The inflammatory biomarker YKL‐40 at admission is a strong predictor of overall mortality

Objectives

YKL‐40 is an inflammatory biomarker associated with disease activity and mortality in patients with diseases characterized by inflammation and tissue remodelling. The aim of this study was to describe the prognostic value of YKL‐40 in an unselected patient population.

Design

In consecutive patients admitted to hospital during a 1‐year period, blood was collected and information regarding final diagnosis and mortality was collected. Median follow‐up time was 11.5 years.

Setting

District hospital, Copenhagen, Denmark.

Patients

A total of 1407 patients >40 years of age were admitted acutely.

Main outcome measure

All‐cause mortality.

Results

Median YKL‐40 was increased in patients (157 μg L^?1, range 13–7704 μg L^?1) compared to healthy controls (40 μg L^?1, range 29–58 μg L^?1; P < 0.001). Patients with YKL‐40 in the highest quartile had a hazard ratio (HR) of 7.1 [95% confidence interval (CI) 4.2–12.0] for all‐cause mortality in the first year and 3.4 (95% CI 2.8–4.2) in the total study period, compared to those in the lowest quartile (HR = 1). The HR for death for all patients with YKL‐40 above the normal age‐corrected 95th percentile was 2.1 (95% CI 1.6–2.7) after 1 year and 1.5 (95% CI 1.3–1.7) during the total study period, compared to patients with YKL‐40 below the age‐corrected 95th percentile. The results of multivariable analysis showed that YKL‐40 was an independent biomarker of mortality; this was most significant in the first year. YKL‐40 was a marker of prognosis in all disease categories. The HR for death was increased in patients with YKL‐40 above the normal age‐corrected 95th percentile in healthy subjects independent of type of disease (all P < 0.001).

Conclusion

The level of YKL‐40 at admission is a strong predictor of overall mortality, independent of diagnosis and could be useful as a biomarker in the acute evaluation of all patients.

     

Estimated glomerular filtration rate and the risk–benefit profile of intensive blood pressure control amongst nondiabetic patients: a post hoc analysis of a randomized clinical trial

Background

The Systolic Blood Pressure Intervention Trial (SPRINT ; ClinicalTrials.gov , NCT 01206062) reported reduced cardiovascular events by intensive blood pressure (BP ) control amongst hypertensive patients without diabetes. However, the risk–benefit profile of intensive BP control may differ across estimated glomerular filtration rate (eGFR ) levels.

Methods

This is a post hoc analysis of the SPRINT . Nondiabetic hypertensive adults (n  = 9361) with eGFR >20 mL per min per 1.73 m² were enrolled from 102 US facilities between November 2010 and March 2013 and were followed up until August 2015 (median follow‐up, 3.26 years). Patients were randomly assigned to either a systolic BP target of <120 or <140 mmHg (for intensive or standard treatment, respectively). The outcomes of interests were the development of (i) fatal and nonfatal major cardiovascular events and (ii) acute kidney injury (AKI ).

Results

The cardiovascular benefit from intensive treatment was attenuated with lower eGFR (P _interaction = 0.019), whereas eGFR did not modify the adverse effect on AKI (P _interaction = 0.179). Amongst 891 participants with eGFR <45 mL per min per 1.73 m², intensive treatment did not reduce the cardiovascular outcome (54/446 vs. 54/445 events in the standard group, respectively; hazard ratio [HR ], 0.92; 95% CI , 0.62–1.38) with an absolute rate difference (ARD ) of ?0.02 (95% CI , ?0.07 to +0.03) per 100 patient‐years, whereas it increased AKI (62/446 vs. 38/445 events in the standard group; HR , 1.73; 95% CI , 1.12–2.66) with an ARD of +1.93 (95% CI , +1.88 to +1.97) per 100 patient‐years.

Conclusions

Intensive BP control may provide little or no benefit and even be harmful for patients with moderate‐to‐advanced chronic kidney disease.

     

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE‐LY trial

Background

Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF.

Objectives

To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE‐LY trial.

Methods

HAS‐BLED, ORBIT, ATRIA and HEMORR₂HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated.

