Identifying the severity of diabetic retinopathy by visual function measures using both traditional statistical methods and interpretable machine learning: a cross-sectional study.

AIMS/HYPOTHESIS: To determine the extent to which diabetic retinopathy severity stage may be classified using machine learning (ML) and commonly used clinical measures of visual function together with age and sex. METHODS: We measured the visual function of 1901 eyes from 1032 participants in the Northern Ireland Sensory Ageing Study, deriving 12 variables from nine visual function tests. Missing values were imputed using chained equations. Participants were divided into four groups using clinical measures and grading of ophthalmic images: no diabetes mellitus (no DM), diabetes but no diabetic retinopathy (DM no DR), diabetic retinopathy without diabetic macular oedema (DR no DMO) and diabetic retinopathy with DMO (DR with DMO). Ensemble ML models were fitted to classify group membership for three tasks, distinguishing (A) the DM no DR group from the no DM group; (B) the DR no DMO group from the DM no DR group; and (C) the DR with DMO group from the DR no DMO group. More conventional multiple logistic regression models were also fitted for comparison. An interpretable ML technique was used to rank the contribution of visual function variables to predictions and to disentangle associations between diabetic eye disease and visual function from artefacts of the data collection process. RESULTS: The performance of the ensemble ML models was good across all three classification tasks, with accuracies of 0.92, 1.00 and 0.84, respectively, for tasks A-C, substantially exceeding the accuracies for logistic regression (0.84, 0.61 and 0.80, respectively). Reading index was highly ranked for tasks A and B, whereas near visual acuity and Moorfields chart acuity were important for task C. Microperimetry variables ranked highly for all three tasks, but this was partly due to a data artefact (a large proportion of missing values). CONCLUSIONS/INTERPRETATION: Ensemble ML models predicted status of diabetic eye disease with high accuracy using just age, sex and measures of visual function. Interpretable ML methods enabled us to identify profiles of visual function associated with different stages of diabetic eye disease, and to disentangle associations from artefacts of the data collection process. Together, these two techniques have great potential for developing prediction models using untidy real-world clinical data.

Assessment of the Classification of Age-Related Macular Degeneration Severity from the Northern Ireland Sensory Ageing Study Using a Measure of Dark Adaptation.

Purpose: To assess the differences in rod-mediated dark adaptation (RMDA) between different grades of age-related macular degeneration (AMD) severity using an OCT-based criterion compared with those of AMD severity using the Beckman color fundus photography (CFP)-based classification and to assess the association between the presence of subretinal drusenoid deposits (SDDs) and RMDA at different grades of AMD severity using an OCT-based classification. Design: Cross-sectional study. Participants: Participants from the Northern Ireland Sensory Ageing study (Queen's University Belfast). Methods: Complete RMDA (rod-intercept time [RIT]) data, CFP, and spectral-domain OCT images were extracted. Participants were stratified into 4 Beckman groups (omitting late-stage AMD) and 3 OCT-based groups. The presence and stage of SDDs were identified using OCT. Main Outcome Measures: Rod-intercept time data (age-corrected). Results: Data from 459 participants (median [interquartile range] age, 65 [59-71] years) were stratified by both the classifications. Subretinal drusenoid deposits were detected in 109 eyes. The median (interquartile range) RMDA for the Beckman classification (Beckman 0-3, with 3 being intermediate age-related macular degeneration [iAMD]) groups was 6.0 (4.5-8.7), 6.6 (4.7-10.5), 5.7 (4.4-7.4), and 13.2 (6-21.1) minutes, respectively. OCT classifications OCT0-OCT2 yielded different median (interquartile range) values: 5.8 (4.5-8.5), 8.4 (5.2-13.3), and 11.1 (5.3-20.1) minutes, respectively. After correcting for age, eyes in Beckman 3 (iAMD) had statistically significantly worse RMDA than eyes in the other Beckman groups (P ≤ 0.005 for all), with no statistically significant differences between the other Beckman groups. Similarly, after age correction, eyes in OCT2 had worse RMDA than eyes in OCT0 (P ≤ 0.001) and OCT1 (P < 0.01); however, there was no statistically significant difference between eyes in OCT0 and eyes in OCT1 (P = 0.195). The presence of SDDs was associated with worse RMDA in OCT2 (P < 0.01) but not in OCT1 (P = 0.285). Conclusions: Eyes with a structural definition of iAMD have delayed RMDA, regardless of whether a CFP- or OCT-based criterion is used. In this study, after correcting for age, the RMDA did not differ between groups of eyes defined to have early AMD or normal aging, regardless of the classification. The presence of SDDs has some effect on RMDA at different grades of AMD severity.

