Metabolic syndrome in Spanish patients with psoriasis needing systemic therapy: Prevalence and association with cardiovascular disease in PSO-RISK, a cross-sectional study

Background: Increasing evidence indicates a relationship between psoriasis and metabolic syndrome (MS). We evaluated the prevalence of MS in patients receiving systemic treatment for psoriasis in Spain, and its relationship to cardiovascular disease (CVD). Methods: This cross-sectional, multicenter, non-interventional study enrolled 368 patients with moderate-to-severe psoriasis requiring systemic treatment. Clinical parameters for psoriasis, CV risk factors, MS and CVD were assessed. Descriptive and logistic regression analyses were performed. Results: 352 patients were included (median psoriasis duration: 18 years, plaque psoriasis [95.7%], psoriatic arthritis [22.8%]). Overall, 132 patients (37.5%) fulfilled diagnostic criteria for MS; the most prevalent MS components were high blood pressure and increased waist circumference. Patients with MS were older, more likely to be obese and to have a sedentary lifestyle and hypercholesterolemia than those without MS. CVD was more prevalent in patients with MS than in those without (29.5% versus 15.9%, p = 0.002), particularly coronary heart disease (CHD), myocardial infarction and heart failure. MS was independently associated with CVD (OR 1.98, p = 0.018) and CHD (OR 2.02, p = 0.044). Conclusion: The prevalence of MS was high among patients with moderate-to-severe psoriasis requiring systemic treatment, and was associated with a higher prevalence of CVD. Dermatologists should consider implementing simple screening protocols

The Prometastatic Microenvironment of the Liver

The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients

Social mobility and healthy behaviours from a gender perspective in the Spanish multicase-control study (MCC-Spain)

[EN] There is evidence for the influence of socioeconomic status (SES) on healthy behaviours but the effect of social mobility (SM) is not yet well known. This study aims to analyse the influence of origin and destination SES (O-SES and D-SES) and SM on healthy behaviours and co-occurrence, from an integrated gender and age perspective. Data were obtained from the controls of MCC-Spain between 2008–2013 (3,606 participants). Healthy behaviours considered: healthy diet, moderate alcohol consumption, non-smoking and physical activity. SM was categorized as stable high, upward, stable medium, downward or stable low. Binary and multinomial logistic regression models were adjusted. Those aged <65, with a low O-SES, D-SES and stable low SM are less likely to have healthy behaviours in the case of both women (physically active: OR = 0.65 CI = 0.45–0.94, OR = 0.71 CI = 0.52–0.98, OR = 0.61 CI = 0.41–0.91) and men (non-smokers: OR = 0.44 CI = 0.26–0.76, OR = 0.54 CI = 0.35–0.83, OR = 0.41 CI 0.24–0.72; physically active: OR = 0.57 CI = 0.35–0.92, OR = 0.64 CI = 0.44–0.95, OR = 0.53 CI = 0.23–0.87). However, for those aged ≥65, this probability is higher in women with a low O-SES and D-SES (non-smoker: OR = 8.09 CI = 4.18–15.67, OR = 4.14 CI = 2.28–7.52; moderate alcohol consumption: OR = 3.00 CI = 1.45–6.24, OR = 2.83 CI = 1.49–5.37) and in men with a stable low SM (physically active: OR = 1.52 CI = 1.02–1.26). In the case of men, the same behaviour pattern is observed in those with a low O-SES as those with upward mobility, with a higher probability of co-occurring behaviours (three-to-four behaviours: OR = 2.00 CI = 1.22–3.29; OR = 3.13 CI = 1.31–7.48). The relationship of O-SES, D-SES and SM with healthy behaviours is complex and differs according to age and gender.S

International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

BACKGROUND: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies

Parametric POMDPs for planning in continuous state spaces

This thesis is concerned with planning and acting under uncertainty in partially-observable continuous domains. In particular, it focusses on the problem of mobile robot navigation given a known map. The dominant paradigm for robot localisation is to use Bayesian estimation to maintain a probability distribution over possible robot poses. In contrast, control algorithms often base their decisions on the assumption that a single state, such as the mode of this distribution, is correct. In scenarios involving significant uncertainty, this can lead to serious control errors. It is generally agreed that the reliability of navigation in uncertain environments would be greatly improved by the ability to consider the entire distribution when acting, rather than the single most likely state. The framework adopted in this thesis for modelling navigation problems mathematically is the Partially Observable Markov Decision Process (POMDP). An exact solution to a POMDP problem provides the optimal balance between reward-seeking behaviour and information-seeking behaviour, in the presence of sensor and actuation noise. Unfortunately, previous exact and approximate solution methods have had difficulty scaling to real applications. The contribution of this thesis is the formulation of an approach to planning in the space of continuous parameterised approximations to probability distributions. Theoretical and practical results are presented which show that, when compared with similar methods from the literature, this approach is capable of scaling to larger and more realistic problems. In order to apply the solution algorithm to real-world problems, a number of novel improvements are proposed. Specifically, Monte Carlo methods are employed to estimate distributions over future parameterised beliefs, improving planning accuracy without a loss of efficiency. Conditional independence assumptions are exploited to simplify the problem, reducing computational requirements. Scalability is further increased by focussing computation on likely beliefs, using metric indexing structures for efficient function approximation. Local online planning is incorporated to assist global offline planning, allowing the precision of the latter to be decreased without adversely affecting solution quality. Finally, the algorithm is implemented and demonstrated during real-time control of a mobile robot in a challenging navigation task. We argue that this task is substantially more challenging and realistic than previous problems to which POMDP solution methods have been applied. Results show that POMDP planning, which considers the evolution of the entire probability distribution over robot poses, produces significantly more robust behaviour when compared with a heuristic planner which considers only the most likely states and outcomes

