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Sara Thønnings,1,2 Filip Jansåker,1,3 Kim Oren Gradel,4,5 Bjarne Styrishave,2 Jenny Dahl Knudsen11Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark; 2Toxicology Laboratory, Analytical BioSciences, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; 5Research Unit of Clinical Epidemiology, Institute of Clinical Research, University of Southern Denmark, Odense, DenmarkObjectives: On January 18, 2010, a part of the capital region of Denmark shifted the empirical treatment of febrile conditions from cefuroxime to piperacillin/tazobactam. We compare empirical treatment with piperacillin/tazobactam versus cefuroxime for Escherichia coli bacteremia with regard to 14 days mortality, in a low prevalence cohort of Extended-spectrum beta-lactamase-producing E. coli.Methods: From January 18, 2010 to December 31, 2012, we conducted a retrospective cohort study including patients with E. coli bacteremia from six university hospitals in Copenhagen, Denmark. Clinical and laboratory information was obtained from a bacteremia research database, including information on comorbidity, and we used Cox proportional hazard analysis to asses all-cause 14 days mortality.Results: A total of 568 patients receiving either cefuroxime (n=377) or piperacillin/tazobactam (n=191) as empirical therapy were included. In the Cox proportional hazard model, cefuroxime treatment was significantly associated with death (mortality rate ratio 3.95, CI 1.12–13.90). Other variables associated with death were health care related infection (MRR 3.20, CI 1.67–6.15), hospital-acquired infection (MRR 2,17, CI 1.02–4.62), admission at intensive care unit (MRR 20.45, 5.31–78.82), and combination therapy with ciprofloxacin (MRR 2.14, CI 0.98–4.68).Conclusion: Empiric cefuroxime treatment of E. coli bacteremia was significantly associated with higher 14 days mortality in comparison with piperacillin/tazobactam.Keywords: piperacillin/tazobactam, cefuroxime, E. coli, bacteremia, mortality

STUDY QUESTION What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans? SUMMARY ANSWER Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes. WHAT IS KNOWN ALREADY Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone. Furthermore, high concentrations of progesterone and 17OH-progesterone within follicles may cause dislodging of cortisol from cortisol binding protein (CBP) thereby activating the biological activity of cortisol. STUDY DESIGN, SIZE, DURATION This prospective cohort study included 50 women undergoing fertility treatment according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS Women donated FF and GCs from one follicle for research purpose aspirated at one of four time points during the process of final maturation of follicles: T  = 0 h, T  = 12 h, T  = 17 h, T  = 32 h. A second sample was collected at oocyte pick up at T  = 36 h. The concentration of cortisol and cortisone together with a range of sex steroids was measured by LC-MS/MS in FF collected at the five time points mentioned above. Whole genome microarray data, validated by q-PCR analysis, was used to evaluate gene expression of CYP11B1 , CYP21A2 , HSD11B1 , HSD11B2 , and NR3C1 in GCs at the same time points. MAIN RESULTS AND THE ROLE OF CHANCE The concentration of cortisol was significantly increased from a few nM at 0 h to around 100–140 nM (P  ≤ 0.0001) at 32–36 h, whilst cortisone was almost constant from 0 to 17 h at a concentration of between 90 and 100 nM being significantly reduced to 25–40 nM (P  ≤ 0.0001) at 32–36 h. This was paralleled by a 690-fold upregulation of HSD11B1 from 0 to 12 h increasing to a more than 20.000-fold change at 36 h. HSD11B2 was quickly downregulated 15- to 20-fold after ovulation induction. Concentrations of progesterone and 17OH-progesterone increased during the ovulatory process to high levels which in essence displaces cortisol from its binding protein CBP due to similar binding affinities. Furthermore, a significant decrease in 11-deoxycortisol expression was seen, but CYP11B1 expression was below detection limit in GCs. LIMITATIONS, REASONS FOR CAUTION The study included women undergoing ovarian stimulation and results may differ from the natural cycle. More observations at each specific time point may have strengthened the conclusions. Furthermore, we have not been able to measure the actual active biological concentration of cortisol. WIDER IMPLICATIONS OF THE FINDINGS For the first time, this study collectively evaluated the temporal pattern of cortisol and cortisone concentrations during human ovulation, rendering a physiological framework for understanding potential dysregulations in the inflammatory reaction of ovulation. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the University Hospital of Copenhagen, Rigshospitalet, and Novo Nordisk Foundation grant number NNF21OC00700556. Interreg V ÔKS through ReproUnion (www.reprounion.eu); Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Heart rates were monitored in situ in the shore crab, Carcinus maenas , in relation to variations in depth, salinity, oxygen tension, temperature, light intensity and pH. Experiments were performed in the Looe Estuary, Cornwall, England and in Batson Creek in the Salcombe-Kingsbridge Estuary, Devon, England. Experiments in the Looe Estuary were conducted in the vicinity of a storm water storage discharge whereas the experiments in Batson Creek were performed on a clean site. Tidal rhythms in heart rates were commonly detected but diel rhythms in heart rate were also observed frequently. Both types of rhythm were more evident in animals from Batson Creek than from Looe. In Batson Creek, 12 out of 15 crabs expressed tidal rhythms in heart rate, whereas 6 out of 15 crabs expressed diel rhythms. In the two studies in the Looe Estuary, 6 out of 15 crabs and 3 out of 15 crabs expressed tidal and diel rhythm in heart rate, respectively. At both experimental sites, heart rates were positively correlated with increasing changes in depth and salinity, whereas heart rates were negatively correlated with light intensity. In addition, heart rates appeared to be positively correlated with increasing oxygen tension in the experiments performed in the Looe Estuary. The study suggests that depth and oxygen availability are more important to in situ heart rates in shore crabs within tidal estuaries than are salinity, light intensity and pH. Also, sewage discharge appears to cause an acute increase in heart rate, which may affect expression of biological rhythms in shore crabs. [ABSTRACT FROM AUTHOR]

Background: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues., Methods: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA., Results: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands., Conclusion: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Connar Westgate reports financial support was provided by Lundbeck Foundation. Rigmor Jensen reports financial support was provided by Lundbeck Foundation. If there are other authors, they 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.)

Background: Idiopathic intracranial hypertension (IIH) is a syndrome exhibiting elevated intracranial pressure (ICP), visual disturbances, and severe headache. IIH primarily affects young obese women, though it can occur in individuals of any age, BMI, and sex. IIH is characterized by systemic metabolic dysregulation with a profile of increased androgen hormones. However, the contribution of obesity/hormonal perturbations to cerebrospinal fluid (CSF) dynamics remains unresolved., Methods: We employed obese female Zucker rats and adjuvant testosterone to reveal IIH causal drivers. ICP and CSF dynamics were determined with in vivo experimentation and magnetic resonance imaging, testosterone levels assessed with mass spectrometry, and choroid plexus function revealed with transcriptomics., Results: Obese rats had undisturbed CSF testosterone levels and no changes in ICP or CSF dynamics. Adjuvant testosterone treatment of obese rats elevated the CSF secretion rate, although with no effect on the ICP, due to elevated CSF drainage capacity of these rats., Conclusions: Obesity in itself therefore does not suffice to recapitulate the IIH symptoms in rats, but modulation of CSF dynamics appears with adjuvant testosterone treatment, which mimics the androgen excess observed in female IIH patients. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of IIH and could potentially serve as a future therapeutic target., (© 2024. The Author(s).)

