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Abstract Background An increase in epidural pressure around the stenosis has been observed in patients with lumbar spinal stenosis (LSS) with positive signs of sedimentation or redundant nerve roots. Further analysis of the pressure conditions in the stenotic area would be of great interest. We hypothesized that it would be possible to determine the physiological parameters of the epidural pulse wave and its course in pathological stenosis as a basis for objective identification of LSS based on pressure using a new measuring method with continuous spatial and temporal resolution. Methods We performed a single‐case proof‐of‐principle in vivo animal trial and used a newly developed hybrid pressure‐measurement probe with a fiber‐tip Fabry–Pérot interferometer and several fiber Bragg gratings (FBG). Results With reproducible precision, we determined the mean epidural pressure to be 7.5 mmHg and the peak‐to‐peak value to be 4–5 mmHg. When analyzing the pressure measured by an FBG array, both the heart and respiratory rates can be precisely determined. This study was the first to measure the pulse wave velocity of the cerebrospinal fluid pressure wave as 0.97 m/s using the newly developed pressure probe. A simulated LSS was detected in real time and located exactly. Conclusions The developed fiber‐optic pressure sensor probe enables a new objective measurement of epidural pressure. We confirmed our hypothesis that physiological parameters of the epidural pulse wave can be determined and that it is possible to identify an LSS.

Objectives Potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) are common in multimorbid patients. This study aims to describe PIMs and PPOs in an open-access outpatient setting and to investigate any association between continuity of care (CoC) and PIMs and PPOs in multimorbid older patients.Design Cross-sectional study using patient-confirmed outpatient medication plans to describe PIMs and PPOs using the ‘Screening Tool of Older Person’s Prescription/Screening Tool to Alert to Right Treatment’ version 2. Four Poisson regressions modelled the number of PIMs and PPOs using context-adapted versions of the Usual Provider of Care (UPC) and the Modified Modified Continuity Index (MMCI) as measures for CoC.Setting Southern Germany, outpatient setting.Participants 321 participants of the LoChro-trial at 12-month follow-up (both arms). The LoChro-trial compared healthcare involving an additional care manager with usual care. Inclusion criteria were age over 64, local residence and scoring over one in the Identification of Older patients at Risk Screening Tool.Primary outcomes Numbers of PIMs and PPOs.Results The mean number of PIMs was 1.5 (SD 1.5), lower than the average number of PPOs at 2.9 (SD 1.7). CoC showed similar results for both indices with a mean of 0.548 (SD 0.279) for MMCI and 0.514 (SD 0.262) for UPC. Both models predicting PPOs indicated more PPOs with higher CoC; statistical significance was only demonstrated for MMCI (MMCI~PPO: Exp(B)=1.42, 95% CI (1.11; 1.81), p=0.004; UPC~PPO: Exp(B)=1.29, 95% CI (0.99; 1.67), p=0.056). No significant association between PIMs and CoC was found (MMCI~PIM: Exp(B)=0.72, 95% CI (0.50; 1.03), p=0.072; UPC~PIM: Exp(B)=0.83, 95% CI (0.57; 1.21), p=0.337).Conclusion The results did not show a significant association between higher CoC and lesser PIMs. Remarkably, an association between increased CoC, represented through MMCI, and more PPOs was found. Consultation of different care providers in open-access healthcare systems could possibly ameliorate under-prescribing in multimorbid older patients.Trial registration German Clinical Trials Register (DRKS): DRKS00013904

Abstract Background Within the ageing population of Western societies, an increasing number of older people have multiple chronic conditions. Because multiple health problems require the involvement of several health professionals, multimorbid older people often face a fragmented health care system. To address these challenges, in a two-group parallel randomized controlled trial, a newly developed care management approach (LoChro-Care) was compared with usual care. Methods LoChro-Care consists of individualized care provided by chronic care managers with 7 to 16 contacts over 12 months. Patients aged 65 + with chronic conditions were recruited from inpatient and outpatient departments. Healthcare utilization costs are calculated by using an adapted version of the generic, self-reporting FIMA©-questionnaire with the application of standardized unit costs. Questionnaires were given at 3 time points (T0 baseline, T1 after 12 months, T2 after 18 months). The primary outcome was overall 3-month costs of healthcare utilization at T1 and T2. The data were analyzed using generalized linear models with log-link and gamma distribution and adjustment for age, sex, level of care as well as the 3-month costs of care at T0. Results Three hundred thirty patients were analyzed. The results showed no significant difference in the costs of healthcare utilization between participants who received LoChro-Care and those who received usual care, regardless of whether the costs were evaluated 12 (adjusted mean difference € 130.99, 95%CI €-1477.73 to €1739.71, p = 0.873) or 18 (adjusted mean difference €192.99, 95%CI €-1894.66 to €2280.65, p = 0.856) months after the start of the intervention. Conclusion This study revealed no differences in costs between older people receiving LoChro-Care or usual care. Before implementing the intervention, further studies with larger sample sizes are needed to provide robust evidence on the cost effects of LoChro-Care. Trial registration German Clinical Trials Register (DRKS): DRKS00013904, https://drks.de/search/de/trial/DRKS00013904 ; date of first registration 02/02/2018.

