A Wolf in Sheep's Clothing: Reuse of Routinely Obtained Laboratory Data in Research.

Electronic health records (EHRs) contain valuable data for reuse in science, quality evaluations, and clinical decision support. Because routinely obtained laboratory data are abundantly present, often numeric, generated by certified laboratories, and stored in a structured way, one may assume that they are immediately fit for (re)use in research. However, behind each test result lies an extensive context of choices and considerations, made by both humans and machines, that introduces hidden patterns in the data. If they are unaware, researchers reusing routine laboratory data may eventually draw incorrect conclusions. In this paper, after discussing health care system characteristics on both the macro and micro level, we introduce the reader to hidden aspects of generating structured routine laboratory data in 4 steps (ordering, preanalysis, analysis, and postanalysis) and explain how each of these steps may interfere with the reuse of routine laboratory data. As researchers reusing these data, we underline the importance of domain knowledge of the health care professional, laboratory specialist, data manager, and patient to turn routine laboratory data into meaningful data sets to help obtain relevant insights that create value for clinical care.

Axial light loss of monocytes as a readily available prognostic biomarker in patients with suspected infection at the emergency department.

OBJECTIVES: To evaluate the prognostic value of the coefficient of variance of axial light loss of monocytes (cv-ALL of monocytes) for adverse clinical outcomes in patients suspected of infection in the emergency department (ED). METHODS: We performed an observational, retrospective monocenter study including all medical patients ≥18 years admitted to the ED between September 2016 and June 2019 with suspected infection. Adverse clinical outcomes included 30-day mortality and ICU/MCU admission <3 days after presentation. We determined the additional value of monocyte cv-ALL and compared to frequently used clinical prediction scores (SIRS, qSOFA, MEWS). Next, we developed a clinical model with routinely available parameters at the ED, including cv-ALL of monocytes. RESULTS: A total of 3526 of patients were included. The OR for cv-ALL of monocytes alone was 2.21 (1.98-2.47) for 30-day mortality and 2.07 (1.86-2.29) for ICU/MCU admission <3 days after ED presentation. When cv-ALL of monocytes was combined with a clinical score, the prognostic accuracy increased significantly for all tested scores (SIRS, qSOFA, MEWS). The maximum AUC for a model with routinely available parameters at the ED was 0.81 to predict 30-day mortality and 0.81 for ICU/MCU admission. CONCLUSIONS: Cv-ALL of monocytes is a readily available biomarker that is useful as prognostic marker to predict 30-day mortality. Furthermore, it can be used to improve routine prediction of adverse clinical outcomes at the ED. CLINICAL TRIAL REGISTRATION: Registered in the Dutch Trial Register (NTR) und number 6916.

Data mining to retrieve smoking status from electronic health records in general practice.

Aims: Optimize and assess the performance of an existing data mining algorithm for smoking status from hospital electronic health records (EHRs) in general practice EHRs. Methods and results: We optimized an existing algorithm in a training set containing all clinical notes from 498 individuals (75 712 contact moments) from the Julius General Practitioners' Network (JGPN). Each moment was classified as either 'current smoker', 'former smoker', 'never smoker', or 'no information'. As a reference, we manually reviewed EHRs. Algorithm performance was assessed in an independent test set (n = 494, 78 129 moments) using precision, recall, and F1-score. Test set algorithm performance for 'current smoker' was precision 79.7%, recall 78.3%, and F1-score 0.79. For former smoker, it was precision 73.8%, recall 64.0%, and F1-score 0.69. For never smoker, it was precision 92.0%, recall 74.9%, and F1-score 0.83. On a patient level, performance for ever smoker (current and former smoker combined) was precision 87.9%, recall 94.7%, and F1-score 0.91. For never smoker, it was 98.0, 82.0, and 0.89%, respectively. We found a more narrative writing style in general practice than in hospital EHRs. Conclusion: Data mining can successfully retrieve smoking status information from general practice clinical notes with a good performance for classifying ever and never smokers. Differences between general practice and hospital EHRs call for optimization of data mining algorithms when applied beyond a primary development setting.

Preventing unnecessary imaging in patients suspect of coronary artery disease through machine learning of electronic health records.

