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The very first days of mammalian embryonic development are accompanied by epigenetic reprogramming and extensive changes in nuclear organization. In particular, genomic regions located at the periphery of the nucleus, termed lamina-associated domains (LADs), undergo major rearrangements after fertilization. However, the role of LADs in regulating gene expression as well as the interplay with various chromatin marks during preimplantation development remains elusive. In this study, we obtained single-cell LAD profiles coupled with the corresponding gene expression readout throughout the first days of mouse development. We detect extensive cell-cell LAD variability at the 2-cell stage, which surprisingly does not seem to functionally affect gene expression. This suggests an unusual uncoupling between 3D-nuclear genome organization and gene expression during totipotent developmental stages. By analyzing LAD dynamics and chromatin states across early developmental stages in an allelic-specific manner, we identify genomic regions that transiently detach from the nuclear lamina and are enriched by non-canonical H3K27me3. Upon maternal knock-out of a component of the Polycomb repressive complex 2 and concomitant loss of H3K27me3 during early embryogenesis, these regions relocate to the lamina at the 2-cell stage. Our results suggest that H3K27me3 is the prime determinant in establishing the atypical distribution of the genome at the nuclear periphery during the first days of embryonic development. This study provides insight into the molecular mechanisms regulating nuclear organization of parental genomes during very early mammalian development.

Gene expression programs result from the collective activity of many regulatory factors. To obtain insight into the mechanisms that govern gene regulation, it is imperative to study their combined mode of action and interconnectivity. However, it has been challenging to simultaneously measure a combination of these factors within one sample. Here, we introduce MAbID, a method that combines genomic profiling of many histone modifications and chromatin-binding proteins in a single reaction. MAbID employs antibody-DNA conjugates to enable genomic barcoding of chromatin at sites of epitope occupancy. This barcoding strategy allows for the combined incubation of multiple antibodies in a single sample to reveal the genomic distributions of many epigenetic states simultaneously. We used MAbID to profile both active and inactive chromatin types in human cell lines and multiplexed measurements in the same sample without loss of data quality. Moreover, we obtained joint measurements of six epitopes covering all major chromatin types in single cells during mousein vitroneural differentiation and captured associated changes in multifactorial chromatin states. Thus, MAbID holds the potential to gain unique insights into the interplay between gene regulatory mechanisms, especially in settings with limited sample material and in single cells.

Purpose To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors. Methods Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors. Results The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3–8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1–0.8). Conclusion Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment.

We examined the contributions of kinesthetic and skin stretch cues to static weight perception. In three psychophysical experiments, several aspects of static weight perception were assessed by asking participants either to detect on which hand a weight was presented or to compare between two weight cues. Two closed-loop controlled haptic devices were used to present cutaneous and kinesthetic weights, in isolation and together, with a precision of 0.05 g. Our results show that combining skin stretch and kinesthetic information leads to better weight detection thresholds than presenting uni-sensory cues does. For supra-threshold stimuli, Weber fractions were 22-44%. Kinesthetic information was less reliable for lighter weights, while both sources of information were equally reliable for weights up to 300 g. Weight was perceived as equally heavy regardless of whether skin stretch and kinesthetic cues were presented together or alone. Data for lighter weights complied with an Optimal Integration model, while for heavier weights, measurements were closer to predictions from a Sensory Capture model. The presence of correlated noise might explain this discrepancy, since that would shift predictions from the Optimal Integration model towards our measurements. Our experiments provide device-independent perceptual measures, and can be used to inform, for instance, skin stretch device design.

ObjectiveTo provide an overview of barriers and facilitators that healthcare professionals (HCPs) perceive regarding the implementation of lifestyle interventions (LIs) in patients with hip and/or knee osteoarthritis (OA).DesignScoping review.Data sourcesThe databases PubMed, Embase, CINAHL, PsycINFO and the Cochrane Library were searched from inception up to January 2021.Eligibility criteriaPrimary research articles with a quantitative, qualitative or mixed-methods design were eligible for inclusion if they reported: (1) perceptions of primary and/or secondary HCPs (population); (2) on implementing LIs with physical activity and/or weight management as key components (concept) and (3) on conservative management of hip and/or knee OA (context). Articles not published in English, German or Dutch were excluded.Data extraction and synthesisBarriers and facilitators were extracted by two researchers independently. Subsequently, the extracted factors were linked to a framework based on the Tailored Implementation for Chronic Diseases checklist.ResultsThirty-six articles were included. In total, 809 factors were extracted and subdivided into nine domains. The extracted barriers were mostly related to non-optimal interdisciplinary collaboration, patients’ negative attitude towards LIs, patients’ low health literacy and HCPs’ lack of knowledge and skills around LIs or promoting behavioural change. The extracted facilitators were mostly related to good interdisciplinary collaboration, a positive perception of HCPs’ own role in implementing LIs, the content or structure of LIs and HCPs’ positive attitude towards LIs.ConclusionsMultiple individual and environmental factors influence the implementation of LIs by HCPs in patients with hip and/or knee OA. The resulting overview of barriers and facilitators can guide future research on the implementation of LIs within OA care. To investigate whether factor frequency is related to the relevance of each domain, further research should assess the relative importance of the identified factors involving all relevant disciplines of primary and secondary HCPs.PROSPERO registration numberCRD42019129348.

