Moral reasoning, moral decision-making, and empathy in Korsakoff's syndrome

Korsakoff's syndrome (KS) is a neuropsychiatric disorder, caused by a vitamin B1 deficiency. Although it is known that patients with KS display diminished theory of mind functioning and frequently exhibit marked antisocial interactions little attention has so far focused on the integrity of moral decision-making abilities, moral reasoning, and empathy. In an experimental cross-sectional design, 20 patients diagnosed with KS, and twenty age-, education-, and gender-equivalent healthy participants performed tests assessing moral decision-making, moral reasoning maturity, empathy, and executive functioning. Participants were administered the Moral Behaviour Inventory (MBI) for everyday moral dilemmas, and ten cartoons of abstract moral dilemmas. Responses were scored according to the Kohlberg stages of moral reasoning. Empathy and executive functioning were assessed with the Interpersonal Reactivity Index (IRI) and the Frontal Assessment Battery (FAB). In contrast to frontal traumatic brain injury patients, KS patients did not display a utilitarian bias, suggesting preserved moral decision-making abilities. Of interest, KS patients had significantly lower levels of moral reasoning maturity on everyday moral dilemmas, and abstract moral dilemmas. In patients, empathy was moderately related to the level of moral maturity on both tasks, while executive functioning was not. In conclusion, KS patients have preserved moral decision-making abilities, but their moral reasoning abilities are poorer in everyday and abstract situations. Lower moral reasoning abilities and lower levels of empathy together may be responsible for adverse social functioning in KS

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

Background Primary and secondary resistance is a major hurdle in cancer immunotherapy. Therefore, a better understanding of the underlying mechanisms involved in immunotherapy resistance is of pivotal importance to improve therapy outcome.Method Here, two mouse models with resistance against therapeutic vaccine-induced tumor regression were studied. Exploration of the tumor microenvironment by high dimensional flow cytometry in combination with therapeutic in vivo settings allowed for the identification of immunological factors driving immunotherapy resistance.Results Comparison of the tumor immune infiltrate during early and late regression revealed a change from tumor-rejecting toward tumor-promoting macrophages. In concert, a rapid exhaustion of tumor-infiltrating T cells was observed. Perturbation studies identified a small but discernible CD163hi macrophage population, with high expression of several tumor-promoting macrophage markers and a functional anti-inflammatory transcriptome profile, but not other macrophages, to be responsible. In-depth analyses revealed that they localize at the tumor invasive margins and are more resistant to Csf1r inhibition when compared with other macrophages. In vivo studies validated the activity of heme oxygenase-1 as an underlying mechanism of immunotherapy resistance. The transcriptomic profile of CD163hi macrophages is highly similar to a human monocyte/macrophage population, indicating that they represent a target to improve immunotherapy efficacy.Conclusions In this study, a small population of CD163hi tissue-resident macrophages is identified to be responsible for primary and secondary resistance against T-cell-based immunotherapies. While these CD163hi M2 macrophages are resistant to Csf1r-targeted therapies, in-depth characterization and identification of the underlying mechanisms driving immunotherapy resistance allows the specific targeting of this subset of macrophages, thereby creating new opportunities for therapeutic intervention with the aim to overcome immunotherapy resistance

Moral reasoning, moral decision-making, and empathy in Korsakoff's syndrome

Korsakoff's syndrome (KS) is a neuropsychiatric disorder, caused by a vitamin B1 deficiency. Although it is known that patients with KS display diminished theory of mind functioning and frequently exhibit marked antisocial interactions little attention has so far focused on the integrity of moral decision-making abilities, moral reasoning, and empathy. In an experimental cross-sectional design, 20 patients diagnosed with KS, and twenty age-, education-, and gender-equivalent healthy participants performed tests assessing moral decision-making, moral reasoning maturity, empathy, and executive functioning. Participants were administered the Moral Behaviour Inventory (MBI) for everyday moral dilemmas, and ten cartoons of abstract moral dilemmas. Responses were scored according to the Kohlberg stages of moral reasoning. Empathy and executive functioning were assessed with the Interpersonal Reactivity Index (IRI) and the Frontal Assessment Battery (FAB). In contrast to frontal traumatic brain injury patients, KS patients did not display a utilitarian bias, suggesting preserved moral decision-making abilities. Of interest, KS patients had significantly lower levels of moral reasoning maturity on everyday moral dilemmas, and abstract moral dilemmas. In patients, empathy was moderately related to the level of moral maturity on both tasks, while executive functioning was not. In conclusion, KS patients have preserved moral decision-making abilities, but their moral reasoning abilities are poorer in everyday and abstract situations. Lower moral reasoning abilities and lower levels of empathy together may be responsible for adverse social functioning in KS

Migration background and COVID-19 related intensive care unit admission and mortality in the Netherlands: A cohort study.

