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ABSTRACTSpecific HBsAg mutations are known to hamper HBsAg recognition by neutralizing antibodies thus challenging HBV-vaccination efficacy. Nevertheless, information on their impact and spreading over time is limited. Here, we characterize the circulation of vaccine-escape mutations from 2005 to 2019 and their correlation with virological parameters in a large cohort of patients infected with HBV genotype-D (N = 947), dominant in Europe. Overall, 17.7% of patients harbours ≥1 vaccine-escape mutation with the highest prevalence in subgenotype-D3. Notably, complex profiles (characterized by ≥2 vaccine-escape mutations) are revealed in 3.1% of patients with a prevalence rising from 0.4% in 2005–2009 to 3.0% in 2010–2014 and 5.1% in 2015–2019 (P = 0.007) (OR[95%CI]:11.04[1.42–85.58], P = 0.02, by multivariable-analysis). The presence of complex profiles correlates with lower HBsAg-levels (median[IQR]:40[0–2905]IU/mL for complex profiles vs 2078[115–6037]IU/ml and 1881[410–7622]IU/mL for single or no vaccine-escape mutation [P

Introduction The success of antiretroviral therapy (ART) has changed HIV from a deadly to a chronic infection, thus increasing the transitioning from infancy toward adulthood. However, the virostatic nature of antiretrovirals maintains viruses in sanctuaries, with reactivation potentials. Because current ARTs are very limited for children, the emergence of new HIV epidemics driven by HIV drug-resistance mutations is favoured. Our systematic review aims to estimate the global burden of archived drug-resistance mutations (ADRMs) and the size of reservoir (HIV-1 DNA load), and their associated factors in children and adolescents.Methods and analysis Papers from the PubMed/MEDLINE, Google Scholar, ScienceDirect, African Journals Online and Academic Medical Education Databases will be systematically identified using the keywords: “HIV-1 reservoirs”, “viral reservoirs”, “HIV-1 DNA”, infants, adolescents, child and children, linked by the following Boolean operators: ‘OR’ and ‘AND’. Randomised and non-randomised trials, cohort studies and cross-sectional studies published in French or English from January 2002 will be included, while case reports, letters, comments, reviews, systematic reviews and meta-analyses, and editorials will be excluded. All studies describing data on ADRMs, HIV-1 DNA load and/or immunological markers among children/adolescents will be eligible. A random-effects model will be used to calculate the pooled prevalence of ADRMs. Data will be reported according to type of viral reservoir (peripheral blood mononuclear cells, CD4 cells), geographical location (country/continent), ethnicity/race, age (infants vs adolescents), gender, HIV-1 clades, ART exposure (naïve vs treated, drug class, type of regimen, age at ART initiation and treatment duration), WHO clinical staging (I, II, III, IV), immune status (immune compromised vs immune competent) and virological response (viraemic vs non-viraemic). Multivariate logistic regression will be performed to determine predictors of HIV reservoir profile in paediatric populations. The primary outcome will be to assess the genotypical and quantitative profile of HIV reservoirs, while the secondary outcomes will be to identify factors associated with ADRMs and reservoir size in paediatric populations.Ethics and dissemination Ethical approval is not applicable for this study as it will be based on published data. Results will be disseminated via a peer-reviewed scientific journal and relevant conferences.PROSPERO registration number CRD42022327625.

As the focus of climate policy shifts from pledges to implementation, there is a growing need to track progress on climate change mitigation at the country level, particularly for the land-use sector. Despite new tools and models providing unprecedented monitoring opportunities, striking differences remain in estimations of anthropogenic land-use CO2 fluxes between, on the one hand, the national greenhouse gas inventories (NGHGIs) used to assess compliance with national climate targets under the Paris Agreement and, on the other hand, the Global Carbon Budget and Intergovernmental Panel on Climate Change (IPCC) assessment reports, both based on global bookkeeping models (BMs). Recent studies have shown that these differences are mainly due to inconsistent definitions of anthropogenic CO2 fluxes in managed forests. Countries assume larger areas of forest to be managed than BMs do, due to a broader definition of managed land in NGHGIs. Additionally, the fraction of the land sink caused by indirect effects of human-induced environmental change (e.g. fertilisation effect on vegetation growth due to increased atmospheric CO2 concentration) on managed lands is treated as non-anthropogenic by BMs but as anthropogenic in most NGHGIs. We implement an approach that adds the CO2 sink caused by environmental change in countries' managed forests (estimated by 16 dynamic global vegetation models, DGVMs) to the land-use fluxes from three BMs. This sum is conceptually more comparable to NGHGIs and is thus expected to be quantitatively more similar. Our analysis uses updated and more comprehensive data from NGHGIs than previous studies and provides model results at a greater level of disaggregation in terms of regions, countries and land categories (i.e. forest land, deforestation, organic soils, other land uses). Our results confirm a large difference (6.7 GtCO2 yr−1) in global land-use CO2 fluxes between the ensemble mean of the BMs, which estimate a source of 4.8 GtCO2 yr−1 for the period 2000–2020, and NGHGIs, which estimate a sink of −1.9 GtCO2 yr−1 in the same period. Most of the gap is found on forest land (3.5 GtCO2 yr−1), with differences also for deforestation (2.4 GtCO2 yr−1), for fluxes from other land uses (1.0 GtCO2 yr−1) and to a lesser extent for fluxes from organic soils (0.2 GtCO2 yr−1). By adding the DGVM ensemble mean sink arising from environmental change in managed forests (−6.4 GtCO2 yr−1) to BM estimates, the gap between BMs and NGHGIs becomes substantially smaller both globally (residual gap: 0.3 GtCO2 yr−1) and in most regions and countries. However, some discrepancies remain and deserve further investigation. For example, the BMs generally provide higher emissions from deforestation than NGHGIs and, when adjusted with the sink in managed forests estimated by DGVMs, yield a sink that is often greater than NGHGIs. In summary, this study provides a blueprint for harmonising the estimations of anthropogenic land-use fluxes, allowing for detailed comparisons between global models and national inventories at global, regional and country levels. This is crucial to increase confidence in land-use emissions estimates, support investments in land-based mitigation strategies and assess the countries' collective progress under the Global Stocktake of the Paris Agreement. Data from this study are openly available online via the Zenodo portal (Grassi et al., 2023) at https://doi.org/10.5281/zenodo.7650360.

