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Abstract Structural- and functional heterogeneity, as well as allosteric regulation, in homo-monomeric enzymes is a highly active area of research. One such enzyme is human nuclear-associated deoxyuridine 5’-triphosphate nucleotidohydrolase (dUTPase), which has emerged as an interesting drug target in combination therapy with traditional nucleotide analogue treatment of cancer. We report, for the first time, a full structural dynamics study of human dUTPase by NMR. dUTPase has been investigated in terms of structural dynamics in its apo form, in complex with the modified substrate resistant to hydrolysis, 2’-deoxyuridine 5’-α,β-imido-triphosphate (dUpNHpp), as well as the product, 2’-deoxy-uridine-monophosphate (dUMP). The apo form of the enzyme displayed slow dynamics in the milli- to microsecond regime in relaxation dispersion experiments, which was further slowed down to observable heterogeneity upon substrate-analogue binding. The results suggest that the non-hydrolysable substrate-analogue traps the enzyme in the conformational isomerization step that has been previously suggested to be part of the enzyme catalysis kinetics cycle. The observed heterogeneity fits well with the pattern expected to emerge from the suggested kinetic model, and no evidence for homotropic allosterism was found. The heatmaps of the slow dynamics, chemical shift perturbation upon substrate binding and conserved regions of the enzyme sequence all displayed a similar pattern, which suggests that the structural dynamics is finely tuned and important for the biological function of the enzyme for binding, conformational shift, catalysis and substrate release.

Background: Tenecteplase is increasingly used off-label as an alternative to alteplase for ischemic stroke thrombolysis. Our aim was to evaluate the safety of tenecteplase versus alteplase in comprehensive real-world data. Methods: We compared the outcomes for adult patients with acute ischemic stroke treated with alteplase or tenecteplase, registered in the Swedish Stroke Register between January 1, 2018 and December 31, 2020. The primary outcome was symptomatic intracerebral hemorrhage or death during hospital stay. Secondary outcomes were death within 90 days, modified Rankin Scale at 90 days, and mean door-to-needle time (DNT). Results: There were no significant differences in age or risk factors between 6,560 patients (45% women, mean age 74) treated with alteplase and 888 patients (43% women, mean age 74) treated with tenecteplase, although tenecteplase was more commonly used in non-university hospitals, hospitals with high use of thrombolysis, and in wake-up strokes. Tenecteplase was not non-inferior compared to alteplase in terms of symptomatic intracerebral hemorrhage or death during hospital stay (13.2% vs. 10.7%, absolute risk difference [95% confidence interval, CI] 2.5% [0.1 to 4.9%], adjusted odds ratio 1.44 [1.07–1.94]). There were no significant differences in functional outcome or death at 90 days, but tenecteplase was associated with decreased DNT (mean difference 9 min). Conclusion: Tenecteplase was not non-inferior in safety outcome, although associated with decreased DNT. As accumulating randomized controlled studies support the non-inferiority of tenecteplase regarding functional outcome, it is important to keep scrutinizing the safety outcomes.

Abstract This study focuses on the effect of an emerging source of waste, lithium iron phosphate (LFP) cathode materials, on the hydrometallurgical recycling of the currently dominant industrial battery waste that is rich in transition metals (Ni, Co, Mn, and Li). The effects of the dosage of LFP, initial acidity, and timing of LFP reductant addition were investigated in sulfuric acid (H2SO4) leaching (t = 3 h, T = 60 °C, ω = 300 rpm). The results showed that addition of LFP increased both transition metal extraction and acid consumption. Further, the redox potential was lowered due to the increased presence of Fe2+. An initial acidity of 2.0 mol/L H2SO4 with acid consumption of 1.3 kg H2SO4/kg black mass provided optimal conditions for achieving a high leaching yield (Co = 100%, Ni = 87.6%, Mn = 91.1%, Li = 100%) and creating process solutions (Co 8.8 g/L, Ni 13.8 g/L, Li 6.7 g/L, Mn 7.6 g/L, P 12.1 g/L) favorable for subsequent hydrometallurgical processing. Additionally, the overall efficiency of H2O2 decreased due to its decomposition by high concentrations of Fe2+ and Mn2+ when H2O2 was added after t = 2 h, leading to only a minor increase in final battery metals extraction levels.

