Independent Use of a Home-Based Telemonitoring App by Older Patients With Multimorbidity and Mild Cognitive Impairment: Qualitative Study.

BACKGROUND: The management of multimorbidity is complex and patients have a high burden of disease. When symptoms of dementia also appear, it becomes even more difficult for patients to cope with their everyday lives and manage their diseases. Home-based telemonitoring may support older patients with multimorbidity and mild cognitive impairment (MCI) in their regular monitoring and self-management. However, to date, there has been no investigation into whether patients with MCI are able to operate a telemonitoring app independently to manage their own diseases. This question has become even more important during the current COVID-19 pandemic to maintain high-quality medical care for this patient group. OBJECTIVE: We examined the following research questions: (1) How do patients with MCI assess the usability of the telemonitoring app? (2) How do patients with MCI assess the range of functions offered by the telemonitoring app? (3) Was there an additional benefit for the patients with MCI in using the telemonitoring app? (4) Were patients with MCI able to use the telemonitoring app independently and without restrictions? (5) To what extent does previous experience with smartphones, tablets, or computers influence the perceived ease of use of the telemonitoring app? METHODS: We performed a formative evaluation of a telemonitoring app. Therefore, we carried out a qualitative study and conducted guided interviews. All interviews were audio-recorded, transcribed verbatim, and analyzed using the Mayring method of structured content analysis. RESULTS: Twelve patients (8 women, 4 men) were interviewed; they had an average age of 78.7 years (SD 5.6) and an average Mini-Mental State Examination score of 24.5 (SD 1.6). The interviews lasted between 17 and 75 minutes (mean 41.8 minutes, SD 19.4). Nine patients reported that the telemonitoring app was easy to use. All respondents assessed the range of functions as good or adequate. Desired functionalities mainly included more innovative and varied educational material, better fit of the telemonitoring app for specific needs of patients with MCI, and a more individually tailored content. Ten of the 12 patients stated that the telemonitoring app had an additional benefit for them. Most frequently reported benefits included increased feeling of security, appreciation of regular monitoring of vital parameters, and increased independence due to telemonitoring. Eight patients were able to operate the app independently. Participants found the app easy to use regardless of whether they had prior experience with smartphones, tablets, or computers. CONCLUSIONS: The majority of examined patients with MCI were capable of operating the telemonitoring app independently. Crucial components in attaining independent use were comprehensive personal support from the start of use and appropriate design features. This study provides initial evidence that patients with MCI could increasingly be considered as a relevant user group of telemonitoring apps.

Multiperspective and Multimethod Evaluation of Flexible and Integrative Psychiatric Care Models in Germany: Study Protocol of a Prospective, Controlled Multicenter Observational Study (PsychCare).

Background: New cross-sectoral mental health care models have been initiated in Germany to overcome the fragmentation of the German health care system. Starting in 2013, flexible and integrative psychiatric care model projects according to §64b SGB V German Social Law (FIT64b) have been implemented. The study "PsychCare" combines quantitative and qualitative primary data with routine health insurance data for the evaluation of these models. Effects, costs and cost-effectiveness from the perspectives of patients, relatives and care providers are compared with standard care. Additionally, quality indicators for a modern, flexible and integrated care are developed. This article describes the rationale, design and methods of the project. Methods: "PsychCare" is built on a multiperspective and multimethod design. A controlled prospective multicenter cohort study is conducted with three data collection points (baseline assessment, follow-up after 9 and 15 months). A total of 18 hospitals (10 FIT64b model and 8 matched control hospitals) have consecutively recruited in- and outpatients with pre-specified common and/or severe psychiatric disorders. Primary endpoints are differences in change of health-related quality of life and treatment satisfaction. Sociodemographic and service receipt data of the primary data collection are linked with routine health insurance data. A cost-effectiveness analysis, a mixed method, participatory process evaluation by means of qualitative surveys and the development of quality indicators are further elements of "PsychCare." Discussion and Practical Implications: The results based on data from different methodological approaches will provide essential conclusions for the improvement of hospital based mental health care in Germany. This should result in the identification of key FIT64b elements that can be efficiently implemented into standard care in Germany and re-structure the care strongly aligned to patient needs. Clinical Trial Registration: German Clinical Trial Register, identifier DRKS 00022535.