Here, we collected 154 plant species in China ancient forests looking for novel efficient bioactive compounds for cancer treatments. We found 600 bioactive phyto-chemicals that induce apoptosis of liver cancer cell in vitro. First, we screen the plant extract's in vitro cytotoxicity inhibition of cancer cell growth using in vitro HepG2 cell lines and MTT cytotoxicity. The results from these initial MTT in vitro cytotoxicity tests show that the most efficient plants towards hepatoma cytoxicity is Cephalotaxus sinensis, mint bush (Elsholtzia stauntonii) and winged spindle tree (Euonymus alatus). We then used in cell-counting kit-8 (CCK-8) to further understand in vivo tumor growth using nude mice and GC-MS and LC-QTOF-MS to analyze the composition of compounds in the extracts. Extracted chemically active molecules analyzed by network pharmacology showed inhibition on the growth of liver cancer cells by acting on multiple gene targets, which is different from the currently used traditional drugs acting on only one target of liver cancer cells. Extracts from Cephalotaxus sinensis, mint bush (Elsholtzia stauntonii) and winged spindle tree (Euonymus alatus) induce apoptosis in hepatoma cancer cell line HepG2 with a killing rate of more than 83% and a tumor size decrease by 62-67% and a killing rate of only 6% of normal hepatocyte LO2. This study highlight efficient candidate species for cancer treatment providing a basis for future development of novel plant-based drugs to help meeting several of the UN SDGs and planetary health., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate., Experimental Approach: Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross-over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT-qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions., Key Results: We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24-h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium-dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes., Conclusions and Implications: Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Female sex is a known risk factor of brain disorders with raised intracranial pressure (ICP) and sex hormones have been suggested to alter cerebrospinal fluid (CSF) dynamics, thus impairing ICP regulation in CSF disorders such as idiopathic intracranial hypertension (IIH). The choroid plexus (CP) is the tissue producing CSF and it has been hypothesized that altered hormonal composition could affect the activity of transporters involved in CSF secretion, thus affecting ICP. Therefore, we aimed to investigate if expression of various transporters involved in CSF secretion at CP were different between males and females and between females in different estrous cycle states. Steroid levels in serum was also investigated., Methods: Female and male rats were used to determine sex-differences in the genes encoding for the transporters Aqp1 and 4, NKCC1, NBCe2, NCBE; carbonic anhydrase enzymes II and III (CA), subunits of the Na + /K + -ATPase including Atp1a1, Atp1b1 and Fxyd1 at CP. The estrous cycle stage metestrus (MET) and estrous (ES) were determined before euthanasia. Serum and CP were collected and subjected to RT-qPCR analysis and western blots. Serum was used to measure steroid levels using liquid chromatography tandem mass spectrometry (LC-MS/MS)., Results: Significant differences in gene expression and steroid levels between males and ES females were found, while no differences were found between male and MET females. During ES, expression of Aqp1 was lower (p < 0.01) and NKCC1 was higher in females compared to males. CAII was lower while CAIII was higher in ES females (p < 0.0001). Gene expression of Atp1a1 was lower in ES compared to male (p = 0.0008). Several of these choroidal genes were also significantly different in MET compared to females in ES. Differences in gene expression during the estrus cycle were correlated to serum level of steroid hormones. Protein expression of AQP1 (p = 0.008) and CAII (p = 0.035) was reduced in ES females compared to males., Conclusions: This study demonstrates for the first time that expression at CP is sex-dependent and markedly affected by the estrous cycle in female rats. Further, expression was related to hormone levels in serum. This opens a completely new avenue for steroid regulation of the expression of CSF transporters and the close link to the understanding of CSF disorders such as IIH., (© 2023. The Author(s).)