Aims: With the ageing European population, the incidence of coronary artery disease (CAD) is expected to rise. This will likely result in an increased imaging use. Symptom recognition can be complicated, as symptoms caused by CAD can be atypical, particularly in women. Early CAD exclusion may help to optimize use of diagnostic resources and thus improve the sustainability of the healthcare system. To develop sex-stratified algorithms, trained on routinely available electronic health records (EHRs), raw electrocardiograms, and haematology data to exclude CAD in patients upfront. Methods and results: We trained XGBoost algorithms on data from patients from the Utrecht Patient-Oriented Database, who underwent coronary computed tomography angiography (CCTA), and/or stress cardiac magnetic resonance (CMR) imaging, or stress single-photon emission computerized tomography (SPECT) in the UMC Utrecht. Outcomes were extracted from radiology reports. We aimed to maximize negative predictive value (NPV) to minimize the false negative risk with acceptable specificity. Of 6808 CCTA patients (31% female), 1029 females (48%) and 1908 males (45%) had no diagnosis of CAD. Of 3053 CMR/SPECT patients (45% female), 650 females (47%) and 881 males (48%) had no diagnosis of CAD. On the train and test set, the CCTA models achieved NPVs and specificities of 0.95 and 0.19 (females) and 0.96 and 0.09 (males). The CMR/SPECT models achieved NPVs and specificities of 0.75 and 0.041 (females) and 0.92 and 0.026 (males). Conclusion: Coronary artery disease can be excluded from EHRs with high NPV. Our study demonstrates new possibilities to reduce unnecessary imaging in women and men suspected of CAD.

Platelet count and indices as postpartum hemorrhage risk factors: a retrospective cohort study.

BACKGROUND: Severe postpartum hemorrhage (SPPH) is the leading cause of maternal mortality and morbidity worldwide. Platelet anomalies frequently occur during pregnancy. However, their role in the etiology of SPPH is largely unknown. OBJECTIVE: To study the relation between platelet parameters and SPPH. METHODS: This retrospective single-center cohort included deliveries between 2009 and 2017. SPPH was defined as ≥1000 ml blood loss within 24 h after delivery. Platelet parameters were measured within 72 h before delivery. Multiple imputation was performed for missing data. Odds ratios were adjusted (aORs) for maternal age, multiple gestation, macrosomia, induction of labor, preeclampsia, and hemolysis, elevated liver enzymes, and low platelets syndrome. RESULTS: A total of 23 205 deliveries were included. Of the 2402 (10.4%) women with thrombocytopenia (<150 × 109 /L), 10.3% developed SPPH, compared with 7.6% of women with a normal platelet count (aOR: 1.34, 95% CI: 1.14-1.59). Women with a platelet count of <50 × 109 /L were most at risk (aOR of 2.24 [1.01-4.94]) compared with the reference group with normal platelet counts; the aOR was 1.22 (0.77-1.93) for the 50-99 × 109 /L platelet count group and 1.31 (1.10-1.56) for the 100-149 × 109 /L platelet count group. Plateletcrit was associated with SPPH (aOR 1.15 [1.08-1.21] per 0.05% decrease), and, although rarely present, a platelet distribution width (PDW) ≥23% (n = 22) also increased the odds of SPPH (aOR 6.05 [2.29-16.20]). CONCLUSION: Different degrees of thrombocytopenia were independently associated with the occurrence of SPPH. Despite their relation to SPPH, plateletcrit and a PDW of ≥23% have limited additional value in addition to platelet count.

Switching TNFα inhibitors: Patterns and determinants.

