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Background To obtain reliable clinical data of human immunodeficiency virus type 1 group O (HIV-1/O) infection, and immunovirological responses to combination antiretroviral therapy (cART), in a large series of 101 patients. Methods Piecewise linear models were used to estimate CD4 count before and after cART initiation. Kaplan-Meier survival curves were used to estimate time to reach clinical stage C before antiretroviral therapy (ART) and to analyze time to achieve a plasma viral load (pVL) <40 copies/mL following cART initiation. Immunovirological response was assessed at the most recent visit in patients on active follow-up. Results Data showed a 16.6% cumulative probability of reaching stage C within 5 years following diagnosis, and a mean CD4 decrease of –30.5 cells/μL/year. cART initiation in ART-naive patients led to a mean CD4 gain of 147 cells/μL after 12 months, and to a median pVL of <40 copies/mL after 3.8 months for 89.3%. Initiation with a nonrecommended nonnucleoside reverse transcriptase inhibitor–based vs a ritonavir-boosted protease inhibitor–based regimen resulted in a much smaller gain of around 100 CD4 cells/μL after 1 year. Patients on follow-up since 2007 had a median CD4 count of 498 cells/μL, and 87% had a pVL <40 copies/mL at the most recent follow-up visit. Conclusions This work provides unique data on HIV-1/O infection, in favor of a milder natural evolution than HIV-1 group M (HIV-1/M) and of a highly efficient current management, based on HIV-1/M guidelines, despite genetic divergence. Studies of comparable HIV-1/M and HIV-1/O populations are needed to confirm these results.

In terms of overall survival (OS), limited data are available for the very long-term outcomes of children treated for optic pathway glioma (OPG) with up-front chemotherapy. Therefore, we undertook this study with the aim of clarifying long-term OS and causes of death in these patients. We initiated and analyzed a historical cohort study of 180 children with OPG treated in France with BB-SFOP chemotherapy between 1990 and 2004. The survival distributions were estimated using Kaplan-Meier method. The effect of potential risk factors on the risk of death was described using Cox regression analysis. The OS was 95% [95% CI: 90.6-97.3] 5 years after diagnosis and significantly decreased over time without ever stabilizing: 91.6% at 10 years [95% CI: 86.5-94.8], 80.7% at 15 years [95% CI: 72.7-86.8] and 75.5% [95% CI: 65.6-83] at 18 years. Tumor progression was the most common cause of death (65%). Age and intracranial hypertension at diagnosis were significantly associated with a worse prognosis. Risk of death was increased by 3.1[95% CI: 1.5-6.2] (p=0.002) for patients less than 1 year old at diagnosis and by 5.2[95% CI: 1.5-17.6] (p=0.007) for patients with initial intracranial hypertension. Boys without diencephalic syndrome had a better prognosis (HR: 0.3 [95% CI: 0.1-0.8], p=0.007). This study shows that i) in children with OPG, OS is not as favorable as previously described and ii) patients can be classified into 2 groups depending on risk factors (age, intracranial hypertension, sex and diencephalic syndrome) with an OS rate of 50.4% at 18 years [95% CI: 31.4-66.6] in children with the worst prognosis. These findings could justify, depending on the initial risk, a different therapeutic approach to this tumor with more aggressive treatment (especially chemotherapy) in patients with high risk factors.

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

Phytochemicals are a potential alternative to antibiotic growth promoters. This study evaluated the effects of phytochemicals (curcuminoids, trans-cinnamaldehyde, and piperine) and monensin on performance and ruminal fermentation during the transition period in grazing dairy cows. In a complete randomized design, 60 Holstein cows (36 multiparous, 24 primiparous; 9 fistulated) were assigned to (1) control (CTL), (2) monensin (MON, 0.30 g/cow/day), or (3) phytochemicals (PHY, 50 g/cow/day) treatment from 30 days prepartum to 60 days postpartum. Prepartum, cows received a total mixed ration (TMR); postpartum, they grazed between a.m. and p.m. milking and were supplemented with TMR. Ruminal fermentation was evaluated at −7, 30, and 60 days postpartum. Prepartum dry matter intake was lower in MON primiparous cows than in CTL and PHY. Additives increased milk yield and lactose percentage in primiparous cows. PHY cows had lower acetate, higher propionate, and reduced acetate-to-propionate and ketogenic-to-glucogenic ratios at 60 days postpartum. MON reduced prepartum protozoa, while PHY increased prepartum branched-chain volatile fatty acids (BCVFAs). Both additives decreased BCVFA and protozoa postpartum. Additives reduced ammonia at 30 days, but only PHY persisted at 60 days. MON and PHY improved primiparous performance, enhanced ruminal fermentation, and promoted glucogenic fermentation while reducing ammonia and protozoa.

Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies. Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies. Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed. Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS1) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor. Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.