Perspectives on expertise in teaching about transgender healthcare: A focus group study with health professional programme teaching staff and transgender community members.

Background: It is well established that transgender people experience considerable health inequities, which are sustained in part by limited teaching about transgender healthcare for trainee health professionals. Aims: The aim of this study was to explore the perspectives of both teaching staff from health professional education programmes and transgender community members on the best ways to teach about transgender healthcare, with a focus on ways of: 1) overcoming barriers to this teaching; and 2) involving community members in this teaching. Methods: A research advisory committee was convened to guide the project and included transgender community members, teaching staff from health professional programmes, and trainee health professionals in Aotearoa/New Zealand. Three preliminary focus groups were held with 10 transgender community members. These community members were then invited to act as transgender community 'ambassadors' in focus groups with teaching staff based on suggestions from the advisory committee. Six focus groups were conducted with 22 teaching staff from a range of health professional education programmes along with at least two transgender community ambassadors. Results: Teaching staff positioned themselves as lacking the expertise to teach about transgender healthcare but also as expert teachers when applying methods such as small group teaching. Transgender participants also positioned themselves as having expertise arising primarily from their own experiences and acknowledged that effective teaching about transgender healthcare would need to cover a diversity of transgender identities and healthcare outside their own experiences. Teaching staff and transgender community members were keen to pool expertise and thus overcome the shared sense of lacking the expertise to teach about transgender healthcare. Discussion: These findings provide insights into the current barriers to teaching about transgender healthcare and provide future directions for staff development on teaching about transgender healthcare and ways of safely involving transgender community members in teaching.

Factors associated with various strategies for maintaining sexual activity after prostate cancer treatment.

Many men experience sexual difficulties after receiving prostate cancer treatment. We investigated sexual and relationship factors associated with management strategies to maintain sexual activity in prostate cancer patients. 210 prostate cancer patients (66.7 ± 7.4 years old) completed our survey online. Higher sexual function distress (Incidence rate ratio, IRR = 0.99, p = 0.005) and less frequent relationship strain (IRR = 1.01, p = 0.002) were associated with trying a higher number of sexual management strategies. Higher sexual function distress was associated with the use of oral medication (Odds Ratio, OR = 0.98, p = 0.026), vacuum erection device (OR = 0.98, p = 0.005), and vibrators (OR = 0.97, p = 0.005). Perceived importance of sexual interaction with a partner was associated with using oral medication (OR = 1.95, p = 0.027). Participant's higher ideal frequency of sexual interaction with a partner was a predictor for the use of vibrators (OR = 1.03, p = 0.024). Less frequent relationship strain was associated with the use of vacuum erection device (OR = 1.03, p = 0.002), and vibrators (OR = 1.02, p = 0.012). Lastly, patients' communication with their partner about sexual intimacy was also associated with use of vacuum erection device (OR = 3.24, p = 0.050, CI 1.0-10.5). Few participants (13-27%) were interested in trying penile implant, penile support device, external penile prosthesis, penile sleeve and anal devices. From our qualitative analyses, the main barriers to retaining sexual activity were erectile dysfunction and psychological issues. Three themes participants found useful to maintain sexual activity: preparatory behaviours for initiating or maintaining erections, adapting their sexual activity to fit with what was now possible, and the importance of the relationship or intimacy with their sexual partner. Psychological and relationship factors contribute to patients' motivation to remain sexually active after treatment.