Abstract Achieving carbon neutrality requires deployment of large-scale renewable energy technologies like solar photovoltaic (PV) panels. Nevertheless, methods to ascertain the overall environmental impacts PVs and further improve their sustainability are under-investigated. In an effort to provide more understanding of this crucial topic, this research focuses on silicon flows—a key element for manufacturing crystalline silicon PVs. Using system dynamics modeling, we conduct a comprehensive environmental cost assessment of the silicon flows used in PVs based on a comparative analysis between the United States and China as the leading global PV manufacturers. Despite the advancement in wafer quality, material usage reductions and overall price decreases achieved in recent decades, our results project a substantial increase in energy and water consumption in China related to Metallurgical Grade Si (MG-Si), Solar Grade Si (SoG-Si) and cell manufacturing by 2030. An approximate 6.5 times increase of energy and water consumption is observed for c-Si cell manufacturing in China between 2010 and 2020. In 2030, increases of 70% in energy consumption and 69% in water use are estimated for Chinese MG-Si and SoG-Si production. The most significant environmental impact is observed in silicon cell and module manufacturing in both countries, particularly concerning GHG, SOx and NOx emissions. This study provides valuable insights into the environmental impacts of these two major solar panel manufacturing countries by examining the silicon life cycle, from production to end-of-life.

Abstract Short tandem repeat (STR) mutations are prevalent in colorectal cancer (CRC), especially in tumours with the microsatellite instability (MSI) phenotype. While STR length variations are known to regulate gene expression under physiological conditions, the functional impact of STR mutations in CRC remains unclear. Here, we integrate STR mutation data with clinical information and gene expression data to study the gene regulatory effects of STR mutations in CRC. We confirm that STR mutability in CRC highly depends on the MSI status, repeat unit size, and repeat length. Furthermore, we present a set of 1244 putative expression STRs (eSTRs) for which the STR length is associated with gene expression levels in CRC tumours. The length of 73 eSTRs is associated with expression levels of cancer-related genes, nine of which are CRC-specific genes. We show that linear models describing eSTR-gene expression relationships allow for predictions of gene expression changes in response to eSTR mutations. Moreover, we found an increased mutability of eSTRs in MSI tumours. Our evidence of gene regulatory roles for eSTRs in CRC highlights a mostly overlooked way through which tumours may modulate their phenotypes. Future extensions of these findings could uncover new STR-based targets in the treatment of cancer.

Abstract The removal of trivalent iron and aluminum was studied from synthetic Li-ion battery leach solution by phosphate and hydroxide precipitation (pH 2.5–4.25, t = 3 h, T = 60 °C). Phosphate precipitation exhibited both crystal nucleation initiation (pH 2 vs. pH 3) as well as complete (~ 99%) Fe and Al removal at lower pH compared to hydroxide precipitation (pH 3 vs. 3.5). The precipitation time of phosphate was shorter (40 min) than that of hydroxide precipitation (80 min). At pH 4 the loss of valuable metals (Li, Ni, Co) in the precipitate was negligible in the phosphate cake, whereas in the hydroxide process the co-precipitation was 4–5% for Li, Ni and Co. The filtration rate of phosphate precipitate was shown to be significantly faster. The presence of fluoride did not have any notable effect on phosphate precipitation, whereas in hydroxide precipitation, it potentially had a negative effect on aluminum extraction.

Abstract Individuals may have a different body odor, when they are sick compared to healthy. In the non-human animal literature, olfactory cues have been shown to predict avoidance of sick individuals. We tested whether the mere experimental activation of the innate immune system in healthy human individuals can make an individuals’ body odor be perceived as more aversive (intense, unpleasant, and disgusting). Following an endotoxin injection (lipopolysaccharide; 0.6 ng/kg) that creates a transient systemic inflammation, individuals smelled more unpleasant compared to a placebo group (saline injection). Behavioral and chemical analyses of the body odor samples suggest that the volatile components of samples from “sick” individuals changed qualitatively rather than quantitatively. Our findings support the hypothesis that odor cues of inflammation in axillary sweat are detectable just a few hours after experimental activation of the innate immune system. As such, they may trigger behavioral avoidance, hence constituting a first line of defense against pathogens of infected conspecifics.

Objectives This study aimed to identify factors related to changes in walking performance in individuals 3 months after a stroke or TIA.Design Cross-sectional study with post hoc analysis of a randomised controlled study.Setting University Hospital, Sweden.Participants 79 individuals, 64 (10) years, 37% women, who were acutely hospitalised because of stroke or TIA between November 2016 and December 2018. Inclusion criteria were patients aged 18 or above and the major eligibility criterion was the ability to perform the 6 min walking test.Intervention The intervention group received standard care plus daily mobile phone text messages (short message service) with instructions to perform regular outdoor walking and functional leg exercises in combination with step counting and training diaries. The control group received standard care.Outcome measures Multivariate analysis was performed and age, sex, group allocation, comorbidity, baseline 6 min walk test, body mass index (BMI), cognition and chair-stand tests were entered as possible determinants for changes in the 6 min walk test.Results Multiple regression analyses showed that age (standardised beta −0.33, 95% CI −3.8 to −1.05, p

