Blockade of PD-1/PD-L1 promotes adoptive T-Cell immunotherapy in a tolerogenic environment

Adoptive cellular immunotherapy using in vitro expanded CD8+ T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC). The coinhibitory receptor programmed death-1 (PD-1), in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8+ T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD-L1 blockade on Tcm-like CD8+ T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8+ T cells. Blockade of PD-1/PDL1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcmlike cells. © 2015 Blake et al.

Prevalence, codetection and seasonal distribution of upper airway viruses and bacteria in children with acute respiratory illnesses with cough as a symptom

Most studies exploring the role of upper airway viruses and bacteria in paediatric acute respiratory infections (ARI) focus on specific clinicaldiagnoses and/or do not account for virus–bacteria interactions. We aimed to describe the frequency and predictors of virus and bacteria codetection in children with ARI and cough, irrespective of clinical diagnosis. Bilateral nasal swabs, demographic, clinical and risk factor data were collected at enrollment in children aged <15 years presenting to an emergency department with an ARI and where cough was a symptom. Swabs were tested by polymerase chain reaction for 17 respiratory viruses and seven respiratory bacteria. Logistic regression was used to investigate associations between child characteristics and codetection of the organisms of interest. Between December 2011 and August 2014, swabs were collected from 817 (93.3%) of 876 enrolled children, median age 27.7 months (interquartile range13.9–60.3 months). Overall, 740 (90.6%) of 817 specimens were positive for any organism. Both viruses and bacteria were detected in 423 specimens (51.8%). Factors associated with codetection were age (adjusted odds ratio (aOR) for age <12 months = 4.9, 95% confidence interval (CI) 3.0, 7.9; age 12 to <24 months = 6.0, 95% CI 3.7, 9.8; age 24 to <60 months = 2.4, 95% CI 1.5, 3.9), male gender (aOR 1.46; 95% CI 1.1, 2.0), child care attendance (aOR 2.0; 95% CI 1.4, 2.8) and winter enrollment (aOR 2.0; 95% CI 1.3, 3.0). Haemophilus influenzae dominated the virus–bacteria pairs. Virus–H. influenzae interactions in ARI should be investigated further, especially as the contribution of nontypeable H. influenzae to acute and chronic respiratory diseases is being increasingly recognized.

Exploring health behaviour determinants of ageing Australians with chronic diseases

Background: Chronic disease presents overwhelming challenges to elderly patients, their families, health care providers and the health care system. The aim of this study was to explore a theoretical model for effective management of chronic diseases, especially type 2 diabetes mellitus and/or cardiovascular disease. The assumed theoretical model considered the connections between physical function, mental health, social support and health behaviours. The study effort was to improve the quality of life for people with chronic diseases, especially type 2 diabetes and/or cardiovascular disease and to reduce health costs. Methods: A cross-sectional post questionnaire survey was conducted in early 2009 from a randomised sample of Australians aged 50 to 80 years. A total of 732 subjects were eligible for analysis. Firstly, factors influencing respondents‘ quality of life were investigated through bivariate and multivariate regression analysis. Secondly, the Theory of Planned Behaviour (TPB) model for regular physical activity, healthy eating and medication adherence behaviours was tested for all relevant respondents using regression analysis. Thirdly, TPB variable differences between respondents who have diabetes and/or cardiovascular disease and those without these diseases were compared. Finally, the TPB model for three behaviours including regular physical activity, healthy eating and medication adherence were tested in respondents with diabetes and/or cardiovascular diseases using Structure Equation Modelling (SEM). Results: This was the first study combining the three behaviours using a TPB model, while testing the influence of extra variables on the TPB model in one study. The results of this study provided evidence that the ageing process was a cumulative effect of biological change, socio-economic environment and lifelong behaviours. Health behaviours, especially physical activity and healthy eating were important modifiable factors influencing respondents‘ quality of life. Since over 80% of the respondents had at least one chronic disease, it was important to consider supporting older people‘s chronic disease self-management skills such as healthy diet, regular physical activity and medication adherence to improve their quality of life. Direct measurement of the TPB model was helpful in understanding respondents‘ intention and behaviour toward physical activity, healthy eating and medication adherence. In respondents with diabetes and/or cardiovascular disease, the TPB model predicted different proportions of intention toward three different health behaviours with 39% intending to engage in physical activity, 49% intending to engage in healthy eating and 47% intending to comply with medication adherence. Perceived behavioural control, which was proven to be the same as self-efficacy in measurement in this study, played an important role in predicting intention towards the three health behaviours. Also social norms played a slightly more important role than attitude for physical activity and medication adherence, while attitude and social norms had similar effects on healthy eating in respondents with diabetes and/or cardiovascular disease. Both perceived behavioural control and intention directly predicted recent actual behaviours. Physical activity was more a volitional control behaviour than healthy eating and medication adherence. Step by step goal setting and motivation was more important for physical activity, while accessibility, resources and other social environmental factors were necessary for improving healthy eating and medication adherence. The extra variables of age, waist circumference, health related quality of life and depression indirectly influenced intention towards the three behaviours mainly mediated through attitude and perceived behavioural control. Depression was a serious health problem that reduced the three health behaviours‘ motivation, mediated through decreased self-efficacy and negative attitude. This research provided evidence that self-efficacy is similar to perceived behavioural control in the TPB model and intention is a proximal goal toward a particular behaviour. Combining four sources of information in the self-efficacy model with the TPB model would improve chronic disease patients‘ self management behaviour and reach an improved long-term treatment outcome. Conclusion: Health intervention programs that target chronic disease management should focus on patients‘ self-efficacy. A holistic approach which is patient-centred and involves a multidisciplinary collaboration strategy would be effective. Supporting the socio-economic environment and the mental/ emotional environment for older people needs to be considered within an integrated health care system.

