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Increasing resistance to antiviral drugs approved for the treatment of influenza urges the development of novel compounds. Ideally, this should be complemented by a careful consideration of the administration route. 6'siallyllactosamine-functionalized β-cyclodextrin (CD-6'SLN) is a novel entry inhibitor that acts as a mimic of the primary attachment receptor of influenza, sialic acid. In this study, we aimed to develop a dry powder formulation of CD-6'SLN to assess its in vivo antiviral activity after administration via the pulmonary route. By means of spray drying the compound together with trileucine, a dispersion enhancer, we created a powder that retained the antiviral effect of the drug, remained stable under elevated temperature conditions and performed well in a dry powder inhaler. To test the efficacy of the dry powder drug against influenza infection in vivo, infected mice were treated with CD-6'SLN using an aerosol generator that allowed for the controlled administration of powder formulations to the lungs of mice. CD-6'SLN was effective in mitigating the course of the disease compared to the control groups, reflected by lower disease activity scores and by the prevention of virus-induced IL-6 production. Our data show that CD-6'SLN can be formulated as a stable dry powder that is suitable for use in a dry powder inhaler and is effective when administered via the pulmonary route to influenza-infected mice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Stellacci is inventor on patent number WO 2018/015465 A1 − Virucidal compounds and uses thereof. Francesco Stellacci and Paulo H. Jacob Silva are co-founders of Asterivir, a start-up company that focuses on developing novel antivirals. The employer of Henderik W. Frijlink holds a license agreement with PureIMS on the Twincer and Cyclops dry powder inhalers. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; nor in the writing of the manuscript or in the decision to submit the article for publication., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The human diet requires a more plant-based approach due to the exhaustive effects animal-based foods have on the environment. However, plant-based proteins generally miss a few or have a lower variety in essential amino acids and are more difficult to digest. Subsequently they might be prone to fermentation by the microbiome in the proximal colon. Proteolytic fermentation can induce microbial-metabolites with beneficial and negative health effects. We review current insight into how balances in saccharolytic and proteolytic fermentation can be maintained when the diet consists predominantly of plant-based proteins. Some proteolytic fermentation metabolites may negatively impact balances in gut microbiota composition in the large intestine and influence immunity. However, proteolytic fermentation can potentially be prevented in the proximal colon toward more saccharolytic fermentation through the addition of non-digestible carbohydrates in the diet. Knowledge on this combination of plant-based proteins and non-digestible carbohydrates on colonic- and general health is limited. Current data suggest that transitioning toward a more plant-based protein diet should be accompanied with a consumption of increased quantities and more complex structures of carbohydrates or by application of technological strategies to enhances digestibility. This can reduce or prevent proteolytic fermentation which might consequently improve human health.

Truncated hemisphere parts were press formed with two commercially available unidirectional thermoplastic composite materials, namely Toray TC1225 and Solvay APC. The width and layup of the laminates were varied to influence the wrinkling severity, to trigger various deformation mechanisms and to influence the amount of in-plane deformation. A total of eight layup/width combinations were selected and formed in triplicate for both materials, resulting in the analysis of 48 parts in total. The wrinkling defects are clearly observed due to an intentional gap between the forming tools at the end of forming. Further, a dot pattern with a resolution of 3 mm was applied to the laminates prior to forming using a photoresist mask, sandblasting and heat resistant spray paint. The locations of the dots before and after forming were measured using photogrammetry and are provided in the dataset as a triangular mesh including a precision metric. Matlab functions, bundled with this dataset, allow for the reproduction of the deformation calculations and averages. Lastly, a Matlab App (GUI) is provided for easy visualization of the data. This dataset can serve as a reference for validation of composite forming simulations., (© 2024 The Author(s).)

Scope: Fructans are a group of dietary fibers which are known to have many beneficial effects including immune-modulating effects. A family of fructans are β-(2,6)-linked levan-type fructans that are known to serve as exopolysaccharides in the cell wall of many species of bacteria including commensal bacteria and probiotics. It is still largely unknown whether and how they can serve as immunomodulating molecules., Results: Microbial β-(2,6)-fructans were found to induce TLR-dependent activation of THP-1 cells, in a dose-dependent fashion. Low molecular weight ( M w ), medium M w and high M w β-(2,6)-fructans activated both TLR2 and 4 in a dose- and molecular weight-dependent fashion. In addition, it was found that β-(2,6)-fructans were able to inhibit signalling of various TLRs with the strongest effect on TLR5 and 8, which were inhibited by all the β-(2,6)-fructans in a dose- and molecular weight-dependent fashion. The final effect of this activation and inhibition of TLRs on cytokine responses in human dendritic cells (DCs) was minor which may be explained by the counter-activating effects of the different β-(2,6)-linked levan-type fructans on inhibition of TLR signalling in the DCs., Conclusion: A mechanism by which exopolysaccharide levan β-(2,6)-fructans can be immune-modulating is by impacting TLR signalling. This knowledge could lead to food in which exopolysaccharide levan β-(2,6)-fructans are added for preventing disorders where TLR-signalling is modulated.

