Search

Objective: To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change., Methods: We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator's, Caregiver's, and Patient's Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale., Results: The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator's, Caregiver's, and Patient's CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient's everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia., Conclusion: Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function., (© 2024. The Author(s).)

Temporal action localization aims to identify the boundaries and categories of actions in videos, such as scoring a goal in a football match. Single-frame supervision has emerged as a labor-efficient way to train action localizers as it requires only one annotated frame per action. However, it often suffers from poor performance due to the lack of precise boundary annotations. To address this issue, we propose a visual analysis method that aligns similar actions and then propagates a few user-provided annotations (e.g., boundaries, category labels) to similar actions via the generated alignments. Our method models the alignment between actions as a heaviest path problem and the annotation propagation as a quadratic optimization problem. As the automatically generated alignments may not accurately match the associated actions and could produce inaccurate localization results, we develop a storyline visualization to explain the localization results of actions and their alignments. This visualization facilitates users in correcting wrong localization results and misalignments. The corrections are then used to improve the localization results of other actions. The effectiveness of our method in improving localization performance is demonstrated through quantitative evaluation and a case study.

Breast milk (BM) plays a crucial role in providing essential fatty acids (FA) and energy for the growing infant. When the mother's own BM is not available, nutritional recommendations suggest donor milk (DM) in clinical and home practices. BM was collected from a variety of donor mothers in different lactation stages. Holder pasteurization (HoP) eliminates potential contaminants to ensure safety. FA content of BM samples from the Breast Milk Collection Center of Pécs, Hungary, were analyzed before and after HoP. HoP decreases the level of C6:0, C8:0, C14:1n-5c, C18:1n-9c, C18:3n-6c, C18:3n-3c, and C20:4n-6c in BM, while C14:0, C16:0, C18:1n-9t, C22:0, C22:1n-9c, C24:0, C24:1n-9c, and C22:6n-3c were found in elevated concentration after HoP. We did not detect time-dependent concentration changes in FAs in the first year of lactation. BM produced for girl infants contains higher C20:2n-6c levels. In the BM of mothers who delivered via cesarean section, C12:0, C15:0, C16:0, C17:0, C18:0, C18:1n-9t, C22:1n-9c levels were higher, while C18:2n-6c, C22:0, C24:0, and C22:6n-3c concentrations were lower compared to mothers who gave birth spontaneously. FAs in BM are constant during the first year of lactation. Although HoP modifies the concentration of different FAs, pasteurized DM provides essential FAs to the developing infant. Current data providing information about the FA profile of BM gives origination to supplementation guidelines.

Growing evidence shows that maternal nutrition from preconception until lactation has an important effect on the development of non-communicable diseases in the offspring. Biological responses to environmental stress during pregnancy, including undernutrition or overnutrition of various nutrients, are transmitted in part by DNA methylation. The aim of the present narrative review is to summarize literature data on altered DNA methylation patterns caused by maternal macronutrient or vitamin intake and its association with offspring's phenotype (obesity and related metabolic changes). With our literature search, we found evidence for the association between alterations in DNA methylation pattern of different genes caused by maternal under- or overnutrition of several nutrients (protein, fructose, fat, vitamin D, methyl-group donor nutrients) during 3 critical periods of programming (preconception, pregnancy, lactation) and the development of obesity or related metabolic changes (glucose, insulin, lipid, leptin, adiponectin levels, blood pressure, non-alcoholic fatty liver disease) in offspring. The review highlights that maternal consumption of several nutrients could individually affect the development of offspring's obesity and related metabolic changes via alterations in DNA methylation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bokor, Csölle, Felső, Vass, Funke, Ertl and Molnár.)

Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N -acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C., Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo., Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred., Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.)., (Copyright © 2024 Massachusetts Medical Society.)

L-cysteine is a proteogenic amino acid with many applications in the pharmaceutical, food, animal feed, and cosmetic industries. Due to safety and environmental issues in extracting L-cysteine from animal hair and feathers, the fermentative production of L-cysteine offers an attractive alternative using renewable feedstocks. Strategies to improve microbial production hosts like Pantoea ananatis , Corynebacterium glutamicum , Pseudomonas sp., and Escherichia coli are summarized. Concerning the metabolic engineering strategies, the overexpression of feedback inhibition-insensitive L-serine O-acetyltransferase and weakening the degradation of L-cysteine through the removal of L-cysteine desulfhydrases are crucial adjustments. The overexpression of L-cysteine exporters is vital to overcome the toxicity caused by intracellular accumulating L-cysteine. In addition, we compiled the process engineering aspects for the bioproduction of L-cysteine. Utilizing the energy-efficient sulfur assimilation pathway via thiosulfate, fermenting cheap carbon sources, designing scalable, fed-batch processes with individual feedings of carbon and sulfur sources, and implementing efficient purification techniques are essential for the fermentative production of L-cysteine on an industrial scale.

We developed a new approach comprised of different visualizations for the comparative spatio-temporal analysis of displacement processes in porous media. We aim to analyze and compare ensemble datasets from experiments to gain insight into the influence of different parameters on fluid flow. To capture the displacement of a defending fluid by an invading fluid, we first condense an input image series to a single time map. From this map, we generate a spatio-temporal flow graph covering the whole process. This graph is further simplified to only reflect topological changes in the movement of the invading fluid. Our interactive tools allow the visual analysis of these processes by visualizing the graph structure and the context of the experimental setup, as well as by providing charts for multiple metrics. We apply our approach to analyze and compare ensemble datasets jointly with domain experts, where we vary either fluid properties or the solid structure of the porous medium. We finally report the generated insights from the domain experts and discuss our contribution's advantages, generality, and limitations.

