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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.

Under Uganda’s decentralised system, rural water service delivery remains to some extent problematic. Several studies attribute the possible causes of deficiencies in the water sector to governance issues. This article applies social network analysis to map upward and downward water-related information flows between the actors of local government from village to district level. Comparing the actual information-sharing network with what’s on paper reveals a less reciprocal and more centralised network than that theoretically envisaged. Some actors, such as the district water officer, are more central than expected in terms of sending and receiving information, while others seem to underperform. Our findings show, however, that it is not the political–administrative information exchange which is the biggest obstacle, but rather information flows between higher (district and sub-county) and lower (parish and village) levels of the local governance structure. Adding water users to the analysis reveals the village chairperson as the most crucial broker of information upward to duty bearers at district level. The limited role of water user committees also becomes apparent. The authors conclude that information communication technology holds potential to overcome some of the bottlenecks (eg distance) hindering the flow of water-related information between actors at different levels.

Background: Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking.Objectives: We sought to investigate the mRNA expression profile overlap between EoE, AA, and AD and to identify the involvement of interleukin 13 (IL-13) in modulating gene expression.Methods: Whole-genome mRNA expression analyses were performed on tissue specimens (biopsies or nasal brushes) from patients with EoE, AD, and AA, and IL-13-stimulated primary human epithelial cells from the esophagus, the skin, and the airways.Results: By human disease expression profiles, EoE evidenced a significantly higher overlap (p = 0.0006) with AD (181 transcripts; 10%) than with AA (124 transcripts, 7%). Only 18 genes were found to be commonly dysregulated among the three diseases; these included filaggrin, histamine receptor H1, claudin 1, cathepsin C, plasminogen activator urokinase receptor, and suppressor of cytokine signaling 3. Ontogenetic analysis revealed a common immune/inflammatory response among the three diseases and a different epithelial response (epidermal cell differentiation) between EoE and AA. The overlap between the IL-13–stimulated epithelial cell transcriptome and the respective disease transcriptome was 22, 9, and 5% in EoE, AD, and AA, respectively, indicating a greater involvement of the IL-13 pathway in EoE than AA (p = 0.0007) or AD (p = 0.02).Conclusion: EoE, AD, and AA share a common set of disease-specific transcripts, highlighting common molecular etiology. Their comparative analysis indicates relatively closer relationships between EoE and AD, particularly centered around IL-13–driven pathways. Therefore, these findings provide an increased rationale for shared therapeutic strategies.

Mesodermal iPSC-derived progenitors (MiPs) can regenerate both skeletal and cardiac muscle. Here, the authors show that a microRNA cocktail stimulates skeletal muscle differentiation and that human MiPs can engraft into striated muscle in mice.

This article reports on a study of the effect of matrilineality on a community's social fabric in the Morogoro region of Tanzania. We used water information-sharing networks as a proxy for social interaction, with water accessibility, functionality, and quality being highly problematic in the area under study. This is a situation that particularly affects women, who are generally responsible for household water provision yet are excluded from water management institutions. Drawing on network and survey data and focus group discussions, the differences in inter-gender interaction, inclusiveness, and women's status were explored by comparing a matrilineal and mixed patri-matrilineal community. We found less gender homophily and exclusion of women divorcees in water-related information networks in the matrilineal community. In both villages, chairmen received and shared most water information while women acted as informal information hubs. While there was no clear difference in women's participation in local water decision-making bodies between the two communities, intrahousehold decision-making data showed that women in the matrilineal community made more decisions on their own regarding water investment. [ABSTRACT FROM AUTHOR]

Specific partially hydrolysed whey-based infant formulas (pHF-W) have been shown to decrease the risk of atopic dermatitis (AD) in infants. Historically, AD has been associated primarily with milk allergy; however, defective skin barrier function can be a primary cause of AD. We aimed to ascertain whether oral supplementation with pHF-W can improve skin barrier function. The effect of pHF-W was assessed on transepidermal water loss (TEWL) and antibody productions in mice epicutaneously exposed to Aspergillus fumigatus. Human primary keratinocytes were stimulated in vitro, and the expression of genes related to skin barrier function was measured. Supplementation with pHF-W in neonatal mice led to a significant decrease in TEWL and total IgE, but not in allergen-specific antibody levels. The whey hydrolysate was sufficient to decrease both TEWL and total IgE. Aquaporin-3 gene expression, linked with skin hydration, was modulated in the skin of mice and human primary keratinocytes following protein hydrolysate exposure. Skin barrier improvement may be an additional mechanism by which pHF-W may potentially reduce the risk of AD development in infants. Further human studies are warranted to confirm the clinical efficacy of these observations.

