Energy Distribution in disordered elastic Networks

Disordered networks are found in many natural and artificial materials, from gels or cytoskeletal structures to metallic foams or bones. Here, the energy distribution in this type of networks is modeled, taking into account the orientation of the struts. A correlation between the orientation and the energy per unit volume is found and described as a function of the connectivity in the network and the relative bending stiffness of the struts. If one or both parameters have relatively large values, the struts aligned in the loading direction present the highest values of energy. On the contrary, if these have relatively small values, the highest values of energy can be reached in the struts oriented transversally. This result allows explaining in a simple way remodeling processes in biological materials, for example, the remodeling of trabecular bone and the reorganization in the cytoskeleton. Additionally, the correlation between the orientation, the affinity, and the bending-stretching ratio in the network is discussed

Just a 'romantic idea'? A theory-based interview study on medication review implementation with pharmacy owners.

Recent legal changes in Germany entitle patients on multiple medications to receive a medication review (MR). However, the provision of MRs is not mandatory and pharmacy owners decide whether to implement this service in their pharmacies. The aim of this study was to determine pharmacy owners' attitudes towards MRs, explore their experiences with MR implementation and examine their perceptions of barriers and facilitators towards implementation of MRs in community pharmacies. Pharmacy owners were invited to participate in semi-structured interviews. Purposive sampling was used with selection criteria being MR-implementation stage, and geographical location of the pharmacy. The topic guide was based on a systematic review and the Framework for Implementation of Services in Pharmacy (FISpH). Interviews were recorded, transcribed verbatim and coded directly against the FISpH. Twenty-one pharmacy owners were interviewed. Despite participants' consistent positive attitude towards MRs, most believed that providing MRs on an economically viable basis would be challenging. Several practical suggestions emerged which would enable community pharmacies a smoother implementation of MRs. Suggestions included employing ‘change facilitators', who visit and support implementing pharmacies; national awareness campaigns targeting patients and health professionals; reducing bureaucracy; continuing professional development; involving technicians in some MR-tasks; and offering an additional incentive to lower the initial implementation threshold. This research identified numerous factors that are likely to increase owners' and managers' support to the idea of MRs. This may be of interest to any country planning implementation of MRs

Facilitating implementation of medication reviews in the community pharmacy setting: an application of the implementation research logic model.

Previous research has identified both determinants and potential strategies to facilitate implementation of medication reviews (MR). A conceptual model which links determinants, strategies to support implementation and mechanisms of change to execute implementation, with projected outcomes is helpful to plan the approach and facilitate MR-implementation. The aim of this research was to apply the Implementation Research Logic Model (ILRM) for the implementation of medication reviews in the German community pharmacy setting, and thus illustrate the links between determinants, strategies, and implementation outcomes. The resulting map is meant to inform and facilitate MR-implementation. The IRLM was populated with determinants (barriers and facilitators structured using the Framework for Implementation of Services in Pharmacy, FISpH), proposed strategies (according to the Expert Recommendations for Implementing Change, ERIC) and mechanisms of change which were identified in an interview study with 21 German pharmacy owners. The research team linked these with 8 implementation outcomes derived from Proctor: acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, sustainability. Twenty strategies from the interview study were mapped against 32 determinants. All strategies were hypothesised to impact on one or several of the 8 implementation outcomes. Depending on pharmacies' implementation stage (exploration, preparation, implementation, and sustainment) the importance of strategies was expected to vary. Strategies such as educational meetings and learning collaboratives can increase perceived appropriateness and boost adoption of MRs which is particularly important for pharmacies in the early exploration stage. Strategies such as receiving support from external implementation advisors as well as recruiting and training internal implementation leaders were deemed particularly important for pharmacies at the preparation stage to strengthen feasibility and fidelity. In later stages (implementation and sustainment) pharmacies were thought to benefit from provision of clinical feedback, obtaining and using patient feedback and re-examining implementation to achieve high fidelity, penetration, and sustainability of MR-provision. Some strategies such as fixed payment and stable delivery contracts were deemed pre-requisites for implementation irrespective of the stage the pharmacy was at. The application of the Implementation Research Logic Model illustrated the relations between determinants, strategies, mechanisms, and implementation outcomes. Future research is needed to ascertain that strategies work as planned and achieve the projected implementation outcomes

Implementation of medication reviews in community pharmacy: reaching consensus on stakeholders' recommendations for mechanisms of change using the nominal group technique.

