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Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.

The air temperature and relative humidity inside refrigerated containers should be kept at optimal conditions to prevent fruit losses. However, each shipment evolves differently in terms of shipping duration and temperature. Moreover, due to the dense stacking of the pallets, non-uniform hygrothermal conditions develop throughout the cargo. Currently, little is known about the fruit quality evolution inside containers, inhibiting proper product management and causing fruit losses to occur. The goal of this study is to identify where and when fruit quality is lost during overseas transport. More specifically, it is aimed to pinpoint where quality issues are expected to occur: consistently on a specific location within the cargo, or only within certain shipments.To achieve this goal, a digital twin was developed of a refrigerated container filled with ‘Valencia’ oranges. This digital twin consisted of a multiphysics model in which airflow, heat, and moisture transport were calculated. Moreover, different fruit quality attributes were predicted. Supply air temperature sensor data of shipments from South Africa to Europe and Asia, as well as the fruit packaging type, were fed to the digital twin. Except for mass loss, the results showed limited quality gradients within the container. Also, when shifting the packaging type, the average quality of the cargo did not change significantly. In contrast to the limited intra-container quality heterogeneity, significant inter-container differences were observed. This indicates the added value of monitoring each shipment. Overall, the digital twin serves as a first step towards real-time quality monitoring within fresh fruit supply chains.

Teesid: Artiklis kirjeldatakse, kuidas on võimalik kogeda ontoloogilist diferentsi – oleva suhtes täiesti teist. Säärane ontoloogiline kogemus leiab siinse arutluse kohaselt aset negatiivsuse, ei(miski) kogemises, mis omakorda seisneb tähendusloome luhtumises olulisimate üldisemate probleemide puhul ning sellega kaasnevas negatiivses häälestuses. Ontoloogilise diferentsi kogemine leiab aset afektiivsel väljal, häälestustes, mis toimivad üldjuhul intentsionaalsete aktide taustal horisondina, kuid muutuvad erilistel puhkudel keskseks, halvates sujuva kogemuse, muutes tähenduslikkuse tõrke sedavõrd intensiivseks, et negatiivne häälestus haarab kogeja läbinisti enda võimusesse. The aim of the article is to describe how it is possible to experience an ontological difference —i.e. something completely different from all beings. Such an ontological experience, the author argues, takes place in the experience of negativity, of nothingness, which in turn consists in the failure of meaning-making in the most important general problems and the negative attunements (Stimmung) that accompanies it. Thus, the experience of ontological difference takes place in the affective field. Experiences of this kind have been analysed to some extent in the light of Martin Heidegger’s thought. The originality of this article lies in its attempt to describe the experience of ontological difference in the vocabulary of classic, Husserl-inspired phenomenology. According to the mainstream interpretation, Heidegger’s ontological radicalism abandons the original idea of phenomenology to remain within the boundaries of things themselves (i.e. given to consciousness as intentional objects). This interpretation is also deepened by Heidegger’s post-turning renunciation of the description of his own thinking as phenomenology. Inspired mainly by Husserl (and often also by the sections of Heidegger’s Being and Time devoted to everyday experience), contemporary phenomenology analyses all kinds of phenomena and spheres of subjectivity given to everyday experience, leaving nothingness, ontological difference, etc. as a mystical-paradoxical remnant about which nothing can be said. In the first chapter of the article, ‘The Radical Failure of Significance in the Clash of Horizons’, ontological experience is reconstructed in terms of the concept of the horizon. Already in his late phenomenology of the lifeworld, Husserl pays considerable attention to the horizonal construction of experience. Horizons in experience are either not given intentionally at all or have a weak, background intentionality. It is true that in ordinary perceptions it is possible to transform the horizon into a full-blooded intentional object. However, according to the discussion here, this is not the case for special boundary horizons, for general horizons that maintain the overall coherence of meaning-making, e.g. world, death, infinity. The urge for meaningful fulfilment inherent in consciousness in general (and philosophy in particular) tries to thematise these too, but unsuccessfully, incompletely. While there is much that is horizontally non-intentional in the simple acts of meaning-making, all the parts play together to produce meaning. In the case of a negative boundary experience, it is the failure that becomes the central seized sense (Auffassungssinn), rather than—which is amplified in the absence of meaningful content, in the case of empty intentionality—the attunement. This is the focus of the second chapter of the article, “Ontological Experience in Negative Attunements”. The chapter begins by discussing the question of the intentionality of attunements, and, following Husserl, arrives at the premise that attunements thus constitute a horizon of emotionality and have an ambiguous intentionality inherent in the horizon. As a horizon, attunement not only organises the general palette of conscious sensations, but also ‘colours’ the experience of all objects, even the world as a universal horizon of all experience. In the ontological experience, only a few particular negative attunements, which, using the vocabulary of existentialism, can also be called marginal experiences, are present. In the case of these strange, frightening (unheimlich) states, the affective horizon intrudes, so to speak buries the person under itself, but not in the manner of an emotion (together with the intentional object in relation to which the emotion is felt), but in a non-objective way, without any apparent cause, thus creating—as in the reflection on the universal horizons discussed above—a total repulsion in the movement from object to object. Such an experience also dispels self-consciousness. Regarding the relationship between the themes explored in the two chapters, the article argues that, while it seems that creative activity (including philosophy) inspired by the fundamental problems of a strained ontology, clashing with so-called universal horizons, is often accompanied by a persistent negative attunement, so that the creative person falls out of everyday life, the causal links between these phenomena remain open. The specificity of the human being does not lie in the mere operation of linguistic meanings, but in the fact that it is inherent to him/her to philosophise: to push towards the most important horizons of experience and to experience in relation to them the failure of the creation of meaning, to experience the ontological differentiation of not-ness. Here, the article remains in the position of the phenomenological epoché: it is not possible to know that such a mode of not-ness is something proper (Ereignis), as Heidegger implies throughout. However, the derivation of such experiences from the valorisation of language, as naturalists and pragmatists proclaim, remains equally unproven. It remains the task of phenomenology to bear the human incongruity, to remain—to paraphrase Husserl’s famous slogan—directed towards the things themselves (zu den Sachen selbst).