Nitric oxide (NO) is involved in a variety of biological functions including blood vessel dilation and neurotransmitter release. In animals, NO has been demonstrated to affect multiple behavioral outcomes, such as memory performance and arousal, whereas this link is less explored in humans. NO is created in the paranasal sinuses and studies show that humming releases paranasal NO to the nasal tract and that NO can then cross the blood brain barrier. Akin to animal models, we hypothesized that this NO may traverse into the brain and positively affect information processing. In contrast to our hypothesis, an articulatory suppression memory paradigm and a speeded detection task found deleterious effects of humming while performing the task. Likewise, we found no effect of humming on emotional processing of photos. In a fourth experiment, participants hummed before each trial in a speeded detection task, but we again found no effect on response time. In conclusion, either nasal NO does not travel to the brain, or NO in the brain does not have the expected impact on cognitive performance and emotional processing in humans. It remains possible that NO influences other cognitive processes not tested for here.

BackgroundMore than a year after recovering from COVID-19, a large proportion of individuals, many of whom work in the healthcare sector, still report olfactory dysfunctions. However, olfactory dysfunction was common already before the COVID-19 pandemic, making it necessary to also consider the existing baseline prevalence of olfactory dysfunction. To establish the adjusted prevalence of COVID-19 related olfactory dysfunction, we assessed smell function in healthcare workers who had contracted COVID-19 during the first wave of the pandemic using psychophysical testing.MethodsParticipants were continuously tested for SARS-CoV-2 IgG antibodies since the beginning of the pandemic. To assess the baseline rate of olfactory dysfunction in the population and to control for the possibility of skewed recruitment of individuals with prior olfactory dysfunction, consistent SARS-CoV-2 IgG naïve individuals were tested as a control group.ResultsFifteen months after contracting COVID-19, 37% of healthcare workers demonstrated a quantitative reduction in their sense of smell, compared to only 20% of the individuals in the control group. Fifty-one percent of COVID-19-recovered individuals reported qualitative symptoms, compared to only 5% in the control group. In a follow-up study 2.6 years after COVID-19 diagnosis, 24% of all tested recovered individuals still experienced parosmia.ConclusionsIn summary, 65% of healthcare workers experienced parosmia/hyposmia 15 months after contracting COVID-19. When compared to a control group, the prevalence of olfactory dysfunction in the population increased by 41 percentage points. Parosmia symptoms were still lingering two-and-a half years later in 24% of SARS-CoV-2 infected individuals. Given the amount of time between infection and testing, it is possible that the olfactory problems may not be fully reversible in a plurality of individuals.

The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the severe zoonotic disease alveolar echinococcosis. New treatment options are urgently needed. Disulfiram and dithiocarbamates were previously shown to exhibit activity against the trematode Schistosoma mansoni. As both parasites belong to the platyhelminths, here we investigated whether these compounds were also active against E. multilocularis metacestode vesicles in vitro. We used an in vitro drug-screening cascade for the identification of novel compounds against E. multilocularis metacestode vesicles with disulfiram and 51 dithiocarbamates. Five compounds showed activity against E. multilocularis metacestode vesicles after five days of drug incubation in a damage marker release assay. Structure–activity relationship analyses revealed that a S-2-hydroxy-5-nitro benzyl moiety was necessary for anti-echinococcal activity, as derivatives without this group had no effect on E. multilocularis metacestode vesicles. The five active compounds were further tested for potential cytotoxicity in mammalian cells. For two compounds with low toxicity (Schl-32.315 and Schl-33.652), IC50 values in metacestode vesicles and IC50 values in germinal layer cells were calculated. The compounds were not highly active on isolated GL cells with IC50 values of 27.0 ± 4.2 µM for Schl-32.315 and 24.7 ± 11.5 µM for Schl-33.652, respectively. Against metacestode vesicles, Schl-32.315 was not very active either with an IC50 value of 41.6 ± 3.2 µM, while Schl-33.652 showed a low IC50 of 4.3 ± 1 µM and should be further investigated in the future for its activity against alveolar echinococcosis.

