Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

[Rehabilitation needs of geriatric patients in subacute inpatient care after acute inpatient hospitalization-a neglected claim]. / Rehabilitationsbedarf geriatrischer Patienten in Kurzzeitpflege nach akutstationärem Aufenthalt ­ ein vernachlässigter Versorgungsanspruch.

BACKGROUND: Geriatric patients after hospitalization often utilize subacute inpatient care (SC); however, little is known about their care and further health status. OBJECTIVE: To identify persons in SC with rehabilitation needs and improvement potential after hospitalization and to describe the care, relevant parameters of the health status as well as use of medical/nursing services in and after SC. METHODS: After positive screening for previous hospitalization and need of rehabilitation with improvement potential in 13 nursing homes, the length of stay, therapeutic treatments and physician contacts in SC as well as functional parameters, pain, quality of life and the utilization of services according to the Social Security Code V (SGB V) and SGB XI were assessed at baseline, at the end and 3 months after SC. RESULTS: A total of 108 (44%) out of 243 screened persons with previous hospitalization had a need of rehabilitation with improvement potential, of whom 57 participated in the study. In SC (median = 26 days) 35% received no therapeutic treatments and 28% had no physician contact. After SC 40% were transferred to rehabilitation. Participants with rehabilitation transition more frequently received therapeutic treatments in SC (p = 0.021) and were less frequently in long-term care 3 months after SC (p = 0.015). CONCLUSION: This study suggests that a high proportion of persons in SC after hospitalization are in need of rehabilitation with improvement potential, which is not sufficiently treated. Regular therapeutic treatments in SC could improve the transition rate to rehabilitation and subsequent home environment.

[Health economic evaluation of rehabilitative short-term care : Analysis of the costs of geriatric patients with and without rehabilitative short-term care after inpatient hospital stay]. / Gesundheitsökonomische Evaluation einer rehabilitativen Kurzzeitpflege : Ermittlung der Kosten von geriatrischen Patienten mit und ohne rehabilitative Kurzzeitpflege nach stationärem Krankenhausaufenthalt.

BACKGROUND: Geriatric patients requiring rehabilitation and admitted to short-term care after an acute inpatient hospital stay seldom receive rehabilitative services later. Rehabilitative short-term care (REKUP) supplements short-term care with rehabilitative measures, aiming to prevent functional restrictions and long-term care. STUDY OBJECTIVE: To conduct a cost and cost-effectiveness analyses of REKUP and provide data for a nationwide rollout. MATERIAL AND METHODS: A non-randomized controlled prospective study was carried out. The intervention group (IG) was paired 1:2 with a control group (KG), resulting in the formation of three collectives with follow-up periods of either 30, 90 or 180 days (each with IG and KG). Using administrative claims data from the AOK Baden-Württemberg, the mean total costs from the perspective of the health insurance were calculated. A potential impact of the intervention on costs was analyzed using the difference in differences approach. RESULTS: The analysis comprised 129 patients (IG 43; KG 86). During the follow-up periods, the IG presented higher rates of rehabilitation and lower rates of long-term care and mortality. Regarding costs, no statistically significant differences were found between the IG and KG in any of the three collectives. For nursing care and medication costs, costs were significantly higher in the follow-up period for the KG, whereas costs for rehabilitation were significantly higher for the IG (p < 0.001). DISCUSSION: Patients receiving REKUP utilize rehabilitation services more often and have a lower likelihood of requiring nursing care or dying with no statistically significant differences in costs. There are potential advantages of REKUP in the target population, which warrant further investigation due to methodological limitations.

[Integrated care concepts and multidisciplinary process chains in a radiological context]. / Integrierte Behandlungskonzepte und multidisziplinär organisierte Prozessketten im radiologischen Kontext.