Results

There were 1182 (6.5%) major bleeding events during a median follow‐up of 2.0 years. For all the four schemes, high‐risk subgroups had higher risk of major bleeding (all P  < 0.001). The ORBIT score showed the best discrimination with c‐indices of 0.66, 0.66 and 0.62, respectively, for major, life‐threatening and intracranial bleeding, which were significantly better than for the HAS‐BLED score (difference in c‐indices: 0.050, 0.053 and 0.048, respectively, all P  < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P  = 0.0019), ATRIA (P  < 0.001) and HEMORR₂HAGES (P  < 0.001) scores. HAS‐BLED score showed a nonsignificant trend for interaction (P  = 0.0607).

Conclusions

Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

     

Sitagliptin improves beta‐cell function in patients with acute coronary syndromes and newly diagnosed glucose abnormalities–the BEGAMI study

Background

Newly detected impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) are common in patients with acute coronary syndrome (ACS; i.e. unstable angina/myocardial infarction) and related to disturbed beta‐cell function. The aim of this study is to test the hypothesis that treatment with a dipeptidyl peptidase‐4 inhibitor initiated soon after a coronary event improves beta‐cell function.

Methods

Acute coronary syndromeACS patients with IGT or T2DM (n = 71), screened by oral glucose tolerance test (OGTT) 4–23 days (median 6 days) after hospital admission, were randomly assigned to sitagliptin 100 mg (n = 34) or placebo (n = 37) and treated for a duration of 12 weeks. All patients received lifestyle advice but no glucose‐lowering agents other than the study drug. The study end‐point was beta‐cell function assessed using the insulinogenic index (IGI = ΔInsulin₃₀/ΔGlucose₃₀), derived from an OGTT, and acute insulin response to glucose (AIRg) assessed by a frequently sampled intravenous glucose tolerance test.

Results

The IGI and AIRg did not differ at baseline between the sitagliptin and placebo groups (69.9 vs. 66.4 pmol mmol^?1 and 1394 vs. 1106 pmol L^?1 min^?1 respectively). After 12 weeks, the IGI was 85.0 in the sitagliptin and 58.1 pmol/mmol in the placebo group (P = 0.013) and AIRg was 1909 and 1043 pmol L^?1 min^?1 (P < 0.0001) in the sitagliptin and placebo groups respectively. Fasting glucose at baseline was 6.1 mmol L^?1 in sitagliptin‐treated patients and 6.0 mmol L^?1 in those who received placebo compared with 5.8 and 5.9 mmol L^?1 respectively, after 12 weeks of treatment. Post load glucose metabolism improved in significantly more sitagliptin‐treated patients compared with the placebo group (P = 0.003). Sitagliptin was well tolerated.

Conclusion

Sitagliptin improved beta‐cell function and glucose perturbations in patients with ACS and newly diagnosed glucose disturbances.

     

What is the outcome in patients with acute leukaemia who survive severe acute graft‐versus‐host disease?

Background

Acute graft‐versus‐host disease (aGVHD ) is a major complication of allogeneic haematopoietic stem cell transplantation (HSCT ). With new promising therapies, survival may improve for severe aGVHD .

Objectives

We wanted to analyze the long‐term outcome in patients who survive severe aGVHD .

Methods

This study was a landmark analysis of 23 567 patients with acute Leukaemia who survived for more than 6 months after HSCT , 2002–2014. Patients alive after severe aGVHD (n = 1738) were compared to controls.

Results

Patients with severe aGVHD had higher non‐relapse mortality (NRM ) and higher rate of extensive chronic GVHD (cGVHD ) than the controls (P < 10^?5). The probability of relapse was significantly lower in the severe aGVHD group, but Leukaemia‐free survival (LFS ) and overall survival were significantly lower than for the controls (P < 10^?5). Five‐year LFS in patients with severe aGVHD was 49%, as opposed to 61% in controls with no or mild GVHD and 59% in patients with moderate GVHD.

Conclusions

HSCT patients who survive severe aGVHD have higher risk of developing extensive cGVHD , a higher NRM , a lower relapse probability, and lower LFS than other HSCT patients. This study is a platform for outcome analysis in patients treated with novel therapies for acute GVHD.

     

Targeted proteomic analysis of habitual coffee consumption

Background

Coffee drinking has been implicated in mortality and a variety of diseases but potential mechanisms underlying these associations are unclear. Large‐scale systems epidemiological approaches may offer novel insights to mechanisms underlying associations of coffee with health.

Objective

We performed an analysis of known and novel protein markers linked to cardiovascular disease and their association with habitual coffee intake in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS , n = 816) and followed up top proteins in the Uppsala Longitudinal Study of Adult Men (ULSAM , n = 635) and EpiHealth (n = 2418).

