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The prevalence and clinical significance of clonal monocytosis
No full textClonal hematopoiesis (CH), the expansion of single hematopoietic stem cell (HSC)-derived lineages driven by somatic mutations, is a common, age-related phenomenon that confers an increased risk of myeloid neoplasia (MN) and non-hematological disorders, such as atherosclerotic cardiovascular disease (ASCVD) and acute kidney injury (AKI)1–6. The presence of CH is known to be associated with alterations in complete blood count (CBC) indices such as the red cell distribution width (RDW), which correlate with risk of progression to MN7–9. In particular, the presence of an unexplained cytopenia in the context of CH, a state known as clonal cytopenia of undetermined significance (CCUS), has been shown to portend a high risk of transformation to MN9. Importantly, CCUS encompasses a spectrum of risk, which can be stratified using clinical and genomic features such as mutation number, cytopenia severity and the presence of splicing factor mutations, as incorporated into the Clonal Hematopoiesis Risk Score (CHRS)9 and Clonal Cytopenia Risk Score (CCRS)10. Individuals with high-risk CCUS exhibit similar overall survival to those with low-risk myelodysplastic syndrome (MDS)11, consistent with CCUS representing a discrete clinico-pathological entity on the biological continuum between CH and overt MDS.
More recently, the terms clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia and monocytosis of undetermined significance (CCMUS) were introduced by the International Consensus Classification of Myeloid Neoplasms (ICC)12 to describe individuals with CH and a concurrent relative or absolute monocytosis (monocytes ≥0.5 x 109/L and ≥10% of leukocytes) with or without cytopenia, respectively, who do not meet diagnostic thresholds for chronic myelomonocytic leukemia (CMML). By design, these entities aim to resolve a diagnostic ambiguity in clinical practice: differentiating clonal monocytosis (with malignant potential) from reactive monocytosis, which is common, may be transient, and is typically benign. Additionally, the definitions of CMUS and CCMUS were conceived to delineate and label the blurred margins between CH with monocytosis and CMML, but their practical relevance to the wider population remains unclear. To date, studies of CH and concurrent monocytosis have focused on curated cohorts from clinical academic centres: a single study of 97 individuals with CCMUS demonstrated that these cases have a mutational spectrum and clinical outcomes reminiscent of CMML10, whilst a study of clinically significant monocytosis showed that amongst individuals with a detectable driver mutation, outcomes were comparable between those meeting the diagnostic criteria for CMML and those who did not13. Amongst individuals in the Lifelines cohort with absolute monocytosis (monocytes ≥1 x 109/L) and CH, the rate of progression to myeloid neoplasia was reported to be low (4/166 individuals), although this study was limited by relatively short follow-up (median 3.8 years)14. Currently, there are no studies assessing the frequency and characteristics of CMUS and CCMUS (as defined by the ICC) at the population level.
