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Movement sensor data from seven static and dynamic dog behaviors (sitting, standing, lying down, trotting, walking, playing, and (treat) searching i.e. sniffing) was collected from 45 middle to large sized dogs with six degree-of-freedom movement sensors attached to the collar and the harness. With 17 dogs the collection procedure was repeated. The duration of each of the seven behaviors was approximately three minutes. The order of the tasks was varied between the dogs and the two repetitions (for the 17 dogs). The behaviors were annotated post-hoc based on the video recordings made with two camcorders during the tests with one second resolution. The annotations were accurately synchronized with the raw movement sensors data.The annotated data was originally used for training behavior classification machine learning algorithms for classifying the seven behaviors. The developed signal processing and classification algorithms are provided together with the raw measurement data and reference annotations. The description and results of the original investigation that the dataset relates to are found in: P. Kumpulainen, A. Valldeoriola Cardó, S. Somppi, H. Törnqvist, H. Väätäjä, P. Majaranta, Y. Gizatdinova, C. Hoog Antink, V. Surakka, M. V. Kujala, O. Vainio, A. Vehkaoja, Dog behavior classification with movement sensors placed on the harness and the collar, Applied Animal behavior Science, 241 (2021), 105,393.

A low level of high density lipoprotein cholesterol (HDL-C) is a powerful risk factor for cardiovascular disease. However, despite the reported key role of apolipo-proteins, specifically, apoA-I, in HDL metabolism, lipid molecular composition of HDL particles in subjects with high and low HDL-C levels is currently unknown. Here lipidomics was used to study HDL derived from well-characterized high and low HDL-C subjects. Low HDL-C subjects had elevated triacylglycerols and diminished lysophosphatidylcholines and sphingomyelins. Using information about the lipid composition of HDL particles in these two groups, we reconstituted HDL particles in silico by performing large-scale molecular dynamics simulations. In addition to confirming the measured change in particle size, we found that the changes in lipid composition also induced specific spatial distributions of lipids within the HDL particles, including a higher amount of triacylglycerols at the surface of HDL particles in low HDL-C subjects. Our findings have important implications for understanding HDL metabolism and function. For the first time we demonstrate the power of combining molecular profiling of lipoproteins with dynamic modeling of lipoprotein structure.

The main antiatherogenic function of HDL is to promote the efflux of cholesterol from peripheral cells and transport it to the liver for excretion in a process termed reverse cholesterol transport. The aim of this study was to evaluate the cholesterol efflux capacity in low- and high-HDL subjects by utilizing monocytes and serum from 18 low-HDL and 15 high-HDL subjects. Low and high HDL levels were defined, respectively, as HDL ≤10th and HDL ≥90th Finnish age/sex-specific percentile. Cholesterol efflux from [3H]cholesterol-oleate-acetyl-LDL-loaded monocyte-derived macrophages to standard apolipoprotein A-I (apoA-I), HDL2, and serum was measured. In addition, cholesterol efflux from acetyl-LDL-loaded human THP-1 macrophages to individual sera (0.5%) derived from the study subjects was evaluated. Cholesterol efflux to apoA-I, HDL2, and serum from macrophage foam cells derived from low- and high-HDL subjects was similar. The relative ABCA1 and ABCG1 mRNA expression levels in unloaded macrophages, as well as their protein levels in loaded macrophage foam cells, were similar in the two study groups. Cholesterol efflux from THP-1 foam cells to serum recovered from high-HDL subjects was slightly higher than that to serum from low-HDL subjects (P = 0.046). Cholesterol efflux from THP-1 macrophages to serum from study subjects correlated with serum apoB (P = 0.033), apoA-I (P = 0.004), apoA-II (P < 0.0001), and the percentage of apoA-I present in the form of preβ-HDL (P = 0.0001). Our data reveal that macrophages isolated from either low- or high-HDL subjects display similar cholesterol efflux capacity to exogenous acceptors. However, sera from low-HDL subjects have poorer cholesterol acceptor ability as compared with sera from high-HDL subjects.

HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.

Preβ-HDL particles act as the primary acceptors of cellular cholesterol in reverse cholesterol transport (RCT). An impairment of RCT may be the reason for the increased risk of coronary heart disease (CHD) in subjects with familial low HDL. We studied the levels of serum preβ-HDL and the major regulating factors of HDL metabolism in 67 subjects with familial low HDL and in 64 normolipidemic subjects. We report that the subjects with familial low HDL had markedly reduced preβ-HDL concentrations compared with the normolipidemic subjects (17.4 ± 7.2 vs. 23.4 ± 7.8 mg apolipoprotein A-I/dl; P < 0.001). A positive correlation was observed between preβ-HDL concentration and serum triglyceride (TG) level (r = 0.334, P = 0.006). In addition, serum TG level was found to be the strongest predictor of preβ-HDL concentration in subjects with familial low HDL. The activities of cholesteryl ester transfer protein and hepatic lipase were markedly increased in subjects with familial low HDL without a significant correlation to preβ-HDL concentration.Our results support the hypothesis that impaired RCT is one mechanism behind the increased risk for CHD in subjects with familial low HDL.

