Racial/Ethnic Disparities in Psychiatric Traits and Diagnoses within a Community-based Sample of Children and Youth: Disparités raciales/ethniques dans les traits et diagnostics psychiatriques au sein d'un échantillon communautaire d'enfants et de jeunes.

OBJECTIVE: Racial/ethnic disparities in the prevalence of psychiatric disorders have been reported, but have not accounted for the prevalence of the traits that underlie these disorders. Examining rates of diagnoses in relation to traits may yield a clearer understanding of the degree to which racial/ethnic minority youth in Canada differ in their access to care. We sought to examine differences in self/parent-reported rates of diagnoses for obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders after adjusting for differences in trait levels between youth from three racial/ethnic groups: White, South Asian and East Asian. METHOD: We collected parent or self-reported ratings of OCD, ADHD and anxiety traits and diagnoses for 6- to 17-year-olds from a Canadian general population sample (Spit for Science). We examined racial/ethnic differences in trait levels and the odds of reporting a diagnosis using mixed-effects linear models and logistic regression models. RESULTS: East Asian (N = 1301) and South Asian (N = 730) youth reported significantly higher levels of OCD and anxiety traits than White youth (N = 6896). East Asian and South Asian youth had significantly lower odds of reporting a diagnosis for OCD (odds ratio [OR]East Asian = 0.08 [0.02, 0.41]; ORSouth Asian = 0.05 [0.00, 0.81]), ADHD (OREast Asian = 0.27 [0.16, 0.45]; ORSouth Asian = 0.09 [0.03, 0.30]) and anxiety (OREast Asian = 0.21 [0.11, 0.39]; ORSouth Asian = 0.12 [0.05, 0.32]) than White youth after accounting for psychiatric trait levels. CONCLUSIONS: These results suggest a discrepancy between trait levels of OCD, ADHD and anxiety and rates of diagnoses for East Asian and South Asian youth. This discrepancy may be due to increased barriers for ethnically diverse youth to access mental health care. Efforts to understand and mitigate these barriers in Canada are needed.

We know that there is there are differences in the prevalence of childhood mental illnesses by race/ethnic group, which may be related to disproportionate access to mental health care. What is unknown is whether there this difference in prevalence is related to differences in the presence of symptoms for mental illness or whether children and youth from marginalized racial/ethnic groups have symptoms but are not getting diagnosed. This information is needed to understand the degree to which children and youth from marginalized race/ethnicity groups are accessing mental health care in Canada. We tested the differences in reported symptoms and diagnosis of three common and impairing childhood-onset disorders (obsessive-compulsive disorder­OCD), attention-deficit/hyperactivity disorder­ADHD and anxiety disorders) in children and youth (6­17 years of age) living in Canada that were from three racial/ethnic groups: White, South Asian and East Asian. East Asian and South Asian youth reported significantly higher levels of OCD and anxiety traits than White youth. However, East Asian and South Asian youth were significantly less likely than White youth to have a reported diagnosis of OCD, ADHD or anxiety even after accounting for symptom levels for each disorder. Our findings suggest that East and South Asian children are less likely than White children to get a diagnosis for common mental illness even if they have symptoms of that mental illness. This gap in receiving a diagnosis might be because of more barriers to mental health care for children and youth from marginalized racial/ethnic groups but we need more research to pinpoint the cause.

Posterior Capsule Reconstruction with Polypropylene Mesh After Total Hip Arthroplasty.

Instability remains a challenge after total hip arthroplasty (THA). We have previously utilized a monofilament polypropylene mesh to reconstruct the posterior capsule for unstable THA. This study identified 24 hips that underwent mesh reconstruction of the posterior capsule for instability. Survivorship was 70.8% at mean 6.5 years (range 6 weeks-20.1 years). Six patients underwent re-operation, and one patient had the mesh removed. Of eight hips, five (62.5%) with a history of prior revision re-dislocated, while only 2/16 hips (12.5%) with no previous revision history re-dislocated (p = 0.02). Posterior capsule reconstruction with polypropylene mesh has reasonable mid-term survivorship in this challenging population. (Journal of Surgical Orthopaedic Advances 32(2):092-096, 2023).

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Is Dislocation Risk due to Posterior Pelvic Tilt Reduced With Direct Anterior Approach Total Hip Arthroplasty?