Protected areas are effective in preserving the height and vertical structure of European forests, according to an analysis of spaceborne data from the Global Ecosystem Dynamics Investigation.

The complete data fusion is a method that combines independent measurements of atmospheric vertical profiles. Recently a new formula for the complete data fusion, which does not contain matrices that can be singular and overcomes the generalized inverse approximation used when singular matrices have to be inverted, has been proposed. We show that the new formula is a generalization of the original one and analyze the analytical relationship between the two formulas when generalized inverse matrices are used for the inversion of singular matrices. We extend the new formula to include interpolation and coincidence errors, which must be considered when the profiles to be fused are measured on different vertical grids and at different times and/or locations. Finally, we use a real measurement of the Infrared Atmospheric Sounding Interferometer (IASI) instrument to show the improved performances of the new formula with respect to the original one.

ABSTRACT: Objectives: The aim of this study was to assess the efficacy of dolutegravir plus lamivudine (DTG+3TC) in a large set of virologically suppressed HIV-1 infected individuals with or without past M184V mutation. Methods: This observational study included individuals who switched to DTG+3TC with ≥1 genotype before switch. Survival analysis was used to evaluate the role of past M184V on virological rebound (VR) or blips after DTG+3TC switch. Results: A total of 712 individuals followed in several clinical centres in France, Italy and Spain were analysed. Past M184V was present in 60 (8.4%) individuals. By 3 years after switch, the overall probability of VR and blips was 6.7% and 6.9%, respectively, without any statistical significance according to the presence/absence of past M184V. A significantly higher probability of VR was found in individuals harbouring M184V before DTG+3TC with a duration of virological suppression (Ts) ≤.3.5 years compared to others (M184V+Ts ≤.3.5 years: 22.7%; M184M+Ts ≤.3.5 years: 9.0%; M184V+Ts >3.5 years: 7.8%; M184M+Ts >3.5 years: 4.9%; P = 0.007). This finding was not confirmed in multivariable models adjusting for behavioural and demographic variables. Genotypic resistance test after VR under DTG+3TC was available for 8/39 individuals; one poorly adherent individual developed M184V. No resistance to INIs was found. Conclusion: In this retrospective observational study, the probability of VR and blips in patients switching to DTG+3TC was very low after 3 years of treatment regardless M184V. The effect of a short duration of previous virological suppression in individuals with M184V remains troubling and needs ad hoc clinical trials to be confirmed.

In the frame of Earth observation remote-sensing data analysis, synergistic retrieval (SR) and complete data fusion (CDF) are techniques used to exploit the complementarity of the information carried by different measurements sounding the same air mass and/or ground pixel. While more difficult to implement due to the required simultaneous access to measurements originating from different instruments, the SR method is sometimes preferred over the CDF method as the latter relies on a linear approximation of the retrieved states as functions of the true atmospheric and/or surface state. In this work, we study the performance of the SR and CDF techniques when applied to simulated measurements of the Far-infrared Outgoing Radiation Understanding and Monitoring (FORUM) and the Infrared Atmospheric Sounding Interferometer – New Generation (IASI-NG) missions that will be operational in a few years, from two polar-orbiting satellites. The study is based on synthetic measurements generated for the two missions in clear-sky atmospheres. The target parameters of the inversion are the vertical profiles of temperature, water vapor and ozone mixing ratios, surface temperature, and spectral emissivity. We find that for exact matching of the measurements, the results of the SR and CDF techniques differ by less than 1/10 of their errors estimated through the propagation of measurement noise. For measurements with a realistic mismatch in space and time, the two methods provide more different results. Still in this case, however, the differences between the results are within the error bars due to measurement noise. We conclude that, when applied to FORUM and IASI-NG missions, the two methods are equivalent from an accuracy point of view.

