pharmacodynamic model. Overall, our study developed a robust in vivo pharmacodynamic model for C5aR1 inhibitors in mice that may assist in preclinical translational studies of therapeutic drug candidates targeting C5a and its receptors., Competing Interests: The authors declare the following competing financial interest(s): TMW and RJC are inventors on patents pertaining to complement inhibitors for inflammatory disease. TMW has previously consulted to Alsonex Pty Ltd, and has received honorarium from Alexion Pharmaceuticals for participation in industry conferences and meetings. He holds no financial interests in either company. Other authors declare that they have no conflict of interest., (© 2021 American Chemical Society.)

The anaphylatoxin C5a is a complement peptide associated with immune-related disorders. C5a binds with equal potency to two GPCRs, C5aR1 and C5aR2. Multiple C5a peptide agonists have been developed to interrogate the C5a receptor function but none show selectivity for C5aR1. To address these limitations, we developed potent and stable peptide C5aR1 agonists that display no C5aR2 activity and over 1000-fold selectivity for C5aR1 over C3aR. This includes BM213, which induces C5aR1-mediated calcium mobilization and pERK1/2 signaling but not β-arrestin recruitment, and BM221, which exhibits no signaling bias. Both ligands are functionally similar to C5a in human macrophage cytokine release assays and in a murine in vivo neutrophil mobilization assay. BM213 showed antitumor activity in a mouse model of mammary carcinoma. We anticipate that these C5aR1-selective agonists will be useful research tools to investigate C5aR1 function.

The complement activation peptide C5a is a key mediator of inflammation that is associated with numerous immune disorders. C5a binds and activates two seven-transmembrane receptors, C5aR1 and C5aR2. Experimentally, C5a is utilized to investigate C5a receptor biology and to screen for potential C5aR1/C5aR2 therapeutics. Currently, laboratory sources of C5a stem from either isolation of endogenous C5a from human serum or most predominantly via recombinant expression. An alternative approach to C5a production is chemical synthesis, which has several advantages, including the ability to introduce non-natural amino acids and site-specific modifications whilst also maintaining a lower probability of C5a being contaminated with microbial molecules or other endogenous proteins. Here, we describe the efficient synthesis of both human (hC5a) and mouse C5a (mC5a) without the need for ligation chemistry. We validate the synthetic peptides by comparing pERK1/2 signaling in CHO-hC5aR1 cells and primary human macrophages (for hC5a) and in RAW264.7 cells (for mC5a). C5aR2 activation was confirmed by measuring β-arrestin recruitment in C5aR2-transfected HEK293 cells. We also demonstrate the functionalization of synthetic C5a through the introduction of a lanthanide chelating cage to facilitate a screen for the binding of ligands to C5aR1. Finally, we verify that the synthetic ligands are functionally similar to recombinant or native C5a by assessing hC5a-induced neutrophil chemotaxis in vitro and mC5a-mediated neutrophil mobilization in vivo . We propose that the synthetic hC5a and mC5a described herein are valuable alternatives to recombinant or purified C5a for in vitro and in vivo applications and add to the growing complement reagent toolbox., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

The complement component C5 inhibitory peptide zilucoplan is currently in phase III clinical trials for myasthenia gravis (MG). Despite being at an advanced stage of clinical development, there have been no published reports in the literature detailing its chemical synthesis. In this work, we describe an approach for the chemical synthesis of zilucoplan and validate that the synthesised compound blocks LPS-induced C5a production from human blood.

