Intrapulmonary Autoantibodies to HSP72 Are Associated with Improved Outcomes in IPF.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF. METHODS: A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF (n = 107) and other interstitial lung disease (ILD) patients (n = 66). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA. RESULTS: Anti-Hsp72 IgG was detectable in the serum and BALf of IPF (n = 107) and other ILDs (n = 66). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (p = 0.026). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85; p = 0.003). In vitro experiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18. CONCLUSION: Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined.

Cardiovascular Disease, Cancer, and Mortality Among People With Type 2 Diabetes and Alcoholic or Nonalcoholic Fatty Liver Disease Hospital Admission.

OBJECTIVE: To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40-89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors. RESULTS: A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality. CONCLUSIONS: Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM.

Association between BMI measured within a year after diagnosis of type 2 diabetes and mortality.

OBJECTIVE: To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to <30 kg/m(2) as a referent group. Deaths within 2 years of BMI determination were excluded. Mean follow-up to death or the end of 2007 was 4.7 years. RESULTS: A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to <25 kg/m(2) (hazard ratio 1.22 [95% CI 1.13-1.32] in men, 1.32 [1.22-1.44] in women) and patients with BMI ≥35 kg/m(2) (for example, 1.70 [1.24-2.34] in men and 1.81 [1.46-2.24] in women for BMI 45 to <50 kg/m(2)). Vascular mortality was higher for each 5-kg/m(2) increase in BMI >30 kg/m(2) by 24% (15-35%) in men and 23% (14-32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA1c, year of diagnosis, lipids, blood pressure, and socioeconomic status. CONCLUSIONS: Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study.

Diabetes treatments and cancer risk: the importance of considering aspects of drug exposure.

Investigations of the association between diabetes, diabetes treatments, and cancer risk have raised several epidemiological challenges. In particular, a patient's exposure to glucose-lowering drugs needs to be represented accurately to allow unbiased assessment of the link between the treatments and cancer risk. Many studies have used a simple binary contrast (exposure to a specific drug vs no exposure), which has potentially serious drawbacks. In addition, methods used to determine the duration and cumulative dose of drug exposure differ widely between studies. In this Review, we discuss representation of drug exposure in pharmacoepidemiological investigations of the connection between diabetes drugs and cancer risk. We identify principles that might improve future research (particularly in observational studies), and consider issues related to reverse causation and detection bias.

Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans.

BACKGROUND: Hypoglycemia is associated with increased cardiovascular mortality, but the reason for this association is poorly understood. We tested the hypothesis that the myocardial blood flow reserve (MBFR) is decreased during hypoglycemia using myocardial contrast echocardiography in patients with type 1 diabetes mellitus (DM) and in healthy control subjects. METHODS AND RESULTS: Twenty-eight volunteers with DM and 19 control subjects underwent hyperinsulinemic clamps with maintained sequential hyperinsulinemic euglycemia (plasma glucose, 90 mg/dL [5.0 mmol/L]) followed by hyperinsulinemic hypoglycemia (plasma glucose, 50 mg/dL [2.8 mmol/L]) for 60 minutes each. Low-power real-time myocardial contrast echocardiography was performed with flash impulse imaging using low-dose dipyridamole stress at baseline and during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia. In control subjects, MBFR increased during hyperinsulinemic euglycemia by 0.57 U (22%) above baseline (B coefficient, 0.57; 95% confidence interval, 0.38 to 0.75; P<0.0001) and decreased during hyperinsulinemic hypoglycemia by 0.36 U (14%) below baseline values (B coefficient, -0.36; 95% confidence interval, -0.50 to -0.23; P<0.0001). Although MBFR was lower in patients with DM at baseline by 0.37 U (14%; B coefficient, -0.37; 95% confidence interval, -0.55 to -0.19; P=0.0002) compared with control subjects at baseline, the subsequent changes in MBFR during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia in DM patients were similar to that observed in control subjects. Finally, the presence of microvascular complications in the patients with DM was associated with a reduction in MBFR of 0.52 U (24%; B coefficient, -0.52; 95% confidence interval, -0.70 to -0.34; P<0.0001). CONCLUSIONS: Hypoglycemia decreases MBFR in both healthy humans and patients with DM. This finding may explain the association between hypoglycemia and increased cardiovascular mortality in susceptible individuals.