Background. Cyclin-dependent kinase 8 (CDK8) is a multifaceted regulator and represents a catalytic component of the transcriptional Mediator complex. CDK8 activity, on the one hand, increases transcriptional elongation by the recruitment of Mediator/super elongation complexes, but, on the other hand, negatively regulates CDK7-controlled transcriptional initiation through inactivating cyclin H phosphorylation. Recently, these combined properties of CDK8 have also suggested its rate-limiting importance for herpesviral replication. Objectives. In this paper, we focused on human cytomegalovirus (HCMV) and addressed the question of whether the pharmacological inhibition or knock-down of CDK8 may affect viral replication efficiency in cell culture models. Methods. A number of human and animal herpesviruses, as well as non-herpesviruses, were used to analyze the importance of CDK8 for viral replication in cell culture models, and to assess the antiviral efficacy of CDK8 inhibitors. Results. Using clinically relevant CDK8 inhibitors (CCT-251921, MSC-2530818, and BI-1347), HCMV replication was found strongly reduced even at nanomolar drug concentrations. The EC50 values were consistent for three different HCMV strains (i.e., AD169, TB40, and Merlin) analyzed in two human cell types (i.e., primary fibroblasts and astrocytoma cells), and the drugs comprised a low level of cytotoxicity. The findings highlighted the following: (i) the pronounced in vitro SI values of anti-HCMV activity obtained with CDK8 inhibitors; (ii) a confirmation of the anti-HCMV efficacy by CDK8–siRNA knock-down; (iii) a CDK8-dependent reduction in viral immediate early, early, and late protein levels; (iv) a main importance of CDK8 for viral late-stage replication; (v) several mechanistic aspects, which point to a strong impact on viral progeny production and release, but a lack of CDK8 relevance for viral entry or nuclear egress; (vi) a significant anti-HCMV drug synergy for combinations of inhibitors against host CDK8 and the viral kinase vCDK/pUL97 (maribavir); (vii) finally, a broad-spectrum antiviral activity, as seen for the comparison of selected α-, β-, γ-, and non-herpesviruses. Conclusions. In summary, these novel data provide evidence for the importance of CDK8 as a positive regulator of herpesviral replication efficiency, and moreover, suggest its exploitability as an antiviral target for novel strategies of host-directed drug development.

Dendritic cells (DC) play a crucial role in generating and maintaining antiviral immunity. While DC are implicated in the antiviral defense by inducing T cell responses, they can also become infected by Cytomegalovirus (CMV). CMV is not only highly species-specific but also specialized in evading immune protection, and this specialization is in part due to characteristic genes encoded by a given virus. Here, we investigated whether rat CMV can infect XCR1+ DC and if infection of DC alters expression of cell surface markers and migration behavior. We demonstrate that wild-type RCMV and a mutant virus lacking the γ-chemokine ligand xcl1 (Δvxcl1 RCMV) infect splenic rat DC ex vivo and identify viral assembly compartments. Replication-competent RCMV reduced XCR1 and MHCII surface expression. Further, gene expression of infected DC was analyzed by bulk RNA-sequencing (RNA-Seq). RCMV infection reverted a state of DC activation that was induced by DC cultivation. On the functional level, we observed impaired chemotactic activity of infected XCR1+ DC compared to mock-treated cells. We therefore speculate that as a result of RCMV infection, DC exhibit diminished XCR1 expression and are thereby blocked from the lymphocyte crosstalk.

Introduction Shingrix, an effective adjuvanted, recombinant herpes zoster vaccine (RZV), has been available since 2018. Immunocompromised patients are known to be predisposed to vaccine failure. In-vitro testing of immunological surrogates of vaccine protection could be instrumental for monitoring vaccination success. So far, no test procedure is available for vaccine responses to RZV that could be used on a routine basis.Methods and analysis This is a single-centre, three-arm, parallel, longitudinal cohort study aspiring to recruit a total of 308 patients (103 with a liver cirrhosis Child A/B, 103 after liver transplantation (both ≥50 years), 102 immunocompetent patients (60–70 years)). Blood samples will be taken at seven data collection points to determine varicella zoster virus (VZV) and glycoprotein E (gE)-specific IgG and T cell responses. The primary study outcome is to measure and compare responses after vaccination with RZV depending on the type and degree of immunosuppression using gE-specific antibody detection assays. As a secondary outcome, first, the gE-specific CD4+ T cell response of the three cohorts will be compared and, second, the gE-VZV antibody levels will be compared with the severity of possible vaccination reactions. The tertiary outcome is a potential association between VZV immune responses and clinical protection against shingles.Ethics and dissemination Ethical approval was issued on 07/11/2022 by the Ethics Committee Essen, Germany (number 22-10805-BO). Findings will be published in peer-reviewed open-access journals and presented at local, national and international conferences.Trial registration number German Clinical Trials Registry (number DRKS00030683).

Abstract Background In the aging population of Western societies, an increasing number of older adults have multiple chronic diseases. As multifaceted health problems imply the involvement of several healthcare professionals, multimorbid older people frequently face a fragmentation of health care. Addressing these challenges, we developed a local, collaborative, stepped, and personalized care management approach (LoChro-Care) and evaluated its effectiveness. Methods A two-group, parallel randomized controlled trial was conducted comparing LoChro-Care recipients (IG) to participants with usual care (CG). Patients aged 65 + with chronic conditions were recruited at inpatient and outpatient departments of the Medical Center, University of Freiburg. Participants were allocated using block randomization (nIG = 261, nCG = 263). LoChro-Care comprised individualized care provided by chronic care managers with 7 to 13 contacts over 12 months. Questionnaires were given at 3 time points (T0: baseline, T1: after 12 months, T2: after 18 months). The primary outcome was the physical, psychological, and social health status represented by a composite score of functional health and depressive symptoms. Secondary outcomes were the participants’ evaluation of their health care situation, health-related quality of life (HRQL), and life-satisfaction (LS). The data were analyzed using linear mixed modelling. Results We analyzed N = 491 participants (nIG = 244, nCG = 247), aged M = 76.78 years (SD = 6.35). For the composite endpoint, neither a significant difference between IG and CG (p = .88) nor a group-time interaction (p = .52; p = .88) could be observed. Participants in both groups showed a significant decline on the primary outcome between T0 and T2 (p