[Association between Socioeconomic Status and Developmental Status: Data Linkage of Results of the Daycare and School Entry Health Examinations of a Saxon Birth Cohort Study]. / Zusammenhang zwischen sozioökonomischem Status und Entwicklungsstand ­ Datenlinkage von Ergebnissen der Kita- und Schulaufnahmeuntersuchung mit einer sächsischen Geburtskohortenstudie.

BACKGROUND: Child development is determined by both biological (e. g. gender, natal maturity) and psychosocial (e. g. socioeconomic status, daycare) factors. OBJECTIVES: To examine how familial socioeconomic status (SES) as well as biological and other psychosocial factors are associated with the state of development of 4- and 6-year-old children. METHODS: Data linkage of primary data from a birth cohort study and routine data from the Saxon public health departments on children born between 2007 and 2008, who underwent both daycare health examination and school entry health examination (N=615), was used to examine speech and motor skills, both fine and gross, for associations with psychosocial and biological factors. Potential associations were tested for significance and shown as odds ratios by using binary logistic regression. RESULTS: There were no noticeable problems in the development of the majority of Saxon children until school entry. Nevertheless, language seems to be a sensitive area of development, since 37% of the children showed problems at both time-points. Furthermore boys, preterm infants and children from a lower socio-economic class were more often affected by developmental delays, with preterm infants with low SES being at very high risk. Furthermore, the point of time of entering daycare seems to be of relevance for child development. CONCLUSIONS: The results are in line with national and international findings. An important new finding is the significantly increased likelihood of having developmental problems when biological and psychosocial risk factors coincide. However, longitudinal analyses are required to study developmental courses and to evaluate measures initiated to combat these issues.

[Methodological Standard for the Development of Quality Indicators within Clinical Practice Guidelines - Results of a structured consensus process]. / Methodischer Standard für die Entwicklung von Qualitätsindikatoren im Rahmen von S3-Leitlinien ­ Ergebnisse einer strukturierten Konsensfindung.

BACKGROUND: Recommendations of evidence- and formally consensus-based clinical practice guidelines (CPGs) represent a valuable source of quality indicators (QIs). Nevertheless, a standardized methodological procedure for developing QIs in the context of CPGs does not yet exist in Germany for all CPGs. For this reason, a methodological standard for the guideline-based development of QIs (QI Standard) was developed based on a structured consensus process involving multiple key stakeholders. METHODS: The proposed content of the QI Standard was derived from evidence, drawing upon results of reviews and qualitative studies, and considered German manuals for guideline-based QI development of two guideline programs. A multi-perspective consensus panel, broadly representing key stakeholders from the German healthcare system with expertise in CPGs and/or quality management, was nominated to vote on recommendations for guideline-based development of QIs. The iterative, structured consensus process included a two-stage online survey based on the Delphi method ("preliminary voting") and a moderated final stakeholder conference where all those recommendations were definitely included in the QI Standard that received approval of more than 75 % (consensus criterion) of the consensus panel. RESULTS: Based on the agreed QI Standard, the QI development process starts with a criteria-based selection of "potential" QIs which - in case of adoption - are published in CPGs as "preliminary" QIs and can achieve the status "final" after successful testing. The QI Standard is composed of a total of 30 recommendations, which are allocated to six areas: A) preparatory work steps for the guideline-based recommendation of QIs, B) QI development group and cooperation with the CPG group, C) development of potential QIs, D) critical appraisal of potential QIs, E) formal adoption and publication as well as F) piloting/testing of preliminary QIs and conversion into final QIs. DISCUSSION: Before the QI Standard can be recommended for implementation in future CPGs, it should have been successfully tested in selected German CPG projects. In addition to methodological requirements for the QI development, it must be ensured that guideline groups have adequate resources for the implementation of the QI Standard. CONCLUSION: By using the QI Standard, scientifically sound and healthcare-relevant QIs can be expected.

International experiences in the development and implementation of guideline-based quality indicators: a qualitative study.

