Multiscale analysis of human tissue engineered matrices for next generation heart valve applications.

Human tissue-engineered matrices (hTEMs) have been proposed as a promising approach for in situ tissue engineered heart valves (TEHVs). However, there is still a limited understanding on how ECM composition in hTEMs develops over tissue culture time. Therefore, we performed a longitudinal hTEM assessment by 1) multiscale evaluation of hTEM composition during culture time (2, 4, 6-weeks), using (immuno)histology, biochemical assays, and mass spectrometry (LC-MS/MS); 2) analysis of protein pathways involved in ECM development using gene set enrichment analysis (GSEA); and 3) assessment of hTEM mechanical characterization using uniaxial tensile testing. Finally, as a proof-of-concept, TEHVs manufactured using 6-weeks hTEM samples were tested in a pulse duplicator. LC-MS/MS confirmed the tissue culture time-dependent increase in ECM proteins observed in histology and biochemical assays, revealing the most abundant collagens (COL6, COL12), proteoglycans (HSPG2, VCAN), and glycoproteins (FN, TNC). GSEA identified the most represented protein pathways in the hTEM at 2-weeks (mRNA metabolic processes), 4-weeks (ECM production), and 6-weeks (ECM organization and maturation). Uniaxial mechanical testing showed increased stiffness and stress at failure, and reduction in strain over tissue culture time. hTEM-based TEHVs demonstrated promising in vitro performance at both pulmonary and aortic pressure conditions, with symmetric leaflet coaptation and no stenosis. In conclusion, ECM protein abundance and maturation increased over tissue culture time, with consequent improvement of hTEM mechanical characteristics. These findings suggest that longer tissue culture impacts tissue organization, leading to an hTEM that may be suitable for high-pressure applications. STATEMENT OF SIGNIFICANCE: It is believed that the composition of the extracellular matrix (ECM) in the human tissue engineered matrices (hTEM) may favor tissue engineered heart valve (TEHV) remodeling upon implantation. However, the exact protein composition of the hTEM, and how this impacts tissue mechanical properties, remains unclear. Hence, we developed a reproducible rotation-based tissue culture method to produce hTEM samples. We performed a longitudinal assessment using different analytical techniques and mass spectrometry. Our data provided an in-depth characterization of the hTEM proteome with focus on ECM components, their development, and how they may impact the mechanical properties. Based on these results, we manufactured functional hTEM-based TEHVs at aortic-like condition in vitro. These outcomes pose an important step in translating hTEM-based TEHVs into clinics and in predicting their remodeling potential upon implantation.

[Artificial intelligence in cardiac surgery]. / Künstliche Intelligenz in der Herzchirurgie.

Less than 10 years ago a breakthrough was made in the world of computer science and artificial intelligence (AI) with the application of deep neural networks, which initially found little attention in medicine. In 2017 the first high-ranking publications on the medical application of AI were published. The potential of AI became known to many both in clinical medicine as well as in clinical and biomedical research. At the end of 2019 a phase of upheaval is occurring: first concepts for regulatory procedures have appeared, a large number of start-ups but also established companies are endeavoring to introduce AI-based medical devices into the market. This article discusses the basic principles for understanding AI-based medical devices as well as an overview of current AI-based solutions specific to cardiac surgery.

Cardiovascular tissue engineering: From basic science to clinical application.

Valvular heart disease is an increasing population health problem and, especially in the elderly, a significant cause of morbidity and mortality. The current treatment options, such as mechanical and bioprosthetic heart valve replacements, have significant restrictions and limitations. Considering the increased life expectancy of our aging population, there is an urgent need for novel heart valve concepts that remain functional throughout life to prevent the need for reoperation. Heart valve tissue engineering aims to overcome these constraints by creating regenerative, self-repairing valve substitutes with life-long durability. In this review, we give an overview of advances in the development of tissue engineered heart valves, and describe the steps required to design and validate a novel valve prosthesis before reaching first-in-men clinical trials. In-silico and in-vitro models are proposed as tools for the assessment of valve design, functionality and compatibility, while in-vivo preclinical models are required to confirm the remodeling and growth potential of the tissue engineered heart valves. An overview of the tissue engineered heart valve studies that have reached clinical translation is also presented. Final remarks highlight the possibilities as well as the obstacles to overcome in translating heart valve prostheses into clinical application.