Background: The rigor and integrity of the published research in nutrition studies has come into serious question in recent years. Concerns focus on the use of flexible data analysis practices and selective reporting and the failure of peer review journals to identify and correct these practices. In response, it has been proposed that journals employ editorial procedures designed to improve the transparency of published research., Objective: The present study examines the adoption of editorial procedures designed to improve the reporting of empirical studies in the field of nutrition and dietetics research., Design: The instructions for authors of 43 journals included in Quartiles 1 and 2 of the Clarivate Analytics' 2018 Journal Citation Report category Nutrition and Dietetics were reviewed. For journals that published original research, conflict of interest disclosure, recommendation of reporting guidelines, registration of clinical trials, registration of other types of studies, encouraging data sharing, and use of the Registered Reports were assessed . For journals that only published reviews, all of the procedures except clinical trial registration were assessed., Results: Thirty-three journals published original research and 10 published only reviews. Conflict of interest disclosure was required by all 33 original research journals. Use of guidelines, trial registration and encouragement of data sharing were mentioned by 30, 27 and 25 journals, respectively. Registration of other studies was required by eight and none offered Registered Reports as a publication option at the time of the review. All 10 review journals required conflict of interest disclosure, four recommended data sharing and three the use of guidelines. None mentioned the other two procedures., Conclusions: While nutrition journals have adopted a number of procedures designed to improve the reporting of research findings, their limited effects likely result from the mechanisms through which they influence analytic flexibility and selective reporting and the extent to which they are properly implemented and enforced by journals., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Although data sharing is one of the primary measures proposed to improve the integrity and quality of published research, studies show it remains the exception not the rule. The current study examines the availability of data in papers reporting the results of analyses of empirical data from original research in high-impact addiction journals. Thirteen high-impact journals with data sharing policies were selected from those included in the substance abuse category of the 2018 Clarivate Analytics' Journal Citation Report. The first 10 full or short original research reports that included empirical data in the most recent complete issue of each journal were electronically searched and reviewed for reference to where their data can be obtained and for a formal data sharing statement. Only eight of the 130 papers contained a data sharing statement in their text or supplementary online materials, and just one contained a direct link to the data analyzed. Data sharing was rare in the 13 high-impact addiction journals reviewed. The nature of the data reported in addiction journals might partly explain this. Currently, data sharing is not a procedure likely to improve the quality and integrity of published addiction research.

Background and Aims: The credibility crisis evident in many academic disciplines has led peer-reviewed journals to implement procedures to reduce use of flexible data analysis practices and selective reporting of results. This exploratory study examined the adoption of six of these procedures by addiction journals., Methods: Thirty-eight high-impact addiction journals were identified using the 2018 Clarivate Analytics Journal Citation Report for 2017 ranks. The online instructions for authors were reviewed for references to six publication procedures: conflict of interest disclosure, reporting guidelines, clinical trial registration, registration of other study designs, data-sharing and registered reports. The webpages of the Center for Open Science and Consolidated Standards of Reporting Trials (CONSORT) were also reviewed for data pertaining to registered reports and reporting guidelines, respectively., Results: The range of procedures adopted by the addiction journals was 0-5, with a mean of 2.66. Conflict-of-interest disclosure was required by all but one journal. Encouraging data-sharing was the next most commonly required procedure. Fewer than half the journals recommended specific reporting guidelines or required registration of clinical trials, and only four required procedures to pre-specify hypotheses and analytical methods., Conclusions: While many addiction journals have adopted publication procedures to improve research integrity, these can be limited by their voluntary nature and monitoring difficulties. More stringent requirements that lock researchers into specific hypotheses and analyses have not been widely adopted., (© 2019 Society for the Study of Addiction.)

Concern about the integrity of empirical research has arisen in recent years in the light of studies showing the vast majority of publications in academic journals report positive results, many of these results are false and cannot be replicated, and many positive results are the product of data dredging and the application of flexible data analysis practices coupled with selective reporting. While a number of potential solutions have been proposed, the effects of these are poorly understood and empirical evaluation of each would take many years. We propose that methods from the systems sciences be used to assess the effects, both positive and negative, of proposed solutions to the problem of declining research integrity such as study registration, Registered Reports, and open access to methods and data. In order to illustrate the potential application of systems science methods to the study of research integrity, we describe three broad types of models: one built on the characteristics of specific academic disciplines; one a diffusion of research norms model conceptualizing researchers as susceptible, "infected" and recovered; and one conceptualizing publications as a product produced by an industry comprised of academics who respond to incentives and disincentives.