Background: After birth, breast milk (BM) is a known essential source of antioxidants for infants. We analyzed the non-enzymatic total antioxidant capacity (TAC), oxygen radical absorbance capacity (ORAC), and glutathione, calcium, transferrin, and total protein levels of human breast milk before and after Holder pasteurization (HoP)., Methods: The collected donor BM samples were pasteurized with HoP., Results: HoP decreased TAC (-12.6%), ORAC (-12.1%), transferrin (-98.3%), and total protein (-21.4%) levels; HoP did not influence the glutathione concentration, and it increased the total calcium (+25.5%) concentration. Mothers who gave birth via Cesarean section had significantly lower TAC in their BM. TAC and glutathione levels were elevated in the BM of mothers over the age of 30. BM produced in the summer had higher glutathione and calcium levels compared to BM produced in the winter. The glutathione concentration in term milk samples was significantly higher in the first two months of lactation compared to the period between the third and sixth months. The transferrin level of BM for female infants was significantly higher than the BM for boys, and mothers with a BMI above 30 had increased transferrin in their samples., Conclusions: Antioxidant levels in human milk are influenced by numerous factors. Environmental and maternal factors, the postpartum age at breast milk collection, and Holder pasteurization of the milk influence the antioxidant intake of the infant.

A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning.

The visualization of results while the simulation is running is increasingly common in extreme scale computing environments. We present a novel approach for in situ generation of image databases to achieve cost savings on supercomputers. Our approach, a hybrid between traditional inline and in transit techniques, dynamically distributes visualization tasks between simulation nodes and visualization nodes, using probing as a basis to estimate rendering cost. Our hybrid design differs from previous works in that it creates opportunities to minimize idle time from four fundamental types of inefficiency: variability, limited scalability, overhead, and rightsizing. We demonstrate our results by comparing our method against both inline and in transit methods for a variety of configurations, including two simulation codes and a scaling study that goes above 19 K cores. Our findings show that our approach is superior in many configurations. As in situ visualization becomes increasingly ubiquitous, we believe our technique could lead to significant amounts of reclaimed cycles on supercomputers.

Less invasive surfactant administration techniques, together with nasal continuous airway pressure (LISA-nCPAP) ventilation, an emerging noninvasive ventilation (NIV) technique in neonatology, are gaining more significance, even in extremely premature newborns (ELBW), under 27 weeks of gestational age. In this review, studies on LISA-nCPAP are compiled with an emphasis on short- and long-term morbidities associated with prematurity. Several perinatal preventative and therapeutic investigations are also discussed in order to start integrated therapies as numerous organ-saving techniques in addition to lung-protective ventilations. Two thirds of immature newborns can start their lives on NIV, and one third of them never need mechanical ventilation. With adjuvant intervention, these ratios are expected to be increased, resulting in better outcomes. Optimized cardiopulmonary transition, especially physiologic cord clamping, could have an additively beneficial effect on patient outcomes gained from NIV. Organ development and angiogenesis are strictly linked not only in the immature lung and retina, but also possibly in the kidney, and optimized interventions using angiogenic growth factors could lead to better morbidity-free survival. Corticosteroids, caffeine, insulin, thyroid hormones, antioxidants, N-acetylcysteine, and, moreover, the immunomodulatory components of mother's milk are also discussed as adjuvant treatments, since immature newborns deserve more complex neonatal interventions., Competing Interests: The authors declare no conflicts of interest.

Introduction: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder. To combat the progressive neurodegeneration in NPC, disease-modifying treatment needs to be introduced early in the course of the disease. The only approved, disease-modifying treatment is a substrate-reduction treatment, miglustat. Given miglustat's limited efficacy, new compounds are under development, including gene therapy; however, many are still far from clinical use. Moreover, the phenotypic heterogeneity and variable course of the disease can impede the development and approval of new agents., Areas Covered: Here, we offer an expert review of these therapeutic candidates, with a broad scope not only on the main pharmacotherapies, but also on experimental approaches, gene therapies, and symptomatic strategies. The National Institute of Health (NIH) database PubMed has been searched for the combination of the words 'Niemann-Pick type C'+ 'treatment' or 'therapy' or 'trial.' The website clinicaltrials.gov has also been consulted., Expert Opinion: We conclude a combination of treatment strategies should be sought, with a holistic approach, to improve the quality of life of affected individuals and their families.

The advancing digitalisation is one of the great challenges of our times. Related activities also concern the wastewater sector. In the field of building construction, one emerging approach is building information modelling (BIM). The presented work investigates to which extent BIM practices have already found their way to wastewater management, and what kind of benefits and constraints are incorporated. Information is collected by means of a literature review and international expert surveys. Results indicate that several BIM-related key elements are already well established in the sector, but not necessarily in the intended manner. Consequently, the digital transition in the wastewater sector is not about replacing existing procedures and techniques but to rethink and optimise them. This primarily concerns data and information management in combination with the application of digital tools. Furthermore, wastewater management requires more integrated approaches, involving interdisciplinary/collaborative concepts and life cycle perspectives. Appropriate change management is necessary to give support and guidance to employees during the transition process. Furthermore, also from the political side, a clear definition and communication of the pursued digital vision is important. This article aims at stimulating discussion and research to optimise wastewater management from the digital perspective.