Abstract Background Older patients are at an increased risk of hospitalization, negatively affecting their health and quality of life. Such patients also experience a lack of physical activity during their inpatient stay, as well as being at increased risk of delirium and inappropriate prescribing. These risk factors can accumulate, promoting a degree of morbidity and the development of cognitive impairment. Methods Through the ReduRisk-program, patients at risk of functional impairment, immobility, falls, delirium or re-hospitalization shortly after hospital discharge, will be identified via risk-screening. These patients will receive an individually tailored, multicomponent and risk-adjusted prevention program. The trial will compare the effectiveness of the ReduRisk-program against usual care in a stepped-wedge-design, with quarterly cluster randomization of six university hospital departments into intervention and control groups. 612 older adults aged 70 years or more are being recruited. Patients in the intervention cluster (n = 357) will receive the ReduRisk-program, comprising risk-adjusted delirium management, structured mobility training and digitally supported planning of post-inpatient care, including polypharmacy management. This study will evaluate the impact of the ReduRisk-program on the primary outcomes of activities of daily living and mobility, and the secondary outcomes of delirium, cognition, falls, grip strength, health-related quality of life, potentially inappropriate prescribing, health care costs and re-hospitalizations. Assessments will be conducted at inpatient admission (t0), at discharge (t1) and at six months post-discharge (t2). In the six-month period following discharge, a health-economic evaluation will be carried out based on routine health insurance data (t3). Discussion Despite the importance of multicomponent, risk-specific approaches to managing older patients, guidelines on their effectiveness are lacking. This trial will seek to provide evidence for the effectiveness of a multicomponent, risk-adjusted prevention program for older patients at risk of functional impairment, immobility, falls, delirium and re-hospitalization. Positive study results would support efforts to improve multicomponent prevention and the management of older patients. Trial registration German Clinical Trials Register, DRKS00025594, date of registration: 09/08/2021.

Objectives Multimorbidity challenges healthcare systems. In Germany, coordination of healthcare for older multimorbid patients remains unstructured.This study aims to identify key themes in the healthcare of these patients and the inter-relationships between them.Design Framework analysis of six cases based on 1-year data of primary and secondary care, patient-answered questionnaires and video material.Setting Southern Germany.Participants Six multimorbid older patients participating in a randomised controlled trial that compared usual care with a local, collaborative, stepped and personalised care management approach for older people with chronic diseases (LoChro-trial). The LoChro care intervention involved a care manager who assisted participants in self-management. The primary outcome was a composite of functional health and depressive symptoms at 12 and 18 months. The LoChro-intervention had no effect on the primary outcome.Primary outcome measure Key themes in the healthcare of older patients with multimorbidity and the inter-relationships between them.Methods One-year data included diagnoses, treatment plans, examinations, assessments and discharge reports. Patient perspectives were assessed using the Patient Assessment of Chronic Illness Care. In three cases, videos of the LoChro intervention showed patients describing their health needs. These data were evaluated by three doctors and public health researchers. Using framework analysis, recurring themes influencing the healthcare situation of multimorbid older patients and their inter-relationships were identified.Results Participants had an average age of 77, with 13 diagnoses, taking eight medications regularly. The five key themes describing the healthcare situation of these multimorbid patients were as follows: insufficient coordination, overuse and underuse of medical care, doctor and patient roles. Each theme covered three to four subcategories. The most significant inter-relationships between these themes were a lack of coordination leading to overuse and underuse of medical care. These were characterised by redundant inpatient stays, potential prescribing omissions and missed examinations. Deficiencies in vaccinations and secondary prevention were also demonstrated.Conclusion Coordination of care for multimorbid older patients in Germany is still deficient. Future healthcare arrangements should be explored with the participation of physicians and patients.Trial registration number LoChro trial: DRKS00013904.

Abstract Background Older patients at risk of functional decline are frequently affected by polypharmacy. This is associated with a further loss of independence. However, a relationship between functional disability and medications, such as ‘Potentially Inappropriate Medications’ (PIMs) and ‘Potential Prescribing Omissions’ (PPOs), as itemised for (de) prescribing in practice-orientated medication lists, has yet to be established. Methods As part of a randomised comparative effectiveness trial, LoChro, we conducted a cross-sectional analysis of the association between PIMs and PPOs measured using the ‘Screening Tool of Older Persons’ Prescription Criteria / Screening Tool To Alert to Right Treatment’ (STOPP/START) Version 2, with functional disability assessed using the ‘World Health Organization Disability Assessment Schedule 2.0’ (WHODAS). Individuals aged 65 and older at risk of loss of independence were recruited from the inpatient and outpatient departments of the local university hospital. Multiple linear regression analysis was used to model the potential prediction of functional disability using the numbers of PIMs and PPOs, adjusted for confounders including multimorbidity. Results Out of 461 patients, both the number of PIMs and the number of PPOs were significantly associated with an increase in WHODAS-score (Regression coefficients B 2.7 [95% confidence interval: 1.5-3.8] and 1.5 [95% confidence interval: 0.2-2.7], respectively). In WHODAS-score prediction modelling the contribution of the number of PIMs exceeded the one of multimorbidity (standardised coefficients beta: PIM 0.20; multimorbidity 0.13; PPO 0.10), whereas no significant association between the WHODAS-score and the number of medications was seen. 73.5 % (339) of the participants presented with at least one PIM, and 95.2% (439) with at least one PPO. The most common PIMs were proton pump inhibitors and analgesic medication, with frequent PPOs being pneumococcal and influenza vaccinations, as well as osteoporosis prophylaxis. Conclusions The results indicate a relationship between inappropriate prescribing, both PIMs and PPOs, and functional disability, in older patients at risk of further decline. Long-term analysis may help clarify whether these patients benefit from interventions to reduce PIMs and PPOs.

