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Muscle lipid content affects many quality features in salmonids in both raw and processed fillets. The objective of the present work was to assess the consequences of 7 generations of divergent selection for muscle adiposity on some rainbow trout flesh quality and muscle parameters. Fish from Lean (L) and Fat (F) lines had a similar body weight but L fish were longer and had consequently lower condition factor values. Carcass yield was not affected, but L fish had lower hepato- and gonado-somatic indexes, a bigger head, and lower fillet yield than F fish. A difference of more than 15 points in mean fat-meter® values (genetic selection criteria) was measured between the two lines. Mean muscle lipid content was 5.0±1.0 % for L line vs 13.5±2.2 % for F line. An absolute difference of more than 6 % was measured in fillet dry matter content between the two lines, for raw, cooked, and smoked fillets. Raw fillets from F fish were lighter (L*>) and more colorful (a* and b*>), but softer than those from the L line. Quality parameters of cooked fillets were very similar between the two lines, whereas smoked fillets exhibited, between the two lines, similar differences than raw fillets. A large difference in white muscle fiber size was observed, fish from F line having higher fiber mean diameter, fewer small fibers, and more large fibers. Sex effects were observed on these immature fish, on classically sex-related traits (GSI and head development), but also on muscle fiber size. Raw fillet color was positively correlated to muscle adiposity whereas mechanical resistance was negatively correlated. Raw fillet mechanical resistance was also negatively correlated to white muscle fiber size. Moreover, smoked fillet quality parameters were correlated to raw fillet ones. The relationships between muscle adiposity, but also muscle cellularity, and fillet quality were discussed.

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BackgroundOne of the first clinical observations of ibrutinib activity in the treatment of chronic lymphocytic leukemia (CLL) is a rapid decline in lymph nodes size. This phenomenon is accompanied by an hyperlymphocytosis, either transient or prolonged, which is associated with distinct clinical responses and thus has an impact on long-term outcomes. Understanding which factors determine distinct disease courses upon ibrutinib treatment remains a scientific challenge.Methods and findingsFrom 2016 to 2021, we conducted a longitudinal and observational study in 2 cohorts of patients with chronic lymphocytic leukemia (CLL) (cohort 1, n = 41; cohort 2, n = 81). These cohorts reflect the well-known clinical features of CLL patients, such as Male/Female sex ratio of 2/1, a median age of 70 years at diagnosis, and include patients in first-line therapy (27%) or relapsed/refractory patients (73%). Blood cell counts were followed for each patient during 2 years of ibrutinib treatment. In addition, immunophenotyping and whole-body magnetic resonance imaging (MRI) were assessed in patients from cohort 1. These data were integrated in a newly built mathematical model, inspired by previous mathematical works on CLL treatment and combining dynamical and statistical models, leading to the identification of biological mechanisms associated with the 2 types of clinical responses. This multidisciplinary approach allowed to identify baseline parameters that dictated lymphocytes kinetics upon ibrutinib treatment. Indeed, ibrutinib-induced lymphocytosis defined 2 CLL patient subgroups, transient hyperlymphocytosis (tHL) or prolonged hyperlymphocytosis (pHL), that can be discriminated, before the treatment, by absolute counts of CD4+ T lymphocytes (p = 0.026) and regulatory CD4 T cells (p = 0.007), programmed cell death protein 1 PD1 (p = 0.022) and CD69 (p = 0.03) expression on B leukemic cells, CD19/CD5high/CXCR4low level (p = 0.04), and lymph node cellularity. We also pinpointed that the group of patients identified by the transient hyperlymphocytosis has lower duration response and a poor clinical outcome. The mathematical approach led to the reproduction of patient-specific dynamics and the estimation of associated patient-specific biological parameters, and highlighted that the differences between the 2 groups were mainly due to the production of leukemic B cells in lymph node compartments, and to a lesser extent to T lymphocytes and leukemic B cell egress into bloodstream. Access to additional data, especially longitudinal MRI data, could strengthen the conclusions regarding leukemic B cell dynamics in lymph nodes and the relevance of 2 distinct groups of patients.ConclusionsAltogether, our multidisciplinary study provides a better understanding of ibrutinib response and highlights new pharmacodynamic parameters before and along ibrutinib treatment. Since our results highlight a reduced duration response and outcome in patients with transient hyperlymphocytosis, our approach provides support for managing ibrutinib therapy after 3 months of treatment.Trial registrationClinicalTrials.gov NCT02824159.