Background: Infants have three options for feeding: their own mother's breast milk, donor milk, or infant formula. Insulin, testosterone, total protein, and albumin levels were measured in breast milk samples from the first 6 months of lactation, in donor milk samples, and in different infant formulas., Methods: Mothers who gave birth to term ( n = 19) or preterm ( n = 19) infants were recruited to collect breast milk samples during the first 6 months of lactation. The Breast Milk Collection Center (Unified Health Institution, Pécs, Hungary) provided 96 donor milk (DM) samples for analysis in our study. Insulin, testosterone, total protein, and albumin levels were measured in breast milk, donor milk, and infant formulas., Results: During the first 2 months of lactation, the concentration of insulin was lower (-27.4%) while the testosterone concentration was higher (+20.8%) compared to the period between the 3rd and 6th months only in the preterm breast milk samples. The infant formulas examined did not contain insulin or testosterone. Holder pasteurization (HoP) did not influence the level of testosterone in human milk, although HoP decreased the insulin (-53.6%) and albumin (-38.6%) concentrations., Conclusions: Diet impacts the hormone intake of infants, underlining the importance of breastfeeding and the possible supplementation of formula-fed infants.

Background and Objectives: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal recessive, neurodegenerative diseases with no available symptomatic or disease-modifying treatments. This clinical trial investigated N-acetyl-l-leucine (NALL), an orally administered, modified amino acid in pediatric (≥6 years) and adult patients with GM2 gangliosidoses., Methods: In this phase IIb, multinational, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life., Results: Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50, p = 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions., Discussion: Treatment with NALL was associated with statistically significant and clinically relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well tolerated, contributing to an overall favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs., Trial Registration Information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019., Classification of Evidence: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses., (© 2022 American Academy of Neurology.)

We introduce an ML-driven approach that enables interactive example-based queries for similar behavior in ensembles of spatiotemporal scientific data. This addresses an important use case in the visual exploration of simulation and experimental data, where data is often large, unlabeled and has no meaningful similarity measures available. We exploit the fact that nearby locations often exhibit similar behavior and train a Siamese Neural Network in a self-supervised fashion, learning an expressive latent space for spatiotemporal behavior. This space can be used to find similar behavior with just a few user-provided examples. We evaluate this approach on several ensemble datasets and compare with multiple existing methods, showing both qualitative and quantitative results.

Maternal exposure to some dietary and environmental factors during embryonic development can affect offspring's phenotype and, furthermore, the risk of developing diseases later in life. One potential mechanism responsible for this early programming may be the modification of the epigenome, such as DNA methylation. Methyl-group donors are essential for DNA methylation and are shown to have an important role in fetal development and later health. The main goal of the present review is to summarize the available literature data on the epigenetic effect (DNA methylation) of maternal methyl-group donor availability on reproductivity, perinatal outcome, and later health of the offspring. In our literature search, we found evidence for the association between alterations in DNA methylation patterns caused by different maternal methyl-group donor (folate, choline, methionine, betaine) intake and reproductivity, birth weight, neural tube defect, congenital heart defect, cleft lip and palate, brain development, and the development of obesity and associated non-communicable diseases in later life. We can conclude that maternal methyl-group donor availability could affect offspring's health via alterations in DNA methylation and may be a major link between early environmental exposure and the development of diseases in the offspring. However, still, further studies are necessary to confirm the associations and causal relationships.

Breastfeeding is widely supported in clinical and home practices, and it is known that different forms of infant feeding differ in hormone content. Thyroid hormones have essential physiological roles. In our study, we examined thyroid-stimulating hormone (TSH), thyroxine, and albumin levels in breast milk produced for term (n = 16) or preterm (n = 15) infants throughout the first 6 months of lactation. Moreover, we analyzed these components in donor human milk and in three different infant formulas. Term and preterm breast milk samples were collected monthly. The two groups had similar levels of TSH (18.4 ± 1.4 vs. 24.7 ± 2.9 nU/L), but term milk contained higher amounts of thyroxine (11,245.5 ± 73.8 vs. 671.6 ± 61.2 nmol/L) during the examination period. The albumin level was significantly higher in preterm breast milk than in term breast milk (328.6 ± 17.1 vs. 264.2 ± 6.8 mg/L). In preterm breast milk we detected downward trends in the levels of TSH (-30.2%) and thyroxine (-29.2%) in the 3rd through 6th month compared to the first 2 months of lactation. Microbiological safety of donor milk was ensured by Holder pasteurization (HoP). From the Breast Milk Collection Center of Pécs, Hungary, we enrolled 44 donor mothers into the study. HoP decreased TSH (-73.8%), thyroxine (-22.4%), and albumin (-20.9%) concentrations. Infant formulas used by the Neonatal Intensive Care Unit of the University of Pécs were found to not contain the investigated hormones, but their albumin levels were similar to the breast milk samples. The present study shows the lack of thyroid hormones in infant formulas compared to human milk and raises the question of whether formula-fed infants should be supplemented with thyroid hormones.

Objective: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients., Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments., Results: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred., Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS., Gov Identifier: NCT03759639., (© 2021. The Author(s).)

Modern machines continuously log status reports over long periods of time, which are valuable data to optimize working routines. Data visualization is a commonly used tool to gain insights into these data, mostly in retrospective (e.g., to determine causal dependencies between the faults of different machines). We present an approach to bring such visual analyses to the shop floor to support reacting to faults in real time. This approach combines spatio-temporal analyses of time series using a handheld touch device with augmented reality for live monitoring. Important information augments machines directly in their real-world context, and detailed logs of current and historical events are displayed on the handheld device. In collaboration with an industry partner, we designed and tested our approach on a live production line to obtain feedback from operators. We compare our approach for monitoring and analysis with existing solutions that are currently deployed.

