Search

Infectious syphilis has increased substantially over the past decade. Targeting limited public health resources toward subpopulations with multiple reinfections may have a large impact in reducing onward transmission within a community.A chart review was conducted for individuals with 4 or more infectious syphilis diagnoses between 2005 and 2014 (the top 1% of all syphilis diagnoses in British Columbia, Canada). We characterized the sociodemographics, partner notification outcomes and social network.Between 2005 and 2014, there were 30 individuals with 4 or more syphilis diagnoses, accounting for 139 diagnoses. All were men who have sex with men and 29 (96%) were human immunodeficiency virus-positive. Of the 139 diagnoses, 65% occurred in the early latent stage of infection, 22% in the secondary stage, and 14% in the primary stage. The median number of sexual partners per diagnosis was 5 (range, 1-50). Among the 838 partners reported, 79% were notifiable, 53% were notified, and 23% were reported to be tested or treated. Sexual network mapping showed that almost half of the members of this group could be linked to one another either directly or indirectly via partners over 10 years. Social network mapping demonstrated high connectivity, with 4 venues associated with almost two thirds of the study population.The connectivity and recurrent diagnoses in this study population suggest potential benefits of targeted interventions to individuals with multiple diagnoses and their partners. Our study highlights the need for enhanced care, increased syphilis testing frequency, and exploring alternative preventative methods among individuals with syphilis rediagnoses to reduce syphilis incidence.

Despite high prevalence of hepatitis C virus (HCV), linkage to care and treatment for Indigenous people is low. In an Indigenous community in Saskatchewan, Canada a retrospective review identified 200 individuals (∼12% prevalence) had HCV antibodies though majority lacked ribonucleic acid (RNA) testing, and few received treatment despite availability of an effective cure. Following Indigenous oral traditions, focus group discussions were held with key community members and leadership. Participants emphasized the need for a community-based screening and treatment programme. A team of community members, peers and healthcare professionals developed a streamlined screening pathway termed 'liver health event' (LHE) to reduce stigma, reach undiagnosed, re-engage previously diagnosed, and ensure rapid linkage to care/treatment. LHEs began December 2016. Statistics were tracked for each event. As of July 2019, there were 10 LHEs with 540 participants, 227 hepatitis C tests and 346 FibroScans completed. This represented 294 unique individuals, of which 64.3% were tested, and of those, 40.8% were Ab positive. Among those positive for antibodies, 41.7% had active hepatitis C infections, and among these, 90% were linked to care, and 14 new positive individuals were identified. Following the success of LHEs, these were adapted and implemented in 10 other communities in this region, resulting in 17 additional LHEs. This intervention is reaching the undiagnosed and linking clients to care through a low-barrier and de-stigmatizing approach. It has facilitated collaboration, knowledge exchange and mentorship between Indigenous communities, significantly impacting health outcomes of Indigenous people in this region.Individuals residing in geographically isolated Indigenous communities often face multiple barriers trying to access healthcare services in Saskatchewan Canada. Consequently, many individuals who have HCV antibody (Ab), often lack confirmatory RNA test and experience delays in linkage to HCV treatment. A collective decision was made by pertinent stakeholders including community members, peers, community healthcare staff, Chief and leadership to improve access to screening and linkage to HCV treatment in community. A streamlined HCV screening pathway referred to as LHEs was developed by an Indigenous community. Since implementation in December 2016, 10 LHEs were delivered in community, with 540 participant visits, 227 hepatitis C tests conducted, and 346 FibroScans completed. Out of 294 unique individuals who attended, 64.3% were tested, and of those, 40.8% were Ab positive. Among those positive for antibodies, 41.7% had active hepatitis C infections, and among these, 90% were linked to care, and 14 new positive individuals were identified. Following the success of the LHEs in reaching the undiagnosed, this screening pathway has been adapted and implemented in at least 10 additional Indigenous communities in Saskatchewan, Canada.

During 2011-16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks.