Background and Purpose: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have demonstrated increased blood coagulation which is thought to contribute to delayed cerebral ischemia (DCI) and to a worse outcome. Therefore, we sought to determine whether this increased blood coagulation, detectable with rotational thromboelastometry (ROTEM), was associated with DCI and neurological outcome., Methods: We conducted a prospective observational study of 60 consecutive adult aSAH patients. ROTEM's EXTEM and FIBTEM assays and D-dimer were analyzed at admission and post-bleed days (PBDs) 2-3, 4-5, 7-8, and 11-12. ROTEM's clot formation time (CFT) represents the stabilization of the clot, and the maximum clot firmness (MCF) the maximum clot strength. Glasgow Outcome Scale extended (GOSe) at three months determined the neurological outcome., Results: DCI incidence was 41.7%. EXTEM-CFT was significantly shorter in patients with unfavorable neurological outcome (GOSe 1-4) on PBDs 4-5 and 7-8, p < 0.05, respectively. FIBTEM-MCF was significantly higher in patients with unfavorable neurological outcomes on PBD 4-5 (p < 0.05), PBD 7-8 (p < 0.05), and PBD 11-12 (p < 0.05). EXTEM-CFT decreased, and FIBTEM-MCF rose during the study period in all patients. Patients with unfavorable neurological outcome had a higher D-dimer at all studied time points, p < 0.05. No difference was found in the ROTEM parameters or D-dimer when assessing patients with and without DCI., Conclusions: Patients were in a state of increased blood coagulation after aSAH, with those with unfavorable neurological outcome being more coagulable than those with favorable outcome. However, increased blood coagulation was not associated with DCI., Clinicaltrials: gov, NCT03985176., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Children with suspected ureteropelvic junction obstruction (UPJO) may present with a paradoxical ipsilateral supranormal differential renal function (snDRF) on 99m Technetium mercaptoacetyltriglycine scintigraphy (MAG3 scan)., Objective: The aim was to investigate the prevalence of snDRF, the risk of pyeloplasty among children with UPJO and snDRF, and to explore the experience of snDRF among international pediatric urologists., Methods: A retrospective cohort study of children with suspected unilateral UPJO who underwent MAG3 scan at four hospitals in Sweden between 2005 and 2020. SnDRF was defined as DRF ≥55%. Normal DRF was defined as DRF 45-54%. Primary outcome was risk of pyeloplasty. Indications for pyeloplasty were loss of >10%-points of differential renal function (DRF), ipsilateral DRF <40%, or symptomatic UPJO. Logistic and cox regressions were performed in univariate and multivariable analyses, adjusting for age, gender, year, laterality, antenatal hydronephrosis, anterior-posterior diameter (APD), and kidney size. An international questionnaire regarding the management of snDRF was developed and distributed to pediatric urologists., Results: The prevalence of snDRF was 19%. SnDRF was more common in boys, children with antenatal hydronephrosis, children undergoing their first MAG3 scan at a younger age, and in the left kidney. After further exclusion of 70 children with DRF <45%, a total of 264 were included for longitudinal follow-up of median 6.6 (IQR 2.5-11.5) years. SnDRF was not associated with increased risk of pyeloplasty (adjusted OR 0.98 (95% CI 0.41-2.33), p = 0.96, and adjusted HR 1.00 (95% CI 0.53-1.91), p = 0.99) or time to pyeloplasty (1.1 years vs. 1.6 years, p = 0.40). Among the 79 surveyed pediatric urologists, a majority would not change clinical UPJO-management based on the presence or absence of ipsilateral snDRF., Discussion: There are only a few studies considering the need of pyeloplasty based on the presence of snDRF and this is the first survey among pediatric urologists on its management. With more included patients than previous studies, this study showed a snDRF prevalence of 19%, congruent with the findings of others. The underlying cause of snDRF is debated, but it cannot solely be explained as an artifact of hydronephrotic kidneys. Further studies on the clinical implications of snDRF are warranted, since DRF influences the decision to operate., Conclusion: A fifth of all children with suspected UPJO presented with ipsilateral snDRF on initial MAG3 scan, and snDRF was not associated with a greater risk of pyeloplasty. Supported by a large group of international pediatric urology colleagues, this study concludes that the same clinical follow-up and management apply, regardless of presence of snDRF., Competing Interests: Conflict of interest None., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Severe hypercholesterolemia (LDL-cholesterol ≥ 5 mmol/l) is a major risk factor for coronary artery disease (CAD). The etiology incudes both genetic and nongenetic factors, but persons carrying mutations in known hypercholesterolemia-associated genes are at significantly higher CAD risk than non-carriers. Yet, a significant proportion of mutation carriers remains undetected while the assessment of genetic candidate variants in clinical practice is challenging., Methods: To address these challenges, we set out to test the utility of a practical approach to leverage data from a large reference cohort, the FinnGen Study encompassing 356,082 persons with extensive longitudinal health record information, to aid the clinical evaluation of single genetic candidate genes variants detected by exome sequence analysis in a target population of 351 persons with severe hypercholesterolemia., Results: We identified 23 rare missense mutations in known hypercholesterolemia genes, 3 of which were previously described mutations (LDLR Pro309Lysfs, LDLR Arg595Gln and APOB Arg3527Gln). Subsequent in silico and clinical assessment of the remaining 20 variants pinpointed two likely hypercholesterolemia-associated variants in LDLR (Arg574Leu and Glu626Lys) and one in LDLRAP1 (Arg151Trp). Heterozygous carriers of the novel LDLR and LDLRAP1 variants received statin treatment more often than non-carriers (OR 2.1, p = 1.8e-6 and OR 1.4, p = 0.001) and untreated carriers had higher risk for ischemic heart disease (OR 2.0, p = 0.03 and OR 1.8, p = 0.008)., Conclusions: Our data elucidate the wide spectrum of genetic variants impacting hypercholesterolemia and demonstrate the utility of a large reference population to assess the heterogeneous impact of candidate gene variants on cardiovascular disease risk., 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 B.V. All rights reserved.)