Since 2022, patients with five or more medicines are eligible for a medication review (MR) in a community pharmacy remunerated by the German health system. However, implementation has been slow, with few pharmacies providing MRs. Stakeholders' input is necessary to detail how implementation strategies can be executed effectively on a national level. Prior research identified "external facilitation" and "altering incentives" as crucial strategies to achieve implementation outcomes. To gather stakeholders’ recommendations for, and obtain consensus on, mechanisms of change that allow implementation strategies to work in practice. The consensus method used was the nominal group technique (NGT) with NGT-discussions held separately with pharmacy owners and pharmacy chambers employees. Votes were summed and the relative importance (rI) calculated, defined as (score achieved for a mechanism)/(maximum possible score) × 100. Content analysis provided context for the highest ranked mechanisms and allowed linking to implementation outcomes. Four NGT-discussions were held in 2023 (n = 2 owners; n = 2 chamber employees) with a total of 17 participants. The overall highest ranked mechanisms were fit-for-purpose software (rI = 154.7) detailed process support (rI = 104.9) and an expert support line (rI = 77.7). These together with financial viability (rI = 40.0) were prioritised by both participant groups. Three mechanisms were favoured for both implementation strategies, namely software, process support and materials (rI = 34.3). This study identified stakeholders' priorities for mechanisms of change to implement MRs in community pharmacies. Focusing efforts on the prioritised mechanisms is likely to significantly advance a national implementation plan for countries which are at an early implementation stage

Quantification of the Temporal Evolution of Collagen Orientation in Mechanically Conditioned Engineered Cardiovascular Tissues

Load-bearing soft tissues predominantly consist of collagen and exhibit anisotropic, non-linear visco-elastic behavior, coupled to the organization of the collagen fibers. Mimicking native mechanical behavior forms a major goal in cardiovascular tissue engineering. Engineered tissues often lack properly organized collagen and consequently do not meet in vivo mechanical demands. To improve collagen architecture and mechanical properties, mechanical stimulation of the tissue during in vitro tissue growth is crucial. This study describes the evolution of collagen fiber orientation with culture time in engineered tissue constructs in response to mechanical loading. To achieve this, a novel technique for the quantification of collagen fiber orientation is used, based on 3D vital imaging using multiphoton microscopy combined with image analysis. The engineered tissue constructs consisted of cell-seeded biodegradable rectangular scaffolds, which were either constrained or intermittently strained in longitudinal direction. Collagen fiber orientation analyses revealed that mechanical loading induced collagen alignment. The alignment shifted from oblique at the surface of the construct towards parallel to the straining direction in deeper tissue layers. Most importantly, intermittent straining improved and accelerated the alignment of the collagen fibers, as compared to constraining the constructs. Both the method and the results are relevant to create and monitor load-bearing tissues with an organized anisotropic collagen network

Effect of Strain Magnitude on the Tissue Properties of Engineered Cardiovascular Constructs

Mechanical loading is a powerful regulator of tissue properties in engineered cardiovascular tissues. To ultimately regulate the biochemical processes, it is essential to quantify the effect of mechanical loading on the properties of engineered cardiovascular constructs. In this study the Flexercell FX-4000T (Flexcell Int. Corp., USA) straining system was modified to simultaneously apply various strain magnitudes to individual samples during one experiment. In addition, porous polyglycolic acid (PGA) scaffolds, coated with poly-4-hydroxybutyrate (P4HB), were partially embedded in a silicone layer to allow long-term uniaxial cyclic mechanical straining of cardiovascular engineered constructs. The constructs were subjected to two different strain magnitudes and showed differences in biochemical properties, mechanical properties and organization of the microstructure compared to the unstrained constructs. The results suggest that when the tissues are exposed to prolonged mechanical stimulation, the production of collagen with a higher fraction of crosslinks is induced. However, straining with a large strain magnitude resulted in a negative effect on the mechanical properties of the tissue. In addition, dynamic straining induced a different alignment of cells and collagen in the superficial layers compared to the deeper layers of the construct. The presented model system can be used to systematically optimize culture protocols for engineered cardiovascular tissues

Colocalization of connexin 36 and corticotropin-releasing hormone in the mouse brain

<p>Abstract</p> <p>Background</p> <p>Gap junction proteins, connexins, are expressed in most endocrine and exocrine glands in the body and are at least in some glands crucial for the hormonal secretion. To what extent connexins are expressed in neurons releasing hormones or neuropeptides from or within the central nervous system is, however, unknown. Previous studies provide indirect evidence for gap junction coupling between subsets of neuropeptide-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Here we employ double labeling and retrograde tracing methods to investigate to what extent neuroendocrine and neuropeptide-containing neurons of the hypothalamus and brainstem express the neuronal gap junction protein connexin 36.</p> <p>Results</p> <p>Western blot analysis showed that connexin 36 is expressed in the PVN. In bacterial artificial chromosome transgenic mice, which specifically express the reporter gene Enhanced Green Fluorescent Protein (EGFP) under the control of the connexin 36 gene promoter, EGFP expression was detected in magnocellular (neuroendocrine) and in parvocellular neurons of the PVN. Although no EGFP/connexin36 expression was seen in neurons containing oxytocin or vasopressin, EGFP/connexin36 was found in subsets of PVN neurons containing corticotropin-releasing hormone (CRH), and in somatostatin neurons located along the third ventricle. Moreover, CRH neurons in brainstem areas, including the lateral parabrachial nucleus, also expressed EGFP/connexin 36.</p> <p>Conclusion</p> <p>Our data indicate that connexin 36 is expressed in subsets of neuroendocrine and CRH neurons in specific nuclei of the hypothalamus and brainstem.</p