Aims: Previous research on whether Hepatitis C Virus (HCV)/HIV coinfection alters the natural history of HIV disease progression shows conflicting findings. The aim of this study is to invest igate whether HCV/HIV coinfection has an adverse effect on the outcome of a CD4 + count < 200 cells/µL

More than doubling the national mean, Saskatchewan has the highest incidence of HIV in Canada. The progression of HIV is characterized by the decline in CD4+ T cells over time and can lead to immunological AIDS. Clinicians in Saskatoon, Saskatchewan, have observed a more rapid progression to AIDS in the recent years. The goal of this retrospective longitudinal cohort study was to investigate the rate of CD4+ cell depletion, as well as to determine the effects of multiple clinical and social factors that may contribute to an accelerated progression of HIV to AIDS in this population., OBJECTIVE: To assess the impact of clinical and social factors unique to HIV-infected adults in Saskatoon, Saskatchewan, regarding the rate of CD4+ count change, and to identify factors associated with a risk of CD4+ count decline. METHODS: A retrospective longitudinal cohort study from medical chart reviews at two clinics was conducted in Saskatoon. Univariate and multivariate linear mixed effects models were used to assess the impact of selected factors on CD4+ count change. RESULTS: Four hundred eleven HIV-infected patients were identified from January 1, 2003 to November 30, 2011. Two hundred eighteen (53%) were male, mean (± SD) age was 35.6 ±10.1 years, 257 (70.8%) were First Nations or Métis, 312 (80.2%) were hepatitis C virus (HCV) coinfected and 300 (73.3%) had a history of injection drug use (IDU). In univariate models, age, ethnicity, HCV, IDU, antiretroviral therapy and social assistance were significant. Using ethnicity, HCV and IDU, three multivariate models (models 1, 2, 3) were built due to high correlation. First Nations or Métis ethnicity, HCV coinfection and a history of IDU were associated with significantly lower CD4+ counts in multivariate models. Older age and social assistance were associated with significantly lower CD4+ counts in models 1 and 3. Age was marginally significant in model 2 (P=0.055). Not prescribed antiretroviral therapy was associated with a significantly negative CD4+ count slope in all multivariate models. CONCLUSION: The unique epidemiology of this HIV-infected population may be contributing to CD4+ count change. Increased attention and resources focused on this high-risk population are needed to prevent disease progression and to improve overall health and quality of life.

BACKGROUND: There is limited knowledge concerning chronic bronchitis (CB) in Canadian Aboriginal peoples.OBJECTIVE: To determine the prevalence (crude and adjusted) of CB and its associated risk factors in Canadian Aboriginal children and youth six to 14 years of age.METHODS: Data from the cross-sectional Aboriginal Peoples Survey were analyzed in the present study. Logistic regression analysis was used to determine risk factors influencing the prevalence of CB among Aboriginal children and youth. The balanced repeated replication method was used to compute standard errors of regression coefficients to account for clustering inherent in the study design. The outcome of interest was based on the question: “Have you been told by a doctor, nurse or other health professional that you have chronic bronchitis?” Demographics, environment and population characteristics (predisposing and enabling resources) were tested for an association with CB.RESULTS: The prevalence of CB was 3.1% for boys and 2.8% for girls. Other significant risk factors of CB were age (OR 1.38 [95% CI 1.24 to 1.52] for 12 to 14 year olds versus six to eight year olds), income (OR 2.28 [95% CI 2.02 to 2.59] for income category DISCUSSION: The prevalence of CB was related to well-known risk factors among adults, including older age and lower annual income.

The complement system is a key component of the innate immune response. Here, we have examined the role of complement anaphylatoxin C5a in an experimental model of Staphylococcus aureus bacteremia. Our data provide compelling evidence for a protective role of C5a during staphylococcal bloodstream infection.

FcγRIV is a relatively new IgG Fc receptor (FcγR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcγRIII, complement and IgG2 subclasses remains uncertain. Here we define FcγRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcγRIV and FcγRIII is critical to mediate certain type II/III autoimmune responses. FcγRIII-deficient mice display compensatory enhanced FcγRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased FcγRIV alone is not sufficient to trigger these diseases in the absence of FcγRIII. Importantly, however, blockade of FcγRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FcγRIII and FcγRIV are each essential to trigger an FcRγ-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcγRIII and FcγRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcγR and C5a anaphylatoxin receptor activation to generate inflammation.

