From morbidity reduction to cost-effectiveness: Enhanced recovery after surgery (ERAS) society recommendations in minimal invasive liver surgery.

PURPOSE: Minimal-invasive liver surgery (MILS) reduces surgical trauma and is associated with fewer postoperative complications. To amplify these benefits, perioperative multimodal concepts like Enhanced Recovery after Surgery (ERAS), can play a crucial role. We aimed to evaluate the cost-effectiveness for MILS in an ERAS program, considering the necessary additional workforce and associated expenses. METHODS: A prospective observational study comparing surgical approach in patients within an ERAS program compared to standard care from 2018-2022 at the Charité - Universitätsmedizin Berlin. Cost data were provided by the medical controlling office. ERAS items were applied according to the ERAS society recommendations. RESULTS: 537 patients underwent liver surgery (46% laparoscopic, 26% robotic assisted, 28% open surgery) and 487 were managed by the ERAS protocol. Implementation of ERAS reduced overall postoperative complications in the MILS group (18% vs. 32%, p = 0.048). Complications greater than Clavien-Dindo grade II incurred the highest costs (€ 31,093) compared to minor (€ 17,510) and no complications (€13,893; p < 0.001). In the event of major complications, profit margins were reduced by a median of € 6,640. CONCLUSIONS: Embracing the ERAS society recommendations in liver surgery leads to a significant reduction of complications. This outcome justifies the higher cost associated with a well-structured ERAS protocol, as it effectively offsets the expenses of complications.

miRNA as potential biomarkers after liver transplantation: A systematic review.

BACKGROUND: Liver transplantation is a life-saving therapy for end-stage liver disease patients, but acute cellular rejection (ACR) and graft complications remain significant postoperative challenges. Early and accurate diagnosis is crucial for timely intervention and improved patient outcomes, but their diagnosis rely currently on invasive biopsy sampling, thus prompting the search for non-invasive Biomarkers. MicroRNA (miRNA) have emerged as promising biomarkers in various pathological conditions, and their potential utility in diagnosing acute cellular rejection after liver transplantation has gained significant interest. METHODS: This systematic review of PubMed, Web of Science, and the ClinicalTrials.gov registry analyzes studies exploring miRNA as biomarkers for ACR and graft dysfunction in liver transplantation (PROSPERO ID CRD42023465278). The Cochrane Collaboration tool for assessing risk of bias was employed. Population data, identified miRNA and their dynamic regulation, as well as event prediction were compared. Data extraction and quality assessment were performed independently by two reviewers. RESULTS: Thirteen studies were included in this systematic review. Various investigated miRNAs were upregulated in association with acute cellular rejection, like miR-122, miR-155, miR-181, miR-483-3p, and miR-885-5p, demonstrating great biomarker potential. Additionally, several studies conducted target gene analysis, revealing insights into cellular mechanisms linked to ACR. Moreover, various miRNA were also capable of predicting different organ complications following transplantation, expanding their versatility. Remaining challenges include the standardization of miRNA profiling, the need for functional validation, and the necessity for long-term studies. CONCLUSION: The results highlight the potential of miRNA as specific, non-invasive biomarkers for ACR and graft dysfunction following liver transplantation. However, further research is needed to validate these findings and establish standardized diagnostic panels to incorporate them into clinical practice and explore miRNA-based therapies in the future.

CD14highCD16+ monocytes are the main producers of Interleukin-10 following clinical heart transplantation.

Introduction: Following heart transplantation, a cascade of immunological responses is initiated influencing the clinical outcome and long-term survival of the transplanted patients. The anti-inflammatory cytokine interleukin-10 (IL-10) was shown to be elevated in the blood of heart transplant recipients directly after transplantation but the releasing cell populations and the composition of lymphocyte subsets following transplantation have not been thoroughly studied. Methods: We identified immune cells by immunophenotyping and analyzed intracellular IL-10 production in peripheral blood mononuclear cells (PBMC) of heart transplanted patients (n= 17) before, directly after and 24h post heart transplantation. The cells were stimulated with lipopolysaccharide or PMA/Ionomycin to enhance cytokine production within leukocytes in vitro. Results and discussion: We demonstrate that intermediate monocytes (CD14highCD16+), but not CD8+ T cells, CD4+ T cells, CD56+ NK cells or CD20+ B cells appeared to be the major IL-10 producers within patients PBMC following heart transplantation. Consequently, the absolute monocyte count and the ratio of intermediate monocytes to classical monocytes (CD14+CD16-) were specifically increased in comparison to pre transplant levels. Hence, this population of monocytes, which has not been in the focus of heart transplantation so far, may be an important modulator of clinical outcome and long-term survival of heart transplant recipients. Alteration of blood-circulating monocytes towards a CD14highCD16+ phenotype could therefore shift the pro-inflammatory immune response towards induction of graft tolerance, and may pave the way for the optimization of immunosuppression.

