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Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.Objectives: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.Methods: In 2566 individuals of the population-based Maastricht Study (age: 60 +/- 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in> 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using theAGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (beta: 0.08; 95% CI: 0.02, 0.13) and SAF (beta: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (beta: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Background & aims: Ageing is associated with an increased risk of frailty, intestinal microbiota perturbations, immunosenescence and oxidative stress. Prebiotics such as galacto-oligosaccharides (GOS) may ameliorate these ageing-related alterations. We aimed to compare the faecal microbiota composition, metabolite production, immune and oxidative stress markers in prefrail elderly and younger adults, and investigate the effects of GOS supplementation in both groups. Methods: In a randomised controlled cross-over study, 20 prefrail elderly and 24 healthy adults received 21.6 g/day BiotisTM GOS (containing 15.0 g/day GOS) or placebo. Faecal 16S rRNA gene-based microbiota and short-chain fatty acids were analysed at 0,1 and 4 weeks of intervention.Volatile organic compounds were analysed in breath, and stimulated cytokine production, CRP, malondialdehyde, trolox equivalent antioxidant capacity (TEAC) and uric acid (UA) in blood at 0 and 4 weeks. Results: Principle coordinate analysis showed differences in microbial composition between elderly and adults (P

BACKGROUND: Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI.METHODS: Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation.RESULTS: MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior.CONCLUSION: Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed.

Objectives We wanted to estimate the magnitude of the risk from all-cause, cause-specific and sex-specific mortality in patients with SLE and relative risks compared with matched controls and to evaluate the influence of exposure to medication on risk of mortality in SLE. Methods We conducted a population-based cohort study using the Clinical Practice Research Datalink, Hospital Episode Statistics and national death certificates (from 1987 to 2012). Each SLE patient (n = 4343) was matched with up to six controls (n = 21 780) by age and sex. Cox proportional hazards models were used to estimate overall and cause-specific mortality rate ratios. Results Patients with SLE had a 1.8-fold increased mortality rate for all-cause mortality compared with age- and sex-matched subjects [adjusted hazard ratio (HR) = 1.80, 95% CI: 1.57, 2.08]. The HR was highest in patients aged 18–39 years (adjusted HR = 4.87, 95% CI: 1.93, 12.3). Mortality rates were not significantly different between male and female patients. Cumulative glucocorticoid use raised the mortality rate, whereas the HR was reduced by 45% with cumulative low-dose HCQ use. Patients with SLE had increased cause-specific mortality rates for cardiovascular disease, infections, non-infectious respiratory disease and for death attributable to accidents or suicide, whereas the mortality rate for cancer was reduced in comparison to controls. Conclusion British patients with SLE had a 1.8-fold increased mortality rate compared with the general population. Glucocorticoid use and being diagnosed at a younger age were associated with an increased risk of mortality. HCQ use significantly reduced the mortality rate, but this association was found only in the lowest cumulative dosage exposure group.

A previous chlamydia infection did not result in fewer pregnant women, but among women with a pregnancy intention, time to pregnancy was longer compared with women without a previous infection. Supplemental digital content is available in the text., Background A Chlamydia trachomatis infection (chlamydia) can result in tubal factor infertility in women. To assess if this association results in fewer pregnant women, we aimed to assess pregnancy incidences and time to pregnancy among women with a previous chlamydia infection compared with women without one and who were participating in the Netherlands Chlamydia Cohort Study (NECCST). Methods The NECCST is a cohort of women of reproductive age tested for chlamydia in a chlamydia screening trial between 2008 and 2011 and reinvited for NECCST in 2015 to 2016. Chlamydia status (positive/negative) was defined using chlamydia screening trial–nucleic acid amplification test results, chlamydia immunoglobulin G presence in serum, or self-reported chlamydia infections. Data on pregnancies were collected via questionnaires in 2015–2016 and 2017–2018. Overall pregnancies (i.e., planned and unplanned) and time to pregnancy (among women with a pregnancy intention) were compared between chlamydia-positive and chlamydia-negative women using Cox regressions. Results Of 5704 women enrolled, 1717 (30.1%; 95% confidence interval [CI], 28.9–31.3) women was chlamydia positive. Overall pregnancy proportions were similar in chlamydia-positive and chlamydia-negative women (49.0% [95% CI, 46.5–51.4] versus 50.5% [95% CI, 48.9–52.0]). Pregnancies per 1000 person-years were 53.2 (95% CI, 51.5–55.0) for chlamydia negatives and 83.0 (95% CI, 78.5–87.9) for chlamydia positives. Among women with a pregnancy intention, 12% of chlamydia-positive women had a time to pregnancy of >12 months compared with 8% of chlamydia negatives (P < 0.01). Conclusions Overall pregnancy rates were not lower in chlamydia-positive women compared with chlamydia-negative women, but among women with a pregnancy intention, time to pregnancy was longer and pregnancy rates were lower in chlamydia-positive women. Trial registration number: Dutch Trial Register NTR-5597.

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.

Objectives To study the effects of running with/without the use of pain killers on urinary neutrophil gelatinase-associated lipocalin (uNGAL) and other parameters of kidney function in recreational runners. Methods Participants of the 10- and 21.1-km Weir Venloop race were enrolled and their urine samples collected before and after the run. Urine dipstick and other conventional tests used to assess kidney function were performed. The presence of ibuprofen, diclofenac, naproxen, and/or paracetamol was assessed by LC-MS/MS. uNGAL was measured with a two-step chemiluminescent immunoassay. Results NSAIDs/analgesics were detected in urine of 5 (14.4%) 10-km runners and 13 (28.9%) 21.1-km runners. Only half-marathon participants showed significant increases in uNGAL (pre: 11.7 [7.1-34.3] ng/mL; post: 33.4 [17.4-50.4] ng/mL;P = .0038). There was a significant effect of NSAID/analgesic use on uNGAL increase (F-2,F- 76 = 4.210,P = .004). Post hoc tests revealed that uNGAL increased significantly in runners who tested positive for ibuprofen/naproxen compared to runners who did not use any medications (P = .045) or those who tested positive for paracetamol (P = .033). Running distance had a significant influence on the increase in uNGAL (F-1,F- 53 = 4.741,P