OBJECTIVES: Evidence-based clinical guidelines play an important role in healthcare and can be a valuable source for quality indicators (QIs). However, the link between guidelines and QI is often neglected and methodological standards for the development of guideline-based QI are still lacking. The aim of this qualitative study was to get insights into experiences of international authors with developing and implementing guideline-based QI. SETTING: We conducted semistructured interviews via phone or skype (September 2017-February 2018) with guideline authors developing guideline-based QI. PARTICIPANTS: 15 interview participants from eight organisations in six European and North American countries. METHODS: Organisations were selected using purposive sampling with a maximum variation of healthcare settings. From each organisation a clinician and a methodologist were asked to participate. An interview guide was developed based on the QI development steps according to the 'Reporting standards for guideline-based performance measures' by the Guidelines International Network. Interviews were analysed using qualitative content analysis with deductive and inductive categories. RESULTS: Interviewees deemed a programmatic approach, involvement of representative stakeholders with clinical and methodological knowledge and the connection to existing quality improvement strategies important factors for developing QI parallel to or after guideline development. Methodological training of the developing team and a shared understanding of the QI purpose were further seen conducive. Patient participation and direct patient relevance were inconsistently considered important, whereas a strong evidence base was seen essential. To assess measurement characteristics interviewees favoured piloting, but often missed implementation. Lack of measurability is still experienced a serious limitation, especially for qualitative aspects and individualised care. CONCLUSION: Our results suggest that developing guideline-based QI can succeed either parallel to or following the guideline process with careful planning and instruction. Strategic partnerships seem key for implementation. Patient participation and relevance, measurement of qualitative aspects and piloting are areas for further development. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00013006).

Nicotinamide Inhibits Self-renewal and Induces Granulocyte Differentiation of Multipotent Progenitor Cells.

Nicotinamide (NAM) a form of vitamin B3, is an essential precursor of NAD. This dinucleotide (pyridine nucleotide) participates in the regulation of fundamental processes including transcription, cell cycle progression and DNA repair. Here we assessed the effect of NAM on myeloid differentiation of the IL-3 dependent, multipotent hematopoietic progenitor cell line FDCP-Mix. We found that NAM reduces the pSTAT5 signaling response, cell cycling and self-renewal potential. It initiates an atypical program of myeloid differentiation that results in the emergence of granulocytic cells in the absence of added myeloid differentiation factors. NAM did not affect the expression the of cell surface granulocyte marker GR1 but led to a strong downregulation of MHC-II molecules. Taken together our data show that NAM induces a differentiation program in hematopoietic progenitors prompting them to undergo differentiation along the granulocyte path without reaching the status of fully developed granulocytes. Graphical abstract.

Individual-Level Linkage of Primary and Secondary Data from Three Sources for Comprehensive Analyses of Low Birthweight Effects.

AIM OF THE STUDY: The linkage of primary and secondary data is becoming an increasingly popular approach in healthcare research, but involves some challenges for all involved parties, for example due to data protection requirements. The aim of this article is to systematically outline the methods used and experiences made during a cohort study in the field of pediatric health care research (EcoCare-PIn) that involved access to and linkage of three different data sources. Particular focus is placed on the necessary regulatory measures with regard to data access and data linkage as well as on data validation to ensure a correct linkage. METHODS: While complying with all relevant data protection requirements, the study realized an individual-level linkage of a) pseudonymized administrative health insurance data from a statutory health insurance on Saxon children born between 2007 and 2013, b) primary data collected via postal questionnaires from parents/caregivers and c) medical data from kindergarten- and school-entry-examinations of Saxon health authorities. The fundamental principle of the concept of data linkage was to strictly separate the sites of data collection and data analysis, which was realized through the involvement of a trust center. RESULTS: Challenges especially pertained to the extensive regulatory pre-requirements for data access as well as to data protection requirements while performing the study. Technical aspects and data validation also required a considerable share of attention and resources. A number of validation routines were applied to avoid incorrect data linkage and to ensure the high quality of the final dataset. Data validation included both plausibility checks within the primary data and consistency checks of information given in primary and secondary data. CONCLUSION: The linkage of primary and secondary data on the individual level offers great opportunities for using the strengths of different data sources synergistically and overcoming some of their limitations. Statutory health insurance data and medical data from kindergarten- and school-entry-examinations of Saxon health authorities are examples of already existing data sources that can complement cost-consuming primary data collections by valuable data sets and open up opportunities for longitudinal analysis.