BackgroundAn ever-increasing number of patients seek health information via the internet. However, there is an overabundance of differing, often low-quality information available, while a lack of health literacy makes it difficult for patients to understand and assess the quality and trustworthiness of the information at hand. The web portal tala-med was thus conceived as an evidence-based, up-to-date, and trustworthy information resource for lower back pain (LBP), which could be used by primary care physicians (PCPs) and patients during and following consultations for LBP. The current evidence demonstrates that patients with LBP could benefit from web portals. However, the use of such portals by patients remains low, thus limiting their effectiveness. Therefore, it is important to explore the factors that promote or hinder the use of web portals and investigate how patients perceive their usability and utility. ObjectiveIn this study, we investigated the acceptance, usability, and utility of the web portal tala-med from the patient perspective. MethodsThis qualitative study was based on telephone interviews with patients who had access to the web portal tala-med from their PCP. We used a semistructured interview guide that consisted of questions about the consultation in which patients were introduced to tala-med, in addition to questions regarding patient perceptions, experiences, and utilization of tala-med. The interviews were recorded, transcribed, and analyzed through framework analysis. ResultsA total of 32 half-hour interviews were conducted with 16 female and 16 male patients with LBP. We identified 5 themes of interest: the use of tala-med by PCPs during the consultation, the use of tala-med by patients, its usability, added values derived from its use, and the resultant effects of using tala-med. PCPs used tala-med as an additional information resource for their patients and recommended the exercises. The patients appreciated these exercises and were willing to use tala-med at home. We also identified factors that promoted or hindered the use of tala-med by patients. Most patients rated tala-med positively and considered it a clear, comprehensible, trustworthy, and practical resource. In particular, the trustworthiness of tala-med was seen as an advantage over other information resources. The possibilities offered by tala-med to recap and reflect on the contents of consultations in a time-flexible and independent manner was perceived as an added value to the PCP consultation. ConclusionsTala-med was well accepted by patients and appeared to be well suited to being used as an add-on to PCP consultations. Patient perception also supports its usability and utility. Tala-med may therefore enrich consultations and assist patients who would otherwise be unable to find good-quality web-based health information on LBP. In addition, our findings support the future development of digital health platforms and their successful use as a supplement to PCP consultations. International Registered Report Identifier (IRRID)RR2-10.1186/s12875-019-0925-8

Abstract Background Patient-centeredness (PC) aims to adapt health care to the individual needs and preferences of patients. An existing integrative model of PC comprises several dimensions of PC which have not yet been investigated from the patients’ perspective. Older patients with multimorbidity represent a target group for patient-centered care, as their care needs are particularly complex and should be addressed individually. We aimed to assess the perspective that older patients with multimorbidity have of patient-centered care and to examine the transferability of the integrative model of PC to this specific population. Method We performed 4 guided focus group interviews with a total of 20 older individuals with multimorbidity. The focus group interviews were audio-recorded and transcribed verbatim. Patients’ statements were content-analyzed applying an a priori designed system of categories that included the dimensions of PC from the integrative model and the additional category ‘prognosis and life expectancy’, which had emerged from an initial literature search on aspects of PC specific to the multimorbid elderly. Results The new category ‘prognosis and life expectancy’ was confirmed and expanded to ‘individual care needs related to aging and chronic disesase’. All dimensions of our integrative PC model were confirmed for older patients with multimorbidity. Among these, we found that eight dimensions (individual care needs related to aging and chronic disease, biopsychosocial perspective, clinician-patient communication, essential characteristics of the clinician, clinician-patient-relationship, involvement of family and friends, coordination and continuity of care, access to care) were complemented by aspects specific to this target population. Conclusions The integrative PC model is applicable to the population of older patients with multimorbidity. For a population-specific adaptation, it might be complemented by the dimension ‘individual care needs in aging and chronic disease’, in conjunction with age-specific aspects within existing dimensions. Together with corresponding results from a Delphi survey, our adapted PC model will serve as the basis for a subsequent systematic review of instruments measuring PC in older patients with multimorbidity. Trial registration PROSPERO ( https://www.crd.york.ac.uk/prospero; CRD42018084057; 2018/02/01), German Clinical Trials Register ( www.drks.de ; DRKS00013309; 2018/01/23).

Abstract Background This article presents the main findings from a meta-analysis of how climate change mitigation policy evaluations have been undertaken in the European Union (EU) and six of its Member States: Austria, Czech Republic, France, Germany, Greece and the United Kingdom. It aims to provide insights into how policy evaluations are carried out and how those practices might be improved. As a first step, this article reviews the literature on the theory and practice of policy evaluations to guide our methodology and further analysis. Results Our sample of 236 policy evaluations in the EU and six Member States covers the period 2010–2016. Compared with the results of a similar meta-analysis carried out covering the period 1998–2007, formal evaluations commissioned by government bodies have been on the rise in 2010–2016. Most evaluations focus on effectiveness and goal achievement and usually forgo a deeper level of reflexivity and/or public participation in the evaluation process. The analysis also reveals the dominance of the energy sector in the sampled evaluations. The article finds that the low number of any policy evaluations in the agriculture, waste or land-use sectors is an area for further investigation. Conclusions The exercise of identifying, coding and categorising these evaluations for 7 years helps to provide insights into the potential use of ex-post evaluations in support of future EU legislative proposals and accompanying impact assessments. Having a good understanding on how a certain policy performed particularly according to evaluation criteria might form the basis for more ambitious climate change mitigation policies in the future. Our analysis further shows that it is crucial and urgent to allocate sufficient resources to the coverage of relatively under-represented sectors, such as land use, land-use change and forestry, and waste.

Background: Infections, major surgeries, and hyperinflammatory syndromes are known to trigger Systemic Inflammatory Response Syndrome (SIRS). Discrimination between infectious and noninfectious inflammation often poses a challenge in chronically ill patients with multiple comorbidities. These patients are routinely treated with a variety of anti-infective medications before a pathogen is identified. With the goal of improving pathogen detection rates and interventions, we evaluated Next Generation Sequencing (NGS) as a highly sensitive and fast means of detecting free microbial DNA in a small amount of serum samples from children with ongoing SIRS. Methods: We describe seven complex pediatric patients of SIRS or prolonged fever (>38.5 °C) >72 hours in which serum samples analyzed by NGS had a major impact on therapy. One patient was analyzed twice. Results: In eight NGS there were six positive results (two bacterial, three viral, one fungal) which were subsequently confirmed by microbiological culture or polymerase chain reaction (PCR) in five of the six NGS. In five of the eight performed NGS, results led to a change of therapy: antibiotic therapy was discontinued in two, escalated in one, an initiated in another; in one an antiviral was administered. Conclusions: NGS may become a valuable addition to infectious disease diagnostics in cases of pediatric SIRS. However, NGS has not yet been validated as a diagnostic method in pediatric as a diagnostic method in pediatric patients and results should therefore be interpreted with caution. Multi-center NGS evaluation studies are currently being planned.