Objetivou-se avaliar a produção, rendimento, qualidade e biometria de frutos de pimenta não pungentes cultivados em ambiente protegido por meio da poda de hastes caulinares e raleio dos frutos. Os tratamentos foram compostos por sistemas de condução das hastes (sem poda e com poda) e raleio (sem raleio e com raleio dos frutos). O delineamento experimental foi blocos casualizados com quatro repetições em esquema fatorial 2 (sem poda e com poda das hastes) x 2 (sem raleio e com raleio dos frutos). Foram avaliados os frutos de quatro plantas por parcela, totalizando oito momentos de colheita. A poda promoveu incremento na fitomassa de frutos totais e comerciais, número de frutos comerciais, comprimento (C), diâmetro (D), relação C/D, sólidos solúveis totáis, pH e acidez total titulável dos frutos de pimenta. O raleio de frutos promoveu incremento do comprimento e diâmetro médio dos frutos de pimenta. Recomenda-se a poda das hastes das plantas de pimenteira para obter maior massa média e diâmetro de frutos.

• Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.

Antiretroviral therapy (ART) has improved the lifespan of people living with HIV. However, their immune system remains in a state of sustained activation/inflammation, which favors viral replication and depletion of helper T-cells with varying profiles according to ART-response. We herein sought to ascertain the inflammatory profile of adolescents living with perinatal HIV-1 infection (ALPHI) receiving ART in an African context. In this cross-sectional and comparative study among ART-experienced ALPHI in Yaoundé-Cameroon, HIV-1 RNA was measured by Abbott Real-time PCR; CD4 cells were enumerated using flow cytometry; serum cytokines were measured by ELISA; HIV-1 proviral DNA was genotyped by Sanger-sequencing; and archived drug resistance mutations (ADRMs) were interpreted using Stanford HIVdb.v9.0.1. Overall, 73 adolescents were enrolled (60 ALPHI and 13 HIV-1 negative peers) aged 15 (13-18) years; 60.00% were female. ART median duration was 92 (46-123) months; median viral load was 3.99 (3.17-4.66) RNA Log10 (copies)/mL and median CD4 count was 326 (201-654) cells/mm3. As compared to HIV-negative adolescents, TNFα was highly expressed among ALPHI (p

Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a rare, life-threatening, pediatric disorder of unknown etiology, whose diagnosis is made difficult by poor knowledge of clinical manifestation, and lack of any confirmatory tests. Children with ROHHAD usually present with rapid onset weight gain which may be followed, over months or years, by hypothalamic dysfunction, hypoventilation, autonomic dysfunction, including impaired bowel motility, and tumors of neural crest origin. Despite the lack of evidence of inheritance in ROHHAD, several studies have been conducted in recent years that have explored possible genetic origins, with unsuccessful results. In order to broaden the search for possible genetic risk factors, an attempt was made to analyse the non-coding variants in two trios (proband with parents), recruited in the Gaslini Children’s Hospital in Genoa (Italy). Both patients were females, with a typical history of ROHHAD. Gene variants (single nucleotide variants, short insertions/deletions, splice variants or in tandem expansion of homopolymeric tracts) or altered genomic regions (copy number variations or structural variants) shared between the two probands were searched. Currently, we have not found any potentially pathogenic changes, consistent with the ROHHAD clinical phenotype, and involving genes, regions or pathways shared between the two trios. To definitively rule out the genetic etiology, third-generation sequencing technologies (e.g., long-reads sequencing, optical mapping) should be applied, as well as other pathways, including those associated with immunological and autoimmune disorders, should be explored, making use not only of genomics but also of different -omic datasets.

Biodiversity relates to ecosystem functioning by modulating biogeochemical cycles of carbon, water, energy, and nutrients within and between multiple biotic and abiotic components of the ecosystems. However, large-scale, systematic measurements of plant biodiversity are still lacking, and the effects of biodiversity on measured biogeochemical processes are understudied. Here, we combined alpha ( α ) and beta ( β ) taxonomic measurements, spectral diversity from satellite observations, structural properties of the vegetation, and climatic drivers to assess the effect of biodiversity on ecosystem functional properties. Ecosystem functional properties were computed from eddy-covariance fluxes at 44 sites of the National Ecological Observatory Network. Based on the spectral variation hypothesis, we used the near-infrared reflectance of vegetation (NIRv) derived from Sentinel-2 satellite imagery to compute Rao’s quadratic entropy (Rao Q), a distance metric related to spatial heterogeneity. Using an automatic model averaging technique, we found that biodiversity proxies hold substantial explanatory power when predicting several ecosystem functions related to carbon and water exchange. In particular, NIRv-based Rao Q (RaoQ _NIRv ) reflected positive biodiversity effects on productivity, as expected from the literature. In contrast, traditional taxonomic α -diversity indices were generally not selected as relevant predictors of the ecosystem functional properties. Yet, β -diversity strongly contributed to the prediction of carbon use efficiency, surface conductance, and water use efficiency. We also found that the RaoQ _NIRv is less affected by issues of saturation and bare soil contribution compared to RaoQ _NDVI . We show that spectral heterogeneity based on remotely sensed NIRv holds the potential for globally characterizing the biodiversity-ecosystem functioning relationship (BEF). While systematic measurements of taxonomic diversity co-located at biogeochemical measurement stations could reduce the uncertainty surrounding the BEF relationship at whole-ecosystem scale, remotely- sensed metrics characterizing important functional and structural diversity aspects of the landscape will be crucial for continuous spatiotemporal monitoring of biodiversity with relevant implications for ecosystem services to humankind.