BACKGROUND:Clinical trials are most informative for evidence-based decision-making when they consistently measure and report outcomes of relevance to stakeholders, especially patients, clinicians, and policy makers. However, sometimes terminology used is interpreted differently by different stakeholders, which might lead to confusion during shared decision making. The construct dialysis adequacy is frequently used, suggesting it is an important outcome both for health care professionals as for patients. OBJECTIVE:To assess the scope and consistency of the construct dialysis adequacy as reported in randomised controlled trials in hemodialysis, and evaluate whether these align to the insights and understanding of this construct by patients. METHODS:To assess scope and consistency of dialysis adequacy by professionals, we performed a systematic review searching the Cochrane Central Register of Controlled Trials (CENTRAL) up to July 2017. We identified all randomised controlled trails (RCT) including patients on hemodialysis and reporting dialysis adequacy, adequacy or adequacy of dialysis and extracted and classified all reported outcomes. To explore interpretation and meaning of the construct of adequacy by patients, we conducted 11 semi-structured interviews with HD patients using thematic analysis. Belgian registration number B670201731001. FINDINGS:From the 31 included trials, we extracted and classified 98 outcome measures defined by the authors as adequacy of dialysis, of which 94 (95%) were biochemical, 3 (3%) non-biochemical surrogate and 2 (2%) patient-relevant. The three most commonly reported measures were all biochemical. None of the studies defined adequacy of dialysis as a patient relevant outcome such as survival or quality of life. Patients had a substantially different understanding of the construct dialysis adequacy than the biochemical interpretation reported in the literature. Being alive, time spent while being on dialysis, fatigue and friendliness of staff were the most prominent themes that patients linked to the construct of dialysis adequacy. CONCLUSION:Adequacy of dialysis as reported in the literature refers to biochemical outcome measures, most of which are not related with patient relevant outcomes. For patients, adequate dialysis is a dialysis that enables them to spend as much quality time in their life as possible.

Markers in monocytes, precursors of macrophages, which are related to CAD, are largely unknown. Therefore, we aimed to identify genes in monocytes predictive of a new ischemic event in patients with CAD and/or discriminate between stable CAD and acute coronary syndrome. We included 66 patients with stable CAD, of which 24 developed a new ischemic event, and 19 patients with ACS. Circulating CD14+ monocytes were isolated with magnetic beads. RNA sequencing analysis in monocytes of patients with (n = 13) versus without (n = 11) ischemic event at follow-up and in patients with ACS (n = 12) was validated with qPCR (n = 85). MT-COI, STRN and COX10 predicted new ischemic events in CAD patients (power for separation at 1% error rate of 0.97, 0.90 and 0.77 respectively). Low MT-COI and high STRN were also related to shorter time between blood sampling and event. COX10 and ZNF484 together with MT-COI, STRN and WNK1 separated ACS completely from stable CAD patients. RNA expressions in monocytes of MT-COI, COX10, STRN, WNK1 and ZNF484 were independent of cholesterol lowering and antiplatelet treatment. They were independent of troponin T, a marker of myocardial injury. But, COX10 and ZNF484 in human plaques correlated to plaque markers of M1 macrophage polarization, reflecting vascular injury. Expression of MT-COI, COX10, STRN and WNK1, but not that of ZNF484, PBMCs paired with that in monocytes. The prospective study of relation of MT-COI, COX10, STRN, WNK1 and ZNF484 with unstable CAD is warranted.

The majority of hospitalizations of patients with sickle cell disease (SCD) are related to painful vaso-occlusive crises (VOCs). Although the pain of VOC is classically nociceptive, neuropathic pain (NP) has also been demonstrated in SCD patients. The aim of our study is to specify the prevalence of NP during VOCs in SCD children using a dedicated scale and to measure its characteristics. We performed a prospective study that included SCD children hospitalized for an acute VOC. The presence of NP was sought with the DN4 scale on the second and fourth days of hospitalization. A total of 54 SCD children were included in the study. Overall, 41% of the patients (n = 22) experienced neuropathic pain during the VOC, mostly at an early stage (Day 2). The median age, the sex ratio, the location of the pain, and the morphine consumption were similar for patients with and without NP. Our study shows that neuropathic pain is very common during VOCs in SCD children. The absence of identified risk factors should prompt us to be vigilant regardless of the patient’s age, sex, and clinical presentation.

