Implementation of dementia care management in routine care (RoutineDeCM): a study protocol for process evaluation.

INTRODUCTION: Dementia care management is a complex intervention intended to support persons with dementia and their (caring) relatives in home-based care arrangements. Dementia care management was developed in the federal state of Mecklenburg-Western Pomerania in Germany and subsequently adapted for the German region of Siegen-Wittgenstein, where it will now be implemented. Four different service providers will carry out the implementation process. This study protocol describes the planned procedures for the parallel evaluation of the implementation process. METHODS AND ANALYSIS: A multiple embedded case study design was chosen for the planned process evaluation. Data collection and analysis will be informed by the Consolidated Framework for Implementation Research, the Expert Recommendations for Implementing Change, the Medical Research Council framework for conducting process evaluations of complex interventions and the Taxonomy of Outcomes for Implementation Research. Information (qualitative and quantitative) will be collected from all stakeholders involved in the dementia care management intervention (ie, dementia care managers, general practitioners, people with dementia). ETHICS AND DISSEMINATION: The process evaluation is conducted in accordance with the Declaration of Helsinki, the recommendations on good scientific practice, the research ethics principles of the Code of Ethics of the German Society of Nursing Science, and on the basis of ethical approval from the Clinical Ethics Committee of University Medicine Greifswald (BB 110/22). The results of the process evaluation will be disseminated through reports to the funders of the study and also as a summary of recommendations for the sustainable implementation of dementia care management for future implementers. We also plan to publish the results of this process evaluation in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05529277, Registered 7 September 2022, https://beta. CLINICALTRIALS: gov/study/NCT05529277.

Perceptions on Extending the Use of Technology after the COVID-19 Pandemic Resolves: A Qualitative Study with Older Adults.

The COVID-19 pandemic of the last two years has affected the lives of many individuals, especially the most vulnerable and at-risk population groups, e.g., older adults. While social distancing and isolation are shown to be effective at decreasing the transmission of the virus, these actions have also increased loneliness and social isolation. To combat social distancing from family and friends, older adults have turned to technology for help. In the health sector, these individuals also had a variety of options that strengthened eHealth care services. This study analyzed the technologies used during the COVID-19 pandemic by a group of older people, as well as explored their expectations of use after the pandemic period. Qualitative and ethnographic interviews were conducted with 10 Portuguese older adults, and data were collected over a period of seven months between 2020 and 2021. The research demonstrated that the use of current and new technologies in the post-pandemic future is likely to be related to overcoming: (i) insecurity regarding privacy issues; (ii) difficulties in using technologies due to the level of use of digital technology; and (iii) the human distancing and impersonal consequences of using these technologies.

Adapting a Dementia Care Management Intervention for Regional Implementation: A Theory-Based Participatory Barrier Analysis.

Dementia is a leading cause of disability and dependency in older people worldwide. As the number of people affected increases, so does the need for innovative care models. Dementia care management (DCM) is an empirically validated approach for improving the care and quality of life for people with dementia (PwD) and caregivers. The aim of this study is to investigate the influencing factors and critical pathways for the implementation of a regionally adapted DCM standard in the existing primary care structures in the German region of Siegen-Wittgenstein (SW). Utilizing participatory research methods, five local health care experts as co-researchers conducted N = 13 semi-structured interviews with 22 local professionals and one caregiver as peer reviewers. Data collection and analysis were based on the Consolidated Framework for Implementation Research (CFIR). Our results show that among the most mentioned influencing factors, three CFIR constructs can be identified as both barriers and facilitators: Patients' needs and resources, Relative advantage, and Cosmopolitanism. The insufficient involvement of relevant stakeholders is the major barrier and the comprehensive consideration of patient needs through dementia care managers is the strongest facilitating factor. The study underlines the vital role of barrier analysis in site-specific DCM implementation.

Implementation of a pan-European ecosystem and an interoperable platform for Smart and Healthy Ageing in Europe: An Innovation Action research protocol.