Abstract The role of aluminum concentration and pH in the purification of waste Li-ion battery leach solution was investigated using NaOH and LiOH as neutralization agents ([H 2 SO 4 ] = 0.313 M, t = 6 h). Solution was prepared from synthetic chemicals to mimic real battery leach solution. Results demonstrate that pH (3.5–5.5) has a significant effect on the precipitation of metals (Fe, Al, Ni, Cu, Co, Mn, and Li), whereas higher temperature (T = 30 and 60 °C) decreases the precipitation pH of metals. Iron and aluminum were both found to precipitate at ca. pH 4 and the presence of aluminum in PLS clearly decreased the separation efficiency of Fe vs. active material metals (Ni, Co, Li). In the absence of dissolved aluminum, Fe precipitated already at pH 3.5 and did not result in the co-precipitation of other metals. Additionally, the Al-free slurry had a superior filtration performance. However, aluminum concentrations of 2 and 4 g/L were found to cause loss of Ni (2–10%), Co (1–2%) and Li (2–10%) to the Fe-Al hydroxide cake at pH 4. The use of LiOH (vs. NaOH) resulted in 50% lower co-precipitation of Ni, Co and Li. Overall, these results demonstrate that hydroxide precipitation can be an effective method to remove iron from battery waste leach solutions at aluminum concentrations of

Abstract Removing function from a developed and functional sensory system is known to alter both cerebral morphology and functional connections. To date, a majority of studies assessing sensory-dependent plasticity have focused on effects from either early onset or long-term sensory loss and little is known how the recent sensory loss affects the human brain. With the aim of determining how recent sensory loss affects cerebral morphology and functional connectivity, we assessed differences between individuals with acquired olfactory loss (duration 7–36 months) and matched healthy controls in their grey matter volume, using multivariate pattern analyses, and functional connectivity, using dynamic connectivity analyses, within and from the olfactory cortex. Our results demonstrate that acquired olfactory loss is associated with altered grey matter volume in, among others, posterior piriform cortex, a core olfactory processing area, as well as the inferior frontal gyrus and angular gyrus. In addition, compared to controls, individuals with acquired anosmia displayed significantly stronger dynamic functional connectivity from the posterior piriform cortex to, among others, the angular gyrus, a known multisensory integration area. When assessing differences in dynamic functional connectivity from the angular gyrus, individuals with acquired anosmia had stronger connectivity from the angular gyrus to areas primary responsible for basic visual processing. These results demonstrate that recently acquired sensory loss is associated with both changed cerebral morphology within core olfactory areas and increase dynamic functional connectivity from olfactory cortex to cerebral areas processing multisensory integration.

Abstract This study evaluated the MRI-derived fat fraction (FF), from a Cooling-reheating protocol, for estimating the cold-induced brown adipose tissue (BAT) metabolic rate of glucose (MRglu) and changes in lipid content, perfusion and arterial blood volume (VA) within cervical-supraclavicular fat (sBAT). Twelve volunteers underwent PET/MRI at baseline, during cold exposure and reheating. For each temperature condition, perfusion and VA were quantified with dynamic [15O]water-PET, and FF, with water-fat MRI. MRglu was assessed with dynamic [18F]fluorodeoxyglucose-PET during cold exposure. sBAT was defined using anatomical criteria, and its subregion sBATHI, by MRglu > 11 μmol/100 cm3/min. For all temperature conditions, sBAT-FF correlated negatively with sBAT-MRglu (ρ ≤ − 0.87). After 3 h of cold, sBAT-FF decreased (− 2.13 percentage points) but tended to normalize during reheating although sBATHI-FF remained low. sBAT-perfusion and sBAT-VA increased during cold exposure (perfusion: + 5.2 ml/100 cm3/min, VA: + 4.0 ml/100 cm3). sBAT-perfusion remained elevated and sBAT-VA normalized during reheating. Regardless of temperature condition during the Cooling-reheating protocol, sBAT-FF could predict the cold-induced sBAT-MRglu. The FF decreases observed after reheating were mainly due to lipid consumption, but could potentially be underestimated due to intracellular lipid replenishment. The influence of perfusion and VA, on the changes in FF observed during cold exposure, could not be ruled out.

Abstract The impoundment of the Three Gorges Dam on the Yangtze River begins in 2003 and a full pool level is first attained in 2010. This process leads to reciprocal adjustments in flow discharge, sediment transport and morphology downstream of the dam. Based on 26-year recorded hydrologic data 1990–2015 and surveyed bathymetries 1998, 2010 and 2015, this study elucidates, before and after the commissioning of the dam, the alterations along the 500-km reach of the river. Two-dimensional numerical simulations are performed to predict future morphological changes by 2025. The analyses demonstrate that the impoundment modulates the seasonal flow discharges and traps an appreciable amount of sediment, resulting in enhanced erosion potential and coarsening of sediment. On a multi-year basis, the maximum discharge varies by a factor of 1.3 and the corresponding suspended load concentration and transport rate differ by a factor of 3.0 and 3.8, respectively. Combinations of surveyed and simulated bathymetries reveal its morphological responses to the changes. A general pattern of erosion is observed along the reach. In its upper 120 km, the process slows down towards 2025. In the middle 200 km, the erosion shifts, following the gradual impounding, to slight deposition, which then shifts back to erosion around September 2018. In the final 180 km, erosion continues without any sign of de-escalation, which is presumedly ascribed to tidal actions. The reach has not yet achieved a hydro-morphological equilibrium; the riverbed down-cutting is supposed to continue for a while. The combination of the field and numerical investigations provides, with the elapse of time, insight into the morpho-dynamics in the 500 km river reach.