The origin of Reptilia and the biostratigraphic and palaeobiogeographic distribution of its early representatives are still poorly understood. An independent source of information may come from the extensive Carboniferous footprint record of reptiles, which is arguably richer and more complete than the skeletal record. Nevertheless, previous studies often failed to provide useful information because they were based on poorly preserved material and/or characters non-exclusive of reptile tracks. In fact, a large part of the supposed early reptile tracks can be assigned to the anamniote ichnotaxon Hylopus hardingi. Here, we revise the ichnotaxon Hylopus hardingi based on anatomy-consistent material, attribute it to anamniote reptiliomorphs, and distinguish it from Notalacerta missouriensis, the earliest ichnotaxon that can be attributed to reptiles, and the somewhat younger Varanopus microdactylus (attributed to parareptiles, such as bolosaurians) and Dromopus lacertoides (attributed to araeoscelid reptiles and non-varanodontine varanopids). These attributions are based on correlating morphofunctional features of tracks and skeletons. Multivariate analysis of trackway parameters indicates that the late Bashkirian Notalacerta missouriensis and Hylopus hardingi differ markedly in their trackway patterns from Late Mississippian Hylopus hardingi and Late Pennsylvanian reptile tracks, which appear to share a derived amniote-like type of gait. While the first occurrence/appearance of reptile tracks in the tetrapod footprint record during the late Bashkirian corresponds to the first occurrence/appearance of reptiles in the skeletal record, footprints significantly enlarge the paleobiogeographic distribution of the group, suggesting an earlier radiation of reptiles during the Bashkirian throughout North America and possibly North Africa. Dromopus appeared in the Kasimovian together with the diapsid group Araeoscelidia, but footprints from Western-European occurrences enlarge the paleobiogeographic distribution of diapsids and varanopids. Varanopus and bolosaurian parareptiles appear in the Gzhelian of North America. Older parareptiles are, however, known from the late Moscovian. In all, the footprint record of early reptiles supplements the skeletal record, suggesting possible future lines of research.

Abstract Invasive mold disease (IMD) of the central nervous system (CNS) is a severe infectious complication in immunocompromised patients, but early microbiological diagnosis is difficult. As data on the value of biomarkers in the CNS are scarce, in particular in children, we retrospectively analyzed the performance of galactomannan (GM) and PCR assays in CNS samples of 15 children with proven and probable CNS IMD and of 32 immunocompromised children without fungal infection. Galactomannan in the cerebrospinal fluid (CSF) was assessed in nine of the 15 pediatric patients and was positive in five of them. Polymerase chain reaction (PCR) was performed in eight of the 15 patients and detected nucleic acids from molds in six patients. Galactomannan and PCR in CNS samples were the only positive microbiologic parameter in the CNS in three and two patients, respectively. In four patients, PCR specified the pathogen detected in microscopy. Galactomannan and PCR results remained negative in the CSF of all immunocompromised children without evidence for CNS IMD. Our data suggest that GM and PCR in CNS specimens are valuable additional tools in diagnosing CNS IMD and should be included in the work up of all pediatric patients with suspected mold disease of the CNS.

Abstract Background Multimorbid older adults suffering from a long-term health condition like depression, diabetes mellitus type 2, dementia or frailty are at high risk of losing their autonomy. Disability and multimorbidity in the older population are associated with social inequality and lead to soaring costs. Our local, collaborative, stepped and personalised care management for older people with chronic diseases (LoChro-Care) aims at improving outcomes for older multimorbid patients with chronic conditions whose social and medical care must be improved. Methods The study will evaluate the effects of LoChro-Care on functional health, depressive symptoms and satisfaction with care, resource utilisation as well as health costs in older persons with long-term conditions. The trial will compare the effectiveness of LoChro-Care and usual care in a cross-sectoral setting from hospital to community care. We will recruit 606 older adults (65+) admitted to local hospital inpatient or outpatient departments who are at risk of loss of independence. Half of them will be randomised to receive the LoChro-Care intervention, comprising seven to 16 contacts with chronic care managers (CCM) within 12 months. The hypothesis that LoChro-Care will result in better patient-centred outcomes will be tested through mixed-method process and outcome evaluation and valid measures completed at baseline and at 12 and 18 months. Cost-effectiveness analyses from the healthcare perspective will include incremental cost-effectiveness ratios. Discussion The trial will provide evidence about the effectiveness of local, collaborative, stepped and personalised care management for multimorbid patients with more than one functional impairment or chronic condition. Positive results will be a first step towards the implementation of a systematic cross-sectoral chronic care management to facilitate the appropriate use of available medical and nursing services and to enhance self-management of older people. Trial registration German Clinical Trials Register (DRKS): DRKS00013904; Trial registration date: 02. February 2018.

Abstract Background Back pain is one of the most frequent causes of health-related work absence. In Germany, more than 70% of adults suffer from at least one back pain episode per annum. It has strong impact on health care costs and patients’ quality of life. Patients increasingly seek health information on the internet. However, judging its trustworthiness is difficult. In addition, physicians who are being confronted with this type of information often experience it to complicate the physician-patient interaction. The GAP trial aims to develop, implement and evaluate an evidence-based, easy-to-understand and trustworthy internet information portal on lower back pain to be used by general practitioners and patients during and after the consultation. Effectiveness of GAP portal use compared to routine consultation on improving communication and informedness of both physicians and patients will be assessed. In addition, effects on health care costs and patients’ days of sick leave will be evaluated. Methods We will conduct a prospective multi-centre, cluster-randomized parallel group trial including 1500 patients and 150 recruiting general practitioners. The intervention group will have access to the GAP portal. The portal will contain brief guides for patients and physicians on how to improve the consultation as well as information on epidemiology, aetiology, symptoms, benefits and harms of treatment options for acute, sub-acute and chronic lower back pain. The GAP portal will be designed to be user-friendly and present information on back pain tailored for either patients or physicians in form of brief fact sheets, educative videos, info-graphics, animations and glossaries. Physicians and patients will assess their informedness and the physician-patient communication in consultations at baseline and at two time points after the consultations under investigation. Days of sick leave and health care costs related to back pain will be compared between control and intervention group using routine data of company health insurance funds. Discussion The GAP-trial intends to improve the communication between physicians and their patients and the informedness of both groups. If proven beneficial, the evidence-based and user-friendly portal will be made accessible for all patients and health professionals in back pain care. Inclusion of further indications might be implemented and evaluated in the long term. Trial registration German Clinical Trials Register DRKS00014279 (registered 27th of April 2018).