In recent years, there has been increased attention to the issue of conflict of interest within prevention research. The aims of this paper are to discuss these developments and to relate them to discussions of conflict of interest in the broader scientific literature. Although there has been concern expressed about the extent to which conflicts of interest can be defined and measured, empirical research suggests that financial conflicts can be easily identified and assessed in meta-analyses focused on their effects on research quality. Research evidence also shows that conflict of interest is associated with use of flexible data analysis practices and the reporting of chance positive findings, both within prevention research and related disciplines such as public health and psychology. However, the overwhelming majority of published studies report positive results, and there are a number of other influences within academia (such as pressure to publish) that account for this and for the use of flexible data analysis practices. Accordingly, introducing measures to improve research quality in general, rather than just focusing on problems specific to research in which there is a clearly identifiable conflict of interest, may prove more effective and less controversial. Most such efforts focus on introducing greater transparency into research design, practice, and reporting. These both curtail employment of flexible data analysis practices and make their use transparent to investigators seeking to assess their effects on research quality. Also, requiring detailed disclosures of conflicts be reported by all investigators (not just senior authors) would improve current disclosure practices.

Introduction and Aims: This study examined whether the introduction of a large number of off-premise alcohol outlets into a city over a brief period of time could affect rates of violent crime., Design and Methods: The study analysed annual counts of violent crime across 172 US Census block groups in Lubbock, Texas from 2006 through 2011. Spatial Poisson models related annual violent crime counts within each block group to off-premise and on-premise alcohol outlets active during this time period as well as neighbourhood socio-demographic characteristics. The effects of alcohol outlets were assessed both within block groups and across adjacent block groups., Results: On-premise outlets had a small, significant positive association with violence within a given block group. A similar well-supported local effect for off-premise outlets was not found. However, the spatially lagged effect for off-sale premises was well-supported, indicating that greater densities of these outlets were related to greater rates of violent crime in adjacent areas., Discussion and Conclusions: While these analyses confirmed a previous time-series analysis in finding no city-wide effect of the increase in off-premise outlets, they do suggest that such outlets in a local area may be related to violence in nearby geographic areas. They indicate the importance of examining neighbourhood-specific effects of alcohol outlets on violence in addition to the city-wide effects. They also present further evidence supporting the need to examine the differential effects of on-sale and off-sale premises., (© 2017 Australasian Professional Society on Alcohol and other Drugs.)

Bariatric surgery, initially intended as a weight-loss procedure, is superior to standard lifestyle intervention and pharmacological therapy for type 2 diabetes in obese individuals. Intensive medical management of hyperglycemia is associated with improved microvascular outcomes. Whether or not the reduction in hyperglycemia observed after bariatric surgery translates to improved microvascular outcomes is yet to be determined. There is substantial heterogeneity in the data relating to the impact of bariatric surgery on diabetic retinopathy (DR), the most common microvascular complication of diabetes. This review aims to collate the recent data on retinal outcomes after bariatric surgery. This comprehensive evaluation revealed that the majority of DR cases remain stable after surgery. However, risk of progression of pre-existing DR and the development of new DR is not eliminated by surgery. Instances of regression of DR are also noted. Potential risk factors for deterioration include severity of DR at the time of surgery and the magnitude of glycated hemoglobin reduction. Concerns also exist over the detrimental effects of postprandial hypoglycemia after surgery. In vivo studies evaluating the chronology of DR development and the impact of bariatric surgery could provide clarity on the situation. For now, however, the effect of bariatric surgery on DR remains inconclusive., Competing Interests: No potential conflict of interest relevant to this article was reported.

Aquamin is a commercially-available supplement derived from the algae species Lithothamnion, which has proven osteogenic potential. By harnessing this potential and combining Aquamin with a collagen scaffold, with architecture and composition optimised for bone repair, the aim of this study was to develop a natural osteo-stimulative bone graft substitute. A fabrication process was developed to incorporate Aquamin into scaffolds to produce collagen-Aquamin (CollAqua) scaffolds at two different Aquamin concentrations, 100F or 500F (equivalent weight% of collagen or five times the weight of collagen respectively). CollAqua constructs had improved mechanical properties which were achieved without reducing the scaffold׳s permeability or porosity below the minimum level required for successful bone tissue engineering. The fabrication process produced a homogenous Aquamin distribution throughout the scaffold. Release kinetics revealed that in the first 12h, the entire Aquamin content was released from the 100F however, less than half of Aquamin in the 500F was released with the remainder released approximately 21 days later giving an initial burst release followed by a delayed release. Osteoblasts cultured on the CollAqua scaffolds showed improved osteogenesis as measured by alkaline phosphatase, osteopontin and osteocalcin expression. This was confirmed by increased mineralisation as determined by von Kossa and Alizarin red staining. In conclusion, a cell and growth factor free collagen-based bone graft substitute with enhanced mechanical properties has been developed. The addition of Aquamin to the collagen biomaterial significantly improved mineralisation by osteoblasts and results in a new product which may be capable of enhancing osteogenesis to facilitate bone repair in vivo., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study examined the effects on motor vehicle crashes of a policy change that led to the introduction of a very large number of off-sale alcohol outlets in Lubbock, Texas. Times-series analysis of total crashes and single-vehicle nighttime (SVN) crashes was used to compare the periods before and after the policy change in Lubbock and in a comparison area. The results of the analysis revealed some weak effects on total crashes, but no statistically significant effects were found for SVN crashes. Possible reasons for the essentially null findings of the current study regarding the effects of the policy change on motor vehicle crashes are discussed. These include the fact that there were a small number of off-sale outlets already present in the community and that motor vehicle travel immediately following alcohol consumption is less likely to occur with alcohol purchased from an off-sale outlet compared to an on-sale outlet.

