Demonstrating the Potential of Using Bio-Based Sustainable Polyester Blends for Bone Tissue Engineering Applications.

Healthcare applications are known to have a considerable environmental impact and the use of bio-based polymers has emerged as a powerful approach to reduce the carbon footprint in the sector. This research aims to explore the suitability of using a new sustainable polyester blend (Floreon™) as a scaffold directed to aid in musculoskeletal applications. Musculoskeletal problems arise from a wide range of diseases and injuries related to bones and joints. Specifically, bone injuries may result from trauma, cancer, or long-term infections and they are currently considered a major global problem in both developed and developing countries. In this work we have manufactured a series of 3D-printed constructs from a novel biopolymer blend using fused deposition modelling (FDM), and we have modified these materials using a bioceramic (wollastonite, 15% w/w). We have evaluated their performance in vitro using human dermal fibroblasts and rat mesenchymal stromal cells. The new sustainable blend is biocompatible, showing no differences in cell metabolic activity when compared to PLA controls for periods 1-18 days. FloreonTM blend has proven to be a promising material to be used in bone tissue regeneration as it shows an impact strength in the same range of that shown by native bone (just under 10 kJ/m2) and supports an improvement in osteogenic activity when modified with wollastonite.

Characteristics of newly diagnosed HIV-positive service users using a pan-London e-sexually transmitted infection screening service.

Maximising opportunities and removing barriers to HIV testing can help reduce the undiagnosed HIV population. Digital STI/HIV screening services have increased in availability and can improve access and testing coverage. We identified the characteristics of individuals who tested HIV positive using a regional, integrated, self-sampling STI service. The e-notes of service users with reactive HIV screening results were reviewed. Between 8 January 2018 and 31 December 2019, 0.097% (144/148,257) users received a reactive HIV result, 30/144 (20.8%) of whom had previously diagnosed HIV infection. All of the remaining 114 users were notified of their screening result, an estimated 109/114 (95.6%) received confirmatory testing (CT) at a sexual health clinic (SHC) and the confirmatory outcome was documented in 102/114 (89.5%) of cases: 34/114 (29.8%)were HIV positive, 68/114 (59.6%) HIV were negative and the result was unknown in 12/114 (10.5%). All new diagnoses transitioned to HIV outpatient care. These individuals were median age 28 years; 94.1% (32/34) male; 88.2% (30/34) men who have sex with men and 11.8% (4/34) heterosexual; 58.8% (20/34) of white/'white other' ethnicity and 42.2% of Black, Asian and minority ethnic group; 50%(17/34) had a concurrent STI; 9% and 21% had never tested for HIV or attended a SHC before. n HIV test reactivity rate of 0.1%(95% CI) was observed. Confirmed new HIV diagnoses comprised 0.023% of all HIV tests performed. All individuals where CT confirmed a new HIV diagnosis transitioned to HIV specialist care.

Recurring Multicentric Granulomatous Cryptococcomas in the Contralateral Cerebral Hemisphere in an Adult Immunocompetent Patient with Known Previous Disease.

BACKGROUND: Fungal mass lesions in the central nervous system rarely reach a size large enough to directly cause neurologic deterioration. In terms of the etiologic incidence of fungal mass lesions in the central nervous system, whereas cryptococcomas may be the most common, they rarely reach any appreciable size. One form of this specific fungal infection, namely the granulomatous form of cryptococcomatosis, challenges this paradigm, and these lesions can reach an alarming size. CASE DESCRIPTION: We previously reported a case of multicentric granulomatous cryptococcomas occurring in an adult immunocompetent male patient published in WORLD NEUROSURGERY in mid-2018. We now report that despite confirmed gross total resection and subsequent neurologic improvement having been achieved at that time, the patient was not compliant with his prescribed adjuvant antifungal medical therapy, and for 6 months was lost to follow-up. We now report that the same patient again presented to our unit in early-2019 with recurrent granulomatous cryptococcomas, of an alarming even larger size, in the contralateral hemisphere. Fortunately, were again were able to successfully manage him surgically and have now adapted our surveillance plan to include booked follow-up magnetic resonance imaging. CONCLUSIONS: According to our review of the English literature, to our knowledge, this is the first report of recurrent granulomatous cryptococcomas occurring in the contralateral hemisphere within 6 months of surgery. The case illustrates the importance of the adjuvant antifungal medial therapy if recurrence is to be avoided.