Aims: The cardio-protective and immuno-regulatory properties of RTP-026, a synthetic peptide that spans the Annexin-A1 (AnxA1) N-terminal region, were tested in rat acute myocardial infarction., Methods and Results: In vitro, selective activation of formyl-peptide receptor type 2 (FPR2) by RTP-026 occurred with apparent EC 50 in the 10-30 nM range. With human primary cells, RTP-026 counteracted extension of neutrophil life-span and augmented phagocytosis of fluorescent E.coli by blood myeloid cells. An in vivo model of rat acute infarction was used to quantify tissue injury and phenotype immune cells in myocardium and blood. The rat left anterior descending coronary artery was occluded and then reopened for 2-hour or 24-hour reperfusion. For the 2-hour reperfusion protocol, RTP-026 (25-500 µg/kg; given i.v. at the start of reperfusion) significantly reduced infarct size by ∼50 %, with maximal efficacy at 50 µg/kg. Analyses of cardiac immune cells showed that RTP-026 reduced neutrophil and classical monocyte recruitment to the damaged heart. In the blood, RTP-026 (50 µg/kg) attenuated activation of neutrophils and monocytes monitored through CD62L and CD54 expression. Modulation of vascular inflammation by RTP-026 was demonstrated by reduction in plasma levels of mediators like TNF-α, IL-1β, KC, PGE 2 and PGF 2α⊡ For the 24-hour reperfusion protocol, RTP-026 (30 µg/kg given i.v. at 0, 3 and 6 h reperfusion) reduced necrotic myocardium by ∼40 %., Conclusions: RTP-026 modulate immune cell responses and decreases infarct size of the heart in preclinical settings. Tempering over-exuberant immune cell activation by RTP-026 is a suitable approach to translate the biology of AnxA1 for therapeutic purposes., Competing Interests: Declaration of Competing Interest Mauro Perretti declares to be a shareholder of Antibe Therapeutics and ResoTher Pharma A/S and a director of William Harvey Research Limited; a scientific advisory board member for Antibe Therapeutics and SynAct Pharma Aps. Mauro Perretti and Jesmond Dalli are a co-inventor on a patent related to AnxA1 pro-resolving peptides (European Patent 3533457 B1). Thomas EN Jonassen is co-founder and shareholder of ResoTher Pharma A/S. Samra Sanni holds managerial position at ResoTher Pharma A/S. ResoTher Pharma A/S owns intellectual property rights on RTP-026., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Antibiotic treatment may reduce the efficacy of cancer immunotherapy by disrupting gut microbiome. We aimed to study the association of antibiotics and survival outcomes in advanced cutaneous melanoma and non-small-cell lung cancer (NSCLC) patients who had received anti-PD-1/L1 monotherapy., Patients and Methods: A total of 222 melanoma and 199 NSCLC patients had received anti-PD-1/L1 monotherapy in 5 Finnish hospitals between January 2014 and December 2020. Clinical characteristics, antibiotic and corticosteroid treatment, and survival outcomes were retrospectively collected from hospital and national medical records., Results: There were 32% of melanoma and 31% of NSCLC patients who had received antibiotic treatment (ABT) 3 months before to 1 month after the first anti-PD-1/L1 antibody infusion. In survival analyses, early antibiotic treatment was associated with inferior overall survival (OS) (ABT 19.2 [17.6-43.7] vs. no ABT 35.6 [29.3-NA] months, P = .033) but not with inferior progression-free survival (PFS) (ABT 5.8 [3.0-12.6] vs. no ABT 10.2 [7.7-15.3] months, P = .3) in melanoma patients and with inferior OS (ABT 8.6 [6.4-12.3] vs. no ABT 18.5 [15.1-21.6] months, P < .001) and PFS (ABT 2.8 [2.1-4.5] vs. no ABT 5.6 [4.4-8.0] months, P = .0081) in NSCLC patients. In multivariable analyses, ABT was not an independent risk-factor for inferior OS and PFS in melanoma but was associated with inferior OS (hazard ratio [HR] 2.12 [1.37-3.28]) and PFS (HR 1.65 [1.10-2.47]) in NSCLC after adjusted for other risk factors., Conclusions: Early ABT was an independent poor risk factor in NSCLC patients who had received anti-PD-1/L1 monotherapy but not in melanoma patients. The weight of ABT as a poor risk factor might depend on other prognostic factors in different cancers., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Solid phase microextraction Arrow and thermal desorption-gas chromatography-mass spectrometry allowed the collection and evaluation of volatile organic compounds (VOCs) emitted by fungal cultures from building insulation materials and in indoor air. Principal component analysis, linear discriminant analysis and supported vector machine were used for visualization and statistical assessment of differences between samples. In addition, a screening tool based on the soft independent modelling of class analogies (SIMCA) was developed for identification of fungal contamination of indoor air. Ten different fungal strains, incubated under ambient and microaerophilic conditions, were analyzed for time period ranging from 5 to 29 days after inoculation resulting in a total of 140 samples. In addition, the effect of additives on the fungal growing media was studied. The total number of compounds and concentration values were used for the evaluation of the results. Clear differences were observed for VOC profiles emitted by different fungal strains by exploiting long chain alcohols (3-octanol, 1-hexanol and 2-octen-1-ol) and sesquiterpenes (farnesene, cuprene). The analysis of glass-wool and cellulose based building insulation materials (3 samples) gave clear differences, mainly for oxygenated compounds (ethyl acetate and hexanal) and benzenoids (benzaldehyde). Moreover, the comparison of indoor air and insulation materials collected from a house with fungal indoor air problems indicated that 42% of the VOCs were found in both samples. The analysis of 52 indoor air samples demonstrated clear differences in their VOC profiles, especially for hydrocarbons, and between control (44 samples) and indoor air problem houses (8 samples). Finally, the SIMCA model enabled to recognize differences between control and fungi contaminated houses with a prediction capacity over 84%., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jose Ruiz-Jimenez, Marja-Liisa Riekkola reports financial support was provided by Jane and Aatos Erkko Foundation. Jose Ruiz-Jimenez, Marja-Liisa riekkola reports financial support was provided by Academy of Finland., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heat exposures occur in many occupations. Heat has been linked to key carcinogenic processes, however, evidence for associations with cancer risk is sparse. We examined potential associations between occupational heat exposure and prostate cancer risk in a multi-country study., Methods: We analysed a large, pooled dataset of 3142 histologically confirmed prostate cancer cases and 3512 frequency-matched controls from three countries: Canada, France, and Spain. Three exposure indices: ever exposure, lifetime cumulative exposure and duration of exposure, were developed using the Finnish Job-Exposure Matrix, FINJEM, applied to the lifetime occupational history of participants. We estimated odds ratios (ORs) and 95% confidence intervals (CIs), using conditional logistic regression models stratified by 5-year age groups and study, adjusting for potential confounders. Potential interactions with exposure to other occupational agents were also explored., Results: Overall, we found no association for ever occupational heat exposure (OR 0.97; 95% CI 0.87, 1.09), nor in the highest categories of lifetime cumulative exposure (OR 1.04; 95% CI 0.89, 1.23) or duration (OR 1.03; 95% CI 0.88, 1.22). When using only the Spanish case-control study and a Spanish Job Exposure Matrix (JEM), some weakly elevated ORs were observed., Conclusions: Findings from this study provide no clear evidence for an association between occupational heat exposure and prostate cancer risk., 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs., (© 2022 by The American Society of Hematology.)

