Digitization of Follow-Up Care in Orthopedic and Trauma Surgery With Video Consultations: Health Economic Evaluation Study From a Health Provider's Perspective.

BACKGROUND: Recommendations for health care digitization as issued with the Riyadh Declaration led to an uptake in telemedicine to cope with the COVID-19 pandemic. Evaluations based on clinical data are needed to support stakeholders' decision-making on the long-term implementation of digital health. OBJECTIVE: This health economic evaluation aims to provide the first German analysis of the suitability of video consultations in the follow-up care of patients in orthopedic and trauma surgery, investigate the financial impact on hospital operations and personnel costs, and provide a basis for decisions on digitizing outpatient care. METHODS: We conducted a randomized controlled trial that evaluated video consultations versus face-to-face consultations in the follow-up care of patients in orthopedic and trauma surgery at a German university hospital. We recruited 60 patients who had previously been treated conservatively or surgically for various knee or shoulder injuries. A digital health app and a browser-based software were used to conduct video consultations. The suitability of telemedicine was assessed using the Telemedicine Satisfaction Questionnaire and the EQ-5D-5L questionnaire. Economic analyses included average time spent by physician per consultation, associated personnel costs and capacities for additional treatable patients, and the break-even point for video consultation software fees. RESULTS: After 4 withdrawals in each arm, data from a total of 52 patients (telemedicine group: n=26; control group: n=26) were used for our analyses. In the telemedicine group, 77% (20/26) of all patients agreed that telemedicine provided for their health care needs, and 69% (18/26) found telemedicine an acceptable way to receive health care services. In addition, no significant difference was found in the change of patient utility between groups after 3 months (mean 0.02, SD 0.06 vs mean 0.07, SD 0.17; P=.35). Treatment duration was significantly shorter in the intervention group (mean 8.23, SD 4.45 minutes vs mean 10.92, SD 5.58 minutes; P=.02). The use of telemedicine saved 25% (€2.14 [US $2.35]/€8.67 [US $9.53]) in personnel costs and increased the number of treatable patients by 172 annually, assuming 2 hours of video consultations per week. Sensitivity analysis for scaling up video consultations to 10% of the hospital's outpatient cases resulted in personnel cost savings of €73,056 (US $ 80,275.39) for a senior physician. A total of 23 video consultations per month were required to recoup the software fees of telemedicine through reduced personnel costs (break-even point ranging from 12-38 in the sensitivity analysis). CONCLUSIONS: Our study supports stakeholders' decision-making on the long-term implementation of digital health by demonstrating that video consultations in the follow-up care of patients in orthopedic and trauma surgery result in cost savings and productivity gains for clinics with no negative impact on patient utility. TRIAL REGISTRATION: German Clinical Trials Register DRKS00023445; https://drks.de/search/en/trial/DRKS00023445.

Economic and Environmental Impact of Digital Health App Video Consultations in Follow-up Care for Patients in Orthopedic and Trauma Surgery in Germany: Randomized Controlled Trial.

BACKGROUND: Following the Riyadh Declaration, digital health technologies were prioritized in many countries to address the challenges of the COVID-19 pandemic. Digital health apps for telemedicine and video consultations help reduce potential disease spread in routine health care, including follow-up care in orthopedic and trauma surgery. In addition to the satisfaction, efficiency, and safety of telemedicine, its economic and environmental effects are highly relevant to decision makers, particularly for the goal of reaching carbon neutrality of health care systems. OBJECTIVE: This study aims to provide the first comprehensive health economic and environmental analysis of video consultations in follow-up care after knee and shoulder interventions in an orthopedic and trauma surgery department of a German university hospital. The analysis is conducted from a societal perspective. We analyze both economic and environmental impacts of video consultations, taking into account the goal of carbon neutrality for the German health care system by 2030. METHODS: We conducted a prospective randomized controlled trial comparing follow-up care with digital health app video consultations (intervention group) to conventional face-to-face consultations in the clinic (control group). Economic impact included the analysis of travel and time costs and production losses. Examination of the environmental impact comprised the emissions of greenhouse gases, carbon monoxide, volatile hydrocarbons, nitrogen oxides, and particulates, and the calculation of environmental costs. Sensitivity analysis included calculations with a higher cost per ton of carbon dioxide equivalent, which gives equal weight to the welfare of present and future generations. RESULTS: Data from 52 patients indicated that, from the patients' point of view, telemedicine helped reduce travel costs, time costs, and production losses, resulting in mean cost savings of €76.52 per video consultation. In addition, emissions of 11.248 kg of greenhouse gases, 0.070 kg of carbon monoxide, 0.011 kg of volatile hydrocarbons, 0.028 kg of nitrogen oxides, and 0.0004 kg of particulates could be saved per patient through avoided travel. This resulted in savings of environmental costs between €3.73 and €9.53 per patient. CONCLUSIONS: We presented the first comprehensive analysis of economic and environmental effects of telemedicine in the follow-up care of patients in orthopedic and trauma surgery in Germany. Video consultations were found to reduce the environmental footprint of follow-up care; saved travel costs, travel time, and time costs for patients; and helped to lower production losses. Our findings can support the decision-making on the use of digital health during and beyond the COVID-19 pandemic, providing decision makers with data for both economic and environmental effects. Thanks to the pragmatic design of our study, our findings can be applied to a wide range of clinical contexts and potential digital health applications that substitute outpatient hospital visits with video consultations. TRIAL REGISTRATION: German Clinical Trials Register DRKS00023445; https://tinyurl.com/4pcvhz4n.