A challenge in the development of dry powder formulations for inhalation is the poor reproducibility of their administration to small laboratory animals. The currently used devices for the pulmonary administration of dry powder formulations to small rodents often function sub-optimally as they use the same puff of air for both powder dispersion and aerosol delivery. As a result, either the air volume and flow rate are too low for complete powder deagglomeration or they are too high for effective aerosol delivery to the lungs of the animal. Therefore, novel and better devices are desired. We here present an aerosol generator designed to administer a pre-generated aerosol to the lungs of mice. By mapping the complex relationship between the airflow rate, delivery time and emitted dose, we were able to control the amount of powder being delivered from the aerosol generator. The emitted aerosol had a size range favorable for lung deposition and could be measured reproducibly. Nevertheless, in vivo fluorescent imaging still revealed considerable differences between the mice in terms of the dose deposited and the distribution of powder over the lungs, suggesting that a certain biological variation in lung deposition is inevitable.

Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrum entry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate (CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans (HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteins through a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated when administered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powder formulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops dry powder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activity against RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring the efficacy of pulmonary administered CD-MUS in animal models of RSV infection., Competing Interests: Declaration of Competing Interest Francesco Stellacci is inventor on patent number WO 2018/015465 A1 - Virucidal compounds and uses thereof. Francesco Stellacci and Paulo H. Jacob Silva are co-founders of Asterivir, a start-up company that focuses on developing novel antivirals. The employer of Henderik W. Frijlink holds a license agreement with PureIMS on the Twincer and Cyclops dry powder inhalers. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; nor in the writing of the manuscript or in the decision to submit the article for publication., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To explore the feasibility of an exergame prototype in residential individuals with major neurocognitive disorder (MNCD)., Materials and Methods: Participants were randomly assigned to a 12-week stepping exergame training or traditional exercise (active control group). Semi-structured interviews were conducted after six and 12 weeks of exergaming. Qualitative data were thematically analysed using NVivo 12. The Short Physical Performance Battery, one minute sit-to-stand test, Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory, Cornell Scale for Depression in Dementia, and Dementia Quality of Life were assessed at baseline and post intervention using a Quade's ANCOVA., Results: Seven older adults with MNCD in the exergame and 11 in the active control group completed the study [mean age = 83.2 ± 6.5 years; 94.4% female; SPPB score = 7.3 ± 2.4]. Results indicated that the VITAAL exergame prototype was experienced as enjoyable and beneficial. The post-MMSE score was higher ( η 2 = .02, p  = 0.01, F  = 8.1) following exergaming versus traditional exercise., Conclusions: The findings suggest that the exergame prototype is accepted by individuals with MNCD residing in a long-term care facility when they are able to participate and under the condition that they are extensively guided. The preliminary efficacy results revealed higher post-MMSE scores after exergaming versus traditional exercise. Future trials should confirm or refute these findings., Trial Registration: The trial was registered in ClinicalTrials.gov (Identifier: NCT04436315)Implications for rehabilitationThe VITAAL exergame prototype is accepted by individuals with MNCD residing in a long-term care facility who are able to participate.Supervision of exergaming by health professionals is essential for successful implementation.The VITAAL exergame prototype might maintain cognitive levels in major neurocognitive disorder longer than walking combined with standardised squatting and stepping exercises.

The emergence of SARS-CoV-2 variants raised questions regarding the durability of immune responses after homologous or heterologous boosters after Ad26.COV2.S-priming. We found that SARS-CoV-2-specific binding antibodies, neutralizing antibodies, and T cells are detectable 5 months after boosting, although waning of antibodies and limited cross-reactivity with Omicron BA.1 was observed., Competing Interests: Potential conflicts of interest. L. G. V. reports research grants from U Needle, MyLife Technologies, and Bavarian Nordic, all outside of the submitted work; consulting fees from Emergent for expert meeting travel vaccines; participation on a scientific advisory board for Geosentinel; and serving as committee member for the National Board Guideline Development Travel Medicine. A. G. reports participation on a data and safety monitoring board (DSMB) IDSCOVA (Establishing the tolerability, safety and immunogenicity of intradermal delivery of mRNA SARS-CoV-2 vaccine in healthy adults) study on intradermal COVID vaccinations and serving as member of national advisory board on coronavirus disease vaccinations for immunocompromised patients. A. L. W. H. reports support for the present research from the Dutch Research Council (ZonMw) to their organization. D. F. P. reports participation on the DSMB of the COBRA-KAI trial (COVID-19 vaccination in patients with reduced B-cell and T-cell immunity: response after vaccination in a kaleidoscopic group of hematologic patients: what's the impact?). V. A. S. H. D. reports research funding outside of the submitted work from ZonMw and EU Horizon 2020, consulting fees for an advisory board meeting from GSK, and honoraria for lectures from Pharming, Takeda. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Galacto-oligosaccharides (GOS) and 2'-fucosyllactose (2'-FL) are non-digestible carbohydrates (NDCs) that are often added to infant formula to replace the functionalities of human milk oligosaccharides (HMOs). It is not known if combining GOS and 2'-FL will affect their fermentation kinetics and subsequent immune-modulatory effects such as AhR-receptor stimulation. Here, we used an in vitro set-up for the fermentation of 2'-FL and GOS, either individually or combined, by fecal microbiota of 8-week-old infants. We found that GOS was fermented two times faster by the infant fecal microbiota when combined with 2'-FL, while the combination of GOS and 2'-FL did not result in a complete degradation of 2'-FL. Fermentation of both GOS and 2'-FL increased the relative abundance of Bifidobacterium , which coincided with the production of acetate and lactate. Digesta of the fermentations influenced dendritic cell cytokine secretion differently under normal conditions and in the presence of the AhR-receptor blocker CH223191. We show that, combining GOS and 2'-FL accelerates GOS fermentation by the infant fecal microbiota of 8-week-old infants. In addition, we show that the fermentation digesta of GOS and 2'-FL, either fermented individually or combined, can attenuate DC cytokine responses in a similar and in an AhR-receptor dependent way.