Transboundary rural communities in West Africa play an important role in the exchange of goods, mainly food, among countries. The COVID-19 pandemic restricted these activities due to the closure of the borders. Semi-structured interviews were conducted in two regions of Senegal and Burkina Faso to examine the impacts of these restrictions on the pillars (availability, access, utilization, and stability) of food security in rural areas on men and women. The data set included 230 interviews, and they were analyzed through thematic content analysis. The results showed a decrease in agricultural production in all the communities due to mainly lack of labor force, and limited access to inputs, resulting in increased post-harvest losses. The disruption of trade and border and market closures affected rural families engaged in transboundary trade. Farmers experienced a sharp loss of household income leading to debts and decapitalization. Availability and diversity of and access to food was also heavily affected. Food security greatly varied among the communities and between countries. Perceptions also varied between men and women in terms of production, mobility, and food consumption. The restriction measures have triggered a spiral of effects and responses seriously impacting long-term food security in already highly vulnerable countries.

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental condition impacting behavior, communication, social interaction and learning abilities. Medical cannabis (MC) treatment can reduce clinical symptoms in individuals with ASD. Cannabis-responsive biomarkers are metabolites found in saliva that change in response to MC treatment. Previously we showed levels of these biomarkers in children with ASD successfully treated with MC shift towards the physiological levels detected in typically developing (TD) children, and potentially can quantify the impact. Here, we tested for the first time the capabilities of machine learning techniques applied to our dynamic, high-resolution and rich feature dataset of cannabis-responsive biomarkers from a limited number of children with ASD before and after MC treatment and a TD group to identify: (1) biomarkers distinguishing ASD and TD groups; (2) non-cannabinoid plant molecules with synergistic effects; and (3) biomarkers associated with specific cannabinoids. We found: (1) lysophosphatidylethanolamine can distinguish between ASD and TD groups; (2) novel phytochemicals contribute to the therapeutic effects of MC treatment by inhibition of acetylcholinesterase; and (3) THC- and CBD-associated cannabis-responsive biomarkers are two distinct groups, while CBG is associated with some biomarkers from both groups.

Abstract Background Understanding drug use and behavior within the PWUD population is crucial to adapt harm reduction and prevention strategies, and provide improved addiction and medical treatment. However, in most countries such as France, the knowledge of drug use behaviors is likely biased as it originates from addiction centers which are attended by only an unknown proportion of PWUD. The objectives of this study were to describe drug use behavior in a population of active PWUD in the urban area of Montpellier, South of France. Methods We implemented a community-based respondent-driven sampling survey (RDSS), a validated strategy to obtain a representative sample of a population, to recruit PWUD in the city. Adult individuals reporting frequent psychoactive drug use other than cannabis, with confirmation by urine test, were eligible. Beside HCV and HIV testing, trained peers interviewed participants on their drug consumption and behavior using standardized questionnaires. Fifteen seeds launched the RDSS. Results During the 11 weeks of the RDSS, 554 actives PWUD were consecutively included. They were mostly men (78.8%), had a median age of 39 years, and only 25.6% had a stable living place. On average, participants consumed 4.7 (± 3.1) different drugs, and 42.6% smoked free-base cocaine. Unexpectedly, heroin and methamphetamine were consumed by 46.8% and 21.5% of participants, respectively. Among the 194 participants injecting drugs, 33% declared sharing their equipment. Conclusion This RDSS highlighted a high consumption of heroin, crack and methamphetamine in this PWUD population. These unexpected results can be explained by low attendance to addiction centers, the source of drug use reports. Despite free care and risk reduction equipment in the city, sharing was very frequent among injectors, challenging the current program of harm reduction.

