Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.

BACKGROUND: Metabolic plasticity gives cancer cells the ability to shift between signaling pathways to facilitate their growth and survival. This study investigates the role of glucose deprivation in the presence and absence of beta-hydroxybutyrate (BHB) in growth, death, oxidative stress and the stemness features of lung cancer cells. METHODS AND RESULTS: A549 cells were exposed to various glucose conditions, both with and without beta-hydroxybutyrate (BHB), to evaluate their effects on apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS) levels using flow cytometry, and the expression of CD133, CD44, SOX-9, and ß-Catenin through Quantitative PCR. The activity of superoxide dismutase, glutathione peroxidase, and malondialdehyde was assessed using colorimetric assays. Treatment with therapeutic doses of BHB triggered apoptosis in A549 cells, particularly in cells adapted to glucose deprivation. The elevated ROS levels, combined with reduced levels of SOD and GPx, indicate that oxidative stress contributes to the cell arrest induced by BHB. Notably, BHB treatment under glucose-restricted conditions notably decreased CD133 expression, suggesting a potential inhibition of cell survival through the downregulation of CD133 levels. Additionally, the simultaneous decrease in mitochondrial membrane potential and increase in ROS levels indicate the potential for creating oxidative stress conditions to impede tumor cell growth in such environmental settings. CONCLUSION: The induced cell death, oxidative stress and mitochondria impairment beside attenuated levels of cancer stem cell markers following BHB administration emphasize on the distinctive role of metabolic plasticity of cancer cells and propose possible therapeutic approaches to control cancer cell growth through metabolic fuels.

Interleukin-1 receptor accessory protein (IL-1RAP): A magic bullet candidate for immunotherapy of human malignancies.

IL-1, plays a role in some pathological inflammatory conditions. This pro-inflammatory cytokine also has a crucial role in tumorigenesis and immune responses in the tumor microenvironment (TME). IL-1 receptor accessory protein (IL-1RAP), combined with IL-1 receptor-1, provides a functional complex for binding and signaling. In addition to the direct role of IL-1, some studies demonstrated that IL1-RAP has essential roles in the progression, angiogenesis, and metastasis of solid tumors such as gastrointestinal tumors, lung carcinoma, glioma, breast and cervical cancers. This molecule also interacts with FLT-3 and c-Kit tyrosine kinases and is involved in the pathogenesis of hematological malignancies such as acute myeloid lymphoma. Additionally, IL-1RAP interacts with solute carrier family 3 member 2 (SLC3A2) and thereby increasing the resistance to anoikis and metastasis in Ewing sarcoma. This review summarizes the role of IL-1RAP in different types of cancers and discusses its targeting as a novel therapeutic approach for malignancies.

Catalase-gold nanoaggregates manipulate the tumor microenvironment and enhance the effect of low-dose radiation therapy by reducing hypoxia.

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC.

Antitumor activities of a novel fluorinated small molecule (A1) in CT26 colorectal cancer cells: molecular docking and in vitro studies.

Chemotherapeutic treatment of colorectal cancer (CRC) has not been satisfactory until now; therefore, the discovery of more efficient medications is of great significance. Based on available knowledge, the CXCL12/CXCR4 axis plays a significant role in tumorigenesis, and inhibition of CXCR4 chemokine receptor with AMD3100 is one of the most known therapeutic modalities in cancer therapy. Herein, N, N''-thiocarbonylbis(N'-(3,4-dimethylphenyl)-2,2,2-trifluoroacetimidamide) (A1) was synthesized as a potent CXCR4 inhibitor. A1 inhibitory activity was first evaluated employing Molecular Docking simulations in comparison with the most potent CXCR4 inhibitors. Then, the antiproliferative and cytotoxic effect of A1 on CT26 mouse CRC cells was investigated by MTT assay technique and compared with those of the control molecule, AMD3100. The impact of the target compounds IC50 on apoptosis, cell cycle arrest, and CXCR4 expression was determined by flow cytometry technique. Our finding demonstrated that A1 induces a cytotoxic effect on CT26 cells at 60 µg/mL concentration within 72 h and provokes cell apoptosis and G2/M cell cycle arrest in comparison with the untreated cells, while AMD3100 did not show a cytotoxic effect up to 800 µg/mL dose. The obtained results show that A1 (at a concentration of 40 µg/mL) significantly reduced the proliferation of CT26 cells treated with 100 ng/mL of CXCL12 in 72 h. Moreover, treatment with 60 µg/mL of A1 and 100 ng/mL of CXCL12 for 72 h significantly decreased the number of cells expressing the CXCR4 receptor compared to the control group treated with CXCL12. Eventually, the obtained results indicate that A1, as a dual-function fluorinated small molecule, may benefit CRC treatment through inhibition of CXCR4 and exert a cytotoxic effect on tumor cells.Communicated by Ramaswamy H. Sarma.