Background: There is no authorized treatment for ataxia telangiectasia (AT). As cerebellar symptoms of storage diseases were improved by acetyl-DL-leucine (ADLL), the authors hypothesized a symptomatic and disease-modifying effect in AT upon supplementation with ADLL., Methods: Six patients were treated with ADLL 3 g/day for 1 week followed by 5g/day for 3 weeks to 1 year. Cerebellar ataxia was evaluated by validated scales. Gaze-holding, saccades and smooth pursuit were examined by video-oculography. Measurements took place at baseline, at 1 month of therapy in 5 patients, and after 6 and 12 months in 1 patient., Results: The Scale for Assessment and Rating of Ataxia changed from the baseline, mean, (SD, min-max) of 22.1 (5.88, 11-28.5) to 18 points (5.39, 8.5-23.5) after 1 month on medication ( P = .0028). All patients demonstrated gaze-holding deficits; 3 patients had central-position downbeat-nystagmus. Mean slow-phase velocity of this nystagmus with the gaze straight-ahead changed from 5.57°/s (1.8, 3.53-6.99) to 4.7°/s (0.79, 3.97-5.56) after 1 month on treatment (1.35, -2.56-4.17) ( P = .046)., Interpretation: ADLL may improve ataxia and ocular stability in AT patients, while the molecular basis still remains to be elucidated. A multicentric, rater-blinded, phase II trial currently investigates the effects of acetyl-L-leucine in AT (NCT03759678).

Breaking news and first-hand reports often trend on social media platforms before traditional news outlets cover them. The real-time analysis of posts on such platforms can reveal valuable and timely insights for journalists, politicians, business analysts, and first responders, but the high number and diversity of new posts pose a challenge. In this work, we present an interactive system that enables the visual analysis of streaming social media data on a large scale in real-time. We propose an efficient and explainable dynamic clustering algorithm that powers a continuously updated visualization of the current thematic landscape as well as detailed visual summaries of specific topics of interest. Our parallel clustering strategy provides an adaptive stream with a digestible but diverse selection of recent posts related to relevant topics. We also integrate familiar visual metaphors that are highly interlinked for enabling both explorative and more focused monitoring tasks. Analysts can gradually increase the resolution to dive deeper into particular topics. In contrast to previous work, our system also works with non-geolocated posts and avoids extensive preprocessing such as detecting events. We evaluated our dynamic clustering algorithm and discuss several use cases that show the utility of our system.

River systems have undergone a massive transformation since the Anthropocene. The natural properties of river systems have been drastically altered and reshaped, limiting the use of management frameworks, their scientific knowledge base and their ability to provide adequate solutions for current problems and those of the future, such as climate change, biodiversity crisis and increased demands for water resources. To address these challenges, a socioecologically driven research agenda for river systems that complements current approaches is needed and proposed. The implementation of the concepts of social metabolism and the colonisation of natural systems into existing concepts can provide a new basis to analyse the coevolutionary coupling of social systems with ecological and hydrological (i.e., 'socio-ecohydrological') systems within rivers. To operationalize this research agenda, we highlight four initial core topics defined as research clusters (RCs) to address specific system properties in an integrative manner. The colonisation of natural systems by social systems is seen as a significant driver of the transformation processes in river systems. These transformation processes are influenced by connectivity (RC 1), which primarily addresses biophysical aspects and governance (RC 2), which focuses on the changes in social systems. The metabolism (RC 3) and vulnerability (RC 4) of the social and natural systems are significant aspects of the coupling of social systems and ecohydrological systems with investments, energy, resources, services and associated risks and impacts. This socio-ecohydrological research agenda complements other recent approaches, such as 'socio-ecological', 'socio-hydrological' or 'socio-geomorphological' systems, by focusing on the coupling of social systems with natural systems in rivers and thus, by viewing the socioeconomic features of river systems as being just as important as their natural characteristics. The proposed research agenda builds on interdisciplinarity and transdisciplinarity and requires the implementation of such programmes into the education of a new generation of river system scientists, managers and engineers who are aware of the transformation processes and the coupling between systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide having trophic and protective functions in neural tissues, including the retina. Previously, we have shown that intravitreal PACAP administration can maintain retinal structure in the animal model of retinopathy of prematurity (ROP). The purpose of this study is to examine the development of ROP in PACAP-deficient and wild-type mice to reveal the function of endogenous PACAP. Wild-type and PACAP-knockout (KO) mouse pups at postnatal day (PD) 7 were maintained at 75% oxygen for 5 consecutive days then returned to room air on PD12 to develop oxygen-induced retinopathy (OIR). On PD15, animals underwent electroretinography (ERG) to assess visual function. On PD16, eyes were harvested for either immunohistochemistry to determine the percentage of the central avascular retinal area or molecular analysis to assess angiogenesis proteins by array kit and anti-apoptotic protein kinase B (Akt) change by western blot. Retinas of PACAP-deficient OIR mice showed a greater central avascular area than that of the wild types. ERG revealed significantly decreased b-wave amplitude in PACAP KO compared to their controls. Several angiogenic proteins were upregulated due to OIR, and 11 different proteins markedly increased in PACAP-deficient mice, whereas western blot analysis revealed a reduction in Akt phosphorylation, suggesting an advanced cell death in the lack of PACAP. This is the first study to examine the endogenous effect of PACAP in the OIR model. Previously, we have shown the beneficial effect of exogenous local PACAP treatment in the rat OIR model. Together with the present findings, we suggest that PACAP could be a novel retinoprotective agent in ROP., (© 2021. The Author(s).)

It is difficult to explore large text collections if no or little information is available on the contained documents. Hence, starting analytic tasks on such corpora is challenging for many stakeholders from various domains. As a remedy, recent visualization research suggests to use visual spatializations of representative text documents or tags to explore text collections. With PyramidTags, we introduce a novel approach for summarizing large text collections visually. In contrast to previous work, PyramidTags in particular aims at creating an improved representation that incorporates both temporal evolution and semantic relationship of visualized tags within the summarized document collection. As a result, it equips analysts with a visual starting point for interactive exploration to not only get an overview of the main terms and phrases of the corpus, but also to grasp important ideas and stories. Analysts can hover and select multiple tags to explore relationships and retrieve the most relevant documents. In this work, we apply PyramidTags to hundreds of thousands of web-crawled news reports. Our benchmarks suggest that PyramidTags creates time- and context-aware layouts, while preserving the inherent word order of important pairs.