Objectives To evaluate effects of mobile phone text-messaging exercise instructions on body composition, cardiometabolic risk markers and self-reported health at 3 months after stroke.Design Randomised controlled intervention study with per-protocol analyses.Setting University Hospital in Sweden.Participants Seventy-nine patients (mean (SD) age 64 (10) years, 37% female) ≥18 years with good motor function (modified Rankin Scale ≤2) and capable to perform 6 min walking test at hospital discharge were randomised to either intervention (n=40) or control group (n=39). Key exclusion criteria: subarachnoid bleeding, uncontrolled hypertension, severe psychiatric problems or cognitive limitations.Interventions The intervention group received beyond standard care, daily mobile phone instructional text messages to perform regular outdoor walking and functional leg exercises. The control group received standard care.Main outcome measures Fat mass and fat-free mass were estimated by bioelectric impedance analysis. Cardiometabolic risk factors like blood lipids, glycated haemoglobin and blood glucose were analysed at baseline and after 3 months.Results Both groups changed favourably in fat-free mass (1.83 kg, 95% CI 0.77 to 2.89; p=0.01, effect size (ES)=0.63 vs 1.22 kg, 95% CI 0.39 to 2.0; p=0.05, ES=0.54) and fat mass (−1.30 kg, 95% CI −2.45 to −0.14; p=0.029, ES=0.41 vs −0.76 kg, 95% CI −1.74 to 0.22; p=0.123, ES=0.28). Also, many cholesterol related biomarkers improved; for example, total cholesterol −0.65 mmol/L, 95% CI −1.10 to −0.2; p=0.06, ES: 0.5 vs −1.1 mmol/L, 95% CI −1.47 to −0.56; p>0.001, ES=0.8. However, there were no between-group differences. At 3 months, 94% and 86%, respectively, reported very good/fairly good health in the text messaging and control groups.Conclusions No clear effect of 3 months daily mobile phone delivered training instructions was detected on body composition, cardiovascular biochemical risk factors or self-perceived health. Further research is needed to evaluate secondary prevention efforts in larger populations after recent stroke.Trial registration number NCT02902367.

Introduction Short forms of the Montreal Cognitive Assessment (MoCA) have allowed quick cognitive screening. However, none of the available short forms has been created or validated in a Swedish sample of patients with stroke.The aim is to develop a short-form Swedish version of the MoCA (s-MoCA-SWE) in a sample of patients with acute and subacute stroke. The specific objectives are: (1) to identify a subgroup of MoCA items that have the potential to form the s-MoCA-SWE; (2) to determine the optimal cut-off value of s-MoCA-SWE for predicting cognitive impairment and (3) and to compare the psychometric properties of s-MoCA-SWE with those of previously developed MoCA short forms.Methods and analysis This is a statistical analysis protocol for a cross-sectional study. The study sample will comprise patients from Väststroke, a local stroke registry from Gothenburg, Sweden and Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke (EFFECTS), a randomised controlled trial in Sweden. The s-MoCA-SWE will be developed by using exploratory factor analysis and the boosted regression tree algorithm. The cut-off value of s-MoCA-SWE for impaired cognition will be determined based on binary logistic regression analysis. The psychometric properties of s-MoCA-SWE will be compared with those of other MoCA short forms by using cross-tabulation and area under the receiving operating characteristic curve analyses.Ethics and dissemination The Väststroke study has received ethical approval from the Regional Ethical Review Board in Gothenburg (346–16) and the Swedish Ethical Review Authority (amendment 2019–04299). The handling of data generated within the framework of quality registers does not require written informed consent from patients. The EFFECTS study has received ethical approval from the Stockholm Ethics Committee (2013/1265-31/2 on 30 September 2013). All participants provided written consent. Results will be published in an international, peer-reviewed journal, presented at conferences and communicated to clinical practitioners in local meetings and seminars.