The two low affinity IgG Fc receptors (FcgammaR), FcgammaRIII and FcgammaRIIB, are coexpressed on myeloid effector cells, and their genes, as reported here, are positively and negatively regulated by both C5a and interferon-gamma through different signaling mechanisms. Two 48- and 43-bp sequences (C5a-inductive region (CIR) and C5a-suppressive region (CSR)) in the FcgammaRIII and FcgammaRIIB 5'-flanking regions that are necessary for C5a induction and suppression, respectively, are defined. Sequence analysis of the CIR and CSR, which localize apart from the interferon-gamma-responsive regions in each gene, revealed the presence of a novel element that differs by two nucleotides between FcgammaRIII and FcgammaRIIB. Mutation analysis of the CIR and CSR showed that this small difference determines inverse responsiveness in an FcgammaR gene context-dependent manner. Our study suggests that C5a uses similar DNA motifs (defined as GTGAXXTCCA) in both pathways of transcriptional induction and suppression of FcgammaRIII and FcgammaRIIB.

Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody-induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcgammaRI and FcgammaRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcgammaR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a--produced by and acting on FcgammaR--and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.

The anaphylatoxin C3a is a proinflammatory mediator generated during complement activation. The tight control of C3a receptor (C3aR) expression is crucial for the regulation of anaphylatoxin-mediated effects. Key factors regulating constitutive expression of the C3aR in the mast cell line HMC-1 and receptor induction by dibutyryl-cAMP in monomyeloblastic U937 cells were determined by functional characterization of the C3aR promoter. Nucleotides -18 to -285 upstream of the translational start site proved to be critical for promoter activity in HMC-1 cells. Binding sites for the transcription factors AP-1 and Ets could be located. Overexpressed c-Jun/c-Fos (AP-1) and Ets-1 led synergistically to increased promoter activity that was substantially reduced by site-directed mutagenesis of the corresponding elements within the C3aR promoter. In HMC-1 cells, Ets interacted directly with the predicted binding motif of the C3aR promoter as determined by electromobility shift assays. AP-1 binding to the C3aR promoter was augmented during C3aR induction in U937 cells. A retroviral gene transfer system was used to express a dominant negative mutant of Ets-1 in these cells. The resulting cells failed to up-regulate the C3aR after stimulation with dibutyryl-cAMP and showed decreased AP-1 binding, suggesting that Ets acts here indirectly. Thus, it was established that Ets and the AP-1 element mediates dibutyryl-cAMP induction of C3aR promoter activity, hence providing a mechanistic explanation of dibutyryl-cAMP-dependent up-regulation of C3aR expression. In conclusion, this study demonstrates an important role of AP-1 and a member of the Ets family in the transcriptional regulation of C3aR expression, a prerequisite for the ability of C3a to participate in immunomodulation and inflammation.

Complement and FcgammaR effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. In this study we show that in the lung Arthus reaction, the initial contact between immune complexes and alveolar macrophages (AM) results in plasma complement-independent C5a production that causes decreased levels of inhibitory FcgammaRIIB, increased levels of activating FcgammaRIII, and highly induced FcgammaR-mediated TNF-alpha and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of G(i)-type G protein signaling in C5aR-mediated control of the regulatory FcgammaR system in vitro, and analysis of the various C5aR-, FcgammaR-, and G(i)-deficient mice verifies the importance of Galpha(i2)-associated C5aR and the FcgammaRIII-FcgammaRIIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR- and FcgammaRIII-positive cells into C5aR- and FcgammaRIII-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or FcgammaRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcgammaRIIB-negative AM results in an enhanced pathology. These data suggest that AM function as a cellular link of C5a production and C5aR activation that uses a Galpha(i2)-dependent signal for modulating the two opposing FcgammaR, FcgammaRIIB and FcgammaRIII, in the initiation of the inflammatory cascade in the lung Arthus reaction.

Infants under 6 months of age are at greatest risk of mortality and severe morbidity from pertussis disease. Interventions that increase pertussis protection in newborns are therefore a clear public health imperative. The objective of this study was to assess maternal pertussis toxin antibody (anti-PT) level as a potential source of mother-to-child transfer of pertussis-associated antibodies that may reduce neonatal risk of pertussis disease. Anti-PT level was assessed in a 2013 cohort of pregnant women from two regions in two Canadian provinces, British Columbia and Nova Scotia. Basic demographics, health, and pertussis immunization history were collected, along with blood specimens. Anti-PT levels were compared for self-reported vaccination status and prior pertussis disease. To assess secular trend, a parallel analysis was also undertaken, using anonymized residual sera from a 1996-1997 cohort of pregnant women in British Columbia. A total of 169 pregnant women participated in the study - 50 from Nova Scotia and 119 from British Columbia. The mean and median age of participants from both sites was 31 years of age (range 16-42 years). The lower limit of quantification of the anti-PT assay was 10 ELISA units per milliliter (EU/ml). Overall, 59% of women had anti-PT levels less than 10 EU/ml and anti-PT level did not differ with time since last self-reported pertussis vaccination (χ(2)(2)=3.166, p=0.205). Among a 1996-1997 cohort of pregnant women in British Columbia, 101 of 200 (51%) had anti-PT levels less than 10 EU/ml. Our study found that most pregnant women in two geographically disparate health regions in Canada have low residual anti-PT levels, may be vulnerable to pertussis infection themselves, and would unlikely be a source of passive ante- or postnatal transfer of anti-PT to their newborn.

