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In this crossover experiment, we investigated the impact of a statement bank, enabling the reuse of previously written feedback (SA condition), on 45 math teachers' feedback for 60 completed linear equation tests, compared to traditional pen-and-paper feedback (PP condition). In the SA condition, teachers were encouraged to use atomic feedback, a set of formulation requirements that makes feedback items significantly more reusable. A previous study found that significantly more feedback was written in the SA condition but did not investigate the content of the feedback. To address this gap, we employed a novel approach of combining text mining with qualitative methods. Results indicate similar wording and sentiments in both conditions. However, SA feedback was more elaborate yet general, focusing on major and minor strengths and deficits, while PP feedback was shorter but more concrete, emphasising main issues. Despite low feedback quality in both conditions, the statement bank led to less effective diagnostic activities, implying that teachers' careless use of statement banks, although convenient, might lead to lower-quality feedback.

This paper studies (trans)national social capital gained through an international study experience in Belgium. Drawing upon a multi-method alumni study, we explore different types of (inter)national networks of male and female graduates, the extent to which different networks remained after graduation as well as effects on personal and professional development and organizational performance. Findings show that graduates have particularly gained networks with non-co-nationals which evolve from bridging relations at the outset to bonding relations while particularly networks with the host population remain limited. After returning home, bonding social interaction relations remain most important, irrespective of the nationality of the graduates, whereas information sharing and collaboration networks survive better among co-nationals, particularly when these are triggered through national alumni chapters. Our study finds network effects on individual's intercultural skills, knowledge and attitudes, their professional career and organizational performance, with intercultural gains being particularly high for networks with non-co-nationals from other continents.

The article deals with the use of the Lithuanian anteriority converb in -us in a certain type of purpose clauses whose implicit subject is coreferential with the (often also implicit) main clause subject or agent (as in kad veltui neišmetus pinigų ‘in order not to throw money away’). The article offers a historical account for its rise based on internal reconstruction. It is argued that the anteriority converb was introduced as a pseudo-conditional strategy used to avoid a factive reading in constructions with evaluative predicates (as in gerai būtų suradus... = gerai būtų, jeigu surastume... ‘it would be a good thing if we found…’). From evaluative constructions the converb then spread to optative clauses with kad tik ‘if only’ (gerai būtų suradus ‘it would be a good thing to find…’ → kad tik suradus... ‘if only one could find…’). Apart from a semantic shift (from evaluative to desiderative/deontic) this also involved a process of syntactic insubordination. In a subsequent process of resubordination, constructions with the anteriority converb finally came to function as adverbial purpose clauses. In the final part of the article it is argued that the negative view prescriptivist sources take of purpose clauses with the anteriority converb might be up for a revision.

Cerebral arteriopathy (CA) in children with sickle cell disease (SCD) is classically described as chronic stenosis of arteries in the anterior brain circulation, leading to ischemic stroke. Some studies have however reported strokes in children with SCD but without CA. In order to better understand the etiology and risk factors of these strokes, we retrospectively analyzed ischemic strokes occurring in a large cohort of children over a 13 year-period. Between 2007 and 2020, 25/1500 children with SCD had an ischemic stroke in our center. Among them, 13 (52%) had CA, described as anatomical arterial stenosis, while 12 (48%) did not. Patients with stroke without CA were older than patients with stroke attributed to SCD-CA (9.0 years old vs 3.6 years old, p=0.008), and had more frequently a SC genotype (25% vs 0% respectively). Their stroke involved posterior circulation more frequently, with cerebellar involvement in 42%. Retained stroke etiologies in patients without typical SCD-related CA were reversible cerebral vasoconstriction syndrome, cerebral fat embolism, arterial thrombosis or thromboembolism, hyperviscosity, vasculitis in a context of infectious meningoencephalitis, and severe hemodynamic failure. No recurrence was observed in the 24 months following stroke, even though 67% of the patients were no longer receiving exchange transfusions in this group. In conclusion, in a cohort of pediatric SCD patients with efficient stroke screening strategy, half of occurring ischemic strokes were related to causes other than CA. They affected a different population of SCD children and systematic long-term transfusion programs may not be necessary in these cases.

Abstract Nasogastric feeding tube insertion is a common but invasive procedure most often blindly placed by nurses in acute and chronic care settings. Although usually not harmful, serious and fatal complications with misplacement still occur and variation in practice still exists. These tubes can be used for drainage or administration of fluids, drugs and/or enteral feeding. During blind insertion, it is important to achieve correct tip position of the tube ideally reaching the body of the stomach. If the insertion length is too short, the tip and/or distal side-openings at the end of the tube can be located in the esophagus increasing the risk of aspiration (pneumonia). Conversely, when the insertion length is too long, the tube might kink in the stomach, curl upwards into the esophagus or enter the duodenum. Studies have demonstrated that the most frequently used technique to determine insertion length (the nose–earlobe–xiphoid method) is too short a distance; new safer methods should be used and further more robust evidence is needed. After blind placement, verifying correct gastric tip positioning is of major importance to avoid serious and sometimes lethal complications.