Simulations of cosmic evolution are a means to explain the formation of the universe as we see it today. The resulting data of such simulations comprise numerous physical quantities, which turns their analysis into a complex task. Here, we analyze such high-dimensional and time-varying particle data using various visualization techniques from the fields of particle visualization, flow visualization, volume visualization, and information visualization. Our approach employs specialized filters to extract and highlight the development of so-called active galactic nuclei and filament structures formed by the particles. Additionally, we calculate X-ray emission of the evolving structures in a preprocessing step to complement visual analysis. Our approach is integrated into a single visual analytics framework to allow for analysis of star formation at interactive frame rates. Finally, we lay out the methodological aspects of our work that led to success at the 2019 IEEE SciVis Contest.

Objective: To characterize ocular motor function in patients with Niemann-Pick disease type C (NPC)., Methods: In a multicontinental, cross-sectional study we characterized ocular-motor function in 72 patients from 12 countries by video-oculography. Interlinking with disease severity, we also searched for ocular motor biomarkers. Our study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in horizontal and vertical planes. Data were compared with those of 158 healthy controls (HC)., Results: Some 98.2% of patients generated vertical saccades below the 95% CI of the controls' peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% CI of HC. The involvement in both downward and upward directions was similar (51°/s (68.9, [32.7-69.3]) downward versus 78.8°/s (65.9, [60.8-96.8]) upward). Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit correlated best to disease severity. Compensating strategies such as blinks to elicit saccades, and head and upper body movements to overcome the gaze palsy, were observed. Vertical reflexive saccades were more impaired and slower than self-paced ones. Gaze-holding was normal. Ocular-motor performance depended on the age of onset and disease duration., Conclusions: This is the largest cohort of NPC patients investigated for ocular-motor function. Vertical supranuclear saccade palsy is the hallmark of NPC. Vertical upward and downward saccades are equally impaired. Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials. Compensating strategies can contribute to establishing a diagnosis., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two-carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. N-acetyl-D,L-leucine is approved in France for vertigo and its L-enantiomer is being developed as a drug for rare and common neurological disorders. However, the precise mechanistic details of how acetylation converts leucine into a drug are unknown. Here we show that acetylation of leucine switches its uptake into cells from the L-type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N-acetyl-L-leucine. MCT1-mediated uptake of a N-acetyl-L-leucine as a prodrug of leucine bypasses LAT1, the rate-limiting step in activation of leucine-mediated signalling and metabolic process inside cells such as mTOR. Converting an amino acid into an anion through acetylation reveals a way for the rational design of drugs to target anion transporters., (© 2021. The Author(s).)

We present a machine learning-based approach for detecting and visualizing complex behavior in spatiotemporal volumes. For this, we train models to predict future data values at a given position based on the past values in its neighborhood, capturing common temporal behavior in the data. We then evaluate the model's prediction on the same data. High prediction error means that the local behavior was too complex, unique or uncertain to be accurately captured during training, indicating spatiotemporal regions with interesting behavior. By training several models of varying capacity, we are able to detect spatiotemporal regions of various complexities. We aggregate the obtained prediction errors into a time series or spatial volumes and visualize them together to highlight regions of unpredictable behavior and how they differ between the models. We demonstrate two further volumetric applications: adaptive timestep selection and analysis of ensemble dissimilarity. We apply our technique to datasets from multiple application domains and demonstrate that we are able to produce meaningful results while making minimal assumptions about the underlying data.

Background/methods: Monogenic diseases are important models for the study of neurodegenerative diseases, such as Parkinson's disease (PD) and dementia. Notably, for some disorders, homozygosity is associated with a complex metabolic disease, while heterozygosity predisposes to late-onset neurodegeneration. For instance, biallelic glucocerebrosidase gene mutations cause Gaucher's disease, while heterozygous mutations are a common genetic risk factor for late-onset PD. Little is known about similar risks of related diseases, such as Niemann-Pick type C (NPC). Given that both conditions map into related, i.e., lysosomal, pathways, we hypothesize a similar risk of single-NPC gene mutations. Indeed, there is increasing evidence based on clinical observations in humans and animal studies. Here we review the current knowledge of NPC heterozygosity., Results: Family history studies suggest a high proportion of late-onset neurodegenerative diseases in NPC families. We identified 19 cases with heterozygous NPC mutations in the literature who presented with a neurodegenerative disease, including levodopa-responsive PD, atypical parkinsonism (PSP, CBD), dystonia or dementia with a mean age at onset of about 57 years (range 8-87). Consistent splenomegaly and mildly abnormal filipin staining results have also been reported in heterozygous gene mutation carriers. Imaging and pathological data support this notion., Discussion/conclusion: This finding has wider implications in so far as NPC-related forms of Parkinsonian syndromes, dementia, motor neuron disease and other neurodegenerative disorders may benefit from NPC-mechanistic therapies, in particular related to lysosomal dysfunction. Further research is warranted to generate systematic data of heterozygous mutation carriers, including longitudinal data.

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1 -/- microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.