The aim of this study was to assess switching patterns and determinants for switching in patients initiating TNFα inhibitor (TNFα-i) treatment. Patients were included who started TNFα-i treatment between July 1, 2012 and December 31, 2017, from three Dutch hospitals, and were diagnosed with rheumatic diseases (RD), inflammatory bowel disease (IBD), or psoriasis. Outcomes were switching, defined as initiating another biological; switching patterns including multiple switches until the end of follow-up; determinants for first switch, assessed using multivariate logistic regression. A total of 2228 patients were included (median age 43.3 years, 57% female), of which 52% (n = 1155) received TNFα-i for RD, 43% (n = 967) for IBD, and 5% (n = 106) for psoriasis. About 16.6% of RD patients, 14.5% of IBD patients, and 16.0% of psoriasis patients switched at least once, mainly to another TNFα-i. TNFα-i dose escalation (OR 13.78, 95% CI 1.40-135.0) and high-dose corticosteroids initiation (OR 3.62, 95% CI 1.10-12.15) were determinants for switching in RD patients. TNFα-i dose escalation (OR 8.22, 95% CI 3.76-17.93), immunomodulator initiation/dose escalation (OR 2.13, 95% CI 1.04-4.34), high-dose corticosteroids initiation (OR 6.91, 95% CI 2.81-17.01) and serum concentration measurement (OR 5.44, 95% CI 2.74-10.79) were determinants for switching in IBD patients. Switching biological treatment occurred in about one in six patients. RD patients with TNFα-i dose escalation and/or high-dose corticosteroids initiation were more likely to switch. IBD patients with TNFα-i or immunomodulator initiation/dose escalation, high-dose corticosteroids initiation or serum concentration measurement were more likely to switch. These findings might help clinicians anticipating switching in TNFα-i treatment.

Intra-Operative Hypotension is a Risk Factor for Post-operative Silent Brain Ischaemia in Patients With Pre-operative Hypertension Undergoing Carotid Endarterectomy.

OBJECTIVE: Intra-operative haemodynamic instability during carotid endarterectomy (CEA) has been associated with an increased risk of procedural stroke. Diffusion weighted imaging (DWI) lesions have been proposed as a surrogate marker for peri-operative silent cerebral ischaemia. This study aimed to investigate the relationship between peri-operative blood pressure (BP) and presence of post-operative DWI lesions in patients undergoing CEA. METHODS: A retrospective analysis was performed based on patients with symptomatic CEA included in the MRI substudy of the International Carotid Stenting Study. Relative intra-operative hypotension was defined as a decrease of intra-operative systolic BP ≥ 20% compared with pre-operative ('baseline') BP, absolute hypotension was defined as a drop in systolic BP < 80  mmHg. The primary endpoint was the presence of any new DWI lesions on post-operative MRI (DWI positive). The occurrence and duration of intra-operative hypotension was compared between DWI positive and DWI negative patients as was the magnitude of the difference between pre- and intra-operative BP. RESULTS: Fifty-five patients with symptomatic CEA were included, of whom eight were DWI positive. DWI positive patients had a significantly higher baseline systolic (186 ± 31 vs. 158 ± 27 mmHg, p = .011) and diastolic BP (95 ± 15 vs. 84 ± 13 mmHg, p = .046) compared with DWI negative patients. Other pre-operative characteristics did not differ. Relative intra-operative hypotension compared with baseline occurred in 53/55 patients (median duration 34 min; range 0-174). Duration of hypotension did not differ significantly between the groups (p = .088). Mean systolic intra-operative BP compared with baseline revealed a larger drop in BP (-37 ± 29 mmHg) in DWI positive compared with DWI negative patients (-14 ± 26 mmHg, p = .024). Absolute intra-operative systolic BP values did not differ between the groups. CONCLUSION: In this exploratory study, high pre-operative BP and a larger drop of intra-operative BP were associated with peri-procedural cerebral ischaemia as documented with DWI. These results call for confirmation in an adequately sized prospective study, as they suggest important consequences for peri-operative haemodynamic management in carotid revascularisation.

Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) after Polytrauma: A Rare Syndrome with Major Consequences.

Nowadays, more trauma patients develop chronic critical illness (CCI), a state characterized by prolonged intensive care. Some of these CCI patients have disproportional difficulties to recover and suffer from recurrent infections, a syndrome described as the persistent inflammation, immunosuppression and catabolism syndrome (PICS). A total of 78 trauma patients with an ICU stay of ≥14 days (CCI patients) between 2007 and 2017 were retrospectively included. Within this group, PICS patients were identified through two ways: (1) their clinical course (≥3 infectious complications) and (2) by laboratory markers suggested in the literature (C-reactive protein (CRP) and lymphocytes), both in combination with evidence of increased catabolism. The incidence of PICS was 4.7 per 1000 multitrauma patients. The sensitivity and specificity of the laboratory markers was 44% and 73%, respectively. PICS patients had a longer hospital stay (median 83 vs. 40, p < 0.001) and required significantly more surgical interventions (median 13 vs. 3, p = 0.003) than other CCI patients. Thirteen PICS patients developed sepsis (72%) and 12 (67%) were readmitted at least once due to an infection. In conclusion, patients who develop PICS experience recurrent infectious complications that lead to prolonged hospitalization, many surgical procedures and frequent readmissions. Therefore, PICS forms a substantial burden on the patient and the hospital, despite its low incidence.