TAE Technologies’ fifth-generation fusion device, C-2W (also called ‘Norman’), is the world’s largest compact-toroid device and has made significant progress in field-reversed configuration (FRC) plasma performance. C-2W produces record breaking, macroscopically stable, high-temperature advanced beam-driven FRC plasmas, dominated by injected fast particles and sustained in steady state, which is primarily limited by neutral-beam (NB) pulse duration. The NB power supply system has recently been upgraded to extend the pulse length from 30 ms to 40 ms, which allows for a longer plasma lifetime and thus better characterization and further enhancement of FRC performance. An active plasma control system is routinely used in C-2W to produce consistent FRC performance as well as for reliable machine operations using magnet coils, edge-biasing electrodes, gas injection and tunable-energy NBs. Google’s machine learning framework for experimental optimization has also been routinely used to enhance plasma performance. Dedicated plasma optimization experimental campaigns, particularly focused on the external magnetic field profile and NB injection (NBI) optimizations, have produced a superior FRC plasma performance; for instance, achieving a total plasma energy of ∼13 kJ, a trapped poloidal magnetic flux of ∼16 mWb (based on the rigid-rotor model) and plasma sustainment in steady state up to ∼40 ms. Furthermore, under some operating conditions, the electron temperature of FRC plasmas at a quiescent phase has successfully reached up to ∼1 keV at the peak inside the FRC separatrix for the first time. The overall FRC performance is well correlated with the NB and edge-biasing systems, where higher total plasma energy is obtained with higher NBI power and applied voltage on biasing electrodes. C-2W operations have now reached a mature level where the machine can produce hot, stable, long-lived, and repeatable plasmas in a well-controlled manner.

The 2019 edition of the IAS-USA drug resistance mutations list updates the Figure last published in January 2017. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The Figure is designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs, and therefore, in making clinical decisions regarding antiretroviral therapy.

ABSTRACT: Objectives: We evaluated virological response and resistance profiles in individuals who were virologically suppressed who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in real life. Methods: Survival analysis was used to assess probability of virological rebound (VR). Cumulative major resistance mutations (MRM) and cumulative genotypic susceptibility score (cGSS) were evaluated before the switch. Results: Overall, 283 individuals virologically suppressed for a median (interquartile [IQR]) time of 7 (3–9) y were analyzed. Of these, 20.8% were in first-line treatment, 13.1% were highly treatment-experienced (HTE), and 8.5% had experienced previous integrase inhibitor (INI)-failures. Before the switch, nucleotide reverse transcriptase inhibitor NRTI MRM prevalence was 29% (M184V:13.8%; any thymidine analogue mutation: 14.1%; K65R: 0.7%; K70E 0.4%); only three (2.1%) individuals showed INI major resistance mutations (Y143C/H/R [n = 1]; Y143C [n = 1]; N155H [n = 1]), and 82.0% of individuals received fully active B/F/TAF. Ninety-six wk after switch, the probability of VR was 5%, with only 12 events of VR at a median (IQR) viremia level of 284 (187–980) copies/mL, mainly transient. No significant associations between virological outcomes and genotypic susceptibility to B/F/TAF were observed. People who experienced previous INI failures showed a significantly higher adjusted hazard ratio (AHR [95% CI]) to experience VR under B/F/TAF (3.9 [1.1–13.4], P = 0.031). This AHR increased in people who experienced INI failures and received partially active B/F/TAF (5.5 [1.4–21.1], P = 0.013). Conclusion: Within 96 wk, a switch to B/F/TAF in individuals who were virologically suppressed ensured a very high rate of virological control in a clinical setting. Previous resistance alone did not affect B/F/TAF response. However, people who had previous INI failures were more prone to losing virological control under B/F/TAF.

A great interest is growing about methods that combine measurements from two or more instruments that observe the same species either in different spectral regions or with different geometries. Recently, a method based on the Kalman filter has been proposed to combine IASI (Infrared Atmospheric Sounding Interferometer) and TROPOMI (TROPOspheric Monitoring Instrument) methane products. We show that this method is equivalent to the Complete Data Fusion method. Therefore, the choice between these two methods is driven only by the advantages of the different implementations. From the comparison of the two methods, a generalization of the Complete Data Fusion formula, which is valid also in the case that the noise error covariance matrices of the fused products are singular, is derived. This comment uses several equations reported in the preprint version of Schneider et al. (2022); therefore, reference is made to the preprint version of this paper.

Abstract The timely and accurate monitoring of forest resources is becoming of increasing importance in light of the multi-functionality of these ecosystems and their increasing vulnerability to climate change. Remote sensing observations of tree cover and systematic ground observations from National Forest Inventories (NFIs) represent the two major sources of information to assess forest area and use. The specificity of two methods is calling for an in-depth analysis of their strengths and weaknesses and for the design of novel methods emerging from the integration of satellite and surface data. On this specific debate, a recent paper by Breidenbach et al. published in this journal suggests that the detection of a recent increase in EU forest harvest rate—as reported in Nature by Ceccherini et al.—is largely due to technical limitations of satellite-based mapping. The article centers on the difficulty of the approaches to estimate wood harvest based on remote sensing. However, it does not discuss issues with the robustness of validation approaches solely based on NFIs. Here we discuss the use of plot data as a validation set for remote sensing products, discussing potentials and limitations of both NFIs and remote sensing, and how they can be used synergistically. Finally, we highlight the need to collect in situ data that is both relevant and compatible with remote sensing products within the European Union.