Investigating relationships between variables in multi-dimensional data sets is a common task for data analysts and engineers. More specifically, it is often valuable to understand which ranges of which input variables lead to particular values of a given target variable. Unfortunately, with an increasing number of independent variables, this process may become cumbersome and time-consuming due to the many possible combinations that have to be explored. In this paper, we propose a novel approach to visualize correlations between input variables and a target output variable that scales to hundreds of variables. We developed a visual model based on neural networks that can be explored in a guided way to help analysts find and understand such correlations. First, we train a neural network to predict the target from the input variables. Then, we visualize the inner workings of the resulting model to help understand relations within the data set. We further introduce a new regularization term for the backpropagation algorithm that encourages the neural network to learn representations that are easier to interpret visually. We apply our method to artificial and real-world data sets to show its utility.

Collaborative exploration of scientific data sets across large high-resolution displays requires both high visual detail as well as low-latency transfer of image data (oftentimes inducing the need to trade one for the other). In this work, we present a system that dynamically adapts the encoding quality in such systems in a way that reduces the required bandwidth without impacting the details perceived by one or more observers. Humans perceive sharp, colourful details, in the small foveal region around the centre of the field of view, while information in the periphery is perceived blurred and colourless. We account for this by tracking the gaze of observers, and respectively adapting the quality parameter of each macroblock used by the H.264 encoder, considering the so-called visual acuity fall-off. This allows to substantially reduce the required bandwidth with barely noticeable changes in visual quality, which is crucial for collaborative analysis across display walls at different locations. We demonstrate the reduced overall required bandwidth and the high quality inside the foveated regions using particle rendering and parallel coordinates.

Storyline visualizations are an effective means to present the evolution of plots and reveal the scenic interactions among characters. However, the design of storyline visualizations is a difficult task as users need to balance between aesthetic goals and narrative constraints. Despite that the optimization-based methods have been improved significantly in terms of producing aesthetic and legible layouts, the existing (semi-) automatic methods are still limited regarding 1) efficient exploration of the storyline design space and 2) flexible customization of storyline layouts. In this work, we propose a reinforcement learning framework to train an AI agent that assists users in exploring the design space efficiently and generating well-optimized storylines. Based on the framework, we introduce PlotThread, an authoring tool that integrates a set of flexible interactions to support easy customization of storyline visualizations. To seamlessly integrate the AI agent into the authoring process, we employ a mixed-initiative approach where both the agent and designers work on the same canvas to boost the collaborative design of storylines. We evaluate the reinforcement learning model through qualitative and quantitative experiments and demonstrate the usage of PlotThread using a collection of use cases.

Hormones are important biological regulators, controlling development and physiological processes throughout life. We investigated pituitary hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and total protein levels during the first 6 months of lactation. Breast milk samples were collected every fourth week of lactation from mothers who gave birth to preterm ( n = 14) or term ( n = 16) infants. Donor milk is suggested when own mother's milk is not available; therefore, we collected breast milk samples before and after Holder pasteurization (HoP) from the Breast Milk Collection Center of Pécs, Hungary. Three infant formulas prepared in the Neonatal Intensive Care Unit of the University of Pécs were tested at three different time points. Our aim was to examine the hormone content of own mother's milk and donor milk. There were no significant changes over time in the concentrations of any hormone. Preterm milk had higher PRL (28.2 ± 2.5 vs 19.3 ± 2.3 ng/mL) and LH (36.3 ± 8.8 vs 15.9 ± 4.1 mIU/L) concentrations than term milk during the first 6 months of lactation. Total protein and FSH concentrations did not differ between preterm and term breast milk. Holder pasteurization decreased the PRL concentration (30.4 ± 1.8 vs 14.4 ± 0.6 ng/mL) and did not affect gonadotropin levels of donor milk. Infant formulas have higher total protein content than breast milk but do not contain detectable levels of pituitary hormones. Differences were detected in the content of pituitary hormones produced for preterm and term infants. Divergence between feeding options offers opportunities for improvement of nutritional guidelines for both hospital and home feeding practices., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T)., Methods/design: The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase., Discussion: The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases., Trial Registration: The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).

Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1 -/- mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1 -/- mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1 -/- mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso -Asp-Gly- Arg ( iso DGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one iso DGR cyclic peptidomimetics containing (1 S ,2 R ) and (1 R ,2 S ) cis -2-amino-1-cyclopentanecarboxylic acid ( cis -β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified α v β 3 and α 5 β 1 receptors using biotinylated vitronectin (α v β 3 ) and fibronectin (α 5 β 1 ) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for α v β 3 over α 5 β 1 . In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin α v β 3 ). The two RGD ligands showed IC 50 values in the same micromolar range as the reference compound ( cyclo [RGDfV]), while for the iso DGR derivative an IC 50 value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and iso DGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the α V β 3 integrin active site, provided a rationale for the behavior of these ligands toward the receptor.

Competing Interests: T.B.-E. received honoraria for lecturing from Actelion and Sanofi-Genzyme.F.P. is a Royal Society Wolfson Research Merit Award holder and a Wellcome Trust Investigator in Science. F.P. is an academic co-founder of IntraBio and a share holder in IntraBio.M.S. is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology and Section Editor of F1000. He has received speaker's honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Grünenthal, GSK, Henning Pharma, Interacoustics, MSD, Otometrics, Pierre-Fabre, TEVA, and UCB. He is a shareholder of IntraBio. He is the distributor of M glasses. He acts as a consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio, and Sensorion.