As life expectancy continues to increase in most EU Member States, smart technologies can help enable older people to continue living at home, despite the challenges accompanying the ageing process. The Innovation Action (IA) SHAPES 'Smart and Healthy Ageing through People Engaging in Supportive Systems' funded by the EU under the Horizon 2020 Research and Innovation Programme (grant agreement number 857159) attends to these topics to support active and healthy ageing and the wellbeing of older adults. This protocol article outlines the SHAPES project's objectives and aims, methods, structure, and expected outcomes. SHAPES seeks to build, pilot, and deploy a large-scale, EU-standardised interoperable, and scalable open platform. The platform will facilitate the integration of a broad range of technological, organisational, clinical, educational, and social solutions. SHAPES emphasises that the home is much more than a house-space; it entails a sense of belonging, a place and a purpose in the community. SHAPES creates an ecosystem - a network of relevant users and stakeholders - who will work together to scale-up smart solutions. Furthermore, SHAPES will create a marketplace seeking to connect demand and supply across the home, health and care services. Finally, SHAPES will produce a set of recommendations to support key stakeholders seeking to integrate smart technologies in their care systems to mediate care delivery. Throughout, SHAPES adopts a multidisciplinary research approach to establish an empirical basis to guide the development of the platform. This includes long-term ethnographic research and a large-scale pan-European campaign to pilot the platform and its digital solutions within the context of seven distinct pilot themes. The project will thereby address the challenges of ageing societies in Europe and facilitate the integration of community-based health and social care. SHAPES will thus be a key driver for the transformation of healthcare and social care services across Europe.

Dual Element (C/Cl) Isotope Analysis Indicates Distinct Mechanisms of Reductive Dehalogenation of Chlorinated Ethenes and Dichloroethane in Dehalococcoides mccartyi Strain BTF08 With Defined Reductive Dehalogenase Inventories.

Dehalococcoides mccartyi strain BTF08 has the unique property to couple complete dechlorination of tetrachloroethene and 1,2-dichloroethane to ethene with growth by using the halogenated compounds as terminal electron acceptor. The genome of strain BTF08 encodes 20 genes for reductive dehalogenase homologous proteins (RdhA) including those described for dehalogenation of tetrachloroethene (PceA, PteA), trichloroethene (TceA) and vinyl chloride (VcrA). Thus far it is unknown under which conditions the different RdhAs are expressed, what their substrate specificity is and if different reaction mechanisms are employed. Here we found by proteomic analysis from differentially activated batches that PteA and VcrA were expressed during dechlorination of tetrachloroethene to ethene, while TceA was expressed during 1,2-dichloroethane dehalogenation. Carbon and chlorine compound-specific stable isotope analysis suggested distinct reaction mechanisms for the dechlorination of (i) cis-dichloroethene and vinyl chloride versus (ii) tetrachloroethene. This differentiation was observed independent of the expressed RdhA proteins. Differently, two stable isotope fractionation patterns were observed for 1,2-dichloroethane transformation, for cells with distinct RdhA inventories. Conclusively, we could link specific RdhA expression with functions and provide an insight into the apparently substrate-specific reaction mechanisms in the pathway of reductive dehalogenation in D. mccartyi strain BTF08. Data are available via ProteomeXchange with identifiers PXD018558 and PXD018595.

Macrophage entrapped silica coated superparamagnetic iron oxide particles for controlled drug release in a 3D cancer model.

Targeted delivery of drugs is a major challenge in treatment of diverse diseases. Systemically administered drugs demand high doses and are accompanied by poor selectivity and side effects on non-target cells. Here, we introduce a new principle for targeted drug delivery. It is based on macrophages as transporters for nanoparticle-coupled drugs as well as controlled release of drugs by hyperthermia mediated disruption of the cargo cells and simultaneous deliberation of nanoparticle-linked drugs. Hyperthermia is induced by an alternating electromagnetic field (AMF) that induces heat from silica-coated superparamagnetic iron oxide nanoparticles (SPIONs). We show proof-of-principle of controlled release by the simultaneous disruption of the cargo cells and the controlled, AMF induced release of a toxin, which was covalently linked to silica-coated SPIONs via a thermo-sensitive linker. Cells that had not been loaded with SPIONs remain unaffected. Moreover, in a 3D co-culture model we demonstrate specific killing of associated tumour cells when employing a ratio as low as 1:40 (SPION-loaded macrophage: tumour cells). Overall, our results demonstrate that AMF induced drug release from macrophage-entrapped nanoparticles is tightly controlled and may be an attractive novel strategy for targeted drug release.

