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The Poltergeist in the machine:Sedimented, semantic, social and spectral perspectives on prediction in the artificial mind
No full textSo-called artificial intelligence (AI) can be said to have as its aim the understanding—and possible imitation—of certain information-processing aspects of the brain, primarily aspects we relate to the concept of mind. Not disregarding evidence for its legitimacy as foundational to what we call mind or cognition, this brain-centric view can be easily challenged if we observe the mind as a pattern distributed across various systems and spatiotemporal scales. An unavoidable aspect of communicating about patterns is the predictive reliance on the capacity for abstraction (i.e., the delineation of transmittable, parsable chunks).All perception abstracts for experience to be possible at all, and one of the main arguments of this work is that the function of abstraction is the effectuation of preferences in favor of the function of persistence. Any perceptual persistence is enactive, perspectivally partial, ecologically embedded, spatiotemporally situated: abstractions can only exist as information processes which are subject to (cases and combinations of) in-definition, intractability, incalculability. Therefore, because of these limits, its effects are always the result of speculatively predictive pattern recombinations. This proposal renders a highly relativistic reality which can only be analyzed by comparing observer-dependent perspectives. To provide an entry into this perspectivism, this project follows an approach that aims at a scale-free analysis of the basic tenets of information-processing observable across all manner of abstracting entities (from bacteria to distributed semantic memory), that is: Active Inference (AIF), a novel field which presents an enactive, generative image of self-organizing processes that persist.The main research questions urging this work are: is philosophy, conceived as vast predictive abstraction—understood under AIF as a process of projective self-evidencing—the limit of AI? Or, alternatively, could AI become the limit of philosophy? Secondly, what kinds of abstractions can this project help engineer, in order to predict the further development of abstractions in/of AI as mind outside or beyond the brain, particularly given the dialectic that AI has inherited its “basic” concepts from philosophy? And finally: considering that philosophy is part and parcel of technocolonialcapitalist complex—particularly so in the context of AI—how to assess its functional implications herein? The proposal made by this project is that, by presenting a series of novel concepts which reorient traditional (sometimes unnecessarily entrenched and monodimensional) ideas about the functions of mind, we can envision novel (sociosemantic) possibilities and therefore challenge current (AI) imaginaries. The technical domain this project explores are processes of (learning) dialogue, broadly construed, and how conceptual-engineering occurs herein. The main conclusion of this project is that if thought is what matters—and its evolving existence is subject to inevitable modulations—and if thought transfers between systems through languages, then a functional analysis of how thought forms and transfers should play a more prominent role in “AI” considerations.These questions will be extensively explored by tracing the implications of the observations above, and by proposing a series of concepts which enable new perspectives on the mind as an artificial, open-ended process. These perspectives are sedimented because they are assumed to emerge from a material history; semantic because they contemplate meaning(s) and possible teleologies; social because they are dialogical and distributed, and spectral because they are transcendentally, existentially haunting: they imply futures past and beyond our own.<br/
Plasma supplemented with glycine is superior to standard plasma in reducing vascular permeability and organ injury via reduction of inflammation in an experimental traumatic shock model