Age-dependent immune responses in COVID-19-mediated liver injury: focus on cytokines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is potentially pathogenic and causes severe symptoms; in addition to respiratory syndromes, patients might experience other severe conditions such as digestive complications and liver complications injury. The abnormality in the liver is manifested by hepatobiliary dysfunction and enzymatic elevation, which is associated with morbidity and mortality. The direct cytopathic effect, immune dysfunction, cytokine storm, and adverse effects of therapeutic regimens have a crucial role in the severity of liver injury. According to aging and immune system alterations, cytokine patterns may also change in the elderly. Moreover, hyperproduction of cytokines in the inflammatory response to SARS-CoV-2 can lead to multi-organ dysfunction. The mortality rate in elderly patients, particularly those with other comorbidities, is also higher than in adults. Although the pathogenic effect of SARS-CoV-2 on the liver has been widely studied, the impact of age and immune-mediated responses at different ages remain unclear. This review discusses the association between immune system responses in coronavirus disease 2019 (COVID-19) patients of different ages and liver injury, focusing on cytokine alterations.

Differential expression levels of ß-catenin are associated with invasive behavior of both functional and non-functional pituitary neuroendocrine tumor (PitNET).

BACKGROUND: Although research continues to elucidate the molecular mechanism underlying pituitary tumor pathogenesis, limited information is available on the potential role and expression profile of ß-catenin in functional and non-functional pituitary neuroendocrine tumors (PitNETs). METHODS AND RESULTS: In the current study, 104 pituitary samples (tumors and cadaveric healthy pituitary tissues) were included and the gene and protein expression levels of ß-catenin were assessed by Real-Time PCR and immunohistochemistry, respectively. The correlation between expression level of ß-catenin and tumor invasive feature and size as well as patient age, gender, and hormonal level was measured. The data showed that PitNET samples expressed higher levels of the ß-catenin gene and protein compared to healthy pituitary tissues. Although there was no difference in ß-catenin expression level between non-functioning (NF-PitNETs) and growth hormone-producing tumors (GH-PitNETs), both tumor types showed significantly elevated ß-catenin levels compared to healthy pituitary tissues. The high level of ß-catenin in the invasive functional and non-functional tumors is indicative of the association of ß-catenin with PitNETs invasion. The expression pattern of the ß-catenin gene and protein was consistently and significantly associated with these tumor types. The correlation between ß-catenin and insulin-like growth factor 1 (IGF-1) in GH-PitNETs indicates the potential relevance of ß-catenin and IGF-1 for GH-PitNETs. CONCLUSIONS: The simultaneous increase in the expression of ß-catenin gene and protein level in PitNET tissues and their relationship to the tumor severity indicates the possible contributing role of ß-catenin and its underlying signaling mediators in PitNET pathogenesis.

Hypothetical versus experienced health state valuation: a qualitative study of adult general public views and preferences.

OBJECTIVES: Responses from hypothetical and experienced valuation tasks of health-related quality of life differ, yet there is limited understanding of why these differences exist, what members of the public think about them, and acceptable resolutions. This study explores public understanding of, opinions on, and potential solutions to differences between hypothetical versus experienced responses, in the context of allocating health resources. METHODS: Six focus groups with 30 members of the UK adult public were conducted, transcribed verbatim, and analysed using framework analysis. Participants self-completed the EQ-5D-5L, before reporting the expected consequences of being in two hypothetical EQ-5D-5L health states for ten years. Second, participants were presented with prior results on the same task from a public (hypothetical) and patient (experienced) sample. Third, a semi-structured discussion explored participants': (1) understanding, (2) opinions, and (3) potential resolutions. RESULTS: Twenty themes emerged, clustered by the three discussion points. Most participants found imagining the health states difficult without experience, with those aligned to mental health harder to understand. Participants were surprised that health resource allocation was based on hypothetical responses. They viewed experienced responses as more accurate, but noted potential biases. Participants were in favour of better informing, but not influencing the public. Other solutions included incorporating other perspectives (e.g., carers) or combining/weighting responses. CONCLUSION: Members of the UK public appear intuitively not to support using potentially uninformed public values to hypothetical health states in the context of health resource allocation. Acceptable solutions involve recruiting people with greater experience, including other/combinations of views, or better informing respondents.