Summary: Vascular calcification is a systemic disease characterized by calcium salt deposition within vascular walls. Here, we present a protocol for establishing an advanced dynamic in vitro co-culture system using endothelial and smooth muscle cells to replicate vascular tissue complexity. We describe steps for cell culture and seeding in a double-flow bioreactor that recreates the action of blood in humans. We then detail the induction of calcification, setting up of the bioreactor, followed by cell viability assessment and calcium quantification. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

We present a brief commentary illustrating the current COVID-19 outpatient treatment options in Italy. We also report our experience setting up a service dedicated to these patients in the wake of the rise in COVID-19 cases observed in January 2022. We also gathered data on the daily costs faced by our outpatient service, based at a tertiary care center located in Florence, Italy. We present them with some considerations on future outlooks on the use of outpatient treatment in COVID-19.

Abstract Neuroblastoma (NB) is a pediatric tumor that originates from neural crest-derived cells undergoing a defective differentiation due to genomic and epigenetic impairments. Therefore, NB may arise at any final site reached by migrating neural crest cells (NCCs) and their progeny, preferentially in the adrenal medulla or in the para-spinal ganglia. NB shows a remarkable genetic heterogeneity including several chromosome/gene alterations and deregulated expression of key oncogenes that drive tumor initiation and promote disease progression. NB substantially contributes to childhood cancer mortality, with a survival rate of only 40% for high-risk patients suffering chemo-resistant relapse. Hence, NB remains a challenge in pediatric oncology and the need of designing new therapies targeted to specific genetic/epigenetic alterations become imperative to improve the outcome of high-risk NB patients with refractory disease or chemo-resistant relapse. In this review, we give a broad overview of the latest advances that have unraveled the developmental origin of NB and its complex epigenetic landscape. Single-cell RNA sequencing with spatial transcriptomics and lineage tracing have identified the NCC progeny involved in normal development and in NB oncogenesis, revealing that adrenal NB cells transcriptionally resemble immature neuroblasts or their closest progenitors. The comparison of adrenal NB cells from patients classified into risk subgroups with normal sympatho-adrenal cells has highlighted that tumor phenotype severity correlates with neuroblast differentiation grade. Transcriptional profiling of NB tumors has identified two cell identities that represent divergent differentiation states, i.e. undifferentiated mesenchymal (MES) and committed adrenergic (ADRN), able to interconvert by epigenetic reprogramming and to confer intra-tumoral heterogeneity and high plasticity to NB. Chromatin immunoprecipitation sequencing has disclosed the existence of two super-enhancers and their associated transcription factor networks underlying MES and ADRN identities and controlling NB gene expression programs. The discovery of NB-specific regulatory circuitries driving oncogenic transformation and maintaining the malignant state opens new perspectives on the design of innovative therapies targeted to the genetic and epigenetic determinants of NB. Remodeling the disrupted regulatory networks from a dysregulated expression, which blocks differentiation and enhances proliferation, toward a controlled expression that prompts the most differentiated state may represent a promising therapeutic strategy for NB.

High quality long-term data sets of altitude-resolved measurements of the atmospheric composition are important because they can be used both to study the evolution of the atmosphere and as a benchmark for future missions. For the final ESA reprocessing of MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) on ENVISAT (ENViromental SATellite) data, numerous improvements were implemented in the Level 2 (L2) processor Optimised Retrieval Model (ORM) version 8.22 (V8) and its auxiliary data. The implemented changes involve all aspects of the processing chain, from the modelling of the measurements with the handling of the horizontal inhomogeneities along the line of sight to the use of the optimal estimation technique to retrieve the minor species, from a more sensitive approach to detecting the spectra affected by clouds to a refined method for identifying low quality products. Improvements in the modelling of the measurements were also obtained with an update of the used spectroscopic data and of the databases providing the a priori knowledge of the atmosphere. The HITRAN_mipas_pf4.45 spectroscopic database was finalised with new spectroscopic data verified with MIPAS measurements themselves, while recently measured cross-sections were used for the heavy molecules. The Level 2 Initial Guess (IG2) data set, containing the climatology used by the MIPAS L2 processor to generate the initial guess and interfering species profiles when the retrieved profiles from previous scans are not available, was improved taking into account the diurnal variation of the profiles defined using climatologies from both measurements and models. Horizontal gradients were generated using the ECMWF ERA-Interim data closest in time and space to the MIPAS data. Further improvements in the L2 V8 products derived from the use of the L1b V8 products, which were upgraded to reduce the instrumental temporal drift and to handle the abrupt changes in the calibration gain. The improvements introduced into the ORM V8 L2 processor and its upgraded auxiliary data, together with the use of the L1b V8 products, lead to the generation of the MIPAS L2 V8 products, which are characterised by an increased accuracy, better temporal stability and a greater number of retrieved species.