Muscular dystrophies are a heterogeneous group of myopathies, characterized by muscle weakness and degeneration, without curative treatment. Mesoangioblasts (MABs) have been proposed as a potential regenerative therapy. To improve our understanding of the in vivo behavior of MABs and the effect of different immunosuppressive therapies, like cyclosporine A or co-stimulation-adhesion blockade therapy, on cell survival noninvasive cell monitoring is required. Therefore, cells were transduced with a lentiviral vector encoding firefly luciferase (Fluc) and the human sodium iodide transporter (hNIS) to allow cell monitoring via bioluminescence imaging (BLI) and small-animal positron emission tomography (PET). Non-H2 matched mMABs were injected in the femoral artery of dystrophic mice and were clearly visible via small-animal PET and BLI. Based on noninvasive imaging data, we were able to show that co-stim was clearly superior to CsA in reducing cell rejection and this was mediated via a reduction in cytotoxic T cells and upregulation of regulatory T cells.

Deformable objects such as ropes, wires, and clothing are omnipresent in society and industry but are little researched in robotics research. This is due to the infinite amount of possible state configurations caused by the deformations of the deformable object. Engineered approaches try to cope with this by implementing highly complex operations in order to estimate the state of the deformable object. This complexity can be circumvented by utilizing learning-based approaches, such as reinforcement learning, which can deal with the intrinsic high-dimensional state space of deformable objects. However, the reward function in reinforcement learning needs to measure the state configuration of the highly deformable object. Vision-based reward functions are difficult to implement, given the high dimensionality of the state and complex dynamic behavior. In this work, we propose the consideration of concepts beyond vision and incorporate other modalities which can be extracted from deformable objects. By integrating tactile sensor cells into a textile piece, proprioceptive capabilities are gained that are valuable as they provide a reward function to a reinforcement learning agent. We demonstrate on a low-cost dual robotic arm setup that a physical agent can learn on a single CPU core to fold a rectangular patch of textile in the real world based on a learned reward function from tactile information.

Impaired physical performance is common in patients on hemodialysis (HD) and is associated with poor prognosis. A patient relevant marker of adequacy of dialysis is lacking. Previous studies evaluated uremic toxicity by assessing the impact of different uremic toxins separately. However, such an approach is most likely not reflective of true uremic toxicity. Therefore, this cross-sectional study aimed to examine if the uremic syndrome, estimated as one composite of different uremic toxins (facilitated by ridge regression method) to reflect the kinetic behavior during dialysis, is associated with physical performance in patients on HD. Levels of p-cresyl glucuronide and sulfate, indole-acetic acid, indoxyl sulfate, uric acid, hippuric acid, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid were assessed and associated by ridge regression to muscle strength, functional exercise capacity, and measures of balance and coordination. 75 HD patients were included (mean age 68 years, 57% male). The composite of different uremic toxins (i.e., uremic load) explained 22% of the variance in handgrip strength. Although there was an association between full body muscle strength and the composite uremic load independent of nutritional status, age and gender, the predictive power of composite uremic load for muscle weakness is limited. Single uremic toxins as well as composite uremic load were not associated with exercise capacity, coordination, and balance, indicating that the degree of uremia does not predict physical performance in patients on HD.

Background: Profits in the biopharmaceutical industry have been scrutinized in social debate. However, drawing conclusions based on industry profitability only is inappropriate as such an analysis does not account for risks faced by investors. This study aims to measure risks and returns in the biopharmaceutical industry and investigates whether risk-adjusted return on investment in the biopharmaceutical industry is higher than that in other industries.Methods: To enable appropriate comparison, we identified six benchmark industries with characteristics that match those of the biopharmaceutical industry: automotive manufacturing, commercial aircraft manufacturing, consumer electronics, packaged food manufacturing, telecom, and oil and gas. For those industries, we selected the top 25 companies per industry, covering 35–65% of industry revenues. Data on return measures (i.e., net profit margin, return on equity, total shareholder return) and risk measures (i.e., volatility of total shareholder return, beta) were derived from Bloomberg over the 2004–2016 period. The Sharpe ratio was calculated as a measure of risk-adjusted return on investment and compared between industries.Results: Net profit margins varied between 12.6 and 19.5% in the biopharmaceutical industry, and ranged from 2.6 to 8.4% in the benchmark industries. Return on equity for the biopharmaceutical industry was above the average for the other industries. Total shareholder returns for the biopharmaceutical industry amounted to 11.7%, ranking fifth across the seven industries. The biopharmaceutical industry ranked sixth among the seven industries regarding beta, and sixth in terms of volatility of total shareholder return. The median Sharpe value for the biopharmaceutical industry ranked fifth of seven industries.Conclusion: Over the 2004–2016 period, the biopharmaceutical industry did not attain risk-adjusted return on investment in excess of that in other industries and, thus, did not outperform these industries.