The superficial dorsal horn (SDH) of the spinal cord contains a diverse array of neurons. The vast majority of these are interneurons, most of which are glutamatergic. These can be assigned to several populations, one of which is defined by expression of gastrin-releasing peptide receptor (GRPR). The GRPR cells are thought to be “tertiary pruritoceptors,” conveying itch information to lamina I projection neurons of the anterolateral system (ALS). Surprisingly, we recently found that GRPR-expressing neurons belong to a morphological class known as vertical cells, which are believed to transmit nociceptive information to lamina I ALS cells. Little is currently known about synaptic circuits engaged by the GRPR cells. Here we combine viral-mediated expression of PSD95-tagRFP fusion protein with super-resolution microscopy to reveal sources of excitatory input to GRPR cells. We find that they receive a relatively sparse input from peptidergic and non-peptidergic nociceptors in SDH, and a limited input from A- and C-low threshold mechanoreceptors on their ventral dendrites. They receive synapses from several excitatory interneuron populations, including those defined by expression of substance P, neuropeptide FF, cholecystokinin, neurokinin B, and neurotensin. We investigated downstream targets of GRPR cells by chemogenetically exciting them and identifying Fos-positive (activated) cells. In addition to lamina I projection neurons, many ALS cells in lateral lamina V and the lateral spinal nucleus were Fos-positive, suggesting that GRPR-expressing cells target a broader population of projection neurons than was previously recognised. Our findings indicate that GRPR cells receive a diverse synaptic input from various types of primary afferent and excitatory interneuron, and that they can activate ALS cells in both superficial and deep regions of the dorsal horn.

BackgroundThe co-occurrence of substance use disorder and mental disorder, known as dual diagnosis, has a distressingly high prevalence among individuals grappling with either of these conditions. Mood disorders, especially depression, constitute a substantial burden for People Who Inject Drugs (PWID) and a significant public health concern in Vietnam. Identifying risk factors for depression in PWID is imperative for the development of targeted interventions.MethodsWe enrolled PWID into a cohort using the respondent-driven sampling method. Over a 36-month period, we systematically tracked the emergence of depression and employed multiple imputation in conjunction with a mixed nonlinear model to pinpoint risk factors for depression in this demographic. At inclusion, depression was screened using the PHQ-2 questionnaire, and subsequent episodes of depression were assessed semi-annually using the CES-D8.ResultsThree hundred and ninety-one PWID (26.6%) were depressed. Major risk factors for depression included being female, not having a permanent residency, having been hospitalized and using methamphetamine more than weekly. Other risk factors included age, being single, not having a health insurance card and not being on methadone.LimitationsThe exclusion of missing visits and social desirability could have led to selection and information biases. In this observational study, confusion biases are possible despite our best efforts.ConclusionDepression is alarmingly frequent in PWID. In this study taking in account the chronological relationship between sociodemographic and clinical factors and depression, risk factors were identified in this specific setting of low-to-middle income country. The findings highlight the need to develop innovative targeted psychiatric interventions with the help of supporting peers.

Abstract Excitatory interneurons in the superficial dorsal horn (SDH) are heterogeneous, and include a class known as vertical cells, which convey information to lamina I projection neurons. We recently used pro-NPFF antibody to reveal a discrete population of excitatory interneurons that express neuropeptide FF (NPFF). Here, we generated a new mouse line (NPFFCre) in which Cre is knocked into the Npff locus, and used Cre-dependent viruses and reporter mice to characterise NPFF cell properties. Both viral and reporter strategies labelled many cells in the SDH, and captured most pro-NPFF-immunoreactive neurons (75–80%). However, the majority of labelled cells lacked pro-NPFF, and we found considerable overlap with a population of neurons that express the gastrin-releasing peptide receptor (GRPR). Morphological reconstruction revealed that most pro-NPFF-containing neurons were vertical cells, but these differed from GRPR neurons (which are also vertical cells) in having a far higher dendritic spine density. Electrophysiological recording showed that NPFF cells also differed from GRPR cells in having a higher frequency of miniature EPSCs, being more electrically excitable and responding to a NPY Y1 receptor agonist. Together, these findings indicate that there are at least two distinct classes of vertical cells, which may have differing roles in somatosensory processing.