Adenovirus species C is associated with chronic suppurative lung diseases in children

Background The role of human adenoviruses (HAdVs) in chronic respiratory disease pathogenesis is recognized. However, no studies have performed molecular sequencing of HAdVs from the lower airways of children with chronic endobronchial suppuration. We thus examined the major HAdV genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (PBB) and mild bronchiectasis (BE). Methods Bronchoalveolar lavage (BAL) samples of 245 children with PBB or mild (cylindrical) BE were included in this prospective cohort study. HAdVs were genotyped (when possible) in those whose BAL had HAdV detected (HAdV+). Presence of bacterial infection (defined as ≥104 colony-forming units/mL) was compared between BAL HAdV+ and HAdV negative (HAdV−) groups. Immune function tests were performed including blood lymphocyte subsets in a random subgroup. Results Species C HAdVs were identified in 23 of 24 (96%) HAdV+ children; 13 (57%) were HAdV-1 and 10 (43%) were HAdV-2. An HAdV+ BAL was significantly associated with bacterial coinfection with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (odds ratio [OR], 3.27; 95% confidence interval, 1.38–7.75; P = .007) and negatively associated with Staphylococcus aureus infection (P = .03). Young age was related to increased rates of HAdV+. Blood CD16 and CD56 natural killer cells were significantly more likely to be elevated in those with HAdV (80%) compared with those without (56.1%) (P = .027). Conclusions HAdV-C is the major HAdV species detected in the lower airways of children with PBB and BE. Younger age appears to be an important risk factor for HAdV+ of the lower airways and influences the likelihood of bacterial coinfection

Chronic disease, geographic location and socioeconomic disadvantage as obstacles to equitable access to e-health

Despite recent public attention to e-health as a solution to rising healthcare costs and an ageingpopulation, there have been relatively few studies examining the geographical pattern of e-health usage. This paper argues for an equitable approach to e-health and attention to the way in which e-health initiatives can produce locational health inequalities, particularly in socioeconomically disadvantaged areas. In this paper, we use a case study to demonstrate geographical variation in Internet accessibility, Internet status and prevalence of chronic diseases within a small district. There are signifi cant disparities in access to health information within socioeconomically disadvantaged areas. The most vulnerable people in these areas are likely to have limited availability of, or access to Internet healthcare resources. They are also more likely to have complex chronic diseases and, therefore, be in greatest need of these resources. This case study demonstrates the importance of an equitable approach to e-health information technologies and telecommunications infrastructure.

The Chronic Heart-Failure Assistance by Telephone (CHAT) Study: Assessment of Telephone Support for Vulnerable Patients with Chronic Disease

Aim: To determine whether telephone support using an evidence-based protocol for chronic heart failure (CHF) management will improve patient outcomes and will reduce hospital readmission rates in patients without access to hospital-based management programs. Methods: The rationale and protocol for a cluster-design randomised controlled trial (RCT) of a semi-automated telephone intervention for the management of CHF, the Chronic Heart-failure Assistance by Telephone (CHAT) Study is described. Care is coordinated by trained cardiac nurses located in Heartline, the national call center of the National Heart Foundation of Australia in partnership with patients’ general practitioners (GPs). Conclusions: The CHAT Study model represents a potentially cost-effective and accessible model for the Australian health system in caring for CHF patients in rural and remote areas. The system of care could also be readily adapted for a range of chronic diseases and health systems. Key words: chronic disease management; chronic heart failure; integrated health care systems; nursing care, rural health services; telemedicine; telenursing

Factors influencing health promotion activities in midlife and older Australian women with a chronic disease

Background: Chronic diseases including type 2 diabetes are a leading cause of morbidity and mortality in midlife and older Australian women. There are a number of modifiable risk factors for type 2 diabetes and other chronic diseases including smoking, nutrition, physical activity and overweight and obesity. Little research has been conducted in the Australian context to explore the perceived barriers to health promotion activities in midlife and older Australian women with a chronic disease. Aims: The primary aim of this study was to explore women’s perceived barriers to health promotion activities to reduce modifiable risk factors, and the relationship of perceived barriers to smoking behaviour, fruit and vegetable intake, physical activity and body mass index. A secondary aim of this study was to investigate nurses’ perceptions of the barriers to action for women with a chronic disease, and to compare those perceptions with those of the women. Methods: The study was divided into two phases where Phase 1 was a cross sectional survey of women, aged over 45 years with type 2 diabetes who were attending Diabetes clinics in the Primary and Community Health Service of the Metro North Health Service District of Queensland Health (N = 22). The women were a subsample of women participating in a multi-model lifestyle intervention, the ‘Reducing Chronic Disease among Adult Australian Women’ project. Phase 2 of the study was a cross sectional online survey of nurses working in Primary and Community Health Service in the Metro North Health Service District of Queensland Health (N = 46). Pender’s health promotion model was used as the theoretical framework for this study. Results: Women in this study had an average total barriers score of 32.18 (SD = 9.52) which was similar to average scores reported in the literature for women with a range of physical disabilities and illnesses. The leading five barriers for this group of women were: concern about safety; too tired; not interested; lack of information about what to do; with lack of time and feeling I can’t do things correctly the equal fifth ranked barriers. In this study there was no statistically significant difference in average total barriers scores between women in the intervention group and those is the usual care group of the parent study. There was also no significant relationship between the women’s socio-demographic variables and lifestyle risk factors and their level of perceived barriers. Nurses in the study had an average total barriers score of 44.48 (SD = 6.24) which was higher than all other average scores reported in the literature. The leading five barriers that nurses perceived were an issue for women with a chronic disease were: lack of time and interferes with other responsibilities the leading barriers; embarrassment about appearance; lack of money; too tired and lack of support from family and friends. There was no significant relationship between the nurses’ sociodemographic and nursing variables and the level of perceived barriers. When comparing the results of women and nurses in the study there was a statistically significant difference in the median total barriers score between the groups (p < 0.001), where the nurses perceived the barriers to be higher (Md = 43) than the women (Md = 33). There was also a significant difference in the responses to the individual barriers items in fifteen of the eighteen items (p < 0.002). Conclusion: Although this study is limited by a small sample size, it contributes to understanding the perception of midlife and older women with a chronic disease and also the perception of nurses, about the barriers to healthy lifestyle activities that women face. The study provides some evidence that the perceptions of women and nurses may differ and argues that these differences may have significant implications for clinical practice. The study recommends a greater emphasis on assessing and managing perceived barriers to health promotion activities in health education and policy development and proposes a conceptual model for understanding perceived barriers to action.