There is growing evidence that infants display preferences for prosocial agents. However, recent studies have reported conflicting results about the impact of appearance on these preferences. The current study investigated the relative influence of behavior and face/race on 6-month-old infants’ evaluation of social agents when these two aspects are in competition. In a short research study featuring animated cartoons where agents interacted in a ball game, we used eye-tracking methodology to assess infants’ preferences (a) for prosocial behavior, (b) for one kind of appearance, represented by race, and (c) when the two aspects were pitted against one another. The two control conditions revealed preferences for prosocial agents and for other-race appearance. No preference could be found at group level in the third condition, where these two aspects competed with each other. However, a profile analysis revealed that when this situation was a source of conflict in terms of the preferences identified in the control conditions, infants prioritized appearance over behavior.

Cytochrome oxidase IV complex regulates energy production in mitochondria. Therefore, we determined the relation of COX genes with atherosclerosis in mice and pigs.First, we compared atherosclerosis in the aortic arch of age-matched (24 weeks) C57BL/6J control (n = 10), LDL-receptor deficient (n = 8), leptin-deficient ob/ob (n = 10), and double knock-out (lacking LDL-receptor and leptin) mice (n = 12). Low aortic mitochondria-encoded cytochrome oxidase 1 in obese diabetic double knock-out mice was associated with a larger plaque area and higher propensity of M1 macrophages and oxidized LDL. Caloric restriction increased mitochondria-encoded cytochrome oxidase 1 and reduced plaque area and oxidized LDL. This was associated with a reduction of titer of anti-oxidized LDL antibodies, a proxy of systemic oxidative stress. Low of mitochondria-encoded cytochrome oxidase 1 was related to low expression of peroxisome proliferative activated receptors α, δ, and γ and of peroxisome proliferative activated receptor, gamma, co-activator 1 alpha reflecting mitochondrial dysfunction. Caloric restriction increased them. To investigate if there was a diabetic/obesity requirement for mitochondria-encoded cytochrome oxidase 1 to be down-regulated, we then studied atherosclerosis in LAD of hypercholesterolemic pigs (n = 37). Pigs at the end of the study were divided in three groups based on increasing LAD plaque complexity according to Stary (Stary I: n = 12; Stary II: n = 13; Stary III: n = 12). Low mitochondria-encoded cytochrome oxidase 1 in isolated plaque macrophages was associated with more complex coronary plaques and oxidized LDL. Nucleus-encoded cytochrome oxidase 4I1 and cytochrome oxidase 10 did not correlate with plaque complexity and oxidative stress. In mice and pigs, MT-COI was inversely related to insulin resistance.Low MT-COI is related to mitochondrial dysfunction, oxidative stress and atherosclerosis and plaque complexity.

From the epidemiologic studies, to the first genome wide association study in 2010, the understanding of the molecular pathogenesis of EoE has been both inspiring and puzzling. Epidemiologic studies have highlighted the contribution of the genetic in the EoE disease by emphasizing the presence of familial type of EoE, but has also revealed the complexity of its transmission that does not follow a Mendelian inheritance. The molecular pathogenesis advances have helped in the understanding of the mechanisms underlying this esophageal inflammation but has also allow the identification of candidate genes for which single nucleotide polymorphisms (SNP) are associated with the disease. Recently, the genome wide analysis of more than half a million single nucleotide polymorphism has allowed the identification of gene variations associated with the EoE disease and has led to substantial advance in the understanding of the molecular mechanisms leading to EoE. Undeniably, EoE is a complex polygenic disease and we certainly are only at the ground level of its detailed comprehension.