Influence of Self-Reported Health Impairments on German EQ-5D-5L Values.

OBJECTIVES: The German EQ-5D-5L value set is based on the average preferences of the general population. Nevertheless, in Germany, there is an ongoing debate about the appropriateness of using general population preferences and whether patient preferences should be used instead. Thus, this research aimed to determine the robustness of the German EQ-5D-5L valuation data for the general population compared with those with health impairments. METHODS: Subgroups were built on the self-reported quality of life, measured with the EQ-5D-5L. To identify which groups significantly influenced the value set, different regression models, including dummy variables for the subgroups, were tested while controlling for preference heterogeneity. Backward selection based on the Akaike information criterion led to significant subgroup dummies, which were analyzed in more detail. For each significant subgroup, the value set model was estimated separately. The models were then compared. Sociodemographics of the subgroups were considered. RESULTS: Three significant dummies were identified: state 11111, severity levels 5 to 7, and self-reported problems with pain/discomfort. The value sets for the 6 subgroups were compared with the national German value set, showing only marginal deviations. The mean absolute deviation ranged from 0.004 to 0.013. No different densities were identified for the decrements of the different value sets. CONCLUSIONS: People with self-reported health impairments do not have different EQ-5D-5L health state preferences compared with the German general population. Further research is needed to determine whether the presence of a chronic health condition has a larger influence on health state valuation than the general population.

Immediate major dynamic changes in the T- and NK-cell subset composition after cardiac transplantation.

Early kinetics of lymphocyte subsets involved in tolerance and rejection following heart transplantation (HTx) are barely defined. Here, we aimed to delineate the early alloimmune response immediately after HTx. Therefore, blood samples from 23 heart-transplanted patients were collected before (pre-), immediately (T0), 24 hours (T24), and 3 weeks (3 wks) after HTx. Immunophenotyping was performed using flow cytometry. A significant increase was detected for terminally differentiated (TEMRA) CD4+ or CD8+ T cells and CD56dim CD16+ NK cells immediately after HTx linked to a decrease in naïve CD8+ and CM CD4+ T as well as CD56bright CD16- NK cells, returning to baseline levels at T24. More detailed analyses revealed increased CD69+ CD25- and diminished CD69- CD25- CD4+ or CD8+ T-cell proportions at T0 associated with decreasing S1PR1 expression. Passenger T and NK cells were found at low frequencies only in several patients at T0 and did not correlate with lymphocyte alterations. Collectively, these results suggest an immediate, transient shift toward memory T and NK cells following HTx. Opposite migratory properties of naïve versus memory T and NK cells occurring in the early phase after HTx could underlie these observations and may impinge on the development of allo-specific immune responses.

EQ-5D-Y Value Set for Germany.

BACKGROUND: Demand is increasing for youth-specific preference-based health-related quality-of-life measures for inclusion in evaluations of healthcare interventions for children and adolescents. The EQ-5D-Youth (EQ-5D-Y) has the potential to become such a preference-based measure. OBJECTIVE: This study applied the recently published EQ-5D-Y valuation protocol to develop a German EQ-5D-Y value set and explored the differences between values given to youth health by parents and non-parents. METHODS: To elicit EQ-5D-Y health state preferences, a representative sample of 1030 adults of the general population completed a discrete choice experiment (DCE) online survey, and 215 adults participated in face-to-face interviews applying composite time trade-off (cTTO). Respondents were asked to consider a 10-year-old child living in the health states. DCE data were modelled using a mixed logit model. To derive the value set, DCE latent scale values were anchored onto adjusted mean cTTO values using a linear mapping approach. RESULTS: Adult respondents considered pain/discomfort and feeling worried/sad/unhappy as the two most important dimensions in terms of youth health. Adjusted mean cTTO values ranged from - 0.350 for health state 33333 to 0.970 for health state 21111. The EQ-5D-Y value set showed a logical order for all parameter estimates, and predicted values ranged from - 0.283 to 1. Differences in preferences by parental status were mainly observed for cTTO results, where mean values were larger for parents than for non-parents. CONCLUSIONS: Applying the valuation protocol, a German EQ-5D-Y value set with internally consistent coefficients was developed. This enables the instrument to be used in economic evaluations of paediatric healthcare interventions.