Abstract Response to ritonavir-boosted-protease inhibitors (PI/r)-based regimen is associated with some Gag mutations among HIV-1 B-clade. There is limited data on Gag mutations and their covariation with mutations in protease among HIV-1 non-B-clades at PI/r-based treatment failure. Thus, we characterized Gag mutations present in isolates from HIV-1 infected individuals treated with a PI/r-regimen (n = 143) and compared them with those obtained from individuals not treated with PI/r (ART-naïve [n = 101] or reverse transcriptase inhibitors (RTI) treated [n = 118]). The most frequent HIV-1 subtypes were CRF02_AG (54.69%), A (13.53%), D (6.35%) and G (4.69%). Eighteen Gag mutations showed a significantly higher prevalence in PI/r-treated isolates compared to ART-naïve (p

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement (P = 0.001) and positivity of autoimmune markers (P = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group (P = 0.01 and P = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed >2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαβ+, CD3+CD25+/CD3HLADR+, TCR αβ+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.

BackgroundThe mother-to-child transmission of HIV-1 (MTCT) remains on the major route of HIV-transmission among pediatric populations in Africa. Though a prevention of MTCT (PMTCT) high-priority country, data on the MTCT burdens in Cameroon remains fragmented.ObjectiveWe sought to assess the pooled MTCT rate, its risk-factors, and to characterize viral reservoirs of infected-children in Cameroon.MethodsAll relevant observational cohort and cross-sectional studies conducted in Cameroon were searched from PubMed, African Journals Online, Google scholar, ScienceDirect and academic medical education databases. Heterogeneity and publication bias were respectively assessed by the I2 statistic and the Egger/funnel plot test. Meta-analysis was performed using the random effects model. MTCT rate >5% was considered as "high". This review was registered in the Prospero database, CRD42021224497.ResultsWe included a total of 29 studies and analyzed 46 684 children born from HIV-positive mothers. The overall rate of MTCT was 7.00% (95% CI = 6.07-8.51). According to regions, the highest burden was in Adamaoua-region (17.51% [95% CI:14.21-21.07]) with only one study found. PMTCT option-B+ resulted in about 25% reduction of MTCT (8.97% [95% CI: 8.71-9.24] without option-B+ versus 2.88% [95% CI: 5.03-9.34] with option-B+). Regarding risk-factors, MTCT was significantly associated with the absence of PMTCT-interventions both in children (OR:5.40 [95% CI: 2.58-11.27]) and mothers (OR: 3.59 [95% CI: 2.15-5.99]). Regarding viral reservoirs, a pro-viral DNA mean of 3.34±1.05 log10/mL was observed among 5/57 children and archived HIV drug resistance mutations were identified in pro-viral DNA marker among 21/79 infected-children.ConclusionIn spite of the dropdown in MTCT following option-B+ implementation, MTCT remains high in Cameroon, with substantial disparities across regions. Thus, in this era of option-B+, achieving MTCT elimination requires interventions in northern-Cameroon. The variation in pro-viral load in infected-children underlines the relevance of characterizing viral reservoirs for possible infection control in tropical settings.

The Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) measured the middle-infrared limb emission spectrum of the atmosphere from 2002 to 2012 on board ENVISAT, a polar-orbiting satellite. Recently, the European Space Agency (ESA) completed the final reprocessing of MIPAS measurements, using version 8 of the level 1 and level 2 processors, which include more accurate models, processing strategies, and auxiliary data. The list of retrieved gases has been extended, and it now includes a number of new species with weak emission features in the MIPAS spectral range. The new retrieved trace species include carbonyl chloride (COCl2), also called phosgene. Due to its toxicity, its use has been reduced over the years; however, it is still used by chemical industries for several applications. Besides its direct injection in the troposphere, stratospheric phosgene is mainly produced from the photolysis of CCl4, a molecule present in the atmosphere because of human activity. Since phosgene has a long stratospheric lifetime, it must be carefully monitored as it is involved in the ozone destruction cycles, especially over the winter polar regions. In this paper we exploit the ESA MIPAS version 8 data in order to discuss the phosgene distribution, variability, and trends in the middle and lower stratosphere and in the upper troposphere. The zonal averages show that phosgene volume mixing ratio is larger in the stratosphere, with a peak of 40 pptv (parts per trillion by volume) between 50 and 30 hPa at equatorial latitudes, while at middle and polar latitudes it varies from 10 to 25 pptv. A moderate seasonal variability is observed in polar regions, mostly between 80 and 50 hPa. The comparison of MIPAS–ENVISAT COCl2 v8 profiles with the ones retrieved from MIPAS balloon and ACE-FTS (Atmospheric Chemistry Experiment – Fourier Transform Spectrometer) measurements highlights a negative bias of about 2 pptv, mainly in polar and mid-latitude regions. Part of this bias is attributed to the fact that the ESA level 2 v8 processor uses an updated spectroscopic database. For the trend computation, a fixed pressure grid is used to interpolate the phosgene profiles, and, for each pressure level, VMR (volume mixing ratio) monthly averages are computed in pre-defined 10∘ wide latitude bins. Then, for each latitudinal bin and pressure level, a regression model has been fitted to the resulting time series in order to derive the atmospheric trends. We find that the phosgene trends are different in the two hemispheres. The analysis shows that the stratosphere of the Northern Hemisphere is characterized by a negative trend of about −7 pptv per decade, while in the Southern Hemisphere phosgene mixing ratios increase with a rate of the order of +4 pptv per decade. This behavior resembles the stratospheric trend of CCl4, which is the main stratospheric source of COCl2. In the upper troposphere a positive trend is found in both hemispheres.