Background Since the coronavirus pandemic in 2020, there is not much reported about the disease course of COVID-19 in patients with allergic diseases. Objectives The aim of this study was to investigate the cumulative incidence and severity of COVID-19 among patients from the allergy department compared with the general Dutch population and people from their household. Design We conducted a comparative longitudinal cohort study. Methods In this study patients of the allergy department were included with their household members as a control group. Data from the beginning of the pandemic were systematically obtained through questionnaires by telephonic interviews and retrieved from electronic patient files between October 15, 2020 and January 29, 2021. Main outcomes were confirmed SARS-CoV-2 infection, disease duration, hospitalization, intensive care admission, and mortality. Questions regarding applied social distancing measures were inventoried as well. Results Three hundred and eighty nine patients (median age 39.1 (18.7-84.7) years, 69.9% female) and 441 household members (median age 42.0 (18.0-91.5), 44.1% female) were included. The cumulative COVID-19 incidence in patients was higher compared with the general population (10.5% vs 5.6%, P Conclusion The cumulative COVID-19 incidence in patients from the allergy cohort was higher compared with the general Dutch population, but similar compared with household members. There was no difference in symptoms, disease duration, or hospitalization rate between the allergy cohort and their household members.

Background Patients with suspected acute coronary syndrome in whom myocardial infarction has been ruled-out are at risk of future adverse cardiac events. However, the optimal approach to risk stratify and investigate these patients is uncertain. Methods We performed a prospective cohort study of 250 patients presenting to the Emergency Department with suspected acute coronary syndrome and troponin concentrations below the sex-specific 99th centile (16 ng/L for women and 34 ng/L for men). Patients were recruited in a 2:1 fashion stratified by peak high-sensitivity cardiac troponin I concentration above and below the early rule-out threshold of 5 ng/L (167 patients with intermediate troponin concentrations between 5 ng/L and the sex-specific 99th centile threshold and 83 patients with troponin concentrations Results Overall, 37.6% (94/250) of patients had normal coronary arteries whilst 36.0% (90/250) and 26.4% (66/250) had non-obstructive and obstructive coronary artery disease, respectively. Patients with intermediate troponin concentrations were more likely to have coronary artery disease than those with troponin concentrations Conclusions In patients with suspected acute coronary syndrome who have myocardial infarction ruled out, those with intermediate cardiac troponin concentrations are three-times more likely to have coronary artery disease than those with low troponin concentrations. Conversely anginal symptoms did not discriminate between those with and without coronary artery disease. Further studies are required to determine if targeting computed tomography coronary angiography to those with intermediate cardiac troponin concentrations can improve the use of preventative medical therapies and clinical outcomes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The British Heart Foundation Odds ratio of coronary artery diseaseCumulative proportion with CAD

CONTEXT Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants. OBJECTIVE Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality. DATA SOURCES Medline was searched for all articles (up to June 2020). STUDY SELECTION All developed or externally validated prognostic models for mortality prediction in liveborn infants born DATA EXTRACTION Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool. RESULTS One hundred forty-four models from 36 studies reporting on model development and 118 models from 34 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 42% and 94% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83–0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81–0.92) for the Clinical Risk Index for Babies II score, 0.86 (95% CI: 0.78–0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score and 0.71 (95% CI 0.61–0.79) for the NICHD model. LIMITATIONS Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded. CONCLUSIONS Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models.