[Methodological Challenges when Using Claims Data of more than 70 Statutory Health Insurances - A Progress Report from the EVA64 Study]. / Methodische Herausforderungen bei der Nutzung von Daten von mehr als 70 gesetzlichen Krankenkassen ­ Ein Werkstattbericht aus der EVA64-Studie.

AIM OF THE STUDY: The adequate and need-based medical care of mentally ill patients places special demands on psychiatric care. The §64b Social Code Book (SGB) V enables mentoring mentally ill people through multiprofessional, cross-sectoral model projects across the treatment phase and implementing new forms of financing. These model projects have been evaluated in a prospective and retrospective claims data-based controlled cohort study (EVA64) since 2015. METHODS: In September 2016 and since then annually, the data transfer of all statutory health insurance funds (SHI) involved in this evaluation took place for the first time on the basis of a consented data set description. For later analysis, the clear identification of the index hospital admission and the assignment to the model or control group are important. The methodological challenges of data provision by the data owner, the formal and content-related data preparation as well as the subsequent establishing of an evaluation data set are discussed in detail. RESULTS: So far, data from 71 SHI has been taken into account. In each case 20 tables with claims data from outpatient and inpatient care (including psychiatric institute outpatient departments [PIA]), drug and medical supplies as well as data from incapacity to work and personal data of the insurees. Not all tables could be filled completely by the SHIs. In addition, updates of the study designs require the adaptation of the data selection process. Even though data sets have been delievered regularly the data preparation process is still not routine. CONCLUSION: The scientific use of claims data of numerous SHIs in the context of an evaluation study represents a great challenge. In the absence of reference values for abnormalities and implausibilities, an a priori determination of test algorithms was limited; instead they had to be updated every year. The individual examination of the data of all health insurance companies remains very complex. The detailed documentation of these algorithms provides support for future comparable studies.

[Development of guideline-based quality indicators: a qualitative study on barriers and facilitating factors from the perspective of S3-guideline authors]. / Entwicklung leitlinienbasierter Qualitätsindikatoren: eine qualitative Studie zu Barrieren und förderlichen Faktoren aus der Sicht von S3-LeitlinienautorInnen.

BACKGROUND: Evidence-based and formally consensus-based clinical practice guidelines (S3-CPGs) are a valuable source for the development of quality indicators (QIs) in Germany. While deriving QIs from guideline recommendations is a mandatory part of the development of S3-CPGs within the National Program for Disease Management Guidelines (DMGP) and the German Guideline Program in Oncology (GGPO), there is no such obligation in the guideline program of the Association of the Scientific Medical Societies in Germany (AWMF) (MS program). Despite that, several S3-CPGs in the MS program have been published with QIs in the last years while some DMGP and one GGPO S3 guidelines have failed to meet this requirement. From the perspective of the guideline authors of all three mentioned programs, the present qualitative study examined why S3-CPGs do or do not contain QIs and explored the factors perceived by authors as either facilitating or hampering in the QI development process. METHODS: Semi-structured interviews were conducted with authors of 22 S3-CPGs, 11 of which represented guidelines containing QIs and 11 of which represented guidelines without QIs. Authors of guidelines containing QIs (n=11) were asked about the perceived decisive reasons for formulating QIs and about facilitators and barriers during the QI development process. Authors of guidelines without QIs (n=11) gave reasons for not formulating QIs. Interviews were analyzed using structuring qualitative content analysis. RESULTS: Within the MS program, not formulating QIs was mainly attributed to the lack of a mandatory requirement and to insufficient funding of guideline projects. Amongst DMGP authors, a low priority of QI development prevailed, which was, for example, due to already existing QIs or to their lacking implementation. In the GGPO guideline examined, not formulating QIs was due to the guideline topic (prevention) - for this topic, there was a lack of suitable evidence and data sources. If QIs were developed, the most important facilitating factor in the development process, across all programs, was the methodological support provided by the guideline program. Important hampering factors included the additional time required for QI development and concerns regarding the implementation of many potential QIs, especially due to a lack of data availability. DISCUSSION: For regular development of QIs within S3-CPG projects, the incorporation of such a requirement in the guideline program is a necessary, but not a sufficient, condition. Other pivotal factors include systematic methodological support, adequate financial and staff resources and the perceived meaningfulness and relevance of guideline-based QI development, measured in terms of the actual implementation of already existing QIs. CONCLUSION: The study reveals starting points for measures to strengthen the consideration of QI development in German S3-CPG projects, especially within the MS program. Without substantial structural changes, especially of the resources of guideline groups, and without an overall concept covering the entire process from QI development to QI implementation, guideline-based QI development will remain heavily dependent on the (self-)motivation of guideline groups.

