AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis.

BACKGROUND: Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor. METHODS: A Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker. RESULTS: Absolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies. CONCLUSIONS: AZD5634 showed favorable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential.

Eosinophil-derived neurotoxin: A biologically and analytically attractive asthma biomarker.

There is a growing body of evidence for the utility of eosinophil-derived neurotoxin (EDN) as a biomarker in asthma, including association with eosinophilic airway inflammation, assessment of disease severity and potential for predicting pathogenic risks, including exacerbations. However, to interpret any biomarker data with confidence, it is first important to understand the preanalytical factors and biological variation that may affect its reliable measurement and results interpretation. In this study we defined the healthy serum EDN reference range for men and women as 1.98 to 26.10 ng/mL, with no significant gender differences. Smoking did not impact the mean EDN levels and no circadian rhythm was identified for EDN, unlike blood eosinophils (EOS) where levels peaked at 00:00h. EDN expression in different cell types was investigated and shown to occur primarily in eosinophils, indicating they are likely to be the main cellular repository for EDN. We also confirm that the quantification of serum EDN is not influenced by the type of storage tube used, and it is stable at ambient temperature or when refrigerated for at least 7 days and for up to one year when frozen at -20°C or -80°C. In summary, EDN is a stable biomarker that may prove useful in precision medicine approaches by enabling the identification of a subpopulation of asthma patients with activated eosinophils and a more severe form of the disease.

INEXAS: A Phase 2 Randomized Trial of On-demand Inhaled Interferon Beta-1a in Severe Asthmatics.

BACKGROUND: Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti-viral cytokine, interferon (IFN)-ß, during URTI, could prevent these exacerbations. OBJECTIVE: To evaluate the efficacy of on-demand inhaled IFN-ß1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI. METHODS: This was a randomized, double-blind, placebo-controlled trial in which patients with severe asthma (GINA 4-5; n = 121) reporting URTI symptoms were randomized to 14 days of once-daily nebulized AZD9412 or placebo. The primary endpoint was severe exacerbations during treatment. Secondary endpoints included 6-item asthma control questionnaire (ACQ-6) and lung function. Exploratory biomarkers included IFN-response markers in serum and sputum, blood leucocyte counts and serum inflammatory cytokines. RESULTS: Following a pre-planned interim analysis, the trial was terminated early due to an unexpectedly low exacerbation rate. Asthma worsenings were generally mild and tended to peak at randomization, possibly contributing to the lack of benefit of AZD9412 on other asthma endpoints. Numerically, AZD9412 did not reduce severe exacerbation rate, ACQ-6, asthma symptom scores or reliever medication use. AZD9412 improved lung function (morning peak expiratory flow; mPEF) by 19.7 L/min. Exploratory post hoc analyses indicated a greater mPEF improvement by AZD9412 in patients with high blood eosinophils (>0.3 × 109 /L) at screening and low serum interleukin-18 relative change at pre-treatment baseline. Pharmacodynamic effect of AZD9412 was confirmed using IFN-response markers. CONCLUSIONS & CLINICAL RELEVANCE: Colds did not have the impact on asthma patients that was expected and, due to the low exacerbation rate, the trial was stopped early. On-demand AZD9412 treatment did not numerically reduce the number of exacerbations, but did attenuate URTI-induced worsening of mPEF. Severe asthma patients with high blood eosinophils or low serum interleukin-18 response are potential subgroups for further investigation of inhaled IFN-ß1a.

Impact of CKD Progression on Cardiovascular Disease Risk in a Contemporary UK Cohort of Individuals With Diabetes.

