Self-interest, positional concerns and distributional considerations in healthcare preferences.

Efficiently allocating scarce healthcare resources requires nuanced understanding of individual and collective interests as well as relative concerns, which may overlap or conflict. This paper is the first to empirically investigate whether and to what extent self-interest (SI), positional concerns (PC) and distributional considerations (DC) simultaneously explain individual decision making related to access to healthcare services. Our investigation is based on a stated choice experiment conducted in two countries with different healthcare systems, the United States (US) and the United Kingdom (UK). The choice experiment is on allocation of medical treatment waiting times for a hypothetical disease. We carry out the investigation under two different perspectives: (i) in a socially inclusive personal perspective decision makers were asked to choose between waiting time distributions for themselves and (ii) in a social perspective decision makers were asked to make similar choices for a close relative or friend of opposite gender. The results obtained by estimating a variety of advanced choice models indicate that DC, SI and PC, in this order of importance, are significant drivers of choice behaviour in our empirical context. These findings are consistent regardless of the choice perspective and the country where decision makers live. Comparing the results from different choice perspectives, we find that US respondents who chose for their close relative or friend attach significantly larger weight to their close relative's or friend's waiting times as well as to the overall distribution of waiting times than US respondents who chose for themselves. Looking at differences between countries, our results show that UK respondents who made choices for themselves placed significantly larger weight on SI and DC than US respondents, while US respondents, in turn, displayed relatively stronger but not significantly different positional concerns than UK respondents. In addition, we observe that UK respondents who chose for their close relative or friend put a larger weight on DC than their US counterparts. We conclude that the methodological (data collection and analysis) approach allows for disentangling the relative importance of the three motivations and discusses the potential implications of these findings for healthcare decision making.

Towards machine learning for moral choice analysis in health economics: A literature review and research agenda.

BACKGROUND: Discrete choice models (DCMs) for moral choice analysis will likely lead to erroneous model outcomes and misguided policy recommendations, as only some characteristics of moral decision-making are considered. Machine learning (ML) is recently gaining interest in the field of discrete choice modelling. This paper explores the potential of combining DCMs and ML to study moral decision-making more accurately and better inform policy decisions in healthcare. METHODS: An interdisciplinary literature search across four databases - PubMed, Scopus, Web of Science, and Arxiv - was conducted to gather papers. Based on the Preferred Reporting Items for Systematic and Meta-analyses (PRISMA) guideline, studies were screened for eligibility on inclusion criteria and extracted attributes from eligible papers. Of the 6285 articles, we included 277 studies. RESULTS: DCMs have shortcomings in studying moral decision-making. Whilst the DCMs' mathematical elegance and behavioural appeal hold clear interpretations, the models do not account for the 'moral' cost and benefit in an individual's utility calculation. The literature showed that ML obtains higher predictive power, model flexibility, and ability to handle large and unstructured datasets. Combining the strengths of ML methods with DCMs has the potential for studying moral decision-making. CONCLUSIONS: By providing a research agenda, this paper highlights that ML has clear potential to i) find and deepen the utility specification of DCMs, and ii) enrich the insights extracted from DCMs by considering the intrapersonal determinants of moral decision-making.

Surgery or comfort care for neonates with surgical necrotizing enterocolitis: Lessons learned from behavioral artificial intelligence technology.