The Complexome of Dehalococcoides mccartyi Reveals Its Organohalide Respiration-Complex Is Modular.

Dehalococcoides mccartyi strain CBDB1 is a slow growing strictly anaerobic microorganism dependent on halogenated compounds as terminal electron acceptor for anaerobic respiration. Indications have been described that the membrane-bound proteinaceous organohalide respiration complex of strain CBDB1 is functional without quinone-mediated electron transfer. We here study this multi-subunit protein complex in depth in regard to participating protein subunits and interactions between the subunits using blue native gel electrophoresis coupled to mass spectrometric label-free protein quantification. Applying three different solubilization modes to detach the respiration complex from the membrane we describe different solubilization snapshots of the organohalide respiration complex. The results demonstrate the existence of a two-subunit hydrogenase module loosely binding to the rest of the complex, tight binding of the subunit HupX to OmeA and OmeB, predicted to be the two subunits of a molybdopterin-binding redox subcomplex, to form a second module, and the presence of two distinct reductive dehalogenase module variants with different sizes. In our data we obtained biochemical evidence for the specificity between a reductive dehalogenase RdhA (CbdbA80) and its membrane anchor protein RdhB (CbdbB3). We also observed weak interactions between the reductive dehalogenase and the hydrogenase module suggesting a not yet recognized contact surface between these two modules. Especially an interaction between the two integral membrane subunits OmeB and RdhB seems to promote the integrity of the complex. With the different solubilization strengths we observe successive disintegration of the complex into its subunits. The observed architecture would allow the association of different reductive dehalogenase modules RdhA/RdhB with the other two protein complex modules when the strain is growing on different electron acceptors. In the search for other respiratory complexes in strain CBDB1 the remarkable result is not the detection of a standard ATPase but the absence of any other abundant membrane complex although an 11-subunit version of complex I (Nuo) is encoded in the genome.

Exploiting the Synthetic Potential of Sesquiterpene Cyclases for Generating Unnatural Terpenoids.

The substrate flexibility of eight purified sesquiterpene cyclases was evaluated using six new heteroatom-modified farnesyl pyrophosphates, and the formation of six new heteroatom-modified macrocyclic and tricyclic sesquiterpenoids is described. GC-O analysis revealed that tricyclic tetrahydrofuran exhibits an ethereal, peppery, and camphor-like olfactoric scent.

Substrate specificity of α-humulene synthase from Zingiber zerumbet Smith and determination of kinetic constants by a spectrophotometric assay.

Terpene synthases are the key enzymes in terpene biosynthesis that provide a structurally complex and highly diverse product spectrum. A suitable and reliable analytical assay is indispensable to measure terpene synthase activity accurately and precisely. In this study, a malachite green assay (MG) was adapted to rapidly assay terpene synthase activity and was validated in comparison to an already established gas chromatography assay. A linear correlation between both assays was observed. Kinetic properties for the previously described sesquiterpene synthase α-humulene synthase (HUM) from Zingiber zerumbet Smith were investigated for the bioconversion of the monoterpene precursors geranyl pyrophosphate (2E-GPP) and neryl pyrophosphate (2Z-NPP) as well as for the sesquiterpene precursor farnesyl pyrophosphate (2E,6E-FPP). Also, gas chromatography mass spectrometry (GS-MS) was carried out to identify the products of the bioconversion of (2E)-GPP and (2Z)-NPP.

Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo.

Conjugates based on nanostructured, superparamagnetic particles, a thermolabile linker and a cytotoxic maytansinoid were developed to serve as a model for tumour-selective drug delivery and release. It combines chemo- with thermal therapy. The linker-modified toxin was prepared by a combination of biotechnology and semisynthesis. Drug release was achieved by hyperthermia through an external oscillating electromagnetic field that induces heat inside the particles. Efficacy of this release concept was demonstrated both for cancer cell proliferation in vitro, and for tumour growth in vivo, in a xenograft mouse model. Biocompatibility studies for these magnetic-nanoparticle/ansamitocin conjugates complement this work.