"It's Not a Great Boulder, It's Just a Piece of Baggage": Older Women's Reflections on Healing from Childhood Sexual Abuse.

In this study, we explored older women's reflections on processes of healing related to childhood sexual abuse (CSA). We aimed to answer questions about how childhood trauma was integrated into the life story and to identify factors or coping strategies that aided, or hindered, healing. Participants within this study included 12 women who were aged 60 or older and had reported CSA as adults at the beginning of the research project, 25 years prior. Qualitative interviews were conducted exploring women's reflections on the place of CSA in their lives over time and factors the participants thought were helpful or unhelpful in being able to come to terms with the abuse. Data were analyzed using thematic analysis, which resulted in three themes related to processes of healing. The themes identified were need for resolution, thinking about it differently, and developing agency over disclosure. The findings show that some form of resolution was needed for the women to recover and move on from their experiences of CSA. The two key strategies used to reach this resolution were reframing their experience or drawing upon positive life philosophies. Decisions around disclosure were also an important part of the healing process, with the women developing an agency over if, and how, they talked to people about their experience. Those women who were not able to make sense of their experience continued to be influenced by the negative feelings and memories associated with the experience. Our findings have implications for health professionals working with those who have experienced trauma. They demonstrate that there are a number of ways that people heal from trauma and find personal resolution across their lifespan.

Evidence for Structural and Functional Damage of the Inner Retina in Diabetes With No Diabetic Retinopathy.

Purpose: To provide structural and functional evidence of inner retinal loss in diabetes prior to vascular changes and interpret the structure-function relationship in the context of an established neural model. Methods: Data from one eye of 505 participants (134 with diabetes and no clinically evident vascular alterations of the retina) were included in this analysis. The data were collected as part of a large population-based study. Functional tests included best-corrected visual acuity, Pelli-Robson contrast sensitivity, mesopic microperimetry, and frequency doubling technology perimetry (FDT). Macular optical coherence tomography volume scans were collected for all participants. To interpret the structure-function relationship in the context of a neural model, ganglion cell layer (GCL) thickness was converted to local ganglion cell (GC) counts. Results: The GCL and inner plexiform layer were significantly thinner in participants with diabetes (P < 0.05), with no significant differences in the macular retinal nerve fiber layer or the outer retina. All functional tests except microperimetry showed a significant loss in diabetic patients (P < 0.05). Both FDT and microperimetry showed a significant relationship with the GC count (P < 0.05), consistent with predictions from a neural model for partial summation conditions. However, the FDT captured additional significant damage (P = 0.03) unexplained by the structural loss. Conclusions: Functional and structural measurements support early neuronal loss in diabetes. The structure-function relationship follows the predictions from an established neural model. Functional tests could be improved to operate in total summation conditions in the macula, becoming more sensitive to early loss.

Sexual assault experiences of university students and disclosure to health professionals and others.

AIMS: The aim of this study was to investigate the number and correlates of sexual assault among students at a campus-based university in Aotearoa New Zealand and to determine how often students disclose such experiences to health professionals, other services and family/friends. METHODS: An online survey based on the Administrator-Researcher Campus Climate Consortium tool was emailed to all students at the main campus of a large university in Aotearoa/New Zealand. It was completed by 1,540 students (8.1% of those emailed) of any gender in July-August 2019. RESULTS: During their time at university to-date, 28% of the sample had experienced at least one form of sexual assault with 14.9% reporting experiences that meet a definition of rape. Sixty-six percent of victims in the sample and 53% of the reported perpetrators had been using alcohol at the time of the assault. Only 8% of those reporting sexual assault in the sample disclosed the assault to a health professional. CONCLUSIONS: Considering the low number of university students disclosing sexual assaults to health professionals or support services, the results of this survey suggest more work is needed to facilitate greater disclosures to health professionals enabling victims to access the services they need regardless of alcohol use.

Assessment of the Vitreomacular Interface Using High-Resolution OCT in a Population-Based Cohort Study of Older Adults.

PURPOSE: To describe the prevalence of vitreomacular interface (VMI) features and their associated risk factors in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) Study. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Noninstitutionalized Northern Irish adults 40 years of age or older. METHODS: Using geographic stratification, a representative sample of people in Northern Ireland was invited to participate in the NICOLA Study. SD OCT images of participants were graded for vitreomacular traction (VMT), macular hole (MH), and epiretinal membrane (ERM) according to the International Vitreomacular Traction Study Group. A subsample was graded in more detail to estimate the prevalence of VMA and VMA area detailing size and location of VMA. Descriptive analysis and risk factors for each VMI feature were determined using generalized estimating equations. Results were standardized to the Northern Ireland population census (2011). MAIN OUTCOME MEASURES: Cohort profile, standardized prevalence, and risk factor associations of each VMI feature. RESULTS: Three thousand three hundred fifty-one NICOLA participants had gradable SD OCT images available for at least 1 eye. The prevalence of VMT was 0.5% (CI, 0.31%-0.70%), that for MH was 0.3% (CI, 0.23%-0.52%), and that for ERM was 7.6% (CI, 7.0%-8.3%). A detailed VMA analysis was performed on a subsample consisting of the first 1481 participants. The prevalence of VMA was 22.6% (CI, 21.1-24.2), and VMA area ranged from 0.25 to 42.7 mm2 (mean, 12.53 mm2; standard deviation, 6.90 mm2). In multivariate analyses, increased age was associated with an increased odds ratio (OR) of VMT, MH, and ERM. VMA area was positively associated with younger age and normal blood pressure. ERM and MH were present more often in more myopic eyes, associated with an increase in levels of high-density lipoprotein (HDL) cholesterol and triglycerides. CONCLUSIONS: The epidemiologic characteristics of VMI features indicated that VMI interactions throughout life are age dependent. Vitreous separation reduced to a greater extent in the horizontal meridians compared with the vertical, differing from previous studies. Future longitudinal studies of the evolution of these VMI changes over time would be of great interest.

Optimising daily diary questionnaires about fatigue, psychological flexibility and well-being: perspectives of people with rheumatic disease.

OBJECTIVES: The aim of this study was to understand the perspectives of people with rheumatic disease have about completing a pilot daily diary questionnaire on fatigue and well-being, with the objective of incorporating these perspectives into future daily studies. METHODS: Twenty-two participants with experience of rheumatic disease-related fatigue attended a focus group and/or an individual interview. Before the focus group or interview, participants completed a one-off quantitative diary about their fatigue and well-being that day. In the focus groups and interviews, participants were asked about their experience completing the questionnaire. Data were analysed using inductive thematic analysis. RESULTS: Three themes were identified. 'Concerns about Misinterpretation and Ambiguity' addressed the elements of the diary questionnaire that were confusing or unclear to participants. 'Desire to Provide Useful and Accurate Information' outlined participants' uncertainty about how to report complex daily experiences. 'Gaining Personal Insight through Diaries' revealed the personal benefits participants gained, particularly the development of insight into their fatigue. CONCLUSIONS: People with rheumatic disease are willing to complete a daily diary questionnaire, but emphasise it is important for diary questionnaires to have clear instructions, questionnaire items and response scales. Addressing these concerns will ensure the reliability and validity of quantitative diary data.

Intraocular pressure (IOP) measurements in keratoconic patients: Do variations in IOP respect variations in corneal thickness and corneal curvature?

PURPOSE: To explore the relationship between intraocular pressure (IOP) measurements and topographical variations in corneal curvature and corneal thickness in a cohort of keratoconic patients presenting to a newly-established regional Keratoconic diagnostic and monitoring clinic in Northern Ireland. METHODS: IOP was recorded, using a hand held ICARE tonometer, at central, nasal and temporal locations on keratoconic corneae of 27 consecutive patients attending clinic. Pachymetry and sagittal keratometry were recorded in matched locations using the Pentacam Topographer. Eyes with history of corneal surgery or anterior surface pathology were excluded. RESULTS: The median (interquartile range) central keratometry, pachymetry (CCT) and IOP measurements for 49 eyes were 44.1D (42.2D-48.1D); 495 µm (460 µm-526 µm); 10 mmHg (8 mmHg-13 mmHg) respectively. Temporal and nasal keratometry, pachymetry, and IOP values, recorded on midline, were temporal 41.9D (40.7D-42.8D); 621 µm (579 µm-650 µm); 14 mmHg (11 mmHg-16 mmHg); nasal 40.8D (39.5D-42.5D); 641 µm (599 µm-698 µm); 13 mmHg (12 mmHg-17 mmHg). A moderate correlation was shown between reduction in CCT and increase in mean central keratometry (Spearman's Coefficient (ρ) -0.72 P = 0.00). A moderate correlation was found between reduction in CCT and reduction in IOP, as recorded centrally (ρ = 0.37 P = 0.01). Mid-peripheral values demonstrated similar trends in the relationship between keratometry and IOP (nasal ρ = -0.47 P = 0.00; temporal ρ = -0.38 P = 0.00) and pachymetry and IOP (nasal ρ = 0.29 P = 0.05; temporal ρ = 0.33 p = 0.02). CONCLUSION: In this pilot study, a positive correlation exists between pachymetry, keratometry and IOP. Topographically variations in intraocular pressure mimic changes in keratometry and pachymetry.

IDENTIFYING FEATURES OF EARLY AND LATE AGE-RELATED MACULAR DEGENERATION: A Comparison of Multicolor Versus Traditional Color Fundus Photography.

PURPOSE: To compare multicolor (MC) and traditional color fundus photography (CFP) in their ability to detect features of early and late age-related macular degeneration (AMD). METHODS: Study design: Observational case series. PARTICIPANTS: fundus images captured using standard CFP and MC imaging from 33 patients attending hospital clinics and 26 participants from the pilot phase of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). Systematic grading of early and late AMD features; (hard drusen, soft drusen, reticular pseudodrusen, pigment clumping, non-geographic atrophy hypopigmentation, atrophy, hemorrhage, and fibrosis) on CFP and MC. RESULTS: There were 105 eyes with gradable images for comparison. Using CFP as the gold standard, sensitivity values for MC ranged from 100% for atrophy, non-geographic atrophy hypopigmentation, and fibrosis to 69.7% for pigment clumping. Specificity values were high: >80% for all features. On using MC as the comparator, CFP had lower sensitivity for the detection of early AMD features (27.8% for reticular drusen to 77.8% for non-geographic atrophy hypopigmention). Analysis of OCT in discrepant cases showed better agreement with MC for all AMD lesions, except hemorrhage and non-geographic atrophy hypopigmentation. For pigment clumping, CFP and MC were in equal agreement with OCT. CONCLUSION: Multicolor retinal imaging allowed for improved detection and definition of AMD features.

Can ultra-wide field retinal imaging replace colour digital stereoscopy for glaucoma detection?

PURPOSE: Ultra-wide field (UWF) retinal imaging (Optomap, Optos plc, Dunfermline, UK) is a novel technique to image the peripheral fundus. The goal of this study was to explore the potential use of UWF imaging to detect glaucoma, and specifically to evaluate the reproducibility of measures of vertical cup-to-disc ratio (VCDR) using ultra-wide field (UWF), and the agreement between UWF and standard colour digital stereoscopy (CDS). METHODS: An observational study. From a population-based epidemiological study we selected 100 eyes from 100 consecutive participants who were imaged using both standard CDS and UWF retinal imaging. Estimation of the VCDR using both modalities was made by a masked glaucoma specialist and two masked independent observers. Reliability and agreement between colour digital stereoscopy and the UWF imaging was assessed by Bland-Altman scatterplots. RESULTS: Intra-observer reproducibility of the UWF imaging in estimating VCDRs produced Limits of Agreement (LOA) ranging from -0.13 to 0.1 (mean 0.02) and -0.14 to 0.14 (mean 0.0004) for observer 1 and 2 respectively. Inter-observer reliability between observer 1 and the glaucoma specialist for VCDR measurements using CDS and UWF produced LOA ranging from -0.37 to 0.15 (mean -0.11) and -0.24 to 0.26 (mean 0.0005) respectively. Bland Altman plots produced LOA of -0.16 to 0.20 (mean 0.02) between the two imaging methods for assessing VCDR when carried out by a glaucoma specialist. CONCLUSION: Grading of UWF imaging has high reproducibility in evaluating VCDR and agreement with stereoscopic optic disc imaging and may be suitable for glaucoma diagnosis in situations where CDS is not available.

The importance of health(ism): A focus group study of lesbian, gay, bisexual, pansexual, queer and transgender individuals' understandings of health.

This study investigated understandings of health among lesbian, gay, bisexual, pansexual, queer and/or transgender people, who are under-represented in research. The study involved 12 focus groups in Aotearoa/New Zealand with 47 participants who identified as lesbian, gay, bisexual, pansexual, queer and/or transgender and responded to an advert inviting participants without chronic illnesses. Three themes were inductively formulated: health is important because education and protection efforts are seen as required to preserve health, health is seen as holistic, and contextual factors are seen as creating health risks. These findings provide insights into how lesbian, gay, bisexual, pansexual, queer and/or transgender people's understandings of health draw upon notions of healthism.

Interaction of Interferon gamma-induced reactive oxygen species with ceftazidime leads to synergistic killing of intracellular Burkholderia pseudomallei.

Burkholderia pseudomallei, a facultative intracellular pathogen, causes severe infections and is inherently refractory to many antibiotics. Previous studies from our group have shown that interferon gamma (IFN-γ) interacts synergistically with the antibiotic ceftazidime to kill bacteria in infected macrophages. The present study aimed to identify the underlying mechanism of that interaction. We first showed that blocking reactive oxygen species (ROS) pathways reversed IFN-γ- and ceftazidime-mediated killing, which led to our hypothesis that IFN-γ-induced ROS interacted with ceftazidime to synergistically kill Burkholderia bacteria. Consistent with this hypothesis, we also observed that buthionine sulfoximine (BSO), another inducer of ROS, could substitute for IFN-γ to similarly potentiate the effect of ceftazidime on intracellular killing. Next, we observed that IFN-γ induced ROS-mediated killing of intracellular but not extracellular bacteria. On the other hand, ceftazidime effectively reduced extracellular bacteria but was not capable of intracellular killing when applied at 10 µg/ml. We investigated the exact role of IFN-γ-induced ROS responses on intracellular bacteria and notably observed a lack of actin polymerization associated with Burkholderia bacteria in IFN-γ-treated macrophages, which led to our finding that IFN-γ-induced ROS blocks vacuolar escape. Based on these results, we propose a model in which synergistically reduced bacterial burden is achieved primarily through separate and compartmentalized killing: intracellular killing by IFN-γ-induced ROS responses and extracellular killing by ceftazidime. Our findings suggest a means of enhancing antibiotic activity against Burkholderia bacteria through combination with drugs that induce ROS pathways or otherwise target intracellular spread and/or replication of bacteria.

Plastid stromules are induced by stress treatments acting through abscisic acid.

Stromules are highly dynamic stroma-filled tubules that extend from the surface of all plastid types in all multi-cellular plants examined to date. The stromule frequency (percentage of plastids with stromules) has generally been regarded as characteristic of the cell and tissue type. However, the present study shows that various stress treatments, including drought and salt stress, are able to induce stromule formation in the epidermal cells of tobacco hypocotyls and the root hairs of wheat seedlings. Application of abscisic acid (ABA) to tobacco and wheat seedlings induced stromule formation very effectively, and application of abamine, a specific inhibitor of ABA synthesis, prevented stromule induction by mannitol. Stromule induction by ABA was dependent on cytosolic protein synthesis, but not plastid protein synthesis. Stromules were more abundant in dark-grown seedlings than in light-grown seedlings, and the stromule frequency was increased by transfer of light-grown seedlings to the dark and decreased by illumination of dark-grown seedlings. Stromule formation was sensitive to red and far-red light, but not to blue light. Stromules were induced by treatment with ACC (1-aminocyclopropane-1-carboxylic acid), the first committed ethylene precursor, and by treatment with methyl jasmonate, but disappeared upon treatment of seedlings with salicylate. These observations indicate that abiotic, and most probably biotic, stresses are able to induce the formation of stromules in tobacco and wheat seedlings.

Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae.

BACKGROUND: The risk of mortality from pneumonia caused by Streptococcus pneumoniae is increased in patients with cirrhosis. However, the specific pneumococcal virulence factors and host immune defects responsible for this finding have not been clearly established. This study used a cirrhotic rat model of pneumococcal pneumonia to identify defect(s) in innate pulmonary defenses in the cirrhotic host and to determine the impact of the pneumococcal toxin pneumolysin on these defenses in the setting of severe cirrhosis. RESULTS: No cirrhosis-associated defects in mucociliary clearance of pneumococci were found in these studies, but early intrapulmonary killing of the organisms before the arrival of neutrophils was significantly impaired. This defect was exacerbated by pneumolysin production in cirrhotic but not in control rats. Neutrophil-mediated killing of a particularly virulent type 3 pneumococcal strain also was significantly diminished within the lungs of cirrhotic rats with ascites. Levels of lysozyme and complement component C3 were both significantly reduced in bronchoalveolar lavage fluid from cirrhotic rats. Finally, complement deposition was reduced on the surface of pneumococci recovered from the lungs of cirrhotic rats in comparison to organisms recovered from the lungs of control animals. CONCLUSION: Increased mortality from pneumococcal pneumonia in this cirrhotic host is related to defects in both early pre-neutrophil- and later neutrophil-mediated pulmonary killing of the organisms. The fact that pneumolysin production impaired pre-neutrophil-mediated pneumococcal killing in cirrhotic but not control rats suggests that pneumolysin may be particularly detrimental to this defense mechanism in the severely cirrhotic host. The decrease in neutrophil-mediated killing of pneumococci within the lungs of the cirrhotic host is related to insufficient deposition of host proteins such as complement C3 on their surfaces. Pneumolysin likely plays a role in complement consumption within the lungs. Our studies, however, were unable to determine whether pneumolysin more negatively impacted this defense mechanism in cirrhotic than in control rats. These findings contribute to our understanding of the defects in innate pulmonary defenses that lead to increased mortality from pneumococcal pneumonia in the severely cirrhotic host. They also suggest that pneumolysin may be a particularly potent pneumococcal virulence factor in the setting of cirrhosis.

Neighbourhood influences on health in Montréal, Canada.

This paper examines neighbourhood effects on health within a large Canadian city--Montréal. Our approach is to consider that individual health outcomes are determined both by individual and neighbourhood characteristics and we consciously take on the problem of neighbourhood definition by developing 'natural' neighbourhoods. Our data come from the Montréal health region sample of the 2000/1 Canadian Community Health Survey, a comprehensive national survey that contains information on health outcomes as well as behavioural and socio-demographic information. Respondents were placed into 'naturally' defined neighbourhoods as opposed to arbitrary geostatistical units, responding to calls in the literature to develop more meaningful units of analysis. We also compare the 'natural' neighbourhood approach with the use of standard census tracts as the unit of analysis. Results show significant between-neighbourhood variation in health status with about 3% of the variance in the Health Utilities Index captured at the neighbourhood level, even after controlling for a variety of socio-demographic and behavioural variables at the individual level. Models using census tracts as the unit of analysis had remarkably similar results to the 'natural' neighbourhood models, suggesting that census tracts are good proxies for natural neighbourhood boundaries in studies of neighbourhood effects on health.