Development of a Novel Human Cell-Derived Tissue-Engineered Heart Valve for Transcatheter Aortic Valve Replacement: an In Vitro and In Vivo Feasibility Study.

Transcatheter aortic valve replacement (TAVR) is being extended to younger patients. However, TAVR-compatible bioprostheses are based on xenogeneic materials with limited durability. Off-the-shelf tissue-engineered heart valves (TEHVs) with remodeling capacity may overcome the shortcomings of current TAVR devices. Here, we develop for the first time a TEHV for TAVR, based on human cell-derived extracellular matrix and integrated into a state-of-the-art stent for TAVR. The TEHVs, characterized by a dense acellular collagenous matrix, demonstrated in vitro functionality under aortic pressure conditions (n = 4). Next, transapical TAVR feasibility and in vivo TEHV functionality were assessed in acute studies (n = 5) in sheep. The valves successfully coped with the aortic environment, showing normal leaflet motion, free coronary flow, and absence of stenosis or paravalvular leak. At explantation, TEHVs presented full structural integrity and initial cell infiltration. Its long-term performance proven, such TEHV could fulfill the need for next-generation lifelong TAVR prostheses.

The impact of pay-for-performance on the quality of care in ophthalmology: Empirical evidence from Germany.

BACKGROUND: Pay-for-performance (P4P) has become a popular approach to increase effectiveness and efficiency in healthcare. So far, there is little evidence regarding the potential of P4P in the German healthcare setting. The aim of this study was to determine the impact of P4P on the quality of care in cataract surgery. METHODS: In 2012, a P4P program was implemented in a German surgical centre for ophthalmology. Five quality measures regarding process quality, outcomes, and patient satisfaction were measured over a period of 4.5 years. The P4P scheme consisted of bonus and penalty payments accounting for five per cent of total compensation. Overall, 1657 P4P cases were examined and compared with 4307 control cases. Interrupted time series and group comparisons were conducted to identify quality and spill-over effects. RESULTS: We found a positive impact on process quality and patient satisfaction before the implementation of the P4P scheme, but declining trends during and after the implementation. Our findings did not show an impact of P4P on outcome measures. Furthermore, P4P did not result in better quality of care, compared with the German hospital-based reimbursement scheme. CONCLUSION: This study did not show any positive long-term effects of the implementation of P4P on quality of care. Therefore, our results do not support the hypothesis that P4P leads to significant improvements in quality of care.

Organ Chips: Quality Assurance Systems in Regenerative Medicine.

A class of novel therapies leverages regenerative cell types in disease microenvironments. This complex interplay challenges established good manufacturing practices, as standards and analytical tools to measure regenerative potency are missing. That is, we can build the product right, but we do not know if we are building the right product. Here, we suggest that organ-chips, biomimetic in vitro phenotyping platforms, can serve as key quality assurance systems in regenerative medicine.

Challenges in tissue engineering - towards cell control inside artificial scaffolds.

Control of living cells is vital for the survival of organisms. Each cell inside an organism is exposed to diverse external mechano-chemical cues, all coordinated in a spatio-temporal pattern triggering individual cell functions. This complex interplay between external chemical cues and mechanical 3D environments is translated into intracellular signaling loops. Here, we describe how external mechano-chemical cues control cell functions, especially cell migration, and influence intracellular information transport. In particular, this work focuses on the quantitative analysis of (1) intracellular vesicle transport to understand intracellular state changes in response to external cues, (2) cellular sensing of external chemotactic cues, and (3) the cells' ability to migrate in 3D structured environments, artificially fabricated to mimic the 3D environment of tissue in the human body.

Non-directed, carbonate-mediated C-H activation and aerobic C-H oxygenation with Cp*Ir catalysts.

The effect of oxidatively stable L- and X-type additives on the activity of Cp*Ir catalyst precursors in the C-H activation of arenes has been studied. Turnover numbers for C-H activation of up to 65 can thus be achieved, as determined by H/D exchange in MeOH-D4. In particular, carbonate additives are found to enhance the C-H activation reactivity of Cp*Ir(H2O)3(OTf)2 () more significantly than L-type ligands investigated in this study. Based on these studies, Cp*Ir/carbonate systems are developed that catalyze the aerobic Csp(3)-H oxygenation of alkyl arenes, employing air as oxidant.

[Internet-based Report Cards for Hospital Choice Making in Germany: A Clinical Area-focused Perspective]. / Internetportale für die Krankenhauswahl in Deutschland: Eine leistungsbereichsspezifische Betrachtung.