Among amniote and non-amniote tetrapod trackways from late Carboniferous to early Permian deposits, certain trackway measures vary notably. Some of this variability can be attributed to evolutionary changes in trackmaker anatomy and locomotion style close to the origin of amniotes. Here we demonstrate that steps in early amniote locomotion evolution can be addressed by applying methods of ancestral state reconstruction on trackway data – a novel approach in tetrapod ichnology. Based on (a) measurements of 186 trackways referred to the Carboniferous and early Permian ichnogenera Batrachichnus, Limnopus, Hylopus, Amphisauropus, Matthewichnus, Ichniotherium, Dimetropus, Tambachichnium, Erpetopus, Varanopus, Hyloidichnus, Notalacerta and Dromopus, (b) correlation of these ichnotaxa with specific groups of amphibian, reptiliomorph, synapsid, and reptilian trackmakers based on imprint morphology and (c) known skeletal-morphology-based phylogenies of the supposed trackmakers, we infer ancestral states for functionally controlled trackway measures in a maximum likelihood approach. The most notable finding of our analysis is a concordant change in trackway parameters within a series of ancestral amniote trackmakers, which reflects an evolutionary change in locomotion: In the ancestors of amniotes and diadectomorphs, an increase in body size was accompanied by a decrease in (normalized) gauge width and glenoacetabular length and by a change in imprint orientation toward a more trackway-parallel and forward-pointing condition. In the subsequent evolution of diadectomorph, synapsid and reptilian trackmakers after the diversification of the clades Cotylosauria (Amniota + Diadectomorpha) and Amniota, stride length increased whereas gauges decreased further or remained relatively narrow within most lineages. In accordance with this conspicuous pattern of evolutionary change in trackway measures, we interpret the body size increase as an underlying factor that triggered the reorganization of the locomotion apparatus. The secondary increase in stride length, which occurred convergently within distinct groups, is interpreted as an increase in locomotion capability when the benefits of reorganization came into effect. The track-trackmaker pair of Ichniotherium sphaerodactylum and Orobates pabsti from the early Permian Bromacker locality of the Thuringian Forest, proposed in earlier studies as a suitable ancestral amniote track-trackmaker model, fits relatively well with our modeled last common ancestor of amniotes – with the caveat that the Bromacker material is younger and some of the similarities appear to be due to convergence.

Background The ratings of physician-patient communication are an important indicator of the quality of health care delivery and provide guidance for many important decisions in the health care setting and in health research. But there is no gold standard to assess physician-patient communication. Thus, depending on the specific measurement condition, multiple sources of variance may contribute to the total score variance of ratings of physician-patient communication. This may systematically impair the validity of conclusions drawn from rating data. Objective To examine the extent to which different measurement conditions and rater perspectives, respectively contribute to the variance of physician-patient communication ratings. Methods Variance components of ratings of physician-patient communication gained from 32 general practitioners and 252 patients from 25 family practices in Germany were analyzed using generalizability theory. The communication dimensions “shared decision making”, “effective and open communication” and “satisfaction” were considered. Results Physician-patient communication ratings most substantially reflect unique rater-perspective and communication dimension combinations (32.7% interaction effect). The ratings also represented unique physician and rater-perspective combinations (16.3% interaction effect). However, physicians’ communication behavior and the observed communication dimensions revealed only a low extent of score variance (1% physician effect; 3.7% communication dimension effect). Approximately half of the variance remained unexplained (46.2% three-way interaction, confounded with error). Conclusion The ratings of physician-patient communication minimally reflect physician communication skills in general. Instead, these ratings exhibit primarily differences among physicians and patients in their tendency to perceive shared decision making and effective and open communication and to be satisfied with communication, regardless of the communication behavior of physicians. Rater training and assessing low inferential ratings of physician-patient communication dimensions should be considered when subjective aspects of rater perspectives are not of interest.

IntroductionElderly, multimorbid patients are a primary target group for patient-centred care, and fostering patient-centredness (PC) in this group has been associated with different healthcare aims such as safety and quality of healthcare. However, evidence on effects of patient-centred interventions is still limited and mixed. In part, the lack of consistent evidence has its roots in a conceptual uncertainty of the term ‘PC’, which also hampers the development of assessment tools for PC. Consequently, reviews on assessment instruments of PC reveal problems regarding the quality of identified assessment instruments and regarding their comparability. Some of these reviews focus on the elderly. However, while the concept of multimorbidity is partly inherent, this focus is not explicit in any of the reviews.The aim of this systematic review is to identify assessment instruments of PC in the multimorbid elderly, using a subgroup-specific definition of PC (‘subgroup-specific integrative model of PC’) as the conceptual underpinning, and to provide a critical quality appraisal of their psychometric properties.Methods and analysisA comprehensive systematic literature search for assessment tools on PC will be conducted in the MEDLINE, CINAHL, EMBASE, PsycINFO, Web of Science and PSYNDEX electronic databases. The search strategy will be informed by the subgroup-specific integrative model of PC. The electronic literature search will be complemented by a hand-search combining citation tracking, search in project databases, and contacting authors from relevant studies/reviews. The literature search (systematic and hand-search) will cover the period from November, 2018 to December 2019.The retrieval of relevant studies will be conducted via title screening, abstract screening, and full-text eligibility assessment applying defined inclusion criteria. Full texts will be independently assessed by two team members. Data from the included articles will be extracted using a standardised extraction form and evaluated based on the COSMIN methodology for systematic reviews of patient-reported outcome measures, which focuses on the methodological quality of included studies as well as on the measurement properties of the assessment instruments. Data extraction and quality assessment will be conducted by two independent reviewers.Ethics and disseminationThe study has received approval from the Ethics Committee of the University of Freiburg (reference number 587/17). The results of the project will be disseminated via scientific oral presentations at national and international conferences and will be published in scientific journals.Trial registration numbersCRD42018084057; DRKS00013309.