SandTraps are efficient, scalable, and mild systems for harvesting, washing and concentrating cells.

Microbial cells vary widely in size, specific density, shearing resistance, oxygen sensitivity and abundance so that differential harvesting and washing procedures are needed to efficiently recover cells from dilute suspensions. We here describe a mild, simple, variable and cost-efficient method to harvest cells on columns packed with silica beads. The method collects and concentrates 40-98% of the cells preserving enzymatic activity and cell viability. The method can be applied for strictly anaerobic microorganisms, is scalable to different culture volumes and can be multiplexed in standardized systems. We see major application potential in harvesting small cells leaking through 0.2µm filters, for harvesting strictly anaerobic cells and for differential harvesting of cells according to cell size using a gradient system.

A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide-Ansamitocin Conjugates for Use in Magnetic Drug Targeting.

A combination of mutasynthesis using a mutant strain of A. pretiosum blocked in the biosynthesis of amino-hydroxybenzoic acid (AHBA) and semisynthesis relying on a Stille cross-coupling step provided access to new ansamitocin derivatives of which one was attached by a thermolabile linker to nanostructured iron oxide particles. When exposed to an oscillating electromagnetic field the resulting iron oxide/ansamitocin conjugate 19 heats up in an aqueous suspension and the ansamitocin derivative 16 is released by means of a retro-Diels-Alder reaction. It exerts strong antiproliferative activity (IC50 =4.8 ng mg-1 ) in mouse fibroblasts. These new types of conjugates have the potential for combating cancer through hyperthermia and chemotherapy using an electromagnetic external trigger.

Preparation of thermocleavable conjugates based on ansamitocin and superparamagnetic nanostructured particles by a chemobiosynthetic approach.

A combination of mutasynthesis, precursor-directed biosynthesis and semisynthesis provides access to new ansamitocin derivatives including new nanostructured particle-drug conjugates. These conjugates are based on the toxin ansamitocin and superparamagnetic iron oxide-silica core shell particles. New ansamitocin derivatives that are functionalized either with alkynyl- or azido groups in the ester side chain at C-3 are attached to nanostructured iron oxide core-silica shell particles. Upon exposure to an oscillating electromagnetic field these conjugates heat up and the ansamitocin derivatives are released by a retro-Diels-Alder reaction. For example, one ansamitocin derivative exerts strong antiproliferative activity against various cancer cell lines in the lower nanomolar range while the corresponding nanostructured particle-drug conjugate is not toxic. Therefore, these new conjugates can serve as dormant toxins that can be employed simultaneously in hyperthermia and chemotherapy when external inductive heating is applied.

Paternal deprivation alters the development of catecholaminergic innervation in the prefrontal cortex and related limbic brain regions.

The impact of paternal care on the development of catecholaminergic fiber innervations in the prefrontal cortex, nucleus accumbens, hippocampus and the amygdala was quantitatively investigated in the biparental Octodon degus. Two age (juvenile, adult) and rearing groups: (1) degus reared without father and (2) degus raised by both parents were compared. Juvenile father-deprived animals showed significantly elevated densities of TH-immunoreactive fibers in all analyzed regions, except in the orbitofrontal cortex, as compared to biparentally reared animals. This difference between the two rearing groups was still evident in adulthood in the prelimbic and infralimbic cortices and in the hippocampal formation. Interestingly, the elevated TH fiber density in both nucleus accumbens subregions was reversed in adulthood, i.e. adult father-deprived animals showed strongly reduced TH fiber densities as compared to biparentally reared animals. We show here that paternal care plays a critical role in the functional maturation of catecholaminergic innervation patterns in prefrontal and limbic brain circuits.

Paternal deprivation alters region- and age-specific interneuron expression patterns in the biparental rodent, Octodon degus.