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Abstract This study assesses the efficacy and exposure–response relationship of omega-3-carboxylic acids (OM-3 CA) in models of crystal-based inflammation. Human THP-1 macrophages and primary peripheral blood mononuclear cells exposed to multiple inflammatory crystal types were used to determine the anti-inflammatory potential of omega-3 (OM-3) fatty acids in vitro. Anti-inflammatory effects of OM-3 CA in vivo were tested in rat monosodium urate (MSU) crystal air pouch and rat knee intra-articular MSU injection models. Acute treatment with the OM-3 fatty acid docosahexaenoic acid suppressed MSU-, cholesterol crystal-, and calcium pyrophosphate crystal-mediated interleukin-1β (IL-1β) production in vitro. In vivo, OM-3 CA dose-dependently reduced crystal-mediated cell migration, exudate volume, and levels of IL-1β and prostaglandin E2. Following intra-articular injection of MSU, treatment with OM-3-CA (1 mL/kg) and indomethacin (1 mg/kg) resulted in similar mean reductions in pain (23% and 41%, respectively) and swelling (58% and 50%, respectively), compared with controls. Additionally, in complex formulations of OM-3 fatty acids, high levels of palmitic acid could reduce the in vivo effect on crystal-mediated IL-1β elevation. OM-3 CA has a broadly efficacious anti-inflammatory effect with a strong exposure–response relationship that could be beneficial in prevention and treatment of crystal arthritis, with potential applications in other IL-1β-mediated diseases.

Drug-based treatment of alveolar echinococcosis (AE) with benzimidazoles is in most cases non-curative, thus has to be taken lifelong. Here, we report on a 56-year-old male AE patient who received standard benzimidazole treatment and biliary plastic stents, and additionally self-medicated himself with the Peruvian plant extract Maca (Lepidium meyenii). After 42 months, viable parasite tissue had disappeared. Based on this striking observation, the anti-echinococcal activity of Maca was investigated in vitro and in mice experimentally infected with Echinococcus multilocularis metacestodes. Albendazole (ABZ)-treated mice and mice treated with an ABZ+Maca combination exhibited a significantly reduced parasite burden compared to untreated or Maca-treated mice. As shown by a newly established UHPLC-MS/MS-based measurement of ABZ-metabolites, the presence of Maca during the treatment did not alter ABZ plasma levels. In vitro assays corroborated these findings, as exposure to Maca had no notable effect on E. multilocularis metacestodes, and in cultures of germinal layer cells, possibly unspecific, cytotoxic effects of Maca were observed. However, in the combined treatments, Maca inhibited the activity of ABZ in vitro. While Maca had no direct anti-parasitic activity, it induced in vitro proliferation of murine spleen cells, suggesting that immunomodulatory properties could have contributed to the curative effect seen in the patient.

Abstract Human brown adipose tissue (BAT), with a major site in the cervical-supraclavicular depot, is a promising anti-obesity target. This work presents an automated method for segmenting cervical-supraclavicular adipose tissue for enabling time-efficient and objective measurements in large cohort research studies of BAT. Fat fraction (FF) and R2 * maps were reconstructed from water-fat magnetic resonance imaging (MRI) of 25 subjects. A multi-atlas approach, based on atlases from nine subjects, was chosen as automated segmentation strategy. A semi-automated reference method was used to validate the automated method in the remaining subjects. Automated segmentations were obtained from a pipeline of preprocessing, affine registration, elastic registration and postprocessing. The automated method was validated with respect to segmentation overlap (Dice similarity coefficient, Dice) and estimations of FF, R2 * and segmented volume. Bias in measurement results was also evaluated. Segmentation overlaps of Dice = 0.93 ± 0.03 (mean ± standard deviation) and correlation coefficients of r > 0.99 (P

CONTEXT:Despite being associated with dependence and social stigma, methadone is a potential end-of-life option in complex cancer pain. OBJECTIVES:To explore attitudes and opinions about methadone and its potential role and current use in complex end-of-life pain. METHODS:Semi-structured interviews (n = 30) with physicians in specialized palliative care, transcribed and analyzed with conventional qualitative content analysis. RESULTS:According to the physicians, patients and relatives expressed unexpectedly few negative attitudes, not affecting methadone's use as an analgesic. Complex pain in bone-metastatic cancer of the prostate, breast and kidney, as well as pancreatic cancer and sarcomas were recurrent suggestions of appropriate indications. Most of the informants stated that they applied a mechanism-based treatment and mainly prescribed low-dose methadone as an add-on to an existing opioid therapy to benefit from methadone´s proposed NMDA-receptor inhibiting properties, e.g. in cases with reduced opioid sensitivity. Despite its complex pharmacokinetics with a long half-life, most informants expressed defined strategies to avoid side-effects such as respiratory depression, especially when initiating treatment in the home-care setting. While many palliative care physicians expressed an overly enthusiastic attitude, others stressed the risks of overconfidence, low precision in use, and overlooked treatment options. Besides the obvious physical pain-relieving effects, they stated that effective pain relief could result in a reduced workload and emotional empowerment, both for physicians and staff. CONCLUSION:Methadone, especially in the form of low-dose add-on to other opioids is widely advocated in Swedish specialized palliative care as a practical and safe method with rapid onset in complex pain situations at the end of life.