Summary: Human cytomegalovirus (HCMV) causes diseases in individuals with immature or compromised immunity. To evade immune control, HCMV evolved numerous antagonists targeting the interferon system at multiple levels. By comparative analysis of naturally arising variants of the most widely studied HCMV strain, AD169, and a panel of targeted mutants, we uncover the UL145 gene as indispensable for STAT2 downregulation. Ribosome profiling confirms the translation of the canonical pUL145 protein (pUL145-Long) and newly identifies a shorter isoform (pUL145-Short). Both isoforms recruit DDB1-containing ubiquitin ligases to induce proteasomal degradation of STAT2. An alanine-scanning mutagenesis discloses the DDB1 interaction motif of pUL145 that resembles the DDB1-binding interface of cellular substrate receptors of DDB1-containing ubiquitin ligases. Thus, pUL145 constitutes a viral DDB1-cullin-associated factor (vDCAF), which mimics cellular DCAFs to exploit the ubiquitin-proteasome system to impede antiviral immunity. Notably, the viral exploitation of the cullins can be targeted to restore the efficacy of the host immune response. : Le-Trilling et al. utilize intra-strain differences occurring in the HCMV strain AD169 to probe into viral IFN antagonism. They uncover UL145 as a key factor for HCMV-encoded STAT2 degradation. The pUL145 proteins constitute druggable viral DCAFs (vDCAFs) that mimic the DDB1-recognizing interface of cellular DCAFs to impede antiviral immunity. Keywords: cytomegalovirus, ULb′, UL145, interferon, STAT2, DDB1, DCAF, pevonedistat, RL1

Highly immunocompromised pediatric and adult hematopoietic cell transplant (HCT) recipients frequently experience respiratory infections caused by viruses that are less virulent in immunocompetent individuals. Most of these infections, with the exception of rhinovirus as well as adenovirus and parainfluenza virus in tropical areas, are seasonal variable and occur before and after HCT. Infectious disease management includes sampling of respiratory specimens from nasopharyngeal washes or swabs as well as sputum and tracheal or tracheobronchial lavages. These are subjected to improved diagnostic tools including multiplex PCR assays that are routinely used allowing for expedient detection of all respiratory viruses. Disease progression along with high mortality is frequently associated with respiratory syncytial virus, parainfluenza virus, influenza virus, and metapneumovirus infections. In this review, we discuss clinical findings and the appropriate use of diagnostic measures. Additionally, we also discuss treatment options and suggest new drug formulations that might prove useful in treating respiratory viral infections. Finally, we shed light on the role of the state of immune reconstitution and on the use of immunosuppressive drugs on the outcome of infection.

XCL1 is the ligand for XCR1, a chemokine receptor uniquely expressed on cross-presenting dendritic cells (DC) in mouse and man. We are interested in establishing therapeutic vaccines based on XCL1-mediated targeting of peptides or proteins into these DC. Therefore, we have functionally analyzed various XCL1 domains in highly relevant settings in vitro and in vivo. Murine XCL1 fused to ovalbumin (XCL1-OVA) was compared to an N-terminal deletion variant lacking the first seven N-terminal amino acids and to several C-terminal (deletion) variants. Binding studies with primary XCR1+ DC revealed that the N-terminal region stabilizes the binding of XCL1 to its receptor, as is known for other chemokines. Deviating from the established paradigm for chemokines, the N-terminus does not contain critical elements for inducing chemotaxis. On the contrary, this region appears to limit the chemotactic action of XCL1 at higher concentrations. A participation of the XCL1 C-terminus in receptor binding or chemotaxis could be excluded in a series of experiments. Binding studies with apoptotic and necrotic XCR1-negative cells suggested a second function for XCL1: marking of stressed cells for uptake into cross-presenting DC. In vivo studies using CD8+ T cell proliferation and cytotoxicity as readouts confirmed the critical role of the N-terminus for antigen targeting, and excluded any involvement of the C-terminus in the uptake, processing, and presentation of the fused OVA antigen. Together, these studies provide basic data on the function of the various XCL1 domains as well as relevant information on XCL1 as an antigen carrier in therapeutic vaccines.

Background: Due to the difficulties in the definite diagnosis, data on brain imaging in pediatric patients with central nervous system (CNS)-invasive mold infection (IMD) are scarce. Our aim was to describe brain imaging abnormalities seen in immunocompromised children with CNS-IMD, and to analyze retrospectively whether specific imaging findings and sequences have a prognostic value. Methods: In a retrospective study of 19 pediatric patients with proven or probable CNS-IMD, magnetic resonance imaging (MRI)-findings were described and analyzed. The results were correlated with outcome, namely death, severe sequelae, or no neurological sequelae. Results: 11 children and 8 adolescents (11/8 with proven/probable CNS-IMD) were included. Seven of the patients died and 12/19 children survived (63%): seven without major neurological sequelae and five with major neurological sequelae. Multifocal ring enhancement and diffusion restriction were the most common brain MRI changes. Diffusion restriction was mostly seen at the core of the lesion. No patient with disease limited to one lobe died. Perivascular microbleeding seen on susceptibility weighted imaging (SWI) and/or gradient-echo/T2* images, as well as infarction, were associated with poor prognosis. Conclusions: The presence of infarction was related to poor outcome. As early microbleeding seems to be associated with poor prognosis, we suggest including SWI in routine diagnostic evaluation of immunocompromised children with suspected CNS-IMD.