Water browning or brownification refers to increasing water color, often related to increasing dissolved organic matter (DOM) and carbon (DOC) content in freshwaters. Browning has been recognized as a significant physicochemical phenomenon altering boreal lakes, but our understanding of its ecological consequences in different freshwater habitats and regions is limited. Here, we review the consequences of browning on different freshwater habitats, food webs and aquatic-terrestrial habitat coupling. We examine global trends of browning and DOM/DOC, and the use of remote sensing as a tool to investigate browning from local to global scales. Studies have focused on lakes and rivers while seldom addressing effects at the catchment scale. Other freshwater habitats such as small and temporary waterbodies have been overlooked, making the study of the entire network of the catchment incomplete. While past research investigated the response of primary producers, aquatic invertebrates and fishes, the effects of browning on macrophytes, invasive species, and food webs have been understudied. Research has focused on freshwater habitats without considering the fluxes between aquatic and terrestrial habitats. We highlight the importance of understanding how the changes in one habitat may cascade to another. Browning is a broader phenomenon than the heretofore concentration on the boreal region. Overall, we propose that future studies improve the ecological understanding of browning through the following research actions: 1) increasing our knowledge of ecological processes of browning in other wetland types than lakes and rivers, 2) assessing the impact of browning on aquatic food webs at multiple scales, 3) examining the effects of browning on aquatic-terrestrial habitat coupling, 4) expanding our knowledge of browning from the local to global scale, and 5) using remote sensing to examine browning and its ecological consequences., 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 © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis is a clinical syndrome resulting from infection followed by inflammation and is one of the significant causes of mortality worldwide. The underlying reason is the host's uncontrolled inflammatory response due to an infection led to multiple organ dysfunction/failure. Neutrophils, an innate immune cell, are forerunners to reach the site of infection/inflammation for clearing the infection and resolute the inflammation during sepsis. A relatively new neutrophil effector function, neutrophil extracellular traps (NETs), have been demonstrated to kill the pathogens by releasing DNA decorated with histone and granular proteins. A growing number of pieces of shreds of evidence suggest that unregulated incidence of NETs have a significant influence on the pathogenesis of sepsis-induced multiple organ damage, including arterial hypotension, hypoxemia, coagulopathy, renal, neurological, and hepatic dysfunction. Thus, excessive production and improper resolution of NETs are of significant therapeutic value in combating sepsis-induced multiple organ failure. The purpose of this review is intended to highlight the role of NETs in sepsis-induced organ failure. Furthermore, the current status of therapeutic strategies to intersect the harmful effects of NETs to restore organ functions is discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sepsis, which includes infection followed by inflammation, is one of the leading causes of death among neonates worldwide. The major attribute of this disease process is dysregulated host response to infection leading to organ dysfunction and potentially death. A comprehensive understanding of the host response as well as the pathogen itself are important factors contributing to outcome. Early diagnosis is paramount, as it leads to accurate assessment and improved clinical management. Accordingly, a number of diagnostic platforms have been introduced to assess the presence of blood stream pathogens in septic neonates. Unfortunately, current point-of-care (POC) methods rely on a single parameter/biomarker and thus lack a comprehensive evaluation. The emerging field of biosensing has, however, resulted in the development of a wide range of analytical devices that may be useful at POC. This review discusses currently available methods to screen the inflammatory process in neonatal sepsis. We describe POC sensor-based methods for single platform multi-analyte detection and highlight the latest advances in this evolving technology. Finally, we critically evaluate the applicability of these POC devices clinically for early diagnosis of sepsis in neonates., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alternative treatment options to glucocorticoids for equine asthma is desirable due to withdrawal time. The objective was to evaluate if serum and Respiratory Gene Technology (RGT), a commercial kit to produce autologous conditioned serum, was effective in reducing bronchoalveolar lavage (BAL) neutrophils and mast cells in racehorses with cytological evidence of mild equine asthma . Thirty-six Standardbred trotters in active training were enrolled in this randomized clinical trial; a healthy control group (n=11), a RGT group (n=12) and a serum group (n=13). Endoscopy including tracheal wash (TW) and BAL was performed before (T0), after a 6-week treatment period including 12 intramuscular injections of RGT or serum (T6) and as a follow-up 10 weeks after treatment (T16). A significant decrease in BAL neutrophils for the RGT group was found between T0 and T6 (P = .002, d=-1.51, CI: -2.43;-0.59) and for the serum group between T0-T6 (P = .002, d=-1.36, CI: -2.26;-0.46). Further, a significant decrease in BAL mast cells between T0-T6 for the both the RGT group (P = .019, d=-1.23, CI: -1.22;-0.34) and the serum group (P= .004, d=-0.81, CI: -1.65;0.04), and further between T0-T16 (RGT P= .011, d=-1.55, CI: -2.62;-0.48; serum P= .044, d=-0.65, CI: -1.68;-0.37). No significant difference in TW cytology was found for any of the time-points. Pro- and anti-inflammatory cytokines were regulated according to treatment. The control group showed no cytological differences between any time-point. Study results showed that intramuscular treatment with both RGT and serum was effective associated with reduction of BAL neutrophils and mast cells in horses with cytological evidence of mild equine asthma. Further large-scale studies are necessary., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The present work is aimed at improving the adhesion of nanomaterials at the interface of solid state working electrodes. Towards this, herein, an efficient method has been proposed that requires the electrode interface to be decorated with an optimally thin layer of Nafion. This selectively permeable layer ensures the stability of the sensor interface, without hampering the transport of biomolecules and electrons. As a case study, here, electrospun Cerium oxide nanofiber (CeNF) modified Glassy carbon electrodes (GCE) have been used as the sensing interface, and stability and performance of the GCE/CeNF/Nafion interface is evaluated using analytical electrochemistry. The CeNF is synthesized via electrospinning and is characterized using X-ray diffraction spectroscopy, Thermal gravimetry, Fourier transform infrared spectroscopy, and Field emission scanning electron microscopy. Further, detection of sepsis specific biomarker TNF-α from spiked buffer samples is demonstrated, as a case study, towards evaluating the effect of Nafion on the interfacial sensitivity. The achieved LOD of GCE/CeNF and GCE/CeNF/Nafion for TNF-α detection were 2.8 fg/mL and 1.2 fg/mL, respectively. A comparative analysis between the Electrochemical impedance spectroscopic (EIS) results of the GCE/CeNF and the GCE/CeNF/Nafion interfaces confirms the improvement in stability, without affecting the sensitivity and the limiting detection., 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 © 2020 Elsevier B.V. All rights reserved.)