No full textBackground: While plasma transfusion is a key resuscitation strategy, its mechanisms of benefit beyond coagulopathy correction remain unclear. Solvent detergent plasma, which contains high glycine levels and lacks inflammatory mediators, may offer advantages over fresh frozen plasma by preserving endothelial integrity and reducing inflammation. This study aimed to test whether plasma containing a high dose of glycine is superior to standard plasma in improving outcomes after traumatic shock by mitigating endothelial damage and inflammation.Study Design and Methods: Anesthetized, fully instrumented Wistar rats (n = 11 per group) were randomly assigned to receive plasma, glycine-supplemented plasma, or crystalloid following polytraumatic injury and shock. The primary outcome was endothelial leakage of the lung. Inflammation and organ failure, as determined by biochemistry and histopathology, were secondary outcomes. Results: Glycine-supplemented plasma, but not plasma, prevented an increase in pulmonary vascular leakage in comparison to crystalloid. Glycine-supplemented plasma resulted in lower systemic levels of syndecan-1 than crystalloid (p <.05). Glycine-supplemented plasma caused less lung injury compared with standard plasma (p <.001) and crystalloids (p <.001). Preservation of the endothelial barrier was associated with lower IL-6 levels and less acidosis in the glycine-supplemented plasma group than in the crystalloid group (p <.05). Discussion: Glycine-supplemented plasma is superior to standard plasma in preventing endothelial permeability, glycocalyx shedding, and lung injury, which may be mediated via inhibition of IL-6 or improvement of acid–base balance. The use of solvent detergent plasma for trauma resuscitation may be more beneficial than standard plasma, partly due to glycine content.</p
Immunoglobulin heavy-chain status and stromal interactions shape ferroptosis sensitivity in chronic lymphocytic leukemia
No full textChronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells. Although targeted therapies have improved outcomes, resistance remains a challenge, particularly in high-risk patients with TP53 mutations or unmutated immunoglobulin heavy-chain variable region (IGHV) genes (U-CLL). Ferroptosis, a regulated, iron-dependent form of cell death, may represent an exploitable vulnerability in CLL; however, its mechanisms and clinical relevance remain poorly understood. Here, we identified IGHV status and microenvironmental cues as determinants of ferroptosis sensitivity. Using CLL cell lines, patient samples, and in vivo models, we show that CLL cells exhibit elevated basal levels of lipid peroxides and labile iron, predisposing them to ferroptosis. However, stromal interactions enhance cystine import and glutathione synthesis, thereby mitigating susceptibility to ferroptosis. Mechanistically, BTK inhibition sensitizes CLL cells to ferroptosis by increasing the transferrin receptor (TFRC, CD71) and increasing the intracellular Fe²⁺ level. High TFRC expression was associated with improved survival in two independent CLL patient cohorts, supporting its therapeutic and prognostic relevance. Combining ibrutinib with the GPX4 inhibitor RSL3 enhances ferroptosis and improves antileukemic efficacy in vivo. CLL cells with mutated IGHV genes (M-CLL) display greater TFRC expression and ferroptosis sensitivity than U-CLL cells do. This resistance can be overcome by ibrutinib-mediated TFRC induction or via metabolic targeting of fatty acid metabolism. Notably, ACSL1 is selectively upregulated in U-CLL cells and represents a targetable metabolic enhancer of ferroptosis sensitivity, as shown in vivo. Our findings reveal that TFRC and ACSL1 are functionally distinct yet targetable nodes that govern ferroptosis vulnerability in CLL patients and may guide novel therapeutic strategies for high-risk patients.</p
DAPAgliflozin for renal protection in heart transplant recipients. Rationale and design of the randomized controlled DAPARHT trial
No full textBackground and aims: Heart transplantation is the preferred treatment for selected patients with end stage heart failure. Kidney function often declines after heart transplantation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) slow the decline in eGFR in different populations. However, the effect of SGLT2i on kidney function in heart transplant recipients is unknown. Methods: The Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT) trial is an investigator initiated, double blind, randomized, placebo-controlled trial designed to assess dapagliflozin's effect on kidney function in heart transplant recipients. Adults heart transplanted at least one year prior to randomization are eligible. Exclusion criteria include an estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m2, diabetes type I, and contraindication to study medication. Four hundred and thirty patients will be randomized 1:1 to receive 12 months blinded treatment with dapagliflozin 10 mg o.d. or placebo, followed by 24-months open-label treatment. The primary endpoint is the chronic slope of the eGFR from two weeks to 12 months after starting randomized treatment. The open-label phase evaluates dapagliflozin's long-term effects on kidney function, clinical outcomes, safety, and tolerability. Enrolment began in June 2022. As of December 18, 2024, 300 patients were enrolled. The mean baseline creatinine was 104 ± 28 µmol/L with corresponding eGFR of 66 ± 22 mL/min/1.73 m2. Estimated last patient visit is in September, 2028. Conclusion: The DAPARHT trial will test whether dapagliflozin improves eGFR slope compared to placebo during one year of follow-up, providing the first randomized evidence of the efficacy of SGLT2i in heart transplant recipients.Trial Registration: Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT), NCT05321706, clinicaltrials.gov.</p