Methods

In PIVUS and ULSAM , coffee intake was measured by 7‐day dietary records whilst a computer‐based food frequency questionnaire was used in EpiHealth. Levels of up to 80 proteins were assessed in plasma by a proximity extension assay.

Results

Four protein–coffee associations adjusted for age, sex, smoking and BMI , met statistical significance in PIVUS (FDR < 5%, P < 2.31 × 10^?3): leptin (LEP ), chitinase‐3‐like protein 1 (CHI 3L), tumour necrosis factor (TNF ) receptor 6 and TNF ‐related apoptosis‐inducing ligand. The inverse association between coffee intake and LEP replicated in ULSAM (β, ?0.042 SD per cup of coffee, P = 0.028) and EpiHealth (β, ?0.025 SD per time of coffee, P = 0.004). The negative coffee–CHI 3L association replicated in EpiHealth (β, ?0.07, P = 1.15 × 10^?7), but not in ULSAM (β, ?0.034, P = 0.16).

Conclusions

The current study supports an inverse association between coffee intake and plasma LEP and CHI 3L1 levels. The coffee–CHI 3L1 association is novel and warrants further investigation given links between CHI 3L1 and health conditions that are also potentially influenced by coffee.

     

Human papillomavirus vaccination of adult women and risk of autoimmune and neurological diseases

Background

Since 2006, human papillomavirus (HPV ) vaccines have been introduced in many countries worldwide. Whilst safety studies have been reassuring, focus has been on the primary target group, the young adolescent girls. However, it is also important to evaluate safety in adult women where background disease rates and safety issues could differ significantly.

Objective

We took advantage of the unique Danish and Swedish nationwide healthcare registers to conduct a cohort study comparing incidence rate ratios (RR s) of 45 preselected serious chronic diseases in quadrivalent HPV (qHPV )‐vaccinated and qHPV ‐unvaccinated adult women 18–44 years of age.

Methods

We used Poisson regression to estimate RR s according to qHPV vaccination status with two‐sided 95% confidence intervals (95% CI s).

Results

The study cohort comprised 3 126 790 women (1 195 865 [38%] Danish and 1 930 925 [62%] Swedish) followed for 16 386 459 person‐years. Vaccine uptake of at least one dose of qHPV vaccine was 8% in the cohort: 18% amongst Danish women and 2% amongst Swedish. We identified seven adverse events with statistically significant increased risks following vaccination—Hashimoto's thyroiditis, coeliac disease, localized lupus erythematosus, pemphigus vulgaris, Addison's disease, Raynaud's disease and other encephalitis, myelitis or encephalomyelitis. After taking multiple testing into account and conducting self‐controlled case series analyses, coeliac disease (RR 1.56 [95% confidence interval 1.29–1.89]) was the only remaining association.

Conclusion

Unmasking of conditions at vaccination visits is a plausible explanation for the increased risk associated with qHPV in this study because coeliac disease is underdiagnosed in Scandinavian populations. In conclusion, our study of serious adverse event rates in qHPV ‐vaccinated and qHPV ‐unvaccinated adult women 18–44 years of age did not raise any safety issues of concern.

     

High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease

Objectives

Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL‐C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL‐C levels/function and CKD progression in patients with different degrees of disease.

Design

A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min^?1] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age‐matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR‐BI) and ATP‐binding cassette transporter A1 (ABCA‐1)‐dependent efflux of cholesterol were measured in CKD patients and in age‐matched control subjects.

Results

Low HDL‐C levels, diabetes and hypertension were associated with reduced GFR. At follow‐up, low HDL‐C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL‐C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917–0.986, P = 0.007), independently of the presence of diabetes. Only SR‐BI‐mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL‐C levels compared to the control group.

Conclusions

CKD patients with low levels of plasma HDL‐C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.

     

Clues for early detection of autoimmune Addison's disease – myths and realities

Background

Early detection of autoimmune Addison's disease (AAD ) is important as delay in diagnosis may result in a life‐threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well‐described, but methodical investigations are scarce.

Objective

Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD .

Material and Methods

A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978–2016. Scrutiny of medical records provided patient data and laboratory values.

