Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study.

Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full-blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow-up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.

[Contribution of equine therapy in the management of post-traumatic stress disorder]. / Apport de la thérapie équine dans la prise en charge du trouble de stress post-traumatique.

For several years, animal-mediated therapies have been used in the treatment of psychiatric patients. Post-traumatic stress disorder has the particularity of being generated by an external event in a person a priori free of mental pathology. In this disorder, various so-called targeted psychotherapies have proven to be effective, including equine therapy.

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

Determinants of Care Pathways for C-PTSD Patients in French Psychotrauma Centers: A Qualitative Study.

In 2018, the International Classification of Diseases (ICD-11) established a novel nosographic category within the stress-specific disorders known as complex post-traumatic stress disorder (C-PTSD). Characterized by distinctive clinical attributes and a limited response to conventional PTSD treatments, C-PTSD has prompted the reconsideration of care methods. Our study's purpose was to explore the intricate factors shaping the care pathways for individuals suffering from C-PTSD. We used a grounded theorization technique involving professionals across a range of specialized French psychotraumatology institutions. The resulting comprehensive theoretical model offers valuable insights into the constitution mechanisms of these pathways, helping elucidate the varying care options. Interestingly, we found that differences in clinical perspectives were determined by the care provider's viewpoint on clinical guidelines, screening tools, and treatment options, but also by structural and organizational factors. The distinctive dynamics and interrelationships identified in our research reveal potential areas of focus for incorporating C-PTSD care more effectively into specialized French trauma centers. This investigation offers a path toward improved understanding and management of C-PTSD, ultimately advancing patient outcomes.

Experiences of Inter-Hospital Transfers (IHT) by Patients and Relatives during the COVID-19 Pandemic in France: A Qualitative Study.

BACKGROUND: The first wave of the COVID-19 epidemic led to a rapid and unexpected saturation of the French ICU, forcing the health care system to adapt. Among other emergency measures, inter-hospital transfers were carried out. OBJECTIVE: To assess the psychological experience of patients and their relatives regarding inter-hospital transfers. METHODS: Semi-structured interviews were conducted with transferred patients and their relatives. A phenomenological study design was used to examine subjective experiences and their meanings for the participants. RESULTS: The analysis found nine axes pertaining to the experiences of IHT (inter-hospital transfers), grouped in three super-ordinate themes: Information about inter-hospital transfers, differences in patients' and relatives' experiences, and host hospital experience. It appears that patients felt little impacted by the transfers, unlike relatives who experienced intense anxiety when the transfer was announced. Good communications between patients and their relatives resulted in a good level of satisfaction regarding their host hospitals. COVID-19 and its somatic consequences seem to have had more psychological impact on the participants than the transfers by themselves. CONCLUSION: Our results suggest that there are limited current psychological consequences of the IHT implemented during the first wave of COVID-19, although the involvement of patients and their relatives in the organization of the IHT at the time of transfer could further limit them.

Factors Associated with Increased or Decreased Stress Level in French Children during the First COVID-19 Lockdown.

In spring 2020, governments of many countries implemented lockdown measures to prevent the spread of the COVID-19 pandemic. Worldwide, the pandemic forced about 1.5 billion children to stay at home for several weeks and to experience homeschooling. The objective of this study was to assess the variation in stress levels and associated factors in school-aged children in France during the first COVID-19 lockdown. A cross-sectional study using an online questionnaire was designed by an interdisciplinary team involving hospital child psychiatrists and school doctors. Between 15 June and 15 July 2020, Educational Academy of Lyon (France) invited the parents of school-aged children to participate in this survey. The first part of the questionnaire concerned the children with data on lockdown conditions, socio-demographic data, daily rhythms (eating and sleeping), perceived stress variations, and feelings. The second part assessed parental perspectives on their child's psychological state and use of the mental health care system. Multivariate logistic regression was performed to identify factors associated with stress variation (increased or decreased). A total of 7218 questionnaires were fully completed by children from elementary school to high school with a balanced sex ratio. In summary, 29% of children reported a higher stress level during the lockdown, 34% reported a lower stress level, and 37% reported no stress variation in the usual situation prior to COVID-19. Parents were most often able to identify signs of increased stress levels in their children. The most influential factors in the variation of stress for children were academic pressure, family relationships, and fear of being infected or infecting a family member with SARS-CoV-2. Our study underlines the high impact of school attendance stressors on children in usual conditions and encourages vigilance for children whose stress levels have decreased during the lockdown but who may have increased difficulty re-exposing themselves upon deconfinement.