Distinct Effects of IL-18 on the Engraftment and Function of Human Effector CD8+ T Cells and Regulatory T Cells

IL-18 has pleotropic effects on the activation of T cells during antigen presentation. We investigated the effects of human IL-18 on the engraftment and function of human T cell subsets in xenograft mouse models. IL-18 enhanced the engraftment of human CD8+ effector T cells and promoted the development of xenogeneic graft versus host disease (GVHD). In marked contrast, IL-18 had reciprocal effects on the engraftment of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the xenografted mice. Adoptive transfer experiments indicated that IL-18 prevented the suppressive effects of Tregs on the development of xenogeneic GVHD. The IL-18 results were robust as they were observed in two different mouse strains. In addition, the effects of IL-18 were systemic as IL-18 promoted engraftment and persistence of human effector T cells and decreased Tregs in peripheral blood, peritoneal cavity, spleen and liver. In vitro experiments indicated that the expression of the IL-18Rα was induced on both CD4 and CD8 effector T cells and Tregs, and that the duration of expression was less sustained on Tregs. These preclinical data suggest that human IL-18 may have use as an adjuvant for immune reconstitution after cytotoxic therapies, and to augment adoptive immunotherapy, donor leukocyte infusions, and vaccine strategies

SARS-CoV-2 Delta-variant breakthrough infections in nursing home residents at midterm after Comirnaty® COVID-19 vaccination

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Delta variant break-through infections in nursing home residents following vaccination with Comirnaty®COVID‐19 vaccine were characterized. In total, 201 participants (median age, 87 years;range, 64–100; 133 female) from two nursing homes in the Valencian community (Spain)were included. SARS‐CoV‐2‐Spike (S) antibody responses were determined by a lateralflow immunocromatography (LFIC) assay and by quantitative electrochemiluminescentassay in LFIC‐negative participants. SARS‐CoV‐2‐S‐IFNγT cells were enumerated by flowcytometry in 10 participants. Nasopharyngeal SARS‐CoV‐2 RNA loads were quantified byreal‐time polymerase chain reaction assays. Vaccine breakthrough COVID‐19 due to theDelta variant occurred in 39 residents (median age, 87 years; range, 69–96; 31 female) ata median of 6.5 months after vaccination (nine requiring hospitalization). Breakthroughinfections occurred at a higher rate(p< 0.0001) in residents who had not been previouslyinfected with SARS‐CoV‐2 (naïve) (33/108; 18%) than in those with prior diagnosis ofSARS‐CoV‐2 infection (experienced) (6/93; 6.4%), and were more likely (p< 0.0001) todevelop in residents who tested negative by LFIC (20/49) at 3 months after vaccinationas compared to their LFIC‐positive counterparts (19/142). Among LFIC‐negativeresidents, a trend towards lower plasma anti‐RBD antibody levels was noticed in thosedeveloping breakthrough infection (p=0.16).SARS‐CoV‐2 RNA loads in nasopharyngealspecimens were lower in SARS‐CoV‐2‐experienced residents (p< 0.001) and in thosetesting positive by LFIC (p=0.13). The frequency of SARS‐CoV‐2‐S‐reactive T cells at3monthswassimilarinLFIC‐negative residents with (n=7) or without (n=3)breakthrough infection. Prior history of SARS‐CoV‐2 infection and detection ofS‐reactive antibodies by LFIC at 3 months is associated with a lower risk of Delta‐variant breakthrough infection in nursing home residents at midterm after Comirnaty®COVID‐19 vaccination.We are grateful to the Vice‐presidency and Ministry of Equality andInclusive Policies of the Valencia Community, the Corporate Associationof Residences and Services for People with Dependency of the ValencianCommunity (AERTE), the Valencia Health System nursing homedepartmental committees, and the staff and residents of the participantnursing homes for their collaboration in developing the ProVaVacprogram. We would also like to thank Ana Berenguer, General Directorof Analysis and Public Policies of the Presidency of the Generalitat.Ignacio Torres (Río Hortega Contract; CM20/00090) and Eliseo Albert(Juan Rodés Contract; JR20/00011) hold contracts funded by the HealthInstitute Carlos III (co‐financed by the European Regional DevelopmentFund, ERDF/FEDER). This study received no public or private funds.Peer reviewe