INTRODUCTION: It remains unclear whether an increased progression rate of chronic kidney disease (CKD) adds predictive information regarding cardiovascular disease (CVD) risk. The aim of this study was to evaluate the association between CKD progression, based on estimated glomerular filtration rate (eGFR) slope estimates and the risk for CVD. METHODS: We compared the updated eGFR slope calculated over multiple overlapping 2-year periods and the updated mean eGFR. Incident CKD subjects were selected from a prevalent population with diabetes (T2DM). Subjects from the UK Clinical Practice Research Data Link GOLD (CPRD) were followed from CKD diagnosis (n = 30,222) until heart failure (HF), myocardial infarction (MI), ischemic stroke (IS), or a composite end point including all 3 event types (MACE plus), mortality, database dropout, or end of study follow-up. RESULTS: Both the updated eGFR slope and updated mean eGFR were associated with MACE plus and HF. Updated eGFR slope decline of > -3 ml/min/1.73 m2 increased the risk for MACE plus (adjusted hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.26-1.67), HF (HR = 1.50; 95% CI, 1.27-1.76), and MI (HR = 1.39; 95% CI, 1.01-1.91). CONCLUSIONS: This study strongly supports current evidence that CKD is an independent risk factor for CVD. From a clinical perspective, both rate of progression and cumulative status of CKD describe distinct aspects of the cardiorenal risk among persons with diabetes. This evidence is essential to enable more timely and improved use of treatments in this population.

Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284.

AIMS: Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and Cmax , respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.

Variable flip angle 3D ultrashort echo time (UTE) T1 mapping of mouse lung: A repeatability assessment.

BACKGROUND: Lung T1 is a potential translational biomarker of lung disease. The precision and repeatability of variable flip angle (VFA) T1 mapping using modern 3D ultrashort echo time (UTE) imaging of the whole lung needs to be established before it can be used to assess response to disease and therapy. PURPOSE: To evaluate the feasibility of regional lung T1 quantification with VFA 3D-UTE and to investigate long- and short-term T1 repeatability in the lungs of naive mice. STUDY TYPE: Prospective preclinical animal study. POPULATION: Eight naive mice and phantoms. FIELD STRENGTH/SEQUENCE: 3D free-breathing radial UTE (8 µs) at 4.7T. ASSESSMENT: VFA 3D-UTE T1 calculations were validated against T1 values measured with inversion recovery (IR) in phantoms. Lung T1 and proton density (S0 ) measurements of whole lung and muscle were repeated five times over 1 month in free-breathing naive mice. Two consecutive T1 measurements were performed during one of the imaging sessions. STATISTICAL TESTS: Agreement in T1 between VFA 3D-UTE and IR in phantoms was assessed using Bland-Altman and Pearson 's correlation analysis. The T1 repeatability in mice was evaluated using coefficient of variation (CV), repeated-measures analysis of variance (ANOVA), and paired t-test. RESULTS: Good T1 agreement between the VFA 3D-UTE and IR methods was found in phantoms. T1 in lung and muscle showed a 5% and 3% CV (1255 ± 63 msec and 1432 ± 42 msec, respectively, mean ± SD) with no changes in T1 or S0 over a month. Consecutive measurements resulted in an increase of 2% in both lung T1 and S0 . DATA CONCLUSION: VFA 3D-UTE shows promise as a reliable T1 mapping method that enables full lung coverage, high signal-to-noise ratio (∼25), and spatial resolution (300 µm) in freely breathing animals. The precision of the VFA 3D-UTE method will enable better design and powering of studies. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies.