Objectives: Aims of this study are to provide (i) a presentation of quality of care information about German hospitals on internet report cards, and (ii) derive a guidance tool for using certain report cards. Methods: We undertook (i) a systematic internet search to identify hospital report cards, (ii) whereby several inclusion and exclusion criteria were applied, (iii) We developed a scheme to describe the presented quality information, (iv) We also analysed the report cards and (v) evaluated the results and derived further usage guidance. Results: 18 report cards were included. 8 report cards present nationwide quality information while ten report cards focus on regional areas. The AOK Krankenhaus-navigator provides the most information about 5 clinical areas of the external quality assurance (§ 137 SGB V). Regarding the remaining 26 clinical areas, the TK Klinikführer, the Barmer Krankenhausnavi, and the Weisse Liste provide the largest amount of quality information. Qualitätskliniken.de reports on 9, the Klinikführer Rheinland on 8, the Bremer Krankenhausspiegel on 4, and the Hamburger Krankenhausspiegel on 2 additional clinical areas. Conclusions: This study shows that a differentiated view for each clinical area is necessary when searching for information about the quality of hospitals. Further studies should assess the quality of the report cards as well as the information that they display.

Non-directed aromatic C-H amination: catalytic and mechanistic studies enabled by Pd catalyst and reagent design.

This manuscript describes the systematic development of pyridine-type ligands, which promote the Pd catalyzed, non-directed amination of benzene in combination with novel, hydroxylamine-based electrophilic amination reagents. DFT calculations and mechanistic experiments provide insights into the factors influencing the arene C-H amination protocol.

[Text Comprehensibility of Hospital Report Cards]. / Verständlichkeit der Texte von Qualitätsvergleichen zu Krankenhausleistungen.

Objectives: Recently, the number of hospital report cards that compare quality of hospitals and present information from German quality reports has greatly increased. Objectives of this study were to a) identify suitable methods for measuring the readability and comprehensibility of hospital report cards, b) to obtain reliable information on the comprehensibility of texts for laymen, c) to give recommendations for improvements and d) to recommend public health actions. Methods: The readability and comprehensibility of the texts were tested with a) a computer-aided evaluation of formal text characteristics (readability indices Flesch (German formula) and 1. Wiener Sachtextformel formula), b) an expert-based heuristic analysis of readability and comprehensibility of texts (counting technical terms and analysis of text simplicity as well as brevity and conciseness using the Hamburg intelligibility model) and c) a survey of subjects about the comprehensibility of individual technical terms, the assessment of the comprehensibility of the presentations and the subjects' decisions in favour of one of the 5 presented clinics due to the better quality of data. In addition, the correlation between the results of the text analysis with the results from the survey of subjects was tested. Results: The assessment of texts with the computer-aided evaluations showed poor comprehensibility values. The assessment of text simplicity using the Hamburg intelligibility model showed poor comprehensibility values (-0.3). On average, 6.8% of the words used were technical terms. A review of 10 technical terms revealed that in all cases only a minority of respondents (from 4.4% to 39.1%) exactly knew what was meant by each of them. Most subjects (62.4%) also believed that unclear terms worsened their understanding of the information offered. The correlation analysis showed that presentations with a lower frequency of technical terms and better values for the text simplicity were better understood. Conclusion: The determination of the frequency of technical terms and the assessment of text simplicity using the Hamburg intelligibility model were suitable methods to determine the readability and comprehensibility of presentations of quality indicators. The analysis showed predominantly poor comprehensibility values and indicated the need to improve the texts of report cards.

[The quality of the German health-care system in an international comparison - a systematic review]. / Die Qualität des deutschen Gesundheitswesens im internationalen Vergleich - Ein systematischer Review.