Assessing Telemedicine Efficiency in Follow-up Care With Video Consultations for Patients in Orthopedic and Trauma Surgery in Germany: Randomized Controlled Trial.

BACKGROUND: Telemedicine can help mitigate important health care challenges, such as demographic changes and the current COVID-19 pandemic, in high-income countries such as Germany. It gives physicians and patients the opportunity to interact via video consultations, regardless of their location, thus offering cost and time savings for both sides. OBJECTIVE: We aimed to investigate whether telemedicine can be implemented efficiently in the follow-up care for patients in orthopedic and trauma surgery, with respect to patient satisfaction, physician satisfaction, and quality of care. METHODS: We conducted a prospective randomized controlled trial in a German university hospital and enrolled 60 patients with different knee and shoulder conditions. For follow-up appointments, patients received either an in-person consultation in the clinic (control group) or a video consultation with their physician (telemedicine group). Patients' and physicians' subsequent evaluations of these follow-up appointments were collected and assessed using separate questionnaires. RESULTS: On the basis of data from 52 consultations after 8 withdrawals, it was found that patients were slightly more satisfied with video consultations (mean 1.58, SD 0.643) than with in-clinic consultations (mean 1.64, SD 0.569), although the difference was not statistically significant (P=.69). After excluding video consultations marred by technical problems, no significant difference was found in physician satisfaction between the groups (mean 1.47, SD 0.516 vs mean 1.32, SD 0.557; P=.31). Further analysis indicated that telemedicine can be applied to broader groups of patients and that patients who have prior experience with telemedicine are more willing to use telemedicine for follow-up care. CONCLUSIONS: Telemedicine can be an alternative and efficient form of follow-up care for patients in orthopedic and trauma surgery in Germany, and it has no significant disadvantages compared with in-person consultations in the clinic. TRIAL REGISTRATION: German Clinical Trials Register DRKS00023445; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023445.

Artificial intelligence in medical education and the meaning of interaction with natural intelligence - an interdisciplinary approach.

Introduction: The practice of medicine is characterized by decision making in which digital techniques can provide good support. In this context, artificial intelligence (AI) is becoming increasingly important. The challenge for physicians, however, is to maintain an overview of the potential applications and usefulness of AI in order to be able to apply it efficiently and safely in their work. Therefore, appropriate skills must be imparted during the course of medical studies so that future practitioners can meet this requirement. Project description: The interdisciplinary research-related teaching and learning project "(Natural) Science and Technology in Medicine - NWTmed" brings together students at the Justus-Liebig-University Giessen (JLU) from the fields of medicine and other (natural) scientific disciplines in structured courses with the aim of thinking, learning, and working in an interdisciplinary and research-oriented manner already during their medical education. With the involvement of local researchers, a "multi-disciplinary" seminar on the basic premises, methods, and applications of AI was established. Results: The participants of the course came from a wide variety of fields of study, which promoted an interdisciplinary exchange and animated discussions. A gain in knowledge and an increase in interest in the topic of AI was noted in the evaluations, and a willingness on the part of the students to pursue further independent study was also expressed. Discussion and conclusion: The topic of AI and its relevance to the field of medicine is not yet sufficiently represented in medical education. It will require integration in the curriculum and performance evaluations as well as interdisciplinary and research-related teaching formats.

Cost-effectiveness of Interferon-free therapy for Hepatitis C in Germany--an application of the efficiency frontier approach.