CCAAT/enhancer binding protein- β (C/EBP β ) is a basic leucine zipper transcription factor that is abundantly expressed in epidermal keratinocytes of skin. In the present study, C/EBP β epidermal specific conditional knockout (CKO β ) SKH1 mice were utilized to interrogate C/EBP β ’s role in lipid biosynthesis and skin barrier integrity. RNAseq data analysis and gene set enrichment analysis of RNA isolated from the epidermis of CKO β and K5Cre control mice revealed that deletion of C/EBP β in epidermis resulted in an enrichment of downregulated genes in gene sets associated with lipid metabolism. Further analysis showed the majority of differentially regulated genes were downregulated in gene sets related to the metabolism/biosynthesis of ceramides, fatty acids, phospholipids, sphingolipids, and cholesterol species in CKO β epidermis. Ingenuity Pathway Analysis predicted inhibition of multiple pathways involving lipid biosynthesis. Lipidomic analysis of epidermis using advanced chemical separations and tandem mass spectrometry identified 470 individual lipids in epidermis with 165 significantly decreased and 82 significantly increased in CKO β epidermis. The lysophospholipids were the most decreased class of lipids, and free fatty acids and ceramides important in barrier formation were also decreased. The sphingomyelin class of lipids was the most increased. High resolution mass spectrometry for cholesterol lipids revealed several cholesterol esters were also dysregulated in CKO β epidermis. Finally, we assessed the functional consequences of the loss C/EBP β on epidermal barrier function and found that basal permeability barrier function as measured by transepidermal water loss (TEWL) was impaired, with an approximate doubling of TEWL in CKO β mice. These results indicate that C/EBP β is a is a major regulator of the epidermal lipidome and the deletion of C/EBP β in epidermis leads to a defect in skin barrier function.

Should indication for transfusion in paediatric palliative care be based on the child’s perspective rather than the biological results? An 8-year-old boy presenting a relapse of a stage IV neuroblastoma received regular blood transfusions. A severe exophtalmia led the doctors to question the transfusion strategy. Over 7.5 months, the child received 56 red blood cell units and 31 platelet units. He was hospitalised 50 times. Indication for blood test and transfusion may be regularly and collegially reassessed. Transfusion needs in a palliative strategy can be as high as in a curative strategy. Practices, benefits but also ethical and public health dimensions should be more studied.

As mental health issues continue to rise in Latin America, the need for research in this field becomes increasingly pressing. This study aimed to explore the perceived barriers and resources for research and publications among psychiatrists and psychiatry trainees from nine Spanish-speaking countries in South America. Data was collected through an anonymous online survey and analyzed using descriptive methods and the SPSS Statistical package. In total, 214 responses were analyzed. Among the participating psychiatrists, 61.8% reported having led a research project and 74.7% of them reported having led an academic publication. As for the psychiatry trainees, 26% reported having conducted research and 41.5% reported having published or attempted to publish an academic paper. When available, having access to research training, protected research time and mentorship opportunities were significant resources for research. Further support is needed in terms of funding, training, protected research time and mentorship opportunities. However, despite their efforts to participate in the global mental health discussion, Latin American psychiatrists and psychiatry trainees remain largely underrepresented in the literature.

L’article porte sur la mobilisation des cheminots marocains, engagés dans les années 1970 par la SNCF comme contractuels, et ayant fait condamner l’entreprise ferroviaire pour discrimination. L’ethnographie du processus judiciaire explore les relations entre mobilisations et action judiciaire et leurs effets sur la formation des collectifs. En revenant sur les conditions d’une action au long cours, exceptionnelle par le nombre de plaignants, et sur les modalités de sa traduction judiciaire, il montre que la judiciarisation participe à la constitution de ce collectif, mais qu’elle fait apparaître une tension entre conscientisation des plaignants et dépossession par les professionnels du droit. The article deals with the mobilization of Moroccan railway workers. The French national train company hired them as contract workers in the 1970s. They achieved to sentence the company for discrimination. The ethnography of the judicial process explores the relationships between mobilization and legal action and their effects on the formation of a collective. The conditions of a long-term action (which was exceptional because of the number of complainants) and of its judicial translation, show that judicialization participated in the constitution of this group. This process reveals a tension between conscientization of complainants and dispossession by legal professionals.

RésuméL’article porte sur la mobilisation des cheminots marocains, engagés dans les années 1970 par la SNCF comme contractuels, et ayant fait condamner l’entreprise ferroviaire pour discrimination. L’ethnographie du processus judiciaire explore les relations entre mobilisations et action judiciaire et leurs effets sur la formation des collectifs. En revenant sur les conditions d’une action au long cours, exceptionnelle par le nombre de plaignants, et sur les modalités de sa traduction judiciaire, il montre que la judiciarisation participe à la constitution de ce collectif, mais qu’elle fait apparaître une tension entre conscientisation des plaignants et dépossession par les professionnels du droit. THE MAKING OF A JUDICIAL COLLECTIVE. THE MOBILIZATION OF MOROCCAN RAILWAY WORKERS AGAINST DISCRIMINATION AT THE SNCF (FRANCE)The article deals with the mobilization of Moroccan railway workers. The French national train company hired them as contract workers in the 1970s. They achieved to sentence the company for discrimination. The ethnography of the judicial process explores the relationships between mobilization and legal action and their effects on the formation of a collective. The conditions of a long-term action (which was exceptional because of the number of complainants) and of its judicial translation, show that judicialization participated in the constitution of this group. This process reveals a tension between conscientization of complainants and dispossession by legal professionals.