The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe: a CENTER-TBI analysis

peer reviewedPurpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01). Conclusions: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources. © 2020, The Author(s)

Frequency of fatigue and its changes in the first 6 months after traumatic brain injury: results from the CENTER-TBI study

peer reviewedBackground: Fatigue is one of the most commonly reported subjective symptoms following traumatic brain injury (TBI). The aims were to assess frequency of fatigue over the first 6 months after TBI, and examine whether fatigue changes could be predicted by demographic characteristics, injury severity and comorbidities. Methods: Patients with acute TBI admitted to 65 trauma centers were enrolled in the study Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). Subjective fatigue was measured by single item on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), administered at baseline, three and 6 months postinjury. Patients were categorized by clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU). Injury severity, preinjury somatic- and psychiatric conditions, depressive and sleep problems were registered at baseline. For prediction of fatigue changes, descriptive statistics and mixed effect logistic regression analysis are reported. Results: Fatigue was experienced by 47% of patients at baseline, 48% at 3 months and 46% at 6 months. Patients admitted to ICU had a higher probability of experiencing fatigue than those in ER and ADM strata. Females and individuals with lower age, higher education, more severe intracranial injury, preinjury somatic and psychiatric conditions, sleep disturbance and feeling depressed postinjury had a higher probability of fatigue. Conclusion: A high and stable frequency of fatigue was found during the first 6 months after TBI. Specific socio-demographic factors, comorbidities and injury severity characteristics were predictors of fatigue in this study. © 2020, The Author(s)

Prise en charge des azoospermies par micro-injection de spermatozoïdes testiculaires ou épididymaires (à propos de 77 patients suivis en médecine de la reproduction)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Past and future events specificity in bipolar disorders

Previous research has shown that the individuals suffering from emotional disorders have specificity of autobiographical memory (AM) deficits. This difficulty to remember specific personal past events seems related to difficulty to project specific oneself into the future (D’Argembeau, Raffard & Van der Linden, 2008). The aim of this study was investigated these impairments in population with bipolar disorders (BD). Participants (19 patients with bipolar disorders and 17 healthy subjects) completed validated French versions (Neumann & Philippot, 2006) of the AMT Williams & Broadbent (1986). Participants were instructed to generate specific past and future memories in response to cues words. For past events, the analyses revealed a significant group by memory interaction (F(2,68) = 4.0 ; p=.023) which indicates that the patients with BD recollected less specific events and more overgeneral events than controls. In the same way, for the future events task, a significant group by memory interaction emerged (F(2,68) = 7.85 ; p<.001) which indicates that the patients with BD were less specific and yielded more overgeneral memories than the control group. Thereby the results are consistent with previous studies that have examined autobiographical memory specificity in patients with BD (Scott et al., 2000; Mansell & Lam, 2004). However, to ours knowledges, the present study is the first to investigate specificity of AM and the abilities to generate specific events for future in patients with bipolar disorders

Autobiographical memory and problem solving in bipolar disorder

Objective: The aim of the present study was to investigate the abilities to remember specific past personal events as well as the abilities to generate specific future events in patients with bipolar disorders (BD). Moreover, the study investigated whether the abilities to generate specific events is related to the abilities to solve interpersonal problems which was measured using the Optional Thinking Test (OTT) (Platt & Spivack, 1977). Method: Nineteen patients with bipolar disorders and 17 healthy subjects completed validated French versions (Neumann & Philippot, 2006) of the AMT Williams & Broadbent (1986). Participants were instructed to generate specific past and future memories in response to cues words. For the OTT, they were asked to yield the most solutions as possible to daily problems. Results: For the past events task, the analysis revealed a significant group by memory interaction (F(2,68) = 4.0 ; p=.023) which indicates that the patients with BD recollected less specific events and more overgeneral events than controls. For the future events task, a significant group by memory interaction emerged (F(2,68) = 7.85 ; p<.001) which indicates that the patients with BD were less specific and yielded more overgeneral memories than the control group. Further, the numbers of specific past and future events were correlated to the numbers of solutions to interpersonal problems (r(36) = .57 ; p<.001, r(36) = .43 ; p=.009, respectively). Conclusion: the results are consistent with previous studies that have examined autobiographical memory (AM) specificity in patients with BD (Scott et al., 2000; Mansell & Lam, 2004). These results support the notion of impairments in imagining specific past and future events BD patients. The difficulty in imagining the future may contribute to relapse. Thus, AM remediation program could be an additional useful tool to develop in CBT for bipolar patients