BACKGROUND: Pelvic tilt affects acetabular anteversion, and thus total hip arthroplasty (THA) dislocation risk. The pubic symphysis-sacrococcygeal distance (PSCD) is an indicator of pelvic tilt, and a PSCD < 0 mm (ie, excessive posterior pelvic tilt) is associated with a 3.7-fold increase in postoperative dislocation rate. However, it is not known if the direct anterior (DA) approach might reduce this dislocation rate, specifically in high-risk populations such as negative PSCD. METHODS: Standing anteroposterior radiographs were reviewed for 510 consecutive DA THAs to determine PSCD. Patients were separated into 2 groups: (1) PSCD > 0 mm (PSCD[+]) and (2) PSCD < 0 mm (PSCD[-]). Incidence of dislocation was determined. We recorded if patients had spinal deformity or lumbar fusion. Continuous variables were analyzed using Student's t-test, categorical variables were analyzed using Fisher's exact test, and a sample size calculation was performed. RESULTS: Three hundred fifty-eight hips (70.2%) were PSCD[+], while 152 hips (29.8%) were PSCD[-]. Three dislocations (3/510 hips, 0.6%) occurred. Two dislocators were in the PSCD[-] group (2/152 hips, 1.3%) and 1 dislocator was in the PSCD[+] group (1/358 hips, 0.3%) (P = .21). Twenty-four patients had degenerative scoliosis (24/510, 4.7%), of which 1 had a dislocation (1/24, 4.2%); 2 dislocations occurred in nonscoliosis patients (2/486, 0.4%) (P = .134). Twenty-seven patients had lumbar spinal fusion (27/510, 5.3%), of which there were no dislocations (0/27, 0.0%); all dislocations were in nonfusion patients (3/483, 0.6%) (P = 1.0). CONCLUSION: We demonstrate no increased risk for THA dislocation in patients with a PSCD < 0 mm who have undergone a DA approach. These data would suggest a protective effect of the DA approach against dislocation, even in historically high-risk populations.

Go the Whole Nine Yards? How Extent of Meat Restriction Impacts Individual Dietary Experience.

This study examined three meat-restricted diets (N = 865)-a vegetarian diet, a reduced-meat diet, and a chicken-free diet-with a focus on the differences in lived dietary experiences operationalized using measures such as satisfaction with food-related life and the theory of planned behavior. The data comes from an online survey of a census-balanced sample of 30,000+ U.S. residents. The findings showed that meat reducers are a larger group than suspected and that there was a statistically significant difference in dietary experiences with vegetarians reporting better experiences with their diet. This research speaks to how the type of meat restriction impacts lived experiences.

Patient and provider perspectives on eHealth interventions in Canada and Australia: a scoping review.

INTRODUCTION: Despite the promises of universal health care in most developed countries, health inequities remain prevalent within and between rural and remote communities. Remote health technologies are often promoted as solutions to increase health system efficiency, to enhance quality of care, and to decrease gaps in access to care for rural and remote communities. However, there is mixed evidence for these interventions, particularly related to how they are received and perceived by health providers and by patients. Health technologies do not always adequately meet the needs of patients or providers. To examine this, a broad-based scoping review was conducted to provide an overview of patient and provider perspectives of eHealth initiatives in rural communities. The unique objective of this review was to prioritize the voices of patients and providers in discussing the disparities between health interventions and needs of people in rural communities. eHealth initiatives were reviewed for rural communities of Australia and Canada, two countries that have similar geographies and comparable health systems at the local level. METHODS: Searches were performed in PubMed, Scopus, and Web of Science with results limited from 2000 to 2018. Keywords included combinations of 'eHealth', 'telehealth', 'telemedicine', 'electronic health', and 'rural/remote'. Individual patient and provider perspectives on health care were identified, followed by qualitative thematic coding based on the type of intervention, the feedback provided, the affected population, geographic location, and category of individual providing their perspective. Quotes from patients and providers are used to illustrate the identified benefits and disadvantages of eHealth technologies. RESULTS: Based on reviewed literature, 90.1% of articles reported that eHealth interventions were largely positive. Articles noted decreased travel time (18%), time/cost saving (15.1%), and increased access to services (13.9%) as primary benefits to eHealth. The most prevalent disadvantages of eHealth were technological issues (24.5%), lack of face-to-face contact (18.6%), limited training (10.8%), and resource disparities (10.8%). These results show where existing eHealth interventions could improve and can inform policymakers and providers in designing new interventions. Importantly, benefits to eHealth extend beyond geographic access. Patients reported ancillary benefits to eHealth that include reduced anxiety, disruption on family life, and improved recovery time. Providers reported closer connections to colleagues, improved support for complex care, and greater eLearning opportunity. Barriers to eHealth are recognized by patient and providers alike to be largely systemic, where lack of rural high-speed internet and unreliability of installed technologies were significant. CONCLUSION: Regional and national governments are seen as the key players in addressing these technical barriers. This scoping review diverges from many reviews of eHealth with the use of first-person perspectives. It is hoped that this focus will highlight the importance of patient voices in evaluating important healthcare interventions such as eHealth and associated technologies.

HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded.

HIV-1 R5 variants exploit CCR5 as a coreceptor to infect both T cells and macrophages. R5 viruses that are transmitted or derived from immune tissue and peripheral blood are mainly inefficient at mediating infection of macrophages. In contrast, highly macrophage-tropic (mac-tropic) R5 viruses predominate in brain tissue and can be detected in cerebrospinal fluid but are infrequent in immune tissue or blood even in late disease. These mac-tropic R5 variants carry envelope glycoproteins (Envs) adapted to exploit low levels of CD4 on macrophages to induce infection. However, it is unclear whether this adaptation is conferred by an increased affinity of the Env trimer for CD4 or is mediated by postbinding structural rearrangements in the trimer that enhance the exposure of the coreceptor binding site and facilitate events leading to fusion and virus entry. In this study, we investigated CD4 binding to mac-tropic and non-mac-tropic Env trimers and showed that CD4-IgG binds efficiently to mac-tropic R5 Env trimers, while binding to non-mac-tropic trimers was undetectable. Our data indicated that the CD4 binding site (CD4bs) is highly occluded on Env trimers of non-mac-tropic R5 viruses. Such viruses may therefore infect T cells via viral synapses where Env and CD4 become highly concentrated. This environment will enable high-avidity interactions that overcome extremely low Env-CD4 affinities.IMPORTANCE HIV R5 variants bind to CD4 and CCR5 receptors on T cells and macrophages to initiate infection. Transmitted HIV variants infect T cells but not macrophages, and these viral strains persist in immune tissue even in late disease. Here we show that the binding site for CD4 present on HIV's envelope protein is occluded on viruses replicating in immune tissue. This occlusion likely prevents antibody binding to this site and neutralization of the virus, but it makes it difficult for virus-CD4 interactions to occur. Such viruses probably pass from T cell to T cell via cell contacts where CD4 is highly concentrated and allows infection via inefficient envelope-CD4 binding. Our data are highly relevant for vaccines that aim to induce antibodies targeting the CD4 binding site on the envelope protein.

No detection of CD4-independent human immunodeficiency virus 1 envelope glycoproteins in brain tissue of patients with or without neurological complications.

Macrophage (mac)-tropic human immnunodeficiency virus type 1 (HIV-1) and simian immnunodeficiency virus (SIV) in brain are associated with neurological disease. Mac-tropic HIV-1 evolves enhanced CD4 interactions that enable macrophage infection via CD4, which is in low abundance. In contrast, mac-tropic SIV is associated with CD4-independent infection via direct CCR5 binding. Recently, mac-tropic simian-human immunodeficiency virus (SHIV) from macaque brain was also reported to infect cells via CCR5 without CD4. Since SHIV envelope proteins (Envs) are derived from HIV-1, we tested more than 100 HIV-1 clade B Envs for infection of CD4-negative, CCR5+ Cf2Th/CCR5 cells. However, no infection was detected. Our data suggest that there are differences in the evolution of mac-tropism in SIV and SHIV compared to HIV-1 clade B due to enhanced interactions with CCR5 and CD4, respectively.

Catamenial Pneumothorax, a Commonly Misdiagnosed Thoracic Condition: Multicentre Experience and Audit of a Small Case Series With Review of the Literature.