Transfusion-related acute lung injury (TRALI) is a life-threatening complication of acute respiratory distress occurring within 6 hours of blood transfusion. TRALI is one of the leading causes of transfusion-related fatalities and specific therapies are unavailable. Neutrophils are recognized as the major pathogenic cells, whereas T regulatory cells and dendritic cells appear to be important for protection against TRALI. The pathogenesis, however, is complex and incompletely understood. It is frequently postulated that the complement system plays an important role in the TRALI pathogenesis. In this article, we assess the evidence regarding the involvement of complement in TRALI from both human and animal studies. We hypothesize about the potential connection between the complement system and neutrophils in TRALI. Additionally, we draw parallels between TRALI and other acute pulmonary disorders of acute lung injury and acute respiratory distress syndrome regarding the involvement of complement. We conclude that, even though a role for complement in the TRALI pathogenesis seems plausible, studies investigating the role of complement in TRALI are remarkably limited in number and also present conflicting findings. Different types of TRALI animal models, diverse experimental conditions, and the composition of the gastrointestinal microbiota may perhaps all be factors which contribute to these discrepancies. More systematic studies are warranted to shed light on the contribution of the complement cascade in TRALI. The underlying clinical condition of the patient, which influences the susceptibility to TRALI, as well as the transfusion factor (antibody-mediated vs non–antibody-mediated), will be important to take into consideration when researching the contribution of complement. This should significantly increase our understanding of the role of complement in TRALI and may potentially result in promising new treatment strategies., Highlights • Studies investigating complement and TRALI are limited in number and present conflicting findings. • Systematic investigation is needed to better understand the contribution of the complement cascade in TRALI. • Future studies in this area should consider both the clinical susceptibility of the patient as well as the effect of transfusion factors.

Contains fulltext : 245483.pdf (Publisher’s version ) (Open Access) OBJECTIVE: This study systematically reviewed the association of psychological problems among cancer patients with healthcare and societal resource use and costs. METHODS: PubMed, PsycINFO, and Embase were searched (until 31 January 2021) for studies on psychological symptoms (anxiety, depression, distress, fear of recurrence) or psychiatric disorders (anxiety, depression, adjustment) and healthcare use (e.g., mental, inpatient healthcare), economic losses by patients and family, economic losses in other sectors (e.g., absence from work), and costs. The search, data extraction, and quality assessment were performed by two authors. RESULTS: Of the 4157 identified records, 49 articles were included (psychological symptoms (n = 34), psychiatric disorders (n = 14), both (n = 1)) which focused on healthcare use (n = 36), economic losses by patients and family (n = 5), economic losses in other sectors (n = 8) and/or costs (n = 13). In total, for 12 of the 94 associations strong evidence was found. Psychological symptoms and psychiatric disorders were positively associated with increased healthcare use (mental, primary, inpatient, outpatient healthcare), losses in other sectors (absence from work), and costs (inpatient, outpatient, total healthcare costs). Moderate evidence was found for a positive association between (any) psychiatric disorder and depression disorder with inpatient healthcare and medication use, respectively. CONCLUSIONS: Psychological problems in cancer patients are associated with increased healthcare use, healthcare costs and economic losses. Further research is needed on psychological problems in relation to understudied healthcare use or costs categories, productivity losses, and informal care costs.

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 x 10(-6)), FHR-2 (p = 1.47 x 10(-4)), FHR-3 (p = 1.05 x 10(-5)) and FHR-4A (p = 1.22 x 10(-2)) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 x 10(-17)), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 x 10(-3) and p = 2.81 x 10(-6), respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 x 10(-16)). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.

A one-pot, three-component, Cu(I)-catalyzed coupling of primary hydrazines, 5-chloropentan-2-one, and terminal alkynes was developed. The resulting 1-aza-6,7-dehydrotropanes compose a new class of substances while related 1-azatropanes are scarcely described in literature and closely resemble tropane alkaloids. Hydrogenation of the double bond in 1-aza-6,7-dehydrotropanes triggered a rearrangement, involving a [1,3]-hydride shift, forming cyclic hydrazones.

Calcium carbide was used in a Cu-I-catalysed three-component coupling with omega-chlorinated ketones and primary amines to generate terminal 2-alkynyl-N-heterocycles. The formation of an imine and the subsequent intramolecular substitution results in an active electrophilic iminium species, which can be alkynylated by in situ formed copper acetylide. A number of aliphatic primary (functionalised) amines and aliphatic or aromatic alkynes together with different alkyl- or aryl-substituted gamma- or delta-chloroketones could be used. Simple acid-base workup instead of column chromatography can be applied to obtain the resulting 2-alkynylpyrrolidines and 2-alkynylpiperidines.

To assess the effect of early life nutrition on structural brain development in 2 cohorts of extremely preterm infants, before and after the implementation of a nutrition regimen containing more protein and lipid.We included 178 infants retrospectively (median gestational age, 26.6 weeks; IQR, 25.9-27.3), of whom 99 received the old nutrition regimen (cohort A, 2011-2013) and 79 the new nutrition regimen (cohort B, 2013-2015). Intake of protein, lipids, and calories was calculated for the first 28 postnatal days. Brain magnetic resonance imaging (MRI) was performed at 30 weeks postmenstrual age (IQR, 30.3-31.4) and term-equivalent age (IQR, 40.9-41.4). Volumes of 42 (left + right) brain structures were calculated.Mean protein and caloric intake in cohort B (3.4 g/kg per day [P .001] and 109 kcal/kg per day [P = .038]) was higher than in cohort A (2.7 g/kg per day; 104 kcal/kg per day). At 30 weeks, 22 regions were significantly larger in cohort B compared with cohort A, whereas at term-equivalent age, only the caudate nucleus was significantly larger in cohort B compared with cohort A.An optimized nutrition protocol in the first 28 days of life is associated with temporarily improved early life brain volumes.