Multicentric Cryptococcomas Mimicking Neoplasia in Immunocompetent Patient.

BACKGROUND: Fungal mass lesions in the central nervous system are, as a group, extremely rare. In this group cryptococcomas are the most common mass lesions seen. These cryptococcomas/mucinous pseudocysts are commonly only 3-10 mm in diameter and occur almost exclusively in the basal ganglia through contiguous spread from a basal meningitis through the Virchow-Robbin perivascular spaces. In rare cases a chronic granulomatous process may lead to formation of mass lesions that have a tumoral appearance. CASE DESCRIPTION: A 19-year-old male presented to our Neurosurgical Unit with a 5-month history of progressive morning headaches. He also complained of progressive weakness of his R upper limb of 3 months' duration. The patient was found to be human immunodeficiency virus negative with a CD4 count of 1763. The patient had no other medical problems. Examination revealed a monoplegia of his R upper limb. While being optimized for surgery, the patient demonstrated progression of his upper limb monoplegia despite preoperative steroid therapy aimed at decreasing the perilesional vasogenic edema. He was booked for emergency resection of 2 lobar mass lesions. Histopathology analysis revealed the 2 specimens had similar features. These specimens were representative of gliotic brain parenchyma involved by extensive cryptococcosis. CONCLUSIONS: Diagnosing the tumoral form of cryptococcosis in immunocompetent patients is a challenge. Primary and secondary brain tumors are usually the first hypotheses in these cases. Thorough preoperative investigation through cerebrospinal fluid sampling and detailed magnetic resonance imaging may lead to consideration of this diagnosis before the histopathologic analysis has been conducted.

An Examination of Gender Differences in the Association of Adolescent Substance use with Eating and Weight Loss Attitudes.

OBJECTIVE: To assess gender differences in the relationship between eating and weight loss attitudes (EWAs), and 30-day tobacco and alcohol use among adolescents, while controlling for potential confounds (age, country of birth, psychological distress, pubertal development, peer alcohol and tobacco use, and sexual activity). METHODS: School students aged between 11 and 17 years (N = 10,273) from high schools in the State of Victoria (Australia) completed surveys in class under conditions of anonymity and confidentiality. RESULTS: The interaction between EWAs and gender was significant for tobacco use but not for alcohol use, indicating that the effect of EWAs on tobacco use, but not alcohol use, vary by gender. CONCLUSIONS: Tobacco use was related to EWAs in adolescent females but not males, and this is consistent with the possibility that females use tobacco in an instrumental fashion to control weight. Implications and Contribution: Female adolescents high in eating and weight loss attitudes were more likely to engage in tobacco use. In contrast, eating and weight loss attitudes were not related to male tobacco use. These results point to the potential importance of developing gender-specific approaches towards addressing problematic behaviors in adolescent populations.

Testing the Social Interaction Learning Model's Applicability to Adolescent Substance Misuse in an Australian Context.

BACKGROUND: Parents and peers both influence the development of adolescent substance misuse, and the Social Interaction Learning (SIL) model provides a theoretical explanation of the paths through which this occurs. OBJECTIVE: The SIL model has primarily been tested with conduct outcomes and in US samples. This study adds to the literature by testing the SIL model with four substance use outcomes in a sample of Australian youth. METHOD: We used structural equation modeling to test the fit of the SIL model to a longitudinal sample (n = 907) of students recruited in grade 5 in Victoria, Australia participating in the International Youth Development Study, who were resurveyed in grades 6 and 10. RESULTS: The model fit was good (χ2(95) = 248.52, p < .001; RMSEA = .04 [90% CI: .036 - .049]; CFI = .94; SRMR = .04). Path estimates from parenting to antisocial behavior and from antisocial behavior to antisocial peers were significant. In turn, having antisocial peers was significantly related to alcohol use, binge drinking, tobacco use, and marijuana use. From parenting, only the direct path to marijuana use was significant, but indirect effects were significant. CONCLUSIONS: The SIL model illustrates that parenting plays an early role in the formation of adolescent peer relations that influence substance misuse and identifies etiological pathways that can guide the targets of prevention. The SIL pathways appear robust to the Australian social and policy context.

Introduction: MHC/KIR and governance of specificity.