BackgroundSince the beginning of the SARS-CoV-2 pandemic, studies have been reporting inconsistently on migration background as a risk factor for COVID-19 outcomes. The aim of this study was to evaluate the association between migration background and clinical outcomes with COVID-19 in the Netherlands.MethodsThis cohort study included 2,229 adult COVID-19 patients admitted in two Dutch hospitals between February 27, 2020 and March 31, 2021. Odds ratios (ORs) for hospital admission, intensive care unit (ICU) admission and mortality with 95% confidence intervals (CIs) were calculated for non-Western (Moroccan, Turkish, Surinamese or other) persons as compared with Western persons in the general population of the province of Utrecht (the Netherlands) as source population. Furthermore, among hospitalized patients, Hazard ratios (HRs) with 95% CIs for in-hospital mortality and intensive care unit (ICU) admission were calculated using Cox proportional hazard analyses. Hazard ratios were adjusted for age, sex, body mass index, hypertension, Charlson Comorbidity Index, chronic corticosteroid use before admission, income, education and population density to investigate explanatory variables.ResultsOf the 2,229 subjects, 1,707 were of Western origin and 522 were of non-Western origin. There were 313 in-hospital deaths and 503 ICU admissions. As compared with persons with a Western origin in the general population of the province of Utrecht, the ORs for non-Western persons was 1.8 (95% CI 1.7-2.0) for hospitalization, 2.1 (95% CI 1.7-2.5) for ICU admission and 1.3 (95% CI 1.0-1.7) for mortality. Among hospitalized patients, HR for ICU admission was 1.1 (95% CI 0.9-1.4) and 0.9 (95% CI 0.7-1.3) for mortality for non-Western hospitalized persons as compared with hospitalized patients of Western origin after adjustment.ConclusionNon-Western persons, including Moroccan, Turkish and Surinamese subjects, had increased risks of hospital admission, ICU admission and COVID-19 related death on a population level. Among hospitalized COVID-19 patients, no association was found between migration background and ICU admission or mortality

Preinduced reovirus-specific T-cell immunity enhances the anticancer efficacy of reovirus therapy

BACKGROUND: Many solid tumors do not respond to immunotherapy due to their immunologically cold tumor microenvironment (TME). We and others found that oncolytic viruses (OVs), including reovirus type 3 Dearing, can enhance the efficacy of immunotherapy by recruiting CD8+ T cells to the TME. A significant part of the incoming CD8+ T cells is directed toward reovirus itself, which may be detrimental to the efficacy of OVs. However, here we aim to exploit these incoming virus-specific T cells as anticancer effector cells. METHODS: We performed an in-depth characterization of the reovirus-induced T-cell response in immune-competent mice bearing pancreatic KPC3 tumors. The immunodominant CD8+ T-cell epitope of reovirus was identified using epitope prediction algorithms and peptide arrays, and the quantity and quality of reovirus-specific T cells after reovirus administration were assessed using high-dimensional flow cytometry. A synthetic long peptide (SLP)-based vaccination strategy was designed to enhance the intratumoral frequency of reovirus-specific CD8+ T cells. RESULTS: Reovirus administration did not induce tumor-specific T cells but rather induced high frequencies of reovirus-specific CD8+ T cells directed to the immunodominant epitope. Priming of reovirus-specific T cells required a low-frequent population of cross-presenting dendritic cells which was absent in Batf3-/- mice. While intratumoral and intravenous reovirus administration induced equal systemic frequencies of reovirus-specific T cells, reovirus-specific T cells were highly enriched in the TME exclusively after intratumoral administration. Here, they displayed characteristics of potent effector cells with high expression of KLRG1, suggesting they may be responsive against local reovirus-infected cells. To exploit these reovirus-specific T cells as anticancer effector cells, we designed an SLP-based vaccination strategy to induce a strong T-cell response before virotherapy. These high frequencies of circulating reovirus-specific T cells were reactivated on intratumoral reovirus administration and significantly delayed tumor growth. CONCLUSIONS: These findings provide proof of concept that OV-specific T cells, despite not being tumor-specific, can be exploited as potent effector cells for anticancer treatment when primed before virotherapy. This is an attractive strategy for low-immunogenic tumors lacking tumor-specific T cells