The main objective of this Campbell systematic review was to provide a systematic review of the evidence on the effects of microcredit on women's control over household spending in developing countries. More specifically, we aimed to answer two related research questions: 1) what does the impact evaluative evidence say about the causal relationship between microcredit and specific dimensions of women's empowerment (women's control over household spending); and 2) what are the mechanisms which mediate this relationship. We prioritise depth of analysis over breadth, thus the scope of this review is narrower than previous systematic reviews on microfinance (Stewart et al., 2010; Duvendack et al. 2011; Stewart et al., 2012). We focused on specific aspects of women's empowerment which allowed us to combine statistical meta‐analysis and realist (context‐mechanism‐outcome) synthesis. From the different searches we identified an initial number of 310 papers that were selected for full text examination. Eventually, 29 papers were retained for further analysis, corresponding to 25 unique studies. In line with three recent other reviews on microfinance (Stewart et al., 2010; Duvendack et al., 2011; Stewart et al. 2012) we found that the microcredit evidence base is extensive, yet most studies are weak methodologically. From those studies deemed comparable and of minimum acceptable quality, we concluded that overall there is no evidence for an effect of microcredit on women's control over household spending. Executive summary BACKGROUND Over the past three decades, microfinance activities have spread across the globe, reaching tens of millions of poor households with tailored financial services. Microfinance can best be described as a field of intervention rather than a particular instrument. Initially, microfinance usually meant microcredit for working capital and very small investments, but increasingly it has been broadened to include savings/deposits, a limited range of micro‐insurance and payment services (including micro‐leasing) as well as a somewhat broader range of credit products for more substantial investments. In this study we focused on microcredit activities, constituting the bulk of microfinance activities across the globe. Microcredit activities have affected the lives of clients and others in multiple ways. The most frequently reported types of effects of credit at individual, enterprise and household level are the following: income, expenditure smoothing, and poverty alleviation effects; business growth and employment effects; schooling effects; and effects in terms of women's empowerment. Despite the diversity in microcredit schemes, many share two characteristics: they target poor women and often rely on some type of group‐based lending. Women's empowerment in relation to microcredit has been studied extensively within the context of this type of microcredit scheme. Most of these studies have been carried out in the context of microcredit group schemes in South Asia. It has been argued that access to microcredit can foster changes in individual attitudes of women (e.g. increased self‐reliance), power relations within the household (e.g. control over resources) and social status. An important dimension of empowerment concerns women's control over household spending. The main assumption is that by providing credit to poor women, their direct control over expenditures within the household increases, with subsequent implications for the status of women and the well‐being of women and other household members. Women's control over household spending is a frequently recurring aspect analyzed within the context of microcredit interventions, which allows us to study whether microcredit targeted at women affects women's control over household spending decisions and the circumstances in which this occurs. Despite the central and recurrent role across studies of this aspect of women's empowerment in relation to microcredit activities, there has been no previous review on this topic. The growing importance of microcredit has resulted in a vast number of research and evaluation studies, including impact studies. Consequently, the microfinance literature harbors a substantial number of synthesis studies which discuss a set of microcredit interventions and aim to generate overall conclusions on their effects. However, most of these studies face limitations in terms of depth of empirical assessment and the extent to which the identified effects can be attributed to microcredit. Moreover, methodological principles regarding comprehensive searches and principles of selection, coding, extraction and aggregation are often lacking in review studies. Partial exceptions are three recent systematic reviews which all differ in scope from the present one (Stewart et al., 2010; Duvendack et al. 2011; Stewart et al., 2012). The reviews respectively focus on microfinance (credit and savings) in Sub‐Sahara Africa, microcredit worldwide, and microfinance worldwide (credit, saving and leasing). Overall, these reviews suggest that the effects of microcredit on women's empowerment are at best mixed. In part this can be explained by the heterogeneity in microcredit interventions, contexts and target groups. However, the existing reviews did not use statistical meta‐analysis to synthesise evidence of effects, nor context‐mechanism‐outcome synthesis to understand the variation in effects. OBJECTIVES The main objective of this study was to provide a systematic review of the evidence on the effects of microcredit on women's control over household spending in developing countries. More specifically, we aimed to answer two related research questions: 1) what does the impact evaluative evidence say about the causal relationship between microcredit and specific dimensions of women's empowerment (women's control over household spending); and 2) what are the mechanisms which mediate this relationship. We prioritise depth of analysis over breadth, thus the scope of this review is narrower than previous systematic reviews on microfinance (Stewart et al., 2010; Duvendack et al. 2011; Stewart et al., 2012). We focused on specific aspects of women's empowerment which allowed us to combine statistical meta‐analysis and realist (context‐mechanism‐outcome) synthesis. CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW We included studies that analyzed the effects of microcredit schemes targeting poor women in low and middle income countries, as defined by the World Bank. Studies that did not include analysis on microcredit and the effect on one or more dimensions (specified in main body of the report) of women's control over household expenditures were excluded. Studies which gave evidence of addressing the attribution problem either through randomised design, quasi‐experimental matching, or regression analysis, were included. In practice, women's control over household spending (as a key dimension of empowerment) is influenced by many different factors. By focusing on those studies which explicitly addressed the challenge of separating the effect of microcredit from other influencing factors, we developed what we consider to be the most credible evidence base for drawing conclusions about the effects of microcredit on women's control over household expenditures in different contexts. SEARCH STRATEGY We conducted a comprehensive search covering all relevant academic databases, internet search engines and web sites with published and unpublished research, and also carried out extensive manual searches of books and additional journals not included in electronic data bases (searches were concluded on December 31, 2011). We used back‐referencing from recent studies as well as citation‐tracking to identify additional relevant studies. Finally, authors of studies which we were unable to retrieve were contacted. In addition, we contacted experts on microcredit and women's empowerment for additional references which we might have missed. Search strategies in databases and journals were adapted for each source. Where possible we used the existing keyword indices of particular databases. In addition, we applied our own list of combinations of keywords covering all relevant terms relating to the independent variable (i.e. credit and its variations) and the dependent variable (i.e. dimensions of women's control over household spending, empowerment). DATA COLLECTION AND ANALYSIS From the different searches we identified an initial number of 310 papers that were selected for full text examination. Eventually, 29 papers were retained for further analysis, corresponding to 25 unique studies. These 25 independent findings were included in the synthesis. However, based on a systematic risk of bias assessment we found that more than half of the included studies had high threats to internal validity. Moreover, only about half of the studies show a clear and coherent link between a theoretical framework on microcredit and women's control over household spending and empirical data analysis. It should be noted that reviewing and synthesizing quantitative results from studies is only one side of the coin. The other side is to understand what makes them work, or what prevents them from working. Consequently, we conducted a qualitative synthesis of the included studies, which focused on identifying the mechanisms which underlie the causal relationship between microcredit and women's control over household spending. RESULTS The results of the meta‐analysis indicated that the effect sizes from experimental studies examining effects of microcredit on women's control over household spending are not statistically significantly different from zero. The effects from quasi‐experimental studies are statistically insignificant overall, and at best of small magnitude for those studies assessed of being of high risk of bias. We conclude that there is no consistent evidence for an effect of microcredit on women's control over household spending. In the qualitative analysis, using Coleman's (1986, 1990) typology of mechanisms, we identified five different situational mechanisms and eight different action‐formation mechanisms. Due to the combination of substantial heterogeneity in contexts (e.g. existing gender relations) and interventions (e.g. microcredit versus microcredit and additional services), and the lack of information in the studies on this heterogeneity, it was not possible to go beyond the identification of mechanisms, in terms of generating empirically tested articulated theories of change which are representative beyond a specific study context. AUTHORS' CONCLUSIONS In line with three recent other reviews on microfinance (Stewart et al., 2010; Duvendack et al., 2011; Stewart et al. 2012) we found that the microcredit evidence base is extensive, yet most studies are weak methodologically. From those studies deemed comparable and of minimum acceptable quality, we concluded that overall there is no evidence for an effect of microcredit on women's control over household spending. Women's control over household resources constitutes an important intermediary dimension in processes of women's empowerment. Given the overall lack of evidence for an effect of microcredit on women's control over household resources it is therefore very unlikely that, overall, microcredit has a meaningful and substantial impact on empowerment processes in a broader sense. While impacts on empowerment may appear to have occurred in particular studies, the high risk of bias of studies providing positive assessments suggests that such findings are of limited validity. Our conclusions on the effects of microcredit on empowerment are also in line with previous systematic reviews by Duvendack et al. (2011) and Stewart (et al. 2010) who report to a limited extent on empowerment effects. Consequently, there appears to be a gap between the often optimistic societal belief in the capacity of microcredit to ameliorate the position of women in decision‐making processes within the household on the one hand, and the empirical evidence base on the other hand. However, our review markedly differs from previous reviews in two regards. First, we specifically focused on microcredit and women's empowerment captured through women's control over household expenditures. Second, as a result of this narrower focus, we were able to conduct statistical meta‐analysis and extract behavioral mechanisms which can help to explain why and how microcredit can make a difference. The advantage of our approach was that the identified mechanisms all stem from studies which show evidence of addressing the attribution problem. Consequently, we can be quite confident of the insights that they provided on the effects of microcredit on women's control over household spending for particular populations of microcredit female clients and their families. Those studies that showed evidence of addressing the attribution problem were relatively weak on underlying theory. Moreover, they often lacked essential information such as the nature of the intervention and how it related to empowerment (e.g. how solidarity groups affect empowerment processes) or the slowly evolving gender relations in different contexts (e.g. the evolution of societal norms and the relationship with power relations in the household). A next logical step would be to undertake a systematic review of qualitative studies which often provide rich and context‐specific information on microcredit and women's decision‐making power in the household. Such a review should ideally build on the mechanisms identified in the present review and would bring us closer to uncovering credible theories of microcredit and the circumstances in which it may change women's decision‐making power.