The MHC controls specificity, to ensure that appropriate immune responses are mounted to invading pathogens whilst maintaining tolerance to the host. It encodes molecules that act as sentinels, providing a snapshot of the health of the interior and exterior of the cell for immune surveillance. To maintain the ability to respond appropriately to any disease requires a delicate balance of expression and function, and many subtleties of the system have been described at the gene, individual and population level. The main players are the highly polymorphic classical MHC class I and class II molecules, as well as some non-classical loci of both types. Transporter associated with antigen processing (TAP) peptide transporters, proteasome components and Tapasin, encoded within the MHC, are also involved in selection of peptide for presentation. The plethora of mechanisms microorganisms use to subvert immune recognition, through blocking these antigen processing and presentation pathways, attests to the importance of HLA in resistance to infection. There is continued interest in MHC genetics in its own right, as well as in relation to KIR, to transplantation, infection, autoimmunity and reproduction. Also of topical interest, cancer immunotherapy through checkpoint inhibition depends on highly specific recognition of cancer peptide antigen and continued expression of HLA molecules. Here, we briefly introduce some background to the MHC/KIR axis in man. This special issue of immunogenetics expands on these topics, in humans and other model species.

User characteristics and effect profile of Butane Hash Oil: An extremely high-potency cannabis concentrate.

BACKGROUND: Recent reports suggest an increase in use of extremely potent cannabis concentrates such as Butane Hash Oil (BHO) in some developed countries. The aims of this study were to examine the characteristics of BHO users and the effect profiles of BHO. DESIGN: Anonymous online survey in over 20 countries in 2014 and 2015. Participants aged 18 years or older were recruited through onward promotion and online social networks. The overall sample size was 181,870. In this sample, 46% (N=83,867) reported using some form of cannabis in the past year, and 3% reported BHO use (n=5922). MEASUREMENTS: Participants reported their use of 7 types of cannabis in the past 12 months, the source of their cannabis, reasons for use, use of other illegal substances, and lifetime diagnosis for depression, anxiety and psychosis. Participants were asked to rate subjective effects of BHO and high potency herbal cannabis. FINDINGS: Participants who reported a lifetime diagnosis of depression (OR=1.15, p=0.003), anxiety (OR=1.72, p<0.001), and a larger number of substance use (OR=1.29, p<0.001) were more likely to use BHO than only using high potency herbal cannabis. BHO users also reported stronger negative effects and less positive effects when using BHO than high potency herbal cannabis (p<0.001) CONCLUSION: Mental health problems and other illicit drug use were associated with use of BHO. BHO was reported to have stronger negative and weaker positive effects than high potency herbal cannabis.

Does gender moderate the relationship between polydrug use and sexual risk-taking among Australian secondary school students under 16 years of age?

INTRODUCTION AND AIMS: This study examines the association of alcohol and polydrug use with risky sexual behaviour in adolescents under 16 years of age and if this association differs by gender. DESIGN AND METHODS: The sample consisted of 5412 secondary school students under 16 years of age from Victoria, Australia. Participants completed an anonymous and confidential survey during class time. The key measures were having had sex before legal age of consent (16 years), unprotected sex before 16 (no condom) and latent-class derived alcohol and polydrug use variables based on alcohol, tobacco, cannabis, inhalants and other illegal drug use in the past month. RESULTS: There were 7.52% and 2.55% of adolescents who reported having sex and having unprotected sex before 16 years of age, respectively. After adjusting for antisocial behaviours, peers' drug use and family and school risk factors, girls were less likely to have unprotected sex (odds ratio = 0.31, P = 0.003). However, the interaction of being female and polydrug use (odds ratio = 4.52, P = 0.004) was significant, indicating that girls who engaged in polydrug use were at higher risk of having unprotected sex. For boys, the effect of polydrug use was non-significant (odds ratio = 1.44, P = 0.310). Discussion and Conclusions For girls, polydrug use was significantly associated with unprotected sex after adjusting for a range of risk factors, and this relationship was non-significant for boys. Future prevention programs for adolescent risky sexual behaviour and polydrug use might benefit from a tailored approach to gender differences. [Chan GCK, Kelly AB, Hides L, Quinn C, Williams JW. Does gender moderate the relationship between polydrug use and sexual risk-taking among Australian secondary school students under 16 years of age? Drug Alcohol Rev 2016;35:750-754].

The relationship between psychological distress and adolescent polydrug use.