BACKGROUND: Fibrinogen and prothrombin have been suggested to become rate limiting in trauma associated coagulopathy. Administration of fibrinogen is now recommended, however, the importance of prothrombin to patient outcome is unknown. METHODS: We have utilized two trauma patient databases (database 1 n = 358 and database 2 n = 331) to investigate the relationship of plasma prothrombin concentration on clinical outcome and coagulation status. Database 1 has been used to assess the relationship of plasma prothrombin to administered packed red blood cells (PRBC), clinical outcome and coagulation biomarkers (Prothrombin Time (PT), ROTEM EXTEM Coagulation Time (CT) and Maximum Clot Firmness (MCF)). ROC analyses have been performed to investigate the ability of admission coagulation biomarkers to predict low prothrombin concentration (database 1), massive transfusion and 24 h mortality (database 1 and 2). The importance of prothrombin was further investigated in vitro by PT and ROTEM assays in the presence of a prothrombin neutralizing monoclonal antibody and following step-wise dilution. RESULTS: Patients who survived the first 24 h had higher admission prothrombin levels compared to those who died (94 vs.67 IU/dL). Patients with lower transfusion requirements within the first 24 h (≤10 units of PRBCs) also had higher admission prothrombin levels compared to patients with massive transfusion demands (>10 units of PRBCs) (95 vs.62 IU/dL). Admission PT, in comparison to admission ROTEM EXTEM CT and MCF, was found to be a better predictor of prothrombin concentration <60 IU/dL (AUC 0.94 in database 1), of massive transfusion (AUC 0.92 and 0.81 in database 1 and 2 respectively) and 24 h mortality (AUC 0.90 and 0.78 in database 1 and 2, respectively). In vitro experiments supported a critical role for prothrombin in coagulation and demonstrated that PT and ROTEM EXTEM CT are sensitive methods to measure low prothrombin concentration. DISCUSSION: Our analyses suggest that prothrombin concentration at admission is predictive of mortality and transfusion and indicates that prothrombin and fibrinogen are rate limiting in coagulopathy. CONCLUSIONS: Admission PT is predictive of low prothrombin concentration and clinical outcome. PT could therefore be used as a surrogate for prothrombin concentration and further evaluation of point-of-care devices for faster PT analysis is warranted.

Colds as predictors of the onset and severity of COPD exacerbations.

RATIONALE: Common colds are associated with acute respiratory symptom exacerbations in COPD patients. OBJECTIVE: To determine exacerbation risk and severity in COPD patients with/without coincident self-reported colds. METHODS: Global initiative for chronic Obstructive Lung Disease stage I-IV COPD patients electronically transmitted respiratory symptom diaries to research staff daily between December 2006 and April 2009. Respiratory symptom worsening prompted contact by a study nurse and patient assessment to determine if a cold was present or an exacerbation underway. A composite daily symptom score was derived for each subject from diarized symptom data. The exacerbation/cold/virus relation was examined using a Poisson regression model, the relation of colds to respiratory symptom severity using generalized estimating equation models. RESULTS: Daily diary transmission compliance of >97% enabled detection of all possible exacerbations. Among 262 exacerbations meeting Anthonisen criteria, 218 (83%) had cold-like symptoms present at their inception, but respiratory viruses were detected in only 106 (40%). Within-subject exacerbation risk was 30 times (95% confidence interval [CI]: 20, 47; P<0.001) greater with colds present. Compared to cold- and virus-negative exacerbations (n=57), the mean increase in composite symptom score in those cold and virus positive (n=79) was 0.93 (95% CI: 0.61, 1.25; P<0.001), cold-positive and virus-negative exacerbations (n=100) 0.51 (95% CI: 0.21, 0.81; P<0.001), cold-negative and virus-positive exacerbations (n=26) 0.58 (95% CI: 0.23, 0.94; P<0.001). CONCLUSION: This study emphasizes the importance of colds in COPD exacerbation risk and severity, even in the absence of virus detection. COPD patients should act promptly when cold symptoms appear to facilitate early intervention for exacerbation prevention or management.

Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment.

A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively. The C1236T, G2677A/T, and C3435T SNPs were determined, and the functionality of P-gp was assessed by flow cytometry (Rhodamine efflux assay). Carriage of the G2677A/T SNP was significantly associated with response (OR = 6.18, p = 0.035), the other SNPs showed trends. Stratified for received treatment, the effect was only present in methylprednisolone treated patients. Mutant allele carriage significantly decreased functionality of P-gp in B cells, though had a smaller impact in other PBMC subtypes. Carriage of a MDR1 SNP was related to a response to methylprednisolone in this study, which his suggests that RA-patients carrying wild-type alleles might benefit from P-gp inhibition or administration of glucocorticoid analogues that are non-P-gp substrates.