The V1 ATPase from the tobacco hornworm Manduca sexta and the Escherichia coli F1 ATPase were characterized by small-angle X-ray scattering (SAXS). The radii of gyration (Rg) of the complexes were 6.2 +/- 0.1 and 4.7 +/- 0.02 nm, respectively. The shape of the M. sexta V1 ATPase was determined ab initio from the scattering data showing six masses, presumed to be the A and B subunits, arranged in an alternating manner about a 3-fold axis. A seventh mass with a length of about 11.0 nm extends perpendicularly to the center of the hexameric unit. This central mass is presumed to be the stalk that connects V1 with the membrane domain (V(O)) in the intact V1V(O)-ATPase. In comparison, the shape of the F1 ATPase from E. coli possesses a quasi-3-fold symmetry over the major part of the enzyme. The overall asymmetry of the structure is given by a stem, assumed to include the central stalk subunits. The features of the V1 and F1 ATPase reveal structural homologies and diversities of the key components of the complexes.

Maintaining confidence in vaccine safety is critical to successful public health immunization programs. Surveillance and assessment of adverse events following immunization (AEFIs) are important for maintaining vaccine safety. The authors describe the evaluation of an initiative at Fraser Health Authority designed to enhance the role of a communicable disease nurse coordinator (CDNC) in assessing AEFI reports, in collaboration with a designated medical health officer (MHO) as required, and providing recommendations to clients and immunization providers. Previously, only MHOs performed this role. This evaluation project demonstrates this initiative's feasibility and provides a roadmap for health authorities interested in pursuing a similar model. MHOs, public health nurses and public health management expressed satisfaction with the process and the quality of the CDNC's recommendations. There was no statistically significant difference in median turnaround time for AEFI reporting date and date of recommendation, indicating this work is completed in as timely a manner by the CDNC as by the MHO. This role provides opportunity for professional growth, facilitates nursing practice to full scope, enables acquisition of specialized knowledge and provides a platform to share nursing expertise at a provincial level.

To characterize and identify determinants of HIV disease progression among a predominantly injection drug use (IDU) HIV population in the highly active antiretroviral therapy era.The present retrospective study was based on 343 HIV patients diagnosed from 2005 to 2010 from two clinics in Saskatoon, Saskatchewan. Disease progression was defined as the time from diagnosis to immunological AIDS (CD4 count200 cells/μL) and death. Uni- and multivariable Cox proportional hazards models were used.Of the 343 patients, 79% had a history of IDU, 77% were hepatitis C virus (HCV) coinfected and 67% were of Aboriginal descent. The one-year and three-year immunological AIDS-free probabilities were 78% and 53%, respectively. The one-year and three-year survival probabilities were 97% and 88%, respectively. Multicollinearity among IDU, HCV and ethnicity was observed and, thus, separate models were built. HCV coinfection (HR 2.9 [95% CI 1.2 to 6.9]) was a significant predictor of progression to immunological AIDS when controlling for baseline CD4 counts, treatment, age at diagnosis and year of diagnosis. For survival, only treatment use was a significant predictor (HR 0.34 [95% CI 0.1 to 0.8]). HCV coinfection was marginally significant (P=0.067).Baseline CD4 count, HCV coinfection, year of diagnosis and treatment use were significant predictors of disease progression. This highlights the importance of early treatment and the need for targeted interventions for these particularly vulnerable populations to slow disease progression.Caractériser et établir les déterminants de la progression du VIH dans une population atteinte du VIH surtout composée d’utilisateurs de drogues injectables (UDI) à une époque d’antirétrovirothérapie très active.La présente étude rétrospective s’est fondée sur 343 patients atteints du VIH diagnostiqués entre 2005 et 2010 dans deux cliniques de Saskatoon, en Saskatchewan. La progression de la maladie était définie comme le moment du diagnostic jusqu’à l’apparition du sida immunologique (numération de CD4 inférieure à 200 cellules/μL), puis jusqu’au décès. Les chercheurs ont utilisé le modèle univariable et multivariable de risques proportionnels de Cox.Sur les 343 patients, 79 % avaient déjà été UDI, 77 % étaient co-infectés par le virus de l’hépatite C (VHC) et 67 % étaient d’origine autochtone. La probabilité de non-apparition de sida immunologique au bout d’un an et de trois ans correspondait à 78 % et à 53 %, respectivement. La probabilité de survie au bout d’un an et de trois ans s’élevait à 97 % et à 88 %, respectivement. Les chercheurs ont observé une multicolinéarité entre les UDI, le VHC et l’ethnie et ont donc préparé des modèles différents. La co-infection par le VHC (RC 2,9 [95 % IC 1,2 à 6,9]) était un prédicteur important de progression en sida immunologique lorsqu’on contrôlait l’effet de la numération de CD4 de référence, du traitement, de l’âge au diagnostic et de l’année de diagnostic. Seule l’utilisation du traitement était une prédicteur important de la survie (RC 0,34 [95 % IC 0,1 à 0,8]). La co-infection par le VHC avait peu d’importance (P=0,067).La numération de CD4 de référence, la co-infection par le VHC, l’année de diagnostic et l’utilisation d’un traitement étaient des prédicteurs importants de progression de la maladie. Ces constatations font ressortir l’importance d’un traitement rapide et la nécessité de procéder à des interventions ciblées pour ces populations particulièrement vulnérables afin de ralentir la progression de la maladie.