HTLV-1 positive and negative T cells cloned from infected individuals display telomerase and telomere genes deregulation that predominate in activated but untransformed CD4+ T cells.

Untransformed HTLV-1 positive CD4(+) cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4(+) cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4(+) but not uninfected CD4(+) or CD8(+) clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4(+) cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression.

Rare Circulating Cells in Familial Waldenström Macroglobulinemia Displaying the MYD88 L265P Mutation Are Enriched by Epstein-Barr Virus Immortalization.

The MYD88 L265P is a recurrent somatic mutation in neoplastic cells from patients with Waldenström Macroglobulinemia (WM). We identified the MYD88 L265P mutation in three individuals from unrelated families, but its presence did not explain the disease segregation within these WM pedigrees. We observed the mutation in these three individuals at high allele fractions in DNA extracted from EBV-immortalized Lymphoblastoid cell lines established from peripheral blood (LCL), but at much lower allele fractions in DNA extracted directly from peripheral blood, suggesting that this mutation is present in a clonal cell subpopulation rather than of germ-line origin. Furthermore, we observed that the MYD88 L265P mutation is enriched in WM families, detected in 40.5% of patients with familial WM or MGUS (10/22 WM, 5/15 MGUS), compared to 3.5% of patients with familial MM or MGUS (0/72 MM, 4/41 MGUS) (p = 10-7). The mutant allele frequency increased with passages in vitro after immortalization with Epstein-Barr virus (EBV) consistent with the MYD88 L265P described gain-of-function proposed for this mutation. The MYD88 L265P mutation appears to be frequently present in circulating cells in patients with WM, and MGUS, and these cells are amenable to immortalization by EBV.

Chromatin redistribution of the DEK oncoprotein represses hTERT transcription in leukemias.

Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.

Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias.

OBJECTIVE: Telomeres are protected by tightly regulated factors and elongated by telomerase. Short and/or deprotected chromosomes are recombinogenic and thereby cancer prone. MATERIALS AND METHODS: Together with the quantification of telomerase activity (TA), measuring telomere length (TL) and expression of the genes that govern telomere protection and elongation are useful for assessing telomere homeostasis. RESULTS: By these means we demonstrate that TL, hTERT, and TA are in the order acute myelogenous leukemia (AML) > T-cell acute lymphoblastic leukemia (T-ALL) > B-cell acute lymphoblastic leukemia (B-ALL) > T-ALL > AML, and B-ALL > AML > T-ALL. AML0 and AML3 display the lowest amounts of hTERT transcripts, and ALL and AML cells with cytogenetic abnormalities possess the shortest telomeres. hTERT expression includes phenotype-specific RNA maturation and correlates with TA but not with TL. A wide ratio of TA to hTERT expression between leukemia subtypes suggests phenotype-specific hTERT post-transcriptional deregulations. B- and T-ALL overexpress Ku70 and Pinx1, T-ALL PTOP and RAP1, and B-ALL TRF2, the expression of which is significantly higher in cases with abnormal karyotype. hTERT transcription and TL correlate with response to intensive chemotherapy, and hTERT and RAD50 are independent prognostic factors for survival. CONCLUSIONS: Each leukemia subtype possesses specific telomere dysregulations that rely on phenotype, karyotype, response to treatment, and survival.