Unexpectedly High Prevalence of Cytomegalovirus DNAemia in Older Children and Adolescents With Perinatally Acquired Human Immunodeficiency Virus Infection.

BACKGROUND: Older children and adolescents with perinatally acquired human immunodeficiency virus (PHIV) infection in Africa experience multiple comorbidities that are not typical of HIV-associated opportunistic infections, including growth impairment and chronic lung disease. We examined associations between plasma cytomegalovirus (CMV) DNA and lung function and growth. METHODS: Plasma CMV DNA loads were measured children aged 6-16 years with PHIV (n = 402) and HIV-uninfected controls (n = 224). The HIV-infected children were either newly diagnosed or known HIV infected and stable on antiretroviral therapy (ART) for >6 months. CMV DNA loads were measured using quantitative polymerase chain reaction. CMV DNAemia was modeled as a time-varying outcome using longitudinal mixed-effects logistic regression. RESULTS: At enrollment, CMV DNAemia ≥1000 copies/mL (defined as "clinically significant") was detected in 5.8% of uninfected children, 14.7% of HIV-infected participants stable on ART, and 22.6% of HIV-infected ART-naive children (χ2 = 23.8, P < .001). The prevalence of CMV DNAemia ≥1000 copies/mL was associated with CD4 counts <350 cells/µL. Among HIV-infected ART-naive children, the presence of CMV DNAemia of ≥1000 copies/mL was independently associated with reduced lung function (adjusted odds ratio [aOR] = 3.23; 95% confidence interval [CI], 1.23-8.46; P = .017). Among ART-treated children, stunting was associated with CMV DNAemia of ≥1000 copies/mL (aOR = 2.79; 95% CI, 0.97-8.02; P = .057). CONCLUSIONS: Clinically significant levels of CMV DNAemia were common in older children with PHIV, even those on ART, suggesting a role for inadequately controlled CMV infection in the pathogenesis of PHIV comorbidities in Africa

Determination of protein composition in milk by mid-infrared spectrometry

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Genetic parameter estimation for major milk fatty acids in Alpine and Saanen primiparous goats

International audienceGenetic parameters for 18 fatty acids or groups of fatty acids (FA), milk production traits, and somatic cell score (SCS) were estimated by restricted maximum likelihood with a repeatability animal model, using 45,259 test-day records from the first lactations of 13,677 Alpine and Saanen goats. Fatty acid data were collected as part of an extensive recording scheme (PhénoFinLait), and sample testing was based on mid-infrared spectra estimates. The total predicted FA content in milk was approximately 3.5% in Alpine and Saanen goats. Goat milk fat showed similar saturated FA to cattle and sheep, but higher contents of capric (C10:0) FA (~9.7g/100g of milk fat). Heritability estimates ranged from 0.18 to 0.49 for FA and estimates were generally higher when FA were expressed in g/100g of milk fat compared with g/100g of milk. In general, the 3 specific short- and medium-chain goat FA, caproic acid (C6:0), caprylic acid (C8:0), and especially capric (C10:0) acid, had among the highest heritability estimates (from 0.21 to 0.37; average of 0.30). Heritability estimates for milk yield, fat and protein contents, and SCS were 0.22, 0.23, 0.39, 0.09, and 0.24, 0.20, 0.40, and 0.15, in Alpine and Saanen goats, respectively. When FA were expressed in g/100g of milk, genetic correlations between fat content and all FA were high and positive. Genetic correlations between the fat content and FA groups expressed in g/100g of fat led to further investigation of the association between fat content and FA profile within milk fat. Accordingly, in both Saanen and Alpine breeds, no significant genetic correlations were found between fat content and C16:0, whereas the correlations between fat content and specific goat FA (C6:0 to C10:0) were positive (0.17 to 0.59). In addition, the genetic correlation between fat content and C14:0 was negative (-0.17 to -0.35). The values of the genetic correlations between protein content and individual FA were similar, although genetic correlations between protein content and FA groups were close to zero. Genetic correlations of milk yield or SCS with the FA profile were weak. Results for genetic parameters for FA, however, should be further validated, because the low predicting ability of certain FA using mid-infrared spectra and the limited calibration data set might have resulted in low accuracy. In conclusion, our results indicated substantial genetic variation in goat milk FA that supported their amenability for genetic selection. In addition, selection on protein and fat contents is not expected to have an undesirable effect on the FA profile in regard to specificity of goat products and human health