Understanding what matters to metastatic castration-resistant prostate cancer (mCRPC) patients when considering treatment options: A US patient preference survey.

BACKGROUND: Understanding how patients perceive the efficacy, safety, and administrative burden of treatments for metastatic castration-resistant prostate cancer (mCRPC) can facilitate shared-decision making for optimal management. This study sought to elicit patient preferences for mCRPC treatments in the US. METHODS: We conducted a cross-sectional survey using the discrete-choice experiment method. Participants were asked to state their choices over successive sets of treatment alternatives, defined by varying levels of treatment attributes: overall survival (OS), months until patients develop a fracture or bone metastasis, likelihood of requiring radiation to control bone pain, fatigue, nausea, and administration (i.e., oral/IV injection/IV infusion). Using mixed logit models, we determined the value (i.e., preference weights) that respondents placed on each attribute. Relative attribute importance (RAI) and marginal rates of substitution (MRS) were calculated to understand patients' willingness to make tradeoffs among different attributes. RESULTS: The final data set numbered 160 participants, with a mean age of 71.6 years old and a mean of 8.96 years since prostate cancer diagnosis. Participants' treatment preferences were as follows: OS (RAI: 31%), bone pain control (23%), nausea (16%), delaying fracture or bone metastasis (15%), fatigue (11%), and administration (3%). The MRS demonstrated that respondents were willing to trade 1.9 months of OS to eliminate moderate nausea and 3.3 months of OS for a reduction in fatigue from severe to mild. CONCLUSIONS: Improving OS is the highest priority for patients with mCRPC, but they are willing to trade some survival to reduce the risk of requiring radiation to control bone pain, delay a fracture or bone metastasis, and experience less severe nausea and fatigue.

Catalase application in cancer therapy: Simultaneous focusing on hypoxia attenuation and macrophage reprogramming.

The tumor microenvironment (TME), as an immunosuppressive milieu, has a critical role in tumor progression and increases resistance to the conventional treatments. Among the abundant immunosuppressive cells in the TME, tumor-associated macrophages (TAMs) could be a promising target for reprogramming and potentiating the local anti-tumor response. On the other hand, hypoxia is a major barrier in treating solid tumors, which aggravates the situation and alleviates the anti-tumor immune responses. Moreover, catalase and catalase-mimicking compounds can efficiently participate in the TAMs polarization and hypoxia attenuation in the TME. In this review, we will introduce a practical and novel approach which can simultaneously reduce hypoxia and polarize TAMs in the TME. Furthermore, catalase therapeutic effects in combination with cancer therapy methods will be fully discussed. This work aims to inspire readers to explore new avenues for designing and development of next-generation catalase-based formulations for cancer therapy.

Patient Preferences for Benefits, Risks, and Administration Route of Hypomethylating Agents in Myelodysplastic Syndromes.

