Computational Modelling of Water Transport in Hydrocolloid Wound Dressing, DuoDERMⓇ CGF, and Design Recommendations

Hydrocolloids, and further hydrogels, have arisen as attractive next-generation wound dressings because of their modularity and ability to retain moisture. Hydrocolloids, like DuoDERM Ⓡ CGF, are intended for partial and full thickness wounds. They may be used for minor burns, cuts, tears, abrasions, as well as lacerations, ulcers, and some traumatic or surgical wounds. A computational simulation of water transport in wounds with hydrocolloid dressings was implemented in order to understand the mechanisms of hydrocolloid wound dressings as they relate to water transport. The ideal dressing will maintain the wounded tissue at physiological water content levels while also retaining moisture within the dressing itself to promote re-epithelialization of tissue. This study aims to determine the effectiveness of current wound dressings with respect to retaining moisture and maintaining the skin at physiological levels of water content. This study further seeks to optimize current wound dressing design parameters in order to improve water retention above the wound bed and maintenance of physiological skin water content. To study the transfer of liquid water in skin and an example hydrocolloid wound dressing, a computational model was built in COMSOL Multiphysics Ⓡ Modeling Software using a multifrontal direct solver (MUMPS). This model primarily detailed water transport processes in the skin (stratum corneum, epidermis, and dermis) with an example hydrocolloid dressing DuoDERM Ⓡ CGF (hydrocolloid and polymeric barrier layer). The use of the model can be extended to larger or smaller wound areas as well as different types of hydrocolloid dressings. The parameters of the materials can be easily altered to fit new materials being simulated, however the model is only valid up to the time right before the hydrocolloid would start to degrade. The model considered the skin layers, wound surface, hydrocolloid, and polymeric barrier layer to be a 2D, axisymmetric cylinder. Water (mass) transport was considered diffusion in porous media in the skin and diffusion in the hydrocolloid and polymeric layers. The swelling effect, typical of hydrocolloids, was modeled using deforming geometry. After validating the model, an objective function was created in order to quantify the performance of the model based on its ability to maintain physiological water content in the skin as well as its ability to retain moisture in the hydrocolloid domain above the wound bed. Using this objective function, the material properties of the hydrocolloid dressing were altered in order to obtain an optimal solution, where the dressing would maintain an ideally moist environment. The results confirmed that the hydrocolloid wound dressing retains moisture but does not satisfactorily maintain wounded tissue near physiological levels of water content. The optimization suggested the variation of two hydrocolloid parameters, the diffusivity and the partitioning coefficient between the skin and hydrocolloid, in order to improve its performance. Lowering the diffusivity of the hydrocolloid resulted in a higher water concentration above the wound bed. Decreasing the partition coefficient (an effect observed by increasing the hydrophobicity of the hydrocolloid) reduced the flux of water from the wound to the dressing. The combined effect of a reduced diffusivity and partition coefficient allowed greater regions of the wound to retain physiological water content levels and improved water retention near the wound bed. These results will inform the design of future generations of wound dressings and elucidate difficulties in the use of hydrophilic wound dressings like hydrocolloids and hydrogels

CSF parameters associated with early MRI activity in patients with MS

Objective To identify CSF parameters at diagnosis of clinically isolated syndrome (CIS) and MS that are associated with early inflammatory disease activity as measured by standardized cerebral MRI (cMRI). Methods One hundred forty-nine patients with newly diagnosed CIS and MS were included in the retrospective study. cMRI at onset and after 12 months was analyzed for T2 and gadolinium-enhancing lesions. CSF was tested for oligoclonal bands and intrathecal synthesis of immunoglobulin G (IgG), A (IgA), andM(IgM) before initiation of disease-modifying therapy (DMT). In a subgroup of patients, CSF and serum samples were analyzed for sCD27, neurofilament light chain, and IgG subclasses 1 and 3. Association between CSF parameters and cMRI activity was investigated by univariable and multivariable regression analysis in all patients, DMT-treated patients, and untreated patients. Results IgG index, sCD27 levels in CSF, and to a lesser extent IgM index were associated with the occurrence of new cMRI lesions. IgG index and sCD27 levels in CSF were highly correlated. In a multivariable analysis, IgG index and to a lesser extent IgM index together with DMT treatment status and gender were strongest predictors of future cMRI activity. Conclusions CSF parameters such as IgG and IgM index are independently associated with future MRI activity and thus might be helpful to support early treatment decisions in patients newly diagnosed with CIS and MS

Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer's patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability

The author's final peer reviewed version can be found by following the URI link. The Publisher's final version can be found by following the DOI link.Aims Amyloid β oligomers (AβO) are potent modulators of Alzheimer’s pathology, yet their impact on one of the earliest brain regions to exhibit signs of the condition, the locus coeruleus (LC), remains to be determined. Of particular importance is whether AβO impact the spontaneous excitability of LC neurons. This parameter determines brain‐wide noradrenaline (NA) release, and thus NA‐mediated brain functions, including cognition, emotion and immune function, which are all compromised in Alzheimer’s. Therefore, the aim of the study was to determine the expression profile of AβO in the LC of Alzheimer’s patients and to probe their potential impact on the molecular and functional correlates of LC excitability, using a mouse model of increased Aβ production (APP‐PSEN1). Methods and Results Immunohistochemistry and confocal microscopy, using AβO‐specific antibodies, confirmed LC AβO expression both intraneuronally and extracellularly in both Alzheimer’s and APP‐PSEN1 samples. Patch clamp electrophysiology recordings revealed that APP‐PSEN1 LC neuronal hyperexcitability accompanied this AβO expression profile, arising from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA‐A receptor (GABAAR) α3 subunit. This altered LC α3‐GABAAR expression profile overlapped with AβO expression in samples from both APP‐PSEN1 mice and Alzheimer’s patients. Finally, strychnine‐sensitive glycine receptors (GlyRs) remained resilient to Aβ‐induced changes and their activation reversed LC hyperexcitability. Conclusions The data suggest a close association between AβO and α3‐GABAARs in the LC of Alzheimer’s patients, and their potential to dysregulate LC activity, thereby contributing to the spectrum of pathology of the LC‐NA system in this condition

Paradigmatic Approach to Support Personalized Counseling With Digital Health (iKNOW)

iKNOW is the first evidence-based digital tool to support personalized counseling for women in Germany with a hereditary cancer risk. The counseling tool is designed for carriers of pathogenic gBRCA (germline breast cancer gene) variants that increase the lifetime risk of breast and ovarian cancer. Carriers of pathogenic variants are confronted with complex, individualized risk information, and physicians must be able to convey this information in a comprehensible way to enable preference-sensitive health decisions. In this paper, we elaborate on the clinical, regulatory, and practical premises of personalized counseling in Germany. By operationalizing these premises, we formulate 5 design principles that, we suggest, are specific enough to develop a digital tool (eg, iKNOW), yet wide-ranging enough to inform the development of counseling tools for personalized medicine more generally: (1) digital counseling tools should implement the current standard of care (eg, based on guidelines); (2) digital counseling tools should help to both standardize and personalize the counseling process (eg, by enabling the preference-sensitive selection of counseling contents from a common information base); (3) digital counseling tools should make complex information easy to access both cognitively (eg, by using evidenced-based risk communication formats) and technically (eg, by means of responsive design for various devices); (4) digital counseling tools should respect the counselee's data privacy rights (eg, through strict pseudonymization and opt-in consent); and (5) digital counseling tools should be systematically and iteratively evaluated with the users in mind (eg, using formative prototype testing to ensure a user-centric design and a summative multicenter, randomized controlled trial). On the basis of these paradigmatic design principles, we hope that iKNOW can serve as a blueprint for the development of more digital innovations to support personalized counseling approaches in cancer medicine

Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

Producción CientíficaAbnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD

Deep Group-wise Variational Diffeomorphic Image Registration

Deep neural networks are increasingly used for pair-wise image registration. We propose to extend current learning-based image registration to allow simultaneous registration of multiple images. To achieve this, we build upon the pair-wise variational and diffeomorphic VoxelMorph approach and present a general mathematical framework that enables both registration of multiple images to their geodesic average and registration in which any of the available images can be used as a fixed image. In addition, we provide a likelihood based on normalized mutual information, a well-known image similarity metric in registration, between multiple images, and a prior that allows for explicit control over the viscous fluid energy to effectively regularize deformations. We trained and evaluated our approach using intra-patient registration of breast MRI and Thoracic 4DCT exams acquired over multiple time points. Comparison with Elastix and VoxelMorph demonstrates competitive quantitative performance of the proposed method in terms of image similarity and reference landmark distances at significantly faster registration