Purpose – The purpose of this study is to identify the most vulnerable households and districts in Northwest Ethiopia and help decision-makers in developing and prioritising effective adaptive strategies and actions. Design/methodology/approach – A multi-scale analytical tool and hazard-generic socio-economic indicators were developed to identify and prioritise the most vulnerable households and districts in Northwest Ethiopia. Categorical principal component analysis with 36 indicators was used to develop weights for different indicators and construct a household intrinsic vulnerability index. Data were collected through key information interviews, focus group discussions and a household survey with 1,602 randomly selected households in three districts of Northwest Ethiopia. Findings – Drawing on intrinsic vulnerability index computation, this study highlights that low levels of education, low access to climate information and credit services, long distance travelled to fetch water and frequent food shortages are the dominant factors contributing to high levels of intrinsic vulnerability at district level, while lack of livelihood support and income diversification are the key drivers of vulnerability at household level. The findings of this study further show that the majority of households (78.01%) falls within the very high to moderately high vulnerable category. Disaggregating the data according to agro-climatic zones highlights that the prevalence of high intrinsic vulnerability is most widespread in the lowland agro-climatic zone (82.64%), followed by the highland (81.97%) and midland zones (69.40%). Practical implications – From a policy intervention vantage point, addressing the drivers of vulnerability provides a reliable approach to reduce the current vulnerability level and manage potential climate change-induced risks of a system. Specifically, reliable information on inherent vulnerability will assist policymakers in developing policies and prioritising actions aimed at reducing vulnerability and assisting in the rational distribution of resources among households at a local level. Originality/value – This study contributes to the existing vulnerability literature by showing how hazard-generic socio-economic indicators in the vulnerability assessment adopted by the IPCC (2014) are important to identify drives of vulnerability which ultimately may feed into a more fundamental treatment of vulnerability.

With only 5.1% of the population fully vaccinated against COVID-19, Tanzania has one of the lowest vaccination rates in the world and after two years of changing policies regarding the disease, the country struggles to get its vaccination campaign on the rails. In this study, we identify the determinants of COVID-19 vaccination willingness in two villages of the Mvomero district in Eastern Tanzania. Based on survey data, we performed univariate analyses to assess differences in vaccination intention for various social groups, and built a four-dimensional multivariate ordered logistic regression model that comprises respondents' personal and socioeconomic characteristics, the channels through which they get their information, their attitudes and perceptions towards COVID-19, and their social network embeddedness. Only 37.0% of the respondents indicated that they would be willing to get vaccinated against COVID-19. Vaccination willingness differed significantly according to gender, age, educational attainment and religion; with men, the elderly, people with post-secondary education and Catholics and Muslims more likely to accept a vaccine. Predictors of vaccination willingness were gender, age, social media and informal contacts as information sources, perceived effectiveness of the vaccine and of alternative medicine, fear of side effects, a general dislike of vaccines, and the proportion of vaccinated people and the highest value of trust in international organisations in one’s network. Although people’s attitudes and perceptions have the largest share of the explanatory value, our model shows that all four of our model’s building blocks were imperative in explaining vaccination willingness. Therefore, our paper presents a compelling case for the inclusion of respondents' social embeddedness as a common dimension for exploratory models of vaccination willingness.

We performed a systematic search of the PubMed database for English-language articles related to the function of adipose-derived stem cells in the pathogenesis of cardiovascular diseases. In preclinical models, adipose-derived stem cells protected arteries and the heart from oxidative stress and inflammation and preserved angiogenesis. However, clinical trials did not reiterate successful treatments with these cells in preclinical models. The low success in patients may be due to aging and metabolic reprogramming associated with the loss of proliferation capacity and increased senescence of stem cells, loss of mitochondrial function, increased oxidative stress and inflammation, and adipogenesis with increased lipid deposition associated with the low potential to induce endothelial cell function and angiogenesis, cardiomyocyte survival, and restore heart function. Then, we identify noncoding RNAs that may be mechanistically related to these dysfunctions of human adipose-derived stem cells. In particular, a decrease in let-7, miR-17-92, miR-21, miR-145, and miR-221 led to the loss of their function with obesity, type 2 diabetes, oxidative stress, and inflammation. An increase in miR-34a, miR-486-5p, and mir-24-3p contributed to the loss of function, with a noteworthy increase in miR-34a with age. In contrast, miR-146a and miR-210 may protect stem cells. However, a systematic analysis of other noncoding RNAs in human adipose-derived stem cells is warranted. Overall, this review gives insight into modes to improve the functionality of human adipose-derived stem cells.

Purpose – This paper explores the relationship between married women's intrahousehold decision-making participation and marital gender roles, next to factors suggested in the household bargaining literature. Additionally, the authors investigate whether women's employment carries the same importance for decision-making participation as contributions to household incomes. Design/methodology/approach – Using 2011/2012 Nicaraguan Demographic and Health Survey (DHS), the authors estimate multinomial logistic regressions for eight decision-making domains, analyzing three levels of decision-making: wife-dominant or sole decisions, joint decision-making (with the partner) and decision-making by someone else. The authors create an additive index for measuring internalized marital gender roles. Findings – Women's intrahousehold decision-making participation is explained differently depending on the decision-making area and level of participation. Women with a better relative position vis-à-vis partners and not following patriarchal gender roles are more likely to make decisions jointly with their partners, but not alone. Women's age and educational level are the strongest predictors in the analysis. Women's employment reduces their decision-making participation in children's disciplining and daily cooking-related decisions. Research limitations/implications – It focuses on married women only, while marital status might be a determinant of decision-making itself and left out the contribution of unearned incomes. Practical implications – Interventions aimed at increasing women's intrahousehold decision-making participation should not only focus on economic endowments but also comprehend the gendered dynamics governing intrahousehold allocation. Originality/value – The study incorporates quantitative measures of marital gender roles in the study of intrahousehold decision-making. It also contributes to the literature with insights from contexts where women's involvement in employment increased against a background of patriarchal gender roles.