Modern patient-centered and cost-efficient care concepts in hospitals require the mapping of multidisciplinary process chains into clinical pathways. Clinical decision support systems and operations research methods use algorithms to classify patients into homogeneous groups and to model a complete clinical pathway for scheduling individual procedures. An improvement of the economic situation of the care facility can be achieved through improved resource utilization, reduced patient waiting times and a shortening of the length of stay. The interdisciplinary use of centrally stored interoperable information and comprehensive care management via information technology (IT) services lay the foundation for the dissolution of traditional IT system architectures in medicine and the development of flexibly integrable modern system platforms. New IT approaches such as the semantically standardized definition of procedures and resource properties, the use of clinical decision support systems and the use of service-oriented system architectures form the basis for the deep integration of radiology services into comprehensive interdisciplinary care concepts.

Post-acute COVID-19 geriatric rehabilitation : A European perspective.

Coronavirus disease 2019 (COVID-19) poses a threat to the health and independence of older people in particular. In this article we elaborate on the content and importance of post-acute COVID-19 geriatric rehabilitation from a European perspective. We explain the geriatric rehabilitation paradox and how this can and should be solved. We also present what post-acute COVID-19 geriatric rehabilitation should entail. This might not only help us to develop better geriatric rehabilitation services, but it should also inform pandemic preparedness in the future.

Minimizing comprehensive geriatric assessment to identify deterioration of physical performance in a healthy community-dwelling older cohort: longitudinal data of the AEQUIPA Versa study.

BACKGROUND: It is important to identify the relevant parameters of physical performance to prevent early functional decline and to prolong independent living. The aim of this study is to describe the development of physical performance in a healthy community-dwelling older cohort aged 70+ years using comprehensive assessment over two years and to subsequently identify the most relevant predictive tests for physical decline to minimize assessment. METHODS: Physical performance was measured by comprehensive geriatric assessment. Predictors for the individual decline of physical performance by Principal Component and k-means Cluster Analysis were developed, and sensitivity and specificity determined accordingly. RESULTS: 251 subjects (Ø 75.4 years) participated in the study. Handgrip strength was low in 21.1%. The follow-up results of tests were divergent. Handgrip strength [- 16.95 (SD 11.55)] and the stair climb power test (power) [- 9.15 (SD 16.84)] yielded the highest percentage changes. Four most relevant tests (handgrip strength, stair climb power time, timed up & go and 4-m gait speed) were identified. A predictor based on baseline data was determined (sensitivity 82%, specificity 96%) to identify subjects characterized by a high degree of physical decline within two years. DISCUSSION: Although the cohort of older adults is heterogeneous, most of the individuals in the study exhibited high levels of physical performance; only a few subjects suffered a relevant decline within the 2-year follow-up. Four most relevant tests were identified to predict relevant decline of physical function. CONCLUSION: In spite of ceiling effects of the geriatric assessment in high-performers, we assume that it is possible to predict an individual's risk of physical decline within 2 years with four tests of a comprehensive geriatric assessment.

Technical note: Validation of an in-house bovine serum enzyme immunoassay for progesterone measurement.