We build a validated physics-based model of a refrigerated container filled with fruit in ventilated packaging. This model of a virtual container is the basis for simulations in an accompanying paper on citrus fruit shipped overseas from South Africa to Europe. The model is used to understand better how the cargo cools and when and where food quality is lost in these supply chains. We build a computational fluid dynamics model with a two-phase porous media approach that simulates the airflow in the container and the cooling process of every fruit. This container can be considered aerodynamically to be a slot-ventilated enclosure. We also model the fruit's thermally-driven quality loss. Using a two-phase porous media approach for the ventilated cargo and modeling temperature-driven fruit quality evolution are two steps forward compared to most existing physics-based refrigerated container models. We validate the porous media model implementation. We define and apply actionable metrics for every fruit inside the cargo, such as remaining shelf life upon arrival and seven-eighths cooling time. • This model can help reduce food loss and increase supply-chain resilience. • This model is an essential building block of a refrigerated container’s digital twin. • This model can support stakeholders in improving cargo temperature control and resulting fruit quality preservation.

This article aims to reconstruct the philosophical message found in Jaan Oks’ fragmentary works “Females” (Emased, 1908), “Flesh” (Ihu, 1908), and “Nameless Beast” (Nimetu elajas, 1909). The author argues that within these works, amidst alternating and colliding voices, a louder and more distinct one emerges – a prophetic-philosophical narrator who uses unfolding sketches to provide broad metaphysical generalizations and assessments, primarily concerning human nature and gender differences. In addition to reconstructing the philosophical positions, these are compared with Friedrich Nietzsche’s views on the same subjects, exploring the extent of Nietzsche’s influence on Oks’ works. In the first step of the interpretation, the article examines how Oks’ texts define human nature. Human beings are reduced to natural creatures lacking a soul, with sexual drive at the core of their essence. A comparison reveals significant similarities between Oks and Nietzsche’s perspectives on human nature. Both also declare the invalidity of Christian moral teachings. However, Oks’ texts do not lead to a ­celebration of the natural human sexual drive; instead, an aversion persists. The article continues with a reconstruction of the philosophical generalizations explaining this situation. In the second step, the article explores the relationship of Oks’ texts with secularization. It becomes apparent that the divine, transcendent sphere cannot be simply erased from Oks’ works, despite declarations to the contrary. For Oks, God remains a problem addressed through blasphemous fantasies in the examined works. Additionally, the hypothetical godless life is not enjoyable for Oks’ philosophical voice; existential meaninglessness dominates. The mood contained in Oks’ works is compared with Nietzsche’s concept of the “death of God”, finding significant similarities. In the third aspect, the article examines the relationships between the two sexes. Here, too, substantial overlaps are identified between Oks and Nietzsche’s perspectives. Both assert an insurmountable tension and conflict between the sexes, emphasizing women’s greater affinity to nature. In Oks’ works, men are attributed the desire to distance themselves from their nature – sexual drive – and retreat into solitude. From this distance, the female sex is insulted and degraded so vehemently and at such great length that a parallel can be drawn to a blasphemous relationship with God. The final section examines the pursuit of detachment from life, of overcoming humanity, attributed to the poet in Oks’ works, comparing it to Nietzsche’s concept of art. Despite several similarities, a significant difference emerges: Nietzsche understands art’s main purpose vitalistically, as a means to overcome decadence, the defining movement of his era. This requires the overcoming of humanity as it exists. Oks’ conception, on the other hand, remains programmatically decadent and is directed towards the decline and end of humankind.