Preclinical evaluation of point-of-care prothrombin time as a biomarker test to guide prothrombin replacement therapy in coagulopathic bleeding.

BACKGROUND: Hemorrhage is still a common cause of death in trauma. Central lab measured prothrombin time (lab PT) is predictive of low prothrombin concentration and clinical outcome in trauma patients, however, treatment guidance is limited by slow turnaround times. Here, we have preclinically evaluated the potential of a point-of-care prothrombin time test (POC PT) as a faster alternative to identify patients with low prothrombin concentration. METHODS: Human whole blood was serially diluted and prothrombin time measured by POC PT (CoaguChek XS Pro, Roche) and lab PT. Recombinant human prothrombin (MEDI8111) was added to human whole blood with or without depletion of prothrombin by pretreatment with prothrombin neutralizing antibodies. RESULTS: There was no observable difference in the sensitivity of either test to dilution at blood volumes of 60-100%. At blood volumes of ≤55% (equivalent to 47 mg/L prothrombin), PT sharply increased, with greater dilutional sensitivity observed in the POC test. Both tests were insensitive to prothrombin up to 194 mg/L added MEDI8111 (equivalent to 328 mg/L prothrombin versus endogenous concentration of 129 mg/L). Depletion of endogenous prothrombin inversely correlated with an increase in PT which returned to baseline following addition of 97 mg/L MEDI8111 or above. Both assays correlated well above 48.5 mg/L added MEDI8111 (65.9 mg/L prothrombin). CONCLUSIONS: Our data supports that POC PT tests, such as the CoaguChek XS Pro, are fit for purpose to confirm a coagulopathic threshold for prothrombin and provide a fast, simple, and mobile method to guide MEDI8111 therapy in bleeding trauma patients.

Contemporary risk estimates of three HbA1c variables in relation to heart failure following diagnosis of type 2 diabetes.

BACKGROUND: We evaluated the association between glycaemic control and the risk of heart failure (HF) in a contemporary cohort of persons followed after diagnosis of type 2 diabetes (T2D). METHODS AND RESULTS: Persons with T2D diagnosed between 1998 and 2012 were retrieved from the Clinical Practice Research Data Link in the UK and followed from diagnosis until the event of HF, mortality, drop out from the database due to any other reason, or the end of the study on 1 July 2015. The association between each of three different haemoglobin A1C (HbA1c) metrics and HF was estimated using adjusted proportional hazard models. In the overall cohort (n=94 332), the increased risk for HF per 1% (10 mmol/mol) increase in HbA1c was 1.15 (95% CI 1.13 to 1.18) for updated mean HbA1c, and 1.06 (1.04 to 1.07) and 1.06 (1.04 to 1.08) for baseline HbA1c and updated latest HbA1c, respectively. When categorised, the hazard risk (HR) for the updated mean HbA1c in relation to HF became higher than for baseline and updated latest HbA1c above HbA1c levels of 9%, but did not differ at lower HbA1c levels. The updated latest variable showed an increased risk for HbA1c <6% (42 mmol/mol) of 1.16 (1.07 to 1.25), relative category 6-7%, while the HRs for updated mean and baseline HbA1c showed no such J-shaped pattern. CONCLUSIONS: Hyperglycaemia is still a risk factor for HF in persons with T2D of similar magnitude as in earlier cohorts. Such a relationship exists for current glycaemic levels, at diagnosis and the overall level but the pattern differs for these variables.

T1 Relaxation Time in Lungs of Asymptomatic Smokers.