Transplantation of bone marrow derived macrophages reduces markers of neuropathology in an APP/PS1 mouse model.

BACKGROUND: We investigated early hallmarks of putative therapeutic effects following systemic transplantation of bone marrow derived macrophages (BM-M) in APP/PS1 transgenic mice. METHOD: BM-M were transplanted into the tail vein and the animals analysed 1 month later. RESULTS: BM-M transplantation promoted the reduction of the amyloid beta [37-42] plaque number and size in the cortex and hippocampus of the treated mice, but no change in the more heavily modified pyroglutamate amyloid beta E3 plaques. The number of phenotypically 'small' microglia increased in the hippocampus. Astrocyte size decreased overall, indicating a reduction of activated astrocytes. Gene expression of interleukin 6 and 10, interferon-gamma, and prostaglandin E receptor 2 was significantly lower in the hippocampus, while interleukin 10 expression was elevated in the cortex of the treated mice. CONCLUSIONS: BM-M systemically transplanted, promote a decrease in neuroinflammation and a limited reversion of amyloid pathology. This exploratory study may support the potential of BM-M or microglia-like cell therapy and further illuminates the mechanisms of action associated with such transplants.

Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease.

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD. GFP-expressing MSCs derived from bone marrow were intranasally administered to 4-week-old R6/2 HD transgenic mice. MSCs were detected in the olfactory bulb, midbrain and striatum five days post-delivery. Compared to phosphate-buffered saline (PBS)-treated littermates, MSC-treated R6/2 mice showed an increased survival rate and attenuated circadian activity disruption assessed by locomotor activity. MSCs increased the protein expression of DARPP-32 and tyrosine hydroxylase (TH) and downregulated gene expression of inflammatory modulators in the brain 7.5 weeks after INA. While vehicle treated R6/2 mice displayed decreased Iba1 expression and altered microglial morphology in comparison to the wild type littermates, MSCs restored both, Iba1 level and the thickness of microglial processes in the striatum of R6/2 mice. Our results demonstrate significantly ameliorated phenotypes of R6/2 mice after MSCs administration via INA, suggesting this method as an effective delivering route of cells to the brain for HD therapy.

Impact of birthweight on health-care utilization during early childhood - a birth cohort study.

BACKGROUND: Comprehensive data are needed to evaluate the burden of low birthweight. Analysis of routine data on health-care utilization during early childhood were used to test the hypothesis that infants with low birthweight have (i) increased inpatient health-care utilization, (ii) higher hospital costs and (iii) different morbidity pattern in early childhood when compared with normal birthweight infants. METHODS: Children born between 2007 and 2013 that were insured at birth with the statutory health insurance AOK PLUS were included (N = 118,166, equaling 49% of the Saxon newborns) and classified into very low (< 1500 g, VLBW), low (1500-2499 g, LBW) birthweight and reference group (> 2500 g). Outcomes were: inpatient health-care utilization quantified by number and length of hospital stays; costs of hospitalizations including medication; reasons of hospitalizations for each year of life (YOL). RESULTS: 72, 38 and 22% of VLBW-, LBW- and reference group were hospitalized after perinatal period within the first YOL with a more than 5-fold increased risk in VLBW to be hospitalized for hemangioma, convulsions, hydrocephalus, hernia and respiratory problems. Median (IQR) cumulative cost of inpatient care during the first four YOLs was 2953 (1213-7885), 1331 (0-3451) and 0 (0-2062) Euro for respective groups. Inpatient early childhood health-care utilization (after first YOL) was higher in VLBW compared to healthy, normal birth weight infants (RR 3.92 [95%-CI 3.63, 4.23]), residents of rural areas (RR 1.37 [95%-CI 1.35, 1.40]) and in boys (RR 1.31 [95%-CI 1.29, 1.33]). CONCLUSION: This large population-based birth-cohort study indicates a high clinical and economic burden of low birthweight which is not restricted to the first year of life.

Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis.

BACKGROUND & AIMS: The mammalian circadian clock controls various aspects of liver metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling as a novel regulator of liver lipid metabolism. Herein, we investigated crosstalk between hepatic Hh signaling and circadian rhythm. METHODS: Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were used for analysis of metabolic alterations and behavior. RESULTS: Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro. Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1 in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely, SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent alterations in various genes, particularly those associated with lipid metabolism. The clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the liver to a high-fat diet or to differently timed starvation. CONCLUSIONS: For the first time, Hh signaling in hepatocytes was found to be time-of-day dependent and to feed back on the circadian clock. Our findings suggest an integrative role of Hh signaling, mediated mainly by GLI factors, in maintaining homeostasis of hepatic lipid metabolism by balancing the circadian clock. LAY SUMMARY: The results of our investigation show for the first time that the Hh signaling in hepatocytes is time-of-day dependent, leading to differences not only in transcript levels but also in the amount of Hh ligands in peripheral blood. Conversely, Hh signaling is able to feed back to the circadian clock.

The influence of cross-sectoral treatment models on patients with mental disorders in Germany: study protocol of a nationwide long-term evaluation study (EVA64).

BACKGROUND: Close, continuous and efficient collaboration between different professions and sectors of care is necessary to provide patient-centered care for individuals with mental disorders. The lack of structured collaboration between in- and outpatient care constitutes a limitation of the German health care system. Since 2012, a new law in Germany (§64b Social code book (SGB) V) has enabled the establishment of cross-sectoral and patient-centered treatment models in psychiatry. Such model projects follow a capitation budget, i.e. a total per patient budget of inpatient and outpatient care in psychiatric clinics. Providers are able to choose the treatment form and adapt the treatment to the needs of the patients. The present study (EVA64) will investigate the effectiveness, costs and efficiency of almost all model projects established in Germany between 2013 and 2016. METHODS/DESIGN: A health insurance data-based controlled cohort study is used. Data from up to 89 statutory health insurance (SHI) funds, i.e. 79% of all SHI funds in Germany (May 2017), on inpatient and outpatient care, pharmaceutical and non-pharmaceutical treatments and sick leave for a period of 7 years will be analyzed. All patients insured by any of the participating SHI funds and treated in one of the model hospitals for any of 16 pre-defined mental disorders will be compared with patients in routine care. Sick leave (primary outcome), utilization of inpatient care (primary outcome), utilization of outpatient care, continuity of contacts in (psychiatric) care, physician and hospital hopping, re-admission rate, comorbidity, mortality, disease progression, and guideline adherence will be analyzed. Cost and effectivity of model and routine care will be estimated using cost-effectiveness analyses. Up to 10 control hospitals for each of the 18 model hospitals will be selected according to a pre-defined algorithm. DISCUSSION: The evaluation of complex interventions is an important main task of health services research and constitutes the basis of evidence-guided advancement in health care. The study will yield important new evidence to guide the future provision of routine care for mentally ill patients in Germany and possibly beyond. TRIAL REGISTRATION: This study was registered in the database "Health Services Research Germany" (trial number: VVfD_EVA64_15_003713 ).

Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health.