Background: Critical decision making in surgical necrotizing enterocolitis (NEC) is highly complex and hard to capture in decision rules due to case-specificity and high mortality risk. In this choice experiment, we aimed to identify the implicit weight of decision factors towards future decision support, and to assess potential differences between specialties or centers. Methods: Thirty-five hypothetical surgical NEC scenarios with different factor levels were evaluated by neonatal care experts of all Dutch neonatal care centers in an online environment, where a recommendation for surgery or comfort care was requested. We conducted choice analysis by constructing a binary logistic regression model according to behavioral artificial intelligence technology (BAIT). Results: Out of 109 invited neonatal care experts, 62 (57%) participated, including 45 neonatologists, 16 pediatric surgeons and one neonatology physician assistant. Cerebral ultrasound (Relative importance = 20%, OR = 4.06, 95% CI = 3.39-4.86) was the most important factor in the decision surgery versus comfort care in surgical NEC, nationwide and for all specialties and centers. Pediatric surgeons more often recommended surgery compared to neonatologists (62% vs. 57%, p = 0.03). For all centers, cerebral ultrasound, congenital comorbidity, hemodynamics and parental preferences were significant decision factors (p < 0.05). Sex (p = 0.14), growth since birth (p = 0.25), and estimated parental capacities (p = 0.06) had no significance in nationwide nor subgroup analyses. Conclusion: We demonstrated how BAIT can analyze the implicit weight of factors in the complex and critical decision for surgery or comfort care for (surgical) NEC. The findings reflect Dutch expertise, but the technique can be expanded internationally. After validation, our choice model/BAIT may function as decision aid.

For Me or for My Relatives? Approximating Self-Protection and Local Altruistic Motivations Underlying Preferences for Public Health Policies Using Risk Perception Metrics.

OBJECTIVES: Research efforts evaluating the role of altruistic motivations behind health policy support are usually based on direct preference elicitation procedures, which may be biased. We propose an indirect measurement approach to approximate self-protection-related and altruistic motivations underlying preferences for public health policies. METHODS: Our new approach relies on associations between on the one hand decision makers' perceived health risk for themselves and for close relatives and on the other hand their observed preferences for health policies that reduce such risks. The approach allows to make a rough distinction between health-related self-protection and local altruistic motives behind preferences for health policies. We illustrate our approach using data obtained from a discrete choice experiment in the context of policies to relax coronavirus-related lockdown measures in The Netherlands. RESULTS: Our results show that the approach is able to uncover that (1) people who think they have a high chance of experiencing health risks from a COVID-19 infection are more willing to accept a societal or personal sacrifice, (2) people with a higher health risk perception for their relatives have a higher willingness to accept sacrifices than people with a higher health risk perception for themselves, and (3) people who perceive that they have a high risk of dying of COVID-19 have a higher willingness to accept sacrifices than those anticipating less severe consequences of COVID-19. CONCLUSIONS: Our method offers a useful proxy metric to distinguish health-related self-protection and local altruism as drivers of citizens' responses to healthcare policies.

Hiding opinions by minimizing disclosed information: an obfuscation-based opinion dynamics model.

In the field of opinion dynamics, the hiding of opinions is routinely modeled as staying silent. However, staying silent is not always feasible. In situations where opinions are indirectly expressed by one's observable actions, people may however try to hide their opinions via a more complex and intelligent strategy called obfuscation, which minimizes the information disclosed to others. This study proposes a formal opinion dynamics model to study the hitherto unexplored effect of obfuscation on public opinion formation based on the recently developed Action-Opinion Inference Model. For illustration purposes, we use our model to simulate two cases with different levels of complexity, highlighting that the effect of obfuscation largely depends on the subtle relations between actions and opinions.

l-arginine and l-NMMA for assessing cerebral endothelial dysfunction in ischaemic cerebrovascular disease: A systematic review.

Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and NG -monomethyl-l-arginine (l-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible according to inclusion and exclusion criteria. Studies investigated the effect of age (n=2), type 2 diabetes mellitus (DM) (n=1), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (n=1), leukoaraiosis (n=1), and prior ischaemic stroke or transient ischaemic attack (TIA) (n=2) on cerebral ED. Most studies applied transcranial Doppler to quantify cerebral ED. Endothelium-dependent vasodilatation (EDV) induced by l-arginine was impaired in elderly and subjects with leukoaraiosis, but enhanced in CADASIL patients. Studies including subjects with prior ischaemic stroke or TIA reported both enhanced and impaired EDV to l-arginine. Responses to l-NMMA deviated between subjects with type 2 DM and the elderly. We found only few studies investigating cerebral endothelial responses to l-arginine and l-NMMA in subjects with vascular risk factors or ischaemic cerebrovascular disease. Inconsistencies in results were most likely due to variations in methods and included subject populations. In order to use cerebral ED as a prognostic marker, further studies are required to evaluate the association to cerebrovascular disease.

