From the Allerød to the mid-Holocene: Palynological evidence from the south basin of the Caspian Sea

This article has been made available through the Brunel Open Access Publishing Fund. Copyright @ The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.Pollen and dinoflagellate cysts have been analysed in a core from the south basin of the Caspian Sea, providing a picture of respectively past vegetation and water salinity for the Late Pleistocene to middle Holocene. A relatively sharp lithological change at 0.86 m depth reflects a shift from detrital silts to carbonates-rich fine silts. From this depth upwards, a Holocene chronology is built based on ten radiocarbon dates on ostracod shells and bulk carbonates. From the vegetation point of view, the Late Pleistocene deserts and steppes were partially replaced in the most sheltered areas by an open woodland with Pinus, Juniperus-Hippophae-Elaeagnus and even Alnus-Quercus-Pterocarya and Fraxinus, related to the Allerød palynozone. This was interrupted by the Younger Dryas palynozone when Artemisia reaches a maximum in a first instance followed by a very dry phase with only a slight return of Pinus and Quercus and the rare presence of Ulmus-Zelkova. From 11.5 to 8.4 cal. ka BP, an open landscape dominated by shrubs such as Ephedra and progressively increasing Quercus appeared. The final spread of diverse evergreen and deciduous trees is delayed and occurs after 8.4 cal. ka BP. It is suggested that this delay is caused by an arid climate in the Early Holocene linked to high insolation and perhaps to a lake effect. The dinocyst assemblages fluctuate between slightly brackish (Pyxidinopsis psilata and Spiniferites cruciformis, 7 psu and lower) and more brackish (Impagidinium caspienense, ∼13 psu). In the Lateglacial (Khvalynian highstand), the assemblages remained dominated by relative low salinity taxa. A late and brief increase of salinity occurred prior to 11.2 cal. ka BP associated with the Mangyshlak lowstand. It is suggested that it was caused by a brief drop in meltwater flow from both the north and the southeast (Uzboy) and a likely evaporation increase. This lowstand occurs quasi at the same time as the end of a longer lowstand in the Black Sea. The freshest waters are then inferred as having occurred between 8.4 and ≤4.4 cal. ka BP, linked to a connection with the Amu Darya and the melting glaciers on the Pamir Mountains. The Caspian Sea is a sensitive environment, easily perturbed by global climatic changes, such as the Allerød and Holocene warming, and the Lateglacial and Younger Dryas cooling, as well as by regional changes in its hydrography, such as shifts in the Eurasian meltwater and the Volga and Amu Darya inflows.Centre National de la Recherche Scientifique, Franc

Hidden genetic variation in LCA9-associated congenital blindness explained by 5′UTR mutations and copy-number variations of NMNAT1

Leber congenital amaurosis (LCA) is a severe autosomal-recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes

Enriched interactions which support speech and language development: short- and medium-term effects (6 months) of parental guidance in logopedics

peer reviewedThe aim of parent based language intervention is to help parents of children with language disorders to play a main part in their child’s linguistic development by adjusting the speech addressed to them. This study focuses on the efficiency of our intervention methods and of indirect therapy. We analyze four dyads filmed at three different points in time: 1) before the intervention;2) directly after the sessions with the speech therapists; 3) six months later. Each film was transcribed and analyzed. The results confirm that parental based language intervention induces long-term changes in the parents’ behavior.La guidance logopédique parentale vise à aider des parents d’enfants en difficulté langagière à tenir un rôle d’acteur principal dans le développement langagier de leurs enfants, en leur fournissant un langage plus adapté à ses difficultés. Cette étude s’intéresse à l’efficacité de cette méthode d’intervention en analysant quatre dyades parent/enfant filmées à trois reprises : avant la prise en charge, directement après les sessions de formation et 6 mois plus tard. Chaque film a été transcrit et analysé. Les résultats confirment que la guidance parentale induit des changements de comportement des parents dont l’effet persiste à long terme