Measuring circulating progesterone (P4) of dairy cows is a key component of many research studies dealing with basic and applied reproduction physiology. The gold standard in dairy cows for the measurement of P4 in serum is radioimmunoassay (RIA), but it generates radioactive waste and requires licensed facilities. The purpose of this study was to develop and validate an in-house competitive enzyme immunoassay (EIA) to measure the P4 concentration in serum of dairy cattle. The secondary objective was to validate a commercial EIA. In the present study, a competitive EIA was developed using commercially available antibodies and conjugates. Ninety-six well microtiter plates were coated with the secondary antibody and incubated overnight. Following a washing step, the wells were blocked using the primary antibody. Serum samples were prepared by first extracting P4 using petroleum ether, then diluted in working conjugate solution. Samples were pipetted into the coated and blocked plates, then the matching HRP conjugate label (P4-3-HRP, East Coast Bio, North Berwick, ME) was added. The plates were incubated for 2 h, then washed. The substrate solution was added, and the plate was incubated up to 1 h at room temperature in the dark until a blue color had developed. A stop solution was added, and the optical density measured on a microplate reader was set at 450 nm. The binding proportion was calculated by a visible spectrum absorbance reader, and the amount of P4 was calculated using a log-logit regression line. The commercial EIA was executed as suggested by the manufacturer. The validation of the in-house EIA was done by calculating the inter- and intraassay coefficients of variation (CV) and evaluating the parallelism of diluted samples. The results from the in-house and commercial EIA were also compared with the ones from the RIA graphically (scatterplots and Bland-Altman plots) and statistically, using the Spearman correlation coefficient (r) and the Cohen's kappa statistics using a threshold of 1.0 ng/mL (κ). For the in-house EIA, the intraassay CV were all <10%, but the interassay for samples with small and large P4 concentration had CV of 12.5 and 11.0%, respectively. The correlations between the results from the EIA and the RIA were strong (in-house: r = 0.90; commercial: r = 0.83). At small concentrations (<1.0 ng/mL), however, the correlation with the gold standard was weak (in-house: r = 0.27; commercial: r = 0.14). This was likely due to the lack of accuracy at small concentrations, also shown by the absence of parallelism in samples ≤0.4 ng/mL. In conclusion, results from both the in-house and commercial EIA strongly correlated with the gold standard, but less so at smaller concentrations. The in-house EIA offers good accuracy to measure P4 in samples with a concentration >0.4 ng/mL, and a perfect agreement with RIA using a threshold of 1.0 ng/mL.

[Psychosocial effects of the pandemic on staff and residents of nursing homes as well as their relatives-A systematic review]. / Psychosoziale Auswirkungen der Pandemie auf Pflegekräfte und Bewohner von Pflegeheimen sowie deren Angehörige ­ Ein systematisches Review.

BACKGROUND: Following the COVID-19 pandemic residents of nursing homes, their visitors and families as well as employees are faced with new challenges. Protective measures have a strong impact on the well-being of all these groups of persons. MATERIAL AND METHODS: A systematic search was carried out for studies investigating the psychosocial consequences of the COVID-19 pandemic for residents, their visitors and families as well as nursing home staff. Results were analyzed by narrative synthesis. RESULTS: A total of 756 studies were screened and 15 studies were included. These studies were conducted between February and June 2020 with participants from 14 countries. Participants reported loneliness, grief and depressive symptoms among residents. Some gave an account of fear as a reaction of residents to social distancing. Residents with cognitive impairment suffered more although there are conflicting reports. The well-being of visitors and friends was compromised and their feeling of loneliness increased. Nursing home personnel reported fear of getting infected and of infecting residents or their own families. Infected workers in the USA expressed anger about a lack of protection. Furthermore, an increase in workload was reported. CONCLUSION: Studies conducted during the first months of the pandemic reported negative consequences for the psychosocial well-being of residents, their visitors and nursing home staff. Individual needs for future support of these groups are distinct and need further evaluation during the on-going pandemic.

[COVID-19 in old age-The geriatric perspective]. / COVID-19 im Alter ­ Die geriatrische Perspektive.

Predominantly the older population is affected by a severe course of COVID-19. The mortality of hospitalized patients with COVID-19 above the age of 80 years is up to 54% in international studies. These observations indicate the necessity to highlight the geriatric perspective on this disease. The diagnostics and treatment of COVID-19 do not differ between younger and older patients but atypical symptoms should be expected more frequently in old age. Older subjects show an increased need for rehabilitation after COVID-19. Paradoxically, increasing rehabilitation demands go along with a reduced availability of geriatric rehabilitation options, the latter being a consequence of closure or downsizing of rehabilitation departments during the pandemic. In general, measures of isolation and quarantine should be diligently balanced as the health and emotional consequences of such measures may be severe in older persons. In light of the poor prognosis of older COVID-19 patients, advanced care planning becomes even more relevant. Caregivers and physicians should be encouraged to compose advanced care directives that also reflect the specific circumstances of COVID-19. Fortunately, current data suggest that the effectiveness of the vaccination with the mRNA-vaccines approved in Germany may be equally high in older compared to younger persons.

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.

BACKGROUND: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). OBJECTIVES: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. METHODS: This was a consensus expert review. RESULTS: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. CONCLUSIONS: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.