INTRODUCTION/BACKGROUND: Therapy with infused or injected hypomethylating agents (HMAs) may lead to higher treatment administration burden (ie, local reaction, visit frequency and duration) vs. oral HMAs.   OBJECTIVES: To reveal preferences of US and Canadian patients with myelodysplastic syndromes (MDS) for HMAs' benefits, risks, and administration burden through an online discrete-choice experiment (DCE). MATERIALS AND METHODS: Choice of DCE attributes and survey development were informed by literature review and interviews with clinicians, MDS patients, and caregivers serving as patient proxies, and patient advocacy groups (PAGs) representatives, including from AAMAC, AAMDS, and MDSF. DCE choice tasks were analyzed using random parameter logit models. Survey patients were recruited by the PAGs via their networks. To understand key preference drivers and how much patients were willing to trade between attributes, we calculated each attribute's relative attribute importance (RAI) and marginal rates of substitution. RESULTS: One hundred eighty-four respondents (including 158 patients; mean age, 67.2 years; male, 50.5%; White, 50.5%; US residents, 88%) completed the survey. MDS risk was low (34.8%), high (30.9%), or unknown (34.2%). RAI (in decreasing order) was as follows: risk of AML (40%), fatigue level (33%), number of visits (12%), mode of administration (6%), visit duration (5%), and administration frequency (4%). Assuming the same risk of AML transformation or level of fatigue, most respondents (76.6%) were predicted to switch to an oral pill if it were available to them. CONCLUSION: Given equivalent effectiveness across HMAs, patients' preferences for HMA administration method should be considered in treatment decision-making to minimize burden and facilitate adherence.

Heterogeneity in preferences for outcomes of integrated care for persons with multiple chronic diseases: a latent class analysis of a discrete choice experiment.

PURPOSE: For an integrated care programme to be successful, preferences of the stakeholders involved should be aligned. The aim of this study is to investigate to which extent outcomes beyond health are valued and to study the heterogeneity of preferences of those involved in integrated care. METHODS: A discrete choice experiment (DCE) was conducted to elicit preferences for eight Triple Aim outcomes, i.e., physical functioning, psychological well-being, social relationships & participation, enjoyment of life, resilience, person-centeredness, continuity of care and total health and social care costs. Stakeholders were recruited among Dutch persons with multi-morbidity, informal caregivers, professionals, payers, and policymakers. A Bayesian mixed-logit model was used to analyse the data. Subsequently, a latent class analysis was performed to identify stakeholders with similar preferences. RESULTS: 739 stakeholders completed the DCE. Enjoyment of life was perceived as the most important outcome (relative importance: 0.221) across stakeholders, while total health and social care costs were perceived as least important (0.063). The latent class analysis identified four classes. The first class (19.9%) put most weight on experience with care outcomes. The second class (39%) favoured enjoyment of life. The third class (18%) focused relatively more on physical health. The fourth class (24%) had the least consistent preferences. CONCLUSION: This study has highlighted the heterogeneity in views of stakeholders in integrated care on what is important in health(care) for persons with multi-morbidity. To accurately value integrated care a variety of outcomes beyond health-e.g., enjoyment of life and experience with care-should be taken into account.

Value-based person-centred integrated care for frail elderly living at home: a quasi-experimental evaluation using multicriteria decision analysis.

OBJECTIVE: To evaluate the value of the person-centred, integrated care programme Care Chain Frail Elderly (CCFE) compared with usual care, using multicriteria decision analysis (MCDA). DESIGN: In a 12-month quasi-experimental study, triple-aim outcomes were measured at 0, 6 and 12 months by trained interviewers during home-visits. SETTING: Primary care, community-based elderly care. PARTICIPANTS: 384 community-dwelling frail elderly were enrolled. The 12-month completion rate was 70% in both groups. Propensity score matching was used to balance age, gender, marital status, living situation, education, smoking status and 3 month costs prior to baseline between the two groups. INTERVENTION: The CCFE is an integrated care programme with unique features like the presence of the elderly and informal caregiver at the multidisciplinary team meetings, and a bundled payment. PRIMARY AND SECONDARY OUTCOMES MEASURES: The MCDA results in weighted overall value scores that combines the performance on physical functioning, psychological well-being, social relationships and participation, enjoyment of life, resilience, person-centredness, continuity of care and costs, with importance weights of patients, informal caregivers, professionals, payers and policy-makers. RESULTS: At 6 months, the overall value scores of CCFE were higher in all stakeholder groups, driven by enjoyment of life (standardised performance scores 0.729 vs 0.685) and person-centredness (0.749 vs 0.663). At 12 months, the overall value scores in both groups were similar from a patient's perspective, slightly higher for CCFE from an informal caregiver's and professional's perspective, and lower for CCFE from a payer's and policy-maker's perspective. The latter was driven by a worse performance on physical functioning (0.682 vs 0.731) and higher costs (€22 816 vs €20 680). CONCLUSIONS: The MCDA indicated that the CCFE is the preferred way of delivering care to frail elderly at 6 months. However, at 12 months, MCDA results showed little difference from the perspective of patients, informal caregivers and professionals, while payers and policy-makers seemed to prefer usual care.