Results

Low sodium occurred in 207 of 247 (84%), but only one‐third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty‐three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L^?1 [1–668]) and significantly lower in individuals with adrenal crisis (38 nmol L^?1 [2–442]) than in those without (81 nmol L^?1 [1–668], P < 0.001).

Conclusion

The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD , and on clinical suspicion bring about assay of cortisol and ACTH . Presence of 21‐hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

     

Occurrence of graft‐versus‐host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT

Background

The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune‐mediated graft‐versus‐leukaemia effects. Previous studies have suggested a strong association between graft‐versus‐host disease (GVHD) occurrence and graft‐versus‐leukaemia effects after allogeneic hematopoietic cell transplantation.

Methods

Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient‐year within sequential 90‐day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time‐dependent covariate.

Results

The study included data from 1068 patients given single (n  = 567) or double (n  = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II–IV acute (HR = 0.8, P  = 0.1) and chronic (HR = 0.65, P  = 0.1) GVHD decreased relapse risk. However, grade II–IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P  = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P  < 0.001) and late (HR = 4.9, P  < 0.001) mortality after UCBT.

Conclusions

The occurrence of grade II–IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft‐versus‐leukemia effect of GVHD.

     

CCL23: a new CC chemokine involved in human brain damage

Background

CCL 23 role in the inflammatory response after acute brain injuries remains elusive. Here, we evaluated whether CCL 23 blood levels associate with acquired cerebral lesions and determined CCL 23 predictive capacity for assessing stroke prognosis. We used preclinical models to study the CCL 23 homologous chemokines in rodents, CCL 9 and CCL 6.

Methods

Baseline CCL 23 blood levels were determined on 245 individuals, including ischaemic strokes (IS ), stroke mimics and controls. Temporal profile of circulating CCL 23 was explored from baseline to 24 h in 20 of the IS . In an independent cohort of 120 IS with a 3‐month follow‐up, CCL 23 blood levels were included in logistic regression models to predict IS outcome. CCL 9/CCL 6 cerebral expression was evaluated in rodent models of brain damage. Both chemokines were also profiled in circulation and histologically located on brain following ischaemia.

Results

Baseline CCL 23 blood levels did not discriminate IS , but permitted an accurate discrimination of patients presenting acute brain lesions (P  = 0.003). IS exhibited a continuous increase from baseline to 24 h in circulating CCL 23 (P  < 0.001). Baseline CCL 23 blood levels resulted an independent predictor of IS outcome at hospital discharge (OR _adj: 19.702 [1.815–213.918], P  = 0.014) and mortality after 3 months (OR _adj: 21.47 [3.434–134.221], P  = 0.001). In preclinics, expression of rodent chemokines in neurons following cerebral lesions was elevated. CCL 9 circulating levels decreased early after ischaemia (P  < 0.001), whereas CCL 6 did not alter within the first 24 h after ischaemia.

Conclusions

Although preclinical models do not seem suitable to characterize CCL 23, it might be a novel promising biomarker for the early diagnosis of cerebral lesions and might facilitate the prediction of stroke patient outcome.

     

Prognostic value of positive T wave in lead aVR in patients with non‐ST segment myocardial infarction

Background

Lead aVR provides prognostic information in various settings in patients with ischemia. We aim to investigate the role of a positive T wave in lead aVR in non‐ST segment myocardial infarction (NSTEMI).

Methods

In a prospective cohort study, we included 400 patients with NSTEMI. Presentation electrocardiogram (ECG) was investigated for presence of a positive T wave as well as ST segment elevation (STE) in aVR and study variables were compared. Predictors of primary outcome defined as hospital major adverse cardiovascular events (MACE) and secondary outcome, defined as three‐vessel coronary disease and/or left main coronary artery stenosis (3VD/LMCA) stenosis in angiography, were determined in multivariate logistic regression analysis.

Results

Patients with a positive T wave in aVR were significantly older and were more likely to be female. Left ventricular ejection fraction was significantly lower in patients of positive T group. Positive T group was more likely to have 3VD/LMCA stenosis (58.3% vs. 19.8%, p < .001). The prevalence of a positive T wave in aVR was significantly higher in MACE group (54.9 % vs. 24.8%, p < .001). However, in multivariate analysis, it was not an independent predictor of MACE (OR: 1.083 95% CI: [0.496–2.365], p: .841). Though, it was independently associated with presence of 3VD/LMCA stenosis (OR: 3.747 95% CI: [2.058–6.822], p < .001).

