Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years

Clonal hematopoiesis (CH), characterized by a fraction of peripheral blood cells carrying an acquired genetic variant, emerges with age. Although in general CH is associated with increased mortality and morbidity, no higher risk of death was observed for individuals ≥80 years. Here, we investigated CH in 621 individuals aged ≥80 years from the population-based LifeLines cohort. Sensitive error-corrected sequencing of 27 driver genes at a variant allele frequency ≥1% revealed CH in the majority (62%) of individuals, independent of gender. The observed mutational spectrum was dominated by DNMT3A and TET2 variants, which frequently (29%) displayed multiple mutations per gene. In line with previous results in individuals ≥80 years, the overall presence of CH did not associate with a higher risk of death (hazard ratio, 0.91; 95% confidence interval, 0.70-1.18; P = .48). Being able to assess the causes of death, we observed no difference between individuals with or without CH, except for deaths related to hematological malignancies. Interestingly, comparison of mutational spectra confined to DNMT3A and TET2 vs spectra containing other mutated genes, showed a higher risk of death when mutations other than DNMT3A or TET2 were present (hazard ratio, 1.48; 95% confidence interval, 1.06-2.08; P = .025). Surprisingly, no association of CH with cardiovascular morbidity was found, irrespective of clone size. Further, CH associated with chronic obstructive pulmonary disease. Data on estimated exposure to DNA damaging toxicities (ie, smoking, a history of cancer [as a proxy for previous genotoxic therapy], and job-related pesticide exposure) showed an association with spliceosome and ASXL1 variants, but not with DNMT3A and TET2 variants

The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients

The Diversity of Religious Diversity. Using Census and NCS Methodology in Order to Map and Assess the Religious Diversity of a Whole Country

Religious diversity is often captured in “mapping studies” that use mostly qualitative methods in order to map and assess the religious communities in a given area. While these studies are useful, they often present weaknesses in that they treat only limited geographic regions, provide limited possibilities for comparing across religious groups and cannot test theories. In this article, we show how a census and a quantitative national congregations study (NCS) methodology can be combined in order to map and assess the religious diversity of a whole country (Switzerland), overcoming the problems mentioned above. We outline the methodological steps and selected results concerning organizational, geographic, structural, and cultural diversity

Appartenances en fête : entre l’ordinaire et le spectaculaire

Résumé Alors que les pratiques religieuses régulières diminuent et que les groupes religieux majoritaires perdent des membres formellement enregistrés, une évènementisation de l'appartenance religieuse peut être observée depuis environ deux décennies. Dans un premier exemple, l'auteure montre que le réseau transnational de la confrérie soufie des Mourides resserre les liens entre adeptes dans un contexte migratoire qui tend à fragiliser les relations sociales. La confrérie y fait face à travers une spectacularisation de la pratique religieuse, occupant l'espace public à Harlem ou, dans une moindre mesure, à Paris. Le second exemple traite du pèlerinage aux Saintes et Saints d'Afrique dans la ville valaisanne de Saint Maurice. Ce dernier fut inventé par l'Église catholique suisse afin d'attirer des migrants africains, mais aussi afin de redynamiser une pratique religieuse ordinaire en perte de vitesse. L'évènement a lieu en même temps que le pèlerinage de Namugongo en Ouganda, réunissant plus d'un demi-million de personnes. Les communautés évènementielles ainsi créées sont-elles durables ou plutôt liquides ? Abstract While regular religious practice is decreasing and the major religious groups are losing formally registered members, a 'spectacularization' of religious belonging can be observed over the last two decades. The author presents two examples to support this argument. In the first, the transnational network of the Murids, a Sufi brotherhood, has tried to reinforce the relations between its members, which become fragile during migration. The brotherhood occupies a public space in Harlem, and, to a lesser extent, in Paris, in a spectacularization of religious belonging, in order to remain attractive to migrants. The second example deals with the pilgrimage dedicated to African Saints in the Swiss town of Saint Maurice. This event was invented by the missionary service of the Swiss Catholic Church in order to attract African migrants, but also in order to make ordinary religious practice more appealing. The event takes place at the same time as the Ugandan pilgrimage of Namugongo, which assembles more than half a million people. However, are these 'event communities' sustainable or ephemeral

Outcome of catheter ablation of non-reentrant ventricular arrhythmias in patients with and without structural heart disease

Background Catheter ablation of non-reentrant, commonly termed idiopathic ventricular arrhythmias (VA) is highly effective in patients without structural heart disease (SHD). Meanwhile, the outcome of catheter ablation of these arrhythmias in patients with SHD remains unclear. This study sought to characterize the outcome of patients with and without SHD undergoing catheter ablation of non-reentrant VA. Methods In this single-centre study the acute and long-term outcome of 266 consecutive patients undergoing catheter ablation of non-reentrant VA was investigated. In 41.0% of patients a SHD was present (n = 109, 80.7% male, age 59.1 +/- 14.7 years), 59.0% had no SHD (n = 157; 44.0% male, age 49.9 +/- 16.5 years). Results Acute procedural success (absence of spontaneous or provoked VA at the end of procedure and within 48 h after the procedure) was achieved in 89.9% of patients with SHD vs. 94.3% without SHD (p = 0.238). During a mean follow-up of 34.7 +/- 15.1 months a repeat catheter ablation was performed in 19.6% of patients with SHD vs. 13.0% without SHD (p = 0.179). Patients with dilated cardiomyopathy (DCM) were the most likely to require a repeat ablation procedure (32.0% of patients with DCM vs. 13.0% without SHD; p = 0.022). Periprocedural complications occurred in 5.5% of patients with SHD vs. 5.7% without SHD (p > 0.999). All complications were managed without sequelae. Conclusions The outcome of catheter ablation of non-reentrant VA in patients with SHD appears good and is comparable to patients without SHD. A slightly higher rate of repeat ablations was observed in patients with DCM