The synthesis of tropanes via a microwave-assisted, stereoselective 6π-electrocyclic ring-opening/ Huisgen [3+2]-cycloaddition cascade of cyclopropanated pyrrole and furan derivatives with electron-deficient dipolarophiles is demonstrated. Starting from furans or pyrroles, 8-aza- and 8-oxabicyclo[3.2.1]octanes are accessible in two steps in dia- and enantioselective pure form, being versatile building blocks for the synthesis of pharmaceutically relevant targets, especially for new cocaine analogues bearing various substituents at the C-6/C-7 positions of the tropane ring system. Moreover, the 2-azabicyclo[2.2.2]octane core (isoquinuclidines), being prominently represented in many natural and pharmaceutical products, is accessible via this approach., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

The analysis of subtle deviations between different versions of historical prints has been a long-standing challenge in art history research. So far, this challenge has required extensive domain knowledge, fine-tuned expert perception, and time-consuming manual labor. In this paper we introduce an explorative visual approach to facilitate fast and accurate support for the task of comparing differences between prints such as engravings and woodcuts. To this end, we have developed a customized algorithm that detects similar stroke-patterns in prints and matches them in order to allow visual alignment and automated deviation highlighting. Our visual analytics system enables art history researchers to quickly detect, document, and categorize qualitative and quantitative discrepancies, and to analyze these discrepancies using comprehensive interactions. To evaluate our approach, we conducted a user study involving both experts on historical prints and laypeople. Using our new interactive technique, our subjects found about 20 percent more differences compared to regular image viewing software as well as "paper-based" comparison. Moreover, the laypeople found the same differences as the experts when they used our system, which was not the case for conventional methods. Informal feedback showed that both laypeople and experts strongly preferred employing our system to working with conventional methods.

Background: After birth, breastfeeding is the exclusive source of hormonal signaling between mother and infant. Hospitalized infants often receive donor milk when their own mother's milk is unavailable., Methods: The presence of insulin, leptin, cortisol, progesterone, and testosterone was examined in samples from milk bank donors and mothers of preterm infants. We further investigated the effect of Holder pasteurization (HoP) on hormone levels., Results: Comparing nonpasteurized samples, leptin levels were nearly threefold higher in milk from mothers of preterm infants versus donated milk, and regardless of milk source, leptin levels were significantly decreased by HoP. Insulin concentrations were also decreased by HoP, and among mothers of preterm infants, obesity was associated with significantly higher content of leptin and insulin. While combined use of donor milk and HoP was associated with cortisol levels nearly threefold higher than those in nonpasteurized own mother's milk, progesterone and testosterone content did not differ by source or pasteurization., Conclusions: The hormonal composition of breast milk is impacted by HoP and maternal obesity. Compared to nonpasteurized maternal milk, use of pasteurized donor milk dramatically decreases the intake of leptin while increasing the intake of cortisol. Further research is necessary to define optimal breast milk processing practices.

As our field matures, evaluation of visualization techniques has extended from reporting runtime performance to studying user behavior. Consequently, many methodologies and best practices for user studies have evolved. While maintaining interactivity continues to be crucial for the exploration of large data sets, no similar methodological foundation for evaluating runtime performance has been developed. Our analysis of 50 recent visualization papers on new or improved techniques for rendering volumes or particles indicates that only a very limited set of parameters like different data sets, camera paths, viewport sizes, and GPUs are investigated, which make comparison with other techniques or generalization to other parameter ranges at least questionable. To derive a deeper understanding of qualitative runtime behavior and quantitative parameter dependencies, we developed a framework for the most exhaustive performance evaluation of volume and particle visualization techniques that we are aware of, including millions of measurements on ten different GPUs. This paper reports on our insights from statistical analysis of this data, discussing independent and linear parameter behavior and non-obvious effects. We give recommendations for best practices when evaluating runtime performance of scientific visualization applications, which can serve as a starting point for more elaborate models of performance quantification.

Magic lens based focus+context techniques are powerful means for exploring document spatializations. Typically, they only offer additional summarized or abstracted views on focused documents. As a consequence, users might miss important information that is either not shown in aggregated form or that never happens to get focused. In this work, we present the design process and user study results for improving a magic lens based document exploration approach with exemplary visual quality cues to guide users in steering the exploration and support them in interpreting the summarization results. We contribute a thorough analysis of potential sources of information loss involved in these techniques, which include the visual spatialization of text documents, user-steered exploration, and the visual summarization. With lessons learned from previous research, we highlight the various ways those information losses could hamper the exploration. Furthermore, we formally define measures for the aforementioned different types of information losses and bias. Finally, we present the visual cues to depict these quality measures that are seamlessly integrated into the exploration approach. These visual cues guide users during the exploration and reduce the risk of misinterpretation and accelerate insight generation. We conclude with the results of a controlled user study and discuss the benefits and challenges of integrating quality guidance in exploration techniques.