This paper critically reviews the published evidence pertaining to Project Towards No Drug Abuse (Project TND). Publications from seven evaluation studies of Project TND are reviewed, and the results from these are discussed as related to the following outcomes: main effects on the use of cigarettes, alcohol and marijuana; main effects on the use of "hard drugs," defined in the evaluations as cocaine, hallucinogens, stimulants, inhalants, ecstasy and other drugs (e.g., depressants, PCP, steroids and heroin); subgroup and interaction analyses of drug use; and violence-related behaviors. Very few main effects have been found for cigarette, alcohol and marijuana use in the Project TND evaluations. While studies do report main effects for hard drug use, these findings are subject to numerous threats to validity and may be attributable to the data analyses employed. Similarly, while isolated subgroup and interaction effects were found for alcohol use among baseline nonusers and some violence-related behaviors in the early Project TND evaluations, these findings have not been replicated in more recent studies and may result from multiple comparisons between study conditions. In conclusion, there is little evidence to support the assertion that Project TND is an effective drug or violence prevention program. The broader implications of these findings for prevention science are discussed and suggestions are made as to how the quality of research in the field might be improved.

Introduction and Aims: To examine the socio-spatial patterning of off-sale and on-sale alcohol outlets following a policy change that ended prohibition of off-sale outlets in Lubbock, Texas., Design and Methods: The spatial patterning of alcohol outlets by licensing type was examined using the k-function difference (D statistic) to compare the relative degree of spatial aggregation of the two types of alcohol outlets and by the spatial scan statistic to identify statistically significant geographic clusters of outlets. The sociodemographic characteristics of the areas containing clusters of outlets were compared with the rest of the city. In addition, the socioeconomic characteristics of census block groups with and without existing on-sale outlets were compared, as were the socioeconomic characteristics of census block groups with and without the newly issued off-sale licenses., Results: The existing on-sale premises in Lubbock and the newly established off-sale premises introduced as a result of the 2009 policy change displayed different spatial patterns, with the latter being more spatially dispersed. A large cluster of on-sale outlets identified in the north-east of the city was located in a socially and economically disadvantaged area of the city., Discussion and Conclusion: The findings support the view that it is important to understand the local context of deprivation within a city when examining the location of alcohol outlets and add to the existing research by drawing attention to the importance of geographic scale in assessing such relationships., (© 2013 Australasian Professional Society on Alcohol and other Drugs.)

Objectives: From 1983 to 2008, the incidence of methamphetamine abuse and dependence (MA) presenting at hospitals in California increased 13-fold. We assessed whether this growth could be characterized as a drug epidemic., Methods: We geocoded MA discharges to residential zip codes from 1995 through 2008. We related discharges to population and environmental characteristics using Bayesian Poisson conditional autoregressive models, correcting for small area effects and spatial misalignment and enabling an assessment of contagion between areas., Results: MA incidence increased exponentially in 3 phases interrupted by implementation of laws limiting access to methamphetamine precursors. MA growth from 1999 through 2008 was 17% per year. MA was greatest in areas with larger White or Hispanic low-income populations, small household sizes, and good connections to highway systems. Spatial misalignment was a source of bias in estimated effects. Spatial autocorrelation was substantial, accounting for approximately 80% of error variance in the model., Conclusions: From 1995 through 2008, MA exhibited signs of growth and spatial spread characteristic of drug epidemics, spreading most rapidly through low-income White and Hispanic populations living outside dense urban areas.