The diagnostic accuracy of carcinoembryonic antigen to detect colorectal cancer recurrence - A systematic review.

INTRODUCTION: Carcinoembryonic Antigen (CEA) has been used as a tumor marker in the follow-up of colorectal cancer for more than 40 years. Controversy exists regarding its diagnostic applicability due to a relatively low sensitivity and a questionable effect on mortality. The aim of this review was to assess the diagnostic accuracy of CEA in detecting recurrence after intended curative surgery for primary colorectal cancer. METHODS: Systematic literature searches were performed in PubMed, EMBASE and Cochrane databases, and articles were chosen based on predefined inclusion criteria. Reference lists from included articles were manually searched for additional publications of relevance. RESULTS: Forty-two original studies with generally representative populations and long follow-up were included. Data were reported on outcomes from 9,834 CEA tests during follow-up. Reporting on the reference standards used was not optimal. Sensitivity of CEA ranged from 17.4 % to 100 %, specificity ranged from 66.1 % to 98.4 %, positive predictive value ranged from 45.8 % to 95.2% and negative predictive value ranged from 74.5 % to 100 %. CONCLUSION: Results point toward a sensitivity of CEA ranging between 50 % and 80 %, and a specificity and negative predictive value above 80 %. Results on positive predictive value showed low reliability. Overall, CEA did not effectively detect treatable recurrences at an early stage, and a clinically relevant effect on patient mortality remains to be proven.

Random regret-based discrete-choice modelling: an application to healthcare.

BACKGROUND: A new modelling approach for analysing data from discrete-choice experiments (DCEs) has been recently developed in transport economics based on the notion of regret minimization-driven choice behaviour. This so-called Random Regret Minimization (RRM) approach forms an alternative to the dominant Random Utility Maximization (RUM) approach. The RRM approach is able to model semi-compensatory choice behaviour and compromise effects, while being as parsimonious and formally tractable as the RUM approach. OBJECTIVES: Our objectives were to introduce the RRM modelling approach to healthcare-related decisions, and to investigate its usefulness in this domain. METHODS: Using data from DCEs aimed at determining valuations of attributes of osteoporosis drug treatments and human papillomavirus (HPV) vaccinations, we empirically compared RRM models, RUM models and Hybrid RUM-RRM models in terms of goodness of fit, parameter ratios and predicted choice probabilities. RESULTS: In terms of model fit, the RRM model did not outperform the RUM model significantly in the case of the osteoporosis DCE data (p = 0.21), whereas in the case of the HPV DCE data, the Hybrid RUM-RRM model outperformed the RUM model (p < 0.05). Differences in predicted choice probabilities between RUM models and (Hybrid RUM-) RRM models were small. Derived parameter ratios did not differ significantly between model types, but trade-offs between attributes implied by the two models can vary substantially. CONCLUSION: Differences in model fit between RUM, RRM and Hybrid RUM-RRM were found to be small. Although our study did not show significant differences in parameter ratios, the RRM and Hybrid RUM-RRM models did feature considerable differences in terms of the trade-offs implied by these ratios. In combination, our results suggest that RRM and Hybrid RUM-RRM modelling approach hold the potential of offering new and policy-relevant insights for health researchers and policy makers.

Lymphocyte homing in xenotransplanted human thyroid tissue can be inhibited by LFA-1 and ICAM-1 antibodies.