PURPOSE: Interest in using T1 as a potential MRI biomarker of chronic obstructive pulmonary disease (COPD) has recently increased. Since tobacco smoking is the major risk factor for development of COPD, the aim for this study was to examine whether tobacco smoking, pack-years (PY), influenced T1 of the lung parenchyma in asymptomatic current smokers. MATERIALS AND METHODS: Lung T1 measurements from 35 subjects, 23 never smokers and 12 current smokers were retrospectively analyzed from an institutional review board approved study. All 35 subjects underwent pulmonary function test (PFT) measurements and lung T1, with similar T1 measurement protocols. A backward linear model of T1 as a function of FEV1, FVC, weight, height, age and PY was tested. RESULTS: A significant correlation between lung T1 and PY was found with a negative slope of -3.2 ms/year (95% confidence interval [CI] [-5.8, -0.6], p = 0.02), when adjusted for age and height. Lung T1 shortens with ageing among all subjects, -4.0 ms/year (95%CI [-6.3, -1.7], p = 0.001), and among the never smokers, -3.7 ms/year (95%CI [-6.0, -1.3], p = 0.003). CONCLUSIONS: A correlation between lung T1 and PY when adjusted for both age and height was found, and T1 of the lung shortens with ageing. Accordingly, PY and age can be significant confounding factors when T1 is used as a biomarker in lung MRI studies that must be taken into account to detect underlying patterns of disease.

Assessing the Relationship between Lung Density and Function with Oxygen-Enhanced Magnetic Resonance Imaging in a Mouse Model of Emphysema.

PURPOSE: A magnetic resonance imaging method is presented that allows for the simultaneous assessment of oxygen delivery, oxygen uptake, and parenchymal density. The technique is applied to a mouse model of porcine pancreatic elastase (PPE) induced lung emphysema in order to investigate how structural changes affect lung function. METHOD: Nine-week-old female C57BL6 mice were instilled with saline or PPE at days 0 and 7. At day 19, oxygen delivery, oxygen uptake, and lung density were quantified from T1 and proton-density measurements obtained via oxygen-enhanced magnetic resonance imaging (OE-MRI) using an ultrashort echo-time imaging sequence. Subsequently, the lungs were sectioned for histological observation. Blood-gas analyses and pulmonary functional tests via FlexiVent were performed in separate cohorts. PRINCIPAL FINDINGS: PPE-challenged mice had reduced density when assessed via MRI, consistent with the parenchyma loss observed in the histology sections, and an increased lung compliance was detected via FlexiVent. The oxygenation levels, as assessed via the blood-gas analysis, showed no difference between PPE-challenged animals and control. This finding was mirrored in the global MRI assessments of oxygen delivery and uptake, where the changes in relaxation time indices were matched between the groups. The heterogeneity of the same parameters however, were increased in PPE-challenged animals. When the oxygenation status was investigated in regions of varying density, a reduced oxygen-uptake was found in low-density regions of PPE-challenged mice. In high-density regions the uptake was higher than that of regions of corresponding density in control animals. The oxygen delivery was proportional to the oxygen uptake in both groups. CONCLUSIONS: The proposed method allowed for the regional assessment of the relationship between lung density and two aspects of lung function, the oxygen delivery and uptake. When compared to global indices of lung function, an increased sensitivity for detecting heterogeneous lung disorders was found. This indicated that the technique has potential for early detection of lung dysfunction-before global changes occur.

The relationship between three eGFR formulas and hospitalization for heart failure in 54 486 individuals with type 2 diabetes.

OBJECTIVE: This study aims to study the association between renal function and hospitalization for heart failure (HF) in individuals with type 2 diabetes. METHODS: Renal function was determined according to three formulas used to estimate glomerular filtration rate (eGFR): Cockcroft-Gault, modified diet in renal disease (MDRD) and chronic kidney disease epidemiology (CKD-EPI). Proportional hazards regression models adjusted for age, sex, HbA1c , blood pressure, smoking and cardiovascular comorbidities were constructed for each eGFR formula to estimate risk of hospitalization for heart failure. Systematic pairwise likelihood ratio tests of nested models were used to compare the predictive power of each eGFR formula. RESULTS: In 54 486 patients, evaluated over a median follow-up of 7.0 years, a total of 5936 (10.9%) developed heart failure, with an excess risk in all eGFR categories below 60 mL/min/1.73 m2 (reference: eGFR >90 mL/min/1.73 m2 ). Hazard ratios ranged from 1.25 to 1.35 for eGFR 45-60 mL/min/1.73 m2 , 1.62 to 1.66 for eGFR 30-45 mL/min/1.73 m2 and 2.18 to 2.52 for eGFR <30 mL/min/1.73 m2 in the three eGFR formulas. In pairwise comparisons, the model with the MDRD variable added significantly more information than the Cockcroft-Gault variable. For the model with the CKD-EPI variable, no clear differences in predictive power for HF hospitalization existed in relation to the other eGFR formulas. CONCLUSION: Patients with type 2 diabetes, with eGFR 45 to 60 mL/min/1.73 m2 , have approximately 25-35% increased risk of hospitalization for HF, increasing with lower eGFR, to 2-2.5 times in those with eGFR <30 mL/min/1.73 m2 . The MDRD formula for calculating eGFR is more predictive of hospitalization for heart failure than the Cockcroft-Gault formula. Copyright © 2016 John Wiley & Sons, Ltd.