In children with sickle cell anemia (SCA), early splenic complications can require splenectomy, but the benefit-to-risk ratio and the age at which splenectomy may be safely performed remain unclear. To address this question, we analyzed the rate of post-splenectomy events in children with SCA splenectomized between 2000-2018 at the Robert Debré University Hospital, Paris, France. A total of 188 children underwent splenectomy, including 101 (11.9%) from our newborn cohort and 87 referred to our center. Median (Q1-Q3) age at splenectomy was 4.1 years (range 2.5-7.3 years), with 123 (65.4%) and 65 (34.6%) children splenectomized at ≥3 years of age or

New data collection methods and processing capabilities facilitate online personalization of advertisements but also challenge youth’s understanding of how these methods work. Teenagers are often unaware of the commercial use of their personal information and are susceptible to the persuasive effects of personalized advertising. This raises questions about their ability to engage in privacy-protecting behaviors. This article examines teenagers’ coping responses to commercial data collection and subsequent personalized advertising, considering their limited knowledge. Ten focus groups with 35 teenagers aged 12–14 were conducted. The findings show that teenagers hold certain folk theories (i.e., incomplete and/or inaccurate representations of reality) about how and why their personal information is being collected for commercial purposes (e.g., commercial data collection is unavoidable or all principles of privacy statements are the same). Their coping responses regarding commercial data collection (e.g., limiting information disclosure or refusing to accept privacy policies) and personalized advertising (e.g., trying to change settings or avoiding interaction) are often based on these folk theories and embedded in their everyday practices. Despite teenagers’ efforts, we argue that their responses might not always be effective. Implications for educators, advertisers, and policymakers are discussed.

In recent years, several high-profile incidents have spurred research into games of timing. A framework emanating from the FlipIt model features two covert agents competing to control a single contested resource. In its basic form, the resource exists forever while generating value at a constant rate. As this research area evolves, attempts to introduce more economically realistic models have led to the application of various forms of economic discounting to the contested resource. This paper investigates the application of a two-parameter economic discounting method, called generalized hyperbolic discounting, and characterizes the game’s Nash equilibrium conditions. We prove that for agents discounting such that accumulated value generated by the resource diverges, equilibrium conditions are identical to those of non-discounting agents. The methodology presented in this paper generalizes the findings of several other studies and may be of independent interest when applying economic discounting to other models.

The ready-mixed concrete delivery (RMC) problem is a scheduling problem, where multiple trucks deliver concrete to order sites abiding by hard constraints in a dynamic environment. It is an NP-hard problem, impractical to solve using exhaustive methods. Thus, it requires heuristic-based approaches for generating sub-optimal schedules. Due to its distributed nature, we address this problem using a decentralised, scalable, cooperative MAS (multiagent system) that dynamically generates schedules. We explore the impact of teamwork by trucks on schedule optimisation. This work illustrates two novel approaches that address the dynamic RMC problem; a Delegate MAS approach and a team-extended approach. We present an empirical study, comparing our novel approaches with existing ones. The evaluation is performed by classifying the RMC case study scenarios into unique stress, scale, and dynamism characteristics. With 40% to 70% improvement over different metrics, the results show that both approaches generate better schedules, and using agent teams augments the performance. Thus, such decentralized MAS with the appropriate coordination approach and teamwork can be used for solving constrained dynamic scheduling problems.

Common symptoms of depressive disorders include anhedonia, sleep problems, and reduced physical activity. Drugs used to treat depression mostly aim to increase serotonin signaling but these can have unwanted side effects. Depression has also been treated by traditional medicine using plants like Centella asiatica (CA) and this has been found to be well tolerated. However, very few controlled studies have addressed CA’s protective role in depression, nor have the active compounds or mechanisms that mediate this function been identified. To address this issue, we used Drosophila melanogaster to investigate whether CA can improve depression-associated symptoms like anhedonia and decreased climbing activity. We found that a water extract of CA provides resilience to stress induced phenotypes and that this effect is primarily due to mono-caffeoylquinic acids found in CA. Furthermore, we describe that the protective function of CA is due to a synergy between chlorogenic acid and one of its isomers also present in CA. However, increasing the concentration of chlorogenic acid can overcome the requirement for the second isomer. Lastly, we found that chlorogenic acid acts via calcineurin, a multifunctional phosphatase that can regulate synaptic transmission and plasticity and is also involved in neuronal maintenance.