BACKGROUND: The approval of direct-acting antivirals for Interferon-free treatment revolutionized the therapy of chronic Hepatitis C infection. As of August 2014, two treatment regimens for genotype 1 infection received conditional approval in the European Union: Sofosbuvir and Ribavirin for 24 weeks and Sofosbuvir and Simeprevir with or without Ribavirin for 12 weeks. We aim to analyze the cost-effectiveness of both regimens in Germany. METHODS: We set up a Markov model with a lifetime horizon to simulate immediate treatment success and long-term disease progression for treatment-naive patients. The model analyzes both short-term and long-term costs and benefits from the perspective of the German Statutory Health Insurance. We apply the efficiency frontier method, which was suggested by German Institute for Quality and Efficiency in Health Care for cost-effectiveness analysis in Germany. RESULTS: The efficiency frontier is defined by dual therapy and first generation direct-acting antiviral Boceprevir, yielding a maximum of € 1,447.69 per additional percentage point of sustained virologic response gained. Even without rebates, Sofosbuvir/Simeprevir is very close with € 1,560.13 per additional percentage point. It is both more effective and less expensive than Sofosbuvir/Ribavirin. CONCLUSIONS: In addition to higher sustained virologic response rates, new direct-acting antivirals save long-term costs by preventing complications such as liver cirrhosis, hepatocellular carcinoma and ultimately liver transplants, thereby offsetting part of higher drug costs. Our findings are in line with the guidance published by German Society for Gastroenterology, Digestive and Metabolic Diseases, which recommends Sofosbuvir/Simeprevir for Interferon ineligible or intolerant patients.

Cost per responder of TNF-α therapies in Germany.

Tumor necrosis factor α (TNF-α) inhibitors ranked highest in German pharmaceutical expenditure in 2011. Their most important application is the treatment of rheumatoid arthritis (RA). Our objective is to analyze cost per responder of TNF-α inhibitors for RA from the German Statutory Health Insurance funds' perspective. We aim to conduct the analysis based on randomized comparative effectiveness studies of the relevant treatments for the German setting. For inclusion of effectiveness studies, we require results in terms of response rates as defined by European League Against Rheumatism (EULAR) or American College of Rheumatology (ACR) criteria. We identify conventional triple therapy as the relevant comparator. We calculate cost per responder based on German direct medical costs. Direct clinical comparisons could be identified for both etanercept and infliximab compared to triple therapy. For infliximab, cost per responder was 216,392 euros for ACR50 and 432,784 euros for ACR70 responses. For etanercept, cost per ACR70 responder was 321,527 euros. Cost was lower for response defined by EULAR criteria, but data was only available for infliximab. Cost per responder is overestimated by 40% due to inclusion of taxes and mandatory rebates in German drugs' list prices. Our analysis shows specific requirements for cost-effectiveness analysis in Germany. Cost per responder for TNF-α treatment in the German setting is more than double the cost estimated in a similar analysis for the USA, which measured against placebo. The difference in results shows the critical role of the correct comparator for a specific setting.

RNase-induced apoptosis: fate of calcium-activated potassium channels.

The connection between the action of microbial RNases and Ca2+-activated K+ (KCa) channels was investigated in human embryo kidney cells HEKhSK4 artificially expressing the channels. These channels protected HEKhSK4 cells from apoptosis induced by binase and 5K charge reversal mutant of RNase Sa. After the first 24h, potassium current increased without increase in intracellular Ca2+, and mitochondrial potential remained high. After 72 h, the concentration of calcium increased and mitochondria lost their potential. Whole-cell recordings of membrane currents through KCa channels in RNase-treated cells demonstrated a biphasic pattern: initially their activity in cell population increased, peaked at 24h, and then gradually decreased. In each individual cell we observed either an increase of the amplitude of KCa current, or a complete shutdown of the channels. The activity of KCa channels could be restored by removing RNases from the media. Based on this pattern and especially its timing, we hypothesize that toxic RNases downregulate KCa channels at the level of transcription or translation. Our results indicate that new anticancer agents could be created on the basis of microbial RNases targeting KCa channels.

Why Escherichia coli alpha-hemolysin induces calcium oscillations in mammalian cells--the pore is on its own.