Supplemental Digital Content is available in the text., Pulsatile blood pressure (BP) confers cardiovascular risk. Whether associations of cardiovascular end points are tighter for central systolic BP (cSBP) than peripheral systolic BP (pSBP) or central pulse pressure (cPP) than peripheral pulse pressure (pPP) is uncertain. Among 5608 participants (54.1% women; mean age, 54.2 years) enrolled in nine studies, median follow-up was 4.1 years. cSBP and cPP, estimated tonometrically from the radial waveform, averaged 123.7 and 42.5 mm Hg, and pSBP and pPP 134.1 and 53.9 mm Hg. The primary composite cardiovascular end point occurred in 255 participants (4.5%). Across fourths of the cPP distribution, rates increased exponentially (4.1, 5.0, 7.3, and 22.0 per 1000 person-years) with comparable estimates for cSBP, pSBP, and pPP. The multivariable-adjusted hazard ratios, expressing the risk per 1-SD increment in BP, were 1.50 (95% CI, 1.33–1.70) for cSBP, 1.36 (95% CI, 1.19–1.54) for cPP, 1.49 (95% CI, 1.33–1.67) for pSBP, and 1.34 (95% CI, 1.19–1.51) for pPP (P

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry.Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages.Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia/PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

BACKGROUND: Urinary bladder cancer (UBC) is one of few cancers with an established gene-environment interaction (GxE) with smoking. However, it is unknown whether the interaction with tobacco use is present non-muscle invasive bladder cancer (NMIBC) and characteristics of prognostic relevance. We aimed to investigate if smoking status and/or smoking intensity interact with the effect of discovered variants on key NMIBC characteristics of tumor grade, stage, size, and patient age within the Bladder Cancer Prognosis Programme (BCPP) cohort. METHODS: Analyzed sample consisted of 546 NMIBC patients with valid smoking data from the BCPP. In a previous genome-wide association study (GWAS), we have identified 61 single nucleotide polymorphisms (SNPs) potentially associated with the NMIBC characteristics of tumor stage, grade, size, and patient age. In the current analysis, we have tested these SNPs for GxE with smoking. RESULTS: Out of 61 SNPs, 10 have showed suggestion (statistical significance level of P

Contains fulltext : 220534.pdf (Publisher’s version ) (Open Access) We performed a retrospective cohort study in the Dutch patient population to identify active substances with a relatively high number of adverse drug reactions (ADRs) potentially related to drug switching. For this, we analyzed drug switches and reported ADRs related to switching between June 1, 2009, and December 31, 2016, for a selection of 20 active substances. We also compared pharmacovigilance analyses based on the absolute, switch-corrected, and user-corrected numbers of ADRs. In total, 1,348 reported ADRs and over 23.8 million drug switches were obtained from the National Health Care Institute in The Netherlands and from Lareb, which is The Netherlands Pharmacovigilance Centre. There was no correlation between the number of ADRs and the number of switches, but, on average, we found 5.7 reported ADRs per 100,000 switches. The number was relatively high for rivastigmine, levothyroxine, methylphenidate, and salbutamol, with 74.9, 50.9, 47.6, and 26.1 ADRs per 100,000 switches, respectively. When comparing analyses using the absolute number and the switch-corrected number of ADRs, we demonstrate that different active substances would be identified as having a relatively high number of ADRs, and different time periods of increased numbers of ADRs would be observed. We also demonstrate similar results when using the user-corrected number of ADRs instead of the switch-corrected number of ADRs, allowing for a more feasible approach in pharmacovigilance practice. This study demonstrates that pharmacovigilance analyses of switch-related ADRs leads to different results when the number of reported ADRs is corrected for the actual number of drug switches.

Summary Chronic kidney disease (CKD) is a risk factor for fractures. However, in hip fracture patients, CKD G3-G5 was associated with a higher mortality risk and not associated with a higher risk of subsequent non-hip fractures compared to eGFR > 60 ml/min. The higher mortality risk may, as competing risk, explain our findings. Introduction Chronic kidney disease (CKD) is a known risk factor for fragility fractures. Patients aged 50+ with a recent fragility fracture have an increased risk of subsequent fractures. Our aim was to evaluate the association between CKD stages G3–G5 versus estimated glomerular filtration rate (eGFR) > 60 ml/min and the risk of a new non-hip fracture or fragility fracture in patients with a first hip fracture. Methods Population-based cohort study using the UK general practices in the Clinical Practice Research Datalink. Associations between CKD stage and first subsequent fracture were determined using Cox proportional hazard analyses to estimate hazard ratios (HRs). To explore the potential competing risk of mortality, cause-specific (cs) HRs for mortality were estimated. Results CKD G3–G5 was associated with a lower risk of any subsequent non-hip fracture (HR: 0.90, 95%CI: 0.83–0.97), but not with the risk of subsequent major non-hip fragility fracture. CKD G3-G5 was associated with a higher mortality risk (cs-HR: 1.05, 95%CI: 1.01–1.09). Mortality risk was 1.5- to 3-fold higher in patients with CKD G4 (cs-HR: 1.50, 95%CI: 1.38–1.62) and G5 (cs-HR: 2.93, 95%CI: 2.48–3.46) compared to eGFR > 60 ml/min. Conclusions The risk of a subsequent major non-hip fragility fractures following hip fracture was not increased in patients with CKD G3–G5 compared to eGFR > 60 ml/min. Mortality risk was higher in both hip fracture and non-hip fracture patients with CKD G4 and G5. The higher mortality risk may, as competing risk, explain our main finding of no increased or even decreased subsequent fracture risk after a hip fracture in patients with CKD G3–G5. Electronic supplementary material The online version of this article (10.1007/s00198-020-05351-x) contains supplementary material, which is available to authorized users.

Background and Purpose The flavonoid quercetin increased the in vitro potency of the alpha(1)-antagonist tamsulosin to reduce phenylephrine-dependent arterial contractions by 10-fold. To examine if this supplement-drug interaction luxates hypotensive and orthostatic events in vivo, several set of studies were conducted in spontaneously hypertensive (SHR) and normotensive (Wistar Kyoto [WKY]) rats.Experimental Approach First, in rats pretreated with quercetin or its vehicle, responses to phenylephrine and tamsulosin were examined. Second, tamsulosin-induced changes in renal, mesenteric, hindquarter and carotid conductance were compared in quercetin- and vehicle-treated rats instrumented with Doppler flow probes. Animals were also placed on a tilt table to record regional haemodynamic changes to orthostatic challenges. Third, adult SHR were instrumented with telemeters to measure 24-hr patterns of BP. Recordings were made before and during a 5-week oral treatment of quercetin. Finally, pre-hypertensive SHR were treated with quercetin from 4 to 8 weeks of age and arterial pressure was measured at 8 and 12 weeks.Key Results Pretreatment with quercetin did not influence the responses to phenylephrine and tamsulosin, in neither WKY nor SHR. While tamsulosin treatment and tilting lowered BP and increased conductance in all vascular beds, effect size was not influenced by pretreatment with quercetin. Prolonged treatment with quercetin, in either prehypertensive SHR or adult SHR with established hypertension did not lower BP.Conclusions and Implications Cumulatively, these data demonstrate that quercetin does not amplify haemodynamic effects of tamsulosin or tilting in vivo in rats and has no effect on BP development in SHR.

Objective: Low-molecular-weight heparins are frequently used to prevent venous thromboembolism. Vasopressor therapy may be associated with inadequate anti-factor Xa activity, thereby increasing the risk of venous thromboembolism. We aimed to assess the association between anti-factor Xa activity and norepinephrine dose in intensive care unit (ICU) patients treated with subcutaneous dalteparin for venous thromboembolism prophylaxis. Materials and methods: This was a prospective observational pilot study in adult ICU patients treated with dalteparin 5,000 RJ subcutaneously once daily and norepinephrine > 0.25 mu g/kg/min. Peak anti-factor Xa activity was monitored and dalteparin doses were adjusted following a predefined dose algorithm. Results: From November 2016 to April 2018, 32 patients were included. No correlation was found between norepinephrine dose and anti-factor Xa activity (r = -0.01, 95% confidence interval = -0.47 - 0.27, p = 0.57). Furthermore, following daltcparin 5,000 RI once daily, 28% of the patients showed anti-factor Xa activity < 0.10 IU/mL. Higher body mass index (BM1) (p < 0.001) but not patients' norepinephrine dose, age, or serum creatinine were risk factors for anti-factor Xa activity < 0.10 IU/mL. Dose increments to 7,500 IU once daily resulted in anti-factor Xa activity >= 0.10 IU/mL in all 5 patients (p = 0.043). Conclusion: In this cohort of ICU patients, no association was found between norepinephrine dose and anti-factor Xa activity following subcutaneous dalteparin 5,000-RJ administration once daily. Furthermore, nearly one-third of the patients showed anti-factor Xa activity below the target concentration for venous thromboembolism prophylaxis. Higher BMI was an independent risk factor for reduced anti-Xa activity.

Aims It is hypothesized that dorsal root ganglion stimulation (DRGS), sharing some of the mechanisms of traditional spinal cord stimulation (SCS) of the dorsal columns, induces gamma-aminobutyric acid (GABA) release from interneurons in the spinal dorsal horn. Methods We used quantitative immunohistochemical analysis in order to investigate the effect of DRGS on intensity of intracellular GABA-staining levels in the L4-L6 spinal dorsal horn of painful diabetic polyneuropathy (PDPN) animals. To establish the maximal pain relieving effect, we tested for mechanical hypersensitivity to von Frey filaments and animals received 30 minutes of DRGS at day 3 after implantation of the electrode. One day later, 4 Sham-DRGS animals and four responders-to-DRGS received again 30 minutes of DRGS and were perfused at the peak of DRGS-induced pain relief. Results No significant difference in GABA-immunoreactivity was observed between DRGS and Sham-DRGS in lamina 1-3 of the spinal levels L4-6 neither ipsilaterally nor contralaterally. Conclusions Dorsal root ganglion stimulation does not induce GABA release from the spinal dorsal horn cells, suggesting that the mechanisms underlying DRGS in pain relief are different from those of conventional SCS. The modulation of a GABA-mediated "Gate Control" in the DRG itself, functioning as a prime Gate of nociception, is suggested and discussed.

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine., Highlights of basic and translational science presented at #ERSCongress 2019 summarising latest research on the lung cell atlas, lung infections, early origins of lung disease and the importance of metabolic alterations in the lung http://bit.ly/2UbdBs4

Background Medication is frequently thrown away after a patient’s discharge from hospital, with undesirable economic and environmental consequences. Because of the rising costs of healthcare, interventions to reduce medication wastage (and associated costs) are warranted. Using Patient’s Own Medication during hospitalisation might decrease medication wastage and associated costs. Objective To study the economic impact of patient’s own medication use on medication waste and hospital staff’s time spent during hospitalisation. Setting In seven Dutch hospitals, of which university, teaching, general, and specialised hospitals, eight different hospital wards, surgical and medical, were selected. Method In this prospective pre-post intervention study data on the economic value of medication waste and time spent by healthcare professionals were collected for a 2 months period each. The economic value of medication waste was defined as the value (€) of wasted medication per 100 patient days. For each ward, time spent on medication process activities was measured 10 times per staff member. The average time spent (in hours) on medication process steps (multiple activities) per staff member per 100 patients and associated salary costs were calculated for both periods. Main outcome measure The primary outcome of the study was the total economic value (€) of wasted medication per 100 patient days. Results Implementation of Patient’s Own Medication decreased the economic value of wasted medication by 39.5% from €3983 to €2411 per 100 patient days. The mean time spent on the total medication process was reduced with 5.2 h per 100 patients (from 112.7 to 104.4 h per 100 patients). We observed a shift in professional activities, as physicians and nurses spent less time on the medication process, whereas pharmacy technicians had a greater role in it. When time spent was expressed as salary; €1219 could be saved per 100 patients. Conclusions This study showed that ‘Patient’s Own Medication' implementation may have a positive economic impact, as the value of medication waste decreases, hospital staff devoted less time on the medication process, and staff deployment is more efficient.

Background Infection with SARS-CoV-2 causes corona virus disease (COVID-19). The most standard diagnostic method is reverse transcription-polymerase chain reaction (RT-PCR) on a nasopharyngeal and/or an oropharyngeal swab. The high occurrence of false-negative results due to the non-presence of SARS-CoV-2 in the oropharyngeal environment renders this sampling method not ideal. Therefore, a new sampling device is desirable. This proof-of-principle study investigated the possibility to train machine-learning classifiers with an electronic nose (Aeonose) to differentiate between COVID-19-positive and negative persons based on volatile organic compounds (VOCs) analysis. Methods Between April and June 2020, participants were invited for breath analysis when a swab for RT-PCR was collected. If the RT-PCR resulted negative, the presence of SARS-CoV-2-specific antibodies was checked to confirm the negative result. All participants breathed through the Aeonose for five minutes. This device contains metal-oxide sensors that change in conductivity upon reaction with VOCs in exhaled breath. These conductivity changes are input data for machine learning and used for pattern recognition. The result is a value between − 1 and + 1, indicating the infection probability. Results 219 participants were included, 57 of which COVID-19 positive. A sensitivity of 0.86 and a negative predictive value (NPV) of 0.92 were found. Adding clinical variables to machine-learning classifier via multivariate logistic regression analysis, the NPV improved to 0.96. Conclusions The Aeonose can distinguish COVID-19 positive from negative participants based on VOC patterns in exhaled breath with a high NPV. The Aeonose might be a promising, non-invasive, and low-cost triage tool for excluding SARS-CoV-2 infection in patients elected for surgery.

A 35-year-old man with generalized insults was admitted to the intensive care unit because of third-line treatment of persistent epileptic insults with antiepileptic drug therapy. Topiramate was added on top of his outpatient regimen in combination with intravenous antiepileptic drugs. Miscommunication and inappropriate topiramate dosing (2,500 mg twice) resulted in an acute topiramate intoxication. Toxicokinetic assessment showed toxic serum topiramate concentration of 55 mg/L and a dose-dependent shift of peak time t(max). According to our modulations, t(max) follows Y = 0.0009X + 2.65, where X is the topiramate dose. Our results have important implications for effectiveness of gut decontamination modalities.

Supplementation with nicotinamide adenine dinucleotide (NAD+) precursors including dietary nicotinamide has been found to boost tissue NAD+ levels and ameliorate oxidative stress-induced damage that contributes to aging and aging-related diseases. The association between dietary NAD+ precursors and patient-reported health-related outcomes in cancer survivors has not been investigated. This study aimed to determine associations of dietary nicotinamide intake with different patient-reported outcomes in colorectal cancer survivors, 2 to 10 years post-diagnosis. A total of 145 eligible participants were recruited into this cross-sectional study. Dietary nicotinamide intake level was calculated based on data from 7-day food diaries. Fatigue was assessed with the Checklist Individual Strength (CIS), which is a subscale of the cancer-specific European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC), and anxiety and depression were assessed with Hospital Anxiety and Depression Scale (HADS). Oxidative stress marker serum protein carbonyl contents and serum NAD+ levels were measured. A hierarchical linear regression model with confounder adjustment was performed to analyze the association of nicotinamide intake, serum protein carbonyl contents, and NAD+ levels with patient-reported outcomes. The median values of daily nicotinamide intake for male and female participants were 19.1 and 14.4 mg, respectively. Daily dietary nicotinamide intake was associated with a lower level of fatigue (β: −14.85 (−28.14, −1.56)) and a lower level of anxiety and depression (β: −4.69 (−8.55, −0.83)). Subgroup analyses by sex showed that a beneficial association between nicotinamide intake and patient-reported outcomes was mainly found in men. To conclude, our findings suggested that higher dietary NAD+ precursor nicotinamide intake was cross-sectionally associated with less patient-reported outcomes in CRC survivors.

The Common Fisheries Policy of the European Union was reformed in 2013 with the aim of improving the sustainability of the fishing sector. The Landing Obligation, a cornerstone of this reform, requires fishers to land their unwanted catch instead of discarding it at sea. Existing literature pays little attention to what becomes of this unwanted catch once it is landed. To further the discourse on the sustainable valorisation of unwanted catch, this study explores whether unwanted catch that is safe for human consumption could be used for improving food security. The paper focuses on Dutch food banks, which deliver critical food aid to over 160,000 individuals yearly but struggle to provide all dependant recipients with nutritionally balanced food parcels. The research question is addressed in two ways. The food bank recipients’ willingness to consume UWC is evaluated quantitatively through a survey. Next to this, data from interviews with relevant stakeholders are analysed qualitatively. Results indicate that the Food Bank Foundation and its recipients are willing to receive this fish if it is safe to consume and accessible. However, various factors such as existing infrastructure, lack of economic incentive to donate, competition from non-food and black markets, and the fishing industry’s conflict with the landing obligation might pose barriers to this kind of valorisation. The dissonance between fisheries, food, and sustainability policies is discussed and identified as a key limiting factor. To bridge the differences between these policy areas, we propose public-private partnerships and voluntary agreements among involved stakeholders.

BACKGROUND: Low-molecular-weight heparins (LMWHs) are used in the prevention and treatment of venous thromboembolism (VTE). Bleeding is the primary major complication of LMWH therapy, which is associated with dose. The administration of appropriate dosages of LMWHs depends on the patient's risk of VTE, risk of bleeding, bodyweight, and renal function. Therefore, LMWH prescribing is prone to errors. However, no earlier study has explored the frequency of prescribing errors with LMWH.PURPOSE: The aim of the study was to determine the frequency and determinants of in-hospital LMWH-prescribing errors.METHODS: A cross-sectional study was conducted to examine the frequency and determinants of LMWH prescribing errors between April and August 2014. We randomly selected 500 patients 18 years and older with at least one LMWH prescription during inpatient hospitalization. A prescribing error was a deviation from the internal hospital guidelines. Logistic regression estimated determinants of prescribing error.RESULTS: A prescribing error was present with 34% of all LMWH users. The most frequently recorded error was a dose that was not adjusted to body weight and/or renal function (85%). Prophylactic LMWH prescribing in medical wards was associated with a higher risk of prescribing error as compared with surgical wards.CONCLUSIONS: The frequency of prescribing errors was 34% in a tertiary care hospital. Being a patient with prophylactic LMWH use on a medical ward is a determinant for LMWH prescribing error. Interventions that will lead to better electronic recording of body weight and more awareness among medical doctors may reduce the total number of prescribing errors.

Background and Objective The sensory cell somata in the DRG contain all equipment necessary for extensive GABAergic signaling and are able to release GABA upon depolarization. With this study, we hypothesize that pain relief induced by conventional dorsal root ganglion stimulation (Con-DRGS) in animals with experimental painful diabetic peripheral neuropathy is related to the release of GABA from DRG neurons. With use of quantitative immunocytochemistry, we hypothesize DRGS to result in a decreased intensity of intracellular GABA-immunostaining in DRG somata. Materials and Methods Female Sprague-Dawley rats (n = 31) were injected with streptozotocin (STZ) in order to induce Diabetes Mellitus. Animals that developed neuropathic pain after four weeks (Von Frey) were implanted with a unilateral DRGS device at L4 (n = 14). Animals were then stimulated for 30 min with Con-DRGS (20 Hz, pulse width = 0.2 msec, amplitude = 67% of motor threshold, n = 8) or Sham-DRGS (n = 6), while pain behavior (von Frey) was measured. DRGs were then collected and immunostained for GABA, and a relation to size of sensory cell soma diameter (small: 12-26 mu m, assumed to be C-fiber related sensory neurons; medium: 26-40 mu m, assumed to be A delta related sensory neurons; and large: 40-54 mu m, assumed to be A beta related sensory neurons) was made. Results DRGS treated animals showed significant reductions in STZ-induced mechanical hypersensitivity. No significant differences in GABA immunostaining intensity per sensory neuron cell soma type (small-, medium-, or large-sized) were noted in DRGs of stimulated (Con-DRGS) animals versus Sham animals. No differences in GABA immunostaining intensity per sensory cell soma type in ipsi- as compared to contralateral DRGs were observed. Conclusion Con-DRGS does not affect the average intracellular GABA immunofluorescence staining intensity in DRG sensory neurons of those animals which showed significant pain reduction. Similarly, no soma size related changes in intracellular GABA immunofluorescence were observed following Con-DRGS.

The International Comet Assay Workshops (ICAW) are a series of scientific conferences dealing with different aspects of the comet assay. The assay itself is a simple method for the detection of DNA strand breaks at the cellular level and can be applied to any cell type derived from different organs and tissues of eukaryotic organisms. Additionally, the comet assay is widely applied in human biomonitoring, ecotoxicology, genotoxicity testing of chemicals, but also in basic research studying the mechanisms of DNA damage and repair. The 2019 ICAW edition gathered about 80 participants with over 30 lecturers, 27 poster presentations and 2 open discussion sessions presenting the latest advances in technical developments as well as applications of the comet assay in genetic toxicology, and environmental and human biomonitoring. This report summarises the important issues that were raised and discussed during the sessions as well as a short synopsis of the papers selected for inclusion in this special issue. Based on the topics presented at the workshop, the assay with its new modifications and applications has a bright future and will for sure stay one of the most popular methods in genetic toxicology and beyond in the years to come.

Supplemental Digital Content is available in the text., Arterial stiffness and wave reflection predict cardiovascular mortality and morbidity and are associated with renal microvascular disease. We hypothesized that the retinal microvascular traits might be associated with central hemodynamic properties. In 735 randomly recruited Flemish (mean age, 50.3 years; 47.1% women), we derived central pulse pressure and carotid-femoral pulse wave velocity by applanation tonometry and calculated forward (Pf) and backward (Pb) pulse waves, using an automated pressure-based wave separation algorithm. We measured central retinal arteriolar (CRAE) and venular equivalent and their ratio, using IVAN software (Vasculomatic ala Nicola, version 1.1). Mean values for pulse wave velocity (n=554), Pf and Pb were 7.50 m/s, 32.0 mm Hg, and 21.5 mm Hg, respectively. In multivariable-adjusted analyses, CRAE was 4.62 µm and 1.26 µm smaller (P≤0.034) for a 1-SD increment in central mean arterial pressure (+11.3 mm Hg) and central pulse pressure (+15.2 mm Hg); a 1-SD increment in the augmentation ratio (+7.0%), aortic pulse wave velocity (+1.66 m/s), Pf (+10.0 mm Hg), and Pb (+8.5 mm Hg), was associated with smaller CRAE; the association sizes were −1.91 µm, −1.59 µm, −1.45 µm, and −2.38 µm (P≤0.014), respectively. Associations of arteriole-to-venule diameter ratio with the central hemodynamic traits mirrored those of CRAE. None of the multivariable-adjusted associations of central retinal venular diameter with the central hemodynamic traits reached significance with the exception of central diastolic blood pressure (−1.62 µm; P=0.030). In conclusion, in the general population, higher central pulse pressure, pulse wave velocity, Pf, and Pb were associated with smaller CRAE.

Summary This study evaluated the 2-year persistence with teriparatide in the Netherlands. Analyses showed that the risk of non-persistence was 28% lower in patients who were followed according to an additional educational and motivational support program. Introduction Until recently, teriparatide (TPTD) was a third-line treatment option for severe osteoporosis in the Netherlands, which could only be prescribed by medical specialists based on a specific medical statement. We aimed to determine whether an educational and motivational support program (EMSP) increased 2-year treatment persistence with TPTD in patients with severe osteoporosis. Methods We evaluated persistence in 1573 Dutch patients treated with TPTD from January 2013 until January 2018. From January 2013 onwards, all patients received a basic support program (BSP) consisting of an educational home visit to initiate TPTD treatment and phone calls (at 1, 2.5 and 8 weeks). Since May 2015, all patients received the EMSP consisting of the BSP extended with evaluation of medication adherence during phone calls, an additional phone call (at 12 months), and motivational letters at 9 and 14 months. Results The EMSP showed a statistically significantly higher 2-year persistence (78%) with TPTD as compared with the BSP (72%). Reasons for treatment discontinuation were comparable between groups, except for the proportion of patients who had stopped TPTD administration due to side effects, which was significantly lower in the EMSP group (8% vs. 15% in BSP, p

Rationale: Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking.Objectives: To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes.Methods: We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (FENO) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count.Measurements and Main Results: In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study (n = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and FENO. Moreover, the combination of FENO, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to FENO or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma.Conclusions: Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.

Background: Few studies have modeled smoking histories by combining smoking intensity and duration to show what profile of smoking behavior is associated with highest risk of bladder cancer. This study aims to provide insight into the association between smoking exposure history and bladder cancer risk by modeling both smoking intensity and duration in a pooled analysis.Methods: We used data from 15 case-control studies included in the bladder cancer epidemiology and nutritional determinants study, including a total of 6,874 cases and 17,727 controls. To jointly interpret the effects of intensity and duration of smoking, we modeled excess odds ratios per pack-year by intensity continuously to estimate the risk difference between smokers with long duration/low intensity and short duration/high intensity.Results: The pattern observed from the pooled excess odds ratios model indicated that for a fixed number of pack-years, smoking for a longer duration at lower intensity was more deleterious for bladder cancer risk than smoking more cigarettes/day for a shorter duration. We observed similar patterns within individual study samples.Conclusions: This pooled analysis shows that long duration/low intensity smoking is associated with a greater increase in bladder cancer risk than short duration/high intensity smoking within equal pack-year categories, thus confirming studies in other smoking-related cancers and demonstrating that reducing exposure history to a single metric such as pack-years was too restrictive.

BackgroundThe prenatal exposure to maternal n-6 and n-3 polyunsaturated fatty acids (PUFAs) might influence the development of social competence and internalizing and externalizing behaviours of the child, because of the numerous functions of PUFAs within the nervous system.MethodsTo analyse the association of selected maternal PUFAs (i.e., AA, EPA, DHA, total n-6, total n-3, and the n-6:n-3 ratio) measured during gestation with childhood social competence and problem behaviours, we examined 311 mother-child pairs from the Maastricht Essential Fatty Acid Birth (MEFAB) cohort. For each woman, PUFA-specific changes in relative concentrations were calculated by identifying the best-fitting curve of PUFA concentration by linear splines of gestational age. The associations of changes in maternal PUFAs in early and late pregnancy with childhood social competence, total problems, internalizing and externalizing behaviours, measured with the Child Behaviour Checklist 4/18 at age 7, were investigated with linear regression analyses adjusted for maternal and children's socio-demographic characteristics.ResultsIn late gestation (i.e., from gestational week 30), an increase in AA was associated with higher social competence, while a decrease in total n-6 was associated with lower externalizing behaviours. No other significant associations were found.DiscussionIn this prospective study, increasing maternal AA and decreasing total n-6 were associated with improved social competence and externalizing behaviours, respectively, in 7-year old children. Nonetheless, the clinical significance of the identified associations is modest and further investigations are warranted to clarify the relationship between maternal AA and total n-6 during pregnancy and childhood social and behavioural development.

PurposeThe association between dietary acrylamide intake and estrogen receptor-positive (ER+) breast cancer risk in epidemiological studies is inconsistent. By analyzing gene-acrylamide interactions for ER+breast cancer risk, we aimed to clarify the role of acrylamide intake in ER+breast cancer etiology.MethodsThe prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69years. At baseline, a random subcohort of 2589 women was sampled from the total cohort for a case-cohort analysis approach. Dietary acrylamide intake of subcohort members (n=1449) and ER+breast cancer cases (n=844) was assessed with a food frequency questionnaire. We genotyped single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism, sex steroid systems, oxidative stress and DNA repair. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis, based on 20.3years of follow-up.ResultsUnexpectedly, there was a statistically non-significant inverse association between acrylamide and ER+breast cancer risk among all women but with no clear dose-response relationship, and no association among never smokers. Among the results for 57 SNPs and 2 gene deletions, rs1056827 in CYP1B1, rs2959008 and rs7173655 in CYP11A1, the GSTT1 gene deletion, and rs1052133 in hOGG1 showed a statistically significant interaction with acrylamide intake for ER+breast cancer risk.ConclusionsThis study did not provide evidence for a positive association between acrylamide intake and ER+breast cancer risk. If anything, acrylamide was associated with a decreased ER+breast cancer risk. The interaction with SNPs in CYP1B1 and CYP11A1 suggests that acrylamide may influence ER+breast cancer risk through sex hormone pathways. This study was funded by the Dutch Cancer Society (KWF), Grant number: UM 2011-5123. Janneke Hogervorst is a postdoctoral research fellow from the Research Foundation-Flanders (FWO), no. 12J9516N. The authors thank the study participants, the Netherlands Cancer Registry, the Dutch Pathology Registry, and the Biobank of the Maastricht University Medical Center. We thank Dr. Sandra Bausch as initiator of the NLCS study, together with Prof. Piet van den Brandt. We also thank Sacha van de Crommert, Jolanda Nelissen, Conny de Zwart, Ellen Dutman, Henny Brants, and Annemie Pisters for their assistance with data entry or data management, Harry van Montfort for programming assistance, and Simone van Breda, Stijn Lumeij, Kristien Lemmens, Joy Goessens, and Leonie Jonkers for technical assistance with DNA isolation and genotyping.

Background/objectives Polyunsaturated fatty acid (PUFA) status during pregnancy has been suggested to influence offspring obesity and cardiometabolic health. We assessed whether prenatal PUFA exposure is associated with rapid infant growth, childhood BMI, and cardiometabolic profile.Subjects/methods In the Dutch MEFAB (n = 266) and Greek RHEA (n = 263) cohorts, we measured n-3 and n-6 PUFA concentrations in cord blood phospholipids, which reflect fetal exposure in late pregnancy. We defined rapid infant growth from birth to 6 months of age as an increase in weight z-score >0.67. We analyzed body mass index (BMI) as continuous and in categories of overweight/obesity at 4 and 6 years. We computed a cardiometabolic risk score at 6-7 years as the sum of waist circumference, non-high-density lipoprotein cholesterol and blood pressure z-scores. Associations of PUFAs with child health outcomes were assessed using generalized linear models for binary outcomes and linear regression models for continuous ones after adjusting for important covariates, and for the pooled estimates, a cohort indicator.Results In pooled analyses, we found no association of PUFA levels with rapid infant growth, childhood BMI (beta per SD increase in the total n-3:n-6 PUFA ratio = -0.04 SD; 99% CI: -0.15, 0.06; P = 0.65 at 4 years, and -0.05 SD; 99% CI: -0.18, 0.08; P = 0.78 at 6 years), and overweight/obesity. We also found no associations for clustered cardiometabolic risk and its individual components. The results were similar across cohorts.Conclusions Our findings suggest that PUFA concentrations at birth are not associated with later obesity development and cardiometabolic risk in childhood.

Background: Pulmonary arterial hypertension (PAH) is a rare, progressive disease of the pulmonary vasculature. Recent advances in pharmacotherapy improved life expectancy of PAH patients and, thus, signified the role of general measures, including diet, in the management of the disease.Methods: In the present narrative review we will briefly summarize information about current and novel PAH therapies and analyze preclinical evidence on the influence of certain nutrients on the pathogenesis of PAH.Results: Although the evidence on the role of dietary deficiencies in the development and progression of PAH in humans is limited, preclinical studies demonstrate that dietary components such as quercetin, genistein, n-3 PUFAs, vitamin D, coenzyme Q10 and resveratrol may influence various aspects of PAH pathobiology.Conclusions: Further research on the role of diet in PAH is needed. Taking into account pleiotropic and subtle effects of dietary constituents as well as the rare and severe nature of PAH, clinical studies on the disease-specific nutritional patterns rather than on single dietary components may help to reveal if diet can be an important tool to improve the efficacy of pharmacotherapy in PAH. (C) 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Ibuprofen is a worldwide used non-steroidal anti-inflammatory drug which may cause acute liver injury (ALI) requiring liver transplantation. We aimed to unveil the molecular pathways involved in triggering ibuprofen-induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen-induced ALI. Next, we assessed the cytotoxicity of ibuprofen in vitro and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c-Jun N-terminal kinase 1 (Jnk1(-/-)) or Jnk2 (Jnk2(-/-)) expression and included investigations using animals with hepatocyte-specific Jnk deletion either genetically (Jnk1(Delta hepa)) or by siRNA (siJnk2(Delta hepa)). We found in human and murine samples of ibuprofen-induced acute liver failure that JNK phosphorylation was increased in the cytoplasm of hepatocytes and other non-liver parenchymal cells (non-LPCs) compared with healthy tissue. In mice, ibuprofen intoxication resulted in a significantly stronger degree of liver injury compared with vehicle-treated controls as evidenced by serum transaminases, and hepatic histopathology. Next, we investigated molecular pathways. PKC alpha, AKT, JNK and RIPK1 were significantly increased 8 h after ibuprofen intoxication. Constitutive Jnk1(-/-) and Jnk2(-/-) deficient mice exhibited increased liver dysfunction compared to wild-type (WT) animals. Furthermore, siJnk2(Delta hepa) animals showed a dramatic increase in biochemical markers of liver function, which correlated with significantly higher serum liver enzymes and worsened liver histology, and MAPK activation compared to Jnk1(Delta hepa) or WT animals. In our study, cytoplasmic JNK activation in hepatocytes and other non-LPCs is a hallmark of human and murine ibuprofen-induced ALI. Functional in vivo analysis demonstrated a protective role of hepatocyte-specific Jnk2 during ibuprofen ALI. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamical changes of organ injury after the onset of chorioamnionitis revealed novel therapeutic windows of opportunity. Importantly, successful development and implementation of therapies in clinical care is currently impeded by a lack of diagnostic tools for early (prenatal) detection and surveillance of intra-amniotic infections. In the current study we questioned whether an intra-amniotic infection could be accurately diagnosed by a specific volatile organic compound (VOC) profile in exhaled breath of pregnant sheep. For this purpose pregnant Texel ewes were inoculated intra-amniotically with Ureaplasma parvum and serial collections of exhaled breath were performed for 6 days. Ureaplasma parvum infection induced a distinct VOC-signature in expired breath of pregnant sheep that was significantly different between day 0 and 1 vs. day 5 and 6. Based on a profile of only 15 discriminatory volatiles, animals could correctly be classified as either infected (day 5 and 6) or not (day 0 and 1) with a sensitivity of 83% and a specificity of 71% and an area under the curve of 0.93. Chemical identification of these distinct VOCs revealed the presence of a lipid peroxidation marker nonanal and various hydrocarbons including n-undecane and n-dodecane. These data indicate that intra-amniotic infections can be detected by VOC analyses of exhaled breath and might provide insight into temporal dynamics of intra-amniotic infection and its underlying pathways. In particular, several of these volatiles are associated with enhanced oxidative stress and undecane and dodecane have been reported as predictive biomarker of spontaneous preterm birth in humans. Applying VOC analysis for the early detection of intra-amniotic infections will lead to appropriate surveillance of these high-risk pregnancies, thereby facilitating appropriate clinical course of action including early treatment of preventative measures for pre-maturity-associated morbidities.

Food businesses in the European Union are preparing for a carbon-neutral future by gradually transitioning to a circular way of operating. Building upon results from the EU REFRESH project, we consider the most valuable food processing by-streams in Europe and discuss potential food safety risks that must be considered while valorizing them for human consumption. These risks are weighed against the nutritional benefits offered by these products and their potential applications in food supply chains. Broadly, we examine whether it is possible for spent grains, cheese whey, fruit and vegetable scraps, meat processing waste, and oilseed cakes and meals to be safe, sustainable, and nutritionally valuable at the same time. The discussion highlights that valorizing by-products obtained from food processing operations is feasible on a large scale only if consumers deem it to be a safe and acceptable practice. Extracting valuable compounds from by-products and using them in the preparation of functional foods could be a way to gain consumer acceptance. Furthermore, we find that current EU food safety legislation does not sufficiently accommodate food processing by-products. A way to bridge this regulatory gap could be through the adoption of private food safety standards that have shown proclivity for sustainability-related issues in food supply chains. Finally, by proposing a decision tree, we show that it is indeed feasible for some food processing by-products to be valorized while ensuring sustainability, food safety, and nutritional relevance.

Fractal analysis provides a global assessment of vascular networks (e.g., geometric complexity). We examined the association of diastolic left ventricular (LV) function with the retinal microvascular fractal dimension. A lower fractal dimension signifies a sparser retinal microvascular network. In 628 randomly recruited Flemish individuals (51.3% women; mean age, 50.8 years), we measured diastolic LV function by echocardiography and the retinal microvascular fractal dimension by the box-counting method (Singapore I Vessel Assessment software, version 3.6). The left atrial volume index (LAVI), e′, E/e′ and retinal microvascular fractal dimension averaged (±SD) 24.3 ± 6.2 mL/m2, 10.9 ± 3.6 cm/s, 6.96 ± 2.2, and 1.39 ± 0.05, respectively. The LAVI, E, e′ and E/e′ were associated (P 2 (95% confidence interval, −1.98 to −1.01), 2.57 cm/s (1.31–3.84), 1.34 cm/s (1.07–1.60), and −0.74 (−0.91 to −0.57), respectively. With adjustments applied for potential covariables, the associations of E peak and E/e′ with the retinal microvascular fractal dimension remained significant (P ≤ 0.020). Over a median follow-up of 5.3 years, 18 deaths occurred. The crude and adjusted hazard ratios expressing the risk of all-cause mortality associated with a 1-SD increment in the retinal microvascular fractal dimension were 0.36 (0.23–0.57; P P = 0.035), respectively. In the general population, a lower retinal microvascular fractal dimension was associated with greater E/e′, a measure of LV filling pressure. These observations can potentially be translated into new strategies for the prevention of diastolic LV dysfunction.

Dicarbonyls are reactive precursors of advanced glycation endproducts. They are formed endogenously and during food processing. Currently, a comprehensive database on dicarbonyls in foods that covers the entire range of food groups is lacking, limiting knowledge about the amount of dicarbonyls that is ingested via food. The aim of this study was to analyze the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) in commonly-consumed products in a Western diet. We validated a UHPLC-MS/MS method to quantify MGO, GO, and 3-DG. We present a dietary dicarbonyl database of 223 foods and drinks. Total dicarbonyl concentrations were highest in dried fruit, Dutch spiced cake, and candy bars (> 400 mg/kg). Total dicarbonyl concentrations were lowest in tea, dairy, light soft drinks, and rice (

Face masks and personal respirators are used to curb the transmission of SARS-CoV-2 in respiratory droplets; filters embedded in some personal protective equipment could be used as a non-invasive sample source for applications, including at-home testing, but information is needed about whether filters are suited to capture viral particles for SARS-CoV-2 detection. In this study, we generated inactivated virus-laden aerosols of 0.3–2 microns in diameter (0.9 µm mean diameter by mass) and dispersed the aerosolized viral particles onto electrostatic face mask filters. The limit of detection for inactivated coronaviruses SARS-CoV-2 and HCoV-NL63 extracted from filters was between 10 to 100 copies/filter for both viruses. Testing for SARS-CoV-2, using face mask filters and nasopharyngeal swabs collected from hospitalized COVID-19-patients, showed that filter samples offered reduced sensitivity (8.5% compared to nasopharyngeal swabs). The low concordance of SARS-CoV-2 detection between filters and nasopharyngeal swabs indicated that number of viral particles collected on the face mask filter was below the limit of detection for all patients but those with the highest viral loads. This indicated face masks are unsuitable to replace diagnostic nasopharyngeal swabs in COVID-19 diagnosis. The ability to detect nucleic acids on face mask filters may, however, find other uses worth future investigation.