2023 European Society of Cardiology guidelines for the management of infective endocarditis:Statement of endorsement by the NVVC Full version
No full textThis review evaluates the 2023 European Society of Cardiology (ESC) guidelines for the management of infective endocarditis (IE) and offers insights into topics particularly relevant to clinical practice in the Netherlands. The multidisciplinary IE Working Group assessed all ESC recommendations and concluded that the majority could be endorsed, albeit with certain modifications. The IE Working Group presents a refined (and simplified) antibiotic prophylactic regimen and an updated table to guide the analysis of suspected blood culture-negative IE. Furthermore, the pivotal role of the Endocarditis Team in the management of patients with suspected and confirmed IE was reaffirmed, along with reinforced recommendations for nearly all cardiac and extracardiac imaging in these cases. Notably, a preliminary recommendation was issued for switching to oral antibiotic therapy in patients with native valve endocarditis caused by viridans streptococci, while awaiting the revision of the Dutch Working Group on Antibiotic Policy (SWAB) IE guideline. In addition, the surgical recommendations were evaluated and revised, including improved clinical criteria in case of cardiac surgery following neurological complications of IE and an advised disregard of the new class I ESC recommendation for surgery in early prosthetic valve endocarditis (< 6 months). Moreover, an additional device recommendation was proposed for the choice of (alternate) devices in case of device reimplantation after IE.</p
The Disease Burden of Helicobacter pylori Beyond Gastric Cancer:Quantifying the Forgotten Potential Benefits of Mass Eradication
No full textBackground & Aims: Although Helicobacter pylori screen-and-treat has demonstrated effectiveness in preventing gastric cancer (GC), the impact on other diseases, such as peptic ulcer disease (PUD), dyspepsia, and gastric lymphomas, is often overlooked in guidelines and policy-analyses. This study quantifies the disease burden attributable to H pylori beyond GC. Methods: A systematic literature search identified studies reporting the relative risk of developing PUD, dyspepsia, or gastric lymphomas due to H pylori to calculate the population attributable fraction (PAF) for each condition. The PAF represents the proportion of disease burden caused by H pylori. Preventable case numbers were calculated based on the risk reduction from eradication, both globally and specific for countries with varying H pylori prevalence. Results: The proportions of PUD, dyspepsia, and gastric lymphoma attributable to H pylori (95% confidence interval) were 57% (44%–68%), 7% (2%–13%), and 33% (12%–53%), respectively, corresponding to 3.5 (2.7–4.2) million, 30 (7.1–52.2) million, and 12,000 (4200–19,100) cases potentially preventable through eradication, globally. Country-specific estimates varied with lowest PAFs (PUD, dyspepsia, gastric lymphomas) observed in the United States (35% [24%–47%], 3% [2%–13%], and 17% [5%–31%]) and highest in South Korea (63% [50%–73%], 9% [2%–15%], and 39% [14%–58%]). However, even in the United States, preventable case numbers remained substantial for PUD (134,000 [93,000–177,000]) and dyspepsia (860,000 [196,000–1.5 million]). Conclusions: Omitting PUD and dyspepsia as outcomes in studies on H pylori screen-and-treat may substantially underestimate benefits. Incorporating these diseases alongside GC into cost-effectiveness and policy analyses, therefore, may improve the evaluation of H pylori screen-and-treat programs. The actual benefit depends on the extent to which H pylori triggers an irreversible pathway to disease early in life.</p
'Identifying Social Factors that Stratify Health Opportunities and Outcomes (ISSHOOs) in Pain Research':Explanation and elaboration to support the standardised reporting of equity-relevant data