Polydrug use is relatively common among adolescents. Psychological distress is associated with the use of specific drugs, and may be uniquely associated with polydrug use. The purpose of this study was to test the association of psychological distress with polydrug use using a large adolescent sample. The sample consisted of 10,273 students aged 12-17 years from the State of Victoria, Australia. Participants completed frequency measures of tobacco, alcohol, cannabis, inhalant, and other drug use in the past 30 days, and psychological distress. Control variables included age, gender, family socioeconomic status, school suspensions, academic failure, cultural background, and peer drug use. Drug-use classes were derived using latent-class analysis, then the association of psychological distress and controls with drug-use classes was modeled using multinomial ordinal regression. There were 3 distinct classes of drug use: no drug use (47.7%), mainly alcohol use (44.1%), and polydrug use (8.2%). Independent of all controls, psychological distress was higher in polydrug users and alcohol users, relative to nondrug users, and polydrug users reported more psychological distress than alcohol users. Psychological distress was most characteristic of polydrug users, and targeted prevention outcomes may be enhanced by a collateral focus on polydrug use and depression and/or anxiety.

A longitudinal study of the association of adolescent polydrug use, alcohol use and high school non-completion.

AIMS: Failure to complete high school predicts substantial economic and social disadvantage in adult life. The aim of this study was to determine the longitudinal association of mid-adolescent polydrug use and high school non-completion, relative to other drug use profiles. DESIGN: A longitudinal analysis of the relationship between polydrug use in three cohorts at grade 9 (age 14-15 years) and school non-completion (reported post-high school). SETTING: A State-representative sample of students across Victoria, Australia. PARTICIPANTS: A total of 2287 secondary school students from 152 high schools. The retention rate was 85%. MEASUREMENTS: The primary outcome was non-completion of grade 12 (assessed at age 19-23 years). At grade 9, predictors included 30-day use of eight drugs, school commitment, academic failure and peer drug use. Other controls included socio-economic status, family relationship quality, depressive symptoms, gender, age and cohort. FINDINGS: Three distinct classes of drug use were identified-no drug use (31.7%), mainly alcohol use (61.8%) and polydrug use (6.5%). Polydrug users were characterized by high rates of alcohol, tobacco and cannabis use. In the full model, mainly alcohol users and polydrug users were less likely to complete school than non-drug users [odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.17-2.03) and OR = 2.51, 95% CI = 1.45-4.33), respectively, P < 0.001]. These effects were independent of school commitment, academic failure, peer drug use and other controls. CONCLUSIONS: Mid-adolescent polydrug use in Australia predicts subsequent school non-completion after accounting for a range of potential confounding factors. Adolescents who mainly consume alcohol are also at elevated risk of school non-completion.

Polysubstance use: diagnostic challenges, patterns of use and health.

PURPOSE OF REVIEW: Polysubstance use is common, particularly amongst some age groups and subcultures. It is also associated with elevated risk of psychiatric and physical health problems. We review the recent research findings, comment on changes to polysubstance diagnoses, report on contemporary clinical and epidemiological polysubstance trends, and examine the efficacy of preventive and treatment approaches. RECENT FINDINGS: Approaches to describing polysubstance use profiles are becoming more sophisticated. Models over the last 18 months that employ latent class analysis typically report a no use or limited-range cluster (alcohol, tobacco and marijuana), a moderate-range cluster (limited range and amphetamine derivatives), and an extended-range cluster (moderate range, and nonmedical use of prescription drugs and other illicit drugs). Prevalence rates vary as a function of the population surveyed. Wide-ranging polysubstance users carry higher risk of comorbid psychopathology, health problems, and deficits in cognitive functioning. SUMMARY: Wide-ranging polysubstance use is more prevalent in subcultures such as 'ravers' (dance club attendees) and those already dependent on substances. Health risks are elevated in these groups. Research into the prevention and treatment of polysubstance use is underdeveloped. There may be benefit in targeting specific polysubstance use and risk profiles in prevention and clinical research.

Is there any evidence of changes in patterns of concurrent drug use among young Australians 18-29 years between 2007 and 2010?

BACKGROUND: A significant minority of Australians engage in concurrent drug use (using more than one drug in a given period). We examined clusters and correlates of concurrent drug use using the latest available nationally representative survey data on Australian young adults. SAMPLE: 3836 participants aged 18-29 years (mean age 24 years) from the 2010 National Drug Strategy Household Survey (NDSHS). METHOD: Clusters were distilled using latent class analysis of past year use of alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, ketamine, GHB, inhalants, steroids, barbiturates, meth/amphetamines, heroin, methadone/buprenorphine, other opiates, painkillers and tranquillisers/sleeping pills. RESULTS: Concurrent drug use in this sample was best described using a 4-class solution. The majority (87.5%) of young adults predominantly used alcohol only (50.9%) or alcohol and tobacco (36.6%). 10.2% reported using alcohol, tobacco, marijuana, and ecstasy, and 2.3% reported using an extensive range of drugs. CONCLUSION: Most drug use clusters were robust in their profile and stable in their prevalence, indicating little meaningful change at the population level from 2007. The targeting of alcohol and tobacco use remains a priority, but openness to experiencing diverse drug-related effects remains a significant concern for 12.5% of young people in this age group.