Decreased eGFR as a Risk Factor for Heart Failure in 13 781 Individuals With Type 1 Diabetes.

BACKGROUND: Impaired renal function is a well-known risk factor of cardiovascular disease, but its relation to heart failure in individuals with type 1 diabetes has been sparsely studied. The aim of our study was to quantify the risk increase for development of heart failure with decreasing kidney function in individuals with type 1 diabetes. METHODS: Three equations were used to calculate eGFR (estimated glomerular filtration rate) for individuals with T1D and no known heart failure in the Swedish National Diabetes Registry. Proportional hazards regression models were constructed to evaluate the association between eGFR and hospitalization for heart failure (HF). RESULTS: Among 13 781 individuals (mean age 41.1 [SD 13.3] years at baseline), 330 (2.4%) were hospitalized for HF over median follow-up of 7.0 years. Renal function was normal (eGFR > 90 mL/min/1.73 m(2)) in 67% of individuals according to the Cockcroft-Gault formula, compared to 51% and 41% according to the Chronic Kidney Disease Epidemiology (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) formulas. For eGFR 45-60 ml/min/1.73 m(2), hazard ratios (HRs) for hospitalization (reference >90 mL/min/1.73 m(2)) were 3.18 (95% CI 2.17, 4.65), 2.12 (1.16, 3.08), and 2.44 (1.69, 3.55) using the Cockcroft-Gault, MDRD, and CKD-EPI formulas. With eGFR <30 ml/min/1.73 m(2) there was a HR of 3.78 (2.15, 5.91), 3.44 (2.14, 5.51), and 3.51 (2.21, 5.51) compared to normal kidney function (>90 mL/min/1.73 m(2)). CONCLUSIONS: In individuals with T1D, risk of hospitalization for heart failure was over 2 times greater at eGFR 45-60 ml/min/1.73 m(2) and more than 3 times greater at eGFR <30 ml/min/1.73 m(2) when compared to normal eGFR.

Contemporary Risk Estimates of Three HbA1c Variables for Myocardial Infarction in 101,799 Patients Following Diagnosis of Type 2 Diabetes.

OBJECTIVE: This study evaluated the risk of myocardial infarction (MI) by impaired glycemic control in a contemporary large cohort of patients with type 2 diabetes followed from diagnosis. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes diagnosed between 1995 and 2011 were retrieved from the Clinical Practice Research Datalink in the U.K., and followed from diagnosis until event of MI or end of study in 2013. Two subcohorts were defined: an early cohort with those diagnosed from 1997 to 2004 and a recent cohort with those diagnosed from 2004 to 2011. Association between each of three HbA1c metrics and MI was estimated using adjusted proportional hazards models. RESULTS: In the overall cohort (n = 101,799), the risk increase for MI per 1% (10 mmol/mol) increase in HbA(1c) was higher for updated latest and updated mean HbA(1c) of 1.11 (95% CI 1.09-1.13) and 1.15 (1.13-1.18) than for baseline HbA(1c) of 1.05 (1.03-1.06). In the early subcohort, the corresponding risk estimates were greater than those in the recent subcohort. When categorized, the updated latest variable showed an increased risk for HbA(1c) <6% (42 mmol/mol), relative category 6-7%, in the recent but not in the early subcohort, with hazard ratios of 1.23 (1.08-1.40) and 1.01 (0.84-1.22), respectively. CONCLUSIONS: The two time-updated HbA(1c) variables show a stronger relation with MI than baseline HbA(1c). The risk association between HbA(1c) and MI has decreased over time. In recently diagnosed patients with type 2 diabetes, an increased risk of MI exists at a current HbA(1c) of <6.0% (42 mmol/mol).

Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects.

This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters.

Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population.

BACKGROUND: Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel. METHODOLOGY/PRINCIPAL FINDINGS: A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRß, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10-11). CONCLUSIONS/SIGNIFICANCE: Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.

Relationship between overweight and obesity with hospitalization for heart failure in 20,985 patients with type 1 diabetes: a population-based study from the Swedish National Diabetes Registry.

OBJECTIVE: To investigate the potential relationship between overweight, obesity, and severe obesity and the risk of hospitalization for heart failure (HF) in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We studied patients with type 1 diabetes included in the Swedish National Diabetes Registry during 1998-2003, and they were followed up until hospitalization for HF, death, or 31 December 2009. Cox regression was used to estimate relative risks. RESULTS: In a sample of 20,985 type 1 diabetic patients (mean age, 38.6 years; mean BMI, 25.0 kg/m(2)), 635 patients were hospitalized with HF as a primary or secondary diagnosis during a median follow-up of 9.1 years. Cox regression adjusting for age, sex, diabetes duration, smoking, HbA1c, systolic and diastolic blood pressures, and baseline and intercurrent comorbidities (including myocardial infarction) showed a significant relationship between BMI and hospitalization for HF (P < 0.0001). In reference to patients in the BMI 20-25 kg/m(2) category, hazard ratios (HRs) were as follows: HR 1.22 (95% CI, 0.83-1.78) for BMI <20 kg/m(2); HR 0.94 (95% CI, 0.78-1.12) for BMI 25-30 kg/m(2); HR 1.55 (95% CI, 1.20-1.99) for BMI 30-35 kg/m(2); and HR 2.90 (95% CI, 1.92-4.37) for BMI ≥ 35 kg/m(2). CONCLUSIONS: Obesity, particularly severe obesity, is strongly associated with hospitalization for HF in patients with type 1 diabetes, whereas no similar relation was present in overweight and low body weight.

Familial risk of premature cardiovascular mortality and the impact of intergenerational occupational class mobility.

The negative impact of low social class on cardiovascular disease (CVD) and mortality has been consistently documented. However, less scientific consistency exists in terms of whether a unique health effect of social mobility from childhood to adulthood prevails. This study explored how childhood and adult social class and the transition between them (social mobility), are related to premature CVD mortality when familial aggregation of CVD among siblings is also considered. The study includes nearly 1.9 million Swedish residents born 1939-1959 distributed over 1,044,725 families, of whom 14,667 died prematurely from CVD in 1990-2003. Information on parental class (1960) and own mid-life occupational class (1990) was retrieved from the respective censuses. Odds ratios for premature CVD mortality according to trajectory-specific social mobility, along with pairwise mean odds ratios for sibling resemblance of premature CVD mortality, were calculated by means of alternating logistic regression. This model calculates the remaining dependency of CVD mortality within sibships after accounting for available risk factors (like parental and adult social class) in the population mean model. Results showed that premature CVD mortality was associated with both parental and own adult social class. A clear tendency for the downwardly mobile to have increased, and for the upwardly mobile to experience a decreased risk of premature CVD mortality was found, as well as a corresponding unique effect of social mobility per se among the manual and non-manual classes. This effect was verified for men, but not for women, when they were analysed separately. The pairwise mean odds ratios for premature CVD mortality among full siblings were 1.78 (95% CI: 1.52-2.08), and were independent of parental CVD mortality and parental or adult occupational class.