BACKGROUND: Catamenial pneumothorax (CP) is an unusual condition affecting premenopausal women and commonly misdiagnosed as simple pneumothorax. It is characterised by its recurrence between the day before and within 72 hours after the onset of menstruation. It has been associated with thoracic endometriosis but the aetiology is not well understood and there is no unified agreement for its optimal management. The aim of this study is to determine the incidence of CP in surgical patients and the results of their treatment. METHODS: Females between the ages of 30 to 50 years with a diagnosis of pneumothorax, admitted for surgery over a 10-year period in four different hospitals were retrospectively reviewed for evidence of CP. An audit of surgical and medical management of the patients with CP and their short to midterm outcomes was performed in addition to a systemic review of the literature on CP. RESULT: A total of 120 premenopausal female patients with a diagnosis of pneumothorax were admitted for Video Assisted Thoracoscopic (VAT) surgery and five women (4.1%) with a mean age of 42.6 years were diagnosed to have CP through surgical and histological findings. The first case was diagnosed 5 years ago and the last three within recent 12 months after the changes in surgical practices of inspecting diaphragmatic surface in suspected cases of CP. Four patients underwent diaphragmatic plication and one patient had a pleural biopsy. All patients underwent talc pleurodesis and hormone therapy in the postoperative period. Short to midterm (mean follow-up period of 25.2 months) results of the patients with CP were encouraging. CONCLUSIONS: It is possible that many of the cohort of premenopausal female patients presenting with recurrent pneumothorax are misdiagnosed as spontaneous pneumothorax (SP) because routine inspection of the diaphragmatic surface is not often performed. A thorough menstrual history and its temporal relation to pneumothorax onset should be assessed on every woman presenting with recurrent pneumothorax and intraoperative exploration of diaphragmatic surface should be performed in the patients with high suspicion of CP as the patients diagnosed with CP have a good outcome with surgery and hormone therapy.

Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications.

Untreated HIV-positive (HIV-1+) individuals frequently suffer from HIV-associated neurocognitive disorders (HAND), with about 30% of AIDS patients suffering severe HIV-associated dementias (HADs). Antiretroviral therapy has greatly reduced the incidence of HAND and HAD. However, there is a continuing problem of milder neurocognitive impairments in treated HIV+ patients that may be increasing with long-term therapy. In the present study, we investigated whether envelope (env) genes could be amplified from proviral DNA or RNA derived from brain tissue of 12 individuals with normal neurology or minor neurological conditions (N/MC individuals). The tropism and characteristics of the brain-derived Envs were then investigated and compared to those of Envs derived from immune tissue. We showed that (i) macrophage-tropic R5 Envs could be detected in the brain tissue of 4/12 N/MC individuals, (ii) macrophage-tropic Envs in brain tissue formed compartmentalized clusters distinct from non-macrophage-tropic (non-mac-tropic) Envs recovered from the spleen or brain, (iii) the evidence was consistent with active viral expression by macrophage-tropic variants in the brain tissue of some individuals, and (iv) Envs from immune tissue of the N/MC individuals were nearly all tightly non-mac-tropic, contrasting with previous data for neuro-AIDS patients where immune tissue Envs mediated a range of macrophage infectivities, from background levels to modest infection, with a small number of Envs from some patients mediating high macrophage infection levels. In summary, the data presented here show that compartmentalized and active macrophage-tropic HIV-1 variants are present in the brain tissue of individuals before neurological disease becomes overt or serious.IMPORTANCE The detection of highly compartmentalized macrophage-tropic R5 Envs in the brain tissue of HIV patients without serious neurological disease is consistent with their emergence from a viral population already established there, perhaps from early disease. The detection of active macrophage-tropic virus expression, and probably replication, indicates that antiretroviral drugs with optimal penetration through the blood-brain barrier should be considered even for patients without neurological disease (neuro-disease). Finally, our data are consistent with the brain forming a sanctuary site for latent virus and low-level viral replication in the absence of neuro-disease.

Surveillance of cancer risks for firefighters, police, and armed forces among men in a Canadian census cohort.

BACKGROUND: Firefighters, police, and armed services may be exposed to hazards such as combustion by-products and shift work. METHODS: The CanCHEC cohort linked 1991 census data to the Canadian cancer registry for follow up. Cox proportional hazards modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate risks for firefighter, police, or armed forces compared to workers in other occupations. RESULTS: The cohort of 1 108 410 men included 4535 firefighters, 10 055 police, and 9165 armed forces. For firefighters, elevated risks were noted for Hodgkin's lymphoma (HR: 2.89, 95%CI: 1.29-6.46), melanoma (HR: 1.67, 95%CI: 1.17-2.37), and prostate cancer (HR: 1.18, 95%CI: 1.01-1.37). Police had elevated risks for melanoma (HR:1.69, 95%CI: 1.32-2.16) and prostate cancer (HR:1.28, 95%CI: 1.14-1.42). No significant associations were found for armed forces workers. CONCLUSIONS: Canadian firefighters, police, and armed services, may be at an increased risk of developing certain cancers. Results suggested that a healthy worker effect may influence risk estimates.

Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).

BACKGROUND: Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. We present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. METHODS: Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. Self-reported occupations were coded using the Standard Occupational Classification (1991) system. Analyses were restricted to employed persons aged 25-74 years at baseline (N = 2,051,315), with follow-up until December 31, 2010. Hazard ratios (HR) and 95% confidence intervals (CI) were modeled using Cox proportional hazards for all workers in agricultural occupations (n = 70,570; 70.8% male), stratified by sex, and adjusted for age at cohort entry, province of residence, and highest level of education. RESULTS: A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. CONCLUSIONS: Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.

A national study of the association between traffic-related air pollution and adverse pregnancy outcomes in Canada, 1999-2008.

Numerous studies have examined the association of air pollution with preterm birth and birth weight outcomes. Traffic-related air pollution has also increasingly been identified as an important contributor to adverse health effects of air pollution. We employed a national nitrogen dioxide (NO2) exposure model to examine the association between NO2 and pregnancy outcomes in Canada between 1999 and 2008. National models for NO2 (and particulate matter of median aerodynamic diameter <2.5µm (PM2.5) as a covariate) were developed using ground-based monitoring data, estimates from remote-sensing, land use variables and, for NO2, deterministic gradients relative to road traffic sources. Generalized estimating equations were used to examine associations with preterm birth, term low birth weight (LBW), small for gestational age (SGA) and term birth weight, adjusting for covariates including infant sex, gestational age, maternal age and marital status, parity, urban/rural place of residence, maternal place of birth, season, year of birth and neighbourhood socioeconomic status and per cent visible minority. Associations were reduced considerably after adjustment for individual covariates and neighbourhood per cent visible minority, but remained significant for SGA (odds ratio 1.04, 95%CI 1.02-1.06 per 20ppb NO2) and term birth weight (16.2g reduction, 95% CI 13.6-18.8g per 20ppb NO2). Associations with NO2 were of greater magnitude in a sensitivity analysis using monthly monitoring data, and among births to mothers born in Canada, and in neighbourhoods with higher incomes and a lower proportion of visible minorities. In two pollutant models, associations with NO2 were less sensitive to adjustment for PM2.5 than vice versa, and there was consistent evidence of a dose-response relationship for NO2 but not PM2.5. In this study of approximately 2.5 million Canadian births between 1999 and 2008, we found significant associations of NO2 with SGA and term birth weight which remained significant after adjustment for PM2.5, suggesting that traffic may be a particularly important source with respect to the role of air pollution as a risk factor for adverse pregnancy outcomes.

The influence of community well-being on mortality among Registered First Nations people.

BACKGROUND: Living in a community with lower socioeconomic status is associated with higher mortality. However, few studies have examined associations between community socioeconomic characteristics and mortality among the First Nations population. DATA AND METHODS: The 1991-to-2006 Census Mortality and Cancer Cohort follow-up, which tracked a 15% sample of Canadians aged 25 or older, included 57,300 respondents who self-identified as Registered First Nations people or Indian band members. The Community Well-Being Index (CWB), a measure of the social and economic well-being of communities, consists of income, education, labour force participation, and housing components. A dichotomous variable was used to indicate residence in a community with a CWB score above or below the average for First Nations communities. Age-standardized mortality rates (ASMRs) were calculated for First Nations cohort members in communities with CWB scores above and below the First Nations average. Cox proportional hazards models examined the impact of CWB when controlling for individual characteristics. RESULTS: The ASMR for First Nations cohort members in communities with a below-average CWB was 1,057 per 100,000 person-years at risk, compared with 912 for those in communities with an above-average CWB score. For men, living in a community with below-average income and labour force participation CWB scores was associated with an increased hazard of death, even when individual socioeconomic characteristics were taken into account. Women in communities with below-average income scores had an increased hazard of death. INTERPRETATION: First Nations people in communities with below-average CWB scores tended to have higher mortality rates. For some components of the CWB, effects remained even when individual socioeconomic characteristics were taken into account.

HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages.