The relationship between chronic disease self-efficacy and nutritional status, functional ability and quality of life in older adults at risk of hospital readmission

Background and significance: Older adults with chronic diseases are at increasing risk of hospital admission and readmission. Approximately 75% of adults have at least one chronic condition, and the odds of developing a chronic condition increases with age. Chronic diseases consume about 70% of the total Australian health expenditure, and about 59% of hospital events for chronic conditions are potentially preventable. These figures have brought to light the importance of the management of chronic disease among the growing older population. Many studies have endeavoured to develop effective chronic disease management programs by applying social cognitive theory. However, limited studies have focused on chronic disease self-management in older adults at high risk of hospital readmission. Moreover, although the majority of studies have covered wide and valuable outcome measures, there is scant evidence on examining the fundamental health outcomes such as nutritional status, functional status and health-related quality of life. Aim: The aim of this research was to test social cognitive theory in relation to self-efficacy in managing chronic disease and three health outcomes, namely nutritional status, functional status, and health-related quality of life, in older adults at high risk of hospital readmission. Methods: A cross-sectional study design was employed for this research. Three studies were undertaken. Study One examined the nutritional status and validation of a nutritional screening tool; Study Two explored the relationships between participants. characteristics, self-efficacy beliefs, and health outcomes based on the study.s hypothesized model; Study Three tested a theoretical model based on social cognitive theory, which examines potential mechanisms of the mediation effects of social support and self-efficacy beliefs. One hundred and fifty-seven patients aged 65 years and older with a medical admission and at least one risk factor for readmission were recruited. Data were collected from medical records on demographics, medical history, and from self-report questionnaires. The nutrition data were collected by two registered nurses. For Study One, a contingency table and the kappa statistic was used to determine the validity of the Malnutrition Screening Tool. In Study Two, standard multiple regression, hierarchical multiple regression and logistic regression were undertaken to determine the significant influential predictors for the three health outcome measures. For Study Three, a structural equation modelling approach was taken to test the hypothesized self-efficacy model. Results: The findings of Study One suggested that a high prevalence of malnutrition continues to be a concern in older adults as the prevalence of malnutrition was 20.6% according to the Subjective Global Assessment. Additionally, the findings confirmed that the Malnutrition Screening Tool is a valid nutritional screening tool for hospitalized older adults at risk of readmission when compared to the Subjective Global Assessment with high sensitivity (94%), and specificity (89%) and substantial agreement between these two methods (k = .74, p < .001; 95% CI .62-.86). Analysis data for Study Two found that depressive symptoms and perceived social support were the two strongest influential factors for self-efficacy in managing chronic disease in a hierarchical multiple regression. Results of multivariable regression models suggested advancing age, depressive symptoms and less tangible support were three important predictors for malnutrition. In terms of functional status, a standard regression model found that social support was the strongest predictor for the Instrumental Activities of Daily Living, followed by self-efficacy in managing chronic disease. The results of standard multiple regression revealed that the number of hospital readmission risk factors adversely affected the physical component score, while depressive symptoms and self-efficacy beliefs were two significant predictors for the mental component score. In Study Three, the results of the structural equation modelling found that self-efficacy partially mediated the effect of health characteristics and depression on health-related quality of life. The health characteristics had strong direct effects on functional status and body mass index. The results also indicated that social support partially mediated the relationship between health characteristics and functional status. With regard to the joint effects of social support and self-efficacy, social support fully mediated the effect of health characteristics on self-efficacy, and self-efficacy partially mediated the effect of social support on functional status and health-related quality of life. The results also demonstrated that the models fitted the data well with relative high variance explained by the models, implying the hypothesized constructs under discussion were highly relevant, and hence the application for social cognitive theory in this context was supported. Conclusion: This thesis highlights the applicability of social cognitive theory on chronic disease self-management in older adults at risk of hospital readmission. Further studies are recommended to validate and continue to extend the development of social cognitive theory on chronic disease self-management in older adults to improve their nutritional and functional status, and health-related quality of life.