Objectives: To identify sociodemographic and clinical factors, health-related quality of life (HRQOL) and head and neck cancer (HNC) symptoms associated with the course of symptoms of anxiety and depression from pretreatment to 24-month follow-up among HNC patients after (chemo)radiation. Materials and methods: Patients (n = 345) completed questionnaires on anxiety and depression (HADS), HRQOL and symptoms (EORTC QLQ-C30/QLQ-H&N35) before treatment, and 6-weeks,3-,6-12-,18-, and 24-months after treatment. Mixed model analyses were used to investigate the course of anxiety and depression from pretreatment to 24-months in relation to factors assessed at baseline, and the course of anxiety and depression from 6- to 24-months, in relation to factors assessed at 6-months. Results: Increased risk for anxiety (HADS-anxiety > 7) was 28.7% among patients before treatment, which declined to 10.0% at 24-months. Increased risk for depression (HADS-depression > 7) was 15.1% before treatment, 18.2% at 3-months, 7.2% at 12-months and 16.0% at 24-months. Factors assessed at baseline which were significantly associated with the course of anxiety were age, pain, problems with social contact, and feeling ill, whereas chemotherapy, worse emotional functioning, speech problems and weight loss were significantly associated with the course of depression. Regarding factors assessed at 6-months, chemotherapy, worse cognitive and social functioning, insomnia, swallowing problems and trouble with social eating were associated with the course of anxiety. Nausea/vomiting, dyspnea, coughing, and feeling ill were associated with the course of depression (p-values < 0.05). Discussion: Factors associated with a worse course of anxiety and depression are younger age, treatment with chemotherapy, worse HRQOL and higher symptom burden.

In this study, we examined the contributions of kinesthetic and skin stretch cues, in isolation and together, to the static perception of weight. In two psychophysical experiments, we asked participants either to detect on which hand a weight was presented or to compare between two weight cues. Two closed-loop controlled haptic devices were used to present weights with a precision of 0.05g to an end-effector held in a pinch grasp. Our results show that combining skin stretch and kinesthetic information leads to better weight detection thresholds than presenting uni-sensory cues does. For supra-threshold stimuli, Weber fractions ranged from 22-44%. Kinesthetic information was less reliable for lighter weights, while both sources of information were equally reliable for weights up to 300g. Our data for lighter weights complied with an Optimal Integration model, while for heavier weights, measurements were closer to predictions from a Sensory Capture model. The difference might be accounted for by the presence of correlated noise across the two cues with heavier weights, which would affect model predictions such that all our data could be explained through an Optimal Integration model. Our experiments provide device-independent measures that can be used to inform, for instance, skin stretch device design.

In this study we investigated the use of simple vibrotactile signals to simulate contact with a virtual object. In particular we explored the relation between properties of the signal and the perceived hardness of the object. The space of stimuli is large, and we have no plausible a priori model for the relationship of parameters to percept. Thus we made use of non-parametric Bayesian methods, in particular utilizing Gaussian process priors. We show that this method both gives insight into the phenomenon of interest and well-predicts a second, separate data set collected via the method of constant stimuli. Thus we argue that it could be a fruitful approach for attacking a variety of perceptual problems.

Mutations in the gene encoding for complement regulator factor H (FH) severely disrupt its normal function to protect human cells from unwanted complement activation, resulting in diseases such as atypical hemolytic uremic syndrome (aHUS). aHUS presents with severe hemolytic anemia, thrombocytopenia, and renal disease, leading to end-stage renal failure. Treatment of severe complement-mediated disease, such as aHUS, by inhibiting the terminal complement pathway, has proven to be successful but at the same time fails to preserve the protective role of complement against pathogens. To improve complement regulation on human cells without interfering with antimicrobial activity, we identified an anti-FH monoclonal antibody (mAb) that induced increased FH-mediated protection of primary human endothelial cells from complement, while preserving the complement-mediated killing of bacteria. Moreover, this FH-activating mAb restored complement regulation in sera from aHUS patients carrying various heterozygous mutations in FH known to impair FH function and dysregulate complement activation. Our data suggest that FH normally circulates in a less active conformation and can become more active, allowing enhanced complement regulation on human cells. Antibody-mediated potentiation of FH may serve as a highly effective approach to inhibit unwanted complement activation on human cells in a wide range of hematological diseases while preserving the protective role of complement against pathogens. ispartof: BLOOD ADVANCES vol:3 issue:4 pages:621-632 ispartof: location:United States status: published

A Cu(I)-catalyzed coupling of a ω-chloro ketone, a primary amine, and an alkyne is described. This protocol allows for the synthesis of α-quaternary carbons in 2-alkynyl-substituted N-heterocycles. The key step is the in situ generation of a cyclic ketiminium species, which has enhanced reactivity for alkynylation compared to acyclic ketiminium species.