Here, we sought to determine the prevalence and significance of CMUS and CCMUS amongst 431,531 United Kingdom Biobank (UKB) participants, through analysis of clinical, genomic and outcome data. We show that CMUS with an absolute (rather than only relative) monocytosis and CCMUS are high-risk clonal entities, strongly associated with incident MN, cardiovascular and renal disease, and propose amendments to further refine the definition of CMUS. Finally, prompted by our finding that monocytosis with SRSF2 mutations is associated with poor outcomes, we develop and validate MoSAIC (Monocytosis with SRSF2 Automatically Inferred from Counts), a scalable machine-learning classifier to infer the presence of monocytosis bearing SRSF2 mutations using complete blood count (CBC) indices alone.</p
Exploratory transcriptomic analysis of mouse articular cartilage in response to tissue inhibitor of metalloproteinase 3 identifies inflammation-associated gene expression changes
No full textNo description supplied</p
Realization of reconfigurable intelligent surfaces with space-time-coded metasurfaces
No full textThis paper presents experimental realization of a reconfigurable intelligent surface (RIS) using space-time-coded metasurfaces to enable concurrent beam steering and data modulation. The proposed approach harnesses the capabilities of metasurfaces, allowing precise temporal control over individual unit cells of the RIS. We show that by employing proper binary codes manipulating the state of unit cells, the RIS can act as a digital data modulator with beam steering capability. We describe the experimental setup and computational tools, followed by validation through harmonic generation and investigation of beam steering and data modulation. Additionally, four digital modulation schemes are evaluated. By implementing customized binary codes, constellations under varying conditions are compared, showcasing the potential for real-world applications. Moreover, we present a methodology to determine the optimal phase distribution over the metasurface when the channel state information (CSI) is unavailable. The proposed approach removes the need for computationally intensive optimization algorithms. This study offers new insights into the practical implementation of RIS for advanced wireless communication systems.</p
Overcoming structural barriers to tuberculosis treatment in Africa through digital technologies
No full textNo description supplied</p
4MOST Cosmology Redshift Survey (CRS): Clustering properties of CRS bright galaxy and luminous red galaxy target catalogues
No full textThe 4-metre Multi-Object Spectroscopic Telescope Cosmology Redshift Survey (4MOST CRS) will obtain 5.4 million spectroscopic redshifts over ~5700 deg2 to map large-scale structure and enable measurements of baryon acoustic oscillations, growth rates via redshift-space distortions, and cross-correlations with weak-lensing surveys. We validate the target selections, photometry, masking, systematics, and redshift distributions of the bright galaxy (BG) and luminous red galaxy (LRG) target catalogues selected from the Dark Energy Spectroscopic Instrument (DESI) Legacy Survey DR10.1 (LS) imaging. We measure the angular two-point correlation function, w(θ), test masking strategies, and recover redshift distributions via cross-correlation with DESI DR1 spectroscopy. For BGs, we adopt LS MASKBITS that veto bright stars and extended sources; for LRGs, we pair these with unblurred coadds of the WISE imaging (unWISE) W1 artefact masks. These choices suppress small-scale excess power without imprinting large-scale modes. A Limber-scaling test across BG r-band magnitude slices shows that, after applying the scaling, the w(θ) curves collapse to a near-common power law, demonstrating photometric uniformity with depth and consistency between the North and South Galactic Caps. Cross-correlations with DESI spectroscopy recover the expected N(z), albeit with high shot noise at the brightest magnitudes. For LRGs, angular clustering in photo-z slices (0.4 ≤ z </p
Updated recommendations for the design of therapeutic trials for neonatal seizures
No full textAbstract: The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren’t sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated. Impact: This review provides an update to the initial recommendations for neonatal seizure treatment trial design, with recommendations regarding: (1) exploratory endpoints to inform future trials, (2) additional key covariates to include, (3) considerations regarding masking of investigators, (3) inclusion of concomitant medications and adverse events, (4) genetic testing, (5) strategies for recruitment and consent, and (6) infrastructure and operational feasibility.</p
CSF hypo-inflammation drives mortality in HIV-associated tuberculous meningitis