This paper provides a critical review of two broad categories of social ecological theories of crime, social integration and place-based theories, and their relationships to spatial assessments of crime patterns. Social integration theories emphasize the role of neighborhood disorganization on crime, while place theories stress the social interactions within and between places as a source of crime. We provide an analysis of the extent to which these two types of theorizing describe processes and mechanisms that are truly ecologic (identify specific interactions between individuals and their environments) and truly spatial (identify specific movement and interaction patterns of individuals and groups) as they endeavor to explain crime outcomes. We suggest that social integration theories do not provide spatial signatures of sufficient specificity to justify the application of spatial statistical techniques as quantitative arbiters of the theory. On the other hand, place based theories go some way toward addressing these issues because the emphasis is placed on understanding the exact physical and social characteristics of place and the activities that occur around locations as sources of crime. Routine activities and crime potential theories attempt to explain clustering or "hot spots" of crime in ways that give clear spatial dimension by looking at micro-spatial interactions between offenders and targets of crime. These theories have strong ecological implications as well, since they contain specific statements about how people use the space around them and how these patterns of use are related to patterns of criminal activity. We conclude by identifying a set of requirements for successful empirical tests of geospatial theories, including the development of valid measures of key theoretical constructs and the formulation of critical empirical assessments of geospatial hypotheses derived from motivating theory.

Aims: To examine the effects on violence of a policy change that ended prohibition of off-sale alcohol outlets in Lubbock, Texas., Methods: Time-series analysis of violent crime data from police records comparing the periods before and after the policy change., Results: The effect of the policy change on both total violent crime and aggregated assault was small and did not approach statistical significance., Conclusions: Increased availability of alcohol through off-sale premises may not influence the type of violence reported to the police in Lubbock, Texas.

Objectives. Despite the increasing evidence of the associations between alcohol availability and violence, there are still inconsistent findings on the effects of on- and off-sale alcohol outlets on violent crime. The aim of this study was to examine spatial associations between on-sale alcohol availability, neighborhood characteristics, and violent crime in a geographically isolated city in Texas. Methods. Geographically weighted regression (GWR) and global regression models were employed to analyze the nature of the spatial relationship between violent crime, neighborhood sociocultural characteristics, and on-sale alcohol environment. Results. We found strong effects of neighborhood characteristics combined with on-sale alcohol availability on violence outcomes. Several neighborhood variables combined with alcohol availability explained about 63% of the variability in violence. An additional 7% was explained by the GWR model, while spatially nonstationary associations between violence and some predictor variables were observed. Conclusions. This study provided more credible evidence of the influence of on-sale alcohol outlets on violence in a unique setting. These findings have important policy implications in addressing the question of public health consequences of alcohol-related violence in local contexts.

The presence of activated intratumoral T cells correlates clinically with better prognosis in patients with cancer. Although tumor vaccines can increase the number of tumor-specific CD8(+) T cells in systemic circulation, they frequently fail to increase the number of active and tumor reactive T cells within the tumor. Here we show that treatment with the pleiotropic cytokine interleukin-10 (IL-10) induces specific activation of tumor-resident CD8(+) T cells as well as their intratumoral expansion in several mouse tumor models. We found that inhibition of T-cell trafficking from lymphoid organs did not impair IL-10-induced tumor rejection or the activation of tumor-resident CD8(+) T cells. Tumor-resident CD8(+) T cells expressed elevated levels of the IL-10 receptor and were directly activated by IL-10, resulting in prominent phosphorylation of STAT3 and STAT1. Although CD4(+) T cells, regulatory T cells, NK cells, and dendritic cells have been reported as prominent targets of IL-10 in the tumor microenvironment, we found that expression of the IL-10R was required only on CD8(+) T cells to facilitate IL-10-induced tumor rejection as well as in situ expansion and proliferation of tumor-resident CD8 T cells. Together, our findings indicate that IL-10 activates CD8(+) T-cell-mediated tumor control and suggest that IL-10 may represent a potential tumor immunotherapy in human patients with cancer.

The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R)(+), RAR-related orphan receptor γt (ROR-γt)(+)CD3(+)CD4(-)CD8(-), stem cell antigen 1 (Sca1)(+) entheseal resident T cells. These cells allow entheses to respond to IL-23 in vitro-in the absence of further cellular recruitment--and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the in vivo expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops in vivo at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.