According to the World Health Organization, women's breast cancer is among the most common cancers with 7.8 million diagnosed cases during 2016-2020 and encompasses 15 % of all female cancer-related mortalities. These mortality events from triple-negative breast cancer are a significant health issue worldwide calling for a continuous search of bioactive compounds for better cancer treatments. Historically, plants are important sources for identifying such new bioactive chemicals for treatments. Here we use high-throughput screening and mass spectrometry analyses of extracts from 100 plant species collected in Chinese ancient forests to detect novel bioactive breast cancer phytochemicals. First, to study the effects on viability of the plant extracts, we used a MTT and CCK-8 cytotoxicity assay employing triple-negative breast cancer (TNBC) MDA-MB-231 and normal epithelial MCF-10A cell lines and cell cycle arrest to estimate apoptosis using flow cytometry for the most potent three speices. Based on these analyses, the final most potent extracts were from the Amur honeysuckle (Lonicera maackii) wood/root bark and Nigaki (Picrasma quassioides) wood/root bark. Then, 5 × 10 6 MDA-MB-231 cells were injected subcutaneously into the right hind leg of nude mice and a tumour was allowed to grow before treatment for seven days. Subsequently, the four exposed groups received gavage extracts from Amur honeysuckle and Nigaki (Amur honeysuckle wood distilled water, Amur honeysuckle root bark ethanol, Nigaki wood ethanol or Nigaki root bark distilled water/ethanol (1:1) extracts) in phosphate-buffered saline (PBS), while the control group received only PBS. The tumour weight of treated nude mice was reduced significantly by 60.5 % within 2 weeks, while on average killing 70 % of the MDA-MB-231 breast cancer cells after 48 h treatment (MTT test). In addition, screening of target genes using the Swiss Target Prediction, STITCH, STRING and NCBI-gene database showed that the four plant extracts possess desirable activity towards several known breast cancer genes. This reflects that the extracts may kill MBD-MB-231 breast cancer cells. This is the first screening of plant extracts with high efficiency in 2 decades, showing promising results for future development of novel cancer treatments., 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 © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The development of cell-based microfluidic assays offers exciting new opportunities in toxicity testing, allowing for integration of new functionalities, automation, and high throughput in comparison to traditional well-plate assays. As endocrine disruption caused by environmental chemicals and pharmaceuticals represents a growing global health burden, the purpose of the current study was to contribute towards the miniaturization of the H295R steroidogenesis assay, from the well-plate to the microfluidic format. Microfluidic chip fabrication with the established well-plate material polystyrene (PS) is expensive and complicated; PDMS and thiol-ene were therefore tested as potential chip materials for microfluidic H295R cell culture, and evaluated in terms of cell attachment, cell viability, and steroid synthesis in the absence and presence of collagen surface modification. Additionally, spike-recovery experiments were performed, to investigate potential steroid adsorption to chip materials. Cell aggregation with poor steroid recoveries was observed for PDMS, while cells formed monolayer cultures on the thiol-ene chip material, with cell viability and steroid synthesis comparable to cells grown on a PS surface. As thiol-ene overall displayed more favorable properties for H295R cell culture, a microfluidic chip design and corresponding cell seeding procedure were successfully developed, achieving repeatable and uniform cell distribution in microfluidic channels. Finally, H295R perfusion culture on thiol-ene chips was investigated at different flow rates (20, 10, and 2.5 µL/min), and 13 steroids were detected in eluting cell medium over 48 h at the lowest flow rate. The presented work and results pave the way for a time-resolved microfluidic H295R steroidogenesis assay., (© 2023. The Author(s).)

Background: Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of IIH pathophysiology. Systemic metabolic dysregulation has been identified in IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved., Methods: Female Wistar rats were either fed a high fat diet (HFD) for 21 weeks or exposed to adjuvant testosterone treatment for 28 days to recapitulate IIH causal drivers. Cerebrospinal fluid (CSF) and blood testosterone levels were determined with mass spectrometry, ICP and CSF dynamics with in vivo experimentation, and the choroid plexus function revealed with transcriptomics and ex vivo isotope-based flux assays., Results: HFD-fed rats presented with increased ICP (65%), which was accompanied by increased CSF outflow resistance (50%) without altered CSF secretion rate or choroid plexus gene expression. Chronic adjuvant testosterone treatment of lean rats caused elevated ICP (55%) and CSF secretion rate (85%), in association with increased activity of the choroid plexus Na + ,K + ,2Cl - cotransporter, NKCC1., Conclusions: HFD-induced ICP elevation in experimental rats occurred with decreased CSF drainage capacity. Adjuvant testosterone, mimicking the androgen excess observed in female IIH patients, elevated the CSF secretion rate and thus ICP. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of IIH., (© 2023. The Author(s).)