Recognition of Salmonella by Dectin-1 induces presentation of peptide antigen to type B T cells.

Type B T cells recognize peptide-MHC class II (pMHCII) isoforms that are structurally distinct from those recognized by conventional type A T cells. These alternative type B conformers result from peptide loading in the absence of HLA-DM. Type A conformers are more stable than type B pMHCII conformers but bind the same peptide in the same register. Here, we show that interaction of Salmonella Typhimurium with bone marrow derived dendritic cells (BMDCs) isolated from C3H/HeNCr1 mice results in enhanced presentation of peptide Ag to type B T cells. The effect could be mimicked by purified PAMPs, the most potent of which were curdlan and zymosan, ß-(1,3)-glucan-containing polymers that are recognized by Dectin-1. Blocking of Dectin-1 with Ab and laminarin inhibited the induction of the type B T-cell response by BMDCs, confirming its role as a PRR for S. Typhimurium. Splenic DCs (sDCs) expressed Dectin-1 but were refractive to the induction of type B responses by S. Typhimurium and curdlan. Type B T cells have been shown to escape thymic tolerance and to transfer pathology in an autoimmune disease model. The induction of type B responses by gram-negative bacteria provides a mechanism by which autoreactive T cells may be produced during infection.

A comparative study of the effect of spray drying and hot-melt extrusion on the properties of amorphous solid dispersions containing felodipine.

OBJECTIVES: To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), by hot-melt extrusion (HME) and spray drying. METHODS: Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40°C/75% RH) over 8 weeks. KEY FINDINGS: Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. CONCLUSIONS: Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations.

Concurrent and simultaneous polydrug use: latent class analysis of an Australian nationally representative sample of young adults.

BACKGROUND: Alcohol use and illicit drug use peak during young adulthood (around 18-29 years of age), but comparatively little is known about polydrug use in nationally representative samples of young adults. Drawing on a nationally representative cross-sectional survey (Australian National Drug Strategy Household Survey), this study examines polydrug use patterns and associated psychosocial risk factors among young adults (n = 3,333; age 19-29). METHOD: The use of a broad range of licit and illicit drugs were examined, including alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, ketamine, GHB, inhalants, steroids, barbiturates, meth/amphetamines, heroin, methadone/buprenorphine, other opiates, painkillers, and tranquilizers/sleeping pills. Latent class analysis was employed to identify patterns of polydrug use. RESULTS: Polydrug use in this sample was best described using a 5-class solution. The majority of young adults predominantly used alcohol only (52.3%), alcohol and tobacco (34.18%). The other classes were cannabis, ecstasy, and licit drug use (9.4%), cannabis, amphetamine derivative, and licit drug use (2.8%), and sedative and alcohol use (1.3%). Young adult males with low education and/or high income were most at risk of polydrug use. CONCLUSION: Almost half of young adults reported polydrug use, highlighting the importance of post-high school screening for key risk factors and polydrug use profiles, and the delivery of early intervention strategies targeting illicit drugs.

The topography of multiple drug use among adolescent Australians: findings from the National Drug Strategy Household Survey.

INTRODUCTION AND AIMS: Despite evidence that many Australian adolescents have considerable experience with various drug types, little is known about the extent to which adolescents use multiple substances. The aim of this study was to examine the degree of clustering of drug types within individuals, and the extent to which demographic and psychosocial predictors are related to cluster membership. DESIGN AND METHOD: A sample of 1402 adolescents aged 12-17 years were extracted from the Australian 2007 National Drug Strategy Household Survey. Extracted data included lifetime use of 10 substances, gender, psychological distress, physical health, perceived peer substance use, socioeconomic disadvantage, and regionality. Latent class analysis was used to determine clusters, and multinomial logistic regression employed to examine predictors of cluster membership. RESULT: There were 3 latent classes. The great majority (79.6%) of adolescents used alcohol only, 18.3% were limited range multidrug users (encompassing alcohol, tobacco, and marijuana), and 2% were extended range multidrug users. Perceived peer drug use and psychological distress predicted limited and extended multiple drug use. Psychological distress was a more significant predictor of extended multidrug use compared to limited multidrug use. DISCUSSION AND CONCLUSION: In the Australian school-based prevention setting, a very strong focus on alcohol use and the linkages between alcohol, tobacco and marijuana are warranted. Psychological distress may be an important target for screening and early intervention for adolescents who use multiple drugs.