Reticulated Platelets as Predictor of Myocardial Injury and 30 Day Mortality After Non-cardiac Surgery.

OBJECTIVE: A pre-operative marker for identification of patients at risk of peri-operative adverse events and 30 day mortality might be the percentage of young, reticulated platelets (pRP). This study aimed to determine the predictive value of pre-operative pRP on post-operative myocardial injury (PMI) and 30 day mortality, in patients aged ≥ 60 years undergoing moderate to high risk non-cardiac surgery. METHODS: The incidence of PMI (troponin I > 0.06 µg/L) and 30 day mortality was compared for patients with normal and high pRP (≥2.82%) obtained from The Utrecht Patient Orientated Database. The predictive pRP value was assessed using logistic regression. A prediction model for PMI or 30 day mortality with known risk factors was compared with a model including increased pRP using the area under the receiving operator characteristics curve (AUROC). RESULTS: In total, 26.5% (607/2289) patients showed pre-operative increased pRP. Increased pRP was associated with more PMI and 30 day mortality compared with normal pRP (36.1% vs. 28.3%, p < .001 and 8.6% vs. 3.6%, p < .001). The median pRP was higher in patients suffering PMI and 30 day mortality compared with not (2.21 [IQR: 1.57-3.11] vs. 2.07 [IQR: 1.52-1.78], p = .002, and 2.63 [IQR: 1.76-4.15] vs. 2.09 [IQR: 1.52-3.98], p < .001). pRP was independently related to PMI (OR: 1.28 [95% CI: 1.04-1.59], p = .02) and 30 day mortality (OR: 2.35 [95% CI: 1.56-3.55], p < .001). Adding increased pRP to the predictive model of PMI or 30 day mortality did not increase the AUROC 0.71 vs. 0.72, and 0.80 vs. 0.81. CONCLUSION: In patients undergoing major non-cardiac surgery, increased pre-operative pRP is related to 30 day mortality and PMI.

A pan-inflammatory microRNA-cluster is associated with orbital non-Hodgkin lymphoma and idiopathic orbital inflammation.

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.

Treatment to Target Using Recombinant Interleukin-1 Receptor Antagonist as First-Line Monotherapy in New-Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five-Year Follow-Up Study.

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage. METHODS: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped. RESULTS: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL-1Ra was equally effective in systemic JIA patients without arthritis at disease onset. CONCLUSION: Treatment to target, starting with first-line, short-course monotherapy with rIL-1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease- and glucocorticoid-related damage in systemic JIA.

A Rise in Neutrophil Cell Size Precedes Organ Dysfunction After Trauma.

INTRODUCTION: Organ dysfunction remains a major cause of morbidity after trauma. The development of organ dysfunction is determined by the inflammatory response, in which neutrophils are important effector cells. A femoral fracture particularly predisposes for the development of organ dysfunction. This study investigated the chronologic relation between neutrophil characteristics and organ dysfunction in trauma patients with a femoral fracture. METHODS: Patients with a femoral fracture presenting at the University Medical Center Utrecht between 2007 and 2013 were included. Data of neutrophil characteristics from standard hematological analyzers were recorded on a daily basis until the 28th day of hospital stay or until discharge. Generalized Estimating Equations were used to compare outcome groups. RESULTS: In total 157 patients were analyzed, of whom 81 had polytrauma and 76 monotrauma. Overall mortality within 90 days was 6.4% (n = 10). Eleven patients (7.0%) developed organ dysfunction. In patients who developed organ dysfunction a significant increase in neutrophil count (P = 0.024), a significant increase in neutrophil cell size (P = 0.026), a significant increase in neutrophil complexity (P < 0.004), and a significant decrease in neutrophil lobularity (P < 0.001) were seen after trauma. The rise in neutrophil cell size preceded the clinical manifestation of organ dysfunction in every patient. CONCLUSION: Patients who develop organ dysfunction postinjury show changes in neutrophil characteristics before organ dysfunction becomes clinically evident. These findings regarding post-traumatic organ dysfunction may contribute to the development of new prognostic tools for immune-mediated complications in trauma patients. LEVEL OF EVIDENCE: Level II, etiologic study.

A single preoperative blood test predicts postoperative sepsis and pneumonia after coronary bypass or open aneurysm surgery.

BACKGROUND: Major surgery comes with a high risk for postoperative inflammatory complications. Preoperative risk scores predict mortality risk but fail to identify patients at risk for complications following cardiovascular surgery. We therefore assessed the value of preoperative red cell distribution width (RDW) as a predictor for pneumonia and sepsis after cardiovascular surgery and studied the relation of RDW with hematopoietic tissue activity. METHODS: RDW is an easily accessible, yet seldomly used parameter from routine haematology measurements. RDW was extracted from the Utrecht Patient Orientated Database (UPOD) for preoperative measurements in patients undergoing open abdominal aortic anuerysm repair (AAA)(N = 136) or coronary artery bypass grafting (CABG)(N = 2193). The cohorts were stratified in tertiles to assess effects over the different groups. Generalized Linear Models were used to determine associations between RDW and postoperative inflammatory complications. Hematopoietic tissue activity was scored using fluor-18-(18F)-deoxyglucose positron emission tomography and associated with RDW using linear regression models. RESULTS: In total, 43(31.6%) and 73 patients (3.3%) suffered from inflammatory complications after AAA-repair or CABG, respectively; the majority being pneumonia in both cohorts. Postoperative inflammatory outcome incidence increased from 19.6% in the lowest to 48.9% in the highest RDW tertile with a corresponding risk ratio (RR) of 2.35 ([95%CI:1.08-5.14] P = 0.032) in AAA patients. In the CABG cohort, the incidence of postoperative inflammatory outcomes increased from 1.8% to 5.3% with an adjusted RR of 1.95 ([95%CI:1.02-3.75] P = 0.044) for the highest RDW tertile compared with the lowest RDW tertile. FDG-PET scans showed associations of RDW with tissue activity in the spleen (B = 0.517 [P = 0.001]) and the lumbar bone marrow (B = 0.480 [P = 0.004]). CONCLUSION: Elevated RDW associates with increased risk for postoperative inflammatory complications and hematopoietic tissue activity. RDW likely reflects chronic low-grade inflammation and should be considered to identify patients at risk for postoperative inflammatory complications following cardiovascular surgery.

Routinely measured hematological parameters and prediction of recurrent vascular events in patients with clinically manifest vascular disease.

BACKGROUND AND AIMS: The predictive value of traditional risk factors for vascular events in patients with manifest vascular disease is limited, underscoring the need for novel biomarkers to improve risk stratification. Since hematological parameters are routinely assessed in clinical practice, they are readily available candidates. METHODS: We used data from 3,922 vascular patients, who participated in the Second Manifestations of ARTerial Disease (SMART) study. We first investigated associations between recurrent vascular events and 22 hematological parameters, obtained from the Utrecht Patient Oriented Database (UPOD), and then assessed whether parameters associated with outcome improved risk prediction. RESULTS: After adjustment for all SMART risk score (SRS) variables, lymphocyte %, neutrophil count, neutrophil % and red cell distribution width (RDW) were significantly associated with vascular events. When individually added to the SRS, lymphocyte % improved prediction of recurrent vascular events with a continuous net reclassification improvement (cNRI) of 17.4% [95% CI: 2.1, 32.1%] and an increase in c-statistic of 0.011 [0.000, 0.022]. The combination of lymphocyte % and neutrophil count resulted in a cNRI of 22.2% [3.2, 33.4%] and improved c-statistic by 0.011 [95% CI: 0.000, 0.022]. Lymphocyte % and RDW yielded a cNRI of 18.7% [3.3, 31.9%] and improved c-statistic by 0.016 [0.004, 0.028]. However, the addition of hematological parameters only modestly increased risk estimates for patients with an event during follow-up. CONCLUSIONS: Several hematological parameters were independently associated with recurrent vascular events. Lymphocyte % alone and in combination with other parameters enhanced discrimination and reclassification. However, the incremental value for patients with a recurrent event was limited.

Commonly available hematological biomarkers are associated with the extent of coronary calcifications.

BACKGROUND AND AIMS: We aimed to improve the understanding of potential associations between commonly available hematological biomarkers and the coronary artery calcification (CAC) score, which may help unravel the pathophysiology of coronary calcifications and subclinical coronary artery disease. METHODS: A cross-sectional study was performed within the Utrecht Patient Oriented Database (UPOD). Patients with suspected or known coronary artery disease who underwent CT CAC scoring as well as standard hematology analysis that was part of routine clinical care (within 3 months of CT acquisition) were included. Complete hematology datasets were extracted from hematology analyzers. Linear regression adjusted for potential confounders was used to assess if hematological biomarkers were related to the CAC score. RESULTS: In total, 1504 patients were included, of whom 43% (n = 647) had a CAC score of 0. Mean age (±SD) was 53 ±â€¯13 years, and 34% of patients were women. Red blood cell distribution width (RDW, ß = 0.20 [0.05-0.36], p=0.007), the fraction of immature reticulocytes (ß = 0.97 [0.10-6.43], p=0.004), coefficient of variation of neutrophil lobularity (ß = 0.13 [0.01-0.25], p=0.040) and mean lymphocyte cell size (ß = 0.21 [0.08-0.34], p=0.001) were positively associated with the CAC score after adjustment for age, sex, body mass index (BMI), diabetes, glomerular filtration rate (GFR) and high-density lipoprotein (HDL). CONCLUSIONS: This study confirms the known association of RDW with the CAC score, and presents the fraction of immature reticulocytes, coefficient of variation of neutrophil lobularity, and mean lymphocyte cell size as new markers associated with a higher CAC score.

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.

BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

The impact of age and sex on the reporting of cough and angioedema with renin-angiotensin system inhibitors: a case/noncase study in VigiBase.

The purpose of this study was to assess the impact of age and sex on the reporting of cough and angioedema related to renin-angiotensin system (RAS) inhibitors. A case/noncase study was performed in VigiBase. Two case groups were identified, reports of cough and reports of angioedema, and noncases were all reports of all other adverse events. Logistic regression analysis was used to assess the association between reporting of cough and angioedema with each class of RAS inhibitors stratified by age/sex and to control for confounding. The reporting of cough with angiotensin-converting enzyme (ACE) inhibitors was significantly higher in women than in men [adjusted reporting odds ratio (ROR): 44.0, 95% CI (43.2-44.8) for women vs. 29.2, 95% CI (28.5-29.9) for men]. There was no difference in reporting of cough linked to angiotensin receptor blockers (ARBs) and aliskiren between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than in women, but for aliskiren, women had a significantly higher ROR than men [adjusted ROR: 5.20, 95% CI (4.18-6.46) for women vs. 3.04, 95% CI (2.30-4.02) for men]. The reporting of cough with ACE inhibitors was increased with age until reaching a plateau at middle adulthood (40-59 years) and the reporting of angioedema with ACE inhibitors was increased with age until elderly (60-79 years). Age had only a slight effect on the reporting of cough and angioedema with ARBs and aliskiren. Both age and sex have substantial effects on the reporting of cough and angioedema with RAS inhibitors and in particular ACE inhibitors. Further study is needed to determine whether these differences mainly express different adverse drug reaction risks in subgroups or also can be explained by factors influencing reporting.

The impact of serum potassium-influencing antihypertensive drugs on the risk of out-of-hospital cardiac arrest: A case-control study.