BackgroundCytochrome oxidase (COX) IV complex regulates energy production in mitochondria. Impaired COX gene expression is related to obesity and type 2 diabetes mellitus, but whether it is directly related to the incidence of cardiovascular events is unknown. We investigated whether COX gene expression in monocytes is predictive for cardiovascular events in coronary artery disease patients. To avoid monocyte isolation from fresh blood, we then aimed to validate our findings in monocyte‐derived microvesicles isolated from plasma. Methods and ResultsWe enrolled 142 consecutive patients undergoing diagnostic coronary angiography between June 2010 and January 2011 and followed 67 patients with stable coronary artery disease prospectively for at least 3 years. Twenty‐two patients experienced a new cardiovascular event (32.8%). Circulating CD14+ monocytes and microvesicles were isolated with magnetic beads, and COX mRNA levels were measured with quantitative polymerase chain reaction, after normalization with 5 validated house‐keeping genes. Patients in the lowest tertile of mitochondrial cytochrome oxidase, subunit I (MT‐COI) in monocytes at baseline had a higher risk for developing a new event after adjusting for age, sex, (ex)smoking, body mass index, blood pressure, diabetes mellitus, low‐density lipoprotein– and high‐density lipoprotein–cholesterol, triglycerides, high‐sensitivity C‐reactive protein, interleukin‐6, and number of diseased vessels (harzard ratio [HR], 3.95; 95% CI, 1.63–9.57). Patients in the lowest tertile of MT‐COI in monocyte‐specific microvesicles had also a higher risk of developing a new event (adjusted HR, 5.00; 95% CI, 1.77–14). ConclusionsIn the current blinded study, low MT‐COI in monocytes of coronary artery disease patients identifies a population at risk for new cardiovascular events. For the first time, we show that signatures in monocyte‐specific microvesicles in plasma have similar predictive properties.