Why Do Adults Value EQ-5D-Y-3L Health States Differently for Themselves Than for Children and Adolescents: A Think-Aloud Study.

OBJECTIVES: Following protocol, adults value EQ-5D-Y-3L health states from the perspective of a 10-year-old child. It remains unclear why adults value health states differently for themselves than for a 10-year-old child and whether the latter perspective is representative of adults' preferences for the 8 to 15 years age range of the EQ-5D-Y-3L. This study examines the reasons underlying (potential) differences in adults' health-state preferences for themselves, a 10-year-old child, and 15-year-old adolescent. METHODS: We conducted semistructured interviews using a think-aloud protocol with 25 participants who performed valuation tasks in July 2020 to August 2020. Using the Framework Method, we developed 28 categories grouped under 5 themes that illustrated the differences emerging from the interviews. RESULTS: Participants (A) deemed it more straining to perform valuation tasks for a 10-year-old child and 15-year-old adolescent than for themselves, (B) had a stable self-image, but varied in whom they imagined as 10-year-old child and 15-year-old adolescent, (C) focused on different dimensions and levels for a 15-year-old adolescent than for a 10-year-old child and themselves, (D) had various thoughts about nonhealth-related factors that influenced their preferences, and (E) gave up relatively few life-years for a 10-year-old child and 15-year-old adolescent, also to avoid others bearing a grudge against them. CONCLUSIONS: Our results indicate that differences in adults' health-state preferences for themselves and a 10-year-old child largely result from differences in thoughts about nonhealth-related factors. They further indicate that health-state preferences for a 10-year-old child may not be representative of such preferences for the full EQ-5D-Y-3L age range.

[Patients, Partners, Professionals, Payers and Policy Makers Preferences for Integrated Care for Multimorbidity in Germany: A Discrete Choice Experiment]. / Präferenzen von Patienten, pflegenden Angehörigen, Leistungserbringern, Kostenträgern und politischen Entscheidungsträgern bei der integrierten Versorgung in Deutschland: Ein Discrete Choice Experiment.

AIM OF THE WORK: The aim of this study was to measure and compare the relative importance that patients with multimorbidity, partners and other informal caregivers, professionals, payers and policy makers attribute to different outcome measures of integrated care (IC) programmes in Germany. METHODS: A DCE was conducted, asking respondents to choose between two IC programmes for persons with multimorbidity. Each IC programme was presented by means of attributes or outcomes reflecting the Triple Aim. They were divided into the outcomes health/ wellbeing, experience with care and costs with in total eight attributes and three levels of performance. RESULTS: The results of n=676 questionnaires showed that the attributes "enjoyment of life" and "continuity of care" received the highest ratings across all stakeholder groups. The lowest relative scores remained for the attribute "total costs" for all stakeholders. The preferences of professionals and informal caregivers differed most distinctly from the patients' preferences. The differences mostly concerned "physical functioning", which was rated highest by patients, and "person centeredness" and "continuity of care", which received the highest ratings from professionals. CONCLUSIONS: The preference heterogeneities identified in relation to the outcomes of IC programmes between different stakeholders highlight the importance of informing professionals and policy makers about the different perspectives in order to optimise the design of IC programmes. The results also support the relevance of joint decision-making and coordination processes between professionals, informal caregivers and patients.

Evaluating Complex Health and Social Care Program Using Multi-Criteria Decision Analysis: A Case Study of "Better Together in Amsterdam North".