Background and purpose: Deep inspiration breath-hold is an established technique to reduce heart dose during breast cancer radiotherapy. However, modern breast cancer radiotherapy techniques with lymph node irradiation often require long beam-on times of up to 5 min. Therefore, the combination with deep inspiration breath-hold (DIBH) becomes challenging. A simple support technique for longer duration deep inspiration breath-hold (L-DIBH), feasible for daily use at the radiotherapy department, is required to maximize heart sparing. Materials and methods: At our department, a new protocol for multiple L-DIBH of at least 2 min and 30 s was developed on 32 healthy volunteers and validated on 8 breast cancer patients during radiotherapy treatment, using a pragmatic process of iterative development, including all major stakeholders. Each participant performed 12 L-DIBHs, on 4 different days. Different methods of pre-oxygenation and voluntary hyperventilation were tested, and scored on L-DIBH duration, ease of use, and comfort. Results: Based on 384 L-DIBHs from 32 healthy volunteers, voluntary hyperventilation for 3 min whilst receiving high-flow nasal oxygen at 40 L/min was the most promising technique. During validation, the median L-DIBH duration in prone position of 8 breast cancer patients improved from 59 s without support to 3 min and 9 s using the technique (p

Tom Holvoet,1,2 Triana Lobaton,2 Pieter Hindryckx2 1Department of Gastroenterology, AZ Nikolaas, Sint-Niklaas, Belgium; 2Department of Gastroenterology, University Hospital Ghent, Ghent, BelgiumCorrespondence: Tom Holvoet Email tom.holvoet@aznikolaas.beAbstract: Acute severe colitis is a severe complication of ulcerative colitis, affecting approximately 20% of patients. For physicians, it remains a challenging condition to treat. Current treatment algorithms have diminished the mortality associated with acute severe ulcerative colitis (ASUC), but colectomy rates remain high (approximately 30%) despite advances in therapy. Colectomy in ASUC is particularly associated with important postoperative complications and morbidity. In this review, reasons for the inability to improve care and avoid evolution to colectomy for ASUC are explored and solutions that might lead to a better management of the disease are investigated.Keywords: acute severe colitis, ulcerative colitis, inflammatory bowel disease

Recent research suggests that infants prefer prosocial behaviour. However, some studies have failed to report this preference, raising the question of which specific parameters allow it to be observed. We attempted to answer this question by investigating whether the preference varies (1) with age (by testing infants aged 6, 12 and 18 months), (2) with type of social behaviour (help, play or share) and (3) when the pro- and antisocial agents' appearance is manipulated (neutral, own-race or other-race faces). To this end, we use an eye-tracking methodology to assess infants' preferences for pro- versus antisocial agents featured in animated cartoons. We found that the prosocial preference was not stable across ages and varied according to social scenario. No sound conclusion could be reached about the influence of faces. Our results raise a new question, concerning the extent to which very young infants perceive prosociality in complex social behaviour.

Background and Aims No consensus exists on optimal strategy to prevent postoperative recurrence [POR] after ileocaecal resection [ICR] for Crohn's disease [CD]. We compared early medical prophylaxis versus expectant management with treatment driven by findings at elective endoscopy 6–12 months after ICR. Methods A retrospective, multicentric, observational study was performed. CD patients undergoing first ICR were assigned to Cohort 1 if a biologic or immunomodulator was [re]started prophylactically after ICR, or to Cohort 2 if no postoperative prophylaxis was given and treatment was started as reaction to elective endoscopic findings. Primary endpoint was rate of endoscopic POR [Rutgeerts >i1]. Secondary endpoints were severe endoscopic POR [Rutgeerts i3/i4], clinical POR, surgical POR, and treatment burden during follow-up. Results Of 346 included patients, 47.4% received prophylactic postoperative treatment [proactive/Cohort 1] and 52.6% did not [reactive/Cohort 2]. Endoscopic POR [Rutgeerts >i1] rate was significantly higher in Cohort 2 [41.5% vs 53.8%, OR 1.81, p  = 0.039] at endoscopy 6–12 months after surgery. No significant difference in severe endoscopic POR was found [OR 1.29, p  = 0.517]. Cohort 2 had significantly higher clinical POR rates [17.7% vs 35.7%, OR 3.05, p  = 0.002] and numerically higher surgical recurrence rates [6.7% vs 13.2%, OR 2.59, p  = 0.051]. Cox proportional hazards regression analysis showed no significant difference in time to surgical POR of proactive versus expectant/reactive approach [HR 2.50, p  = 0.057]. Quasi-Poisson regression revealed a significantly lower treatment burden for immunomodulator use in Cohort 2 [mean ratio 0.53, p  = 0.002], but no difference in burden of biologics or combination treatment. Conclusions The PORCSE study showed lower rates of endoscopic POR with early postoperative medical treatment compared with expectant management after first ileocaecal resection for Crohn's disease. [ABSTRACT FROM AUTHOR]