Conclusion

Though positive T wave in lead aVR was more common in patients with MACE; it was not an independent predictor. Additionally, a positive T wave in aVR was an independent predictor of 3VD/LMCA stenosis in NSTEMI.

     

Supplemental oxygen therapy does not affect the systemic inflammatory response to acute myocardial infarction

Background

Oxygen therapy has been used routinely in normoxemic patients with suspected acute myocardial infarction (AMI ) despite limited evidence supporting a beneficial effect. AMI is associated with a systemic inflammation. Here, we hypothesized that the inflammatory response to AMI is potentiated by oxygen therapy.

Methods

The DET ermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO 2X‐AMI ) multicentre trial randomized patients with suspected AMI to receive oxygen at 6 L min^?1 for 6–12 h or ambient air. For this prespecified subgroup analysis, we recruited patients with confirmed AMI from two sites for evaluation of inflammatory biomarkers at randomization and 5–7 h later. Ninety‐two inflammatory biomarkers were analysed using proximity extension assay technology, to evaluate the effect of oxygen on the systemic inflammatory response to AMI .

Results

Plasma from 144 AMI patients was analysed whereof 76 (53%) were randomized to oxygen and 68 (47%) to air. Eight biomarkers showed a significant increase, whereas 13 were decreased 5–7 h after randomization. The inflammatory response did not differ between the two treatment groups neither did plasma troponin T levels. After adjustment for increase in troponin T over time, age and sex, the release of inflammation‐related biomarkers was still similar in the groups.

Conclusions

In a randomized controlled setting of normoxemic patients with AMI , the use of supplemental oxygen did not have any significant impact on the early release of systemic inflammatory markers.

     

Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non–flow‐limiting coronary artery stenosis

Background

Experimental evidence suggests that ranolazine decreases susceptibility to ischemia‐induced arrhythmias independent of effects on coronary artery blood flow.

Objective

In symptomatic diabetic patients with non–flow‐limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, we explored whether ranolazine reduces T‐wave heterogeneity (TWH), an electrocardiographic (ECG) marker of arrhythmogenic repolarization abnormalities shown to predict sudden cardiac death.

Methods

We studied all 16 patients with analyzable ECG recordings during rest and exercise tolerance testing before and after 4 weeks of ranolazine in the double‐blind, crossover, placebo‐controlled RAND‐CFR trial (NCT01754259). TWH was quantified without knowledge of treatment assignment by second central moment analysis, which assesses the interlead splay of T waves in precordial leads about a mean waveform. Myocardial blood flow (MBF) was measured by positron emission tomography.

Results

At baseline, prior to randomization, TWH during rest was 54 ± 7 μV and was not altered following placebo (47 ± 6 μV, p = .47) but was reduced by 28% (to 39 ± 5 μV, p = .002) after ranolazine. Ranolazine did not increase MBF at rest. Exercise increased TWH after placebo by 49% (to 70 ± 8 μV, p = .03). Ranolazine did not reduce TWH during exercise (to 75 ± 16 μV), and there were no differences among the groups (p = .95, ANOVA). TWH was not correlated with MBF at rest before (r² = .07, p = .36) or after ranolazine (r² = .23, p = .06).

Conclusions

In symptomatic diabetic patients with non‐flow‐limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, ranolazine reduced TWH at rest but not during exercise. Reduction in repolarization abnormalities appears to be independent of alterations in MBF.

     

Smoking,plasma cotinine and risk of atrial fibrillation: the Hordaland Health Study

Background

Cigarette smoking has been identified as a major modifiable risk factor for coronary heart disease and mortality. However, findings on the relationship between smoking and atrial fibrillation (AF ) have been inconsistent. Furthermore, findings from previous studies were based on self‐reported smoking.

Objective

To examine the associations of smoking status and plasma cotinine levels, a marker of nicotine exposure, with risk of incident AF in the Hordaland Health Study.

Methods

We conducted a prospective analysis of 6682 adults aged 46‐74 years without known AF at baseline. Participants were followed via linkage to the Cardiovascular Disease in Norway (CVDNOR ) project and the Cause of Death Registry. Smoking status was assessed by both questionnaire and plasma cotinine levels.