Escherichia coli alpha-hemolysin (HlyA), archetype of a bacterial pore-forming toxin, has been reported to deregulate physiological Ca2+ channels, thus inducing periodic low-frequency Ca2+ oscillations that trigger transcriptional processes in mammalian cells. The present study was undertaken to delineate the mechanisms underlying the Ca2+ oscillations. Patch-clamp experiments were combined with single cell measurements of intracellular Ca2+ and with flowcytometric analyses. Application of HlyA at subcytocidal concentrations provoked Ca2+ oscillations in human renal and endothelial cells. However, contrary to the previous report, the phenomenon could not be inhibited by the Ca2+ channel blocker nifedipine and Ca2+ oscillations showed no constant periodicity at all. Ca2+ oscillations were dependent on the pore-forming activity of HlyA: application of a nonhemolytic but bindable toxin had no effect. Washout experiments revealed that Ca2+ oscillations could not be maintained in the absence of toxin in the medium. Analogously, propidium iodide flux into cells occurred in the presence of HlyA, but cells rapidly became impermeable toward the dye after toxin washout, indicating resealing or removal of the membrane lesions. Finally, patch-clamp experiments revealed temporal congruence between pore formation and Ca2+ influx. We conclude that the nonperiodic Ca2+ oscillations induced by HlyA are not due to deregulation of physiological Ca2+ channels but derive from pulsed influxes of Ca2+ as a consequence of formation and rapid closure of HlyA pores in mammalian cell membranes.

Rare earth ions block the ion pores generated by the class II fusion proteins of alphaviruses and allow analysis of the biological functions of these pores.

Recently, class II fusion proteins have been identified on the surface of alpha- and flaviviruses. These proteins have two functions besides membrane fusion: they generate an isometric lattice on the viral surface and they form ion-permeable pores at low pH. An attempt was made to identify inhibitors for the ion pores generated by the fusion proteins of the alphaviruses Semliki Forest virus and Sindbis virus. These pores can be detected and analysed in three situations: (i) in the target membrane during virus entry, by performing patch-clamp measurements of membrane currents; (ii) in the virus particle, by studying the entry of propidium iodide; and (iii) in the plasma membrane of infected cells, by Fura-2 fluorescence imaging of Ca2+ entry into infected cells. It is shown here that, at a concentration of 0.1 mM, rare earth ions block the ion permeability of alphavirus ion pores in all three situations. Even at a concentration of 0.5 mM, these ions do not block formation of the viral fusion pore, as they do not inhibit entry or multiplication of alphaviruses. The data indicate that ions flow through the ion pores into the virus particle in the endosome and from the endosome into the cytoplasm after fusion of the viral envelope with the endosomal membrane. These ion flows, however, are not necessary for productive infection. The possibility that the ability of class II fusion proteins to form ion-permeable pores reflects their origin from protein toxins that form ion-permeable pores, and that entry via class II fusion proteins may resemble the entry of non-enveloped viruses, is discussed.

Functional transfer of eukaryotic expression plasmids to mammalian cells by Listeria monocytogenes: a mechanistic approach.

BACKGROUND: Cystic fibrosis (CF) is one of the most common monogenic disorders in the caucasian population. Gene therapy for CF is principally feasible and bacterial transfer systems might provide novel possibilities for therapy. However, transfection efficiencies are low and need to be improved. Thus, more detailed understanding of the DNA transfer mechanism is necessary to systematically eliminate these restrictions. METHODS: Functional transfer of GFP-CFTR (cystic fibrosis transmembrane conductance regulator) to eukaryotic cells using attenuated Listeria monocytogenes mediated gene transfer (bacteriofection) was shown by fluorescent microscopy, flow cytometry, immunoblotting and whole cell patch clamping. The characteristics of plasmid transfer were studied by use of electron and fluorescence microscopy, flow cytometry and Southern blotting. Polymerase chain reaction (PCR) was used to screen the genome of bacteriofected cells for cotransfer of chromosomal bacterial DNA. RESULTS: Correct intracellular localization and functionality of the GFP-CFTR fusion protein after bacteriofection was shown. Efficient bacterial lysis and release of bacterial content was demonstrated using antibiotics to kill intracellular bacteria. Although only low transfection rates were observed, high numbers of transferred plasmids were detected in host cells under these conditions. However, they were associated with high molecular weight entities and not available to cytosolic transcription. Cotransfer of bacterial genomic DNA was observed in transfectants but occurred at low frequencies. CONCLUSIONS: In this work we demonstrate that low rates of bacteria-mediated transfection are not due to poor invasion of bacteria, insufficient bacterial lysis, or plasmid DNA degradation. Our data suggest that the transferred plasmid DNA is associated with higher macromolecular structures inhibiting nuclear transport and transgene transcription.