OBJECTIVES: Homing of lymphocytes is an important factor with respect to the initiation of the autoimmune process in Graves' disease (GD). As previously shown, human lymphocytes, particularly of intrathyroidal origin, derived from patients with GD, are able to migrate into normal xenotransplanted thyroid tissue and induce functional and histological changes. The aim of this study was to investigate the effect of LFA-1 and ICAM-1 antibodies on the homing of lymphocytes of different origin into xenografted human thyroid tissue. METHODS: Eighty-five nude mice bearing 8-week-old xenografts of normal human thyroid tissue were treated twice with anti-CD 54 (anti-ICAM-1), anti-CD 11a (anti-LFA-1), a combination of both, or, serving as controls, iso-antibodies without specific binding capacity or saline. Thereafter, intrathyroidal (ITL) or peripheral blood lymphocytes (PBL) obtained from 4 patients with GD or saline were injected into the animals (i.v., 0.2 mL, 10(6) cells). After 48 hours the mice were sacrificed and transplants as well as mice thyroids were examined by immunohistochemical staining with Ki67, CD3, HLA-II (DAKO, Hamburg), IgG, CD44, ICAM-1, and VCAM-1 (Immunotech, Hamburg). RESULTS: Pretreatment with anti-ICAM-1 and anti-LFA-1 decreased lymphocyte homing (CD3-staining), and expression of HLA-II, IgG, CD44, and VCAM-1 in the transplants. CONCLUSION: Our data show that [ICAM-1/LFA-1 stimulated (induced)] lymphocyte homing and subsequently thyrocyte proliferation are inhibited by ICAM-1 and LFA-1 antibodies in xenotransplanted thyroid tissue. This suggests that ICAM1 and LFA-1 play an important role in the early steps of autoimmune thyroid disease. The inhibition/suppression of ICAM-1 and LFA-1 interaction by respective antibodies, as demonstrated in the present study, may provide a new concept for prophylaxis and therapy.

Expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and homing factor CD44 after engraftment of Graves' lymphocytes in xenotransplanted human thyroid tissue in athymic nude mice.

The expression of adhesion molecules on thyrocytes and endothelium cells plays an important role in the pathogenesis of Graves' disease (GD). The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1), and the homing receptor CD44 are responsible for the specific migration of lymphocytes in autoimmune thyroid diseases (AITD) (homing). Eight weeks after transplantation of thyroid tissue from 26 patients with nonautoimmune thyroid disease (nontoxic nodular goiter [NTG]) into nude mice, peripheral (PBL) and intrathyroidal lymphocytes (ITL) from 14 patients with NTG and 12 patients with GD were grafted into the animals. Two days after lymphocyte engraftment, the thyroid transplants were examined histologically (HE) and immunohistologically stained with monoclonal antibodies directed against ICAM-1, VCAM-1, and CD44. After injection of GD lymphocytes, thyroid transplants expressed significantly more ICAM-1, VCAM-1, and CD44 than after injection of NTG lymphocytes. This expression was even more pronounced after grafting of GD intrathyroidal lymphocytes. Our data demonstrate that only GD lymphocytes induce the expression of adhesion molecules and homing factor CD44, both of which play an important role in the migration of lymphocytes and induction of the autoimmune process.

In vivo microscopy of murine islets of Langerhans: increased adhesion of transferred lymphocytes to islets depends on macrophage-derived cytokines in a model of organ-specific insulitis.

Environmental factors contribute to the pathogenesis of type 1 diabetes (insulin-dependent diabetes mellitus). Multiple low doses of streptozotocin (MLDS) induce hyperglycaemia and insulitis in mice. Previously we demonstrated that adhesion of lymphocytes to endothelium of islets is only increased when donor animals were diabetic and recipient mice had received 5 mg/kg streptozotocin (STZ). Therefore we used streptozotocin to evaluate the immunological relevance of such an irritation of islets. Lymphocytes, separated from diabetic mice (MLDS), were fluorescently labelled and injected to recipient mice that had received 5 mg/kg STZ. With in vivo microscopy we measured lymphocyte flow and adherence in islets. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in the pancreas was assessed using immunohistochemistry. Very late antigen-4 (VLA-4) and leucocyte function-associated antigen-1 (LFA-1) expression on transferred lymphocytes was measured with flow cytometry. Pretreatment of recipients with antibodies to cytokines or silica reduced lymphocyte adherence to islet endothelium from 2.04% (goat immunoglobulin G; IgG) or 1.82% (rat IgG) to 0.47, 0.58, 0.39 or 0. 19% for monoclonal antibody (mAb) interferon-gamma (IFN-gamma), polyclonal antibody (pAb) tumour necrosis factor-alpha (TNF-alpha), pAb interleukin (IL)-1alpha or silica, respectively. Reduced adhesion was associated with a decreased expression of VCAM-1 and ICAM-1 in islets of treated recipients compared with mice treated with 5 mg/kg STZ alone. In conclusion, pretreatment of recipients with 5 mg/kg STZ leads to an increased expression of adhesion molecules in the islets and lymphocyte adhesion to islet endothelium in vivo, demonstrating an immune response of the islets. Prevention of increased expression of ICAM-1 or VCAM-1 and reduction of lymphocyte adhesion in islets by silica or antibody indicate an involvement of macrophages and macrophage derived cytokines in the generation of this immune response.