Development of selected bacterial groups of the rectal microbiota of healthy calves during the first week postpartum.

AIMS: The intestinal microbiota of newborn calves is largely unexplored even if it is of great significance for their future health. Therefore, the aim of the study was to gain a better insight into the development dynamics of certain bacterial groups during the first week of life. METHODS AND RESULTS: Faecal samples of healthy Simmental calves (dual-purpose breed; n = 80), bottle fed and raised in a dairy farm were taken immediately after birth and at 6/12/24/48/72/168 h (h) after birth. Samples were analysed using cultural, biochemical and molecular-biological methods. The aerobe, anaerobe, Enterobacteriaceae and Enterococcus counts of healthy calves increased significantly between 6 and 24 h postpartum (P <0·05). Apart from the anaerobes, bacterial counts decreased after reaching a plateau at 24-48 h. Enterococcus faecalis was detected in significantly higher counts compared to E. faecium (P <0·05). Lactobacilli developed more slowly and increased until day 7 after birth to a mean value of 6·8 × 107  CFU per g. MALDI-TOF analysis of 2338 lactobacilli isolates resulted in 36 different species. CONCLUSIONS: Lactobacillus reuteri became the most common Lactobacillus sp. during the first week of life. SIGNIFICANCE AND IMPACT OF THE STUDY: This fact seems to be very important for the calf's intestinal health because L. reuteri is known to show in vitro bactericidal effects against bacterial pathogens and anti-infective activities against rotaviruses and Cryptosporidium parvum.

Prediction of hospital visits for the general inpatient care using floating catchment area methods: a reconceptualization of spatial accessibility.

BACKGROUND: The adequate allocation of inpatient care resources requires assumptions about the need for health care and how this need will be met. However, in current practice, these assumptions are often based on outdated methods (e.g. Hill-Burton Formula). This study evaluated floating catchment area (FCA) methods, which have been applied as measures of spatial accessibility, focusing on their ability to predict the need for health care in the inpatient sector in Germany. METHODS: We tested three FCA methods (enhanced (E2SFCA), modified (M2SFCA) and integrated (iFCA)) for their accuracy in predicting hospital visits regarding six medical diagnoses (atrial flutter/fibrillation, heart failure, femoral fracture, gonarthrosis, stroke, and epilepsy) on national level in Germany. We further used the closest provider approach for benchmark purposes. The predicted visits were compared with the actual visits for all six diagnoses using a correlation analysis and a maximum error from the actual visits of ± 5%, ± 10% and ± 15%. RESULTS: The analysis of 229 million distances between hospitals and population locations revealed a high and significant correlation of predicted with actual visits for all three FCA methods across all six diagnoses up to ρ = 0.79 (p < 0.001). Overall, all FCA methods showed a substantially higher correlation with actual hospital visits compared to the closest provider approach (up to ρ = 0.51; p < 0.001). Allowing a 5% error of the absolute values, the analysis revealed up to 13.4% correctly predicted hospital visits using the FCA methods (15% error: up to 32.5% correctly predicted hospital). Finally, the potential of the FCA methods could be revealed by using the actual hospital visits as the measure of hospital attractiveness, which returned very strong correlations with the actual hospital visits up to ρ = 0.99 (p < 0.001). CONCLUSION: We were able to demonstrate the impact of FCA measures regarding the prediction of hospital visits in non-emergency settings, and their superiority over commonly used methods (i.e. closest provider). However, hospital beds were inadequate as the measure of hospital attractiveness resulting in low accuracy of predicted hospital visits. More reliable measures must be integrated within the proposed methods. Still, this study strengthens the possibilities of FCA methods in health care planning beyond their original application in measuring spatial accessibility.

Risk of traumatic intracranial haemorrhage is increased in older people exposed to oral anticoagulation with phenprocoumon.