Recent research has elucidated circulating levels of almost all factor H-related (FHR) proteins. Some of these proteins are hypothesized to act as antagonists of the important complement regulator factor H (FH), fine-tuning complement regulation on human surfaces. For the CFHR4 splice variants FHR-4A and FHR-4B, the individual circulating levels are unknown, with only total levels being described. Specific reagents for FHR-4A or FHR-4B are lacking due to the fact that the unique domains in FHR-4A show high sequence similarity with FHR-4B, making it challenging to distinguish them. We developed an assay that specifically measures FHR-4A using novel, well-characterized monoclonal antibodies (mAbs) that target unique domains in FHR-4A only. Using various FHR-4A/FHR-4B-specific mAbs, no FHR-4B was identified in any of the serum samples tested. The results demonstrate that FHR-4A is the dominant splice variant of CFHR4 in the circulation, while casting doubt on the presence of FHR-4B. FHR-4A levels (avg. 2.55 +/- 1.46 mu g/mL) were within the range of most of the previously reported levels for all other FHRs. FHR-4A was found to be highly variable among the population, suggesting a strong genetic regulation. These results shed light on the physiological relevance of the previously proposed role of FHR-4A and FHR-4B as antagonists of FH in the circulation.

Recent research has elucidated circulating levels of almost all factor H-related (FHR) proteins. Some of these proteins are hypothesized to act as antagonists of the important complement regulator factor H (FH), fine-tuning complement regulation on human surfaces. For the CFHR4 splice variants FHR-4A and FHR-4B, the individual circulating levels are unknown, with only total levels being described. Specific reagents for FHR-4A or FHR-4B are lacking due to the fact that the unique domains in FHR-4A show high sequence similarity with FHR-4B, making it challenging to distinguish them. We developed an assay that specifically measures FHR-4A using novel, well-characterized monoclonal antibodies (mAbs) that target unique domains in FHR-4A only. Using various FHR-4A/FHR-4B-specific mAbs, no FHR-4B was identified in any of the serum samples tested. The results demonstrate that FHR-4A is the dominant splice variant of CFHR4 in the circulation, while casting doubt on the presence of FHR-4B. FHR-4A levels (avg. 2.55 ± 1.46 µg/mL) were within the range of most of the previously reported levels for all other FHRs. FHR-4A was found to be highly variable among the population, suggesting a strong genetic regulation. These results shed light on the physiological relevance of the previously proposed role of FHR-4A and FHR-4B as antagonists of FH in the circulation.

The sustainable development agenda 2030 calls for achievement of certain targets to ensure access to water and sanitation for all. Multi-stakeholder partnerships and the use of data and modelling tools are conditioning elements for their achievement. In this article, we demonstrate that participatory modelling supports informed and participatory decision making in complex river basins. An adapted companion modelling approach is presented to support collective action by reducing disputes and enhancing collaboration among stakeholders. The co-development and use of empirical models for understanding the complexity of the physical system is combined with the use of role-playing games to ensure the active involvement of stakeholders. The approach is implemented in a top-down water quality planning process in Turkey. Results show its suitability for managing water quality in complex river basins in an inclusive manner and its substantial benefits in developing stakeholders’ capacities and creating a cooperative environment.

In a previous study, we found that the accuracy of human haptic perception of force direction is not very high. We also found an effect of physical force direction on the error subjects made, resulting in ‘error patterns’. In the current study, we assessed the between- and within-subject variation of these patterns. The within-subject variation was assessed by measuring the error patterns repeatedly over time for the same set of subjects. Many of these patterns were correlated, which indicates that they are fairly stable over time and thus subject-specific. The between-subject analysis, conversely, yielded hardly any significant correlations. We also measured general subject parameters that might explain this between-subject variation, but these parameters did not correlate with the error patterns. Concluding, we found that the error patterns of haptic perception of force direction are subject-specific and probably governed by an internal subject parameter that we did not yet discover.