Purpose: This study investigated the experiences of participation in a standing balance exergame program amongst people with major neurocognitive disorder (MNCD) within residential care settings., Materials and Methods: A qualitative descriptive study was conducted in participants with MNCD recruited from two residential settings. Participants exergamed for 15 min, three times per week for 8 weeks. Semi-structured interviews were conducted in all participants of the trial after 4 and 8 weeks. Audio files were transcribed and subsequently a thematic content analysis was performed using NVivo 12. Activity logs including adherence and attrition rates were kept., Results: Thirty-one participants with MNCD participated (median age = 85 (67-93) years; 77.4% women; Mini-Mental State Examination score = 19 (10-25)). Four broad themes emerged: (1) cognitive effects; (2) physical effects; (3) psychosocial effects and (4) motivators. The tailored exergame program was perceived as enjoyable. It stimulated participants' attention, concentration, reaction time, and memory. Participants reported improvements in balance, flexibility, and gait. Exergaming made participants energetic and calm. The attrition rate was 0% and the mean attendance rate was 79.3%., Conclusions: The results indicate that standing balance exergaming is feasible, beneficial, and engaging in people with MNCD.Implications for rehabilitationExergames present a personalised intervention for engaging people with major neurocognitive disorder in physical activity.An exergame intervention is feasible and highly appreciated in this population.Exergames should be adapted to the individuals' needs and possibilities in order to enhance motivation and learning.

Most influenza vaccines are administered via intramuscular injection which has several disadvantages that might jeopardize the compliance of vaccinees. Intradermal administration of dissolving-microneedle-arrays (dMNAs) could serve as minimal invasive alternative to needle injections. However, during the production process of dMNAs antigens are subjected to several stresses, which may reduce their potency. Moreover, the needles need to have sufficient mechanical strength to penetrate the skin and subsequently dissolve effectively to release the incorporated antigen. Here, we investigated whether blends of trehalose and pullulan are suitable for the production of stable dMNA fulfilling these criteria. Our results demonstrate that production of trehalose/pullulan-based dMNAs rendered microneedles that were sharp and stiff enough to pierce into ex vivo human skin and subsequently dissolve within 15 min. The mechanical properties of the dMNAs were maintained well even after four weeks of storage at temperatures up to 37°C. In addition, immunization of mice with influenza antigens via both freshly prepared dMNAs and dMNAs after storage (four weeks at 4°C or 37°C) resulted in antibody titers of similar magnitude as found in intramuscularly injected mice and partially protected mice from influenza virus infection. Altogether, our results demonstrate the potential of trehalose/pullulan-based dMNAs as alternative dosage form for influenza vaccination., Competing Interests: Declaration of Interests 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The wind energy sector is growing rapidly. Wind turbines are increasing in size, leading to higher tip velocities. The leading edges of the blades interact with rain droplets, causing erosion damage over time. In order to mitigate the erosion, coating materials are required to protect the blades. To predict the fatigue lifetime of coated substrates, the Springer model is often used. The current work summarizes the research performed using this model in the wind energy sector and studies the sensitivity of the model to its input parameters. It is shown that the Springer model highly depends on the Poisson ratio, the strength values of the coating and the empirically fitted a2 constant. The assumptions made in the Springer model are not physically representative, and we reasoned that more modern methods are required to accurately predict coating lifetimes. The proposed framework is split into three parts-(1) a contact pressure model, (2) a coating stress model and (3) a fatigue strength model-which overall is sufficient to capture the underlying physics during rain erosion of wind turbine blades. Possible improvements to each of the individual aspects of the framework are proposed.