No full textBACKGROUND: Outcomes in tuberculous meningitis (TBM) are closely linked to host inflammation. Anti-inflammatory corticosteroid therapy improves survival in HIV-negative TBM, but not in people with HIV. In people with HIV, TBM is fatal in 40-50% of cases. Therefore, we investigated how mortality is associated with the local immune response in people with HIV-associated TBM. METHODS: We measured baseline concentrations of immune signalling mediators in cerebrospinal fluid (CSF) of 149 adults with HIV in Uganda, who presented with definite or probable TBM. Participants received both antimycobacterial and corticosteroid therapy. RESULTS: At baseline, non-survivors had more severe TBM disease and lower blood CD4 T cells than survivors. Mortality at 90 days was strongly associated with CSF hypo-inflammation. CSF interferon gamma (IFN-γ) was most differentially expressed by survivors (2.2 log2-fold change higher, p=.003), and 90-day mortality was lower with increasing concentrations (Tertile-1=50%, Tertile-2=41%, Tertile-3=18%; p=.006). Even among people who successfully mounted a CSF cellular immune response (>5 white cells/μL CSF), those with low CSF IFN-γ had higher risk of death (Hazard Ratio =3.10 (1.44-6.68). Interleukin-13 had a more complex relationship, with lower mortality among people with intermediate CSF interleukin-13 concentrations but higher at the two extremes (Tertile-1=45%, Tertile-2=22%, Tertile-3=40%; p=.017). Of all sub-groups, those with both peripheral CD4 depletion and low CSF IFN-γ had the highest mortality (63%). CONCLUSIONS: In adults with HIV-associated TBM receiving dexamethasone, mortality was strongly associated with CSF hypo-inflammation. Although steroids may be appropriate in those with high inflammation, personalized approaches to immunotherapy are likely necessary to improve outcomes.</p
Against fascist fantasies: theorizing racial capitalism in (Post)Imperial Europe
No full textThis issue examines the history and contemporary articulations of racial capitalism within Europe. Challenging the idea that Europe is a homogeneous white entity, it interrogates how racialization and colonization have long been central to capital accumulation within the heart of empire. Today Europe's (post)imperial present remains underwritten by neocolonial relations of extraction, projects of Indigenous dispossession, and racialized regimes for controlling the mobility and availability of labor. Migrant guest workers helped build many European welfare states, even as they were denied full rights and citizenship. Extraction economies in the Arctic and northern Fennoscandia continue to dispossess and displace Europe's Indigenous peoples, while destroying planetary conditions for life. And the common market increased labor mobility within the EU while opening up central and eastern Europe to capital and closing the border to migrants from Europe's former colonies and refugees fleeing US‐led wars. With specters of fascism and racialized moral panics over immigration and (white) demographic decline on the rise, this special issue contends that reckoning with Europe's links to racial capitalism, both historical and contemporary, is not only diagnostically probative but also politically urgent.</p
Shakespeare’s impersonations: Ariosto and the game of 'sorti' in Much Ado About Nothing
No full text'Much Ado About Nothing', first published in 1600, is a play of dissimulation. Complex disguises, literal and emotional, persuade individuals into both declarations and disavowals of feelings. Claudio, in particular, is duped into humiliating his betrothed Hero by an elaborate trick in which she is made to seem unfaithful through a proxy performance of erotic arousal. It has long been assumed that a direct or indirect source for this major element in Shakespeare’s plot derives from Canto V of Ariosto’s Orlando Furioso, in which the servant Dalinda impersonates Ginevra on the balcony, to the most painful chagrin of Ginevra’s lover Ariodante. However, Shakespeare’s interest in dissimulation goes much further than this. Dissimulatio is the Latin rhetorical term in which the whole point is that the distinction between real and simulated feeling is often impossible to decipher, as Cicero and Quintilian discussed on several occasions. Moreover, the idea of impersonation merges with the developing discourse of personation on the stage: the ability of an actor to simulate the feelings of a different person, even without disguise. By ‘traveling through a textual labyrinth’, as Umberto Eco puts it, this essay investigates the presence of Ariosto’s Orlando Furioso among the complex sources of this Shakespearean play, whose comedic plot apropos of an unjustly accused character may reveal elements of tribute to Giordano Bruno’s ‘heroic’ pursuit of truth. In doing so, we aim to discern how Ariosto’s allegoric effects are diffused in Shakespeare’s play of betrayed emotions and epistemic quest.</p
The European Arrest Warrant as a transnational policing tool
No full textThe European Arrest Warrant is a transnational policing tool. It facilitates the transfer of law enforcement power from the requesting state, across national boundaries, to co-opt the criminal justice agencies of the executing state. The warrant is given effect by police in the executing state through the application of coercive force. Based on empirical data collected between 2016 and 2017 this paper explores the European Arrest Warrant (EAW) from the perspective of the police agencies involved in its operation. It describes the pivotal role that law enforcement agencies play in Europe’s system of surrender, arguing that the EAW (and its post-Brexit successor is a mechanism for the mutual recognition of the use of force, the defining feature of the police.</p