BACKGROUND: Hospital admissions resulting from traumatic intracranial haemorrhages (TIH) in older people are increasing. There are concerns regarding an increased risk of a TIH in people taking oral anticoagulants (OAC) like phenprocoumon. AIMS: The aim of this study was to estimate the incremental risk of a TIH associated with OAC in older people. Furthermore, this study explored differences in risk according to functional status. METHODS: The study took data from a large German health insurance provider and combined hospital diagnoses with data regarding drug dispensing to estimate rates of a TIH in people with and without exposure to phenprocoumon. Analyses were stratified by sex and by severe functional impairment as disclosed by the long-term care insurance provider. RESULTS: Overall, exposure to OAC resulted in 2.7 times higher rates of TIH. People with severe functional impairment had a higher baseline risk of TIH than people without severe functional impairment. However, the incremental risk in those exposed to OAC was similar among people with and without severe functional impairment (standardised incidence rate difference 15.73 (95% CI 7.84; 23.61) and 12.10 (95% CI 9.63; 14.57) per 10,000 person-years, respectively). CONCLUSIONS: OAC increases the risk of TIH considerably. The incremental risk of TIH in those exposed to OAC is comparable between people with and without severe functional impairment. The presence of severe functional impairment per se should not exclude such patients from the potential benefits of OAC. For now, the prescription should be personalized based on individual fall risk factors and risk-taking behaviour.

Sarcopenia and myosteatosis in patients undergoing curative radiotherapy for head and neck cancer: Impact on survival, treatment completion, hospital admission and cost.

BACKGROUND: Computed tomography (CT) is the gold standard of body composition analysis at the tissue-organ level. The present study aimed to determine the impact of CT-defined sarcopenia and myosteatosis on outcomes, including overall survival, unplanned hospital admissions and related costs, in patients who had completed treatment of curative intent for head and neck cancer (HNC). METHODS: Retrospective observational study of patients undergoing radiotherapy of curative intent ± other treatment modalities for HNC. Tissue density data derived at the third lumbar vertebra (L3) were evaluated with sarcopenia defined per sex-specific published threshold values for skeletal muscle index, stratified by body mass index and mean skeletal muscle attenuation in HU (Hounsfield units). RESULTS: Pre- or post-treatment images were available for 79/98 patients (80.6%) and 61/98 patients (62.2%), respectively. Sarcopenia was present in 42/79 patients pre-treatment and 36/61 patients post-treatment, whereas myosteatosis was present in 63/79 patients pre-treatment and 48/61 patients post-treatment. In patients with pre- and post-treatment images (n = 60), the median (range) percentage weight change was -8.5% (-29.9 to +11.7). On multivariable analysis, a post-treatment sarcopenia hazard ratio of 3.87 (95% confidence interval = 1.22-12.24, P = 0.021) and a pre-treatment myosteatosis hazard ratio of 8.86 (95% confidence interval = 1.12-69.88, P = 0.038) were independent predictors of reduced overall survival. There was no difference in radiotherapy or chemotherapy treatment completion based on pre-treatment sarcopenia status. The mean (SD) difference unplanned hospital admission cost was $15 846 ($17 707) for patients without sarcopenia versus $47 945 ($82 688) for patients with sarcopenia at any time point (P = 0.077). CONCLUSIONS: As CT-defined sarcopenia and myosteatosis hold clinically meaningful prognostic value, muscle status evaluation is recommended in routine clinical practice.

[Consent management and workflows for cross-sectoral patient records and teleconsultations]. / Consent Management und Workflows für intersektorale Patientenakten und Telekonsile.

Cross-enterprise electronic patient records are a key element in the design of interoperable medical care networks and process chains. However, the different requirements concerning type, performance and quality assurance of available communication services within the different healthcare sectors still require that the hospitals participate in various secure communication networks which have to be bridged for cross-sectoral communication. Cross-institutional pathways for telemedicine, however, can be mapped both within and across sectoral boundaries via automated process chains using the IHE (Integrating the Healthcare Enterprise) defined integration profile CrossEnterprise Document Sharing (XDS) and associated integration profiles. The provision of medical documents in a cross-institutional patient record outside of defined medical pathways requires differentiated authorization management. In this respect, consent documents according to the IHE APPC (Advanced Patient Privacy Consents) profile enable the documentation of the patient's consent, including information about planned authorized people, document types, period and type of document access allowed. Providing access control to medical documentation by the patients themselves is an essential part of the required focusing of medical services on patients. New interoperability standards optimized for use on mobile devices, such as FHIR (Fast Healthcare Interoperability Resources), will enable simplified delivery of patient-centered health records and other medical services on mobile platforms in the future.