FcgammaRIV is a relatively new IgG Fc receptor (FcgammaR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcgammaRIII, complement and IgG2 subclasses remains uncertain. Here we define FcgammaRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcgammaRIV and FcgammaRIII is critical to mediate certain type II/III autoimmune responses. FcgammaRIII-deficient mice display compensatory enhanced FcgammaRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased FcgammaRIV alone is not sufficient to trigger these diseases in the absence of FcgammaRIII. Importantly, however, blockade of FcgammaRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FcgammaRIII and FcgammaRIV are each essential to trigger an FcRgamma-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcgammaRIII and FcgammaRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcgammaR and C5a anaphylatoxin receptor activation to generate inflammation.

The complement system is a key component of the innate immune response. Here, we have examined the role of complement anaphylatoxin C5a in an experimental model of Staphylococcus aureus bacteremia. Our data provide compelling evidence for a protective role of C5a during staphylococcal bloodstream infection.

Fcγ receptors (FcγRs) on mononuclear phagocytes trigger autoantibody and immune complex–induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRγ-based activation is critical in the pathogenesis of these diseases, although the contribution of FcγR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum–resident calcium sensor, STIM1, cannot activate FcγR-induced Ca2+ entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcγR activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunologic diseases.

Fcgamma receptors (FcgammaR) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in IC-induced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3Kgamma abrogates C5aR signaling that is crucial for FcgammaR-mediated activation of lung macrophages. Thus, in PI3Kgamma(-/-) mice, IgG IC-induced FcgammaR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kgamma(-/-) mice but was impaired in PI3Kdelta(-/-) mice. Consequently, class IA PI3Kdelta deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kgamma and PI3Kdelta coordinate the inflammatory effects of C5aR and FcgammaR and define PI3Kdelta as a novel and essential element of FcgammaR signaling in the generation of C5a in IC disease.