Deprivation is an independent predictor of 1-year mortality in outpatients with chronic obstructive pulmonary disease

Deprivation is linked to increased incidence in a number of chronic diseases but its relationship to chronic obstructive pulmonary disease (COPD) is uncertain despite suggestions that the socioeconomic gradient seen in COPD is as great, if not greater, than any other disease (Prescott and Vestbo).1 There is also a need to take into account the confounding effects of malnutrition which have been shown to be independently linked to increased mortality (Collins et al).2 The current study investigated the influence of social deprivation on 1-year survival rates in COPD outpatients, independently of malnutrition. 424 outpatients with COPD were routinely screened for malnutrition risk using the ‘Malnutrition Universal Screening Tool’; ‘MUST’ (Elia),3 between July and May 2009; 222 males and 202 females; mean age 73 (SD 9.9) years; body mass index 25.8 (SD 6.3) kg/m2. Each individual's deprivation was calculated using the index of multiple deprivation (IMD) which was established according to the geographical location of each patient's address (postcode). IMD includes a number of indicators covering economic, housing and social issues (eg, health, education and employment) into a single deprivation score (Nobel et al).4 The lower the IMD score, the lower an individual's deprivation. The IMD was assigned to each outpatient at the time of screening and related to1-year mortality from the date screened. Outpatients who died within 1-year of screening were significantly more likely to reside within a deprived postcode (IMD 19.7±SD 13.1 vs 15.4±SD 10.7; p=0.023, OR 1.03, 95% CI 1.00 to 1.06) than those that did not die. Deprivation remained a significant independent risk factor for 1-year mortality even when adjusted for malnutrition as well as age, gender and disease severity (binary logistic regression; p=0.008, OR 1.04, 95% CI 1.04 to 1.07). Deprivation was not associated with disease-severity (p=0.906) or body mass index, kg/m2 (p=0.921) using ANOVA. This is the first study to show that deprivation, assessed using IMD, is associated with increased 1-year mortality in outpatients with COPD independently of malnutrition, age and disease severity. Deprivation should be considered in the targeted management of these patients.

Improving self care of patients with chronic disease using online personal health record

BACKGROUND: Effective management of chronic diseases such as prostate cancer is important. Research suggests a tendency to use self-care treatment options such as over-the-counter (OTC) complementary medications among prostate cancer patients. The current trend in patient-driven recording of health data in an online Personal Health Record (PHR) presents an opportunity to develop new data-driven approaches for improving prostate cancer patient care. However, the ability of current online solutions to share patients' data for better decision support is limited. An informatics approach may improve online sharing of self-care interventions among these patients. It can also provide better evidence to support decisions made during their self-managed care. AIMS: To identify requirements for an online system and describe a new case-based reasoning (CBR) method for improving self-care of advanced prostate cancer patients in an online PHR environment. METHOD: A non-identifying online survey was conducted to understand self-care patterns among prostate cancer patients and to identify requirements for an online information system. The pilot study was carried out between August 2010 and December 2010. A case-base of 52 patients was developed. RESULTS: The data analysis showed self-care patterns among the prostate cancer patients. Selenium (55%) was the common complementary supplement used by the patients. Paracetamol (about 45%) was the commonly used OTC by the patients. CONCLUSION: The results of this study specified requirements for an online case-based reasoning information system. The outcomes of this study are being incorporated in design of the proposed Artificial Intelligence (Al) driven patient journey browser system. A basic version of the proposed system is currently being considered for implementation.

Peripheral compartment innate immune response to Haemophilus influenzae and Streptococcus pneumoniae in chronic obstructive pulmonary disease patients.

Alterations in innate immunity that predispose to chronic obstructive pulmonary disease (COPD) exacerbations are poorly understood. We examined innate immunity gene expression in peripheral blood polymorphonuclear leukocytes (PMN) and monocytes stimulated by Haemophilus influenzae and Streptococcus pneumoniae. Thirty COPD patients (15 rapid and 15 non-rapid lung function decliners) and 15 smokers without COPD were studied. Protein expression of IL-8, IL-6, TNF-α and IFN-γ (especially monocytes) increased with bacterial challenge. In monocytes stimulated with S. pneumoniae, TNF-α protein expression was higher in COPD (non-rapid decliners) than in smokers. In co-cultures of monocytes and PMN, mRNA expression of TGF-β1 and MYD88 was up-regulated, and CD14, TLR2 and IFN-γ down-regulated with H. influenzae challenge. TNF-α mRNA expression was increased with H. influenzae challenge in COPD. Cytokine responses were similar between rapid and non-rapid decliners. TNF-α expression was up-regulated in non-rapid decliners in response to H. influenzae (monocytes) and S. pneumoniae (co-culture of monocytes and PMN). Exposure to bacterial pathogens causes characteristic innate immune responses in peripheral blood monocytes and PMN in COPD. Bacterial exposure significantly alters the expression of TNF-α in COPD patients, although not consistently. There did not appear to be major differences in innate immune responses between rapid and non-rapid decliners.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.