OBJECTIVES: Studies assessing the quality of the German health-care system in an international comparison come to different results. Therefore, this review aims to investigate how the German health-care system is evaluated in comparison to other health-care systems by reviewing international publications. Results show starting points for ways to improve the German health-care system, to maintain and expand its strengths as well as to derive strategies for solving identified problems. METHODS: A systematic review searching different databases [library catalogues, WorldCat (including MEDLINE and OAIster-search), German National Library, Google Scholar and others]. Search requests were addressed to English or German language publications for the time period 2000-2010 (an informal search was conducted in October 2011 for an update). Results of the identified studies were aggregated and main statements derived. RESULTS: In total, 13 publications assessing the German health-care system in an international comparison were identified. These comparisons are based on 377 measures. After aggregation, 244 substantially different indicators remained, which were dedicated to 14 categories. It became apparent that the German health-care system can be characterised by a high level of expenses, a well-developed health-care infrastructure as well as a high availability of personal and material resources. Outcome measures demonstrate heterogeneous results. It can be stated that, particularly in this field, there is potential for further improvement. The utilisation of health-care services is high, the access is mostly not regulated and out of pocket payments can pose a barrier for patients. Waiting times are not regarded as a major weakness. Although civic satisfaction seems to be acceptable, a large portion of the citizens calls for elementary modifications. Especially, more patient-centred health-care delivery should be addressed as well as management of information and the adoption of meaningful electronic assistance systems. CONCLUSION: The presented results show starting points on the way to further improve the German health-care system. It is necessary to maintain and expand its strengths as well as to derive strategies for solving identified weaknesses. This can be done with confidence since, according to Donabedian, a high structural quality represents an important fundament to improve outcome and process measures.

[Efficacy and efficiency of searches for a physician using physician search and evaluation portals in comparison with Google]. / Effektivität und Effizienz der Arztsuche mit Arztsuch- und Bewertungsportalen und Google.

OBJECTIVES: The Internet provides ways for patients to obtain information about doctors. The study poses the question whether it is possible and how long it takes to find a suitable doctor with an Internet search. It focuses on the effectiveness and efficiency of the search. Specialised physician rating and searching portals and Google are analysed when used to solve specific tasks. METHODS: The behaviour of volunteers when searching a suitable ophthalmologist, dermatologist or dentist was observed in a usability lab. Additionally, interviews were carried out by means of structured questionnaires to measure the satisfaction of the users with the search and their results. Three physician rating and searching portals that are frequently used in Germany (Jameda.de, DocInsider.de and Arztauskunft.de) were analysed as well as Google. RESULTS: When using Arztauskunft and Google most users found an appropriate physician. When using Docinsider or Jameda they found fewer doctors. Additionally, the time needed to locate a suitable doctor when using Docinsider and Jameda was higher compared to the time needed when using the Arztauskunft and Google. The satisfaction of users who used Google was significantly higher in comparison to those who used the specialised physician rating and searching portals. CONCLUSION: It emerged from this study that there is no added value when using specialised physician rating and searching portals compared to using the search engine Google when trying to find a doctor having a particular specialty. The usage of several searching portals is recommended to identify as many suitable doctors as possible.

[Public reporting in health care: the impact of publicly reported quality data on patient steerage]. / Public Reporting im Gesundheitswesen: Die Auswirkungen veröffentlichter Qualitätsdaten auf die Patientensteuerung.

BACKGROUND: Public reporting (PR) has been gaining more weight as a mechanism for patient steerage. According to the theory of PR, patients use information about the quality of health care providers before making decisions and selecting health-care providers. This paper contributes further knowledge on the effectiveness of PR and identifies critical success factors. These should be taken into account when implementing PR in the German health care system. METHODOLOGY: The peer-reviewed English, Spanish, and German language literature was searched in the following five databases: The Cochrane Library, Medline (via PubMed), ISI Web of Knowledge, EconLit, and PsycINFO (since 2005). In addition, reference lists of the included studies and reviews were screened in order to identify previously published studies. RESULTS: In total, 21 studies were identified regarding the impact of 12 different PR instruments on patient steerage. An impact could be demonstrated in 9 studies, 7 studies showed mixed results, while 5 studies could not show any effect on patient steerage. 20 studies were carried out in the US environment, 1 study in Germany. The most researched instrument is the New York State Cardiac Surgery Reporting System (N=8). CONCLUSION: PR can be effective in steering patients when seeking a health-care provider, especially for elective procedures. To be successful, information provided must be reliable, easily understandable, should further represent real news, and be disseminated widely. Besides this, it has to be applicable and modifiable according to individual preferences.

Public reporting in Germany: the content of physician rating websites.