Abstract Domestic cats' varying home range sizes are connected to their impact on wildlife. Most of the previous studies suffered from lacking causality or small sample sizes. To overcome these limitations, we conducted a comprehensive study involving 55 owned domestic cats in a French suburban area where each cat was monitored during one or nine sessions over 5 years and all four seasons. We tracked the cats using GPS technology while controlling for the device used for monitoring, climatic conditions, environmental changes, and their degree of roaming. Using linear mixed‐effect models, we found that age and sex significantly predict home range size. Younger cats tend to have larger home ranges and male cats have larger home ranges compared to females. We also found that the device used during the monitoring influenced the size of the home range. Surprisingly, climatic conditions, surrounding environment and degree of roaming had no significant impact. When considering our models, most of the variability in home range size was due to random effects that accounted for the identity of cats which were monitored one or more times. Therefore, a deeper understanding of intrinsic and extrinsic factors influencing home range size in domestic cats is crucial. This includes investigating individual behavior, breed‐specific traits, and the role of owner care but also reassessing management solutions for reducing cat roaming and not only focusing on restrictive ones. Identifying these factors will enable the development of more effective management.

ObjectivesThe defining achievement of a multi-marathoner is completing 100 marathons. This study aimed to comprehensively document the phenomenon of multi-marathoning, addressing its demographics, culture and participatory nature, filling a gap in peer-reviewed research on the topic. Additionally, it aimed to provide recommendations for multi-marathon governing bodies, event organisers, health professionals and participants to address identified issues.MethodsA global survey was distributed to participants and individuals interested in multi-marathoning. It was distributed with support from major national and international multi-marathon clubs through their social media channels, email groups and newsletters. The survey was conducted anonymously and online.ResultsThe survey garnered responses from 830 participants across 40 countries, with an average marathon completion count of 146.54 (SD 201.83) per respondent. Gender distribution showed 60.69% men, 39.3% women and 0.1% gender variant/non-conforming. Respondents' average ages were 51.6 (SD 9.96) years for men, 48.83 (SD 9.15) years for women and 35.00 (SD 8.76) years for gender variant/non-conforming. As participants age, social and travel motivations surpass competitiveness. A majority (57%) of respondents had at least one contravention to the pre-participation screening questionnaire PARQ-+ and 67% reported taking pain relief medication around events. Notably, 93% of respondents reported multi-marathoning as beneficial for their mental health.DiscussionMulti-marathoning accommodates older athletes, but a significant gender imbalance exists in participation levels. Long-term health implications warrant attention from governing bodies, event organisers, health professionals and participants alike. Multi-marathoners should seek medical advice before participation, utilise modern equipment for health monitoring and optimise training accordingly.ConclusionRecommendations include encouraging diversity at events, ensuring event directors have well-resourced health plans and promoting participants' proactive health management before and during their involvement in the sport. This study not only advances our understanding of multi-marathoning as a sport but also contributes to theoretical frameworks such as SDT and HBM.

Background Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8+ T cells and whether they have prognostic relevance.METHODS We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).Results We show that senescent-like bone marrow CD8+ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival (OS). We defined what we believe to be new immune effector dysfunction (IED) signatures using 2 gene expression profiling platforms and reported that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes; these scores were a more powerful predictor of OS than 2017-ELN risk or leukemia stem cell (LSC17) scores. IED expression signatures also identified an ICB-unresponsive tumor microenvironment and predicted significantly shorter OS.Conclusion The IED scores provided improved AML-risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.TRIAL REGISTRATION ClinicalTrials.gov; NCT02845297.FUNDING John and Lucille van Geest Foundation, Nottingham Trent University’s Health & Wellbeing Strategic Research Theme, NIH/NCI P01CA225618, Genentech-imCORE ML40354, Qatar National Research Fund (NPRP8-2297-3-494).

DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice were used as donors in allo-BMT models. Mice receiving allo-BMT from KO donors developed severe acute graft-versus-host disease (aGVHD), with increases in inflammatory cytokine levels and organ histopathology scores. KO T cells migrated and proliferated in secondary lymphoid organs earlier and demonstrated an advantage in trafficking to the small intestine. Donor T cell subsets were purified after BMT for whole-genome bisulfite sequencing (WGBS) and RNA-Seq. KO T cells had global methylation similar to that of WT cells, with distinct, localized areas of hypomethylation. Using a highly sensitive computational method, we produced a comprehensive profile of the altered epigenome landscape. Hypomethylation corresponded with changes in gene expression in several pathways of T cell signaling and differentiation. Additionally, Dnmt3a-KO T cells resulted in superior graft-versus-tumor activity. Our findings demonstrate a critical role for DNMT3a in regulating T cell alloreactivity and reveal pathways that control T cell tolerance. These results also provide a platform for deciphering clinical data that associate donor DNMT3a mutations with increased GVHD, decreased relapse, and improved survival.

Articles about doing a PhD tend to focus on the difficulties faced by research students. Here we argue that the scientific community should also highlight the positive elements of the PhD experience.

Purpose: Recurrent head and neck cancers are associated with significant morbidity and mortality. Outcomes of multiple courses of radiation have not yet been described. Methods and Materials: A single institution database was queried to retrospectively review treatment plans and select patients who underwent ≥ 3 courses of radiation to the head and neck region. Results: Thirty-three patients were found to have ≥ 3 courses of radiation with overlapping fields. Median local recurrence free survival after last course of reirradiation was 9.1 months and median overall survival was 10 months. Grade 3 and above toxicities were reported in 15 patients (45%). Grade 4 and above toxicities were reported in seven patients (21%). There was no grade 5 toxicity. 20 patients (61%) underwent subsequent therapies following completion of repeat reirradiation. Conclusions: Repeat reirradiation to the head and neck region is feasible and carries significant risks that are most appropriately managed with a multi-disciplinary team and must be balanced against the potential for local control and opportunities for emerging systemic therapies.

Background: Dual lipid-lowering and anti-inflammatory properties of statins may lead to survival benefits in patients with rheumatoid arthritis (RA). However, data on this topic are limited, and the role of statins in RA remains unclear.Objectives: To examine the association of statin use with overall mortality among patients with RA in a general population context.Methods: We conducted an incident user cohort study with time-stratified propensity score matching using a UK general population database. The study population included individuals aged ≥20 years who had a diagnosis of RA and had used at least one disease-modifying antirheumatic drug (DMARD) between January 2000 and December 2012. To closely account for potential confounders, we compared propensity score matched cohorts of statin initiators and comparators (non-initiators) within 1-year cohort accrual blocks.Results: 432 deaths occurred during follow-up (mean 4.51 years) of the 2943 statin initiators for an incidence rate of 32.6/1000 person-years (PY), while the 513 deaths among 2943 matched comparators resulted in an incidence rate of 40.6/1000 PY. Baseline characteristics were well-balanced across the two groups. Statin initiation was associated with a 21% lower risk of all-cause mortality (HR=0.79, 95% CI 0.68 to 0.91). When we defined RA by its diagnosis code alone (not requiring DMARD use), the corresponding HR was 0.81 (95% CI 0.74 to 0.90).Conclusions: Statin initiation is associated with a lower risk of mortality among patients with RA. The magnitude of association is similar to that seen in previous randomised trials among the general population. [ABSTRACT FROM AUTHOR]

With advances in allogeneic hematopoietic stem cell transplant (allo-HCT), disease relapse has replaced transplant-related mortality as the primary cause of treatment failure for patients with acute myeloid leukemia (AML). The efficacy of allo-HCT in AML is a consequence of a graft-versus-leukemia (GVL) effect that is mediated by T lymphocytes, and unique mechanisms of immune evasion underlying post-allo-HCT AML relapses have recently been characterized. Relapsed AML following allo-HCT presents a particularly vexing clinical challenge because transplant-related toxicities, such as graft-versus-host (GVHD) and infections, increase the risk of treatment-related morbidity and mortality. In general, the prognosis of relapsed AML following allo-HCT is poor with most patients failing to achieve a subsequent remission and 2-year survival consistently

Abstract: HLA haploidentical hematopoietic cell transplantation (haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) is an alternative strategy when a matched sibling donor (MSD) is not available. We performed a systematic review and meta-analysis to compare the outcomes of MSD vs haplo-HCT. Eleven studies (1410 haplo-HCT and 6396 MSD recipients) were meta-analyzed. All studies were retrospective and high quality, and 9 were multicenter. Haplo-HCT was associated with ~50% lower risk of chronic graft-versus-host disease (GVHD) (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.41-0.74), but higher risk of nonrelapse mortality (HR, 1.36; 95% CI, 1.12-1.66). Relapse, survival, acute GVHD, and GVHD-free relapse-free survival were not significantly different between the groups. Deciphering the relative contribution of PT-Cy and HLA disparity to the observed outcome differences between the groups requires further research.

Abstract: Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; P = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted.

Artikkel analüüsib meie digitaalsusest küllastunud elu Friedrich Nietzsche filosoofia perspektiivist, lähtudes küsimusest, kas digikeskkondades töös olevad suundumused senise inimliku iseduse fragmenteerimiseks võivad olla sillaks üleinimese suunas liikumisel. Esimeses osas visandatakse Zygmunt Baumani ja Rein Raua dialoogi põhjal peamised digikeskkondade laialdase levikuga kaasnevad isedust kujundavad aspektid, mis on autorite meelest ohtudeksväljakutseteks senisele inimsusele. Teises osas esitatakse tõlgendus üleinimese tähendusest ja mõiste seostumisest teiste peamiste ideedega Nietzsche filosoofias. Arutluse tulemusena asutakse kaitsma üleinimese hoiakulist tõlgendust. Viimases osas hinnatakse kõiki eelnevalt piiritletud digikeskkondade levikuga seotud aspekte ning jõutakse järeldusele, et kuigi need süvendavad üldjoontes juba Nietzsche ajal ilmnenud massiühiskonna tendentse, ei determineeri tehnoloogia üheselt iseduse moodustamise mehhanisme ega välista üleinimese suunas liikumist. The article analyses our digitally saturated life from the viewpoint of Friedrich Nietzsche’s philosophy, starting off with the question whether the trends, which are at present actively fragmenting human selfhood in digital environments, could act as bridges for the movement towards overman. The first part of the article sketches, based on the dialogue between Zygmunt Bauman and Rein Raud, the main selfhood-shaping aspects which accompany the spread of digital environments and which could, according to the authors, challenge or threaten the humanity. The authors point out seven main problems: the fragmenting of selfhood in online environments; impossibility of developing or expressing originality; excessive convenience, especially in human relations and communication; wide-spread dependence on the content offered by digital environments; damage to mental capacity; too little physical activity, and the polarisation of viewpoints due to the sound box of virtual communication. Many of the listed problems are still older than the accelerated spreading of computer networks, but they have become more pressing due this process. The second part of the article offers an interpretation of Nietzsche’s concept of overman. The use of the concept of overman is not strictly specified in Nietzsche’s work, it is often presented in the form of hints and metaphors. In order to reach the interpretation, the concept under discussion has to be put into relation to several other unclear concepts, which makes the developing of the interpretation the most complicated and substantial task in the article. To establish the first starting point, the article argues that Nietzsche was not a humanist, that the overcoming of man is a clear intention in his thinking, expressed also by the concept of overman. For Nietzsche, the future of man was not decided by biological or technical aspects but, rather, by cultural-psychological aspects. Nietzsche believed that a whole set of preconditions and beliefs, which are essential for being a human and which he called higher values, were disintegrating during his lifetime. Thus, overcoming man was not only his normative objective, but also an inevitable process which had already started in the conditions of the well-established cultural contingency. Next, the article specifies the aspiration to overcome man, listing the main attitudes and characteristics of the modern man which should, by Nietzsche, be overcome. These include: life-denying and weakness-cultivating monotheistic religion and the morals it supports; all kinds of beliefs in the primacy of the soul (and its immortality) and the marginalisation of the body; herd instincts and the moulding of humans into an identical mass, including the cult of equality and democratism; any kind of belief in progress, including belief in scientific progress as a hidden form of teleological explanation of the world; techniques of self-creation which cultivate the persistent identity and stability of a person and discourage experimentation; hedonism, and the avoiding of suffering and making it pointless. These attitudes are deeply rooted in in the modern Western people, but according to Nietzsche’s view, they are unavoidably disappearing in the nihilistic processes of the era. Nietzsche outlines five possible strategies for coping: conservatism, the attempt to preserve the existing absolute-based values; passive nihilism, fading and declining, and Doomsday predictions; active nihilism, the destruction of everything and the enjoyment of this process; retreating into hedonism and refusing to think about great matters – in Nietzsche’s terminology – the last man; striving to live towards overman, or the total and extreme nihilism. The article proceeds to analyse the reasons why Nietzsche believes that man should overcome these characteristics also in the normative meaning. The question why Nietzsche despises hedonism and man’s search for a stable form of existence acquires a central position here. In order to find answers, it is necessary to move from Nietzsche’s anthropology to his metaphysics and to introduce the concept of the will to power. The article avoids robustly vitalistic interpretations of Nietzsche’s philosophy and interprets, using the model of the hermeneutic circle, the will to power and perspectivism and their interactive aspects. The article states that for Nietzsche, the world, which is understood as the will to power, does not submit to inevitability or laws but is indeterminable, and man is indeterminable as well. Nietzsche denies the self-sufficiency of selfhood as a Cartesian subject, as well as the freedom of will, which does not mean the acknowledgment of determinism in the light of mechanism, but means the affirmation of indeterminism. For Nietzsche, human selfhood has two opposing characteristics – self-preservation and self-overcoming. He believes that the soul is formed by the plurality of urges and affects, and self-preservation or self-control manifests in the ability to mould this plurality into a hierarchical unity and to preserve this unity. However, a person with open senses, a “free soul”, can be overwhelmed by the abundance of life and the multitude of competing urges and affects. The experimental existence, suggested by Nietzsche, means that a person does not retreat into a stable pattern of self-preservation, but moves further, does not avoid suffering and in the dusky regions of self-creation, risks the disintegration of selfhood in the sea of affects. Following these lines of interpretation, the article reaches a clear interpretation of the concept of overman, stating that overman is not, and cannot be, a (future) being, expressed by describing a set of certain characteristics, but it is an attitude – a risky experimental break from the mechanisms of identity preservation – openness to unknown. The third part of the article examines, based on the above results, all the seven digitalisation-related problems, listed in the first part, and evaluates their status from the viewpoint of living towards overman. Results of the evaluation are divided into unambiguously good – for the phenomena that develop the overhuman potentiality, unambiguously bad – for the phenomena that favour the retreat into the existing selfhood, and relatively good – for the phenomena that break down the existing humanity and accelerate the processes of nihilism. According to the author, fragmentation of selfhood is unambiguously good from the overhuman point of view; excessive convenience and impossibility of originality are unambiguously bad. Polarisation is a relatively good phenomenon. The rest of the problems – damage to mental capacity, too little physical activity and the spread of dependencies – cannot be unambiguously evaluate and the article points out both their good and bad aspects. The article concludes with the statement that some of the trends, which are at present actively fragmenting the existing human selfhood in digital environments, could act as bridges for the movement towards overman (in the meaning of attitude, of living towards overman, given to this concept in the article).