Incidence of lung and HPV-associated malignancies in HIV-infected patients

OBJECTIVE: Cancers represent one of the leading cause of mortality/morbidity in patients living with HIV (PLHIV) in industrialized countries. The objective of our study was to compare incidence of lung and HPV-related cancers among PLHIV with general population over the 2010-2017 period.Design: Prospective and multicenter cohort study. METHODS: The study included patients with lung and HPV-related cancers from the ANRS CO3 Aquitaine cohort (PLHIV) and the general population-based cancer registry in Gironde area. We calculated incidence rates (IR) for 100,000 Person Year (PY) and Incidence Rate Ratios (IRR). RESULTS: Among the 3,572 PLHIV, 70 cancers were diagnosed in 68 patients including 35 lung and 35 HPV-related cancers (18 oropharyngeal, 11 anal, 6 cervix). IR of lung and HPV-related-cancers were 311.1 in PLHIV and 209.8 in general population for 100,000 PY, respectively. IRR were significantly increased in PLHIV for lung 1.8 [1.4; 2.2] and HPV-related cancer 1.3 [1.0; 1.6] and particularly high for patients between 40-49 years-old (IRR 4.4 [2.3; 8.4] for lung cancer and 3.7 [2.1; 6.5] for HPV-related cancer). CONCLUSIONS: We emphasized the persistent high risk of lung and HPV-related cancer despite advent of antiretroviral therapies, particularly in the age strata of 40-49 years. Screening procedures should take into account this finding

Involvement of the Pituitary-Specific Transcription Factor Pit-1 in Somatolactotrope Cell Growth and Death: An Approach Using Dominant-Negative Pit-1 Mutants

International audienceThe anterior pituitary-specific transcription factor Pit-1 was initially identified and cloned as a transactivator of the prolactin (PRL) and GH genes and later as a regulator of the TSHb gene. It was found to be a major developmental regulator, because natural Pit-1 gene mutations cause a dwarf phenotype in mice and cause combined pituitary hormone deficiency associated with pituitary hypoplasia in humans. To further investigate the growth-promoting effects of Pit-1, we used a strategy based on the use of dominant-negative Pit-1 mutants as an alternative means of inactivating endogenous Pit-1 functions. R271W, a Pit-1 mutant identified in one allele in patients with severe combined pituitary hormone deficiency, and Pit-1Delta1-123, a deletion mutant in which only the DNA binding domain of Pit-1 is conserved, were generated, and their ability to abolish the effects of the endogenous native Pit-1 in the differentiated proliferating somatolactotrope GH4C1 cell line was investigated. Enforced expression of the dominant-negative mutants in GH4C1 cells using recombinant lentiviral vectors decreased the levels of expression of known Pit-1 target genes such as PRL and GH, abolished the hormone release, and reduced cell viability by decreasing the growth rate and inducing apoptosis via a caspase-independent pathway. These results show for the first time that the growth-promoting effects of Pit-1 are at least partly due to the fact that this transcription factor prevents apoptotic cell death

Time to treatment initiation and HIV viral suppression in people diagnosed with HIV-1 during COVID-19 pandemic in ex-Aquitaine, France (ANRS CO3 AQUIVIH-NA Cohort-QuAliCOV Study)

International audienceThe Covid-19 pandemic's impact on initiation and effectiveness of antiretroviral therapy (ART) in people diagnosed with HIV remains unclear. We evaluated critical delays in HIV care in people diagnosed before and during the pandemic in ex-Aquitaine, France. We considered adults diagnosed with HIV-1 in 2018-2021 and enrolled in the ANRS CO3 AQUIVIH-NA and followed them until 10/10/2022 for those diagnosed during the pandemic (1/4/2020 - 31/12/2021) and until 31/03/2020 for historical controls. We compared their characteristics at inclusion and the median time between diagnosis and ART initiation, ART initiation and viral suppression and diagnosis and virological suppression (effective management). 83 individuals were diagnosed during the pandemic versus 188 during the pre-pandemic period. Median follow-up was 549 (IQR: 329-713) days. Populations were similar in terms of sex, age, HIV transmission group, hospital type, and clinical characteristics at diagnosis, however, fewer were foreign-born during the pandemic (15.7% versus 33.5%, p=0.003). The probability of ART initiation, therapeutic success, effective management was higher in PLWH diagnosed during the pandemic in adjusted analyses (HR 2.0 95%CI. 1.5-2.7, HR 1.7 95%CI. 1.2-2.3, HR 1.8 95%CI. 1.3-2.6, respectively). Those diagnosed during the pandemic were 2.3 (95%CI: 1.2-4.1) times more likely to be virologically suppressed within 6 months of diagnosis compared to historical controls. Pandemic-related reorganizations may have resulted in newly diagnosed PLWH being prioritized, however, the lower proportion of foreign-born PLWH diagnosed during the pandemic period, likely due to reduced migration and potential delays in diagnosis, may contribute to these preliminary findings

PLA2R1 Mediates Tumor Suppression by Activating JAK2

International audienceLittle is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling