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Background: Climate change is expected to elevate exposure to several environmental health risk factors, including extreme environmental temperatures, air pollution and airborne allergenic pollen. Given their interconnected effects on respiratory and cardiovascular diseases, it is crucial to evaluate these exposures simultaneously. Yet, comprehensive efforts to do so remain limited. This research aims to develop an approach using modelled data, in conjunction with health-based threshold values, to assess whether, where and when there is simultaneous threshold exceedance of heat, air pollution and airborne allergenic pollen in Europe. Methods: Hourly exposure data for the three stressors were sourced from three models (air pollution: LOTOS-EUROS, pollen: Copernicus Atmosphere Monitoring Service, meteorological conditions: ECMWF) for 2021 and 2022. Thresholds for each stressor that indicate the boundary of acceptable limits were based on officially established tresholds or literature recommendations. The result is a 0.1°x0.1° resolution grid (approximately 10 km x 10 km) for each stressor, with each cell representing whether exposure met or exceeded the threshold. Findings: Simultaneous threshold exceedance of air pollution and heat is occurring in various degrees throughout Europe. In the summer of 2022, the exceedances ranged from below 1% in large parts of Northern Europe to as much as 25% of the time in the Mediterranean area. An assessment of monthly threshold exceedance patterns shows a dynamic and changing co-exposure pattern across the year, which differs per region. Interpretation: This work lays out a robust approach to assess simultaneous threshold exceedances of multiple environmental health risk stressors. This approach can guide policy makers in pinpointing high-risk areas particularly vulnerable to simultaneous threshold exceedances, and develop mitigation strategies for those areas. Funding: Internal funding from TNO.

Background: Alcohol misuse among medical professionals poses a significant concern, and there is a lack of clarity in (inter)national guidelines regarding alcohol use during work. Moreover, there exists an insufficient body of research on the specific impact of alcohol on fine motor skills within the medical sector, specifically surgery. This study aims to investigate the impact of alcohol on fine motor skills in a minimally invasive surgical setting. Methods: A cross-sectional study was conducted at Lowland Science on August 19th, 20th, and 21st, 2022, during the Lowlands music festival in Biddinghuizen, the Netherlands. Participants were divided into five groups based on measured alcohol consumption. Exclusion criteria included drug use, prior surgical experience, being underage, and previous participation. The main outcomes were the number of correctly transferred rings during the PEG transfer task and the number of errors. Blood alcohol concentration (BAC) was measured using a breathalyser. Results: A total of 1056 participants were included in the study. The results indicated an inverse relationship between BAC levels and surgical performance, with higher alcohol levels associated with a decrease in performance (p = 0.023). However, there was no significant difference in the number of errors among the five groups (p = 0.597). The group with the highest alcohol consumption (BAC >0.08 %) exhibited significantly worse performance compared to the group with a BAC of 0.0 % (p = 0.002). Conclusion: This study uncovers a negative impact of increased alcohol intake on fine motor skills in a minimally invasive surgery simulation exercise. While there was no effect on the occurrence of errors. Professional medical organizations should reconsider and explicate their position on alcohol use in (surgical) healthcare.

Purpose: To assess whether contralateral parenchymal enhancement (CPE) on MRI is associated with gene expression pathways in ER+/HER2-breast cancer, and if so, whether such pathways are related to survival. Methods: Preoperative breast MRIs were analyzed of early ER+/HER2-breast cancer patients eligible for breast-conserving surgery included in a prospective observational cohort study (MARGINS). The contralateral parenchyma was segmented and CPE was calculated as the average of the top-10% delayed enhancement. Total tumor RNA sequencing was performed and gene set enrichment analysis was used to reveal gene expression pathways associated with CPE (N = 226) and related to overall survival (OS) and invasive disease-free survival (IDFS) in multivariable survival analysis. The latter was also done for the METABRIC cohort (N = 1355). Results: CPE was most strongly correlated with proteasome pathways (normalized enrichment statistic = 2.04, false discovery rate = .11). Patients with high CPE showed lower tumor proteasome gene expression. Proteasome gene expression had a hazard ratio (HR) of 1.40 (95% CI = 0.89, 2.16; P = .143) for OS in the MARGINS cohort and 1.53 (95% CI = 1.08, 2.14; P = .017) for IDFS, in METABRIC proteasome gene expression had an HR of 1.09 (95% CI = 1.01, 1.18; P = .020) for OS and 1.10 (95% CI = 1.02, 1.18; P = .012) for IDFS. Conclusion: CPE was negatively correlated with tumor proteasome gene expression in early ER+/HER2-breast cancer patients. Low tumor proteasome gene expression was associated with improved survival in the METABRIC data.

Objective: SGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molecular effects of 5 weeks of dapagliflozin treatment on skeletal muscle metabolism in type 2 diabetes patients. Methods: Twenty-six type 2 diabetes mellitus patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. Skeletal muscle acetylcarnitine levels, intramyocellular lipid (IMCL) content and phosphocreatine (PCr) recovery rate were measured by magnetic resonance spectroscopy (MRS). Ex vivo mitochondrial respiration was measured in skeletal muscle fibers using high resolution respirometry. Intramyocellular lipid droplet and mitochondrial network dynamics were investigated using confocal microscopy. Skeletal muscle levels of acylcarnitines, amino acids and TCA cycle intermediates were measured. Expression of genes involved in fatty acid metabolism were investigated. Results: Mitochondrial function, mitochondrial network integrity and citrate synthase and carnitine acetyltransferase activities in skeletal muscle were unaltered after dapagliflozin treatment. Dapagliflozin treatment increased intramyocellular lipid content (0.060 (0.011, 0.110) %, p = 0.019). Myocellular lipid droplets increased in size (0.03 μm2 (0.01–0.06), p

Drinking water companies must limit their effects on climate change. Therefore, in this study, we conducted a hybrid life cycle assessment (LCA) for a new drinking water treatment plant (DWTP) to be built in 2025 and expected to be operational until 2075. We focused on obtaining a nearly complete carbon footprint (CF), including both construction (activities and materials) and operation phases. We compared three DWTP concepts: (i) conventional treatment followed by granular activated carbon (GAC) and ultrafiltration; (ii) conventional treatment followed by reverse osmosis; and (iii) capillary nanofiltration followed by GAC. As the DWTP is to be built in The Netherlands, we considered the current plans of the European Union for reducing CFs using two future scenarios (reductions of 80% and 100% in 2050). We found that the CF of the construction over the lifetime of the DWTP accounts for 20–70% of the total (excluding beneficial effects), depending mainly on the electricity used (Dutch mix, solar, or wind) and the future scenario. This means that the construction phase should be investigated in detail to obtain a complete and accurate estimate of the total CF of drinking water production for new DWTPs.

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (

Background: Type 2 diabetes patients and individuals at risk of developing diabetes are characterized by metabolic inflexibility and disturbed glucose homeostasis. Low carnitine availability may contribute to metabolic inflexibility and impaired glucose tolerance. Here, we investigated whether carnitine supplementation improves metabolic flexibility and insulin sensitivity in impaired glucose tolerant (IGT) volunteers. Methods: Eleven IGT- volunteers followed a 36-day placebo- and L-carnitine treatment (2 g/day) in a randomised, placebo-controlled, double blind crossover design. A hyperinsulinemic-euglycemic clamp (40 mU/m2/min), combined with indirect calorimetry (ventilated hood) was performed to determine insulin sensitivity and metabolic flexibility. Furthermore, metabolic flexibility was assessed in response to a high-energy meal. Skeletal muscle acetylcarnitine concentrations were measured in vivo using long echo time proton magnetic resonance spectroscopy (1H-MRS, TE=500 ms) in the resting state (7:00AM and 5:00PM) and after a 30-min cycling exercise. Twelve normal glucose tolerant (NGT) volunteers were included without any intervention as control group. Results: Metabolic flexibility of IGT-subjects completely restored towards NGT control values upon carnitine supplementation, measured during a hyperinsulinemic-euglycemic clamp and meal test. In muscle, carnitine supplementation enhanced the increase in resting acetylcarnitine concentrations over the day (delta 7:00 AM versus 5:00 PM) in IGT-subjects. Furthermore, carnitine supplementation increased post-exercise acetylcarnitine concentrations and reduced long-chain acylcarnitine species in IGT-subjects, suggesting the stimulation of a more complete fat oxidation in muscle. Whole-body insulin sensitivity was not affected. Conclusion: Carnitine supplementation improves acetylcarnitine formation and rescues metabolic flexibility in IGT-subjects. Future research should investigate the potential of carnitine in prevention/treatment of type 2 diabetes. Keywords: L-carnitine, Metabolic flexibility, Insulin sensitivity, Acetylcarnitine, Impaired glucose tolerance, Hyperinsulinemic-euglycemic clamp

Objective: Skeletal muscle mitochondrial function and energy metabolism displays day-night rhythmicity in healthy, young individuals. Twenty-four-hour rhythmicity of metabolism has been implicated in the etiology of age-related metabolic disorders. Whether day-night rhythmicity in skeletal muscle mitochondrial function and energy metabolism is altered in older, metabolically comprised humans remains unknown. Methods: Twelve male overweight volunteers with impaired glucose tolerance and insulin sensitivity stayed in a metabolic research unit for 2 days under free living conditions with regular meals. Indirect calorimetry was performed at 5 time points (8 AM, 1 PM, 6 PM, 11 PM, 4 AM), followed by a muscle biopsy. Mitochondrial oxidative capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Results: Mitochondrial oxidative capacity did not display rhythmicity. The expression of circadian core clock genes BMAL1 and REV-ERBα showed a clear day-night rhythm (p

The application of zero liquid discharge (ZLD) results in the generation of solid residual streams, which are often not fit for reuse. In this study, we assessed the separation of natural organic matter (NOM) and sodium chloride (NaCl) by nanofiltration (NF), electrodialysis (ED) and ion exchange (IEX) in reverse osmosis brine (RO-brine) and by the extraction of impurities from salt (SALEX) in the generated mixed solids of a full-scale ZLD water treatment plant.The NaCl recovery by NF, ED and IEX ranged 69-99% and the rejection of NOM ranged 18–19%, 43–65% and 53–76%, respectively. The recovery of NaCl by SALEX ranged 52–99%, while the rejection of NOM ranged 59–92%. The results show that NOM and NaCl can be separated both in RO-brine and mixed solids, opening opportunities for recovery of reusable salt from brines in ZLD.

Objective: Resveratrol supplementation improves metabolic health in healthy obese men, but not in patients with type 2 diabetes (T2D) when given as add-on therapy. Therefore, we examined whether resveratrol can enhance metabolic health in men at risk of developing T2D. Additionally, we examined if resveratrol can stimulate brown adipose tissue (BAT). Methods: Thirteen male first degree relatives (FDR) of patients with T2D received resveratrol (150 mg/day) and placebo for 30 days in a randomized, placebo controlled, cross-over trial. Results: Resveratrol significantly improved ex vivo muscle mitochondrial function on a fatty acid-derived substrate. However, resveratrol did not improve insulin sensitivity, expressed as the rate of glucose disposal during a two-step hyperinsulinemic-euglycemic clamp. Also, intrahepatic and intramyocellular lipid content, substrate utilization, energy metabolism, and cold-stimulated 18F-FDG glucose uptake in BAT (n = 8) remained unaffected by resveratrol. In vitro experiments in adipocytes derived from human BAT confirmed the lack of effect on BAT. Conclusions: Resveratrol stimulates muscle mitochondrial function in FDR males, which is in concordance with previous results. However, no other metabolic benefits of resveratrol were found in this group. This could be attributed to subject characteristics causing alterations in metabolism of resveratrol and thereby affecting resveratrol's effectiveness. ClinicalTrials.gov ID: NCT02129595. Keywords: Resveratrol, Type 2 diabetes, Pre-diabetes, Insulin sensitivity, Mitochondrial function, Brown adipose tissue

Objective: A disturbed day-night rhythm is associated with metabolic perturbations that can lead to obesity and type 2 diabetes mellitus (T2DM). In skeletal muscle, a reduced oxidative capacity is also associated with the development of T2DM. However, whether oxidative capacity in skeletal muscle displays a day-night rhythm in humans has so far not been investigated. Methods: Lean, healthy subjects were enrolled in a standardized living protocol with regular meals, physical activity and sleep to reflect our everyday lifestyle. Mitochondrial oxidative capacity was examined in skeletal muscle biopsies taken at five time points within a 24-hour period. Results: Core-body temperature was lower during the early night, confirming a normal day-night rhythm. Skeletal muscle oxidative capacity demonstrated a robust day-night rhythm, with a significant time effect in ADP-stimulated respiration (state 3 MO, state 3 MOG and state 3 MOGS, p

The novel non-peripheral octa-substituted zinc(II) phthalocyanines with 3- and 4-pyridinepropoxy substituents were synthesized via cyclization of substituted phthalonitriles and further characterized. Their photodynamic and sonodynamic activity were then assessed toward bacteria and cancer cells. Additionally, inhibition activity against common human enzymes was evaluated. The singlet oxygen generation (with 1,3-diphenylisobenzofuran - DPBF as an unspecific chemical quencher of singlet oxygen) were measured under light irradiation, whereas under ultrasounds (1 MHz, 3 W) the stability of DPBF in the presence of sensitizer was evaluated. Both phthalocyanines revealed high photostability in DMSO and moderate in DMF, whereas the sonostability in DMF was moderate. Calculated light-induced singlet oxygen generation quantum yields were similar for both compounds and oscillated around 0.33 in DMF and 0.67 in DMSO. Sonodynamic manner revealed moderately high DPBF decomposition upon 1 MHz. Significant bacterial reduction was noted in both photodynamic and sonodynamic manner, reaching >3 log reduction against MRSA and S. epidermidis. Both compounds showed ca. 50 % viability reduction toward hypopharyngeal tumor (FaDu). Moreover, up to 60 % viability reduction was observed in squamous cell carcinoma (SCC-25). In summary, this molecular building of the efficient phthalocyanine-based sensitizer is a potential therapeutic for photodynamic and sonodynamic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)