[Cross-enterprise interoperability : Challenges and principles for technical implementation]. / Einrichtungsübergreifende Interoperabilität : Herausforderungen und Grundlagen für die technische Umsetzung.

Demographic change, the migration of medical professionals and economic constraints are leading to an increasing specialisation and concentration of resources in the healthcare sector. The digital mapping of cross-enterprise process chains between different medical care levels in turn requires digital networking and syntactical and semantical interoperability in information exchange. Cross-enterprise electronic patient records based on the Cross-Enterprise Document Sharing (XDS.b) integration profile defined by the Integrating the Healthcare Enterprise (IHE) initiative are the basis of the digital exchange of medical information between patients and service providers. Syntactical interoperability is ensured by the object definitions in the XDS Affinity domain and the Clinical Document Architecture (CDA) document format. Semantical interoperability is achieved by the use of standardized terminology and code systems. Terminology servers make it easy to deploy standard ontologies and translate proprietary code systems. New interoperability standards, e.g. based on Fast Healthcare Interoperability Resources (FHIR), are being developed to facilitate the exchange of structured medical information objects on mobile platforms in the future.

Risk of institutionalization following fragility fractures in older people.

Previously independent living older people suffering fractures of the hip have a high risk of new admission to a nursing home during the subsequent months. This study shows that older people admitted to hospital for fractures of the pelvis and spine have a similar risk of admission to a nursing home. INTRODUCTION: Fall-related fractures are a serious threat to the health and well-being of older persons. Long-term consequences of hip fractures such as institutionalization and mortality are well-known. The impact of other fragility fractures is less well-understood. The aim of this study was to estimate risks of institutionalization and death for different fragility fractures and compare them with the corresponding risks after hip fracture. METHODS: Data was retrieved from a German health insurance company. Between 2005 and 2008 more than 56,000 community-dwelling people with a hospital admission or discharge diagnosis of a fracture of the femur, spine, pelvis, proximal humerus, distal radius, tibia, or fibula were included. Crude and age-adjusted 6-month incidence rates for institutionalization and death were calculated. To compare the risks of institutionalization or mortality of non-hip fractures with the risk after hip fracture, multivariate regression models were applied. RESULTS: Crude institutionalization rates and mortality were highest in patients with hip fracture. However, after adjustment for age, functional status, and comorbidity, risks of institutionalization after fractures of pelvis (relative risk (RR), 0.94; 95% confidence interval (CI) 0.86; 1.02 in women and 0.89; 95% CI 0.70; 1.12 in men), and spine (RR, 0.95; 95% CI 0.87; 1.03 in women and 0.91; 95% CI 0.76; 1.08 in men) were not statistically different compared to the risk after hip fracture. CONCLUSIONS: The risk of institutionalization after fractures of the spine and pelvis was similar to the risk after hip fracture. These fracture sites seem to be associated with a significant decline in physical function.

An ex vivo RNA trans-splicing strategy to correct human generalized severe epidermolysis bullosa simplex.