No full textBACKGROUND: The 'ISSHOOs (Identifying Social factors that Stratify Health Opportunities and Outcomes) in pain research' project endeavoured to address the paucity and inconsistency of equity-relevant, socio-demographic data collection and reporting in human adult pain research. The resulting 'ISSHOOs Recommendations' provide a data collection tool that has practical utility, is globally and cross-culturally relevant, adaptable, and freely accessible.OBJECTIVE: This explanation and elaboration manuscript is a companion to the ISSHOOs Recommendations. It aims to elaborate on the published recommendations and provide practical guidance to broaden understanding and facilitate use.METHODS: We provide item specific information relevant to each of the eight items in Set A (the minimum dataset) - including relevant background, rationale and guidance for item tailoring to suit specific populations and contexts. We discuss the selection of a sub-set of relevant items from Set B (the extended, optional dataset) and suggest how the ISSHOOs data have the potential to complement efforts to address equity concerns in analyses, interpretation and reporting.CONCLUSION: It is timely and important to improve and standardise the reporting of equity-relevant, socio-demographic data in pain research. The ISSHOOs recommendations, supported by this manuscript, have the potential to promote equity-relevant awareness and understanding and advance progress towards reducing health inequities for people with pain.</p
Young Spanish Women Migrants as Au Pairs in the UK:Cleaning and Childcare During the COVID-19 Pandemic
No full textSince the 2008 financial crisis, the UK has emerged as a popular destination for young Spanish women navigating labour precariousness through (formerly intra-European Union) migration. Many adopt the au pair pathway as a strategic means to improve their English language skills and enhance future employability. However, while framed as a “cultural exchange”, the au pair scheme has faced sustained critique for masking a reality often characterised by precarious work, exploitation, and even abuse due to the great dependency of au pairs on host families and the various forms of worker control au pairs are exposed to. These dynamics were only exacerbated during the COVID-19 pandemic. Drawing on seven qualitative interviews with au pairs with a Spanish migration background and direct experience as an au pair by one of this article’s authors, this article applies the labour process theory (LPT) to interrogate the deterioration of living and working conditions for au pairs in the UK. The analysis demonstrates how the interplay of three distinct worker control mechanisms, intersecting with gendered vulnerabilities, intensified the subjugation of this specific group of domestic and care workers during the global health crisis.</p
On working across disciplinary boundaries: PFAS as state-facilitated corporate environmental crime
No full textUnderstanding PFAS pollution requires more than toxicology and epidemiology. This blog shows how a criminological lens helps explain how PFAS pollution emerged, why it persisted for decades, and how responsibility is still shifted onto affected communities
Checkpoint Blockade Combinations in Tumor Mutational Burden/Load-High Tumors:Insights from the Atezolizumab + Bevacizumab and Nivolumab + Ipilimumab Cohorts in the Drug Rediscovery Protocol
No full textPURPOSE: To evaluate the efficacy of atezolizumab plus bevacizumab (atezo + beva) in tumors with high tumor mutational burden (TMB; number of mutations per megabase) and nivolumab plus ipilimumab (nivo + ipi) in tumors with high TMB or tumor mutational load (TML; total number of nonsynonymous mutations across the genome).PATIENTS AND METHODS: Patients with treatment-refractory, solid tumors were treated in the Drug Rediscovery Protocol (2023-509152-33-00). Patients with microsatellite-stable tumors harboring a TML of 200 to 1,000 or TMB of 11 to 24 (Oncomine) or 15 to 39 (TSO500) were eligible for nivo + ipi. Similar patients with a panel-independent TMB ≥16 received atezo + beva. Clinical benefit (CB; confirmed objective response or stable disease ≥16 weeks) was the primary endpoint. Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. RESULTS: Among 25 evaluable patients with 14 different tumor types treated with atezo + beva, the CB rate was 60% [95% confidence interval (CI), 39-79], with an objective response rate of 24% (95% CI, 9-45) and a median duration of response of 25.0 months (95% CI, 13.8-not applicable). In the nivo + ipi cohort, the CB rate was 50% (95% CI, 29-71) and objective response rate was 37.5% (95% CI, 19-59) among 24 evaluable patients with 13 distinct tumor types. The median duration of response was not reached after a median follow-up of 36 months. In both cohorts, responses were observed only in patients with TMB >20, and TMB and (clonal) TML were significantly correlated with response. Various markers of adaptive immune infiltration were associated with longer progression-free survival. CONCLUSIONS: Atezo + beva and nivo + ipi showed durable responses in patients with TMB >20, underscoring their tumor-agnostic efficacy in this patient population.</p