Time course study of oxidative and nitrosative stress and antioxidant enzymes in K(2)Cr(2)O(7)-induced nephrotoxicity

BACKGROUND: Potassium dichromate (K(2)Cr(2)O(7))-induced nephrotoxicity is associated with oxidative and nitrosative stress. In this study we investigated the relation between the time course of the oxidative and nitrosative stress with kidney damage and alterations in the following antioxidant enzymes: Cu, Zn superoxide dismutase (Cu, Zn-SOD), Mn-SOD, glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT). METHODS: Nephrotoxicity was induced in rats by a single injection of K(2)Cr(2)O(7). Groups of animals were sacrificed on days 1,2,3,4,6,8,10, and 12. Nephrotoxicity was evaluated by histological studies and by measuring creatinine clearance, serum creatinine, blood urea nitrogen (BUN), and urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and total protein. Oxidative and nitrosative stress were measured by immunohistochemical localization of protein carbonyls and 3-nitrotyrosine, respectively. Cu, Zn-SOD, Mn-SOD, and CAT were studied by immunohistochemical localization. The activity of total SOD, CAT, GPx, and GR was also measured as well as serum and kidney content of chromium and urinary excretion of NO(2 )(-)/NO(3)(-). Data were compared by two-way analysis of variance followed by a post hoc test. RESULTS: Serum and kidney chromium content increased reaching the highest value on day 1. Nephrotoxicity was made evident by the decrease in creatinine clearance (days 1–4) and by the increase in serum creatinine (days 1–4), BUN (days 1–6), urinary excretion of NAG (days 1–4), and total protein (day 1–6) and by the structural damage to the proximal tubules (days 1–6). Oxidative and nitrosative stress were clearly evident on days 1–8. Urinary excretion of NO(2)(-)/NO(3)(- )decreased on days 2–6. Mn-SOD and Cu, Zn-SOD, estimated by immunohistochemistry, and total SOD activity remained unchanged. Activity of GPx decreased on days 3–12 and those of GR and CAT on days 2–10. Similar findings were observed by immunohistochemistry of CAT. CONCLUSION: These data show the association between oxidative and nitrosative stress with functional and structural renal damage induced by K(2)Cr(2)O(7). Renal antioxidant enzymes were regulated differentially and were not closely associated with oxidative or nitrosative stress or with kidney damage. In addition, the decrease in the urinary excretion of NO(2)(-)/NO(3)(- )was associated with the renal nitrosative stress suggesting that nitric oxide was derived to the formation of reactive nitrogen species involved in protein nitration

Experiences of key stakeholders with the implementation of medication reviews in community pharmacies: a systematic review using the Consolidated Framework for Implementation Research (CFIR).

Background: Though medication reviews have shown positive patient outcomes, they are still not widely implemented in community pharmacies. Published reviews on their implementation often include several other pharmacy services, making them non-specific. Using the Consolidated Framework for Implementation Research (CFIR) to focus solely on the experiences of different stakeholders with the implementation of medication reviews will help to better understand relevant facilitators and barriers. Objectives: To critically appraise, synthesise and present the available evidence on experiences of key stakeholders with the implementation of medication reviews and to identify barriers and facilitators to its implementation in community pharmacies. Methods: A systematic literature search was conducted in four databases for studies published in English, Spanish or German. Key search terms included: implementation, pharmac*, medication review, facilitator, barrier. Study selection, quality assessment and data extraction were performed by two independent reviewers. Findings were mapped directly against the constructs of the CFIR. Results: Out of 924 retrieved records 24 articles from 9 countries met the inclusion criteria. Key facilitators identified included pharmacists' openness to practice change and a high degree of patient satisfaction post medication review. Attracting patients to the service was stated as challenging due to an unawareness of the scope and potential benefit of a medication review. The dominant barrier was inadequate remuneration, as it impacted all additional resourcing and ultimately the viability of the service. Further barriers included difficult professional relationships with doctors and little mandate from health authorities. Most reports were from the employed pharmacists’ perspective and concerned the inner setting, other perspectives were under-reported. Conclusions: Results of this systematic review illustrate different stakeholders' experiences and add to the understanding of challenges in the implementation process. Nevertheless, findings also highlight how scarce reporting of external stakeholders’ views is and that filling this gap can unveil hidden barriers and facilitators. Registration: PROSPERO register (CRD 42019122836)