Nutritional support and functional capacity in chronic obstructive pulmonary disease: A systematic review and meta-analysis

Currently there is confusion about the value of using nutritional support to treat malnutrition and improve functional outcomes in chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to clarify the effectiveness of nutritional support in improving functional outcomes in COPD. A systematic review identified 12 RCTs (n = 448) in stable COPD patients investigating the effects of nutritional support [dietary advice (1 RCT), oral nutritional supplements (ONS; 10 RCTs), enteral tube feeding (1 RCT)] versus control on functional outcomes. Meta-analysis of the changes induced by intervention found that whilst respiratory function (FEV(1,) lung capacity, blood gases) was unresponsive to nutritional support, both inspiratory and expiratory muscle strength (PI max +3.86 SE 1.89 cm H(2) O, P = 0.041; PE max +11.85 SE 5.54 cm H(2) O, P = 0.032) and handgrip strength (+1.35 SE 0.69 kg, P = 0.05) were significantly improved, and associated with weight gains of ≥ 2 kg. Nutritional support produced significant improvements in quality of life in some trials, although meta-analysis was not possible. It also led to improved exercise performance and enhancement of exercise rehabilitation programmes. This systematic review and meta-analysis demonstrates that nutritional support in COPD results in significant improvements in a number of clinically relevant functional outcomes, complementing a previous review showing improvements in nutritional intake and weight.

Ureaplasma parvum serovar 3 multiple banded antigen size variation after chronic intra-amniotic infection/colonization

Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero ureaplasma infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2x107 colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n=8; C69, n=4); day 117 (7d Up, n=8; C7, n=2); and day 121 (3d Up, n=8; C3, n=2) of gestation (term=145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of ureaplasma infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to ureaplasma infection. For the first time we have shown that the degree of ureaplasma MBA variation in vivo increased with the duration of gestation.

Mid-gestation intra-amniotic infection with Ureaplasma parvum is resolved within spiny mice (Acomys cahirinus) by term delivery: but caused chronic infection of fetal lungs and placentae

Background: Ureaplasma species in amniotic fluid at the time of second-trimester amniocentesis increases the risk of preterm birth, but most affected pregnancies continue to term (Gerber et al. J Infect Dis 2003). We aimed to model intra-amniotic (IA) ureaplasma infection in spiny mice, a species with a relatively long gestation (39 days) that allows investigation of the disposition and possible clearance of ureaplasmas in the feto-placental compartment. Method: Pregnant spiny mice received IA injections of U. parvum serovar 6 (10µL, 1x104 colony-forming-units in PBS) or 10B media (10µL; control) at 20 days (d) of gestation (term=39d). At 37d fetuses (n=3 ureaplasma, n=4 control) were surgically delivered and tissues were collected for; bacterial culture, ureaplasma mba and urease gene expression by PCR, tissue WBC counts and indirect fluorescent antibody (IFA) staining using anti-ureaplasma serovar 6 (rabbit) antiserum. Maternal and fetal plasma IgG was measured by Western blot. Results: Ureaplasmas were not detected by culture or PCR in fetal or maternal tissues but were visualized by IFA within placental and fetal lung tissues, in association with inflammatory changes and elevated WBC counts (p<0.0001). Anti-ureaplasma IgG was detected in maternal (2/2 tested) and fetal (1/2 tested) plasma but not in controls (0/3). Conclusions: IA injection of ureaplasmas in mid-gestation spiny mice caused persistent fetal lung and placental infection even though ureaplasmas were undetectable using standard culture or PCR techniques. This is consistent with resolution of IA infection, which may occur in human pregnancies that continue to term despite detection of ureaplasmas in mid-gestation.