BACKGROUND: Physician rating websites (PRWs) are gaining in popularity among patients seeking quality information about physicians. However, little knowledge is available about the quantity and type of information provided on the websites. OBJECTIVE: To determine and structure the quantity and type of information about physicians in the outpatient sector provided on German-language physician rating websites. METHODS: In a first step, we identified PRWs through a systematic internet search using German keywords from a patient´s perspective in the two search engines Google and Yahoo. Afterwards, information about physicians available on the websites was collected and categorised according to Donabedian´s structure/process/outcome model. Furthermore, we investigated whether the information was related to the physician himself/ herself or to the practice as a whole. RESULTS: In total, eight PRWs were detected. Our analysis turned up 139 different information items on eight websites; 67 are related to the structural quality, 4 to process quality, 5 to outcomes, and 63 to patient satisfaction/experience. In total, 37% of all items focus specifically on the physician and 63% on the physician's practice. In terms of the total amount of information provided on the PRWs, results range from 61 down to 13.5 items. CONCLUSIONS: A broad range of information is available on German PRWs. While structural information can give a detailed overview of the financial, technical and human resources of a practice, other outcome measures have to be interpreted with caution. Specifically, patient satisfaction results are not risk-adjusted, and thus, are not appropriate to represent a provider's quality of care. Consequently, neither patients nor physicians should yet use the information provided to make their final decision for or against an individual physician.

Delayed two-step free wall rupture of the right and left ventricular wall after myocardial infarction.

We present a 68-year-old female who suffered extensive complications after severe myocardial infarction (MI) in the circumflex (CX) territory. At 24 hours after the initial event, the patient presented with a covered right ventricular free wall rupture (FWR) which was followed by a rupture of the left posterior wall ten days later. We report here on a rare case of delayed two-step biventricular FWR after severe MI in the CX territory.

Relative concentrations of haemostatic factors and cytokines in solvent/detergent-treated and fresh-frozen plasma.

BACKGROUND: Indications, efficacy, and safety of plasma products are highly debated. We compared the concentrations of haemostatic proteins and cytokines in solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). METHODS: Concentrations of the following parameters were measured in 25 SDP and FFP samples: fibrinogen (FBG), factor (F) II, F V, F VII, F VIII, F IX, F X, F XIII, von Willebrand factor (vWF), D-Dimers, ADAMTS-13 protease, tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-8, and IL-10. RESULTS: Mean FBG concentrations in SDP and FFP were similar, but in FFP, the range was larger than in SDP (P<0.01). Mean F II, F VII, F VIII, F IX, and F XIII levels did not differ significantly. Higher concentrations of F V (P<0.01), F X (P<0.05), vWF (P<0.01), and ADAMTS-13 (P<0.01) were found in FFP. With the exception of F VIII and F IX, the range of concentrations for all of these factors was smaller (P<0.05) in SDP than in FFP. Concentrations of TNF-α, IL-8, and IL-10 (all P<0.01) were higher in FFP than in SDP, again with a higher variability and thus larger ranges (P<0.01). CONCLUSIONS: Coagulation factor content is similar for SDP and FFP, with notable exceptions of less F V, vWF, and ADAMTS-13 in SDP. Cytokine concentrations (TNFα, IL-8, and IL-10) were significantly higher in FFP. The clinical relevance of these findings needs to be established in outcome studies.

Sternal plate closure: indications, surgical procedure and follow-up.

OBJECTIVES: Titanium plate osteosynthesis (Synthes) is an alternative option for sternal closure. The indications and time point of application are still debated. This study investigated the application and feasibility of this technique after median sternotomy. METHODS: Forty-one patients (29 M/12F, mean age 63 ± 17 years) received the plate system for complicated sternal conditions. Indications, intraoperative course and postoperative follow-up were assessed. RESULTS: Sternal deformity was present in 5 % (2/41), sternal fractures in 17 % (7/41), bone defect in 12 % (5/41), wire loosening in 39 % (16/41) and pseudoarthrosis in 27 % (11/41). 54 % (22/41) of patients showed concomitant sternal infection. Two intraoperative complications were noted: mammary artery injury (1 patient), pleural injury (1 patient). At discharge the patients reported no pain (90 %, 37/41) or only occasional discomfort (10 %, 4/41). Postoperative complications were subcutaneous hematoma in 12 % (5/41), seroma in 12 % (5/41) and sternal reinfection in 7 % (3/41). 12 % (5/41) showed occasional discomfort and 7 % (3/41) had persistent pain leading to plate removal. CONCLUSION: The Titanium Sternal Fixation System is comfortable and easy to use. It can be used to treat a wide spectrum of indications, especially for pseudoarthrosis, an entity which has not yet received sufficient attention.