Although force-feedback devices are already being used, the human ability to perceive forces has not been documented thoroughly. The haptic perception of force direction and magnitude has mostly been studied in discrimination tasks in the direction of gravity. In our study, the influence of physical force direction on haptic perception of force magnitude and direction was studied in the horizontal plane. Subjects estimated the direction and magnitude of a force exerted on their stationary hand. A significant anisotropy in perception of force magnitude and direction was found. Force direction data showed significant subject-dependent distortions at various physical directions. Normalized force magnitude data showed a consistent elliptical pattern, with its minor axis pointing roughly from the subject’s hand to his/her shoulder. This pattern could be related to arm stiffness or manipulability patterns, which are also ellipse-shaped. These ellipses have an orientation consistent with the distortion measured in our study. So, forces in the direction of highest stiffness and lowest manipulability are perceived as being smaller. It therefore seems that humans possess a ‘sense of effort’ rather than a ‘sense of force’, which may be more useful in everyday life. These results could be useful in the design of haptic devices.

While quite some research has focussed on the accuracy of haptic perception of distance, information on the precision of haptic perception of distance is still scarce, particularly regarding distances perceived by making arm movements. In this study, eight conditions were measured to answer four main questions, which are: what is the influence of reference distance, movement axis, perceptual mode (active or passive) and stimulus type on the precision of this kind of distance perception? A discrimination experiment was performed with 12 participants. The participants were presented with two distances, using either a haptic device or a real stimulus. Participants compared the distances by moving their hand from a start to an end position. They were then asked to judge which of the distances was the longer, from which the discrimination threshold was determined for each participant and condition. The precision was influenced by reference distance. No effect of movement axis was found. The precision was higher for active than for passive movements and it was a bit lower for real stimuli than for rendered stimuli, but it was not affected by adding cutaneous information. Overall, the Weber fraction for the active perception of a distance of 25 or 35 cm was about 11% for all cardinal axes. The recorded position data suggest that participants, in order to be able to judge which distance was the longer, tried to produce similar speed profiles in both movements. This knowledge could be useful in the design of haptic devices.

Visuo-haptic biases are observed when bringing your unseen hand to a visual target. The biases are different between, but consistent within participants. We investigated the usefulness of adjusting haptic guidance to these user-specific biases in aligning haptic and visual perception. By adjusting haptic guidance according to the biases, we aimed to reduce the conflict between the modalities. We first measured the biases using an adaptive procedure. Next, we measured performance in a pointing task using three conditions: (1) visual images that were adjusted to user-specific biases, without haptic guidance, (2) veridical visual images combined with haptic guidance, and (3) shifted visual images combined with haptic guidance. Adding haptic guidance increased precision. Combining haptic guidance with user-specific visual information yielded the highest accuracy and the lowest level of conflict with the guidance at the end point. These results show the potential of correcting for user-specific perceptual biases when designing haptic guidance.

In a previous study, we found the perception of force magnitude to be anisotropic in the horizontal plane. In the current study, we investigated this anisotropy in three dimensional space. In addition, we tested our previous hypothesis that the perceptual anisotropy was directly related to anisotropies in arm dynamics. In experiment 1, static force magnitude perception was studied using a free magnitude estimation paradigm. This experiment revealed a significant and consistent anisotropy in force magnitude perception, with forces exerted along the line between hand and shoulder being perceived as 50% smaller than forces exerted perpendicular to this line. In experiment 2, postural arm dynamics were measured using stochastic position perturbations exerted by a haptic device and quantified through system identification. By fitting a mass-damper-spring model to the data, the stiffness, damping and inertia parameters could be characterized in all the directions in which perception was also measured. These results show that none of the arm dynamics parameters were oriented either exactly perpendicular or parallel to the perceptual anisotropy. This means that endpoint stiffness, damping or inertia alone cannot explain the consistent anisotropy in force magnitude perception.

Please cite this paper as: Becker J, van Rijswijk J, Versteijnen B, Evers A, van den Akker E, van Beek E, Bolte A, Rijnders R, Mol B, Moons K, Porath M, Drogtrop A, Schuitemaker N, Willekes C, Westerhuis M, Visser G, Kwee A. Is intrapartum fever associated with ST-waveform changes of the fetal electrocardiogram? A retrospective cohort study. BJOG 2012;119:1410–1416. Objective To investigate the association between maternal intrapartum fever and ST-waveform changes of the fetal electrocardiogram. Design Retrospective cohort study. Setting Three academic and six non-academic teaching hospitals in the Netherlands. Population Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. Methods We studied 142 women with fever (≥38.0°C) during labour and 141 women with normal temperature who had been included in two previous studies. In both groups, we counted the number and type of ST-events and classified them as significant (intervention needed) or not significant, based on STAN® clinical guidelines. Main outcome measures Number and type of ST-events. Results Both univariable and multivariable regression analysis showed no association between the presence of maternal intrapartum fever and the number or type of ST-events. Conclusions Maternal intrapartum fever is not associated with ST-segment changes of the fetal electrocardiogram. Interpretation of ST-changes in labouring women with fever should therefore not differ from other situations.