Alternariol (AOH), alternariol monomethyl-ether (AME), and tenuazonic acid (TeA) are major mycotoxins produced by fungi of the genus Alternaria and are common contaminants of food products such as fruits, vegetables, cereals and grains. Alternaria mycotoxins are known to cause relevant economic losses and to have a negative impact on human and animal health. EFSA stated in its scientific opinion that data on the toxicity of Alternaria mycotoxins in humans and livestock are generally lacking, precluding proper hazard characterization. This study aimed to fill some knowledge gaps by studying the in vitro cytotoxicity toward human intestinal epithelial cells (Caco-2) and hepatocytes (HepG2). Cytotoxic properties were assessed by flow cytometric analyses of remaining viable cells (i.e., propidium iodide negative) after mycotoxin exposure for 24–48 h versus solvent control. Treatment of cells with single doses of AOH, AME, and TeA resulted in a dose-dependent loss of cell viability for both cell lines. Half maximal effective concentrations (EC50) of the different mycotoxins were comparable for the two cell lines. On HepG2 cells, EC50 values varying between 8 and 16, 4 and 5, and 40 and 95 μg/mL were calculated for AOH, AME, and TeA, respectively. On Caco-2 cells, EC50 values of 19 μg/mL and varying between 6 and 23, and 60 and 90 μg/mL were calculated for AOH, AME, and TeA, respectively. A general relative cytotoxicity ranking of about 1 = 1 >>> 3 was obtained for AOH, AME, and TeA, respectively. Treatment of both cell lines with combined binary and ternary mixtures of AOH, AME, and TeA in a 1:1:3 ratio, also showed a dose-dependent decrease in cell viability. For both cell lines, the binary combination of especially AME and TeA (1:3 ratio) but also of AOH and AME (1:1 ratio) significantly increased the cytotoxicity compared to the single compound toxicity, although mainly at the highest concentrations tested. The ternary combinations of AOH, AME, and TeA induced only a slight increase in cytotoxicity compared to the single mycotoxins, again at the highest concentrations tested.

Inflammation contributes to the development of metabolic disease through incompletely understood mechanisms. Here the authors report that deletion of the transcription factor KLF2 in myeloid cells leads to increased feeding and weight gain in mice with concomitant peripheral and central tissue inflammation, while overexpression protects against diet-induced metabolic disease.

Stem cell-based therapies are a promising approach for the treatment of degenerative muscular diseases; however, clinical trials have shown inconclusive and even disappointing results so far. Noninvasive cell monitoring by medicine imaging could improve the understanding of the survival and biodistribution of cells following injection. In this study, we assessed the canine sodium iodide symporter (cNIS) reporter gene as an imaging tool to track by single-photon emission computed tomography (SPECT/CT) transduced canine myoblasts after intramuscular (IM) administrations in dogs. cNIS-expressing cells kept their myogenic capacities and showed strong 99 mTc-pertechnetate (99 mTcO4−) uptake efficiency both in vitro and in vivo. cNIS expression allowed visualization of cells by SPECT/CT along time: 4 h, 48 h, 7 days, and 30 days after IM injection; biopsies collected 30 days post administration showed myofiber’s membranes expressing cNIS. This study demonstrates that NIS can be used as a reporter to track cells in vivo in the skeletal muscle of large animals. Our results set a proof of concept of the benefits NIS-tracking tool may bring to the already challenging cell-based therapies arena in myopathies and pave the way to a more efficient translation to the clinical setting from more accurate pre-clinical results.

Abstract Background Impaired physical function due to muscle weakness and exercise intolerance reduces the ability to perform activities of daily living in patients with end-stage kidney disease, and by consequence, Health-Related Quality of Life (HRQoL). Furthermore, the risk of falls is an aggregate of physical function and, therefore, could be associated with HRQoL as well. The present study examined the associations between objective and subjective measures of physical function, risk of falls and HRQoL in haemodialysis patients. Methods This cross-sectional multicentre study included patients on maintenance haemodialysis. Physical function (quadriceps force, handgrip force, Sit-to-Stand, and six-minute walking test), the risk of falls (Tinetti, FICSIT-4, and dialysis fall index) and HRQoL (PROMIS-29 and EQ-5D-3 L) were measured and analysed descriptively, by general linear models and logistic regression. Results Of the 113 haemodialysis patients (mean age 67.5 ± 16.1, 57.5% male) enrolled, a majority had impaired quadriceps force (86.7%) and six-minute walking test (92%), and an increased risk of falls (73.5%). Whereas muscle strength and exercise capacity were associated with global HRQoL (R2 = 0.32) and the risk of falls, the risk of falls itself was related to psycho-social domains (R2 = 0.11) such as depression and social participation, rather than to the physical domains of HRQoL. Objective measures of physical function were not associated with subjective fatigue, nor with subjective appreciation of health status. Conclusions More than muscle strength, lack of coordination and balance as witnessed by the risk of falls contribute to social isolation and HRQoL of haemodialysis patients. Mental fatigue was less common than expected, whereas, subjective and objective physical function were decreased.

BackgroundPhysical performance is an important determinant of quality of life in patients on haemodialysis. An association between physical performance and survival could further enhance the importance of physical performance. We aimed to assess the association between different measures of physical performance and survival in dialysis patients.Methods117 patients on haemodialysis were included from December 2016 and followed up to September 2020. Muscle strength (quadriceps, handgrip strength, and sit-to-stand), exercise capacity (six-minute walking test, 6MWT) and the risk of falls (Dialysis Fall Index, Tinetti, and Frailty and Injuries: Cooperative Studies of Intervention Techniques) were measured at the time of inclusion. Hospitalisation, morbidity (Davies Stoke index) and death were recorded. Data were analysed by least squares linear regression models and competing risks survival hazard models.ResultsDuring the observation period (median 33, min 30 max 45 months), 45 patients died (= 38.5%), resulting in a mortality rate of 15% per year. Cardiovascular disease (42.9%) was the most common cause of death. All domains of physical performance were associated with mortality, with the highest hazards for an increased risk of falls (Hazard Ratio (HR) = 20.4, p = 0.003) and poor exercise capacity (HR = 7.4, pConclusionsThe 6MWT is associated with mortality in patients on haemodialysis and can be considered as a valid assessment tool to identify high-risk patients.