Background: There is still a lack of knowledge regarding the natural course of resolution of hydronephrosis after pyeloplasty, and no consensus exists on how resolution of hydronephrosis is defined or when resolution is expected to occur., Objective: To determine when resolution of hydronephrosis occurs following pyeloplasty, by type of obstruction and by surgical approach., Methods: This retrospective study included 125 children age <15 years treated with pyeloplasty and followed for two years with repeated ultrasound and MAG3 scan. Children with single kidneys, bilateral disease, and without hydronephrosis were excluded. Children with re-interventions were excluded in the evaluation of hydronephrosis but not in terms of success rate. Outcomes time to resolution of hydronephrosis (Anterior-Posterior diameter (APD) <10 mm or >50% reduction of APD) and 2-year success rate. Exposure was surgical approach and type of obstruction (intrinsic/extrinsic). Survival analysis was performed, adjusting for age, gender, year, laterality, preoperative renal function on MAG3, calyces dilatation and APD in the multivariable analysis., Results: At 12 months and 24 months follow-up, 90% and 93% had reached resolution, respectively. All children with persistent dilatation had improved drainage and stable or improved function on MAG3. There was no difference in time to resolution of hydronephrosis between open versus robotic-assisted laparoscopic surgery (adjusted HR 0.90, [0.54-1.52], p = 0.70), nor between different types of obstruction (aHR 0.84 [0.53-1.34], p = 0.47). Eight children had re-intervention, all identified within 3 months after primary surgery, and four had a postoperative drop on MAG3, giving a total success rate of 91% (121/135)., Discussion: The vast majority of cases resolve and do so within 12 months from surgery. Since the improvement of hydronephrosis seems small between the first and second year after surgery, the value of follow-up beyond 12 months could be questioned. Based on the present study and previous literature we would recommend that children with persisting dilatation should continue their follow-up with ultrasound beyond 12 months. Children with complete resolution of their hydronephrosis at 12 months do not likely benefit from further follow-up. The same follow-up protocol should be applied, regardless of whether the obstruction is intrinsic or extrinsic in nature, or the surgery is performed with open or robotic-assisted approach. Overall, the definition of resolution of hydronephrosis varies in the literature and have impact on the results and may compromise comparisons., Conclusion: Surgical approach or type of obstruction does not seem to affect time to resolution of hydronephrosis after pyeloplasty in children. Follow-up with ultrasound beyond 12 months does not seem to benefit children with complete resolution., Competing Interests: Conflict of interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Genetic factors modify serum 25-hydroxyvitamin D [25(OH)D] concentration and can affect the optimal intake of vitamin D., Objectives: We aimed to personalize vitamin D supplementation by applying knowledge of genetic factors affecting serum 25(OH)D concentration., Methods: We performed a genome-wide association study of serum 25(OH)D concentration in the Finnish Health 2011 cohort (n = 3339) using linear regression and applied the results to develop a population-matched genetic risk score (GRS) for serum 25(OH)D. This GRS was used to tailor vitamin D supplementation for 96 participants of a longitudinal Digital Health Revolution (DHR) Study. The GRS, serum 25(OH)D concentrations, and personalized supplementation and dietary advice were electronically returned to participants. Serum 25(OH)D concentrations were assessed using immunoassays and vitamin D intake using FFQs. In data analyses, cross-sectional and repeated-measures statistical tests and models were applied as described in detail elsewhere., Results: GC vitamin D-binding protein and cytochrome P450 family 2 subfamily R polypeptide 1 genes showed genome-wide significant associations with serum 25(OH)D concentration. One single nucleotide polymorphism from each locus (rs4588 and rs10741657) was used to develop the GRS. After returning data to the DHR Study participants, daily vitamin D supplement users increased from 32.6% to 60.2% (P = 6.5 × 10-6) and serum 25(OH)D concentration from 64.4 ± 20.9 nmol/L to 68.5 ± 19.2 nmol/L (P = 0.006) between August and November. Notably, the difference in serum 25(OH)D concentrations between participants with no risk alleles and those with 3 or 4 risk alleles decreased from 20.7 nmol/L to 8.0 nmol/L (P = 0.0063)., Conclusions: We developed and applied a population-matched GRS to identify individuals genetically predisposed to low serum 25(OH)D concentration. We show how the electronic return of individual genetic risk, serum 25(OH)D concentrations, and factors affecting vitamin D status can be used to tailor vitamin D supplementation. This model could be applied to other populations and countries., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Surface water browning affects boreal lakes in the Northern Hemisphere. This process is expected to increase with global warming. Boreal lakes are the most numerous lakes on Earth. These ecosystems are particularly sensitive to disturbances due to their low biodiversity compared to other aquatic environments. The recent darkening of surface water is expected to hinder key ecosystem processes, particularly through lower primary productivity and loss of biodiversity. However, studies based on long-term data collections have rarely been conducted on the ecological consequences of water browning on aquatic food webs, especially concerning its impacts on invertebrate communities. For the first time, our analysis based on two decades of data collection in Finnish lakes highlighted a relation between water browning and a decline in aquatic macroinvertebrate abundances. Aquatic invertebrates are the main food resource for many secondary predators such as fish and waterbirds, hence such effect on their populations may have major consequences for boreal ecosystem functioning., 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 © 2020 Elsevier B.V. All rights reserved.)

Flexion of the horse's head and neck during dressage riding reduces the pharyngeal lumen with the risk of increased upper airway resistance and upper airway obstructions. According to the Fédération Equestre Internationale, hyperflexion is achieved through force, whereas the position low-deep-round is nonforced. The objectives of this study were to evaluate (1) applied rein tension and (2) dynamic structural disorders in the upper airways in dressage horses in different gaits and different head-neck positions (HNPs). Overground endoscopy (OGE) and rein tension were evaluated in 13 clinically healthy and high-performance Warmblood dressage horses while being ridden in a standardized program comprised of four different gaits (halt, walk, trot, and canter) and in four HNPs (unrestrained, competition frame, hyperflexion, and low-deep-round). All included horses were able to achieve the desired HNPs. The HNP low-deep-round showed significantly lower rein tension than competition frame (P < .001) and hyperflexion (P < .001). An association was found between dynamic structural disorders in the upper airway tract evaluated by OGE and head-neck flexion, but this association was not linked to the degree of flexion. The HNP hyperflexion was neither associated with greater rein tension nor severe dynamic structural disorders than the HNP competition frame. This study confirms that low-deep-round is a nonforced position, in contrast to hyperflexion. Further studies are needed to evaluate whether dynamic structural disorders are a result of flexion or if the degree of flexion has an impact., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear., Objective: This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes., Methods: The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period., Results: Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P < .0001) and VLDL 1 triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P < .0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in "remnant-like particles" cholesterol (by 29%; P < .0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL 2 cholesterol by 50% (P < .0001) and VLDL 2 triglyceride by 29% (P < .0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P < .001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P < .01)., Conclusion: Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals., (Copyright © 2020. Published by Elsevier Inc.)