Graminan-type fructans (GTFs) have demonstrated immune benefits. However, mechanisms underlying these benefits are unknown. We studied GTFs interaction with Toll-like receptors (TLRs), performed molecular docking and determined their impact on dendritic cells (DCs). Effects of GTFs were compared with those of inulin-type fructans (ITFs). Whereas ITFs only contained β(2→1)-linked fructans, GTFs showed higher complexity as it contains additional β(2→6)-linkages. GTFs activated NF-κB/AP-1 through MyD88 and TRIF pathways. GTFs stimulated TLR3, 7 and 9 while ITFs activated TLR2 and TLR4. GTFs strongly inhibited TLR2 and TLR4, while ITFs did not inhibit any TLR. Molecular docking demonstrated interactions of fructans with TLR2, 3, and 4 in a structure dependent fashion. Moreover, ITFs and GTFs attenuated pro-inflammatory cytokine production of stimulated DCs. These findings demonstrate immunomodulatory effects of GTFs via TLRs and attenuation of cytokine production in dendritic cells by GTFs and long-chain ITF., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human milk oligosaccharides (hMOs) are unique bioactive components in human milk. 3-Fucosyllactose (3-FL) is an abundantly present hMO that can be produced in sufficient amounts to allow application in infant formula. Lacto- N -triaose II (LNT2) can be obtained by acid hydrolysis of lacto- N -neotetraose (LNnT). Both 3-FL and LNT2 have been shown to have health benefits, but their impact on infant microbiota composition and microbial metabolic products such as short-chain fatty acids (SCFAs) is unknown. To gain more insight in fermentability, we performed in vitro fermentation studies of 3-FL and LNT2 using pooled fecal microbiota from 12-week-old infants. The commonly investigated galacto-oligosaccharides (GOS)/inulin (9 : 1) served as control. Compared to GOS/inulin, we observed a delayed utilization of 3-FL, which was utilized at 60.3% after 36 h of fermentation, and induced the gradual production of acetic acid and lactic acid. 3-FL specifically enriched bacteria of Bacteroides and Enterococcus genus. LNT2 was fermented much faster. After 14 h of fermentation, 90.1% was already utilized, and production of acetic acid, succinic acid, lactic acid and butyric acid was observed. LNT2 specifically increased the abundance of Collinsella , as well as Bifidobacterium. The GOS present in the GOS/inulin mixture was completely fermented after 14 h, while for inulin, only low DP was rapidly utilized after 14 h. To determine whether the fermentation might lead to enhanced colonization of commensal bacteria to gut epithelial cells, we investigated adhesion of the commensal Lactobacillus plantarum WCFS1 to Caco-2 cells. The fermentation digesta of LNT2 collected after 14 h, 24 h, and 36 h, and GOS/inulin after 24 h of fermentation significantly increased the adhesion of L. plantarum WCFS1 to Caco-2 cells, while 3-FL had no such effect. Our findings illustrate that fermentation of hMOs is very structure-dependent and different from the commonly applied GOS/inulin, which might lead to differential potencies to stimulate adhesion of commensal cells to gut epithelium and consequent microbial colonization. This knowledge might contribute to the design of tailored infant formulas containing specific hMO molecules to meet the need of infants during the transition from breastfeeding to formula.

Scope : Non-digestible carbohydrates (NDCs) such as native chicory inulin and 2'-fucosyllactose (2'-FL) are added to infant formula to mimic some of the human milk oligosaccharide (HMO) functions. It is unknown whether combining inulin and 2'-FL influences their fermentation kinetics and whether the immune-modulatory effects of these NDCs are different under normal and inflammatory-prone Th2-polarizing conditions. Methods and results : We investigated the in vitro fermentation of 2'-FL and native chicory inulin, fermented individually and combined, using fecal inocula of 8-week-old infants. Native inulin was fermented in a size-dependent fashion and expedited the fermentation of 2'-FL. Fermentation of both native inulin and 2'FL increased the relative abundance of Bifidobacterium , which coincided with the production of acetate and lactate. The fermentation digesta of all fermentations differentially influenced both dendritic cell and T-cell cytokine responses under normal culture conditions or in presence of the Th2-polarizing cytokines IL-33 and TSLP, with the most pronounced effect for IL-1β in the presence of TSLP. Conclusions : Our findings show that native inulin can expedite the fermentation of 2'-FL by infant fecal microbiota and that these NDC fermentation digesta have different effects under normal and Th2-polarizing conditions, indicating that infants with different immune backgrounds might benefit from tailored NDC formulations.

Introduction: Pectins have anti-inflammatory properties on intestinal immunity through direct interactions on Toll-like receptors (TLRs) in the small intestine or via stimulating microbiota-dependent effects in the large intestine. Both the degree of methyl-esterification (DM) and the distribution of methyl-esters (degree of blockiness; DB) of pectins contribute to this influence on immunity, but whether and how the DB impacts immunity through microbiota-dependent effects in the large intestine is unknown. Therefore, this study tests pectins that structurally differ in DB in a mouse model with Citrobacter rodentium induced colitis and studies the impact on the intestinal microbiota composition and associated attenuation of inflammation., Methods and Results: Both low and high DB pectins induce a more rich and diverse microbiota composition. These pectins also lower the bacterial load of C. rodentium in cecal digesta. Through these effects, both low and high DB pectins attenuate C. rodentium induced colitis resulting in reduced intestinal damage, reduced numbers of Th1-cells, which are increased in case of C. rodentium induced colitis, and reduced levels of GATA3 + Tregs, which are related to tissue inflammation., Conclusion: Pectins prevent C. rodentium induced colonic inflammation by lowering the C. rodentium load in the caecum independently of the DB., (© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Scope: Next to galacto-oligosaccharides (GOS), starch-derived isomalto-oligosaccharide preparation (IMO) and isomalto/malto-polysaccharides (IMMP) could potentially be used as prebiotics in infant formulas. However, it remains largely unknown how the specific molecular structures of these non-digestible carbohydrates (NDCs) impact fermentability and immune responses in infants., Methods and Results: In vitro fermentation of GOS, IMO and IMMP using infant fecal inoculum of 2- and 8-week-old infants shows that only GOS and IMO are fermented by infant fecal microbiota. The degradation of GOS and IMO coincides with an increase in Bifidobacterium and production of acetate and lactate, which is more pronounced with GOS. Individual isomers with an (1↔1)-linkage or di-substituted reducing terminal glucose residue are more resistant to fermentation. GOS, IMO, and IMMP fermentation digesta attenuates cytokine profiles in immature dendritic cells (DCs), but the extent is dependent on the infants age and NDC structure., Conclusion: The IMO preparation, containing reducing and non-reducing isomers, shows similar fermentation patterns as GOS in fecal microbiota of 2-week-old infants. Knowledge obtained on the substrate specificities of infant fecal microbiota and the subsequent regulatory effects of GOS, IMO and IMMP on DC responses might contribute to the design of tailored NDC mixtures for infants of different age groups., (© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Pultruded fiber-reinforced polymer composites are susceptible to microstructural nonuniformity such as variability in fiber volume fraction (Vf), which can have a profound effect on process-induced residual stress. Until now, this effect of non-uniform Vf distribution has been hardly addressed in the process models. In the present study, we characterized the Vf distribution and accompanying nonuniformity in a unidirectional fiber-reinforced pultruded profile using optical light microscopy. The identified nonuniformity in Vf was subsequently implemented in a mesoscale thermal-chemical-mechanical process model, developed explicitly for the pultrusion process. In our process model, the constitutive material behavior was defined locally with respect to the corresponding fiber volume fraction value in different-sized representative volume elements. The effect of nonuniformity on the temperature and cure degree evolution, and residual stress was analyzed in depth. The results show that the nonuniformity in fiber volume fraction across the cross-section increased the absolute magnitude of the predicted residual stress, leading to a more scattered residual stress distribution. The observed Vf gradient promotes tensile residual stress at the core and compressive residual stress at the outer regions. Consequently, it is concluded that it is essential to take the effects of nonuniformity in fiber distribution into account for residual stress estimations, and the proposed numerical framework was found to be an efficient tool to study this aspect.