Food allergies have become a major healthcare concern, hence preventive efforts to ensure oral tolerance induction to newly introduced antigens are particularly relevant. Given that transforming growth factor-β (TGF-β) plays a key role in immune tolerance, we tested whether an infant formula enriched with TGF-β would improve oral tolerance induction. A partially hydrolyzed whey protein-based formula was enriched with cow’s-milk-derived TGF-β (TGF-β-enriched formula) by adding a specific whey protein isolate (WPI). The manufacturing process was optimized to achieve a concentration of TGF-β within the range of human breast milk concentrations. Protection from allergic sensitization and immune response was assessed in a mouse model. Adult mice received the TGF-β-enriched formula, a control non-enriched formula, or water ad libitum for 13 days before sensitization and suboptimal tolerization to ovalbumin (OVA). When compared to non-tolerized mice, suboptimally-tolerized mice supplemented with the TGF-β-enriched formula showed significantly lower levels of total immunoglobulin-E (IgE) and OVA-specific (IgG1). Mouse mast-cell protease-1 (mMCP-1) and cytokine levels were also significantly decreased in suboptimally-tolerized mice fed the TGF-β-enriched formula. In conclusion, oral supplementation with cow’s-milk-derived TGF-β decreased allergic responses to newly introduced allergens and thus reduced the risk of developing food allergy.