OBJECTIVES: Multi-criteria decision analysis (MCDA) has been recommended to support policy making in healthcare. However, practical applications of MCDA are sparse. One potential use for MCDA is for the evaluation of programs for complex and vulnerable patients. These complex patients benefit from integrated care programs that span healthcare and social care and aim to improve more than just health outcomes. MCDA can evaluate programs that aim to improve broader outcomes because it allows the evaluation of multiple outcomes alongside each other. In this study, we evaluate an innovative integrated care program in the Netherlands using MCDA. METHODS: We used an innovative MCDA framework with broad outcomes of health, well-being, and cost to evaluate the Better Together in Amsterdam North (BSiN) program using preferences of patients, partners, providers, payers, and policy makers in the Netherlands. BSiN provides case management support for a period of 6 months. Seven outcomes that previous research has deemed important to complex patients were measured, including physical functioning and social relationships and participation. RESULTS: We find that the program improved the overall MCDA score marginally, and, thus, after 6 and after 12 months, BSiN was preferred to usual care by all stakeholders. BSiN was preferred to usual care, mostly owing to improvements in psychological well-being and social relationships and participation. CONCLUSIONS: The integrated healthcare and social care program BSiN in the Netherlands was preferred to usual care according to an MCDA evaluation. MCDA seems a useful method to evaluate complex programs with benefits beyond health.

Bundled payments for chronic diseases increased health care expenditure in the Netherlands, especially for multimorbid patients.

Bundled payments aim to stimulate the integration of healthcare services and ultimately reduce healthcare expenditure growth through improved quality of care. The Netherlands introduced bundled payments for chronic diseases in 2010 by reimbursing providers annually for a bundle of primary care services related to COPD, Diabetes, or Vascular Risk Management. We aimed to assess the long-term effects of these bundled payments on healthcare expenditure. We used health insurance claims data from 2008 to 2015 to compare the healthcare expenditure between everyone who was included in bundled payments and a control group. We performed a difference-in-difference analysis in combination with propensity score matching and found that bundled payments consistently increased health care expenditure over seven years. The average half-year increase was €233 (95%CI: 204-262) for DM2, €609 (95%CI: 533-686) for COPD, and €231 (95%CI: 208-254) for VRM, representing 13%, 52%, and 20% of 2008 half-year cost. The increase was higher for those with multimorbidity compared to those without multimorbidity. This suggests that the expectations of the bundled payments are yet to be fulfilled.

The disease burden of multimorbidity and its interaction with educational level.

INTRODUCTION: Policies to adequately respond to the rise in multimorbidity have top-priority. To understand the actual burden of multimorbidity, this study aimed to: 1) estimate the trend in prevalence of multimorbidity in the Netherlands, 2) study the association between multimorbidity and physical and mental health outcomes and healthcare cost, and 3) investigate how the association between multimorbidity and health outcomes interacts with socio-economic status (SES). METHODS: Prevalence estimates were obtained from a nationally representative pharmacy database over 2007-2016. Impact on costs was estimated in a fixed effect regression model on claims data over 2009-2015. Data on physical and mental health and SES were obtained from the National Health Survey in 2017, in which the Katz-10 was used to measure limitations in activities of daily living (ADL) and the Mental Health Inventory (MHI) to measure mental health. SES was approximated by the level of education. Generalized linear models (2-part models for ADL) were used to analyze the health data. In all models an indicator variable for the presence or absence of multimorbidity was included or a categorical variable for the number of chronic conditions. Interactions terms of multimorbidity and educational level were added into the previously mentioned models. RESULTS: Over the past ten years, there was an increase of 1.6%-point in the percentage of people with multimorbidity. The percentage of people with three or more conditions increased with +2.1%-point. People with multimorbidity had considerably worse physical and mental health outcomes than people without multimorbidity. For the ADL, the impact of multimorbidity was three times greater in the lowest educational level than in the highest educational level. For the MHI, the impact of multimorbidity was two times greater in the lowest than in the highest educational level. Each additional chronic condition was associated with a greater worsening in health outcomes. Similarly, for costs, where there was no evidence of a diminishing impact of additional conditions either. In patients with multimorbidity total healthcare costs were on average €874 higher than in patients with a single morbidity. CONCLUSION: The impact of multimorbidity on health and costs seems to be greater in the sicker and lower educated population.

Comparing patients' and other stakeholders' preferences for outcomes of integrated care for multimorbidity: a discrete choice experiment in eight European countries.