Background: It is currently unknown whether exergaming is efficacious in people with major neurocognitive disorder (MNCD) residing in long-term care facilities. This pilot randomized controlled trial (RCT) explored the efficacy of a stepping exergame program on gait speed, balance, mobility, reaction time, cognitive and neuropsychiatric outcomes, quality of life, and daily life functioning in people with MNCD residing in long-term care facilities., Methods: Participants were randomly assigned to 8 weeks, three times weekly, 15 min of exergaming versus watching preferred music videos. The exergame device consisted of a pressure-sensitive step training platform on which participants performed stepping movements to play the games. The device automatically adapted the training level to the participants' capabilities. The Short Physical Performance Battery (SPPB), step reaction time test (SRTT), Montréal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Dementia Quality of Life (DQoL), and Katz Activities of Daily Living (Katz ADL) were assessed at baseline and post-intervention. A Quade's non-parametric ANCOVA controlling for baseline values with post hoc Bonferroni correction (p < 0.00625) was used to analyze pre- and post-differences between the groups. Partial eta-squared (η 2 p) effect sizes were calculated., Results: Forty-five of 55 randomized inpatients with mild to moderate MNCD (Mini-Mental State Examination score = 17.2 ± 4.5; aged 70-91; 35 women) completed the study. The exergame group (n = 23) demonstrated improvements in gait speed (p < 0.001, η 2 p  = 0.41), total SPPB (p < 0.001, η 2 p  = 0.64), SRTT (p<0.001, η 2 p  = 0.51), MoCA (p<0.001, η 2 p  = 0.38), and reductions in CSDD (p<0.001, η 2 p  = 0.43) compared to the control group (n = 22). There were no differences in NPI (p = 0.165, η 2 p  = 0.05), DQoL (p = 0.012, η 2 p  = 0.16), and ADL (p = 0.008, η 2 p  = 0.16) post-intervention scores between the experimental and control group, albeit DQol and ADL measures showed large effect sizes in the exergame group. The mean attendance rate was 82.9% in the exergame group and 73.7% in the music control group. There were no study-related adverse events reported by the participants, nor observed by the research team., Conclusions: The findings of this pilot RCT suggest that an individually adapted exergame training improves lower extremity functioning, cognitive functioning and step reaction time and symptoms of depression in inpatients with MNCD residing in long-term care facilities., Trial Registration: ClinicalTrials.gov, NCT04436302.

Human milk is the gold standard for newborn infants. Breast milk not only provides nutrients, it also contains bioactive components that guide the development of the infant's intestinal immune system, which can have a lifelong effect. The bioactive molecules in breast milk regulate microbiota development, immune maturation and gut barrier function. Human milk oligosaccharides (hMOs) are the most abundant bioactive molecules in human milk and have multiple beneficial functions such as support of growth of beneficial bacteria, anti-pathogenic effects, immune modulating effects, and stimulation of intestine barrier functions. Here we critically review the current insight into the benefits of bioactive molecules in mother milk that contribute to neonatal development and focus on current knowledge of hMO-functions on microbiota and the gastrointestinal immune barrier. hMOs produced via genetically engineered microorganisms are now applied in infant formulas to mimic the nutritional composition of breast milk as closely as possible, and their prospects and scientific challenges are discussed in depth.

Human milk (HM) is the gold standard for the nutrition of infants. An important component of HM is human milk oligosaccharides (hMOs), which play an important role in gut microbiota colonization and gut immune barrier establishment, and thereby contribute to the maturation of the immune system in early life. Guiding these processes is important as disturbances have life-long health effects and can lead to the development of allergic diseases. Unfortunately, not all infants can be exclusively fed with HM. These infants are routinely fed with infant formulas that contain hMO analogs and other non-digestible carbohydrates (NDCs) to mimic the effects of hMOs. Currently, the hMO analogs 2'-fucosyllactose (2'-FL), galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), and pectins are added to infant formulas; however, these NDCs cannot mimic all hMO functions and therefore new NDCs and NDC mixtures need to become available for specific groups of neonates like preterm and disease-prone neonates. In this review, we discuss human data on the beneficial effects of infant formula supplements such as the specific hMO analog 2'-FL and NDCs as well as their mechanism of effects like stimulation of microbiota development, maturation of different parts of the gut immune barrier and anti-pathogenic effects. Insights into the structure-specific mechanisms by which hMOs and NDCs exert their beneficial functions might contribute to the development of new tailored NDCs and NDC mixtures. We also describe the needs for new in vitro systems that can be used for research on hMOs and NDCs. The current data suggest that "tailored infant formulas" for infants of different ages and healthy statuses are needed to ensure a healthy development of the microbiota and the gut immune system of infants.

Scope: Inulin-type fructans are commonly applied in infant formula to support development of gut microbiota and immunity. These inulin-type fructans are considered to be fermented by gut microbiota, but it is unknown how fermentation impacts immune modulating capacity and whether the process of fermentation is dependent on the infant's age., Methods and Results: The in vitro fermentation of chicory fructo-oligosaccharides (FOS) and native inulin are investigated using pooled fecal inocula of two- and eight-week-old infants. Both inocula primarily utilize the trisaccharides in FOS, while they almost completely utilize native inulin with degree of polymerization (DP) 3-8. Fecal microbiota of eight-week-old infants degrades longer chains of native inulin up to DP 16. This correlates with a higher abundance of Bifidobacterium and higher production of acetate and lactate after 26 h of fermentation. Fermented FOS and native inulin attenuate pro-inflammatory cytokines produced by immature dendritic cells (DCs), but profiles and magnitude of attenuation are stronger with native inulin than with FOS., Conclusion: The findings demonstrate that fermentation of FOS and native inulin is dependent on the infant's age and fructan structure. Fermentation enhances attenuating effects of pro-inflammatory responses in DCs, which depend mainly on microbial metabolites formed during fermentation., (© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background : Non-digestible carbohydrates are added to infant formula to mimic the effects of human milk oligosaccharide by acting as prebiotics and stimulating the immune system. Although not yet used in infant formulas, β-glucans are known to have beneficial health effects, and are therefore of potential interest for supplementation. Methods and results : We investigated the in vitro fermentation of native and endo-1,3(4)-β-glucanase-treated oat β-glucan using pooled fecal inocula of 2- and 8-week-old infants. While native oat β-glucan was not utilized, both inocula specifically utilized oat β-glucan oligomers containing β(1→4)-linkages formed upon enzyme treatment. The fermentation rate was highest in the fecal microbiota of 2-week-old infants, and correlated with a high lactate production. Fermentation of media supplemented with native and enzyme-treated oat β-glucans increased the relative abundance of Enterococcus and attenuated pro-inflammatory cytokine production (IL-1β, IL-6, TNFα) in immature dendritic cells. This attenuating effect was more pronounced after enzyme treatment. This attenuation might result from the enhanced ability of fermented oat β-glucan to stimulate Dectin-1 receptors. Conclusion : Our findings demonstrate that endo-1,3(4)-β-glucanase treatment enhances the fermentability of oat β-glucan and attenuates pro-inflammatory responses. Hence, this study shows that especially enzyme-treated oat β-glucans have a high potential for supplementation of infant formula., Competing Interests: The authors declare no conflict of interest.

Advanced thermoplastic composites manufacturing using laser assisted tape placement or winding (LATP/LATW) is a challenging task as monitoring and predicting nip point (bonding) temperature are difficult especially on curved surfaces. A comprehensive numerical analysis of the heat flux and temperature distribution near the nip point is carried out in this paper for helical winding of fiber reinforced thermoplastic tapes on a cylindrically shaped mandrel. An optical ray-tracing technique is coupled with a numerical heat transfer model in the process simulation tool. The developed optical-thermal model predictions were compared with experimental data available in literature to validate its effectiveness. The influences of winding/placement angle, mandrel curvature and tape width on the incident angles, the laser absorbed intensity, and the process temperature distribution are studied extensively using the validated model. Winding/placement angle has a considerable effect on the temperature distribution. Increase in winding angle results in a higher temperature for tape due to more reflections coming from the substrate. On the other hand, substrate temperature decreases as the winding angle increases due to a decrease in the laser incident angles based on the local surface curvature. An increase in mandrel curvature results in higher nip point temperatures for substrate and lower one for tape. Different mandrel sizes for 90 ∘ placement path do not have a strong effect on the substrate process temperature as for other winding angles because of less curvature change of the corresponding irradiated area. Tape width causes local temperature variations at the edges of the tape/substrate. In order to obtain the desired process temeprature during LATW or LATP processes, the laser intensity distribution on the tape and substrate surfaces should be regulated.