BACKGROUND:Predicting which children will go on to develop mental health symptoms as adolescents is critical for early intervention and preventing future, severe negative outcomes. Although many aspects of a child's life, personality, and symptoms have been flagged as indicators, there is currently no model created to screen the general population for the risk of developing mental health problems. Additionally, the advent of machine learning techniques represents an exciting way to potentially improve upon the standard prediction modelling technique, logistic regression. Therefore, we aimed to I.) develop a model that can predict mental health problems in mid-adolescence II.) investigate if machine learning techniques (random forest, support vector machines, neural network, and XGBoost) will outperform logistic regression. METHODS:In 7,638 twins from the Child and Adolescent Twin Study in Sweden we used 474 predictors derived from parental report and register data. The outcome, mental health problems, was determined by the Strengths and Difficulties Questionnaire. Model performance was determined by the area under the receiver operating characteristic curve (AUC). RESULTS:Although model performance varied somewhat, the confidence interval overlapped for each model indicating non-significant superiority for the random forest model (AUC = 0.739, 95% CI 0.708-0.769), followed closely by support vector machines (AUC = 0.735, 95% CI 0.707-0.764). CONCLUSION:Ultimately, our top performing model would not be suitable for clinical use, however it lays important groundwork for future models seeking to predict general mental health outcomes. Future studies should make use of parent-rated assessments when possible. Additionally, it may not be necessary for similar studies to forgo logistic regression in favor of other more complex methods.

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The growing grey seal (Halichoerus grypus) population in the Baltic Sea has created conflicts with local fisheries, comparable to similar emerging problems worldwide. Adequate information on the foraging habits is a requirement for responsible management of the seal population. We investigated the applicability of available dietary assessment methods by comparing morphological analysis and DNA metabarcoding of gut contents (short-term diet; n = 129/125 seals, respectively), and tissue chemical markers i.e. fatty acid (FA) profiles of blubber and stable isotopes (SIs) of liver and muscle (mid- or long-term diet; n = 108 seals for the FA and SI markers). The methods provided complementary information. Short-term methods indicated prey species and revealed dietary differences between age groups and areas but for limited time period. In the central Baltic, herring was the main prey, while in the Gulf of Finland percid and cyprinid species together comprised the largest part of the diet. Perch was also an important prey in the western Baltic Proper. The DNA analysis provided firm identification of many prey species, which were neglected or identified only at species group level by morphological analysis. Liver SIs distinguished spatial foraging patterns and identified potentially migrated individuals, whereas blubber FAs distinguished individuals frequently utilizing certain types of prey. Tissue chemical markers of adult males suggested specialized feeding to certain areas and prey, which suggest that these individuals are especially prone to cause economic losses for fisheries. We recommend combined analyses of gut contents and tissue chemical markers as dietary monitoring methodology of aquatic top predators to support an optimal ecosystem-based management.

Humans are exposed to aldehydes in a variety of environmental situations. Aldehydes generally have a strong odor and are highly irritating to the mucous membranes. Knowledge about odor perception and especially irritation potency in humans is thus essential in risk assessment and regulation, e.g. setting occupational exposure limits. However, data on odor and irritation are lacking or limited for several aldehydes. The aim of the study was to determine the odor and lateralization thresholds of some commonly occurring aldehydes. Acrolein and crotonaldehyde where chosen as they are formed when organic material is heated or burned, e.g. during cigarette smoking. n-Hexanal was also included as it is emitted from wood pellets and fibreboard.To study odor and lateralization thresholds of these aldehydes, a novel, inexpensive olfactometer was designed to enable delivery of reliable and stable test concentrations and thus valid measures of thresholds. The delivery system consists of seven syringe pumps, each connected to a Tedlar bag containing a predefined concentration of the tested aldehyde vapor. To validate the threshold measures, a test-retest was performed with a separate method, namely odor delivery via amber bottles. Twenty healthy naïve individuals were tested.The median odor thresholds of acrolein, crotonaldehyde and hexanal were 17, 0.8, and 97 ppb, respectively. No lateralization threshold could be identified for acrolein (highest tested concentration was 2 940 ppb in 5 subjects), whereas the medians were 3 and 390 ppb for the latter two. In addition, odor thresholds for n-hexanal were also determined using two methods where similar results were obtained, suggesting that the olfactometer presentation method is valid.We found olfactory detection and lateralization thresholds (except for acrolein) in alliance with, or lower than, previously reported in naïve subjects. The new olfactometer allows better control of presentations timing and vapor concentration.