Immunologic effects of human peripheral and intrathyroidal lymphocytes on xenotransplanted human thyroid tissue in athymic nude mice.

T cells are intimately involved in the etiology and pathogenesis of human autoimmune thyroid disease. In order to further elucidate the immunologic mechanisms leading to Graves' disease (GD), we investigated the effects of human lymphocytes derived from patients with autoimmune and nonautoimmune thyroid diseases on human thyroid tissue xenotransplanted into nude mice. Eight weeks after transplantation of thyroid tissue from 26 patients with nonautoimmune thyroid disease (nontoxic nodular goiter [NTG]) into nude mice, peripheral (PBL) and intrathyroidal lymphocytes (ITL) from 14 patients with NTG and 12 patients with GD were engrafted into the animals. ITL and PBL subsets were analyzed by flow cytometer before engraftment. Two days after lymphocyte engraftment, the thyroid transplants were examined histologically (HE) as well as immunohistologically by staining with monoclonal antibodies directed against CD3 (T-cell activation and signal transduction), immunoglobulin G (IgG), HLA class II and CD31 (human endothelium). After injection of GD lymphocytes, thyroid transplants contained significantly more CD3, HLA class II, and CD4 expressing cells. Engrafted PBL and especially ITL from patients with GD specifically migrated into human thyroid transplants but not into the mouse thyroids, induced expression of class II products and led to IgG production by plasma cells. Persistence of human endothelium has been proven by positive CD31 staining. In conclusion, our data demonstrate that an organ-specific immune response is induced only by GD lymphocytes that migrate specifically into the thyroid transplants. Persistence of human endothelial cells in the transplants suggests that homing in this in vivo model reflects the situation in GD patients.

Effect of Graves' intrathyroidal lymphocytes. Effect of Graves' disease intrathyroidal lymphocytes (ITL) on xenotransplants of human thyroid tissue in athymic nude mice.

It has been suggested that ITL are of importance in the pathogenesis of human autoimmune thyroid disease. Aim of our study was to investigate function and morphology of xenotransplanted human thyroid tissue in nude mice following systemic application of lymphocyte preparations from patients with Graves' disease (GD) and non-toxic nodular goiter (NTG). ITL obtained from 13 patients with GD and peripheral blood lymphocytes (PBL) from 12 patients with NTG were injected into nude mice bearing 8 weeks old xenografts of normal human thyroid tissue. ITL- and PBL-subsets were analyzed by flow cytometer (FACScan) before engraftment. Two days after injection the thyroid transplants were examined histologically (HE) as well as immunohistologically by staining with: CD3, CD31, CD45R, HLA class II, ICAM-1, VCAM-1, IgG, IgM and Ki67. Flow cytometry showed a significant higher number of the lymphocyte-subsets CD3, DR+ and CD4 in GD-ITL as compared to the subsets in NTG-ITL. After injection of GD-ITL to the nude mice also a significant higher number of CD3+ human lymphocytes was found in the transplants. GD-lymphocytes stimulated thyroid tissue function significantly more pronounced than NTG-lymphocytes (histomorphological evaluation). In addition, a significant increase of HLA-class II, ICAM-1-, VCAM-1-, CD45-expression and number of Ig presenting plasma cells were observed only after injection of GD-ITL. Our data demonstrate, for the first time in vivo (nude mouse model), that GD-lymphocytes of both peripheral and intrathyroidal origin selectively migrate into human thyroid transplants ("homing"). They survive there for at least two days and induce significant functional as well as histological changes, like expression of gene products and IgG synthesis. These results suggest an important role of ITL in the pathogenetic mechanisms and clinical course of GD.