Although the use of theories and evidence is often stressed in the development of health promotion interventions, this does not guarantee the success of an intervention. Thus, we need to reflect on intervention development processes that use different types of theories and evidence. In this paper, we provide a reflective discussion on how we identified evidence-based behavior change techniques and counseling themes for a health promotion intervention. In addition, we discuss the challenges that we encountered and what we learned during the process: a) a lack of previous research and meta-analyses, b) inconsistencies in evidence, c) integrating evidence and theories that have different starting points, and d) collaborating with researchers who represent different evidence and theories. During the process, we benefitted from having the clear goal of conducting evidence- and theory-based work. We solved the challenges by, for example, utilizing different types of evidence and being reflective about the reasons behind any inconsistencies in the evidence. In retrospect, we would have benefitted from closer collaboration between the teams that worked separately with different evidence. These kinds of reflective descriptions of development processes and the challenges encountered during them may help other researchers and professionals avoid encountering the same challenges., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Protein engineering shows a wide range of possibilities for designing properties in novel materials. Following inspiration from natural systems we have studied how combinations or duplications of protein modules can be used to engineer their interactions and achieve functional properties. Here we used cellulose binding modules (CBM) coupled to spider silk N-terminal domains that dimerize in a pH-sensitive manner. We showed how the pH-sensitive switching into dimers affected cellulose binding affinity in relation to covalent coupling between CBMs. Finally, we showed how the pH-sensitive coupling could be used to assemble cellulose nanofibers in a dynamic pH-dependent way. The work shows how novel proteins can be designed by linking functional domains from widely different sources and thereby achieve new functions in the self-assembly of nanoscale materials., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous study from this lab has discerned oxidative, nitrosative stress and their relationship with cytokines contributing to the severity of sepsis and organ dysfunction. Cytokines are known to induce neutrophil extracellular traps (NETs) formation via free radicals generation. Hyper-activation of neutrophil leads to the increased NETs formation or ineffective clearance of NETs would likely increase the risk of auto-antibody generation against NETs components and being partly responsible for the sepsis severity and organ dysfunction. The present study was undertaken to further assess the status of NETs formation and their correlation with severity of sepsis, with the cytokines and organ dysfunction., Methods: The level of NETs formation, DNA release, elastase release, and inflammatory cytokines was determined in 80 sepsis patients and 45 healthy volunteers. Their linearity with organ parameters and associations with sepsis severity were also assessed., Results: NETs formation experiment was carried out and it was significantly higher in sepsis (70%) compared to control (30%). NETs % were positively correlated with severity of sepsis and organ dysfunction. Pearson's correlation coefficient demonstrated a direct relation between NETs components and organ parameters with Sepsis severity scores., Conclusion: NETs formation is significantly higher due to which it is contributing to the sepsis severity and organ failure., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The effect of processing on starch digestibility, predicted glycemic indices (pGI), polyphenol contents and alpha amylase inhibitory properties of beans (Phaseolis vulgaris) and breadfruit (Treculia africana) was studied. Total starch ranged from 4.3 to 68.3g/100g, digestible starch ranged from 4.3 to 59.2 to 65.7g/100g for the raw and processed legumes; Resistance starch was not detected in most of the legumes except in fried breadfruit and the starches in both the raw and processed breadfruit were more rapidly digested than those from raw and cooked beans. Raw and processed breadfruit had higher hydrolysis curves than raw and processed beans with the amylolysis level in raw breadfruit close to that of white bread. Raw beans had a low glycemic index (GI); boiled beans and breadfruit had intermediate glycemic indices respectively while raw and fried breadfruit had high glycemic indices. Aqueous extracts of the food samples had weak α-amylase inhibition compared to acarbose. The raw and processed legumes contained considerable amounts of dietary phenols and flavonoids. The significant correlation (r=0.626) between α-amylase inhibitory actions of the legumes versus their total phenolic contents suggests the contribution of the phenolic compounds in these legumes to their α-amylase inhibitory properties., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH)., Methods: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a))., Results: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220., Conclusions: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although mechanical cues are known to affect stem cell fate and mechanobiology, the significance of such stimuli on the osteogenic differentiation of human adipose stem cells (hASCs) remains unclear. In this study, we investigated the effect of long-term mechanical stimulation on the attachment, osteogenic differentiation and mechanical properties of hASCs. Tailor-made, pneumatic cell stretching devices were used to expose hASCs to cyclic equiaxial stretching in osteogenic medium. Cell attachment and focal adhesions were visualised using immunocytochemical vinculin staining on days 3 and 6, and the proliferation and alkaline phosphatase activity, as a sign of early osteogenic differentiation, were analysed on days 0, 6 and 10. Furthermore, the mechanical properties of hASCs, in terms of apparent Young's modulus and normalised contractility, were obtained using a combination of atomic force microscopy based indentation and computational approaches. Our results indicated that cyclic equiaxial stretching delayed proliferation and promoted osteogenic differentiation of hASCs. Stretching also reduced cell size and intensified focal adhesions and actin cytoskeleton. Moreover, cell stiffening was observed during osteogenic differentiation and especially under mechanical stimulation. These results suggest that cyclic equiaxial stretching modifies cell morphology, focal adhesion formation and mechanical properties of hASCs. This could be exploited to enhance osteogenic differentiation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this paper is to bridge gaps between biomarker and whole organism responses related to oil based offshore discharges. These biomarker bridges will facilitate acceptance criteria for biomarker data linked to environmental risk assessment and translate biomarker results to higher order effects. Biomarker based species sensitivity distributions (SSD biomarkers ) have been constructed for relevant groups of biomarkers based on laboratory data from oil exposures. SSD curves express the fraction of species responding to different types of biomarkers. They have been connected to SSDs for whole organism responses (WORs) constructed in order to relate the SSD biomarkers to animal fitness parameters that are commonly used in environmental risk assessment. The resulting SSD curves show that biomarkers and WORs can be linked through their potentially affected fraction of species (PAF) distributions, enhancing the capability to monitor field parameters with better correlation to impact and risk assessment criteria and providing improved chemical/biological integration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Offshore oil and gas activities are required not to cause adverse environmental effects, and risk based management has been established to meet environmental standards. In some risk assessment schemes, Risk Indicators (RIs) are parameters to monitor the development of risk affecting factors. RIs have not yet been established in the Environmental Risk Assessment procedures for management of oil based discharges offshore. This paper evaluates the usefulness of biomarkers as RIs, based on their properties, existing laboratory biomarker data and assessment methods. Data shows several correlations between oil concentrations and biomarker responses, and assessment principles exist that qualify biomarkers for integration into risk procedures. Different ways that these existing biomarkers and methods can be applied as RIs in a probabilistic risk assessment system when linked with whole organism responses are discussed. This can be a useful approach to integrate biomarkers into probabilistic risk assessment related to oil based discharges, representing a potential supplement to information that biomarkers already provide about environmental impact and risk related to these kind of discharges., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine a suitable set of biomarker based methods for environmental monitoring in sub-arctic and temperate offshore areas using scientific knowledge on the sensitivity of fish species to dispersed crude oil. Threshold values for environmental monitoring and risk assessment were obtained based on a quantitative comparison of biomarker responses. Turbot, halibut, salmon and sprat were exposed for up to 8 weeks to five different sub-lethal concentrations of dispersed crude oil. Biomarkers assessing PAH metabolites, oxidative stress, detoxification system I activity, genotoxicity, immunotoxicity, endocrine disruption, general cellular stress and histological changes were measured. Results