Globally, major efforts are being made to restore peatlands to maximise their resilience to anthropogenic climate change, which puts continuous pressure on peatland ecosystems and modifies the geography of the environmental envelope that underpins peatland functioning. A probable effect of climate change is reduction in the waterlogged conditions that are key to peatland formation and continued accumulation of carbon (C) in peat. C sequestration in peatlands arises from a delicate imbalance between primary production and decomposition, and microbial processes are potentially pivotal in regulating feedbacks between environmental change and the peatland C cycle. Increased soil temperature, caused by climate warming or disturbance of the natural vegetation cover and drainage, may result in reductions of long-term C storage via changes in microbial community composition and metabolic rates. Moreover, changes in water table depth alter the redox state and hence have broad consequences for microbial functions, including effects on fungal and bacterial communities especially methanogens and methanotrophs. This article is a perspective review of the effects of climate change and ecosystem restoration on peatland microbial communities and the implications for C sequestration and climate regulation. It is authored by peatland scientists, microbial ecologists, land managers and non-governmental organisations who were attendees at a series of three workshops held at The University of Manchester (UK) in 2019–2020. Our review suggests that the increase in methane flux sometimes observed when water tables are restored is predicated on the availability of labile carbon from vegetation and the absence of alternative terminal electron acceptors. Peatland microbial communities respond relatively rapidly to shifts in vegetation induced by climate change and subsequent changes in the quantity and quality of below-ground C substrate inputs. Other consequences of climate change that affect peatland microbial communities and C cycling include alterations in snow cover and permafrost thaw. In the face of rapid climate change, restoration of a resilient microbiome is essential to sustaining the climate regulation functions of peatland systems. Technological developments enabling faster characterisation of microbial communities and functions support progress towards this goal, which will require a strongly interdisciplinary approach.

Replacing fish meal and oil in trout diets with plant-derived ingredients is a contemporary challenge to move towards more sustainable aquaculture practices. However, such dietary replacement causes hepatic metabolic changes that have not yet been elucidated. Here, we aimed to decipher the effect of a 100% plant-based diet on the hepatic global DNA methylation landscape in trout and assess whether changes depend on fish genetic background. We analysed the global methylome and the expression of DNA (de)methylation-related genes of three isogenic lines that exhibit similar growth when fed a marine resource-based diet (M diet), but differ in their responses to a plant-based diet (V diet). Our results revealed that the V diet induced a decrease in 5-cytosine combined with an increase in 5-hydroxymethylcytosine in two of the three analysed lines. For one of these 2 affected lines, when fed the M diet but at the same feed intake of the V diet (MR), no methylome differences were highlighted between M and MR or between MR and V-fed trout whereas for the other affected line, M fed trout displayed a divergent methylome profile from MR and V fed fish. DNA (de)methylation-related genes were also affected by the V or MR diets. Our findings showed that the global hepatic methylome of trout is affected by a V diet, depending on genetic background. This latter effect seems to be due to either a decreased feed intake alone or combined with the effect of the dietary composition per se.

Este artigo trata da atuação do Observatório Covid-19, projeto da Presidência da Fiocruz e agente catalisador na produção e disseminação de informações sobre a pandemia no cenário brasileiro. Suas atividades resultaram na constituição de um arquivo digital, associado à ideia de “memória do projeto”, cujas características oriundas do cenário de emergência sanitária nos interessa investigar. O artigo tem por objetivo geral refletir sobre a criação e funcionamento do Observatório Covid-19 com foco nos desafios relativos à gestão dos documentos e informações provenientes de suas ações. Para tal, utilizam-se como insumos teóricos conceitos dos campos da ciência da informação, arquivologia, memória social e história das ciências e da saúde, além de informações provenientes de entrevista e fontes documentais. Os resultados indicam que a emergência sanitária impactou em diversos aspectos a produção, gestão, tramitação e preservação do arquivo.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is widely used for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). A prominent effect of ibrutinib is to disrupt the retention of CLL cells from supportive lymphoid tissues, by altering BTK-dependent adhesion and migration. To further explore the mechanism of action of ibrutinib and its potential impact on non-leukemic cells, we quantified multiple motility and adhesion parameters of human primary CLL cells and non-leukemic lymphoid cells. In vitro, ibrutinib affected CCL19-, CXCL12- and CXCL13-evoked migration behavior of CLL cells and non-neoplastic lymphocytes, by reducing both motility speed and directionality. De-phosphorylation of BTK induced by ibrutinib in CLL cells was associated with defective polarization over fibronectin and inability to assemble the immunological synapse upon B-cell receptor engagement. In patients’ samples collected during a 6-month monitoring of therapy, chemokine-evoked migration was repressed in CLL cells and marginally reduced in T cells. This was accompanied by profound modulation of the expression of chemokine receptors and adhesion molecules. Remarkably, the relative expression of the receptors governing lymph node entry (CCR7) versus exit (S1PR1) stood out as a reliable predictive marker of the clinically relevant treatment-induced lymphocytosis. Together, our data reveal a multifaceted modulation of motility and adhesive properties of ibrutinib on both CLL leukemic cell and T-cell populations and point to intrinsic differences in CLL recirculation properties as an underlying cause for variability in treatment response.