Results

A total of 538 participants developed AF over a median follow‐up period of 11 years. Using questionnaire data, current smoking (HR : 1.41, 95% CI : 1.09–1.83), but not former smoking (HR : 1.03, 95% CI : 0.83–1.28), was associated with an increased risk of AF after adjustment for gender, age, body mass index, hypertension, physical activity and education. Using plasma cotinine only, the adjusted HR (95% CI ) was 1.40 (1.12–1.75) for participants with cotinine ≥85 nmol L^?1 compared to those with cotinine <85 nmol L^?1. However, the risk increased with elevated plasma cotinine levels until 1199 nmol L^?1 (HR : 1.55, 95% CI : 1.16–2.05 at the third group vs. the reference group) and plateaued at higher levels.

Conclusions

Current, but not former smokers, had a higher risk of developing AF . Use of plasma cotinine measurement corroborated this finding.

     

Acute effect of multiple ozone metrics on mortality by season in 34 Chinese counties in 2013–2015

Background

Although numerous multicentre studies have estimated the association between ozone exposure and mortality, there are currently no nationally representative multicentre studies of the ozone–mortality relationship in China.

Objective

To investigate the effect on total (nonaccidental) and cause‐specific mortality of short‐term exposure to ambient ozone, and examine different exposure metrics.

Methods

The effects of short‐term exposure to ozone were analysed using various metrics (daily 1‐h maximum, daily 8‐h maximum and daily average) on total (nonaccidental) and cause‐specific (circulatory and respiratory) mortality from 2013 to 2015 in 34 counties in 10 cities across China. We used distributed lag nonlinear models for estimating county‐specific relative risk of mortality and combined the county‐specific relative rates by conducting a random‐effects meta‐analysis.

Results

In all‐year analyses, a 10 μg m^?3 increase in daily average, daily 1‐h maximum and daily 8‐h maximum ozone at lag02 corresponded to an increase of 0.6% (95% CI : 0.33, 0.88), 0.26% (95% CI : 0.12, 0.39) and 0.37% (95% CI : 0.2, 0.55) in total (nonaccidental) mortality, 0.66% (95% CI : 0.28, 1.04), 0.31% (95% CI : 0.11, 0.51) and 0.39% (95% CI : 0.16, 0.62) in circulatory mortality, and 0.57% (95% CI : ?0.09, 1.23), 0.11% (95% CI : ?0.22, 0.44) and 0.22% (95% CI : ?0.28, 0.72) in respiratory mortality, respectively. These estimates had a different seasonal pattern by cause of death. In general, the seasonal patterns were consistent with the times of year when ozone concentrations are highest.

Conclusions

Our findings suggest that in China, the acute effects of ozone are more closely related to daily average exposure than any other metric.

     

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts

Background

Subclinical hyperthyroidism (SH yper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear.

Objective

To investigate the association between subclinical thyroid dysfunction and bone loss.

Methods

Individual participant data analysis was performed after a systematic literature search in MEDLINE /EMBASE (1946–2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD ) measurements. We classified thyroid status as euthyroidism (thyroid‐stimulating hormone [TSH ] 0.45–4.49 mIU/L), SH yper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SH ypo, TSH ≥ 4.50–19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X‐ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random‐effects two‐step approach.

Results

Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SH ypo and 284 (5.2%) had SH yper. During 36 569 person‐years of follow‐up, those with SH yper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = ?0.18 (95% CI: ?0.34, ?0.02; I ² = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = ?0.14 (95% CI: ?0.38, 0.10; I ² = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: ?0.30, 0.36; I ² = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = ?0.59; [95% CI: ?0.99, ?0.19]) and total hip region (%ΔBMD = ?0.46 [95% CI: ?1.05, ?0.13]). In contrast, SH ypo was not associated with bone loss at any site.

Conclusion

Amongst adults, SH yper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

     

Transglutaminase type 2 plays a key role in the pathogenesis of Mycobacterium tuberculosis infection

Background

Mycobacterium tuberculosis (MTB ), the aetiological agent of tuberculosis (TB ), is capable of interfering with the phagosome maturation pathway, by inhibiting phagosome–lysosome fusion and the autophagic process to ensure survival and replication in macrophages. Thus, it has been proposed that the modulation of autophagy may represent a therapeutic approach to reduce MTB viability by enhancing its clearance.

Objective

The aim of this study was to investigate whether transglutaminase type 2 (TG 2) is involved in the pathogenesis of MTB .