Aims: US college drinking data and a simple population model of alcohol consumption are used to explore the impact of social and contextual parameters on the distribution of light, moderate and heavy drinkers. Light drinkers become moderate drinkers under social influence, moderate drinkers may change environments and become heavy drinkers. We estimate the drinking reproduction number, R(d) , the average number of individual transitions from light to moderate drinking that result from the introduction of a moderate drinker in a population of light drinkers., Design and Settings: Ways of assessing and ranking progression of drinking risks and data-driven definitions of high- and low-risk drinking environments are introduced. Uncertainty and sensitivity analyses, via a novel statistical approach, are conducted to assess R(d) variability and to analyze the role of context on drinking dynamics., Findings: Our estimates show R(d) well above the critical value of 1. R(d) estimates correlate positively with the proportion of time spent by moderate drinkers in high-risk drinking environments. R(d) is most sensitive to variations in local social mixing contact rates within low-risk environments. The parameterized model with college data suggests that high residence times of moderate drinkers in low-risk environments maintain heavy drinking., Conclusions: With regard to alcohol consumption in US college students, drinking places, the connectivity (traffic) between drinking venues and the strength of socialization in local environments are important determinants in transitions between light, moderate and heavy drinking as well as in long-term prediction of the drinking dynamics., (© 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.)

C17 was first described about ten years ago as a gene expressed in CD34+ cells. A more recent study has suggested a role for C17 in chondrogenesis and development of cartilage. However, based on sequence analysis, we believe that C17 has homology to IL-2 and hence we present the hypothesis that C17 is a cytokine possessing immune-regulatory properties. We provide evidence that C17 is a secreted protein preferentially expressed in chondrocytes, hence in cartilage-rich tissues. Systemic expression of C17 in vivo reduces disease in a collagen antibody-induced arthritis model in mice (CAIA). Joint protection is evident by delayed disease onset, minimal edema, bone protection and absence of diverse histological features of disease. Expression of genes typically associated with acute joint inflammation and erosion of cartilage or bone is blunted in the presence of C17. Consistent with the observed reduction in bone erosion, we demonstrate reduced levels of RANKL in the paws and sera of mice over-expressing C17. Administration of C17 at the peak of disease, however, had no effect on disease progression, indicating that C17's immune-regulatory activity must be most prominent prior to or at the onset of severe joint inflammation. Based on this data we propose C17 as a cytokine that s contributes to immune homeostasis systemically or in a tissue-specific manner in the joint.

Paired immunoglobulin-like type 2 receptors (PILRs) inhibitory PILRalpha and activating PILRbeta are predominantly expressed on myeloid cells. Their functions in host defense and inflammation are largely unknown, and in this study, we evaluated their roles in an acute Staphylococcus aureus pneumonia model. Compared to their respective controls, Pilrb(-/-) mice or mice in which PILRalpha was activated with an agonistic antibody showed improved clearance of pulmonary staphylococci and improved survival. These mice had reduced serum or bronchoalveolar lavage fluid levels of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and IL-6 and elevated levels of gamma interferon (IFN-gamma), IL-12, and IL-10. In contrast, mice in which PILRbeta was activated had increased lung bacterial burdens and higher mortality coupled with an intense proinflammatory response with highly elevated levels of IL-1beta, TNF-alpha, and IL-6. Treatment groups with reduced bacterial burdens had higher levels of Keratinocyte-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2), and MIP-1alpha in bronchoalveolar lavage fluid and an increased influx of neutrophils and macrophages to the lungs. Consistent with our in vivo findings, bone marrow-derived macrophages from Pilrb(-/-) mice released significantly less IL-1beta and TNF-alpha and more IFN-gamma and IL-12 than did the wild-type macrophages when directly stimulated with heat-killed S. aureus. To our knowledge, this is the first evidence that S. aureus directly interacts with PILRbeta. It provides a mechanism by which manipulating the balance in favor of an inhibitory PILR signal, by activation of PILRalpha or deletion of PILRbeta, helps to control acute S. aureus-mediated pneumonia and attenuate the inflammatory response. These results highlight the importance of PILRs in innate immunity and the control of inflammation.