Citations

Abstract Background: amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease, characterised by the progressive degeneration of upper and lower motor neurons in the brain and spinal cord. Despite substantial advances in the understanding of underlying disease mechanisms, effective therapies remain lacking. Methods: we generated spinal cord organoids from patient-derived induced pluripotent stem cells and matched isogenic controls to model in vitro the molecular pathology associated with the hexanucleotide repeat expansion within the C9orf72 gene. Results: C9orf72 organoids displayed delayed neuronal maturation, axonal degeneration, mitochondrial abnormalities, enhanced apoptotic signaling, and accumulation of dipeptide repeat proteins. Integrated multi-omics analyses revealed a consistent down-regulation of Netrin-1 at both the transcript and protein levels across patient-derived organoids, suggesting that its loss may contribute to impaired neuronal connectivity, compromised axonal integrity, and increased motor neuron vulnerability in C9orf72 amyotrophic lateral sclerosis. Conclusions: together, these findings establish patient-derived spinal cord organoids as a biologically relevant and in vitro model that recapitulates key cellular and molecular hallmarks of C9orf72-associated amyotrophic lateral sclerosis. This platform provides a valuable framework to deepen disease mechanisms, toward the development of new effective therapeutic strategies.

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Purpose of review This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses and mitigate glucocorticoid (GC)-related morbidity. Recent findings The standard of care for GCA has traditionally involved prolonged use of GC, and recent studies are exploring faster GC tapering regimens in an effort to reduce adverse effects while maintaining disease control. Randomized clinical trials have highlighted the efficacy of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in reducing disease flares and sparing GCs. However, the optimal treatment duration with TCZ is unknown and patients remain at risk of relapse after treatment discontinuation. An unmet therapeutic need persists for patients who are not candidates for TCZ, and for those who have inadequate response to this biologic. Therefore, investigations into alternative therapies such as targeting interleukin-17A, blocking T-cell activation or inhibiting the Janus kinase–signal transducer and activator of transcription pathway, showcase potential avenues for tailored treatments. Summary While GCs remain the cornerstone of therapy, TCZ emerges as a promising GC-sparing agent. Ongoing research targeting different pathways implicated in GCA pathogenesis have led to encouraging results. However, the preliminary nature of these findings necessitates larger randomized controlled trials to establish their efficacy conclusively.

AbstractINTRODUCTIONDementia with Lewy bodies (DLB) is typically characterized by parietal, temporal, and occipital atrophy, but less is known about the newly defined prodromal phases. The objective of this study was to evaluate structural brain alterations in prodromal DLB (p‐DLB) as compared to healthy controls (HC) and full‐blown dementia (DLB‐DEM).METHODSThe study included 42 DLB patients (n = 20 p‐DLB; n = 22 DLB‐DEM) and 27 HC with a standardized neurological assessment and 3‐tesla magnetic resonance imaging. Voxel‐wise analyses on gray‐matter and cortical thickness were implemented to evaluate differences between p‐DLB, DLB‐DEM, and HC.RESULTSp‐DLB and DLB‐DEM exhibited reduced occipital and posterior parieto‐temporal volume and thickness, extending from prodromal to dementia stages. Occipital atrophy was more sensitive than insular atrophy in differentiating p‐DLB and HC. Occipital atrophy correlated to frontotemporal structural damage increasing from p‐DLB to DLB‐DEM.DISCUSSIONOccipital and posterior‐temporal structural alterations are an early signature of the DLB continuum and correlate with a long‐distance pattern of atrophy.

Abstract Basophils infiltrate the skin and other tissues as part of T lymphocyte and/or antibody-mediated immune responses to certain protein antigens, viruses, tumors, and parasites. Although basophils may comprise a significant fraction of leukocytes in these reactions, their precise role has been poorly understood. Guinea pigs expressing acquired immunity to the tick Amblyomma americanum develop basophil- and eosinophil-rich cutaneous inflammatory responses at tick feeding sites, and tick rejection is associated with extensive local basophil degranulation. We report that a specific anti-basophil serum (ABS) eliminate basophils at tick feeding sites and abolished immunity to A. americanum. ABS does not react with eosinophils and did not reduce blood or bone marrow eosinophils; however, ABS-treated animals had diminished eosinophils at tick feeding sites, perhaps because these sites were deficient in basophil-derived eosinophil-chemotactic factors. AES treatment markedly reduced feeding site eosinophils, did not affect basophil levels, and partially impaired tick resistance. Taken together, our experiments suggest cooperation between basophils and eosinophils in the expression of immunity to ticks in guinea pigs.

Abstract Aims Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. Methods and results We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65–0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96–1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. Conclusion In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. Study registration number This study is registered in PROSPERO (CRD42021258603). Key Question A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. Key Finding In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. Take Home Message A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.