showed that PAH metabolites, CYP1A/EROD, DNA adducts and histopathology rendered the most robust results across the different fish species, both in terms of sensitivity and dose-responsiveness. The reported results contributed to forming links between biomonitoring and risk assessment procedures by using biomarker species sensitivity distributions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The functional properties of extremophilic Dictyoglomus thermophilum xylanase (XYNB) and the N-terminal disulphide-bridge mutant (XYNB-DS) were studied at high pressure and temperature. The enzymes were quite stable even at the pressure of 500MPa at 80°C. The half-life of inactivation in these conditions was over 30h. The inactivation at 80°C in atmospheric pressure was only 3-times slower. The increase of pressure up to 500MPa at 80°C decreased only slightly the enzyme's stability, whereas in 500MPa the increase of temperature from 22 to 80°C decreased significantly more the enzyme's stability. While the high temperature (80-100°C) decreased the enzyme reaction with short xylooligosaccharides (xylotetraose and xylotriose), the high pressure (100-300MPa) had an opposite effect. The temperature of 100°C strongly increased the Km but did not affect the kcat to the same extent, thus indicating that the interaction of the substrate with the active site suffers before the catalytic reaction begins to decrease as the temperature rises. Circular dichroism spectroscopy showed the high structural stability of XYNB and XYNB-DS at 93°C., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Operational discharges of produced water and drill cuttings from offshore oil and gas platforms are a continuous source of contaminants to continental shelf ecosystems. This paper reviews recent research on the biological effects of such discharges with focus on the Norwegian Continental Shelf. The greatest concern is linked to effects of produced water. Alkylphenols (AP) and polyaromatic hydrocarbons (PAH) from produced water accumulate in cod and blue mussel caged near outlets, but are rapidly metabolized in cod. APs, naphtenic acids, and PAHs may disturb reproductive functions, and affect several chemical, biochemical and genetic biomarkers. Toxic concentrations seem restricted to <2 km distance. At the peak of discharge of oil-contaminated cuttings fauna disturbance was found at more than 5 km from some platforms, but is now seldom detected beyond 500 m. Water-based cuttings may seriously affect biomarkers in filter feeding bivalves, and cause elevated sediment oxygen consumption and mortality in benthic fauna. Effects levels occur within 0.5-1 km distance. The stress is mainly physical. The risk of widespread, long term impact from the operational discharges on populations and the ecosystem is presently considered low, but this cannot be verified from the published literature., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The manufacturing of tablets involves many unit operations that possess multivariate and complex characteristics. The interactions between the material characteristics and process related variation are presently not comprehensively analyzed due to univariate detection methods. As a consequence, current best practice to control a typical process is to not allow process-related factors to vary i.e. lock the production parameters. The problem related to the lack of sufficient process understanding is still there: the variation within process and material properties is an intrinsic feature and cannot be compensated for with constant process parameters. Instead, a more comprehensive approach based on the use of multivariate tools for investigating processes should be applied. In the pharmaceutical field these methods are referred to as Process Analytical Technology (PAT) tools that aim to achieve a thorough understanding and control over the production process. PAT includes the frames for measurement as well as data analyzes and controlling for in-depth understanding, leading to more consistent and safer drug products with less batch rejections. In the optimal situation, by applying these techniques, destructive end-product testing could be avoided. In this paper the most prominent multivariate data analysis measuring tools within tablet manufacturing and basic research on operations are reviewed., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: Describing and analyzing speaker selection in conversations between the health nurse and parents in maternity clinics., Methods: The data consisted of ten video-recorded encounters in maternity clinics. Using conversation analysis, we investigated 89 sequences of interaction in which the health nurse asks a question that is verbally addressed to both parents., Results: There was an observable pattern of selecting mothers as principal respondents by all participants of the encounters in maternity clinics. In a few deviant cases, fathers were selected as principal respondents. A typical practice of speaker selection was the gaze direction of the health nurse towards the recipient (usually the mother) at the closure of her question. Various situational elements also influenced which one of the parents answered the question. The deviant cases in which fathers were selected as principal respondents were mainly explainable by the use of the questionnaire designed to facilitate talking about psycho-social issues connected with the transition to parenthood., Conclusion: Particular interactional circumstances and practices can break the pattern of selecting mothers as respondents to questions addressed to both parents., Practice Implications: Fathers could easily be engaged in conversations through gaze. Also the questionnaire seems promising in engaging fathers in conversations in clinics., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs., Methods: Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and triglycerides in the very low-density lipoprotein 1 and 2 (VLDL(1) and VLDL(2)) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and triglycerides in the chylomicron, VLDL(1) and VLDL(2) fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting., Results: Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL(1) particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial triglycerides with less accumulation of apoB100 in the VLDL(1) fraction and a faster transfer of apoB100 into the VLDL(2) fraction. In contrast, fasting VLDL(1) secretion does not predict postprandial triglyceride accumulation., Conclusions: Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Concern has been raised over whether environmental release of alkylphenols (AP) in produced water (PW) discharges from the offshore oil industry could impose a risk to the reproduction of fish stocks in the North Sea. An environmental risk assessment (ERA) was performed to determine if environmental exposure to PW APs in North Sea fish populations is likely to be high enough to give effects on reproduction endpoints. The DREAM (Dose related Risk and Effect Assessment Model) software was used in the study and the inputs to the ERA model included PW discharge data, fate information of PW plumes, fish distribution information, as well as uptake and elimination information of PW APs. Toxicodynamic data from effect studies with Atlantic cod (Gadus morhua) exposed to APs were used to establish a conservative environmental risk threshold value for AP concentration in seawater. By using the DREAM software to 1) identify the areas of highest potential risk and 2) integrate fish movement and uptake/elimination rates of APs for the chosen areas we found that the environmental exposure of fish to APs from PW is most likely too low to affect reproduction in wild populations of fish in the North Sea. The implications related to risk management of offshore PW and uncertainties in the risk assessment performed are discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Mussels (Mytilus edulis) were continuously exposed to dispersed crude oil (0.015-0.25mg/l) for 7 months covering the whole gamete development cycle. After 1 month exposure to 0.25 mg oil/l, the level of alkali-labile phosphates (ALP) and the volume density of atretic oocytes in female gonads were higher than those in the gonads of control females, indicating that oil affected the level of vitellogenin-like proteins and gamete development. Spawning of mussels was induced after 7 months oil exposure. Parental oil exposure did not affect subsequent fertilization success in clean seawater but this was reduced in 0.25 mg oil/l. Parental exposure to 0.25 mg oil/l caused both slow development and a higher percentage of abnormalities in D-shell larvae 2 days post-fertilization; reduced growth 7 days post-fertilization. These effects were greatly enhanced when larval stages were maintained at 0.25 mg oil/l. Similar studies are warranted for risk assessment prognosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Adult shrimps (Pandalus borealis) and their embryos were exposed to an oil-water dispersion (OWD) at concentrations of 0.015, 0.06 and 0.25 mg/L using a continuous flow system. Lysosomal membrane stability was analysed in haemocytes using the neutral red retention assay and an alkaline unwinding assay was used to measure DNA damage in hepatopancreas tissue. Exposure to oil induced concentration and time dependent biomarker responses in adult shrimps together with the accumulation of PAH in their tissues. Oil exposure of shrimp embryos caused increased mortality in the resultant larvae, even if the larvae were kept in clean water after hatching. There were minor differences observed in larval stage development times in the first part of the experiments. The fatty acid composition of embryos exposed to oil was different to that of non-exposed larvae. PAH tissue concentration and biomarker responses correlated to the reduced survival of the shrimp larvae., (Copyright © 2010. Published by Elsevier Ltd.)