Author Correction: https://doi.org/10.1038/s41598-021-98620-6. The original version of this Article contained errors: The spelling of the author Monica Neri was incorrectly given as Neri Monica; Additionally, Affiliation 39 was incorrectly given as ‘National Institute of Health, Lisbon, Portugal’, the correct affiliation is listed below: National Institute of Health Doutor Ricardo Jorge, Porto, Portugal. The original Article has been corrected. [Abstract] The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan–Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p

Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use. Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect..

While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.

Smokers are exposed to more than 6000 toxic smoke components including volatile organic compounds (VOCs). The objective is to investigate VOCs levels in blood and exhaled breath and their relation, upon smoking three types of cigarettes of one brand with varying declared tar, nicotine and carbon monoxide (TNCO) yields according to ISO 3308. Furthermore, we aim to identify the relevance of these declared yields for human smokers exposed to VOCs. Blood and exhaled breath were sampled from twelve male volunteers directly before and 10 minutes after smoking cigarettes on 3 days (day 1 Marlboro Red (regular), day 2 Marlboro Prime (highly ventilated, low-TNCO), day 3 Marlboro Prime with blocked filter ventilation (taped)). Our results show that levels of toluene, ethylbenzene, m/p-xylene, o-xylene, and 2,5-dimethylfuran in both blood and exhaled breath increase after smoking a cigarette. Overall, no strong correlation was found between VOC levels in exhaled breath and VOC levels in blood because of variations between the individual smoking volunteers. More research is required in order to use exhaled breath sampling as a non-invasive quantitative marker for volatile toxicants from cigarette smoke exposure in risk assessment. However, we also show that the increases in concentrations in blood and exhaled breath for each smoker are within the same range for all three cigarette types smoked. The differences in declared TNCO yields, as determined with machine smoking according to ISO 3308 regime, are thus irrelevant for the assessment of human exposure of VOCs, which is important for the risk assessment of inhaling mainstream cigarette smoke. Lastly, cigarettes with lower declared TNCO levels may expose smokers to similar or even higher levels of smoke toxicants. Clinical trial registration: NCT03498053.

Background In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated. Methods In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups. Results Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015). Conclusions The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Background For a patient, drug switches are not desirable (either between a brand-name drug and a generic drug, or between two generic drugs of the same active substance). Research into the causes of drug switches, and related adverse drug reactions, is hampered by the absence of quantitative data on drug switches. Methods We describe the frequency of drug switches in the Netherlands for a selection of active substances. A retrospective cohort study was conducted using the Drug Information System of the National Health Care Institute in the Netherlands. We studied the Dutch patient population from mid-2009 to 2016. The selection of active substances (n = 20) was made based on a report by Lareb, the Netherlands Pharmacovigilance Centre, on adverse drug reactions related to drug switching, and we used qualitative and quantitative descriptive analyses. A drug switch is defined as the replacement of a patient’s prescribed drug with a similar drug from a different manufacturer. Results We identified 23.8 million drug switches on a total of 206 million (11.6%) similar drug dispenses. The frequency of drug switches demonstrated a yearly peak in the period from January to March. In some months, for atorvastatin, losartan, pantoprazole, and irbesartan, more than 60% of similar drug dispenses were drug switches. Most drug switches (80.3%) were between two generic drugs, and 0.12% of these involved a drug from a European parallel import. The proportion of drug switches between two brand-name drugs decreased from 14.5 to 5.53% during our study period, and of these, 86.5% involved a drug from a European parallel import. Conclusions Drug switching is common in the Netherlands, and most of the drug switches we studied are between generic drugs. The observed annual peak of drug switches is most likely explained by a specific Dutch reimbursement policy. Not only are the data valuable as is, but they also serve as a first step towards elucidating the reasons for the occurrence of these drug switches. In addition, these data can be used to put into perspective the adverse drug reactions associated with drug switching.

The performance of the MSD immunoassay, as an allergy blood test, was compared to the skin prick test (SPT; golden standard in clinical practices) and ImmunoCAP™ assay (most commonly used blood test). The MSD immunoassay, detecting sIgE against respiratory allergens, showed high sensitivity and specificity (compared to the ImmunoCAP™ assay or SPT), and low inter‐ and intra‐assay variation with good reproducibility., Summary Allergic sensitization is commonly assessed in patients by performing the skin prick test (SPT) or determining specific immunoglobulin (IgE) levels in blood samples with the ImmunoCAP™ assay, which measures each allergen and sample separately. This paper explores the possibility to investigate respiratory allergies with a high throughput method, the Meso Scale Discovery (MSD) multiplex immunoassay, measuring IgE levels in low volumes of blood. The MSD multiplex immunoassay, developed and optimized with standards and allergens from Radim Diagnostics, was validated against the SPT and the ImmunoCAP assay. For 18 adults (15 respiratory allergy patients and three controls), blood collection and the SPT were performed within the same hour. Pearson correlations and Bland–Altman analysis showed high comparability of the MSD multiplex immunoassay with the SPT and the ImmunoCAP assay, except for house dust mite. The sensitivity of the MSD multiplexed assay was ≥78% for most allergens compared to the SPT and ImmunoCAP assay. Additionally, the specificity of the MSD multiplex immunoassay was ≥ 87% – the majority showing 100% specificity. Only the rye allergen had a low specificity when compared to the SPT, probably due to cross‐reactivity. The reproducibility of the MSD multiplex immunoassay, assessed as intra‐ and interassay reproducibility and biological variability between different sampling moments, showed significantly high correlations (r = 0·943–1) for all tested subjects (apart from subject 13; r = 0·65–0·99). The MSD multiplex immunoassay is a reliable method to detect specific IgE levels against respiratory allergens in a multiplexed and high‐throughput manner, using blood samples as small as from a finger prick.

The use of vitamin B6 supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. The present study focused on the pharmacokinetics of vitamin B6. Twelve healthy volunteers were daily supplemented with either 50 mg pyridoxine or pyridoxal-phosphate for one week. On days 1, 3 and 7, blood samples were taken after oral intake of the supplements. Plasma levels of different vitamers of B6 were determined with ultra-performance liquid chromatography–tandem mass spectrometry. Additionally, reported adverse reactions related to polyneuropathy and vitamin B6 supplements were analyzed. At day 1, pyridoxine only increased after supplementation with pyridoxine during the 4 h analysis. At days 3 and 7, average plasma pyridoxal-phosphate and pyridoxal concentrations significantly increased after supplementation with both vitamers. Average plasma pyridoxine concentrations only significantly increased after 3 and 7 days of supplementation with pyridoxine. Large individual differences in plasma levels of B6 vitamers were seen at all days. Also, individual differences concerning dose and plasma levels were determined in the reported complaints. Our results show that there is a clear inter-individual difference in kinetics of vitamin B6, potentially explaining differences in sensitivity to vitamin B6 toxicity.