Results

We have shown that either genetic or pharmacological inhibition of TG 2 leads to a marked reduction in MTB replicative capacity. Infection of TG 2 knockout mice demonstrated that TG 2 is required for MTB intracellular survival in macrophages and host tissues. The same inhibitory effect can be reproduced in vitro using Z‐DON , a specific inhibitor of the transamidating activity of TG 2. Massive cell death observed in macrophages that properly express TG 2 is hampered by the absence of the enzyme and can be largely reduced by the treatment of wild‐type macrophages with the TG 2 inhibitor. Our data suggest that reduced MTB replication in cells lacking TG 2 is due to the impairment of LC 3/autophagy homeostasis. Finally, we have shown that treatment of MTB ‐infected murine and human primary macrophages with cystamine, a TG 2 inhibitor already tested in clinical studies, causes a reduction in intracellular colony‐forming units in human macrophages similar to that achieved by the anti‐TB drug capreomycin.

Conclusion

These results suggest that inhibition of TG 2 activity is a potential novel approach for the treatment of TB .

     

Left atrial rather than left ventricular impaired mechanics are associated with the pro‐fibrotic ST2 marker and outcomes in heart failure with preserved ejection fraction

Aims

Left ventricular (LV ) mechanics have been extensively investigated in heart failure with preserved ejection fraction (HF pEF ) overshadowing for a long time the potential role of left atrium (LA ) in that setting. Soluble suppression of tumorigenicity‐2 receptor (ST 2) is a novel biomarker of pro‐fibrotic burden in HF . We hypothesized that due to the thinner LA wall, the fibrotic myocardial changes in HF pEF as indicated by elevated ST 2 levels might more readily be reflected by impairments in the LA rather than the LV performance.

Methods and Results

In 86 patients with HF pEF , enrolled in the Karolinska Rennes (KaRen) biomarker prospective substudy, global LA strain (GL ‐LS ) along with other echocardiographic as well as haemodynamic parameters and ST 2 levels were measured. ST 2 levels were inversely associated with LA ‐GS (r  = ?0.30, P  = 0.009), but not with LA size, LV geometry, systolic or diastolic LV function (P  > 0.05 for all). Furthermore, symptom severity correlated with ST 2 and LA ‐GS , but not with LV structural or functional indices. Finally, during a median 18‐month follow‐up, LA ‐GS independently predicted the composite endpoint of HF hospitalization and all‐cause mortality, even after adjustment for potential clinical and cardiac mechanical confounders, including LV global longitudinal strain and filling pressures (odds ratio: 4.15; confidence interval: 1.2–14, P  = 0.023).

Conclusions

Reduced LA ‐GS but not LV functional systolic and diastolic parameters were associated with the pro‐fibrotic ST 2 marker, HF symptoms and outcome in HF pEF .

     

Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized,placebo‐controlled,double‐blind,clinical trial

Background

The importance of the gut microbiome for bone metabolism in mice has recently been demonstrated, but no studies are available in humans. Lactobacillus reuteri ATCCPTA 6475 (L. reuteri 6475) has been reported to increase bone mineral density (BMD ) in mice but its effect on the human skeleton is unknown. The objective of this trial was to investigate if L. reuteri 6475 affects bone loss in older women with low BMD .

Methods

In this double‐blind, placebo‐controlled study, women from the population who were 75 to 80 years old and had low BMD were randomized to orally receive 10¹⁰ colony‐forming units of L. reuteri 6475 daily or placebo. The predefined primary end‐point was relative change after 12 months in tibia total volumetric BMD (vBMD ).

Results

Ninety women were included and 70 completed the study. L. reuteri 6475 reduced loss of total vBMD compared to placebo both in the intention‐to‐treat (ITT ) analysis [?0.83% (95% confidence interval [CI ], ?1.47 to ?0.19%) vs. ?1.85% (95% CI , ?2.64 to ?1.07%); mean difference 1.02% (95% CI , 0.02–2.03)] and per protocol analysis [?0.93% (95% CI , ?1.45 to ?0.40) vs. ?1.86% (95% CI , ?2.35 to ?1.36); mean difference 0.93% (95% CI , 0.21–1.65)]. In general, similar but smaller effects were observed in the secondary bone variable outcomes, but these differences did not reach statistical significance in the ITT population. Adverse events did not differ between groups.

Conclusions

Supplementation with L. reuteri 6475 should be further explored as a novel approach to prevent age‐associated bone loss and osteoporosis.