Does context matter for the relationship between deprivation and all-cause mortality? The West vs. the rest of Scotland.

BACKGROUND: A growing body of research emphasizes the importance of contextual factors on health outcomes. Using postcode sector data for Scotland (UK), this study tests the hypothesis of spatial heterogeneity in the relationship between area-level deprivation and mortality to determine if contextual differences in the West vs. the rest of Scotland influence this relationship. Research into health inequalities frequently fails to recognise spatial heterogeneity in the deprivation-health relationship, assuming that global relationships apply uniformly across geographical areas. In this study, exploratory spatial data analysis methods are used to assess local patterns in deprivation and mortality. Spatial regression models are then implemented to examine the relationship between deprivation and mortality more formally. RESULTS: The initial exploratory spatial data analysis reveals concentrations of high standardized mortality ratios (SMR) and deprivation (hotspots) in the West of Scotland and concentrations of low values (coldspots) for both variables in the rest of the country. The main spatial regression result is that deprivation is the only variable that is highly significantly correlated with all-cause mortality in all models. However, in contrast to the expected spatial heterogeneity in the deprivation-mortality relationship, this relation does not vary between regions in any of the models. This result is robust to a number of specifications, including weighting for population size, controlling for spatial autocorrelation and heteroskedasticity, assuming a non-linear relationship between mortality and socio-economic deprivation, separating the dependent variable into male and female SMRs, and distinguishing between West, North and Southeast regions. The rejection of the hypothesis of spatial heterogeneity in the relationship between socio-economic deprivation and mortality complements prior research on the stability of the deprivation-mortality relationship over time. CONCLUSIONS: The homogeneity we found in the deprivation-mortality relationship across the regions of Scotland and the absence of a contextualized effect of region highlights the importance of taking a broader strategic policy that can combat the toxic impacts of socio-economic deprivation on health. Focusing on a few specific places (e.g. 15% of the poorest areas) to concentrate resources might be a good start but the impact of socio-economic deprivation on mortality is not restricted to a few places. A comprehensive strategy that can be sustained over time might be needed to interrupt the linkages between poverty and mortality.

Effect of socioeconomic status on mortality among people with type 2 diabetes: a study from the Scottish Diabetes Research Network Epidemiology Group.

OBJECTIVE: The study objective was to describe the effect of socioeconomic status (SES) on mortality among people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We used a population-based national electronic diabetes database for 35- to 84-year-olds in Scotland for 2001-2007 linked to mortality records. SES was derived from an area-based measure with Q5 and Q1 representing the most deprived and affluent quintiles, respectively. Poisson regression was used to estimate relative risks (RRs) for mortality among people with type 2 diabetes compared with the population without diabetes stratified by age (35-64 and 65-84 years), sex, duration of diabetes (< 2 and ≥ 2 years), and SES. RESULTS: Complete data were available for 210,994 eligible individuals (99.4%), and there were 33,842 deaths. Absolute mortality from all causes among people with type 2 diabetes increased with increasing age and socioeconomic deprivation and was higher for men than women. RR for mortality associated with type 2 diabetes was highest for women aged 35-64 years in Q1 with diabetes duration < 2 years at 4.83 (95% CI 3.15-7.40) and lowest for men aged 65-84 years in Q5 with diabetes duration ≥ 2 years at 1.13 (1.03-1.24). CONCLUSIONS: SES modifies the association between type 2 diabetes and mortality so that RR for mortality is lower among more deprived populations. Age, sex, and duration of diabetes also interact with type 2 diabetes to influence RR of mortality. Differences in prevalence of comorbidities may explain these findings.

Patient involvement in assessing consultation quality: a quantitative study of the Patient Enablement Instrument in Poland.