Multiple pressures as urbanization, densification and climate change lead to the need for adaptation of sewer systems within urban environments. To increase the adaptive capacity of stormwater management systems, there is a shift towards decentralized nature-based solutions (NBS). Especially in densely built areas the availability of land can be a limiting factor for the implementation of NBS. To consider the spatial framework conditions in planning we developed an integrated modelling framework for prioritizing sites for NBS implementation for stormwater management within built urban structures. The implementation potential of NBS from a settlement structure model and a street typology model are combined with the discharge reduction potential from a sewer model. In effectiveness matrices priorities for stormwater management sites for individual NBS are identified. This modelling framework offers a transparent and flexible approach to decision making for the implementation of NBS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Niemann-Pick disease type C1 (NPC1) is a rare autosomal-recessive lysosomal storage disorder presenting with a broad clinical spectrum ranging from a severe infantile-onset neurovisceral disorder to late-onset neurodegenerative disease. Optical coherence tomography (OCT) is established to detect retinal degeneration in vivo. We examined NPC1-patients (NPC1-P), clinically asymptomatic NPC1-mutation carriers (NPC1-MC), and healthy controls (HC) to (1) identify retinal degeneration in NPC1-disease and (2) to investigate possible subclinical retinal degeneration in NPC1-MC., Methods: Fourteen NPC1-P, 17 NPC1-MC, and 31 age-matched HC were examined using spectral-domain OCT. Neurological examinations, clinical scales [modified Disability Rating Scale (mDRS); Scale for the Rating and Assessment of Ataxia (SARA); Spinocerebellar Ataxia Functional Index (SCAFI)], and video-oculography (VOG) were correlated with OCT data., Results: Macular retinal nerve fiber layer and volumes of combined ganglion cell and inner plexiform layer were significantly lower in NPC1-P compared to HC [mRNFL (µm):0.13 ± 0.01 vs. 0.14 ± 0.02; p = 0.01; GCIPL (mm 3 ):0.60 ± 0.05 vs. 0.62 ± 0.04; p = 0.04]. No significant differences were found in NPC1-MC in comparison to HC. In NPC1-P, the amplitude of upward vertical saccades showed positive associations with peripapillary RNFL (ρ = 0.645; p < 0.05), and thinned GCIP (ρ = 0.609; p < 0.05), but not in NPC1-MC. In NPC1-P correlations between combined outer plexiform layer and outer nuclear layer (OPONL) with mDRS (r = - 0.617; p < 0.05) and GCIP with SARA (r = - 0.622; p < 0.05) were observed. Furthermore, in NPC1-MC, motor scores were negatively associated with pRNFL (ρ = - 0.677; p < 0.01)., Conclusions: Using OCT, we showed retinal degeneration in NPC1-P and significant correlation between retinal neuroaxonal degeneration with clinical measurements. We observed a non-significant trend of retinal degeneration in NPC1-MC correlating with subclinical motor abnormalities. Based on these preliminary data, OCT may be an important marker of neurodegeneration in NPC1-disease after onset of clinical symptoms.

In the U.S., HIV incidence is highest among Black men who have sex with men (MSM) but PrEP uptake is low, in part due to lack of normative support for using PrEP. This research pilot tested a social network-level intervention designed to increase PrEP use willingness, interest, and peer supports among Black MSM in Milwaukee. Five community social networks ( n  = 40 participants) of racial minority MSM were assessed at baseline with measures of PrEP knowledge, interest, attitudes, and action taking. Persons most interconnected with others in each network attended an intervention that provided training to increase knowledge about PrEPbenefits, address PrEP concerns, endorse PrEP use as a symbol of pride and health, and deliver these messages to others in their social networks. All network members were re-administered the same measures at 3-month followup. Significant increases over time were found in network members' PrEP knowledge, attitudes, norm perceptions, self-efficacy, and willingness to use PrEP. Participants more often talked with friends about HIV and with their health care providers about PrEP. The percentage of participants who reported using PrEP increased from 3% to 11%. Larger-scale evaluations of this intervention model are needed.

Numerous studies indicate that smoking during pregnancy exerts harmful effects on fetal brain development. The aim of this study was to determine the influence of maternal smoking during pregnancy on the early physical and neurobehavioral development of newborn rats. Wistar rats were subjected to whole-body smoke exposure for 2 × 40 min daily from the day of mating until day of delivery. For this treatment, a manual closed-chamber smoking system and 4 research cigarettes per occasion were used. After delivery the offspring were tested daily for somatic growth, maturation of facial characteristics and neurobehavioral development until three weeks of age. Motor coordination tests were performed at 3 and 4 weeks of age. We found that prenatal cigarette smoke exposure did not alter weight gain or motor coordination. Critical physical reflexes indicative of neurobehavioral development (eyelid reflex, ear unfolding) appeared significantly later in pups prenatally exposed to smoke as compared to the control group. Prenatal smoke exposure also resulted in a delayed appearance of reflexes indicating neural maturity, including hind limb grasping and forelimb placing reflexes. In conclusion, clinically relevant prenatal exposure to cigarette smoke results in slightly altered neurobehavioral development in rat pups. These findings suggest that chronic exposure of pregnant mothers to cigarette smoke (including passive smoking) results in persisting alterations in the developing brain, which may have long-lasting consequences supporting the concept of developmental origins of health and disease (DoHAD).

Objective: To characterize subclinical abnormalities in asymptomatic heterozygote NPC1 mutation carriers as markers of neurodegeneration., Methods: Motor function, cognition, mood, sleep, and smell function were assessed in 20 first-degree heterozygous relatives of patients with Niemann-Pick disease type C (NPC) (13 male, age 52.7 ± 9.9 years). Video-oculography and abdominal ultrasound with volumetry were performed to assess oculomotor function and size of liver and spleen. NPC biomarkers in blood were analyzed. 18 F-fluorodesoxyglucose PET was performed (n = 16) to detect patterns of brain hypometabolism., Results: NPC heterozygotes recapitulated characteristic features of symptomatic NPC disease and demonstrated the oculomotor abnormalities typical of NPC. Hepatosplenomegaly (71%) and increased cholestantriol (33%) and plasma chitotriosidase (17%) levels were present. The patients also showed signs seen in other neurodegenerative diseases, including hyposmia (20%) or pathologic screening for REM sleep behavior disorder (24%). Cognitive function was frequently impaired, especially affecting visuoconstructive function, verbal fluency, and executive function. PET imaging revealed significantly decreased glucose metabolic rates in 50% of participants, affecting cerebellar, anterior cingulate, parieto-occipital, and temporal regions, including 1 with bilateral abnormalities., Conclusion: NPC heterozygosity, which has a carrier frequency of 1:200 in the general population, is associated with abnormal brain metabolism and functional consequences. Clinically silent heterozygous gene variations in NPC1 may be a risk factor for late-onset neurodegeneration, similar to the concept of heterozygous GBA mutations underlying Parkinson disease., (© 2020 American Academy of Neurology.)