AIMS: Sudden cardiac arrest (SCA) is a complex multifactorial event and most commonly caused by ventricular tachycardia/ fibrillation (VT/ VF). Some antihypertensive drugs could induce hypokalaemia or hyperkalaemia, which may increase susceptibility to VT/VF and SCA. OBJECTIVE: To assess the association between different classes of antihypertensive drugs classified according to their potential impact on serum potassium levels and the occurrence of out-of-hospital cardiac arrest (OHCA) based on VT/VF. METHODS: A case-control study was performed among current users of antihypertensive drugs. Cases were OHCA victims with electrocardiogram documented VT/VF drawn from the AmsteRdam REsuscitation STudies (ARREST) registry, and controls were non-OHCA individuals from the PHARMO database. Antihypertensive drugs were classified into: (i) antihypertensives with neutral effect on serum potassium levels; (ii) hypokalaemia-inducing antihypertensives; (iii) hyperkalaemia-inducing antihypertensives; (iv) combination of antihypertensives with hypo- and hyperkalaemic effects. RESULTS: We included 1345 cases and 4145 controls. The risk of OHCA was significantly increased among users of hypokalaemia-inducing antihypertensives [adjusted odds ratio (OR) 1.39; 95% confidence interval (CI) 1.10-1.76] and among users of a combination of antihypertensives with hypo- and hyperkalaemic effects (adjusted OR 1.42; 95%CI 1.17-1.72) vs. users of antihypertensives with neutral effect. There was no difference in OHCA risk between users of hyperkalaemia-inducing antihypertensives vs. users of antihypertensive drugs with neutral effect (adjusted OR 1.15; 95%CI 0.95-1.40). CONCLUSION: The risk of OHCA is significantly increased in patients who were current users of hypokalaemia-inducing antihypertensives and patients using a combination of antihypertensives with hypo- and hyperkalaemic effects.

Trends in breast cancer incidence among women with type-2 diabetes in British general practice.

AIMS: To quantify breast cancer incidence in women with type-2 diabetes and assess age-standardized trends in invasive breast cancer incidence over time and by age groups. METHODS: A population-based cohort study was conducted using the British general practice database (Clinical Practice Research Datalink) using data from 1989 to 2012. All adult women prescribed anti-hyperglycemic medication were selected and matched (1:1) on age and clinical practice to a reference cohort without diabetes. RESULTS: During approximately 1.6 million person years (py), 2371 breast cancer cases were diagnosed in the diabetes cohort (n=147,998) and 2252 in the reference cohort (n=147,998). Incidence of breast cancer, overall or by age groups, among women with diabetes remained stable over time. The (overall) age-standardized breast cancer IR per 100,000 py of the diabetes cohort (150, 95%CI:143-157) resembled that observed in the reference cohort (148, 95%CI:141-156); with an incidence rate ratio (IRR) of 1.01 (95%CI:0.94-1.08, p>0.05). CONCLUSIONS: Currently, around 2880 women with type-2 diabetes are diagnosed with breast cancer per year in the United Kingdom. However, breast cancer incidence remained stable in the last 10 years and seems to be comparable in women with and without diabetes.

The High Impact of Penicillin Allergy Registration in Hospitalized Patients.

BACKGROUND: Suspected penicillin allergy (Pen-A) is often not verified or excluded by diagnostic testing. OBJECTIVE: To assess the prevalence and impact of Pen-A registration in a Dutch University Medical Center. METHODS: In a prospective matched cohort study, all admitted patients (July 2013-July 2014) who underwent a pharmacotherapeutic interview were selected. Patients with a registered Pen-A were matched on age, sex, and department of admission with up to 3 patients without a registered Pen-A. Relative risks (RRs) of receiving a reserve antibiotic, death during hospitalization, and rehospitalization were compared in the 2 cohorts. The number and type of antibiotics prescribed during admission and duration of hospitalization were compared. RESULTS: Of 17,959 patients, 1010 (5.6%) patients (66.7% women; median age, 55 years) had a Pen-A registration. These patients had a higher risk of receiving reserve antibiotics (RR, 1.38; 95% CI, 1.22-1.56) and of being rehospitalized within 12 weeks (RR, 1.28; 95% CI, 1.10-1.49). A significantly larger proportion of Pen-A registered patients received reserve antibiotics such as tetracyclines (1.8% vs 0.8%), macrolides/lincosamides/streptogramins (12.5% vs 4.9%), and quinolones (7.9% vs 4.3%) or received 2 or more types of antibiotics during hospitalization (21.7% vs 16.9%). CONCLUSIONS: Prevalence of Pen-A registration in hospitalized patients is high, has high impact on antibiotic prescribing, and is associated with a higher risk of readmission. Verification of the Pen-A in hospitalized patients might restrict the use of reserve antibiotics and improve patient outcome.