Salmonella polarises peptide-MHC-II presentation towards an unconventional Type B CD4+ T-cell response.

Distinct peptide-MHC-II complexes, recognised by Type A and B CD4(+) T-cell subsets, are generated when antigen is loaded in different intracellular compartments. Conventional Type A T cells recognize their peptide epitope regardless of the route of processing, whereas unconventional Type B T cells only recognise exogenously supplied peptide. Type B T cells are implicated in autoimmune conditions and may break tolerance by escaping negative selection. Here we show that Salmonella differentially influences presentation of antigen to Type A and B T cells. Infection of bone marrow-derived dendritic cells (BMDCs) with Salmonella enterica serovar Typhimurium (S. Typhimurium) reduced presentation of antigen to Type A T cells but enhanced presentation of exogenous peptide to Type B T cells. Exposure to S. Typhimurium was sufficient to enhance Type B T-cell activation. Salmonella Typhimurium infection reduced surface expression of MHC-II, by an invariant chain-independent trafficking mechanism, resulting in accumulation of MHC-II in multi-vesicular bodies. Reduced MHC-II surface expression in S. Typhimurium-infected BMDCs correlated with reduced antigen presentation to Type A T cells. Salmonella infection is implicated in reactive arthritis. Therefore, polarisation of antigen presentation towards a Type B response by Salmonella may be a predisposing factor in autoimmune conditions such as reactive arthritis.

The influence of parents, siblings and peers on pre- and early-teen smoking: a multilevel model.

INTRODUCTION AND AIMS: Despite considerable success in tobacco control, many teenagers in Australia and other industrialised countries still smoke tobacco. There is mixed evidence on the relative influence of proximal social networks (parents/siblings/peers) on pre- and early-teen smoking, and no research has examined how these influences compare after accounting for school- and community-level effects.The aim of this study was to compare the relative influences of parents, siblings and peers, after accounting for school- and community-level variation in smoking. DESIGN AND METHODS: A cross-sectional fixed and random effects model of smoking prevalence was used, with individuals (n = 7314) nested within schools (n = 231) nested within communities (n = 30). Grade 6 and 8 students (modal ages 11 and 13 years) completed an on-line survey. Key variables included parent/sibling/peer use. Controls included alcohol involvement, sensation seeking, pro-social beliefs, laws/norms about substance use and school commitment. RESULTS: There was significant variation in smoking at both the school and community levels, supporting the need for a multilevel model. Individual-level predictors accounted for much of the variance at higher levels. The strongest effects were for number of friends who smoke, sibling smoking and alcohol involvement. Smaller significant effects were found for parent smoking. At the community level, socioeconomic disadvantage was significant, but community-level variance in pro-social and drug-related laws/norms was not related to smoking. DISCUSSION AND CONCLUSIONS: Cross-level interactions were generally non-significant. Early teenage smoking was best explained by sibling and peer smoking, and individual risks largely accounted for the substantial variation observed across schools and communities. In terms of future tobacco control, findings point to the utility of targeting families in disadvantaged communities.

Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation.

The biochemical basis for complement acting directly on antigen-presenting cells to enhance their function in T-cell stimulation has been unclear. Here we present evidence that engagement of C3a receptor (C3aR) on the surface of dendritic cells (DCs) leads to alterations in the level of intracellular cyclic adenosine monophosphate (cAMP), a potent negative regulator of inflammatory cytokines. C3aR activation-induced depression of cAMP was associated with enhanced capacity of DCs for antigen uptake and T-cell stimulation. Conversely, C3aR-deficient DCs showed elevation of cAMP and impaired properties for antigen uptake and immune stimulation. Similarities in the phenotype of C3-deficient and C3aR-deficient DCs suggest that local production of C3 with extracellular metabolism to C3a is an important driver of DC alterations in cAMP. The finding of a link between complement and adaptive immune stimulation through cAMP offers new insight into how innate and adaptive immunity combine to generate efficient effector and memory responses.