Ichniotherium tracks with a relatively short pedal digit V (digit length ratio V/IV < 0.6) form the majority of yet described Late Carboniferous to Early Permian diadectomorph tracks and can be related to a certain diadectid clade with corresponding phalangeal reduction that includes Diadectes and its close relatives. Here we document the variation of digit proportions and trackway parameters in 25 trackways (69 step cycles) from nine localities and seven further specimens with incomplete step cycles from the type locality of Ichniotherium cottae (Gottlob quarry) in order to find out whether this type of Ichniotherium tracks represents a homogeneous group or an assemblage of distinct morphotypes and includes variability indicative for evolutionary change in trackmaker locomotion. According to our results, the largest sample of tracks from three Lower Permian sites of the Thuringian Forest, commonly referred to I. cottae, is not homogeneous but shows a clear distinction in pace length, pace angulation, apparent trunk length and toe proportions between tracks from Bromacker quarry and those from the stratigraphically older sites Birkheide and Gottlob quarry. Three Late Carboniferous trackways of Ichniotherium with relatively short pedal digit V from Haine’s Farm, Ohio, and Alveley near Birmingham, United Kingdom, that have been referred to the ichnotaxa “Baropus hainesi,” “Megabaropus hainesi” and “Ichniotherium willsi,” respectively, share a marked outward rotation of foot imprints with respect to walking direction. Apart from this feature they are in many aspects similar to the Birkheide and Gottlob records of I. cottae. With the possible exception of the Maroon Formation (Early Permian, Colorado) sample, Early Permian Ichniotherium trackways with a relatively short pedal digit V fall into the morphological spectrum of the three well defined “Hainesi–Willsi,” “Birkheide–Gottlob” and “Bromacker” morphotypes. With their more obtuse pace angulations and higher body-size-normalized pace and stride lengths the Bromacker type tracks imply higher walking speeds of their trackmakers compared to all other Ichniotherium tracks. More generally, a trend towards higher locomotion capability from the last common ancestor of all Ichniotherium producers to the last common ancestor of all “Ichniotherium with relatively short pedal digit V” and from the latter to the trackmakers of the mid-Early Permian Bromacker type can be deduced—with the reservation that overall sample size is relatively small, making this scenario a preliminary assessment. Whether the presumed advancements represent a more general pattern within diadectomorphs remains open until the non-European Ichniotherium trackway record improves. Ichnotaxonomic implications are discussed.

Polyomaviruses are small, non-enveloped viruses with a circular double-stranded DNA genome. Using a generic polyomavirus PCR targeting the VP1 major structural protein gene, a novel polyomavirus was initially identified in resected human liver tissue and provisionally named Human Polyomavirus 12 (HPyV12). Its 5033 bp genome is predicted to encode large and small T antigens and the 3 structural proteins VP1, VP2 and VP3. Phylogenetic analyses did not reveal a close relationship to any known human or animal polyomavirus. Investigation of organs, body fluids and excretions of diseased individuals and healthy subjects with both HPyV12-specific nested PCR and quantitative real-time PCR revealed additional virus-positive samples of resected liver, cecum and rectum tissues and a positive fecal sample. A capsomer-based IgG ELISA was established using the major capsid protein VP1 of HPyV12. Seroprevalences of 23% and 17%, respectively, were determined in sera from healthy adults and adolescents and a pediatric group of children. These data indicate that the virus naturally infects humans and that primary infection may already occur in childhood.

Background The positive effects of the Dutch Community Occupational Therapy in Dementia programme on patients' daily functioning were not found in a multicentre randomised controlled trial (RCT) in Germany.Objectives To evaluate possible effect modification on the primary outcome within the German RCT with regard to (1) participant characteristics, (2) treatment performance and (3) healthcare service utilisation; and (4) to compare the design and primary outcome between the German and the original Dutch study.Methods (1) The impact of participant baseline data on the primary outcome was analysed in exploratory ANCOVA and regression analyses. (2) Therapists completed questionnaires on context and performance problems. The main problems were identified by a qualitative content analysis and focus-group discussion. Associations of the primary outcome with scores of participant adherence and treatment performance were evaluated by regression analysis. (3) Utilisation rates of healthcare services were controlled for significant group differences. (4) Differences in the Dutch and German study design were identified, and the primary outcome was contrasted at the item level.Results (1) Participant characteristics could not explain more than 5% of outcome variance. (2) The treatment performance of some active intervention components was poor but not significantly associated with the primary outcome. (3) There were no significant group differences in the utilisation of healthcare resources. (4) In contrast to the Dutch waiting-control group, the active intervention in the German control group may have reduced group differences in the current RCT. The German patients demonstrated a higher independence at baseline and less improvement in instrumental activities of daily living.Conclusion The differences in outcome may be explained by a more active control treatment, partially poor experimental treatment and less room for improvement in the German sample. Future cross-national transfers should be prepared by pilot studies assessing the applicability of the intervention and patient needs specific to the target country.Trial registration International Clinical Trials Registry Platform, DRKS00000053.

Objective To compare the benefits and harms of a Dutch 10-session Community Occupational Therapy programme for patients with Alzheimer's disease with the impact of a one session consultation at home in German routine healthcare.Design A seven-centre, parallel group, active controlled randomised controlled trial. Patients and carers were not masked. Assessors were fully blind for treatment allocation for one of two primary-outcome measurements.Setting Patients' homes.Participants Patients with mild to moderate Alzheimer's disease (Mini-Mental State Examination 14–24), living in the community with primary carer available and without severe depression or behavioural symptoms, were eligible.Interventions Experimental 10 home visits within 5 weeks by an occupational therapist, educating patients in the performance of simplified daily activities and in the use of aids to compensate for cognitive decline; and educating carers in coping with behaviour of the patient and in giving supervision to the patient. Control one home visit including individual counselling of patient and carer and explanation of a leaflet on coping with dementia in daily life.Outcome measures The primary outcome was the patient's daily functioning measured with the Interview of Deterioration in Daily activities in Dementia and the Perceive, Recall, Plan and Perform System of Task Analysis. Assessments were at baseline, 6, 16 and 26 weeks, with a postal assessment at 52 weeks.Results 141 patients were 1:1 randomised to the experimental (N=71) and control group (N=70). Data for 54 and 50 participants were analysed. Patients' daily functioning did not differ significantly between the experimental and control group at week 6, 16, 26 or 52 and remained stable over 26 weeks in both groups. No adverse events were associated with the interventions.Conclusions In German healthcare, a Dutch 10-session community occupational therapy was not better than a one-session consultation for the daily functioning of patients with Alzheimer's disease. Further research on the transfer of complex psychosocial is needed.International Clinical Trials Registry Platform DRKS00000053; Funded by the German Federal Ministry of Health.