The desired performance of nucleic acid testing (NAT) may vary if used for disease diagnosis or for the evaluation of the therapeutic efficacy of a treatment, although in most cases, the same assay is used. However, these tests may not be affordable in many situations including in low/middle income countries that in response have developed domestic assays. Given the example of HCV NAT among people who inject drugs in Vietnam, we aimed at evaluating a domestic assay versus an FDA- and CE-approved assay. This cross-evaluation revealed that (i) the domestic assay had a poorer sensitivity with a threshold of detection above 104 IU/mL, and (ii) the FDA-approved assay had a percentage of false negative results close to 1%. Together, in the present study, the domestic assay had a performance compatible with diagnosis purposes (given that this population was 70% HCV seropositive) but not compatible with HCV treatment monitoring (given that treatment failures are rare and the observed viremia frequently below the threshold of detection). This study highlights the need for a proper evaluation of HCV RNA domestic assays in order to efficiently contribute to the WHO HCV elimination target by 2030.

Commercial redfish fishery, which has been under a moratorium since 1995 in the Gulf of St. Lawrence, is about to reopen. Since the 1990s, the social-ecological system (SES) of redfish (Sebastes spp.) fishery in Quebec has undergone many changes: abundance of available resources, climate change, warming waters, new fisheries management principles, market transformation, et cetera. In order not to reproduce the mistakes of the second half of the 20th century leading to overexploitation of groundfish, including redfish, the actors that make up this SES must develop new practices to respond to changes. In this context, we conducted semi-structured interviews with 34 actors involved in the SES of redfish fishery in Quebec and identified the practices implemented to respond to changes. Interpreting the practices of the actors makes it possible to understand their social representations of redfish fishing. These representations determine a paradigmatic framework in which the actions of the actors take place, reflecting the behaviour of the SES in the face of disturbances. Our study reveals the absence of transformation of the SES, through the anchoring of an extractive and sectoral model concerning the use of natural resources in Canada. It also highlights a naturalistic approach preventing the establishment of an intrinsic value assigned to the ecosystems, and an omnipresence of technical innovation to the detriment of social innovation in the fisheries sector.

Abstract Background High numbers of women experience a traumatic birth, which can lead to childbirth-related post-traumatic stress disorder (CB-PTSD) onset, and negative and pervasive impacts for women, infants, and families. Policies, suitable service provision, and training are needed to identify and treat psychological morbidity following a traumatic birth experience, but currently there is little insight into whether and what is provided in different contexts. The aim of this knowledge mapping exercise was to map policy, service and training provision for women following a traumatic birth experience in different European countries. Methods A survey was distributed as part of the COST Action “Perinatal mental health and birth-related trauma: Maximizing best practice and optimal outcomes”. Questions were designed to capture country level data; care provision (i.e., national policies or guidelines for the screening, treatment and/or prevention of a traumatic birth, service provision), and nationally mandated pre-registration and post-registration training for maternity professionals. Results Eighteen countries participated. Only one country (the Netherlands) had national policies regarding the screening, treatment, and prevention of a traumatic birth experience/CB-PTSD. Service provision was provided formally in six countries (33%), and informally in the majority (78%). In almost all countries (89%), women could be referred to specialist perinatal or mental health services. Services tended to be provided by midwives, although some multidisciplinary practice was apparent. Seven (39%) of the countries offered ‘a few hours’ professional/pre-registration training, but none offered nationally mandated post-registration training. Conclusions A traumatic birth experience is a key public health concern. Evidence highlights important gaps regarding formalized care provision and training for care providers.

Phenotypic plasticity is a key component of the ability of organisms to respond to changing environmental conditions. In this study, we aimed to study the establishment of DNA methylation marks in response to an environmental stress in rainbow trout and to assess whether these marks depend on the genetic background. The environmental stress chosen here was temperature, a known induction factor of epigenetic marks in fish. To disentangle the role of epigenetic mechanisms such as DNA methylation in generating phenotypic variations, nine rainbow trout isogenic lines with no genetic variability within a line were used. For each line, half of the eggs were incubated at standard temperature (11°C) and the other half at high temperature (16°C), from eyed-stage to hatching. In order to gain a first insight into the establishment of DNA methylation marks in response to an early temperature regime (control 11°C vs. heated 16°C), we have studied the expression of 8 dnmt3 (DNA methyltransferase) genes, potentially involved in de novo methylation, and analysed global DNA methylation in the different rainbow trout isogenic lines using LUMA (LUminometric Methylation Assay). Finally, finer investigation of genome-wide methylation patterns was performed using EpiRADseq, a reduced-representation library approach based on the ddRADseq (Double Digest Restriction Associated DNA) protocol, for six rainbow trout isogenic lines. We have demonstrated that thermal history during embryonic development alters patterns of DNA methylation, but to a greater or lesser extent depending on the genetic background.