This article is a Heideggerian inquiry into the possibility of ontological experience, that is, the possibility of experiencing the ontological difference, something wholly distinct from beings. Heidegger, as we know, articulated this as the question of Being. It is a paradoxical question that cannot, at first sight, be answered phenomenologically (in the Husserlian style): if any conscious experience presupposes the constitution of an intentional object in the act of experience, there must be something in any experience. In this article, I set out to defend the position that ontological experience is possible and central to the human existence. This view rests on the Heideggerian notion of the affective grounds of all thinking, the attunement of any experience by moods. I will argue that: 1) any thinking is attuned by moods; 2) ontological experience (i.e. experiencing something wholly distinct from beings) occurs in certain negative moods. 3) ontological experience is possible only through failure, a malfunction in the fulfilment of meaning; 4) ontological experience is possible in art rather than in science (or in some rigorous philosophy).

Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, post-transplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for ex vivo T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matched-related and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.

Abstract: Peripheral blood stem cell transplantation (PBSCT) offers a curative option for sickle cell disease (SCD). Although HLA-matched sibling transplantation is promising, the vast majority of patients lack such a donor. We sought to develop a novel nonmyeloablative HLA-haploidentical PBSCT approach that could safely be used for patients with severe organ damage. Based on findings in our preclinical model, we developed a phase 1/2 trial using alemtuzumab, 400 cGy total body irradiation, and escalating doses of posttransplant cyclophosphamide (PT-Cy): 0 mg/kg in cohort 1, 50 mg/kg in cohort 2, and 100 mg/kg in cohort 3. A total of 21 patients with SCD and 2 with β-thalassemia received a transplant. The mean hematopoietic cell transplant–specific comorbidity index of 6 reflected patients with cirrhosis, heart failure, and end-stage renal disease. The engraftment rate improved from 1 (33%) of 3 in cohort 1 to 5 (63%) of 8 in cohort 2 and 10 (83%) of 12 in cohort 3. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. There was no transplant-related mortality, and overall survival was 87%. At present, 0% in cohort 1, 25% in cohort 2, and 50% in cohort 3 remain free of their disease. There was no grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). Therefore, PT-Cy improves engraftment and successfully prevents severe GVHD after nonmyeloablative conditioning in patients with SCD who are at high risk for early mortality. Additional strategies are necessary to decrease the graft rejection rate and achieve a widely available cure for all patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT00977691.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.

Although there have been some recent breakthroughs of unifying political leadership, this essay addresses the emerging trend of today's lack of unifying political leadership. Too often political leaders are utilizing different forms of violence to divide societies and countries. In this essay, I will draw on Pope Francis’ 2017 World Day of Peace message on nonviolence to provide a way forward to more unifying political leadership. I will use this touchstone document to help clarify the value of seeing cultural, structural, and direct violence as an integrated whole we need to address together as missionary disciples. In the context of the Catholic Nonviolence Initiative, I will articulate how a just peace ethic offers key advantages to do that work, and thus, enables the cultivation of more unifying political leadership. Then I will provide practical suggestions for how Catholic ethicists could better network to advance this transformative approach.

Abstract: Allogeneic blood or marrow transplantation (BMT) candidates may lack HLA-matched, related haploidentical, and unrelated umbilical cord options. Barriers to partially HLA-mismatched, unrelated donor (mMUD) BMT include excess graft-versus-host disease (GVHD), graft failure, and death. We prospectively studied nonmyeloablative (NMA) mMUD BMT with high-dose posttransplantation cyclophosphamide (PTCy) for patients with hematologic malignancies. Three transplants were performed with busulfan/fludarabine conditioning, with subsequent change to fludarabine/Cy/total body irradiation (flu/Cy/TBI). Twenty mMUD transplants are reported using flu/Cy/TBI, T-cell replete bone marrow grafts, and PTCy, mycophenolate mofetil, and sirolimus or tacrolimus (1 patient) for GVHD prophylaxis. The median patient age was 56. Of these unrelated grafts, 45% had ≥2 mismatched HLA loci, 25% had ≥3 mismatched loci, and 50% had HLA-C mismatches. No graft failure or grades 3-4 acute GVHD occurred. The median times to neutrophil recovery (≥500/µL) and platelet recovery (≥20 000/µL) were 19 days and 31 days, respectively. Full-donor chimerism was achieved in 95% of evaluable patients by day 60. The 180-day probability of grades 2-4 acute GVHD (all grade 2) was 25%, and the 1-year probability of any chronic GVHD was 16% (none severe). The 2-year nonrelapse mortality probability was 6%. With 4-year median follow-up, the 1-year progression-free and overall survival probabilities were 65% and 75%, respectively. NMA, T-cell replete mMUD BMT is thus a potentially viable option for patients without other suitable donors. This trial was registered at www.clinicaltrials.gov as #NCT01203722.