This study aimed to examine the ability of ulvan, a water-soluble polysaccharide from the green seaweed Ulva fasciata, to provide protection and induce resistance in wheat against the hemibiotrophic fungus Zymoseptoria tritici. Matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) analysis indicated that ulvan is mainly composed of unsaturated monosaccharides (rhamnose, rhamnose-3-sulfate, and xylose) and numerous uronic acid residues. In the greenhouse, foliar application of ulvan at 10 mg.ml–1 2 days before fungal inoculation reduced disease severity and pycnidium density by 45 and 50%, respectively. Ulvan did not exhibit any direct antifungal activity toward Z. tritici, neither in vitro nor in planta. However, ulvan treatment significantly reduced substomatal colonization and pycnidium formation within the mesophyll of treated leaves. Molecular assays revealed that ulvan spraying elicits, but does not prime, the expression of genes involved in several wheat defense pathways, including pathogenesis-related proteins (β-1,3-endoglucanase and chitinase), reactive oxygen species metabolism (oxalate oxidase), and the octadecanoid pathway (lipoxygenase and allene oxide synthase), while no upregulation was recorded for gene markers of the phenylpropanoid pathway (phenylalanine ammonia-lyase and chalcone synthase). Interestingly, the quantification of 83 metabolites from major chemical families using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) in both non-infectious and infectious conditions showed no substantial changes in wheat metabolome upon ulvan treatment, suggesting a low metabolic cost associated with ulvan-induced resistance. Our findings provide evidence that ulvan confers protection and triggers defense mechanisms in wheat against Z. tritici without major modification of the plant physiology.

Withania somnifera (WS) extracts have been used in traditional medicine for millennia to promote healthy aging and wellbeing. WS is now also widely used in Western countries as a nutritional supplement to extend healthspan and increase resilience against age-related changes, including sleep deficits and depression. Although human trials have supported beneficial effects of WS, the study designs have varied widely. Plant material is intrinsically complex, and extracts vary widely with the origin of the plant material and the extraction method. Commercial supplements can contain various other ingredients, and the characteristics of the study population can also be varied. To perform maximally controlled experiments, we used plant extracts analyzed for their composition and stability. We then tested these extracts in an inbred Drosophila line to minimize effects of the genetic background in a controlled environment. We found that a water extract of WS (WSAq) was most potent in improving physical fitness, while an ethanol extract (WSE) improved sleep in aged flies. Both extracts provided resilience against stress-induced behavioral changes. WSE contained higher levels of withanolides, which have been proposed to be active ingredients, than WSAq. Therefore, withanolides may mediate the sleep improvement, whereas so-far-unknown ingredients enriched in WSAq likely mediate the effects on fitness and stress-related behavior.

Iron deficiency is known to aggravate the prognosis of patients with heart failure. Iron has functions in the mitochondrial respiratory chain. In patients with reduced mitochondrial respiration, the mitochondrial ratio between the level of nicotinamide adenine dinucleotide and its reduced form decreases. Due to the mitochondrial-lysosomal interplay, decreased mitochondrial respiration also leads to inhibition of lysosomal hydrolysis. As a result, cobalamin and iron will be trapped in lysosomes. This will, even if iron and cobalamin have been consumed and absorbed in sufficient amounts, lead to their functional deficiencies.1 Functional iron deficiency can further impede mitochondrial respiration. Increased plasma levels of methylmalonic acid were shown to predict all-cause and cardiovascular mortality in the general population. Treatments targeting mitochondrial and lysosomal function may correct the functional deficiencies and improve prognosis in a subgroup of patients with heart failure, notably those with skeletal muscle wasting. Methylmalonic acid levels may be used for monitoring response to treatment, thereby identifying patients of the subgroup in which disease outcome may improve.

Cardiovascular diseases (CVDs) represent the largest contributor to mortality worldwide. Identification of novel therapeutic targets and biomarkers for CVDs is urgently needed. Circular RNAs (circRNAs) are endogenous, abundant, and stable non-coding RNAs formed by back-splicing events. Their role as regulators of gene expression has been increasingly reported. Notably, circRNAs mediate essential physiological and pathological processes in the cardiovascular system. Our first aim, therefore, is to summarize recent advances in the role of circRNAs in cardiac development as well as in pathogenesis of various CVDs. Because circRNAs are stable in circulation and their dynamic changes may reflect different disease stages, they are considered ideal biomarkers. Therefore, our second aim is to review studies that have identified circulating circRNAs as biomarkers for CVDs. Finally, we discuss the shortage of functional studies and the limitations of available clinical studies and provide future perspectives. Keywords: cardiovascular disease, circular RNA, myocardial infarction, heart failure, cardiomyopathy, atherosclerosis, fibrosis, endothelial dysfunction, therapeutic targets, biomarkers