Exploring adaptation pathways into an uncertain future can support decisionmaking in achieving sustainable water management in a changing environment. Our objective is to develop and test a method to identify such pathways by including dynamics from natural variability and the interaction between the water system and society. Present planning studies on long-term water management often use a few plausible futures for one or two projection years, ignoring the dynamic aspect of adaptation through the interaction between the water system and society. Our approach is to explore pathways using multiple realisations of transient scenarios with an Integrated Assessment Meta Model (IAMM). This paper presents the first application of the method using a hypothetical case study. The case study shows how to explore and evaluate adaptation pathways. With the pathways it is possible to identify opportunities, threats, timing and sequence of policy options, which can be used by policymakers to develop water management roadmaps into the future. By including the dynamics between the water system and society, the influence of uncertainties in both systems becomes clearer. The results show, among others, that climate variability rather than climate change appears to be important for taking decisions in water management.

Development of sustainable water management strategies involves identification of vulnerability and adaptation possibilities, followed by an effect analysis of these adaptation strategies under different possible futures. Recent scenario studies on water management were mainly ‘what-if’ assessments in one or two future situations. The future is, however, more complex and dynamic. It involves general trends and unexpected events in both the water and the social system. Moreover, the two systems interact: society responds to events and the state of the water system changes in response to management. In this paper we discuss a transdisciplinary approach. Key elements in the concept are (1) the model of pressure, state, impact and response, (2) the Perspectives method to consider uncertainties of social and natural systems and (3) the evaluation of the system using transient scenarios in which we consider time series of trends, events and interaction between the water system and society. The effect analysis is executed with an integrated assessment meta-model based on simple cause–effect relations and response curves.

Aim To detect features that might lead to the early diagnosis and treatment of aceruloplasminemia, as initiation of treatment before the onset of neurological symptoms is likely to prevent neurological deterioration. Methods The PubMed and OMIM databases were searched for published cases of aceruloplasminemia. Diagnostic criteria for aceruloplasminemia were undetectable or very low serum ceruloplasmin, hyperferritinemia and low transferrin saturation. Clinical, biochemical and radiological data on the presentation and follow-up of the cases were extracted and completed through e-mail contact with all authors. Results We present an overview of 55 aceruloplasminemia cases, including three previously unreported cases. Diabetes mellitus was the first symptom related to aceruloplasminemia in 68.5% of the patients, manifesting at a median age of 38.5 years, and often accompanied by microcytic or normocytic anaemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients and was found 12.5 years before the onset of neurological symptoms. Conclusions There is a diagnostic window during which diabetes and anaemia are present although there is an absence of neurological symptoms. Screening for aceruloplasminemia in adult non-obese individuals presenting with antibody-negative, insulin-dependent diabetes mellitus and unexplained anaemia is recommended. The combination of ferritin and transferrin saturation provides a sensitive initial measure for aceruloplasminemia.

Bisphosphonates (BPS) inhibit bone resorption and are divided into two classes according to their chemical structure and mechanism of action: nonnitrogen containing BPS such as etidronate and clodronate that are of low potency and inhibit osteoclast function via metabolism into toxic ATP-metabolites and nitrogen-containing BPS (NBPS), such as alendronate and risedronate that inhibit the enzyme of the mevalonate biosynthetic pathway farnesyl pyrophosphate synthase (FPPS), resulting in inhibition of the prenylation of small GTP-binding proteins in osteoclasts and disruption of their cytoskeleton. Previously, studies in various cell types suggested, however, that pamidronate functions by mechanism(s) additional or independent of the mevalonate pathway. To examine if such mechanism(s) are also involved in the action of NBPS on osteoclastic bone resorption, we examined the action of alkyl and heterocyclic NBPS with close structural homology on FPPS/isopentenyl pyrophosphate isomerase (IPPI) activity, on osteoclastic resorption, and on reversibility of this effect with GGOH. As expected, both pamidronate and alendronate suppressed bone resorption and FPPS/IPPI activity, the latter with greater potency than the first. Surprisingly, however, unlike alendronate, the antiresorptive effect of pamidronate was only partially reversible with GGOH, indicating the involvement of mechanism(s) of action additional to that of suppression of FPPS. Comparable results were obtained with the heterocyclic NBP NE-21650, a structural analog of risedronate. Thus, despite an effect on FPPS, the actions on bone resorption of some NBPS may involve mechanisms additional to suppression of FPPS. These findings may lead to identification of additional pathways that are important for bone resorption and may help to differentiate among members of the NBP class which are currently distinguished only according to their potency to inhibit bone resorption.