BACKGROUND: Promoting a more patient-responsive service has been the focus of policy initiatives in newer EU states. One measure of success should be the patient's assessment of their consultation with their doctor. OBJECTIVES: To measure consultation quality in Polish primary care using patient enablement (a patient-driven instrument developed in the UK) and to test its theoretical framework. To compare the patient enablement outcome of different types of doctor delivering primary care in Poland following reform. DESIGN: Cross-sectional quantitative questionnaire survey. SETTING: Random sample of primary care doctors practising within a 60-km radius of Gdansk, Poland. SUBJECTS AND OUTCOME MEASURES: Patient Enablement Instrument and correlates were measured in 7924 consecutive adult consultations of 48 doctors, stratified according to training: family medicine specialists (diploma holders), non-diplomates and general medicine doctors (polyclinic internists). RESULTS: Completion was high (78%). The mean patient enablement score in Poland was 4.0 (SD 3.3) and mean consultation length was 10.3 min (SD 5.4 min). Consultation length and knowing the doctor are independently related to patient enablement in the Polish context. Variation between doctors is significant, but earlier differences in enablement between alternative providers have largely been ameliorated in practice. CONCLUSION: It is feasible to use patient enablement on a large scale at routine consultation in primary care in Poland: acceptability was good in diverse environments. The internal consistency of enablement and its relationships broadly mirror those found in the UK. The effect of patient expectations shaped by social and cultural issues influencing enablement outcome requires further investigation.

Does usage of domestic heating influence internal environmental conditions and health?

BACKGROUND: Housing conditions are recognised as an important determinant of health. In the UK, interventions to improve domestic heating are in place with the expectation that they will improve health. As a component of evaluating such policies, this study assesses whether specific health outcomes are significantly associated with the extent and duration of domestic heating use, either directly or via a possible mediating effect of internal environmental conditions. METHODS: Baseline data from a prospective controlled study evaluating the health effects of a publicly-funded programme of heating improvements in Scotland were used to assess associations among heating use, internal conditions, and three specific health outcomes. RESULTS: There were significant associations (P < 0.01) between measures of heating use and the presence of environmental problems in the home, such as mould and condensation. The presence of such problems was, in turn, found to be significantly predictive of two health outcomes derived from the SF-36 (P < 0.01) and of adult wheezing (P < 0.05). The direction of significant associations was highly consistent: greater levels of heating were associated with reduced likelihood of environmental problems, and the presence of environmental problems was linked to poorer health status. Heating use was not directly associated with the health outcomes considered. CONCLUSIONS: The study findings are consistent with a conceptual model in which health may be influenced by usage patterns of domestic heating, via the mediating effect of poor internal environmental conditions. Since these findings are based on cross-sectional data, interpretation must be carried out cautiously. However, if confirmed by planned future work they have important implications for policy initiatives relating to domestic heating and fuel poverty.

Non-English speakers consulting with the GP in their own language: a cross-sectional survey.

The Patient Enablement Instrument (PEI) gives counterintuitive results with patients who normally speak non-English languages at home. The aim of this study was to find out more about why patients speaking languages other than English were more enabled in a shorter time than English-speaking patients. A cross-sectional consultation-based questionnaire survey was conducted of 2052 adult patients speaking languages other than English compared with 23790 English-speaking patients in four contrasting study areas in the UK Highest PEI scores in shortest consultation times were associated with South Asian language-speaking patients consulting in their own language. Multiple regression analysis showed that the language factors had an independent effect. We therefore conclude that these patients derive particular benefit from general practice consultations in their own language. Enablement may have a different meaning for patients speaking languages other than English.

The development of a routine NHS data-based index of performance in general practice (NHSPPI).

OBJECTIVES: The aim of this study was to compare two different approaches to the measurement of quality in general practice: data derived from routine NHS data sets and results from an index derived from patient-collected data. METHODS: A secondary analysis of existing data sets and a cross-sectional survey were carried out in Lothian, Coventry, Oxfordshire and west London. The subjects comprised randomly selected and consenting practices, and a sample of patients within these practices. A National Health Service Practice Performance Index (NHSPPI) was constructed from 16 routinely available NHS performance indicators. The Consultation Quality Index (CQI) combines the Patient Enablement Instrument (PEI) with a measure of how well the patient knew the doctor, and with observed consultation length. RESULTS: Scores for 12 of the 16 indicators varied significantly across the four regions. Mean practice NHSPPI score overall was 21.6 (SD 4.3), which varied significantly across regions. NHSPPI was predicted by practice list size, weighted deprivation index and proportion of other language patients in the practice, although their effects could not be separated. Overall there was no correlation between NHSPPI and CQI, although the prescribing component of the index was positively correlated to mean consultation length and negatively correlated with how well patients knew their doctors. CONCLUSIONS: Good quality care as assessed by patients on completion of their consultation is independent of good quality care as assessed by best available measures of practice performance. We suggest that the CQI and the NHSPPI are at least as ready for use as other measures of performance in general practice.