Toll-like receptor 8 (TLR-8) plays a role in the pathogenesis of autoimmune disorders and associated gastrointestinal symptoms that reduce quality of life of patients. Dietary interventions are becoming more accepted as mean to manage onset, progression, and treatment of a broad spectrum of inflammatory conditions. In this study, we assessed the impact of N -glycans derived from bovine lactoferrin (bLF) on the inhibition of TLR-8 activation. We investigated the effects of N -glycans in their native form, as well as in its partially demannosylated and partially desialylated form, on HEK293 cells expressing TLR-8, and in human monocyte-derived dendritic cells (MoDCs). We found that in HEK293 cells, N -glycans strongly inhibited the ssRNA40 induced TLR-8 activation but to a lesser extent the R848 induced TLR-8 activation. The impact was compared with a pharmaceutical agent, i.e., chloroquine (CQN), that is clinically applied to antagonize endosomal TLR- activation. Inhibitory effects of the N -glycans were not influenced by the partially demannosylated or partially desialylated N -glycans. As the difference in charge of the N -glycans did not influence the inhibition capacity of TLR-8, it is possible that the inhibition mediated by the N -glycans is a result of a direct interaction with the receptor rather than a result of pH changes in the endosome. The inhibition of TLR-8 in MoDCs resulted in a significant decrease of IL-6 when cells were treated with the unmodified (0.5-fold, p < 0.0001), partially demannosylated (0.3-fold, p < 0.0001) and partially desialylated (0.4-fold, p < 0.0001) N -glycans. Furthermore, the partially demannosylated and partially desialylated N -glycans showed stronger inhibition of IL-6 production compared with the native N -glycans. This provides evidence that glycan composition plays a role in the immunomodulatory activity of the isolated N -glycans from bLF on MoDCs. Compared to CQN, the N -glycans are specific inhibitors of TLR-8 activation and of IL-6 production in MoDCs. Our findings demonstrate that isolated N -glycans from bLF have attenuating effects on TLR-8 induced immune activation in HEK293 cells and human MoDCs. The inhibitory capacity of N -glycans isolated from bLF onTLR-8 activation may become a food-based strategy to manage autoimmune, infections or other inflammatory disorders., (Copyright © 2020 Figueroa-Lozano, Valk-Weeber, Akkerman, Abdulahad, van Leeuwen, Dijkhuizen and de Vos.)

Printing arrays of responsive spots for multiplexed sensing with electrochemical readout requires new molecules and precise, high-throughput deposition of active compounds on microelectrodes with spatial control. We have designed and developed new redox-responsive polymers, featuring a poly(ferrocenylsilane) (PFS) backbone and side groups with disulfide units, which allow an efficient and stable bonding to Au substrates, using sulfur-gold coupling chemistry in a "grafting-to" approach. The polymer molecules can be employed for area selective molecular sensing following their deposition by high-precision inkjet printing. The new PFS derivatives, which serve as "molecular inks", were characterized by 1 H NMR, 13 C NMR, and FTIR spectroscopies and by gel permeation chromatography. The viscosity and surface tension of the inks were assessed by rheology and pendant drop contact angle measurements, respectively. Commercial microelectrode arrays were modified with the new PFS ink by using inkjet printing in the "drop-on-demand" mode. FTIR spectroscopy, AFM, and EDX-SEM confirmed a successful, spatially localized PFS modification of the individual electrodes within the sensing cells of the microelectrode arrays. The potential application of these devices to act as an electrochemical sensor array was demonstrated with a model analyte, ascorbic acid, by using cyclic voltammetry and amperometric measurements.

In this research non-collinear wave mixing is used as a non-destructive testing method where the amplitude of the scattering wave contains information on the condition of a material. The practical implementation of non-collinear wave mixing as a non-destructive testing technique is limited by many factors such as the geometry and shape of the structure, the accessibility to the specimen's surfaces and the ultrasonic sensors available to perform measurements. A novel approach to steer the propagation direction of a generated wave from the mixing of two incident acoustic waves is proposed. The angle of the scattering wave is controlled by the frequencies of the two interaction waves, rather than by the angle between these waves. The scattering amplitude was analytically solved for the longitudinal plus shear interaction process. The analytical solution was validated with experiments. The model qualitatively agrees with the experiments. Furthermore, the possibility to use a wider range of excitation frequencies of the incident waves was found. This is a great advantage in applications where the space and access to the specimen under test is limited., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Human milk (HM) is the golden standard for nutrition of newborn infants. Human milk oligosaccharides (HMOs) are abundantly present in HM and exert multiple beneficial functions, such as support of colonization of the gut microbiota, reduction of pathogenic infections and support of immune development. HMO-composition is during lactation continuously adapted by the mother to accommodate the needs of the neonate. Unfortunately, for many valid reasons not all neonates can be fed with HM and are either totally or partly fed with cow-milk derived infant formulas, which do not contain HMOs. These cow-milk formulas are supplemented with non-digestible carbohydrates (NDCs) that have functional effects similar to that of some HMOs, since production of synthetic HMOs is challenging and still very expensive. However, NDCs cannot substitute all HMO functions. More efficacious NDCs may be developed and customized for specific groups of neonates such as pre-matures and allergy prone infants. Here current knowledge of HMO functions in the neonate in view of possible replacement of HMOs by NDCs in infant formulas is reviewed. Furthermore, methods to expedite identification of suitable NDCs and structure/function relationships are reviewed as in vivo studies in babies are impossible.