[Spontaneous Hashimoto-like thyroiditis in cats]. / Spontane Hashimoto-artige Thyreoiditis im Modell der Katze.

A breeding line of domestic cats spontaneously developing symptoms of hypothyroidism between the 40th and 60th day of life (fur changes, loss of appetite, growth retardation), elevated levels of antibodies against microsomal structures and thyroglobulin, and lymphocytic thyroid infiltration has been recently established at our facility. Aim of our studies was to examine the effect of high iodine ingestion or prophylactic thyroid hormone therapy on functional and morphological characteristics of this Hashimoto-like thyroiditis in cat. From birth to day 80 of life cats were treated with iodine (n = 9; 0.1 mg/l) or thyroxin (n = 13; 2.0 micrograms/ kg/d) respectively. Untreated animals served as controls (n = 12). Cat-serum was tested for thyroid function (TT3, TT4). After 8 weeks the thyroid tissue was submitted to routine histological processing (H&E) and the inflammatory activity was scored. Additionally immunohistological staining was performed for MIB-1, IgG, IgM and MHCII expression. Both untreated hypothyroid (UHC) as well as iodine-treated (IC) cats revealed a significantly higher degree of thyroid inflammation and higher tissue levels of IgM as the thyroxin-substituted animals (TC). Epithelial proliferation decreased significantly in the IC and TC groups as compared to the untreated controls. No significant differences regarding IgG production and HLAII expression were detectable. Early thyroid hormone therapy significantly decreases both incidence and activity of autoimmune thyroiditis in cats as measured by inflammatory infiltration, IgM production and epithelial proliferation. Animals with excess iodide intake, however, show an aggravation of the autoimmune inflammatory activity.

[Effect of intrathyroidal lymphocytes of Graves' disease patients on xenograft thyroid tissue in the athymic nude mouse]. / Einfluss intrathyreoidaler Lymphozyten von Basedow-Patienten auf xenotransplantiertes Schilddrüsengewebe in der thymusaplastischen Nacktmaus.

In this study we investigated the functional and morphological properties of xenotransplanted human thyroid tissue in nude mice following systemic application of intrathyroidal lymphocyte preparations from patients with Graves' disease (GD) and non-toxic nodular goiter (NTG). Thyroid tissue samples from 17 NTG-patients were transplanted into athymic nude mice for a period of 4-5 weeks. Aliquots of lymphocyte preparations from both peripheral blood samples (PBL) and thyroid tissue (ITL) of 13 patients with GD and 12 patients with NTG were analyzed by flow-cytometry (CD3, CD4, CD8, CD56) and injected (i.v.) into transplanted nude mice. Animals injected with saline solution served as a control. After 48 h transplants were harvested and histological (H&E) as well as immunohistological evaluation was performed (MHCII, IgG, IgM). Control animals and mice treated with both PBL and ITL from NTG patients showed regular thyroid tissue without lymphocytic infiltrates or local expression of human immunoglobulins. Application of PBL and ITL of GD patients caused scant to moderate lymphocytic infiltrates with detection of human immunoglobulin production. Injection of GD-ITL was accompanied by a significantly higher proportion of intrathyroidal CD3+ lymphocytes and MHCII expression of adjacent thyroid epithelium as compared to injection of GD-PBL preparations. Our results demonstrate that GD-lymphocytes of both peripheral but especially intrathyroidal origin migrate specifically to human thyroid transplants in the nude mouse model, survive for at least two days, secrete immunoglobulins and induce MHCII expression.