IntroductionMany studies have explored patients' experiences of dialysis and other treatments for kidney failure. This is the first qualitative multi-site international study of how staff perceive the process of a patient's transition from peritoneal dialysis to in-centre haemodialysis. Current literature suggests that transitions are poorly coordinated and may result in increased patient morbidity and mortality. This study aimed to understand staff perspectives of transition and to identify areas where clinical practice could be improved.MethodsSixty-one participants (24 UK and 37 Australia), representing a cross-section of kidney care staff, took part in seven focus groups and sixteen interviews. Data were analysed inductively and findings were synthesised across the two countries.ResultsFor staff, good clinical practice included: effective communication with patients, well planned care pathways and continuity of care. However, staff felt that how they communicated with patients about the treatment journey could be improved. Staff worried they inadvertently made patients fear haemodialysis when trying to explain to them why going onto peritoneal dialysis first is a good option. Despite staff efforts to make transitions smooth, good continuity of care between modalities was only reported in some of the Australian hospitals where, unlike the UK, patients kept the same consultant. Timely access to an appropriate service, such as a psychologist or social worker, was not always available when staff felt it would be beneficial for the patient. Staff were aware of a disparity in access to kidney care and other healthcare professional services between some patient groups, especially those living in remote areas. This was often put down to the lack of funding and capacity within each hospital.ConclusionsThis research found that continuity of care between modalities was valued by staff but did not always happen. It also highlighted a number of areas for consideration when developing ways to improve care and provide appropriate support to patients as they transition from peritoneal dialysis to in-centre haemodialysis.

Background. The field of CTO PCI is expanding, but successful and safe percutaneous coronary intervention (PCI) of coronary chronic total occlusions (CTO) requires a substantial resource and experience investment. We aimed to assess temporal trends in strategies and outcomes of 2 dedicated programs for CTO PCI. Methods. Between 2011 and 2020, 920 CTO PCI procedures were prospectively included at 2 referral centres in Belgium. Temporal trends were assessed, and logistic regression models were built to identify predictors of outcome. Results. Despite an increase in lesion complexity (the J-CTO score increased from 1.3 in year 1 to 1.7–2.0 in years 8-9, p

Nitrous oxide (N2O) is widely used as an anesthetic or an analgesic. N2O prolonged and recurrent administration is known to affect vitamin B12 metabolism with subsequent clinical consequences. We report herein the case of a 13-year-old girl with sickle cell disease exhibiting severe neurological and biochemical signs of functional vitamin B12 deficiency due to prolonged and repeated exposure to N2O. This was an incentive to prospectively investigate functional vitamin B12 deficiency in patients affected by sickle cell disease regularly exposed to N2O. We measured plasma concentrations of vitamin B12, total homocysteine, methionine and methylmalonic acid in 39 patients with sickle cell disease between 2015 and 2016. No patients developed neurological symptoms related to N2O administration but 19 patients (49%) had biochemical abnormalities suggesting mildly disturbed vitamin B12 metabolism e.g. decreased B12 vitamin, hypomethioninemia, or slightly increased methylmalonic acid or homocysteine. The clinical case highlight the potential severe deleterious effects of N2O over exposure on B12 vitamin metabolism in particular in patients affected with sickle cell disease. Conversely, when used without excess even repeatedly, there seem to be no overt clinically relevant abnormalities in vitamin B12 metabolism as observed on the cohort of 39 sickle cell disease affected patients.

The article overviews the vicissitudes of the Saussurean notion of the two-sided linguistic sign in 20th-century linguistics. After having held centre stage for several decades in the Praguian and Copenhagian traditions of structuralism, this notion was sidelined if not rejected in the modular architecture of mainstream Generative Grammar, but has since been vindicated in the most influential linguistic schools to emerge in the wake of, and in reaction to, the Chomskyan revolution, viz. Cognitive Grammar and Construction Grammar. While the Saussurean theory of the linguistic sign may be claimed to be of foundational importance for the properly linguistic study of language, it was left for de Saussure’s successors to explore the implications and antinomies of the two-sided sign model. The article discusses a number of problems for the theory of the sign, such as the division between linguistically encoded and contextual meaning, the challenge of polysemy, the fluidity of the conventionalized linguistic sign in the continuous flow of diachronic processes, the Hjelmslevian dichotomy of semantic form and semantic substance, the place of syntax in a theory of the sign, etc.

BackgroundSickle cell disease (SCD) patients with asthma have an increased rate of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) episodes when compared to those without asthma. We hypothesized that either asthma diagnosis or bronchodilator treatment might aggravate SCD via their modulating effect on the autonomic nervous system (ANS).MethodsCross-sectional evaluation of heart rate variability (HRV) during pulmonary function tests, including salbutamol administration, in children with SCD receiving asthma treatment or not when compared to asthmatic children without SCD matched for ethnicity.ResultsSCD children with asthma (n = 30, median age of 12.9 years old) were characterized by a reduced FEV1/FVC ratio, an increased bronchodilator response, and a greater incidence of VOC and ACS when compared to SCD children without asthma (n = 30, 12.7 years). Children with asthma without SCD (n = 29, 11.4 years) were characterized by a higher exhaled NO fraction than SCD children. SCD children when compared to non-SCD children showed reduced HRV [total power, low (LF) and high (HF, vagal tone) frequencies], which was further worsened by salbutamol administration in all the groups: reduction in total power and HF with an increase in LF/HF ratio. After salbutamol, the LF/HF ratio of the SCD children was higher than that of the non-SCD children. The two groups of SCD children were similar, suggesting that asthma diagnosis per se did not modify ANS functions.ConclusionSCD children are characterized by impaired parasympathetic control and sympathetic overactivity that is worsened by salbutamol administration.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT04062409.