Protein-bound uremic toxins (PBUTs) play a role in the multisystem disease that children on hemodialysis (HD) are facing, but little is known about their levels and protein binding (%PB). In this study, we evaluated the levels and %PB of six PBUTs cross-sectionally in a large pediatric HD cohort (n = 170) by comparing these with healthy and non-dialysis chronic kidney disease (CKD) stage 4–5 (n = 24) children. In parallel β2-microglobulin (β2M) and uric acid (UA) were evaluated. We then explored the impact of age and residual kidney function on uremic toxin levels and %PB using analysis of covariance and Spearman correlation coefficients (rs). We found higher levels of β2M, p-cresyl glucuronide (pCG), hippuric acid (HA), indole acetic acid (IAA), and indoxyl sulfate (IxS) in the HD compared to the CKD4–5 group. In the HD group, a positive correlation between age and pCG, HA, IxS, and pCS levels was shown. Residual urine volume was negatively correlated with levels of β2M, pCG, HA, IAA, IxS, and CMPF (rs −0.2 to −0.5). In addition, we found overall lower %PB of PBUTs in HD versus the CKD4–5 group, and showed an age-dependent increase in %PB of IAA, IxS, and pCS. Furhtermore, residual kidney function was overall positively correlated with %PB of PBUTs. In conclusion, residual kidney function and age contribute to PBUT levels and %PB in the pediatric HD population.

Background: Over the years, Communities of Practice have gained popularity as a capacity-building method among Monitoring and Evaluation practitioners. Yet, thus far, relatively little is known about their effectiveness. Objectives: This article focuses on National Evaluation Societies as Communities of Practice that aim to contribute to the monitoring and evaluation capacity building of their members. Method: Drawing upon a survey of 35 National Evaluation Societies in 33 low- and middle-income countries, we explore to what extent capacity building efforts have been successful and what factors explain the relative success or failure in capacity building. We rely upon Qualitative Comparative Analysis as we are particularly interested in different pathways to ensure successful National Evaluation Societies. Results: Our findings highlight that regular face-to-face contact is a particularly important element. This does not entirely come as a surprise, as monitoring and evaluation capacity building often implies tacit knowledge that is most effectively shared face-to-face. Furthermore, capacity building in conducting and, particularly, using evaluations entails building networks among the monitoring and evaluation supply and demand side which can most easily be done through regular face-to-face interaction. Conclusion: Our findings are not only theoretically interesting, they are also policy relevant; they hint at the fact that in an era of quick advances in technology, investing in face-to-face contact among members remains important.

Numerous neurodegenerative and neuromuscular disorders are associated with cell-specific depletion in the human body. This imbalance in tissue homeostasis is in healthy individuals repaired by the presence of endogenous stem cells that can replace the lost cell type. However, in most disorders, a genetic origin or limited presence or exhaustion of stem cells impairs correct cell replacement. During the last 30 years, methods to readily isolate and expand stem cells have been developed and this resulted in a major change in the regenerative medicine field as it generates sufficient amount of cells for human transplantation applications. Furthermore, stem cells have been shown to release cytokines with beneficial effects for several diseases. At present however, clinical stem cell transplantations studies are struggling to demonstrate clinical efficacy despite promising preclinical results. Therefore, to allow stem cell therapy to achieve its full potential, more insight in their in vivo behavior has to be achieved. Different methods to noninvasively monitor these cells have been developed and are discussed. In some cases, stem cell monitoring even reached the clinical setting. We anticipate that by further exploring these imaging possibilities and unraveling their in vivo behavior further improvement in stem cell transplantations will be achieved.

PAR MODĀLĀS PARTIKULAS lai FUNKCIJĀM UN GRAMATISKO STATUSUKopsavilkumsLatviešu valodas gramatikās partikula lai parasti tiek minēta tikai kā analītisko imperatīva formu sastāvdaļa (lai nāk, lai neaizmirstam). Šai rakstā tiek aplūkoti trīs partikulas lai lietošanas tipi: (1) teikumos ar pamudinājuma vai vēlējuma nozīmi (Lai viņi nāk), (2) deontiskajos jautājumos (Ko lai es daru! Ko lai es būtu darījis!), un (3) teikumos ar vērtējuma (neaprobēšanas vai šaubu) nozīmi (Viņš lai būtu palīdzējis slepkavām?). Autors cenšas parādīt, ka pirmā (dažreiz arī otrā) tipa teikumos partikulai lai piemīt teikuma partikulas īpašības, kamēr otrā un trešā tipa teikumos iezīmējas tendence šai partikulai veidot ar verbu ciešāku sakopojumu, kas gan nelīdzinās analītisko verbu formu statusam, bet zināmā mērā atgādina savienojumus ar modālajiem verbiem. ‘Formveidojošas partikulas’ statusa, ko partikulai lai piedēvē gramatikās, šim vārdam nav nekur.