The observations acquired during the full mission of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) instrument, aboard the European Space Agency Environmental Satellite (Envisat), have been analysed with version 8.22 of the Optimised Retrieval Model (ORM), originally developed as the scientific prototype of the ESA level-2 processor for MIPAS observations. The results of the analyses have been included into the MIPAS level-2 version 8 (level2-v8) database containing atmospheric fields of pressure, temperature, and volume mixing ratio (VMR) of MIPAS main targets H2O, O3, HNO3, CH4, N2O, and NO2, along with the minor gases CFC-11, ClONO2, N2O5, CFC-12, COF2, CCl4, CF4, HCFC-22, C2H2, CH3Cl, COCl2, C2H6, OCS, and HDO. The database covers all the measurements acquired by MIPAS in the nominal measurement mode of the full resolution (FR) part of the mission (from July 2002 to March 2004) and all the observation modes of the optimised resolution (OR) part (from January 2005 to April 2012). The number of species included in the MIPAS level2-v8 dataset makes it of particular importance for the studies of stratospheric chemistry. The database is considered by ESA the final release of the MIPAS level-2 products. The ORM algorithm is operated at the vertical grid coincident to the tangent altitudes of the observations or to a subset of them, spanning (in the nominal mode) the altitude range from 6 to 68 km in the FR phase and from 6 to 70 km in the OR period. In the latitude domain, FR profiles are spaced by about 4.7∘, while the OR profiles are spaced by about 3.7∘. For each retrieved species, the auxiliary data and the retrieval choices are described. Each product is characterised in terms of the retrieval error, spatial resolution, and “useful” vertical range in both phases of the MIPAS mission. These depend on the characteristics of the measurements (spectral and vertical resolution of the measurements), the retrieval choices (number of spectral points included in the analyses, number of altitudes included in the vertical retrieval grid), and the information content of the measurements for each trace species. For temperature, water vapour, ozone, and nitric acid, the number of degrees of freedom is significantly larger in the OR phase than in the FR one, mainly due to the finer vertical measurement grid. In the FR phase, some trace species are characterised by a smaller retrieval error with respect to the OR phase, mainly due to the larger number of spectral points used in the analyses, along with the reduced vertical resolution. The way of handling possible caveats (negative VMR, vertical grid representation) is discussed. The quality of the retrieved profiles is assessed through four criteria, two providing information on the successful convergence of the retrieval iterations, one on the capability of the retrieval to reproduce the measurements, and one on the presence of outliers. An easy way to identify and filter the problematic profiles with the information contained in the output files is provided. MIPAS level2-v8 data are available to the scientific community through the ESA portal (https://doi.org/10.5270/EN1-c8hgqx4).

ABSTRACT To ensure the long-term efficacy of dolutegravir (DTG), we evaluated the genotypic profile in viral reservoirs among patients on third-line (3L) antiretroviral therapy (ART) in Cameroon, according to prior exposure to raltegravir (RAL). A facility-based study was conducted from May through December 2021 among patients on 3L ART from HIV treatment centers in Yaoundé and Douala. Viral load was measured, and genotyping was performed on plasma RNA and proviral DNA. HIV-1 drug resistance mutations were interpreted using HIVdb.v9.1 and phylogeny analysis was performed using MEGA.v7, with P < 0.05 considered significant. Of the 12,093 patients on ART, 53 fully met our inclusion criteria. The median (IQR) age was 51 years (40 to 55 years), and the male/female ratio was 4/5. The median duration on integrase strand-transfer inhibitors (INSTI)-containing regimens was 18 months (12 to 32 months), and 15.09% (8/53) were exposed to RAL. The most administered 3L ART was TDF+3TC+DTG+DRV/r (33.96%, 18/53). Only 5.66% (3/53) had unsuppressed viremia (>1000 copies/mL). Resistance testing in proviral DNA was successful for 18/22 participants and revealed 1/18 patients (5.56%, in the RAL-arm) with archived mutations at major resistance positions (G140R and G163R). Five subtypes were identified, CRF02_AG (12/18), CRF22_01AE (3/18), A1 (1/18), G (1/18), and F2 (1/18). In Cameroon, 3L-experienced patients had a good virological response with a low level of archived mutations in the integrase. This finding underscored the use of DTG-containing ART for heavily treated patients in similar programmatic settings. However, patients with prior exposure to RAL should be closely monitored following a stratified or personalized approach to mitigate risks of INSTI-resistance, alongside pharmacovigilance. IMPORTANCE We described the analysis of the genotypes of the population within third-line antiviral therapy in Cameroon, with a focus on defining the effects of prior raltegravir (RAL) treatment and resistance mutations for current dolutegravir (DTG) treatment. While supporting the current transition to DTG-containing ART in resource-limited settings toward the achievement of the UNAIDS’ goal of HIV elimination by 2030, our findings suggested that RAL-exposed patients may need a specific monitoring approach either in a stratified or personalized model of third-line ART to ensure the long-term success of DTG-containing regimens.