In a first set of experiments, it was examined if, with four selected medium-chain fatty acids (MCFAs) (C6:0–C12:0) containing fat sources (coconut, MCTAG1, MCTAG2, butter) and six lipases, under gastric simulated conditions (pH 3 to 6, 3 h incubation, 37°C, with complex substrate), appropriate amounts of MCFAs could be liberated, which could provide a valuable alternative for nutritional antibiotics used in piglet nutrition. Depending on the conditions applied, up to 20% of the MCFAs could be enzymatically released into the medium. In a second set of experiments, the generation and antimicrobial effects of MCFAs from three selected MCFA-containing fat sources (coconut, MCTAG1 and MCTAG2) and one appropriate microbial lipase, applied under different combinations and concentrations, were studied. A minimal concentration of 0.35 g per 100 g incubation fluid or 0.025 M MCFAs in the medium (e.g., stomach, proximal gut) appears to be necessary to obtain a significant (>10-fold) suppression of the flora. This amount can be obtained by choosing an appropriate combination of sources and doses of fat and lipases. The in vitro protocol used offers an excellent tool for the screening of the numerous combinations of MCFA-containing fat sources and lipolytic enzymes for their usefulness as feed supplements which comply with the above conditions, which are generally accepted as the prerequisite for obtaining growth promotion.

In a previous study, we found that the accuracy of human haptic perception of force direction is not very high. We also found an effect of physical force direction on the error subjects made, resulting in ‘error patterns’. In the current study, we assessed the between- and within-subject variation of these patterns. The within-subject variation was assessed by measuring the error patterns repeatedly over time for the same set of subjects. Many of these patterns were correlated, which indicates that they are fairly stable over time and thus subject-specific. The between-subject analysis, conversely, yielded hardly any significant correlations. We also measured general subject parameters that might explain this between-subject variation, but these parameters did not correlate with the error patterns. Concluding, we found that the error patterns of haptic perception of force direction are subject-specific and probably governed by an internal subject parameter that we did not yet discover.

Objective: Among women with a history of preeclampsia the prevalence of hemodynamic and clotting disorders is elevated. In this study we tested the hypothesis that the normal cyclic variation in hemodynamic and renal function parameters with the menstrual cycle that is seen among healthy women would be preserved in women with a history of preeclampsia irrespective of whether they had an underlying hemodynamic or clotting disorder. Study Design: We compared the hemodynamic and volume cyclic variations during the menstrual cycle among women with a history of preeclampsia (n = 39) with those among healthy parous control women (control group, n=10). The participants with a history of preeclampsia were subdivided into groups of women with hypertension with or without thrombophilia (hypertension group, n=10), women with a normotension and a thrombophilic disorder (thrombophilia group, n=17), and women without either of these abnormalities (symptom-free group, n=12). We measured ≥5 months post partum, once during the follicular phase of the menstrual cycle (day 5 ± 2) and once during the luteal phase (day 22 ± 2), the following variables: body weight and length, mean arterial pressure, heart rate, cardiac output, plasma volume, glomerular filtration rate, effective renal plasma flow, and concentrations of renal volume homeostatic hormones, reproductive hormones, and catecholamines. From the measured data we calculated body mass index, cardiac index, left ventricular work, total peripheral and renal vascular resistances, effective renal blood flow, and renal filtration fraction. Results: The hypertension group differed from the control group in having higher baseline (follicular phase) values for cardiac output, cardiac output, left ventricular work, renal vascular resistance, and atrial natriuretic peptide and norepinephrine levels. The symptom-free group differed from the control group in having a lower baseline plasma volume and higher baseline cardiac output and left ventricular work values. Women in the thrombophilia group were comparable to those in the control group with respect to baseline hemodynamic and renal function variables except for a higher renal vascular work value. In the control group heart rate, plasma volume, effective renal plasma volume, effective renal blood flow, and concentrations of renin-angiotensin-aldosterone system hormones and norepinephrine were increased during the luteal phase with respect to values during the follicular phase, whereas the renal vascular resistance and atrial natriuretic peptide values were decreased. In the three subgroups of women with a history of preeclampsia this cyclic pattern with the menstrual cycle was preserved for most of these parameters. Conclusion: Although baseline hemodynamic and volume status among women with a history of preeclampsia differed from that among healthy parous control subjects, the cyclic variation with the menstrual cycle was largely preserved. (Am J Obstet Gynecol 2000;182:1127-34.)