Surveillance of ARV safety in pregnancy and breastfeeding: towards a new framework

INTRODUCTION: As new antiretrovirals (ARVs), including long‐acting ARVs for treatment and prevention, are approved and introduced, surveillance during pregnancy must become the safety net for evaluating birth outcomes, especially those that are rare and require large numbers of observations. Historically, drug pharmacovigilance in pregnancy has been limited and fragmented between different data sources, resulting in inadequate data to assess risk. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network and World Health Organization convened a Workshop which reviewed strengths and weaknesses of existing programs and discussed an improved framework to integrate existing safety data sources and promote harmonization and digitalization. DISCUSSION: This paper highlights that although robust sources of safety data and surveillance programs exist, key challenges remain, including unknown denominators, reporting bias, under‐reporting (e.g. in voluntary registries), few data sources from resource‐limited settings (most are in North America and Europe), incomplete or inaccurate data (e.g. within routine medical records). However, recent experiences (e.g. with safety signals) and current innovations (e.g. electronic record use in resource‐limited settings and defining adverse outcomes) provide momentum and building blocks for a new framework for active surveillance of ARV safety in pregnancy. A public health approach should be taken using data from existing sources, including registries of pregnancy ARV exposure and birth defects; observational surveillance and cohort studies; clinical trials; and real‐world databases. Key facilitators are harmonization and standardization of outcomes, sharing of materials and tools, and data linkages between programs. Other key facilitators include the development of guidance to estimate sample size and duration of surveillance, ensuring strategic geographic diversity, bringing partners together to share information and engaging the community of women living with HIV. CONCLUSIONS: Looking ahead, critical steps to safely introduce new ARVs include (1) adopting harmonized standards for measuring adverse maternal, birth and infant outcomes; (2) establishing surveillance centres of excellence in areas with high HIV prevalence with harmonized data collection and optimized electronic health records linking maternal/infant data; and (3) creating targets and evaluation goals for reporting progress on implementation and quality of surveillance in pregnancy. The platform will be leveraged to ensure that appropriate contributions and strategic actions by relevant stakeholders are implemented

Peripapillary intrachoroidal cavitation at the crossroads of peripapillary myopic changes

AIM: To analyze the prevalence of peripapillary intra-choroidal cavitation (PICC) in eyes with gamma peripapillary atrophy (γPPA), in eyes with peripapillary staphyloma (PPS) and in those combining γPPA and PPS and to analyze border tissue discontinuity in PICC. METHODS: This prospective cross-sectional non interventional study included highly myopic eyes. Non-highly myopic eyes were used as control. Radial and linear scans centered on the optic nerve head were performed using spectral-domain optical coherence tomography. Variables were analyzed along the twelve hourly optical coherence tomography sections in both eyes of each subject. RESULTS: A total of 667 eyes of 334 subjects were included: 229 (34.3%) highly myopic eyes and 438 (65.7%) non highly myopic eyes. The mean age of the highly myopic group was 48.99±17.81y. PICC was found in a total of 40 eyes and in 13.2% (29/220) of highly myopic eyes. PICC was found in 10.4% (40/386) of eyes with γPPA, in 20.5% (40/195) of eyes with PPS and in 22.7% (40/176) of those combining γPPA and PPS. All the eyes with PICC showed the co-existence of γPPA and PPS whereas none of the eyes presenting only one of these entities exhibited PICC. A border tissue discontinuity in the γPPA area was found in all eyes with PICC. CONCLUSION: We confirm the presence of a border tissue discontinuity in the γPPA area of all eyes with PICC. These findings suggest the involvement of mechanical factors in the pathogenesis of PICC which may contribute to PICC-related visual field defects

Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases.

International audienceBACKGROUND: Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times-to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naïve approach) on parametric maximum likelihood estimation of time-to-onset distribution. METHODS: Both approaches, naïve or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF-¿ treatment from the French pharmacovigilance is presented. RESULTS: The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1. CONCLUSIONS: It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria