Rural and urban patterns of severe injuries and hospital mortality in Australia: An analysis of the Australia New Zealand Trauma Registry: 2015-2019.

INTRODUCTION: In Australia, people living in rural areas, compared to major cities are at greater risk of poor health. There is much evidence of preventable disparities in trauma outcomes, however research quantifying geographic variations in injuries, pathways to specialised care and patient outcomes is scarce. AIMS: (i) To analyse the Australia New Zealand Trauma Registry (ATR) data and report patterns of serious injuries according to rurality of the injury location ii) to examine the relationship between rurality and hospital mortality and iii) to compare ATR death rates with all deaths from similar causes, Australia-wide. METHOD: A retrospective cohort study of patients in the ATR from 1st July 2015 to 30th June 2019 was conducted. Descriptive analyses of trauma variables according to rurality was performed. Logistic regression quantified the moderating effect of rurality on trauma variables and hospital mortality. Australian death data on similar injuries were sourced to quantify the additional mortality attributable to severe injury occurring outside Major Trauma Centres (MTCs). RESULTS: Compared to major cities, rural patients were younger, more likely to have spinal cord injuries, and sustain traffic-related injuries that are 'off road'. Injuries occurring outside people's homes are more likely. Mortality risk was greater for patients sustaining severe traumatic brain injury (TBI) spinal cord injury (SCI) and head trauma in addition to intentional injuries. Compared to the ATR data, Australian population-wide trauma mortality rates showed diverging trends according to rurality. The ATR only captures 14.1% of all injury deaths occurring in major cities and, respectively, 6.3% and 3.2% of deaths in regional and remote areas. CONCLUSION: Compared to major cities, injuries occurring in rural areas of Australia often involve different mechanisms and result in different types of severe injuries. Patients with neurotrauma and intentional injuries who survived to receive definitive care at a MTC were at higher risk of hospital death. To inform prevention strategies and reduce morbidity and mortality associated with rural trauma, improvements to data systems are required that involve data linkage and include information about patient care from pre-hospital providers, regional hospitals and major trauma centres.

Systematic approach to school-based assessments for autism spectrum disorders to reduce inequalities: a feasibility study in 10 primary schools.

OBJECTIVES: This was a pilot study to explore whether the Early Years Foundation Stage Profile (EYFSP) carried out by UK teachers within the 'reception' year, combined with the Social Communication Questionnaire (SCQ), can lead to early identification of children with autism spectrum disorders (ASD) and early access to intervention and can reduce inequity in access to assessment and intervention. DESIGN: Pragmatic prospective cohort. SETTING: Ten primary schools from the SHINE project in Bradford. PARTICIPANTS: 587 pupils from 10 schools who transitioned from reception to year 1 in July 2017 and had the EYFSP completed were included in the final study. INTERVENTIONS: The assessment involved a multidisciplinary team of three staff who completed Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule Version 2, classroom observations with an ASD checklist, a teacher-based ASD questionnaire and a final consensus meeting. PRIMARY OUTCOME MEASURE: National Institute for Health and Care Excellence guideline-compliant clinical diagnosis of ASD. SECONDARY OUTCOME MEASURES: Age of diagnosis, demographic data and feasibility parameters. RESULTS: Children with low scores on the EYFSP were more likely to score above the SCQ threshold of 12, indicating potential autism (50% compared with 19% of children with high scores on the EYFSP (p<0.001)). All children scoring above the SCQ threshold received a full autism assessment; children who scored low on the EYFSP were more likely to be diagnosed with autism (and other developmental issues) compared with those who did not. CONCLUSIONS: We identified nine new children with a diagnosis of ASD, all from ethnic minorities, suggesting that this process may be addressing the inequalities in early diagnosis found in previous studies. All children who scored above the SCQ threshold required support (ie, had a neurodevelopmental disorder), indicating the EYFSP questionnaire captured 'at-risk' children.

Neighbourhood greenspace and physical activity and sedentary behaviour among older adults with a recent diagnosis of type 2 diabetes: a prospective analysis.

OBJECTIVES: Greenspace is one of the important factors that can promote an active lifestyle. Thus, greener surroundings may be a motivating factor for people with newly diagnosed diabetes to engage in more physical activity. Given that diagnosis of type 2 diabetes (T2D) may serve as a window opportunity for behavioural modification, we hypothesise that the association between neighbourhood greenspace and physical activity among people with newly diagnosed T2D may be greater than those not diagnosed with T2D. The aim of this study was to investigate the association between access to greenspace and changes in physical activity and sedentary behaviour, and whether these associations differed by T2D. DESIGN: Prospective cohort. SETTING: New South Wales, Australia. METHODS: We used self-reported information from the New South Wales 45 and Up Study (baseline) and a follow-up study. Information on sitting, walking and moderate to vigorous physical activity was used as outcomes. The proportion of greenspace within 500 m, 1 km and 2 km road network buffers around participant's residential address was generated as a proxy measure for access to greenspace. The association between the access to greenspace and the outcomes were explored among the newly diagnosed T2D group and those without T2D. RESULTS: Among New T2D, although no significant changes were found in the amount of walking with the percentage of greenspace, increasing trends were apparent. There was no significant association between the percentage of greenspace and changes in amount of moderate to vigorous physical activity (MVPA). Among No T2D, there were no significant associations between the amount of MVPA and walking, and percentage of greenspace. For changes in sitting time, there were no significant associations with percentage of greenspace regardless of buffer size. CONCLUSIONS: In this study, there was no association between access to greenspace at baseline and change in walking, MVPA and sitting time, regardless of T2D status.

Long-term nitrogen dioxide exposure assessment using back-extrapolation of satellite-based land-use regression models for Australia.

Assessing historical exposure to air pollution in epidemiological studies is often problematic because of limited spatial and temporal measurement coverage. Several methods for modelling historical exposures have been described, including land-use regression (LUR). Satellite-based LUR is a recent technique that seeks to improve predictive ability and spatial coverage of traditional LUR models by using satellite observations of pollutants as inputs to LUR. Few studies have explored its validity for assessing historical exposures, reflecting the absence of historical observations from popular satellite platforms like Aura (launched mid-2004). We investigated whether contemporary satellite-based LUR models for Australia, developed longitudinally for 2006-2011, could capture nitrogen dioxide (NO2) concentrations during 1990-2005 at 89 sites around the country. We assessed three methods to back-extrapolate year-2006 NO2 predictions: (1) 'do nothing' (i.e., use the year-2006 estimates directly, for prior years); (2) change the independent variable 'year' in our LUR models to match the years of interest (i.e., assume a linear trend prior to year-2006, following national average patterns in 2006-2011), and; (3) adjust year-2006 predictions using selected historical measurements. We evaluated prediction error and bias, and the correlation and absolute agreement of measurements and predictions using R2 and mean-square error R2 (MSE-R2), respectively. We found that changing the year variable led to best performance; predictions captured between 41% (1991; MSE-R2 = 31%) and 80% (2003; MSE-R2 = 78%) of spatial variability in NO2 in a given year, and 76% (MSE-R2 = 72%) averaged over 1990-2005. We conclude that simple methods for back-extrapolating prior to year-2006 yield valid historical NO2 estimates for Australia during 1990-2005. These results suggest that for the time scales considered here, satellite-based LUR has a potential role to play in long-term exposure assessment, even in the absence of historical predictor data.

Reconceptualising risk: Perceptions of risk in rural and remote maternity service planning.

OBJECTIVE: to explore perceptions and examples of risk related to pregnancy and childbirth in rural and remote Australia and how these influence the planning of maternity services. DESIGN: data collection in this qualitative component of a mixed methods study included 88 semi-structured individual and group interviews (n=102), three focus groups (n=22) and one group information session (n=17). Researchers identified two categories of risk for exploration: health services risk (including clinical and corporate risks) and social risk (including cultural, emotional and financial risks). Data were aggregated and thematically analysed to identify perceptions and examples of risk related to each category. SETTING: fieldwork was conducted in four jurisdictions at nine sites in rural (n=3) and remote (n=6) Australia. PARTICIPANTS: 117 health service employees and 24 consumers. MEASUREMENTS AND FINDINGS: examples and perceptions relating to each category of risk were identified from the data. Most medical practitioners and health service managers perceived clinical risks related to rural birthing services without access to caesarean section. Consumer participants were more likely to emphasise social risks arising from a lack of local birthing services. KEY CONCLUSIONS: our analysis demonstrated that the closure of services adds social risk, which exacerbates clinical risk. Analysis also highlighted that perceptions of clinical risk are privileged over social risk in decisions about rural and remote maternity service planning. IMPLICATIONS FOR PRACTICE: a comprehensive analysis of risk that identifies how social and other forms of risk contribute to adverse clinical outcomes would benefit rural and remote people and their health services. Formal risk analyses should consider the risks associated with failure to provide birthing services in rural and remote communities as well as the risks of maintaining services.

Diagnosing Potentially Preventable Hospitalisations (DaPPHne): protocol for a mixed-methods data-linkage study.

INTRODUCTION: Rates of potentially preventable hospitalisations (PPH) are used as a proxy measure of effectiveness of, or access to community-based health services. The validity of PPH as an indicator in Australia has not been confirmed. Available evidence suggests that patient-related, clinician-related and systems-related factors are associated with PPH, with differences between rural and metropolitan settings. Furthermore, the proportion of PPHs which are actually preventable is unknown. The Diagnosing Potentially Preventable Hospitalisations study will determine the proportion of PPHs for chronic conditions that are deemed preventable and identify potentially modifiable factors driving these, in order to develop effective interventions to reduce admissions and improve measures of health system performance. METHODS AND ANALYSIS: This mixed methods data linkage study of approximately 1000 eligible patients with chronic PPH admissions to one metropolitan and two regional hospitals over 12 months will combine data from multiple sources to assess the: extent of preventability of chronic PPH admissions; validity of the Preventability Assessment Tool (PAT) in identifying preventable admissions; factors contributing to chronic PPH admissions. Data collected from patients (quantitative and qualitative methods), their general practitioners, hospital clinicians and hospital records, will be linked with routinely collected New South Wales (NSW) Admitted Patient Data Collection, the NSW Registry of Births, Death and Marriages death registration and Australian Bureau of Statistics mortality data. The validity of the PAT will be assessed by determining concordance between clinician assessment and that of a 'gold standard' panel. Multivariable logistic regression will identify the main predictor variables of admissions deemed preventable, using study-specific and linked data. ETHICS AND DISSEMINATION: The NSW Population and Health Services Research Ethics Committee granted ethical approval. Dissemination mechanisms include engagement of policy stakeholders through a project Steering Committee, and the production of summary reports for policy and clinical audiences in addition to peer-review papers.

The role of social isolation in frequent and/or avoidable hospitalisation: rural community-based service providers' perspectives.

BACKGROUND: Research on frequent or avoidable hospital admission has not focussed on the perspectives of service providers or rural settings. The link between social isolation and admission is not well explored, although social isolation is known to have negative health effects. OBJECTIVE: This paper reports further analysis from a study investigating service providers' perspectives on factors influencing frequent hospital admission in older patients with chronic disease, and explores the perceived role of social isolation. METHODS: Semi-structured interviews with 15 purposively sampled community-based service providers in rural New South Wales, Australia were thematically analysed. RESULTS: Social isolation was repeatedly identified as an important contributory factor in frequent and/or avoidable admission. Patients were described as socially isolated in three broad and interrelating ways: living alone, not socialising and being isolated from family. Social isolation was perceived to contribute to admission by limiting opportunities offered by social interaction, including opportunities for: improving mental health, pain tolerance and nutritional status; facilitating access to services; reinforcing healthful behaviours; and providing a monitoring role. CONCLUSIONS: Social isolation is perceived to contribute to admission in ways that may be amenable to intervention. Further research is needed to understand patients' perspectives on the role of social isolation in admission, in order to inform policy and programs aimed at reducing hospitalisation among older people with chronic disease. WHAT IS KNOWN ABOUT THE TOPIC? Social isolation has been shown to adversely affect physical health and mental health and wellbeing across a range of populations. However, less is known about the influence of social isolation on hospital admission among older people with chronic disease, and in particular in instances where admission might have been avoided. WHAT DOES THIS PAPER ADD? This paper adds to our understanding of the ways in which social isolation might link to hospital admission among older people with chronic conditions. It does this by reporting the perspectives of community-based service providers with many years' experience of working with this patient group. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Practitioners need to consider the wider determinants of hospital admission among older patients with chronic disease, including social structures and support. For policy makers the implications are to review support for such patients and explore the possible impact of reducing social isolation on hospital admission.

The study design and methodology for the ARCHER study--adolescent rural cohort study of hormones, health, education, environments and relationships.

BACKGROUND: Adolescence is characterized by marked psychosocial, behavioural and biological changes and represents a critical life transition through which adult health and well-being are established. Substantial research confirms the role of psycho-social and environmental influences on this transition, but objective research examining the role of puberty hormones, testosterone in males and oestradiol in females (as biomarkers of puberty) on adolescent events is lacking. Neither has the tempo of puberty, the time from onset to completion of puberty within an individual been studied, nor the interaction between age of onset and tempo. This study has been designed to provide evidence on the relationship between reproductive hormones and the tempo of their rise to adult levels, and adolescent behaviour, health and wellbeing. METHODS/DESIGN: The ARCHER study is a multidisciplinary, prospective, longitudinal cohort study in 400 adolescents to be conducted in two centres in regional Australia in the State of New South Wales. The overall aim is to determine how changes over time in puberty hormones independently affect the study endpoints which describe universal and risk behaviours, mental health and physical status in adolescents. Recruitment will commence in school grades 5, 6 and 7 (10-12 years of age). Data collection includes participant and parent questionnaires, anthropometry, blood and urine collection and geocoding. Data analysis will include testing the reliability and validity of the chosen measures of puberty for subsequent statistical modeling to assess the impact over time of tempo and onset of puberty (and their interaction) and mean-level repeated measures analyses to explore for significant upward and downward shifts on target outcomes as a function of main effects. DISCUSSION: The strengths of this study include enrollment starting in the earliest stages of puberty, the use of frequent urine samples in addition to annual blood samples to measure puberty hormones, and the simultaneous use of parental questionnaires.

Small area estimation of sparse disease counts using shared component models-application to birth defect registry data in New South Wales, Australia.

In the field of disease mapping, little has been done to address the issue of analysing sparse health datasets. We hypothesised that by modelling two outcomes simultaneously, one would be able to better estimate the outcome with a sparse count. We tested this hypothesis utilising Bayesian models, studying both birth defects and caesarean sections using data from two large, linked birth registries in New South Wales from 1990 to 2004. We compared four spatial models across seven birth defects: spina bifida, ventricular septal defect, OS atrial septal defect, patent ductus arteriosus, cleft lip and or palate, trisomy 21 and hypospadias. For three of the birth defects, the shared component model with a zero-inflated Poisson (ZIP) extension performed better than other simpler models, having a lower deviance information criteria (DIC). With spina bifida, the ratio of relative risk associated with the shared component was 2.82 (95% CI: 1.46-5.67). We found that shared component models are potentially beneficial, but only if there is a reasonably strong spatial correlation in effect for the study and referent outcomes.

Putative GTPase GIMAP1 is critical for the development of mature B and T lymphocytes.

The guanosine triphosphatases (GTPases) of the immunity-associated protein (GIMAP) family of putative GTPases has been implicated in the regulation of T-lymphocyte development and survival. A mouse conditional knockout allele was generated for the immune GTPase gene GIMAP1. Homozygous loss of this allele under the influence of the lymphoid-expressed hCD2-iCre recombinase transgene led to severe (> 85%) deficiency of mature T lymphocytes and, unexpectedly, of mature B lymphocytes. By contrast there was little effect of GIMAP1 deletion on immature lymphocytes in either B or T lineages, although in vitro studies showed a shortening of the survival time of both immature and mature CD4(+) single-positive thymocytes. These findings show a vital requirement for GIMAP1 in mature lymphocyte development/survival and draw attention to the nonredundant roles of members of the GIMAP GTPase family in these processes.

Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain.

Russell bodies (RBs) are intracellular inclusions filled with protein aggregates. In diverse lymphoid disorders these occur as immunoglobulin (Ig) deposits, accumulating in abnormal plasma or Mott cells. In heavy-chain deposition disease truncated antibody heavy-chains (HCs) are found, which bear a resemblance to diverse polypeptides produced in Ig light-chain (LC)-deficient (L(-/-)) mice. In L(-/-) animals, the known functions of LC, providing part of the antigen-binding site of an antibody and securing progression of B-cell development, may not be required. Here, we show a novel function of LC in preventing antibody aggregation. L(-/-) mice produce truncated HC naturally, constant region (C)gamma and Calpha lack C(H)1, and Cmicro is without C(H)1 or C(H)1 and C(H)2. Most plasma cells found in these mice are CD138(+) Mott cells, filled with RBs, formed by aggregation of HCs of different isotypes. The importance of LC in preventing HC aggregation is evident in knock-in mice, expressing Cmicro without C(H)1 and C(H)2, which only develop an abundance of RBs when LC is absent. These results reveal that preventing antibody aggregation is a major function of LC, important for understanding the physiology of heavy-chain deposition disease, and in general recognizing the mechanisms, which initiate protein conformational diseases.

Light chain-deficient mice produce novel multimeric heavy-chain-only IgA by faulty class switching.

Recently, we identified that diverse heavy chain (H-chain)-only IgG is spontaneously produced in light chain (L-chain)-deficient mice (L(-/-) with silenced kappa and lambda loci) despite a block in B cell development. In murine H-chain IgG, the first Cgamma exon, C(H)1, is removed after DNA rearrangement and secreted polypeptides are comparable with camelid-type H-chain IgG. Here we show that L(-/-) mice generate a novel class of H-chain Ig with covalently linked alpha chains, not identified in any other healthy mammal. Surprisingly, diverse H-chain-only IgA can be released from B cells at levels similar to conventional IgA and is found in serum and sometimes in milk and saliva. Surface IgA without L-chain is expressed in B220(+) spleen cells, which exhibited a novel B cell receptor, suggesting that associated conventional differentiation events occur. To facilitate the cellular transport and release of H-chain-only IgA, chaperoning via BiP association seems to be prevented as only alpha chains lacking C(H)1 are released from the cell. This appears to be accomplished by imprecise class-switch recombination (CSR) from Smu into the alpha constant region, which removes all or part of the Calpha1 exon at the genomic level.

Socioeconomic and maternal determinants of small-for-gestational age births: patterns of increasing disparity.

OBJECTIVE: To better characterize the relation between socioeconomic disadvantage and small-for-gestational age births (SGA). DESIGN: Analysis of data from a mandatory population-based surveillance system. SETTING: Public or private hospitals and at home. POPULATION: All 877,951 singleton births occurring in New South Wales, Australia, between 1994 and 2004. METHODS: Multilevel models were developed to determine the factors associated with babies weighing less than the 3rd percentile for gestation and gender. MAIN OUTCOME MEASURES: Odds of SGA. RESULTS: The risk of SGA increased with increasing socioeconomic disadvantage. Smoking accounted for approximately 40% of the increased risk associated with socioeconomic disadvantage, and delayed antenatal care approximately 5%. While the absolute rate of SGA remained stable over the study period, the odds of SGA in mothers living in the most disadvantaged areas compared to those in the least disadvantaged areas increased from approximately 1.7 to 2.2. This trend persisted after accounting for maternal smoking. The risk of SGA over this period also increased in mothers commencing antenatal care after the first trimester. After accounting for smoking, socioeconomic disadvantage and clinical conditions, mothers under 21 years of age were at reduced risk of SGA, but mothers over 35 were at increased risk. CONCLUSIONS: Socioeconomic disadvantage remains one of the dominant determinants of SGA, even in a developed country with universal insurance. This relation appears to be strengthening. Smoking patterns, inadequate antenatal care and clinical conditions partially account for this association and trend, however, most is mediated by other factors.

Influence of socioeconomic and cultural factors on rural health.

OBJECTIVE: To provide a framework for investigating the influence of socioeconomic and cultural factors on rural health. DESIGN: Discussion paper. RESULTS: Socioeconomic and cultural factors have long been thought to influence an individual's health. We suggest a framework for characterising these factors that comprises individual-level (e.g. individual socioeconomic status, sex, race) and neighbourhood-level dimensions (population composition, social environment, physical environment) operating both independently and through interaction. Recent spatial research suggests that in rural communities, socioeconomic disadvantage and indigenous status are two of the greatest underlying influences on health status. However, rural communities also face additional challenges associated with access to, and utilisation of, health care. The example is given of procedural angiography for individuals with an acute coronary event. CONCLUSIONS: Socioeconomic and cultural factors specific to rural Australia are key influences on the health of residents. These range from individual-level factors, such as rural stoicism, poverty and substance use norms, to neighbourhood-level social characteristics, such as lack of services, migration out of rural areas of younger community members weakening traditionally high levels of social cohesion, and to environmental factors, such as climate change and access to services.

Socioeconomic disadvantage and acute coronary events: a spatiotemporal analysis.

BACKGROUND: The associations between socioeconomic disadvantage and ischemic heart disease are not well understood. We explore the relationship between socioeconomic factors and acute coronary events using spatiotemporal analysis. METHODS: We studied all deaths from acute myocardial infarction and hospital admissions for acute coronary syndrome and related revascularization procedures for the state of New South Wales, Australia, from 1996 through 2002. We used conditional autoregressive models to describe how characteristics of subjects' place of residence (socioeconomic disadvantage, proportion of the population of indigenous background, and metropolitan versus nonmetropolitan area) influenced admissions and mortality. RESULTS: There were 32,534 deaths due to acute myocardial infarction and 129,045 admissions for acute coronary syndrome. We found a relationship between increasing socioeconomic disadvantage and mortality (unadjusted relative risk for highest quartile of disadvantage relative to lowest = 1.40; 95% confidence interval = 1.27-1.54) as well as admissions (1.41; 1.28-1.55). After accounting for admission rates, socioeconomic disadvantage was associated with lower rates of angiography (0.75; 0.63-0.88) and interventional angiography (0.70; 0.56-0.85). After adjusting for socioeconomic disadvantage, areas with higher proportions of the population identified as indigenous had higher rates of admission and mortality, while residency in the state capital was associated with higher admission rates and more interventional angiography. After accounting for admission rates, the association of socioeconomic disadvantage with mortality was reduced. CONCLUSIONS: Socioeconomic disadvantage increases both the risk of acute coronary syndrome and related mortality. A contributing factor appears to be a reduced chance of receiving appropriate care. Regions with a higher proportion of indigenous residents show risk beyond the effects of general socioeconomic disadvantage, while residents of metropolitan communities had increased utilization of more recent interventions.

Air pollution and ED visits for asthma in Australian children: a case-crossover analysis.

OBJECTIVE: We aimed to determine the effects of ambient air pollutants on emergency department (ED) visits for asthma in children. METHODS: We obtained routinely collected ED visit data for asthma (ICD9 493) and air pollution (PM(10), PM(2.5), O(3), NO(2), CO and SO(2)) and meteorological data for metropolitan Sydney for 1997-2001. We used the time stratified case-crossover design and conditional logistic regression to model the association between air pollutants and ED visits for four age-groups (1-4, 5-9, 10-14 and 1-14 years). Estimated relative risks for asthma ED visits were calculated for an exposure corresponding to the inter-quartile range in pollutant level. We included same day average temperature, same day relative humidity, daily temperature range, school holidays and public holidays in all models. RESULTS: Associations between ambient air pollutants and ED visits for asthma in children were most consistent for all six air pollutants in the 1-4 years age-group, for particulates and CO in the 5-9 years age-group and for CO in the 10-14 years age-group. The greatest effects were most consistently observed for lag 0 and effects were greater in the warm months for particulates, O(3) and NO(2). In two pollutant models, effect sizes were generally smaller compared to those derived from single pollutant models. CONCLUSION: We observed the effects of ambient air pollutants on ED attendances for asthma in a city where the ambient concentrations of air pollutants are relatively low.

Heavy chain-only antibodies are spontaneously produced in light chain-deficient mice.

In healthy mammals, maturation of B cells expressing heavy (H) chain immunoglobulin (Ig) without light (L) chain is prevented by chaperone association of the H chain in the endoplasmic reticulum. Camelids are an exception, expressing homodimeric IgGs, an antibody type that to date has not been found in mice or humans. In camelids, immunization with viral epitopes generates high affinity H chain-only antibodies, which, because of their smaller size, recognize clefts and protrusions not readily distinguished by typical antibodies. Developmental processes leading to H chain antibody expression are unknown. We show that L(-/-) (kappa(-/-)lambda(-/-)-deficient) mice, in which conventional B cell development is blocked at the immature B cell stage, produce diverse H chain-only antibodies in serum. The generation of H chain-only IgG is caused by the loss of constant (C) gamma exon 1, which is accomplished by genomic alterations in C(H)1-circumventing chaperone association. These mutations can be attributed to errors in class switch recombination, which facilitate the generation of H chain-only Ig-secreting plasma cells. Surprisingly, transcripts with a similar deletion can be found in normal mice. Thus, naturally occurring H chain transcripts without C(H)1 (V(H)DJ(H)-hinge-C(H)2-C(H)3) are selected for and lead to the formation of fully functional and diverse H chain-only antibodies in L(-/-) animals.

Evaluating the effect of neighbourhood weight matrices on smoothing properties of Conditional Autoregressive (CAR) models.

BACKGROUND: The Conditional Autoregressive (CAR) model is widely used in many small-area ecological studies to analyse outcomes measured at an areal level. There has been little evaluation of the influence of different neighbourhood weight matrix structures on the amount of smoothing performed by the CAR model. We examined this issue in detail. METHODS: We created several neighbourhood weight matrices and applied them to a large dataset of births and birth defects in New South Wales (NSW), Australia within 198 Statistical Local Areas. Between the years 1995-2003, there were 17,595 geocoded birth defects and 770,638 geocoded birth records with available data. Spatio-temporal models were developed with data from 1995-2000 and their fit evaluated within the following time period: 2001-2003. RESULTS: We were able to create four adjacency-based weight matrices, seven distance-based weight matrices and one matrix based on similarity in terms of a key covariate (i.e. maternal age). In terms of agreement between observed and predicted relative risks, categorised in epidemiologically relevant groups, generally the distance-based matrices performed better than the adjacency-based neighbourhoods. In terms of recovering the underlying risk structure, the weight-7 model (smoothing by maternal-age 'Covariate model') was able to correctly classify 35/47 high-risk areas (sensitivity 74%) with a specificity of 47%, and the 'Gravity' model had sensitivity and specificity values of 74% and 39% respectively. CONCLUSION: We found considerable differences in the smoothing properties of the CAR model, depending on the type of neighbours specified. This in turn had an effect on the models' ability to recover the observed risk in an area. Prior to risk mapping or ecological modelling, an exploratory analysis of the neighbourhood weight matrix to guide the choice of a suitable weight matrix is recommended. Alternatively, the weight matrix can be chosen a priori based on decision-theoretic considerations including loss, cost and inferential aims.

Transcription of productive and nonproductive VDJ-recombined alleles after IgH allelic exclusion.

The process of allelic exclusion ensures that each B cell expresses a B-cell receptor encoded by only one of its Ig heavy (IgH) and light (IgL) chain alleles. Although its precise mechanism is unknown, recruitment of the nonfunctional IgH allele to centromeric heterochromatin correlates with the establishment of allelic exclusion. Similarly, recruitment in activated splenic B cells correlates with cell division. In the latter, the recruited IgH allele was reported to be transcriptionally silent. However, it is not known whether monoallelic recruitment during establishment of allelic exclusion correlates with transcriptional silencing. To investigate this, we assessed the transcriptional status of both IgH alleles in single primary cells over the course of B-cell development, using RNA fluorescence in situ hybridization. Before allelic exclusion both alleles are transcribed. Thereafter, in pre-BII and subsequent developmental stages both functional and nonfunctional VDJ- and DJ-transcription is observed. Thus, after the establishment of IgH allelic exclusion, monoallelic recruitment to heterochromatin does not silence VDJ- or DJ-transcription, but serves another purpose.