Introduction The province of Saskatchewan has the highest incidence of HIV in Canada, and high AIDS-related morbidity and mortality. The HIV infected population in Saskatchewan is unique in Canada because the majority of cases are among individuals of First Nations and Metis ethnicity, the proportion of women who are infected is significantly greater than in other areas of the country, and the most commonly reported exposure is injection drug user (IDU). The highest proportion of cases occur in Saskatoon. Objectives The objectives of this study were (1) to identify factors associated with trends in CD4 count and (2) to identify characteristics of individuals exhibiting faster and slower rates of CD4 cell decline. Methods This is a retrospective longitudinal study from a medical chart review at the Positive Living Program and the Westside Community Clinic in Saskatoon. Inclusion criteria was HIV diagnosis between 1 January 2003 and 30 November 2011, and 18 years of age at time of diagnosis. Results Mean follow-up time for the 457 eligible patients was 46.3 (SD±26.8) months. 254 (53.6%) were male, average age at diagnosis was 35.6 (SD±10.14) years, and 279 (61.1%) were First Nations or Metis. Average baseline log viral load and CD4 count were 4.4 (SD±0.96) and 377.7 cells/mm 3 (SD±232.9), respectively. 340 (74.4%) were Hepatitis C virus (HCV) coinfected, 333 (72.9%) had a history of IDU and 143 (31.1%) were infected with a sexually transmitted infection (STI). 279 (61.1%) patients were recipients of antiretroviral therapy (ARV) during follow-up. 197 (43.1%) were diagnosed with AIDS, either clinical or immunological. 33 (7.2%) were deceased from any cause. Due to high colinearity between First Nations or Metis ethnicity, HCV-coinfection and IDU, three separate multivariate mixed effects models were built. In the first model, First Nations or Metis ethnicity (p=0.028), receipt of ARV (p Conclusions First Nations or Metis ethnicity, HCV coinfection, history of IDU, receipt of social assistance and ARV were identified as factors associated with a more rapid CD4 decline. Individuals exhibiting such factors might benefit from more frequent follow-up by clinicians and earlier initiation of ARV.

BACKGROUND In light of accumulated scientific evidence of the secondary preventive benefits of antiretroviral therapy, a growing number of jurisdictions worldwide have formally started to implement HIV Treatment as Prevention (TasP) programs. To date, no gold standard for TasP program monitoring has been described. Here, we describe the design and methods applied to TasP program process monitoring in British Columbia (BC), Canada. METHODS Monitoring indicators were selected through a collaborative and iterative process by an interdisciplinary team including representatives from all 5 regional health authorities, the BC Centre for Disease Control (BCCDC), and the BC Centre for Excellence in HIV/AIDS (BC-CfE). An initial set of 36 proposed indicators were considered for inclusion. These were ranked on the basis of 8 criteria: data quality, validity, scientific evidence, informative power of the indicator, feasibility, confidentiality, accuracy, and administrative requirement. The consolidated list of indicators was included in the final monitoring report, which was executed using linked population-level data. RESULTS A total of 13 monitoring indicators were included in the BC TasP Monitoring Report. Where appropriate, indicators were stratified by subgroups of interest, including HIV risk group and demographic characteristics. Six Monitoring Reports are generated quarterly: 1 for each of the regional health authorities and a consolidated provincial report. CONCLUSIONS We have developed a comprehensive TasP process monitoring strategy using evidence-based HIV indicators derived from linked population-level data. Standardized longitudinal monitoring of TasP program initiatives is essential to optimize individual and public health outcomes and to enhance program efficiencies.

Background The effectiveness of paraprofessional home-visitations on improving the circumstances of disadvantaged families is unclear. The purpose of this paper is to systematically review the effectiveness of paraprofessional home-visiting programs on developmental and health outcomes of young children from disadvantaged families. Methods A comprehensive search of electronic databases (e.g., CINAHL PLUS, Cochrane, EMBASE, MEDLINE) from 1990 through May 2012 was supplemented by reference lists to search for relevant studies. Through the use of reliable tools, studies were assessed in duplicate. English language studies of paraprofessional home-visiting programs assessing specific outcomes for children (0-6 years) from disadvantaged families were eligible for inclusion in the review. Data extraction included the characteristics of the participants, intervention, outcomes and quality of the studies. Results Studies that scored 13 or greater out of a total of 15 on the validity tool (n = 21) are the focus of this review. All studies are randomized controlled trials and most were conducted in the United States. Significant improvements to the development and health of young children as a result of a home-visiting program are noted for particular groups. These include: (a) prevention of child abuse in some cases, particularly when the intervention is initiated prenatally; (b) developmental benefits in relation to cognition and problem behaviours, and less consistently with language skills; and (c) reduced incidence of low birth weights and health problems in older children, and increased incidence of appropriate weight gain in early childhood. However, overall home-visiting programs are limited in improving the lives of socially high-risk children who live in disadvantaged families. Conclusions Home visitation by paraprofessionals is an intervention that holds promise for socially high-risk families with young children. Initiating the intervention prenatally and increasing the number of visits improves development and health outcomes for particular groups of children. Future studies should consider what dose of the intervention is most beneficial and address retention issues.