BACKGROUND: Generalized severe epidermolysis bullosa simplex (EBS-gen sev) is a genetic blistering skin disease in which autosomal dominant mutations in either the keratin KRT5 or KRT14 genes lead to impaired function of the intermediate filament cytoskeleton in the basal epidermis. Here we present an ex vivo RNA trans-splicing-based therapeutic approach to correct the phenotype. OBJECTIVES: To correct a mutation within exon 1 of the KRT14 gene, using a 5'-trans-splicing approach, where any mutation within the first seven exons could be replaced by a single therapeutic molecule. METHODS: A therapeutic RNA trans-splicing molecule containing wild-type exons 1-7 was stably transduced into an EBS patient-derived keratinocyte line. Trans-splicing was confirmed via reverse-transcriptase polymerase chain reaction, Western blotting and immunofluorescence microscopy. Skin equivalents generated from corrected keratinocytes were grafted onto nude mice and analysed about 8 weeks post-transplantation for regular epidermal stratification, trans-splicing-induced green fluorescent protein expression and blistering. RESULTS: Transplanted skin equivalents generated from trans-splicing-corrected patient keratinocytes showed a stable and blister-free epidermis. KRT14 correction disrupted EBS-gen sev-associated proinflammatory signalling, as shown at the mRNA and protein levels. Disruption of the pathogenic feedback loop in addition to overall downregulation of KRT14 expression highlighted the effect of KRT14 correction on the EBS pathomechanism. CONCLUSIONS: Our data demonstrate that trans-splicing-mediated mRNA therapy is an effective method for the correction of dominantly inherited KRT14 mutations at the transcriptional level. This results in the rescue of the EBS-gen sev phenotype and stabilization of the epidermis in a xenograft mouse model.

Increased tumour cell PD-L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas.

BACKGROUND: Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated. OBJECTIVES: We aimed to identify immunological differences between ulcerated and non-ulcerated primary melanomas concerning both innate and adaptive immunity and to correlate these with clinical outcome. METHODS: Formalin-fixed paraffin-embedded primary melanomas from 112 patients (pts) were analysed by immunohistochemistry. The expression of various markers identifying tumour-infiltrating lymphocytes, macrophages and dendritic cells was evaluated semi-quantitatively by three independent investigators. Tumour cell expression of programmed death-ligand 1 (PD-L1), transporter of antigen processing 1 and the MxA protein was also analysed. RESULTS: Recurrence occurred in 21/56 pts (37.5%) with ulcerated vs. 14/56 pts (25.0%) with non-ulcerated tumours (P = 0.15). Tumour ulceration was associated with more frequent development of brain metastasis (17.6 vs. 3.6% of pts, P = 0.015). Immunohistochemistry showed an association of ulceration with the presence of intratumoural CD68+ macrophages (P = 0.028) as well as with increased numbers of intratumoural CD11c+ dendritic cells (P = 0.014) and CD163+ macrophages (P = 0.001). PD-L1 positivity (expression in >1% of tumour cells) was more frequent in ulcerated than non-ulcerated tumours [40 (72.7%) vs. 25 (44.6%), P = 0.003]. A positive correlation between intratumoural CD11c+ (Spearman's correlation coefficient ρ: 0.42) and CD163+ (ρ: 0.31) cell count and frequency of tumour cell PD-L1 expression was detected. CONCLUSIONS: Our results confirm the adverse clinical outcome associated with primary melanoma ulceration, particularly concerning the risk of recurrence and subsequent development of brain metastases. The observed immunological differences suggest a conceivable role of increased intratumoural macrophage and dendritic cell counts associated with enhanced tumour cell PD-L1 expression potentially contributing to the immunosuppressive, growth-promoting microenvironment of ulcerated primary melanomas.

[Bony knee injuries in childhood and adolescence]. / Knöcherne Knieverletzungen im Kindes- und Jugendalter.

While fractures around the knee are known to be rare, physicians have encountered a rise in the frequency due to the increased participation of children and adolescents in high-impact sports at a younger age. Even if the treatment of fractures in some cases resembles that in adults, the diagnostics and treatment in childhood and adolescence require a hígh level of experience in order avoid possible sequelae and to enable early recognition. Thorough diagnostics using clinical and imaging investigations as well as a precise weighing up of the treatment are essential to minimize differences in leg length and axial malpositioning of the leg. A decision between conservative and operative treatment is made for both the femur and tibia depending on the type of fracture. Decisive is the degree of dislocation of the fracture. In operative treatment, the axis conform reduction and subsequent stress stable treatment are particularly decisive. Avulsion trauma, bony avulsions of the intercondylar eminence and patellar injuries are also treated conservatively with immobilization or surgically with the aid of various fixation techniques, depending on the degree of dislocation.