The impact of paternal care on the postnatal development of inhibitory neuronal subpopulations in prefrontal and limbic brain regions was studied in the rodent Octodon degus. Comparing offspring from biparental families with animals raised by a single mother revealed region-specific deprivation-induced changes in the density of PARV- and CaBP-D28k expressing cells. Some deprivation-induced changes were only seen at P21: elevated CaBP-D28k-positive neurons in the orbitofrontal cortex, CA1, CA3, and dentate gyrus (DG) and elevated PARV-positive neurons in the lateral orbitofrontal, prelimbic/infralimbic (PL/IL), DG and CA1, nucleus accumbens, and amygdala. Some deprivation-induced changes were obvious in both age groups: increased CaBP-D28k-positive neurons in the nucleus accumbens shell and increased PARV-positive neurons in the ventral orbitofrontal. Some deprivation-induced changes were only seen in adulthood: increased CaBP-D28k-positive neurons in the amygdala and decreased PARV-positive neurons in the PL/IL and in CA3. In CA1, PARV-positive neurons were increased at P21 and decreased in adulthood. The functional significance of the deprivation-induced changes in PARV-positive neurons, which are involved in gamma oscillations and thereby affect information processing and which appear to be key players for critical period plasticity in sensory cortex development, as well as the behavioral implications remain to be further elucidated.

Paternal deprivation induces dendritic and synaptic changes and hemispheric asymmetry of pyramidal neurons in the somatosensory cortex.

Similar to maternal care, paternal care is a source of neonatal sensory stimulation, which in primates and rodents has been shown to be essential for developing structure and function of sensory cortices. The aim of our study in the biparental rodent Octodon degus was to assess the impact of paternal deprivation on dendritic and synaptic development in the somatosensory cortex. We (i) quantified the amount of paternal care in relation to total parental investment and (ii) compared dendritic and synaptic development of pyramidal neurons in the somatosensory cortex of animals raised by a single mother or by both parents. On the behavioral level we show that paternal care comprises 37% of total parent-offspring interactions, and that the somatosensory stimulation provided by the fathers primarily consists of huddling, licking/grooming, and playing. On the morphological level we found that, compared with offspring raised by both parents (mother and father), the father-deprived animals displayed significantly reduced spine numbers on the basal dendrites of pyramidal neurons. Furthermore, paternal deprivation induces hemispheric asymmetry of the dendritic morphology of somatosensory pyramidal neurons. Father-deprived animals show shorter and less complex basal dendrites in the left somatosensory cortex compared with the right hemisphere. These findings indicate that paternal deprivation results in delayed or retarded dendritic and synaptic development of somatosensory circuits.

Repeated neonatal separation stress alters the composition of neurochemically characterized interneuron subpopulations in the rodent dentate gyrus and basolateral amygdala.

Emotional experience during early life has been shown to interfere with the development of excitatory synaptic networks in the prefrontal cortex, hippocampus, and the amygdala of rodents and primates. The aim of the present study was to investigate a developmental "homoeostatic synaptic plasticity" hypothesis and to test whether stress-induced changes of excitatory synaptic composition are counterbalanced by parallel changes of inhibitory synaptic networks. The impact of repeated early separation stress on the development of two GABAergic neuronal subpopulations was quantitatively analyzed in the brain of the semiprecocial rodent Octodon degus. Assuming that PARV- and CaBP-D28k-expression are negatively correlated to the level of inhibitory activity, the previously described reduced density of excitatory spine synapses in the dentate gyrus of stressed animals appears to be "amplified" by elevated GABAergic inhibition, reflected by reduced PARV- (down to 85%) and CaBP-D28k-immunoreactivity (down to 74%). In opposite direction, the previously observed elevated excitatory spine density in the CA1 region of stressed animals appears to be amplified by reduced inhibition, reflected by elevated CaPB-D28k-immunoreactivity (up to 149%). In the (baso)lateral amygdala, the previously described reduction of excitatory spine synapses appears to be "compensated" by reduced inhibitory activity, reflected by dramatically elevated PARV- (up to 395%) and CaPB-D28k-immunoreactivity (up to 327%). No significant differences were found in the central nucleus of the amygdala, the piriform, and somatosensory cortices and in the hypothalamic paraventricular nucleus. Thus during stress-evoked neuronal and synaptic reorganization, a homeostatic balance between excitation and inhibition is not maintained in all regions of the juvenile brain.