PURPOSE:Malnutrition is prevalent in patients on dialysis and is associated with morbidity and mortality. Nutritional status can be assessed by a variety of biochemical and physical parameters or nutritional assessment scores. Most of these methods are expensive or cumbersome to use and are not suitable for routine repetitive follow-up in dialysis patients. The Mini Nutritional Assessment (MNA) has a short form screening set (MNA-SF), which would be suitable as a screening tool, but has not been validated yet in dialysis patients. We aimed to assess whether the MNA is an appropriate tool for identifying nutritional problems in dialysis patients. METHOD:MNA, routine biochemistry, physical parameters, comorbidities were assessed in cross-sectional multicentric cohorts of hemodialysis and peritoneal dialysis patients with a longitudinal follow up of 2 years for mortality. RESULTS:In this cohort of 216 patients, mortality was 27.3% at a follow up of 750±350 days. The mean MNA-SF score was 9.9±1.8, with 30.1%, 59.3% and 10.6% of patients categorized as having normal nutritional status, at risk for malnutrition and malnourished, respectively. The screening score was associated with mortality (HR 0.86, 95% CI 0.75-0.98 per point). With normal nutrition as reference, adjusted mortality was 2.50 (95% CI 1.16-5.37) and 3.89 (95% CI 1.48-10.13) for patients at risk for malnutrition and with malnutrition, respectively. After recalibrating the MNA full score for the specificity of some of its domains for dialysis patients, the MNA-SF had a good sensitivity and specificity for not being well nourished (0.95 and 0.63 respectively) in the full score, and a high negative predictive value (0.91). CONCLUSION:The MNA-SF is independently associated with 2 year mortality in dialysis patients. It has a high negative predictive value for excluding being at risk or having malnutrition in the full score. Therefore, it can be advocated as a screening tool for nutritional status in dialysis patients.

BackgroundPhysical impairments are common in uraemia, as reflected by the high risk of falls of haemodialysis (HD) patients. Furthermore, these patients often suffer from malnutrition.ObjectiveUp to now, it is unknown which aspects of physical performance are predominantly driven by malnutrition in HD patients. As this answer could steer different interventions, the aim of this study was to evaluate the cross-sectional relationship between nutritional status, muscle strength, exercise capacity and the risk of falls.MethodsThis study recruited HD patients between December 2016 and March 2018 from two hospital-based and five satellite dialysis units (registration number on clinicaltrial.gov: NCT03910426). The mini-nutritional assessment scale as well as objective measures of protein-energy wasting were obtained (total iron-binding capacity, total protein levels, and CRP). Physical assessment included muscle strength (quadriceps, handgrip force, and sit-to-stand test), exercise capacity (six-minute walking test) and the risk of falls (Tinetti, FICSIT, and dialysis fall index). Their interrelationship was analysed by ridge regression models.ResultsOut of 113 HD patients (mean age 67 years ± 16.1, 57.5% male) 36.3% were malnourished according to the mini-nutritional assessment scale and a majority had impaired quadriceps force (86.7%), six-minute walking test (92%), and an increased risk of falls (73.5%). Total protein and CRP levels were identified as relevant nutritional factors in the association with physical performance. Nutritional parameters explained 9.2% of the variance in the risk of falls and 7.6% of the variance in exercise capacity. No conclusive association was found between nutritional status and muscle strength.ConclusionProtein-energy wasting is a determinant of the risk of falls and exercise capacity in patients on HD. The association between malnutrition and muscle weakness remains inconclusive.

BackgroundNumerous studies have shown that specific components of breast milk, considered separately, are associated with disease status in the mother or the child using univariate analyses. However, very few studies have considered multivariate analysis approaches to evaluate the relationship between multiple breast milk components simultaneously.AimHere we aimed at visualizing breast milk component complex interactions in the context of the allergy status of the mother or the child.MethodsMilk samples were collected from lactating mothers participating in the Leipziger Forschungszentrum für Zivilisationskrankheiten (LIFE) Child cohort in Leipzig, Germany. A total of 156 breast milk samples, collected at 3 months after birth from mother/infant pairs, were analyzed for 51 breast milk components. Correlation, principal component analysis (PCA) and graphical discovery analysis were used.ResultCorrelations ranging from 0.40 to 0.96 were observed between breast milk fatty acid and breast milk phospholipids levels and correlations ranging from 0 to 0.76 between specific human milk oligosaccharides (HMO) were observed. No separation of the data based on the risk of allergy in the infants was identified using PCA. When graphical discovery analysis was used, dependencies between maternal plasma immunoglobulin E (IgE) level and the breast milk immune marker transforming growth factor-beta 2 (TGF-ß2), between TGF-ß2, breast milk immunoglobulin A (IgA) and TGF-ß1 as well as between breast milk total protein and birth weight were observed. Graphical discovery analysis also exemplifies a possible competition for the fucosyl group between 2'FL, LNFP-I and 3'FL in the HMO group. Additionally, dependencies between immune component IgA and specific HMO (6'SL and blood group A antigen tetraose type 5 or PI-HMO) were identified.ConclusionGraphical discovery analysis applied to complex matrices such as breast milk composition can aid in understanding the complexity of interactions between breast milk components and possible relations to health parameters in the mother or the infant. This approach can lead to novel discoveries in the context of health and diseases such as allergy. Our study thus represents the first attempt to visualize the complexity and the inter-dependency of breast milk components.