Multipotent Adult Progenitor Cells (MAPCs) are one potential stem cell source to generate functional hepatocytes or β-cells. However, human MAPCs have less plasticity than pluripotent stem cells (PSCs), as their ability to generate endodermal cells is not robust. Here we studied the role of 14 transcription factors (TFs) in reprogramming MAPCs to induced endodermal progenitor cells (iENDO cells), defined as cells that can be long-term expanded and differentiated to both hepatocyte- and endocrine pancreatic-like cells. We demonstrated that 14 TF-iENDO cells can be expanded for at least 20 passages, differentiate spontaneously to hepatocyte-, endocrine pancreatic-, gut tube-like cells as well as endodermal tumor formation when grafted in immunodeficient mice. Furthermore, iENDO cells can be differentiated in vitro into hepatocyte- and endocrine pancreatic-like cells. However, the pluripotency TF OCT4, which is not silenced in iENDO cells, may contribute to the incomplete differentiation to mature cells in vitro and to endodermal tumor formation in vivo. Nevertheless, the studies presented here provide evidence that reprogramming of adult stem cells to an endodermal intermediate progenitor, which can be expanded and differentiate to multiple endodermal cell types, might be a valid alternative for the use of PSCs for creation of endodermal cell types.

In this research, ultrasonic pulse echo measurements are used to quantify through thickness chemical degradation in thin mortar specimens. The degradation level is predicted using the time of travel of the acoustic wave through the thickness of the structure. The front and back wall interaction reflections are used to obtain additional information from very early stage degradation. The pulse-velocity of sound waves as a function of the thickness of the layers within the structure is described. With knowledge of the pulse-velocity in pristine and fully degraded conditions, it is possible to determine the complete range of degradation length over the layer thickness. The method is applicable for leaching of calcium and acidic attack. The acoustic measurements were verified with destructive testing. The correlation between the acoustic and non-acoustic experiments agree with the described pulse-velocity and degraded depth function. The method based on ultrasonic measurements can be implemented in other thin-layered structures.

The effect of osmotic shock, enzymatic incubation, pulsed electric field, and high shear homogenization on the release of water-soluble proteins and carbohydrates from the green alga Ulva lactuca was investigated in this screening study. For osmotic shock, both temperature and incubation time had a significant influence on the release with an optimum at 30 °C for 24 h of incubation. For enzymatic incubation, pectinase demonstrated being the most promising enzyme for both protein and carbohydrate release. Pulsed electric field treatment was most optimal at an electric field strength of 7.5 kV cm -1 with 0.05 ms pulses and a specific energy input relative to the released protein as low as 6.6 kWh kg prot -1 . Regarding literature, this study reported the highest protein (~ 39%) and carbohydrate (~ 51%) yields of the four technologies using high shear homogenization. Additionally, an energy reduction up to 86% was achieved by applying a novel two-phase (macrostructure size reduction and cell disintegration) technique.

The increased usage of fiber reinforced polymer composites in load bearing applications requires a detailed understanding of the process induced residual stresses and their effect on the shape distortions. This is utmost necessary in order to have more reliable composite manufacturing since the residual stresses alter the internal stress level of the composite part during the service life and the residual shape distortions may lead to not meeting the desired geometrical tolerances. The occurrence of residual stresses during the manufacturing process inherently contains diverse interactions between the involved physical phenomena mainly related to material flow, heat transfer and polymerization or crystallization. Development of numerical process models is required for virtual design and optimization of the composite manufacturing process which avoids the expensive trial-and-error based approaches. The process models as well as applications focusing on the prediction of residual stresses and shape distortions taking place in composite manufacturing are discussed in this study. The applications on both thermoset and thermoplastic based composites are reviewed in detail.

Background: Gaining insight in long-term health-related quality of life more than 1year after oesophagectomy will assist clinical decision-making and inform patients about the long-term consequences of surgery., Methods: In this cross-sectional study, all consecutive patients who underwent oesophageal resection with gastric interposition for cancer at a tertiary referral centre between January 2007 and July 2012 were included. European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and QLQ-OES18 were sent to all patients alive without recurrence more than 1year after surgery., Results: The questionnaires were completed by 92 of 100 patients. Median duration of follow-up after surgery at completing the questionnaire was 36months (range: 12-75). Global quality of life scores were similar to a general population reference group (76±19 versus 78±17; p=0.26). However, patients scored significantly worse compared to the general population reference group on physical-, role-, cognitive- and social functioning (p<0.001). Neoadjuvant therapy and minimally invasive oesophagectomy were associated with significantly better health-related quality of life (HRQL) and symptom scores (p<0.05)., Conclusion: Global HRQL more than 1year after oesophagectomy with gastric tube reconstruction is comparable to the general Dutch background population, while specific functional and symptom scores are significantly worse. Neoadjuvant therapy and minimally invasive surgery are associated with quality of life benefits in long-term survivors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Waiting times for cardiac surgery is a significant problem in the medical world. The fact that patients' length of stay varies considerably makes effective hospital operation a difficult job. This paper analyzes patients' length of stay in hospital wards following cardiac surgery. Three scenarios for hospital management are presented and evaluated using Markov chain theory and simulation experiments. The aim of our analyses is to examine unused bed capacity in hospital wards. This makes it possible to attain a more efficient allocation of hospital beds. The results presented in this paper provide useful insight into relationships between patients' length of stay, bed availability, and hospital waiting lists.