Calcium dependent protein kinases are unique to plants and certain parasites and comprise an N-terminal segment and a kinase domain that is regulated by a C-terminal calcium binding domain. Since the proteins are not found in man they are potential drug targets. We have characterized the calcium binding lobes of the regulatory domain of calcium dependent protein kinase 3 from the malaria parasite Plasmodium falciparum. Despite being structurally similar, the two lobes differ in several other regards. While the monomeric N-terminal lobe changes its structure in response to calcium binding and shows global dynamics on the sub-millisecond time-scale both in its apo and calcium bound states, the C-terminal lobe could not be prepared calcium-free and forms dimers in solution. If our results can be generalized to the full-length protein, they suggest that the C-terminal lobe is calcium bound even at basal levels and that activation is caused by the structural reorganization associated with binding of a single calcium ion to the N-terminal lobe.

Twin studies of hoarding symptoms indicate low to moderate heritability during adolescence and considerably higher heritability in older samples, suggesting dynamic developmental etiological effects. The aim of the current study was to estimate the relative contribution of additive genetic and environmental effects to hoarding symptoms during adolescence and young adulthood and to estimate the sources of stability and change of hoarding symptoms during adolescence.Univariate model-fitting was conducted in three cohorts of twins aged 15 (n = 7,905), 18 (n = 2,495) and 20-28 (n = 6,218). Longitudinal analyses were conducted in a subsample of twins for which data on hoarding symptoms was available at both age 15 and 18 (n = 1,701).Heritability estimates for hoarding symptoms at ages 15, 18 and 20-28 were 41% (95% confidence interval [CI]: 36-45%), 31% (95% CI: 22-39%) and 29% (95% CI: 24-34%) respectively. Quantitative sex-differences emerged in twins aged 15 at which point the heritability in boys was 33% (95% CI: 22-41%) and 17% (95% CI: 0-36%) in girls. Shared environmental effects played a negligible role across all samples with the exception of girls aged 15 where they accounted for a significant proportion of the variance (22%; 95% CI 6-36%). The longitudinal bivariate analyses revealed a significant phenotypic correlation of hoarding symptoms between ages 15 and 18 (0.40; 95% CI: 0.36-0.44) and a strong but imperfect genetic correlation (0.75; 95% CI: 0.57-0.94). The bivariate heritability was estimated to 65% (95% CI: 50-79%).Hoarding symptoms are heritable from adolescence throughout young adulthood, although heritability appears to slightly decrease over time. Shared environmental effects contribute to hoarding symptoms only in girls at age 15. The stability of hoarding symptoms between ages 15 and 18 is largely explained by genetic factors, while non-shared environmental factors primarily have a time-specific effect. The findings indicate that dynamic developmental etiological effects may be operating across the life span.

The Swedish Register of Palliative Care (SRPC) is a national quality register that collects data about end-of-life care from healthcare providers that care for dying patients. Data are used for quality control and research. Data are mainly collected with an end-of-life questionnaire (ELQ), which is completed by healthcare staff after the death of a patient. A previous validity assessment of the ELQ showed insufficient validity in some items including symptom relief. The aim of this study was to examine the validity of the revised ELQ.Data from 100 consecutive patients' medical records at two specialised palliative care units were used to complete new ELQs, which were then compared to the ELQ registrations from the SRPC for the same patients. The level of agreement was calculated for each ELQ item. To account for the possibility of the agreement occurring by chance, Cohen's kappa was calculated for suitable items. To examine the extent of registration mistakes when transferring the paper form to the web, the original paper versions of the ELQ filled out at the units were compared to data from the ELQs reported to the SRPC.Level of agreement between ELQ registrations from the SRPC and the new ELQs based on the medical records varied between 0.55 and 1.00, where 24 items showed level of agreement above 0.80 and 9 items showed level of agreement below 0.80. Cohen's kappa with 95% confidence intervals was calculated for 24 items. The kappa values showed that two items had poor agreement, four fair agreement, 11 moderate agreement, five good agreement and two very good agreement. The level of agreement varied between 0.93 and 1.00 when comparing the ELQ registrations in the SRPC and the paper forms.The revised ELQ contains more items with high levels of agreement between registrations in the SRPC and notes in the patients' medical records when compared to the previous version. Validating issues around symptom assessment remains a challenge in our model of quality assessment.