The EQ-HWB: Overview of the Development of a Measure of Health and Wellbeing and Key Results.

OBJECTIVES: Existing measures for estimating quality-adjusted life-years are mostly limited to health-related quality of life. This article presents an overview of the development the EQ-HWB (EQ Health and Wellbeing), which is a measure that encompasses health and wellbeing. METHODS: Stages: (1) Establishing domains through reviews of the qualitative literature informed by a conceptual framework. (2) Generation and selection of items to cover the domains. (3) Face validation of these items through qualitative interviews with 168 patients, social care users, general population, and carers across 6 countries (Argentina, Australia, China, Germany, United Kingdom, United States). (4) Extensive psychometric testing of candidate items (using classical, factor analysis, and item response theory methods) on > 4000 respondents in the 6 countries. Stakeholders were consulted throughout. RESULTS: A total of 32 subdomains grouped into 7 high-level domains were identified from the qualitative literature and 97 items generated to cover them. Face validation eliminated 36 items, modified 14, and added 3. Psychometric testing of 64 items found little difference in missing data or problems with response distribution, the conceptual model was confirmed except in China, and most items performed well in the item response theory in all countries. Evidence was presented to stakeholders in 2 rounds of consultation to inform the final selection of items for the EQ-HWB (25-item) and the short version of EQ-HWB (9-items). CONCLUSIONS: EQ-HWB measures have been developed internationally for evaluating interventions in health, public health, and social care including the impact on patients, social care users, and carers.

Generation, Selection, and Face Validation of Items for a New Generic Measure of Quality of Life: The EQ-HWB.

OBJECTIVES: This article aims to describe the generation and selection of items (stage 2) and face validation (stage 3) of a large international (multilingual) project to develop a new generic measure, the EQ-HWB (EQ Health and Wellbeing), for use in economic evaluation across health, social care, and public health to estimate quality-adjusted life-years. METHODS: Items from commonly used generic, carer, social care, and mental health quality of life measures were mapped onto domains or subdomains identified from a literature review. Potential terms and items were reviewed and refined to ensure coverage of the construct of the domains/subdomain (stage 2). Input on the potential item pool, response options, and recall period was sought from 3 key stakeholder groups. The pool of candidate items was tested in qualitative interviews with potential future users in an international face validation study (stage 3). RESULTS: Stage 2 resulted in the generation of 687 items. Predetermined selection criteria were applied by the research team resulting in 598 items being dropped, leaving 89 items that were reviewed by key stakeholder groups. Face validation (stage 3) tested 97 draft items and 4 response scales. A total of 47 items were retained and 14 were modified, whereas 3 were added to the candidate pool of items. This resulted in a 64-item set. CONCLUSIONS: This international multiculture, multilingual study with a common methodology identified many items that performed well across all countries. These were taken to the psychometric testing along with modified and new items for the EQ-HWB.

Developing and testing a cognitive bolt-on for the EQ-5D-Y (Youth).

PURPOSE: The aim of this study was to develop and test a cognitive dimension as a bolt-on for the German version of the EQ-5D-Y (Youth). METHODS: A literature review and six focus groups with children and adolescents were used to develop the cognitive dimension for the EQ-5D-Y. In a two-phase pretest, the acceptability, feasibility and performance of this dimension were assessed (phase 1: qualitative face-to-face interviews, phase 2: standard pretest in a clinical setting). In total, 280 children and adolescents participated in this study. RESULTS: School performance, concentration, memory and learning ability represent the most important components of cognitive functioning in children and adolescents. Hence, those components were incorporated into the cognitive dimension of the EQ-5D-Y by adding four items. For children and adolescents living with a rheumatic disorder or type 1 diabetes mellitus, the EQ-5D-Y plus a cognitive bolt-on demonstrated good acceptability, feasibility and performance. The cognitive items improved the explanatory power for the EQ visual analogue scale (EQ-VAS). Factor analysis has shown that a reduction of the cognitive bolt-on into one or two item(s) is justifiable. CONCLUSION: By enhancing the EQ-5D-Y with a cognitive bolt-on, we developed an instrument that incorporates current findings on Health-Related Quality of Life (HRQoL) and is suitable for the target population. Empirical results of this study show that cognitive functioning is an important part of HRQoL assessment in children and adolescents. The inclusion of a cognitive dimension in the EQ-5D-Y improves the HRQoL measurement.

To What Extent Do Patient Preferences Differ From General Population Preferences?

OBJECTIVES: In some countries including Germany, value sets based on general population preferences are not acceptable for decision-makers in healthcare because the impact of the reference group-general population versus patients-on utility decrements is questioned. The objective of this study was to explore potential differences in patient versus general population health preferences and a way of combining both preferences in economic evaluation. METHODS: EQ-5D-5L general population preferences were available from national value sets in Germany and Spain. Patient preferences were obtained by conducting discrete choice experiments with patients with rheumatism and patients with diabetes mellitus in Germany and Spain using an online panel. The econometric approach was based on the conditional logit framework. Latent values were anchored using the national value sets. RESULTS: A total of 1700 patients (Germany, n = 937; Spain, n = 763) were included in the analysis. In both countries, patients gave more importance to mobility, self-care, or usual activities and less importance to pain/discomfort and anxiety/depression than the general population. The size of these differences was larger in Germany than in Spain. In Germany, preferences reported by both patient groups were more similar than in Spain. CONCLUSION: Patient preferences differ from preferences derived from the general population. In contrast to the general population, patients gave more importance to the functional dimensions than to symptoms in both countries. The extent of the differences depends on the disease and the country. For countries preferring patient preferences, a possible way of incorporating the patient perspective in health state valuation was suggested and needs to be further explored.

Comparison of Adult and Adolescent Preferences Toward EQ-5D-Y-3L Health States.

OBJECTIVES: The international EQ-5D-Y-3L valuation protocol suggests obtaining preferences for EQ-5D-Y-3L health states from a sample of the general adult population. There is discussion around involving children and adolescents in the processes of preference elicitation and decision making. The objective of this study was to compare the preferences for EQ-5D-Y-3L obtained from adolescents for themselves to those of adults considering a hypothetical 10-year-old child in Germany, Slovenia, and Spain. METHODS: A sample of a minimum of 700 adolescents and 1000 adults in each country was recruited through online panels. An online discrete choice experiment was used to obtain health-state preferences. For the purposes of comparison, all coefficients were rescaled to a 1 (best) to 0 (worst) scale. The differences between preferences in both samples were analyzed via the relative attribute importance of health dimensions from the mixed logit models. RESULTS: Statistically significant differences between the preferences for EQ-5D-Y-3L states given by the 2 samples were observed in all 3 countries. The overall relative attribute importance was similar between adolescents and adults; adolescents usually gave more importance to mobility and self-care, and less to anxiety/depression. The rank-order of the dimension levels between adults and adolescents differs in all 3 countries. CONCLUSIONS: Preferences toward EQ-5D-Y-3L states differ if estimated by adults taking the perspective of a child or by the adolescents themselves. Although it seems possible to obtain adolescents' preferences for inclusion in EQ-5D-Y-3L value sets, the desirability and acceptance of their preferences by researchers and decision makers need to be explored further.

A French Value Set for the EQ-5D-5L.

OBJECTIVE: The objective of this study was to develop a French value set for the EQ-5D-5L, for academic and clinical research, and for regulatory requirements for price-setting of drugs and medical devices. METHOD: This study used the standardized valuation protocol developed by EuroQol, using computer-assisted personal interview software. A representative sample of 1048 French residents were interviewed by a market research company, under the supervision of the research team. Health states were valued using composite time trade-off and a discrete choice experiment. Modeling was used to create values for the 3125 possible health states. The composite time trade-off data were modeled using a Tobit model with censored observations at -1 and correcting for heteroscedasticity. A conditional logit model was used for the discrete choice results, and both models were combined using a hybrid model. An adjusted hybrid model was tested to correct for imbalance in the sample on age and sex compared with the general population. A comparison with the 3-level (3L) value set was performed. RESULTS: The adjusted model was preferred to comply with the representativeness of the general population. It provided a value set for which all coefficients were logically consistent. Values ranged from - 0.525 to 1. The distribution of values presented a shift towards higher values versus the 3L value set. Ranking of dimensions changed. Pain and discomfort and mobility were the dimensions with the highest potential for disutility compared with mobility and self-care for the 3L instrument. CONCLUSIONS: This study provides a value set based on societal preferences of the French population, using an improved descriptive instrument of health-related quality-of-life health states. It will contribute to improve the quality of cost-effectiveness analysis in the French context and help stimulate disease-specific quality-of-life references for academic-, institutional-, and industry-promoted studies.

Overview, Update, and Lessons Learned From the International EQ-5D-5L Valuation Work: Version 2 of the EQ-5D-5L Valuation Protocol.

A standardized 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L) valuation protocol was first used in national studies in the period 2012 to 2013. A set of problems encountered in this initial wave of valuation studies led to the subsequent refinement of the valuation protocol. To clarify lessons learned and how the protocol was updated when moving from version 1.0 to the current version 2.1 and 2.0, this article will (1) present the challenges faced in EQ-5D-5L valuation since 2012 and how these were resolved and (2) describe in depth a set of new challenges that have become central in currently ongoing research on how EQ-5D-5L health states should be valued and modeled.

German Value Set for the EQ-5D-5L.

OBJECTIVES: The objective of this study was to develop a value set for EQ-5D-5L based on the societal preferences of the German population. As the first country to do so, the study design used the improved EQ-5D-5L valuation protocol 2.0 developed by the EuroQol Group, including a feedback module as internal validation and a quality control process that was missing in the first wave of EQ-5D-5L valuation studies. METHODS: A representative sample of the general German population (n = 1158) was interviewed using a composite time trade-off and a discrete choice experiment under close quality control. Econometric modeling was used to estimate values for all 3125 possible health states described by EQ-5D-5L. The value set was based on a hybrid model including all available information from the composite time trade-off and discrete choice experiment valuations without any exclusions due to data issues. RESULTS: The final German value set was constructed from a combination of a conditional logit model for the discrete choice experiment data and a censored at -1 Tobit model for the composite time trade-off data, correcting for heteroskedasticity. The value set had logically consistent parameter estimates (p < 0.001 for all coefficients). The predicted EQ-5D-5L index values ranged from -0.661 to 1. CONCLUSIONS: This study provided values for the health states of the German version of EQ-5D-5L representing the preferences of the German population. The study successfully employed for the first time worldwide the improved protocol 2.0. The value set enables the use of the EQ-5D-5L instrument in economic evaluations and in clinical studies.

Valuation of the EQ-5D-5L with composite time trade-off for the German population - an exploratory study.

BACKGROUND: The EuroQol Group has extended the severity levels of the EQ-5D from three to five (EQ-5D-5L). There are valuation studies worldwide planned in order to convert the EQ-5D-5L health states into a single preference-based summary score based on country-specific value sets of social health status preference valuations. The EuroQol Group developed an internationally standardised EQ-5D-5L valuation protocol. Based on the experiences of the first wave of valuation studies applying the protocol, a number of modifications to the implementation of composite time trade-off (cTTO) were proposed and tested in an exploratory study in Germany. METHODS: The aim of the study is to test the improved EQ-5D-5L valuation protocol 1.1 and the implementation of three modifications: (1) introduction of ranking task, (2) separating time trade-off (TTO) tasks for health states "Better Than Dead"(BTD)/"Worse Than Dead" (WTD), (3) allow for removal of problematic valuations from the cTTO data (the feedback module). Data were collected in computer assisted personal interviews with 200 members of the German general public. RESULTS: In comparison to the first wave of valuation studies a higher data quality can be observed in both study arms: increasing number of WTD valuations, reduced inconsistencies for health state 55555 as well as higher values for mild health states. Comparing both study arms, mean observed cTTO value for severity 6 is higher in the test arm. The proportion of inconsistent cTTO responses is lower in the test arm than in the control arm and is further reduced by the feedback module. The ranking task prolongs the interview without the desired effect. CONCLUSIONS: Both study arms yielded higher data quality in comparison to the first wave of EQ-5D-5L valuation studies. The valuation protocol combined with an intensive interviewer training and close data monitoring showed a high feasibility and acceptability to the respondents of the general population as well as the interviewers in Germany. Based on the results of this study and other countries, the separation of TTO tasks for health states BTD/WTD and the feedback module will be implemented in the valuation study for the EQ-5D-5L for Germany.

Brain stem lesions after head injury.

There is little knowledge on the morphology of the brain stem in survivors of head injury, as CT fails to shown brain stem lesions, and neuropathological data is only available from autopsies. As magnetic resonance imaging (MRI) sheds new light on morphological lesions of the brain, the authors investigated 100 patients with a severe head injury. MRI was performed in a prospective study within the first seven days after head injury while the patients were still in coma and on ventilation. Relating the location of the lesions as depicted by MRI with the initial CT scan and outcome, death appeared to be closely linked to the phenomenon of bilateral pontine lesions. The extent of supratentorial lesions had no bearing on survival at all in the absence of brain stem lesions. Altogether the brain stem was affected in 52%. Obviously the occurrence of bilateral upper pontine lesions is of highest predictive value for a fatal outcome. Severe destruction of supratentorial white matter as demonstrated by MRI is not related to increased mortality, as long as the brain stem is spared.