A simple, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of m-nisoldipine and its three metabolites in rat plasma has been developed using nitrendipine as an internal standard (IS). Following liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a reverse phase C(18) column and analyzed by MS in the multiple reaction monitoring (MRM) mode. To avoid contamination by residual sample in the injection syringe, a special injection protocol was developed. We found that m-nisoldipine, metabolite M1 and IS could be ionized under positive or negative electrospray ionization conditions, whereas metabolite M and M2 could only be ionized in the positive mode. The mass spectrometry fragmentation pathways for these analytes are analyzed and discussed herein. The total analysis time required less than 5 min per sample. We employed this method successfully to study the metabolism of m-nisoldipine when it was orally administered to rats at a dose of 9 mg/kg. Three metabolites of m-nisoldipine and an unknown compound of molecular weight 386 were found for the first time in rat plasma. The concentration of the potentially active metabolite was approximately equal to its parent compound concentration., (Copyright © 2010. Published by Elsevier B.V.)

A low level of high density lipoprotein cholesterol (HDL-C) is a powerful risk factor for cardiovascular disease. However, despite the reported key role of apolipo-proteins, specifically, apoA-I, in HDL metabolism, lipid molecular composition of HDL particles in subjects with high and low HDL-C levels is currently unknown. Here lipidomics was used to study HDL derived from well-characterized high and low HDL-C subjects. Low HDL-C subjects had elevated triacylglycerols and diminished lysophosphatidylcholines and sphingomyelins. Using information about the lipid composition of HDL particles in these two groups, we reconstituted HDL particles in silico by performing large-scale molecular dynamics simulations. In addition to confirming the measured change in particle size, we found that the changes in lipid composition also induced specific spatial distributions of lipids within the HDL particles, including a higher amount of triacylglycerols at the surface of HDL particles in low HDL-C subjects. Our findings have important implications for understanding HDL metabolism and function. For the first time we demonstrate the power of combining molecular profiling of lipoproteins with dynamic modeling of lipoprotein structure.

The withdrawing Arctic ice edge will facilitate future sea transport and exploration activities in the area, which calls for the establishment of relevant cold water monitoring species. The present study presents first results of field baseline levels for core oil pollution biomarkers in Polar cod (Boreogadussaida) sampled from pristine, Arctic waters. Furthermore, biomarker response levels were characterized in controlled laboratory exposure experiments running over 2 weeks. Fish exposed to a simulated petrogenic spill (1ppm dispersed, crude oil) exhibited elevated hepatic EROD activity, bile PAH-metabolites, and hepatic DNA-adducts, whereas male individuals exposed to simulated produced water (30ppb nonylphenol) exhibited a strong induction of plasma vitellogenin. In conclusion, the results demonstrated low and robust biomarker baseline levels that were clearly different from exposure responses. In combination with its high abundance and circumpolar distribution, the Polar cod seems well qualified for oil pollution monitoring in Arctic waters., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Mytilus edulis and Chlamys islandica were exposed to nominal dispersed crude oil concentrations in the range 0.015-0.25 mg/l for one month. Five biomarkers (enzymatic and cellular responses) were analysed together with bioaccumulation of PAHs at the end of exposure. In both species, PAH tissue residues reflected the exposure concentration measured in the water and lipophilicity determined the bioaccumulation levels. Oil caused biomarker responses in both species but more significant alterations in exposed C. islandica were observed. The relationships between exposure levels and enzymatic responses were apparently complex. The integrated biomarker response related against the exposure levels was U-shaped in both species and no correlation with total PAH body burden was found. For the monitoring of chronic offshore discharges, dose- and time-related events should be evaluated in the selection of biomarkers to apply. From this study, cellular damages appear more fitted than enzymatic responses, transient and more complex to interpret.

A biotest system for environmentally realistic exposure of fish to produced water (PW) was developed and tested. Authentic PW was collected at an oil production platform in the North Sea and preserved by freezing in multiple aliquots a 25L. After transport to the test laboratory onshore, daily PW aliquots were thawed, homogenised and administered to the test fish, Atlantic cod (Gadus morhua), in two diluted exposure concentrations, 0.1% and 0.5%, during a 15 d period, using a continuous flow-through exposure setup. Positive control groups were exposed to two crude oil treatments for comparison. Chemical analyses showed that alkylphenol (AP) and PAH concentrations in PW exposure waters were very low. Observations of significantly increased AP and PAH metabolite levels in PW exposed fish demonstrated the suitability of the biotest system for its use in biological exposure/effect studies of PW, and it also demonstrated the sensitivity of bile metabolites as PW exposure markers in fish. The relevance of the biotest system for PW effect studies and for validating modelled environmental risk estimates of PW dischargers from offshore oil production is discussed.

The main antiatherogenic function of HDL is to promote the efflux of cholesterol from peripheral cells and transport it to the liver for excretion in a process termed reverse cholesterol transport. The aim of this study was to evaluate the cholesterol efflux capacity in low- and high-HDL subjects by utilizing monocytes and serum from 18 low-HDL and 15 high-HDL subjects. Low and high HDL levels were defined, respectively, as HDL < or =10(th) and HDL > or =90(th) Finnish age/sex-specific percentile. Cholesterol efflux from [(3)H]cholesterol-oleate-acetyl-LDL-loaded monocyte-derived macrophages to standard apolipoprotein A-I (apoA-I), HDL(2), and serum was measured. In addition, cholesterol efflux from acetyl-LDL-loaded human THP-1 macrophages to individual sera (0.5%) derived from the study subjects was evaluated. Cholesterol efflux to apoA-I, HDL(2), and serum from macrophage foam cells derived from low- and high-HDL subjects was similar. The relative ABCA1 and ABCG1 mRNA expression levels in unloaded macrophages, as well as their protein levels in loaded macrophage foam cells, were similar in the two study groups. Cholesterol efflux from THP-1 foam cells to serum recovered from high-HDL subjects was slightly higher than that to serum from low-HDL subjects (P = 0.046). Cholesterol efflux from THP-1 macrophages to serum from study subjects correlated with serum apoB (P = 0.033), apoA-I (P = 0.004), apoA-II (P < 0.0001), and the percentage of apoA-I present in the form of prebeta-HDL (P = 0.0001). Our data reveal that macrophages isolated from either low- or high-HDL subjects display similar cholesterol efflux capacity to exogenous acceptors. However, sera from low-HDL subjects have poorer cholesterol acceptor ability as compared with sera from high-HDL subjects.

Fisheries have been vital to coastal communities around the North Sea for centuries, but this semi-enclosed sea also receives large amounts of waste. It is therefore important to monitor and control inputs of contaminants into the North Sea. Inputs of effluents from offshore oil and gas production platforms (produced water) in the Norwegian sector have been monitored through an integrated chemical and biological effects programme since 2001. The programme has used caged Atlantic cod and blue mussels. PAH tissue residues in blue mussels and PAH bile metabolites in cod have confirmed exposure to effluents, but there was variation between years. Results for a range of biological effects methods reflected exposure gradients and indicated that exposure levels were low and caused minor environmental impact at the deployment locations. There is a need to develop methods that are sufficiently sensitive to components in produced water at levels found in marine ecosystems.

The amounts of drug and excipient were predicted from ATR-FTIR spectra using two multi-way modelling techniques, parallel factor analysis (PARAFAC) and multi-linear partial least squares (N-PLS). Data matrices consisted of dissolved and undissolved parallel samples having different drug content and spectra, which were collected at axially cut surface of the flat-faced matrix tablets. Spectra were recorded comprehensively at different points on the axially cut surface of the tablet. The sample drug concentrations varied between 2 and 16% v/v. The multi-way methods together with ATR-FTIR spectra seemed to represent an applicable method for the determination of drug and excipient distribution in a tablet during the release process. The N-PLS calibration method was more robust for accurate quantification of the amount of components in the sample whereas the PARAFAC model provided approximate relative amounts of components.

HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.