During entry of alphaviruses, the E1 glycoprotein molecules probably form two separate populations that generate either a fusion pore or ion-permeable pores.

Studies using the alphavirus Semliki Forest virus have indicated that the viral E1 fusion protein forms two types of pore: fusion pores and ion-permeable pores. The formation of ion-permeable pores has not been generally accepted, partly because it was not evident how the protein might form these different pores. Here it is proposed that the choice of the target membrane determines whether a fusion pore or ion-permeable pores are formed. The fusion protein is activated in the endosome and for steric reasons only a fraction of the activated molecules can interact with the endosomal membrane. This target membrane reaction forms the fusion pore. It is proposed that the rest of the activated molecules interact with the membrane in which the protein is anchored and that this self-membrane reaction leads to formation of ion-permeable pores, which can be detected in the target membrane after fusion of the viral membrane into the target membrane.

Cytotoxicity of RNases is increased by cationization and counteracted by K(Ca) channels.

K(Ca) channels are involved in control of cell proliferation and differentiation. Here we have revealed their role in overcoming the RNase-induced cytotoxicity. Toxic effects of Streptomyces aureofaciens RNases Sa, Sa2, Sa3, and of RNase Sa charge reversal mutants on the human embryonic kidney cell lines differing only by the presence of K(Ca) channels were characterized. In contrast to other RNases, a basic variant of RNase Sa and RNase Sa3 exhibit significant cytotoxic activity of the same order of magnitude as onconase. Our data indicate the absence of a correlation between catalytic activity and stability of RNases and cytotoxicity. On the other hand, cationization enhances toxic effect of an RNase indicating the major role of a positive charge. Essentially lower sensitivity to cytotoxic microbial RNases of cells expressing K(Ca) channels was found. These results suggest that cells without the K(Ca) channel activity cannot counteract toxic effect of RNases.

The membrane proteins of flaviviruses form ion-permeable pores in the target membrane after fusion: identification of the pores and analysis of their possible role in virus infection.

Recently, we presented evidence that the E1 fusion protein of the alphavirus Semliki Forest virus forms ion-permeable pores in the target membrane after fusion. We proposed that the homologous fusion proteins of flaviviruses and hepatitis C virus form similar pores. To test this hypothesis for the E fusion protein of flaviviruses, the release of [(3)H]choline from liposomes by the flavivirus West Nile (WN) virus was determined. [(3)H]Choline was released at mildly acid pH. The pH threshold depended on the lipid composition. Release from certain liposomes was activated even at neutral pH. To identify the generation of individual pores, single cells were investigated with the patch-clamp technique. The formation of individual pores during low pH-induced WN virus entry at the plasma membrane occurred within seconds. These experiments were performed in parallel with Semliki Forest virus. The results indicated that, similar to alphavirus infection, infection with flaviviruses via endosomes leads to the formation of ion-permeable pores in the endosome after fusion, which allows the flow of protons from the endosome into the cytoplasm during virus entry. However, in vitro translation experiments of viral cores showed that, in contrast to alphaviruses, which probably need this proton flow for core disassembly, the genome RNA of WN virus present in the viral core is directly accessible for translation. For entry of flaviviruses, therefore, a second pathway for productive infection may exist, in which fusion of the viral membrane is activated at neutral pH by contact with a plasma membrane of appropriate lipid composition.

Listeriolysin of Listeria monocytogenes forms Ca2+-permeable pores leading to intracellular Ca2+ oscillations.

Listeriolysin (LLO) is a major virulence factor of Listeria monocytogenes, a Gram-positive bacterium that can cause life-threatening diseases. Various signalling events and cellular effects, including modulation of gene expression, are triggered by LLO through unknown mechanisms. Here, we demonstrate that LLO applied extracellularly at sublytic concentrations causes long-lasting oscillations of the intracellular Ca2+ level of human embryonic kidney cells; resulting from a pulsed influx of extracellular Ca2+ through pores that are formed by LLO in the plasma membrane. Calcium influx does not require the activity of endogenous Ca2+ channels. LLO-formed pores are transient and oscillate between open and closed states. Pore formation and Ca2+ oscillations were also observed after exposure of cells to native Listeria monocytogenes. Our data identify LLO as a tool used by Listeria monocytogenes to manipulate the intracellular Ca2+ level without direct contact of the bacterium with the target cell. As Ca2+ oscillations modulate cellular signalling and gene expression, our findings provide a potential molecular basis for the broad spectrum of Ca2+-dependent cellular responses induced by LLO during Listeria infection.