The use of herbal products is booming all over the world because of being believed as safer than conventional drugs and free of side effects. However, there are untrustworthy manufacturers who adulterate herbal products by adding conventional drugs which might eventually lead to microbial resistance and herb-to-drug interactions. There is a need to develop methods for detecting adulterants in herbal products. A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneous identification and determination of conventional antimalarials (chloroquine, quinine, sulfadoxine, pyrimethamine, mefloquine, lumefantrine, amodiaquine, artemisinin, dihydroartemisinin, artesunate and artemether) in herbal products was developed. Stable isotopically labelled compounds (artemether-d 3 , quindine-d 3 , and sulfadoxine-d 3 ) were used as internal standards (ISs) for quantitative analysis. Extraction of analytes was performed using methanol: water: formic acid (90:10:0.1, v/v) and chromatographic separation was done in a gradient mode using mobile phase A: Ultrapure water containing 0.1% formic acid and 1 mM ammonium formate and mobile phase B: Acetonitrile/methanol (50:50) containing 0.1% formic acid and 1 mM ammonium formate. The calibration curves were linear (r 2  ≥ 0.991) over the range of 0.001-0.3 µg mL -1 for all compounds. The limit of detection (LOD) ranged from 0.002 to 0.02 μg mL -1 while the limit of quantification (LOQ) ranged from 0.006 to 0.08 μg mL -1 . Accuracy, expressed as recovery of spiked herbal products ranged from 52 to 128%. The precision, expressed as percent relative standard deviation (%RSD) at two concentration levels, ranged from 1.0 to 13.8%. The matrix effect expressed as the matrix factor (MF) ranged from 0.77 to 0.97. The developed method was used to identify and quantify conventional antimalarials in herbal product samples from Tanzania. Ten out of 50 herbal products were found to contain amodiaquine, sulfadoxine, pyrimethamine, mefloquine, dihydroartemisinin, artemether and lumefantrine. The developed method is considered a valuable tool for getting a better understanding of the adulteration of conventional antimalarials in herbal products., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Aims: It remains unknown whether the consistently observed increase in haematocrit with sodium-glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF)., Methods and Results: The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I-III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8-4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59-0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86-1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (p interaction  >0.05)., Conclusion: These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) are chemicals that undergo long-range transport to the Arctic. These chemicals possess endocrine disruptive properties raising concerns for development and reproduction. Here, we report the relationship between concentrations of testosterone (T) and persistent organic pollutant (POPs) in 40 East Greenland male polar bears ( Ursus maritimus ) sampled during January to September 1999-2001. The mean ± standard concentrations of blood T were 0.31 ± 0.49 (mean ± SD) ng/mL in juveniles/subadults (n = 22) and 3.58 ± 7.45 ng/mL in adults (n = 18). The ∑POP concentrations (mean ± SD) in adipose tissue were 8139 ± 2990 ng/g lipid weight (lw) in juveniles/subadults and 11,037 ± 3950 ng/g lw in adult males, respectively, of which Σpolychlorinated biphenyls (ΣPCBs) were found in highest concentrations. The variation in T concentrations explained by sampling date (season), biometrics and adipose tissue POP concentrations was explored using redundancy analysis (RDA). The results showed that age, body length, and adipose lipid content in adult males contributed (p = 0.02) to the variation in POP concentrations. However, although some significant relationships between individual organochlorine contaminants and T concentrations in both juveniles/subadults and adult polar bears were identified, no significant relationships (p = 0.32) between T and POP concentrations were identified by the RDAs. Our results suggest that confounders such as biometrics and reproductive status may mask the endocrine disruptive effects that POPs have on blood T levels in male polar bears, demonstrating why it can be difficult to detect effects on wildlife populations., Competing Interests: 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., (© 2023 The Authors.)