ABSTRACT In keeping with the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 causative agent, PCR assays have been developed to rapidly detect SARS-CoV-2 variants, which have emerged since the first (Alpha) variant was identified. Based on specific assortment of SARS-CoV-2 spike-protein mutations (ΔH69/V70, E484K, N501Y, W152C, L452R, K417N, and K417T) among the major variants known to date, Seegene Allplex SARS-CoV-2 Variants I and Variants II assays have been available since a few months before the last (Omicron) variant became predominant. Using S gene next-generation sequencing (NGS) as the SARS-CoV-2 variant identification reference method, we assessed the results of SARS-CoV-2-positive nasopharyngeal swab samples from two testing periods, before (n = 288, using only Variants I) and after (n = 77, using both Variants I and Variants II) the appearance of Omicron. The Variants I assay allowed correct identification for Alpha (37/37), Beta/Gamma (28/30), or Delta (220/221) variant-positive samples. The combination of the Variants I and Variants II assays allowed correct identification for 61/77 Omicron variant-positive samples. While 16 samples had the K417N mutation undetected with the Variants II assay, 74/77 samples had both ΔH69/V70 and N501Y mutations detected with the Variants I assay. If considering only the results by the Variants I assay, 6 (2 Beta variant positive, 1 Delta variant positive, and 3 Omicron variant positive) of 365 samples tested in total provided incorrect identification. We showed that the Variants I assay alone might be more suitable than both the Variants I and Variants II assays to identify currently circulating SARS-CoV-2 variants. Inclusion of additional variant-specific mutations should be expected in the development of future assays. IMPORTANCE Omicron variants of SARS-CoV-2 pose more important public health concerns than the previously circulating Alpha or Delta variants, particularly regarding the efficacy of anti-SARS-CoV-2 vaccines and therapeutics. Precise identification of these variants highly requires performant PCR-based assays that allow us to reduce the reliance on NGS-based assays, which remain the reference method in this topic. While the current epidemiological SARS-CoV-2 pandemic context suggests that PCR assays such as the Seegene Variants II may be dispensable, we took advantage of NGS data obtained in this study to show that the array of SARS-CoV-2 spike protein mutations in the Seegene Variants II assay may be suboptimal. This reinforces the concept that initially developed PCR assays for SARS-CoV-2 variant detection could be no longer helpful if the SARS-CoV-2 pandemic evolves to newly emerging variants.

The impact of psychosocial and behavioral factors on Cancer Related Cognitive Impairment manifestations is still under debate. Study’s purpose is to determine the prevalence rate of cancer related cognitive impairment in a cohort of Italian breast cancer patients and to evaluate the implication of specific behavioral factors. For these purposes, a total of 233 women (106 breast cancer patients and 127 age-matched controls without oncological diagnosis) completed a questionnaire investigating cognitive functionality (FACT-Cog v3.0), sociodemographic characteristics, clinical information, psychosocial and behavioral factors (cognitive reserve, sleep quality, dietary habits, physical activity). The results indicated a higher prevalence rate of subjective cognitive complaints in breast cancer patients (37%) compared to a representative sample of women in the same age group without an oncological diagnosis (p

The overall increase in cardiovascular diseases and, specifically, the ever-rising exposure to cardiotoxic compounds has greatly increased in vivo animal testing; however, mainly due to ethical concerns related to experimental animal models, there is a strong interest in new in vitro models focused on the human heart. In recent years, human pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) emerged as reference cell systems for cardiac studies due to their biological similarity to primary CMs, the flexibility in cell culture protocols, and the capability to be amplified several times. Furthermore, the ability to be genetically reprogrammed makes patient-derived hiPSCs, a source for studies on personalized medicine. In this mini-review, the different models used for in vitro cardiac studies will be described, and their pros and cons analyzed to help researchers choose the best fitting model for their studies. Particular attention will be paid to hiPSC-CMs and three-dimensional (3D) systems since they can mimic the cytoarchitecture of the human heart, reproducing its morphological, biochemical, and mechanical features. The advantages of 3D in vitro heart models compared to traditional 2D cell cultures will be discussed, and the differences between scaffold-free and scaffold-based systems will also be spotlighted.

(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In the present work, we structurally evaluated the impact of RdRp mutations found at baseline in 39 patients treated with remdesivir and associated with a different degree of antiviral response in vivo. (2) Methods: A refined bioinformatics approach was applied to assign SARS-CoV-2 clade and lineage, and to define RdRp mutational profiles. In line with such a method, the same mutations were built and analyzed by combining docking and thermodynamics evaluations with both molecular dynamics and representative pharmacophore models. (3) Results: Clinical studies revealed that patients bearing the most prevalent triple mutant P323L+671S+M899I, which was present in 41% of patients, or the more complex mutational profile P323L+G671S+L838I+D738Y+K91E, which was found with a prevalence of 2.6%, showed a delayed reduced response to remdesivir, as confirmed by the increase in SARS-CoV-2 viral load and by a reduced theoretical binding affinity versus RdRp (ΔGbindWT = −122.70 kcal/mol; ΔGbindP323L+671S+M899I = −84.78 kcal/mol; ΔGbindP323L+G671S+L838I+D738Y+K91E = −96.74 kcal/mol). Combined computational approaches helped to rationalize such clinical observations, offering a mechanistic understanding of the allosteric effects of mutants on the global motions of the viral RNA synthesis machine and in the changes of the interactions patterns of remdesivir during its binding.