OBJECTIVES: To measure relative preferences for outcomes of integrated care of patients with multimorbidity from eight European countries and compare them to the preferences of other stakeholders within these countries. DESIGN: A discrete choice experiment (DCE) was conducted in each country, asking respondents to choose between two integrated care programmes for persons with multimorbidity. SETTING: Preference data collected in Austria (AT), Croatia (HR), Germany (DE), Hungary (HU), the Netherlands (NL), Norway (NO), Spain (ES), and UK. PARTICIPANTS: Patients with multimorbidity, partners and other informal caregivers, professionals, payers and policymakers. MAIN OUTCOME MEASURES: Preferences of participants regarding outcomes of integrated care described as health/well-being, experience with care and cost outcomes, that is, physical functioning, psychological well-being, social relationships and participation, enjoyment of life, resilience, person-centredness, continuity of care and total costs. Each outcome had three levels of performance. RESULTS: 5122 respondents completed the DCE. In all countries, patients with multimorbidity, as well as most other stakeholder groups, assigned the (second) highest preference to enjoyment of life. The patients top-three most frequently included physical functioning, psychological well-being and continuity of care. Continuity of care also entered the top-three of professionals, payers and policymakers in four countries (AT, DE, HR and HU). Of the five stakeholder groups, preferences of professionals differed most often from preferences of patients. Professionals assigned lower weights to physical functioning in AT, DE, ES, NL and NO and higher weights to person-centredness in AT, DE, ES and HU. Payers and policymakers assigned higher weights than patients to costs, but these weights were relatively low. CONCLUSION: The well-being outcome enjoyment of life is the most important outcome of integrated care in multimorbidity. This calls for a greater involvement of social and mental care providers. The difference in opinion between patients and professionals calls for shared decision-making, whereby efforts to improve well-being and person-centredness should not divert attention from improving physical functioning.

Lead-free transparent shields for diagnostic X-rays: Monte Carlo simulation and measurements.

In recent years, the preference for using lead-free radiation protection shields has increased because of concerns regarding lead poisoning and leakage. In medical and research laboratories, glass shields are preferred because of their transparency. In this study, various glass shields were examined and compared based on the international standards. One commercially available lead-based shield, four recently studied shields, and three new lead-free shields were considered, and their shielding factors were calculated. We presented three glasses based on borate, phosphate, and silicate compounds, which were named Ir1, Ir2, and Ir3, respectively. Based on the International Electrotechnical Commission standard (IEC 61331), the air-kerma ratios (attenuation ratios) and lead equivalent values were derived using Monte Carlo N-Particle eXtended (MCNPX) calculations, and mass attenuation coefficients and effective atomic numbers (Zeff) of all the shields were obtained from XCOM database, in the diagnostic X-ray energy range of 40-120 keV. In addition, some measurements were performed for the reference (lead-based) glass to validate the simulations. The above-mentioned factors for silicate-bismuth-based (Ir3) and borosilicate-barium-based (Tu) glasses were found to be higher than the others and comparable to those of commercially available lead-based glass. In conclusion, Ir3 and Tu glasses were found to be the preferred lead-free transparent shields in the diagnostic X-ray energy range.

Effect of Reflection and Deliberation on Health State Values: A Mixed-Methods Study.

BACKGROUND: Health economists ask members of the general public to value health states, but it is recognized that individuals construct their preferences during the valuation tasks. Conventional methods rely on one-off interviews that do not give participants time to reflect and deliberate on their preferences. OBJECTIVE: This study investigates the effect of reflection and deliberation on health state preferences using the EQ-5D questionnaire and time trade-off valuation method. METHODS: A novel concurrent explanatory mixed-methods design is used to investigate the explanation for the quantitative findings. RESULTS: A total of 57 participants in the United Kingdom valued health states before and after a group-based deliberation exercise. There were large changes in health state values at the individual level, but the changes canceled out at the aggregate level. The mixed-methods findings suggest deliberation did not reveal new information or reduce inconsistencies in reasoning but rather focused on an exchange of personal subjective beliefs. In cases of disagreement, the participants accepted but did not adopt other participants' opinions. Participants remained uncertain about the relevance of their experiences and about their values. CONCLUSIONS: The evidence suggests that reflection and deliberation, as designed in this study, are unlikely to result in large systematic changes of health state values. The uncertainties expressed by participants means future research should investigate whether preferences are informed or whether providing participants with more information helps them construct their preferences with more certainty. The mixed-methods design used is a promising design to help elucidate the reasons for quantitative findings.