BACKGROUND: Mesenchymal stem cells (MSCs) show therapeutic efficacy in many different age-related degenerative diseases, including Alzheimer's disease. Very little is currently known about whether or not aging impacts the transplantation efficiency of MSCs. METHODS: In this study, we investigated the distribution of intravenously transplanted syngeneic MSCs derived from young and aged mice into young, aged, and transgenic APP/PS1 Alzheimer's disease mice. MSCs from male donors were transplanted into female mice and their distribution pattern was monitored by PCR using Y-chromosome specific probes. Biodistribution of transplanted MSCs in the brains of APP/PS1 mice was additionally confirmed by immunofluorescence and confocal microscopy. RESULTS: Four weeks after transplantation into young mice, young MSCs were found in the lung, axillary lymph nodes, blood, kidney, bone marrow, spleen, liver, heart, and brain cortex. In contrast, young MSCs that were transplanted into aged mice were only found in the brain cortex. In both young and aged mouse recipients, transplantation of aged MSCs showed biodistribution only in the blood and spleen. Although young transplanted MSCs only showed neuronal distribution in the brain cortex in young mice, they exhibited a wide neuronal distribution pattern in the brains of APP/PS1 mice and were found in the cortex, cerebellum, hippocampus, olfactory bulb, and brainstem. The immunofluorescent signal of both transplanted MSCs and resident microglia was robust in the brains of APP/PS1 mice. Monocyte chemoattractant-1 levels were lowest in the brain cortex of young mice and were significantly increased in APP/PS1 mice. Within the hippocampus, monocyte chemoattractant-1 levels were significantly higher in aged mice compared with younger and APP/PS1 mice. CONCLUSIONS: We demonstrate in vivo that MSC biodistribution post transplantation is detrimentally affected by aging and neuronal health. Aging of both the recipient and the donor MSCs used attenuates transplantation efficiency. Clinically, our data would suggest that aged MSCs should not be used for transplantation and that transplantation of MSCs into aged patients will be less efficacious.

Helping Alliance and Unmet Needs in Routine Care of People With Severe Mental Illness Across Europe: A Prospective Longitudinal Multicenter Study.

The helping alliance (HA) refers to the collaborative bond between patient and therapist, including shared goals and tasks. People with severe mental illness have a complex mixture of clinical and social needs. Using mixed-effects regression, this study examined in 588 people with severe mental illness whether an increase in the HA is associated with fewer unmet needs over time, and whether change in the HA precedes change in unmet needs. It was found that a reduction in unmet needs was slower in patients with higher HA (B = 0.04, p < 0.0001) only for patient-rated measures. Improvement in both patient-rated and staff-rated HA over time was associated with fewer subsequent patient-rated (B = -0.10, p < 0.0001) and staff-rated (B = -0.08, p = 0.0175) unmet needs. With positive changes in the HA preceding fewer unmet needs, findings provide further evidence for a causal relationship between alliance and outcome in the treatment of people with severe mental illness.

[Principles for the evaluation of telemedicine applications: Results of a systematic review and consensus process]. / Grundsätze für die Evaluation telemedizinischer Anwendungen ­ Ergebnisse eines systematischen Reviews und Konsens-Verfahrens.

BACKGROUND: The limited number of telemedicine applications being transferred to standard medical care in Germany may to some extent be explained by deficits in the current evaluation practice. Effectiveness and cost effectiveness can only be demonstrated to decision makers and potential users with methodologically sound and fully published evaluations. There is a lack of well-founded and mandatory standards for adequate, comparable evaluations of telemedicine applications. METHODS: As part of the project CCS Telehealth Eastern Saxony (CCS THOS), a systematic review on evaluation concepts for telemedicine applications (search period until September 2014, databases Medline, Embase, HTA-Database, DARE, NHS EED) as well as an additional selective literature search were conducted. Suggestions for evaluation fundamentals were derived from the results. These suggestions were subjected to a formal consensus process (nominal group process) with relevant stakeholder groups (healthcare payers, healthcare providers, health policy representatives, researchers). RESULTS: 19 papers were included in the systematic review. In accordance with the predefined inclusion criteria, each presented an evaluation concept for telemedicine applications that was based upon a systematic review and/or a consensus process. Via a formal consensus process, the suggestions for evaluation principles derived from the review and the selective literature search (23 papers) resulted in ten agreed evaluation principles. Eight of them were unanimously agreed upon, two were arrived at with one abstention each. The principles enclose criteria for the planning, conduct and reporting of telemedicine evaluations. Adherence to them is obligatory for users of the telemedical infrastructure provided by CCS THOS. Furthermore, right from the beginning the intention was very much for these principles to be seized upon by other projects and initiatives. CONCLUSIONS: The agreed evaluation principles for telemedicine applications are the first in Germany to be based both upon evidence and consensus. Due to the methodology of development, they have a strong scientific and health policy legitimation. Therefore, and because of their general applicability, adherence to these principles beyond the context of the telemedicine platform developed within CCS THOS is recommended, namely throughout the German telemedicine scene.

Sox2 Suppresses Gastric Tumorigenesis in Mice.

Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2(+) cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes.

Early comprehensive care of preterm infants-effects on quality of life, childhood development, and healthcare utilization: study protocol for a cohort study linking administrative healthcare data with patient reported primary data.

BACKGROUND: About 9 % of all children in Germany are born preterm. Despite significant improvements of medical care, preterm infants are at a greater risk to develop short and long term health complications. Negative consequences of preterm birth include neurodevelopmental disabilities, behavioral problems or learning disorders. Most data on effects of prematurity are derived from single or multi-center studies and not population-based. Since some of the long term problems of preterm delivery are associated with a disturbed parent-child interaction originating in the neonatal period, several intervention programs became available aiming to strengthen the early parent-child relationship. However, there is insufficient knowledge regarding the psychosocial and socioeconomic impact of these interventions. Prior to introducing them into routine care, those effects have to be rigorously evaluated. The population-based cohort study EcoCare-PIn (Early comprehensive Care of Preterm Infants-effects on quality of life, childhood development, and healthcare utilization) will investigate the following primary research questions: 1) What are the short- and long-term consequences of preterm birth with regard to parental stress, parent-child relationship, childhood development, quality of life and healthcare utilization including costs? 2) Does early family-centered psychosocial care prevent the hypothesized negative consequences of preterm birth on the above mentioned outcomes? METHODS/DESIGN: EcoCare-PIn examines the research questions by means of a linkage of a) pseudonymized administrative individual-level claims data from the German statutory health insurance AOK PLUS on approximately 140,000 children born between 2007 and 2013 in Saxony, and b) primary data collected from the parents/caregivers of all very low birth weight (<1,500 g; n = 1,000) and low birth weight infants (1,500 to 2,500 g; n = 5,500) and a matched sample of infants above 2,500 g birth weight (n = 10,000). DISCUSSION: In Saxony, approximately 50 % of all individuals are insured at the AOK PLUS. The linkage of patient-level administrative and primary data is a novel approach in neonatal research and probably the only way to overcome shortcomings of studies solely relying on one data source. The study results are based on an observation period of up to 8 years and will directly inform perinatal healthcare provision in Saxony and Germany as a whole.

The stroke east Saxony pilot project for organized post-stroke care: a case-control study.

BACKGROUND: Low adherence to secondary prevention guidelines in stroke survivors may increase the risk for recurrent stroke and adversely impact quality of life. We aimed to determine the feasibility of a self-developed standardized post-stroke pathway and its impact on secondary stroke prevention and long-term outcome in patients with acute stroke. METHODS: Consecutive patients with acute stroke were prospectively included in a standardized post-stroke pathway accomplished through a single certified CM (case manager), which comprised educational discussions and quarterly checkups for vascular risk factors and adherence to antithrombotic/anticoagulant medication in addition to usual care. At 12 months, we compared achieved target goals for secondary prevention, functional outcome, stroke recurrence, and vascular death with age- and gender-matched controls that received only usual care after stroke. RESULTS: We included 45 cases and 45 controls. The following target goals were more frequently achieved in CM-patients than in controls: blood pressure (100% vs. 46.2%, P < 0.001), cholesterol (100% vs. 74.4%, P < 0.001), and body mass index (67.4% vs. 46.2%, P = 0.052). The CM-intervention emerged as an independent predictor of favorable functional outcome (mRS ≤ 2) at 12 months after adjusting for stroke severity and systemic thrombolysis (OR: 4.27; 95%CI:1.2-15.21; P = 0.025). Quality of life was rated significantly higher in CM-patients than in controls (P = 0.049). As opposed to controls, none of the cases experienced a recurrent stroke (0% vs. 13.3%; P = 0.026) or suffered from vascular death (0% vs. 6.7%; P = 0.242). CONCLUSIONS: Our pilot data suggest that organized post-stroke care enhances achievement of secondary prevention goals. Its possible effect on stroke recurrence, long-term disability, and quality of life is currently investigated in a prospective cohort study.