BACKGROUND: Non-mac-tropic HIV-1 R5 viruses are predominantly transmitted and persist in immune tissue even in AIDS patients who carry highly mac-tropic variants in the brain. Non-mac-tropic R5 envelopes (Envs) require high CD4 levels for infection contrasting with highly mac-tropic Envs, which interact more efficiently with CD4 and mediate infection of macrophages that express low CD4. Non-mac-tropic R5 Envs predominantly target T-cells during transmission and in immune tissue where they must outcompete mac-tropic variants. Here, we investigated whether Env+ pseudoviruses bearing transmitted/founder (T/F), early and late disease non-mac-tropic R5 envelopes mediated more efficient infection of CD4+ T-cells compared to those with highly mac-tropic Envs. RESULTS: Highly mac-tropic Envs mediated highest infectivity for primary T-cells, Jurkat/CCR5 cells, myeloid dendritic cells, macrophages, and HeLa TZM-bl cells, although this was most dramatic on macrophages. Infection of primary T-cells mediated by all Envs was low. However, infection of T-cells was greatly enhanced by increasing virus attachment with DEAE dextran and spinoculation, which enhanced the three Env+ virus groups to similar extents. Dendritic cell capture of viruses and trans-infection also greatly enhanced infection of primary T-cells. In trans-infection assays, non-mac-tropic R5 Envs were preferentially enhanced and those from late disease mediated levels of T-cell infection that were equivalent to those mediated by mac-tropic Envs. CONCLUSIONS: Our results demonstrate that T/F, early or late disease non-mac-tropic R5 Envs do not preferentially mediate infection of primary CD4+ T-cells compared to highly mac-tropic Envs from brain tissue. We conclude that non-macrophage-tropism of HIV-1 R5 Envs in vitro is determined predominantly by a reduced capacity to target myeloid cells via low CD4 rather than a specific adaptation for T-cells entry that precludes macrophage infection.

Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes.

BACKGROUND: HIV-1 variants carrying non-macrophage-tropic HIV-1 R5 envelopes (Envs) are predominantly transmitted and persist in immune tissue even in AIDS patients who have highly macrophage-tropic variants in the brain. Non-macrophage-tropic R5 Envs require high levels of CD4 for infection contrasting with macrophage-tropic Envs, which can efficiently mediate infection of cells via low CD4. Here, we investigated whether non-macrophage-tropic R5 Envs from the acute stage of infection (including transmitted/founder Env) mediated more efficient infection of ectocervical explant cultures compared to non-macrophage-tropic and highly macrophage-tropic R5 Envs from late disease. RESULTS: We used Env+ pseudovirions that carried a GFP reporter gene to measure infection of the first cells targeted in ectocervical explant cultures. In straight titrations of Env+ pseudovirus supernatants, mac-tropic R5 Envs from late disease mediated slightly higher infectivities for ectocervical explants although this was not significant. Surprisingly, explant infection by several T/F/acute Envs was lower than for Envs from late disease. However, when infectivity for explants was corrected to account for differences in the overall infectivity of each Env+ pseudovirus (measured on highly permissive HeLa TZM-bl cells), non-mac-tropic early and late disease Env+ pseudoviruses mediated significantly higher infection. This observation suggests that cervical tissue preferentially supports non-mac-tropic Env+ viruses compared to mac-tropic viruses. Finally, we show that T-cells were the main targets for infection regardless of whether explants were stimulated with T-cell or monocyte/macrophage cytokines. There was no evidence of macrophage infection even for pseudovirions carrying highly mac-tropic Envs from brain tissue or for the highly mac-tropic, laboratory strain, BaL, which targeted T-cells in the explant tissue. CONCLUSIONS: Our data support ectocervical tissue as a favorable environment for non-mac-tropic HIV-1 R5 variants and emphasize the role of T-cells as initial targets for infection even for highly mac-tropic variants.

Social determinants of lung cancer incidence in Canada: A 13-year prospective study.

BACKGROUND: The risk of lung cancer has been shown to be inversely related to socioeconomic status (SES). Because the Canadian Cancer Registry does not contain socioeconomic data, the 1991 Canadian Census Cohort was used to study social determinants of lung cancer risk in the general Canadian population. DATA AND METHODS: This study examines incidence rates of lung cancer and histologic subtypes by educational attainment, income and occupation in a broadly representative sample of Canadians aged 25 or older. Data for the 1991 Canadian Census Cohort were analyzed. The cohort comprised 2,734,835 individuals, among whom 215,700 new cancer cases were diagnosed from 1991 through 2003. Age-standardized incidence rates were calculated by age, sex, and SES using the direct method. Rate ratios, rate differences, and excess incidence were also calculated. RESULTS: An inverse risk between lung cancer incidence and educational attainment, income and occupation emerged among men and women, and a stepped negative gradient in RRs was evident for all SES variables and age groups. If all cohort members had experienced the rate of those with a university degree, lung cancer incidence would have been 56% lower in men and 55% lower in women. If all cohort members had experienced the incidence rate of those in the highest income quintile, incidence would have been 33% lower in men and 25% lower in women. If all cohort members had experienced the rate of those in managerial occupations, incidence would have been 54% lower in men and 44% lower in women. INTERPRETATION: A negative gradient in lung cancer risk was evident for all SES variables studied.