Abstract In haploidentical stem cell transplantations (haplo-SCT), nearly all patients have more than one donor. A key issue in the haplo-SCT setting is the search for the best donor, because donor selection can significantly impact the incidences of acute and chronic graft-versus-host disease, transplant-related mortality, and relapse, in addition to overall survival. In this review, we focused on factors associated with transplant outcomes following unmanipulated haplo-SCT with anti-thymocyte globulin (ATG) or after T-cell-replete haplo-SCT with post-transplantation cyclophosphamide (PT/Cy). We summarized the effects of the primary factors, including donor-specific antibodies against human leukocyte antigens (HLA); donor age and gender; killer immunoglobulin-like receptor-ligand mismatches; and non-inherited maternal antigen mismatches. We also offered some expert recommendations and proposed an algorithm for selecting donors for unmanipulated haplo-SCT with ATG and for T-cell-replete haplo-SCT with PT/Cy.

Based on anatomical connectivity and basic response characteristics, primate auditory cortex is divided into a central core surrounded by belt and parabelt regions. The encoding of pitch, a prototypical element of sound identity, has been studied in primary auditory cortex (A1) but little is known about how it is encoded and represented beyond A1. The caudal auditory belt and parabelt cortical fields process spatial information but also contain information on non-spatial aspects of sounds. In this study, we examined neuronal responses in these areas to pitch-varied marmoset vocalizations, to derive the consequent representation of pitch in these regions and the potential underlying mechanisms, to compare to the encoding and representation of pitch of the same sounds in A1. With respect to response patterns to the vocalizations, neurons in caudal medial belt (CM) showed similar short-latency and short-duration response patterns to A1, but caudal lateral belt (CL) neurons at the same hierarchical level and caudal parabelt (CPB) neurons at a higher hierarchical level showed delayed or much delayed response onset and prolonged response durations. With respect to encoding of pitch, neurons in all cortical fields showed sensitivity to variations in the vocalization pitch either through modulation of spike-count or of first spike-latency. The utility of the encoding mechanism differed between fields: pitch sensitivity was reliably represented by spike-count variations in A1 and CM, while first spike-latency variation was better for encoding pitch in CL and CPB. In summary, our data show that (a) the traditionally-defined belt area CM is functionally very similar to A1 with respect to the representation and encoding of complex naturalistic sounds, (b) the CL belt area, at the same hierarchical level as CM, and the CPB area, at a higher hierarchical level, have very different response patterns and appear to use different pitch-encoding mechanisms, and (c) caudal auditory fields, proposed to be specialized for encoding spatial location, can also contain robust representations of sound identity.

Severe radiation-related lymphopenia is common and associated with decreased survival in patients with several solid tumors. As the mechanisms underlying systemic lymphopenia are poorly understood, we developed an animal model to study the effects of brain radiation on lymphocytes and cytokines. C57 BL/6 and BALB/c mice received focal brain irradiation (4 Gy x 10 fractions or 2 Gy x 30 fractions). Weekly total lymphocyte counts (TLC), lymphocyte subsets and cytokines in blood and lymph nodes were measured. Non-irradiated lymph nodes were collected and examined before, during, and after radiation. We found that systemic TLC decreased rapidly irrespective of mouse strain or radiation schedule. 4 Gy x 10 resulted in a 42% and 75% & 70% and 49% TLC reduction in C57 BL/6 and BALB/c mice respectively. 2 Gy x 30 caused a 70% / 49% decrease in TLC in C57 BL/6 and BALB/c. Similar trends were seen for total T cells, CD4+, regulatory T and CD8+ cells. Changes in lymph node architecture and cellular composition correlated with the development of systemic lymphopenia. Three weeks after radiation, TLC returned to 60–80% of baseline, preceded by increased IL-7 levels in the lymph nodes. Focal brain radiation in mice results in significant systemic lymphodepletion.

We examine the interaction between DNA molecules immersed in an aqueous solution of oppositely charged, trivalent spermidine molecules. The DNA molecules are modeled as planar, likecharged surfaces immersed in an aqueous solution of multivalent, rod-like ions consisting of rigidly bonded point charges. An approximate field theory is used to determine the properties of this system from the weak to the intermediate through to the strong coupling regimes. In the weak coupling limit, the interaction between the charged surfaces is only repulsive, whereas in the intermediate coupling regime, the rod-like ions with spatial charge distribution can induce attractive force between the charged surfaces. In the strong coupling limit, the inter-ionic charge correlations induce attractive interaction at short separations between the surfaces. This theoretical study can give new insights in the problem of interaction between DNA molecules mediated by trivalent spermidine molecules.

Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; clinicaltrials.gov Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor α, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-α all had high areas under the curve of 0.74–0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor α were associated with grade II–IV and III–IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.

Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02–11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III–IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41–55%) and 53% (95% CI: 46–61%) after myeloablative HLA-matched related, 42% (95% CI: 34–52%) and 52% (95% CI: 44–62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40–50%) and 50% (95% CI: 45–55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.

Šiuolaikinėje kontinentinėje filosofijoje dažna yra karteziškojo subjekto kritika ir bandymai su­kurti post-subjektiyvistinę filosofiją. Vakarų kultūros žmonės dažnai apibūdinami kaip gyvenantys nuolatinėje tapatybės krizėje. Klausimas „kas bus po subjekto?“ yra kertinis tiek filosofijoje, tiek vakariečių kasdienybėje. Šiame tarpdalykiniame tyrime mes teigiame, jog esama rimtų šeiminių panašumų tarp post-subjektyvistinės filosofijos ir animistinės religijos tikslų. Pirmiausia aprašomi trys principai, sudarantys kontekstą, be kurio neįmanoma suprasti animistinės subjektyvumo traktuotės: Vienybės principas, Pusiausvyros principas ir Poliarinių priešybių mąstymas. Šie principai toliau plėtoja tinklinio mąstymo idėją, aprašytą ankstesniame mūsų straipsnyje. Paskui palyginama animistinė subjektyvumo traktuotė su šiuolaikine subjekto kritika. Nors ir nekeliame normatyvaus reikalavimo prikelti animizmą, negalime atmesti galimybės, jog animistinių principų tyrimas sudarys prielaidas lokaliems postmodernios subjekto krizės sprendimams.

The criticisms of Anne Winter and Matthias Kortmann of Winners and Losers enable Leo and Jan Lucassen to revise and explain more clearly a number of key arguments of their book. These particularly concern questions about the aim and usefulness of comparisons in time and space. Regarding the spatial comparisons (especially with Germany and Belgium), the authors have tried to show in which respects Dutch migration history is unique and where more general mechanisms were at play. Concerning the comparison of the post-war immigration dynamics with the Early Modern Period, Leo and Jan Lucassen argue that this yields much more than one would assume at first sight. It forces us to think systematically about what is similar and what is different, but it also sheds new light on apparently familiar and unproblematic cases. This response is part of the discussion forum 'Winnaars en verliezers' (Leo Lucassen and Jan Lucassen).

Artiklis käsitletakse nihilistliku kirjandusloome võimalusi eesti luule näitel. Nihilismi ei mõisteta artiklis väärtusprobleemina, vaid ontoloogilise probleemina. Nihilistlikku kirjandusloomet käsitletakse taotlusena tuua sõnasse teine, eimiski. Artikli teoreetiline raamistik toetub põhiliselt Gianni Vattimo languse ontoloogia kontseptsioonile, aga ka Friedrich Nietzsche, Martin Heideggeri ja Maurice Blanchot' töödele. Samuti analüüsitakse artikli teoreetilises osas eimiski väljendamise võimalusi eesti keeles, tuginedes Uku Masingu ning Jaan Kaplinski mõttekäikudele. Luuletajatest käsitletakse artiklis enim Jaan Oksa ja Juhan Liivi. Analüüsi käigus tuuakse esile järgmised eimiskiga seotud poeetilised figuurid: ootus ja luhtumus, langus ja loojak, hullus, surm. Analüüsi tulemusena selgub, et nihilistlik loome on eesti luules tugevalt esindatud, kuid ei filosoofias ega luules pole võimalik saavutada otsest juurdepääsu eimiskile, tuleb piirduda aimamisega, vihjamisega.

Marijke van Faassen, Polder en emigratie. Het Nederlandse emigratiebestel in internationaal perspectief 1945-1967 (Dissertatie Rijksuniversiteit Groningen 2014; Den Haag: Huygens ing, 2014, 515 pp., ISBN 978 90 367 7176 4).

Pagrindinis XX a. kontinentinės filosofijos motyvas buvo metafizikos kritika. Ankstesnės filosofinės sistemos buvo imtos laikyti pernelyg stingios, imta ieškoti būdų išvengti metafizinio hierarchinio mąstymo. Pasitelkiant religijų ir filosofijos istorijos sintezę, šiame straipsnyje teigiama, jog įmanoma aptikti gausybę stulbinančių panašumų tarp animizmo ir XX a. filosofinio mąstymo. Straipsnyje aptariami skirtumai tarp tinklinio mąstymo ir hierarchinio mąstymo. Tinklinis mąstymas analizuojamas pasitelkiant du motyvus: daugiadimensiškumą ir bendrųjų sielų tinklą. Animizmas naudojamas kaip pagrindinis pavyzdys nusakant motyvų reikšmę mąstymui ir praktikai. Taip pat aprašomas hierarchinio mąstymo atsiradimas ir sklaida.