Maternal and community predictors of gastroschisis and congenital diaphragmatic hernia in Canada.

PURPOSE: The incidence of gastroschisis (GS) has increased globally. Maternal age and smoking are risk factors and aboriginal communities may be more commonly affected. Factors leading to this increased incidence are otherwise unclear. We investigate maternal sociodemography, air pollution and personal risk factors comparing mothers of infants with GS with a control group of infants with diaphragmatic hernia (CDH) in a large population-based analysis. METHODS: Data were collected from a national, disease-specific pediatric surgical database (May 2006-June 2013). Maternal community sociodemographic information was derived from the Canadian 2006 Census. Univariate and multivariable analyses were performed examining maternal factors related to diagnosis of GS. RESULTS: GS infants come from poorer, less educated communities with more unemployment, less pollution, fewer immigrants, and more aboriginal peoples than infants with CDH. Teen maternal age, smoking, and illicit drug use, are associated with GS. CONCLUSION: Mothers of infants with GS are younger, more likely to smoke and come from socially disadvantaged communities with higher proportions of aboriginal peoples but lower levels of air pollution compared to mothers of CDH infants. Identification of maternal risks provides direction for prenatal screening and public health interventions.

Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism.

HIV-1 R5 viruses vary extensively in their capacity to infect macrophages. R5 viruses that confer efficient infection of macrophages are able to exploit low levels of CD4 for infection and predominate in brain tissue, where macrophages are a major target for infection. HIV-1 R5 founder viruses that are transmitted were reported to be non-macrophage-tropic. Here, we investigated the sensitivities of macrophage-tropic and non-macrophage-tropic R5 envelopes to neutralizing antibodies. We observed striking differences in the sensitivities of Env(+) pseudovirions to soluble CD4 (sCD4) and to neutralizing monoclonal antibodies (MAbs) that target the CD4 binding site. Macrophage-tropic R5 Envs were sensitive to sCD4, while non-macrophage-tropic Envs were significantly more resistant. In contrast, all Envs were sensitive to VRC01 regardless of tropism, while MAb b12 conferred an intermediate neutralization pattern where all the macrophage-tropic and about half of the non-macrophage-tropic Envs were sensitive. CD4, b12, and VRC01 share binding specificities on the outer domain of gp120. However, these antibodies differ in their ability to induce conformational changes on the trimeric envelope and in specificity for residues on the V1V2 loop stem and ß20-21 junction that are targets for CD4 in recruiting the bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity to inhibition by these reagents and provide an insight into the envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism.

Indirect adjustment for multiple missing variables applicable to environmental epidemiology.

OBJECTIVES: Develop statistical methods for survival models to indirectly adjust hazard ratios of environmental exposures for missing risk factors. METHODS: A partitioned regression approach for linear models is applied to time to event survival analyses of cohort study data. Information on the correlation between observed and missing risk factors is obtained from ancillary data sources such as national health surveys. The relationship between the missing risk factors and survival is obtained from previously published studies. We first evaluated the methodology using simulations, by considering the Weibull survival distribution for a proportional hazards regression model with varied baseline functions, correlations between an adjusted variable and an adjustment variable as well as selected censoring rates. Then we illustrate the method in a large, representative Canadian cohort of the association between concentrations of ambient fine particulate matter and mortality from ischemic heart disease. RESULTS: Indirect adjustment for cigarette smoking habits and obesity increased the fine particulate matter-ischemic heart disease association by 3%-123%, depending on the number of variables considered in the adjustment model due to the negative correlation between these two risk factors and ambient air pollution concentrations in Canada. The simulations suggested that the method yielded small relative bias (<40%) for most cohort designs encountered in environmental epidemiology. CONCLUSIONS: This method can accommodate adjustment for multiple missing risk factors simultaneously while accounting for the associations between observed and missing risk factors and between missing risk factors and health endpoints.