Abstract A recently developed Phox2a::Cre mouse line has been shown to capture anterolateral system (ALS) projection neurons. Here, we used this line to test whether Phox2a-positive cells represent a distinct subpopulation among lamina I ALS neurons. We show that virtually all lamina I Phox2a cells can be retrogradely labelled from injections targeted on the lateral parabrachial area (LPb), and that most of those in the cervical cord also belong to the spinothalamic tract. Phox2a cells accounted for ~ 50–60% of the lamina I cells retrogradely labelled from LPb or thalamus. Phox2a was preferentially associated with smaller ALS neurons, and with those showing relatively weak neurokinin 1 receptor expression. The Phox2a cells were also less likely to project to the ipsilateral LPb. Although most Phox2a cells phosphorylated extracellular signal-regulated kinases following noxious heat stimulation, ~ 20% did not, and these were significantly smaller than the activated cells. This suggests that those ALS neurons that respond selectively to skin cooling, which have small cell bodies, may be included among the Phox2a population. Previous studies have defined neurochemical populations among the ALS cells, based on expression of Tac1 or Gpr83. However, we found that the proportions of Phox2a cells that expressed these genes were similar to the proportions reported for all lamina I ALS neurons, suggesting that Phox2a is not differentially expressed among cells belonging to these populations. Finally, we used a mouse line that resulted in membrane labelling of the Phox2a cells and showed that they all possess dendritic spines, although at a relatively low density. However, the distribution of the postsynaptic protein Homer revealed that dendritic spines accounted for a minority of the excitatory synapses on these cells. Our results confirm that Phox2a-positive cells in lamina I are ALS neurons, but show that the Phox2a::Cre line preferentially captures specific types of ALS cells.

Summary: Background: In most low-to-middle-income countries, HIV control at the population level among people who inject drugs (PWID) remains a major challenge. We aimed to demonstrate that an innovative intervention can identify HIV-positive PWID in the community who are not treated efficiently, and get them treated efficiently. Methods: Between 2016 and 2020, we implemented an intervention consisting of mass HIV screening of PWID using three annual respondent-driven sampling surveys (RDSS) and a post-intervention evaluation RDSS in community-based organisation (CBO) sites, coupled with peer support to facilitate/improve access to antiretroviral and methadone therapy in Haiphong, Vietnam. The primary outcome was the proportion of identified uncontrolled HIV-positive PWID who achieved viral control. We also estimated the potential effect of the intervention on the proportion of PWID with HIV RNA >1000 copies/mL among all PWID during the study period. Findings: Over the three RDSS, 3150 different PWID were screened, i.e. two-thirds of the estimated population size. They all injected heroin, their median age was of 39 years, 95% were male, 26.5% were HIV-infected, and 78.6% of the latter had HIV RNA ≤1000 copies/mL. Among the 177 PWID identified with an unsuppressed viral load, 73 (41.2%) achieved viral suppression at the final visit. HIV viremia decreased from 7.2% at baseline to 2.9% at the final RDSS (p

Abstract In the ANRS 12174 trial, HIV-exposed uninfected African neonates who received lopinavir-ritonavir (LPV/r) prophylaxis for 1 year exhibited slower growth from birth to week 50 compared with those receiving lamivudine (3TC). We assessed whether this difference in growth persisted over time, and was accompanied by differences in neuropsychological and clinical outcomes. Between February 2017 and February 2018, we conducted a cross-sectional clinical evaluation among former trial participants who completed the 50-week follow-up and who were not HIV-infected. In addition to clinical examination, neuropsychological outcomes were assessed using the tests Kaufman-ABCII, Test of Variables of Attention, Movement Assessment Battery for Children and the Strengths and Difficulties questionnaire, parent version. Of 1101 eligible children, aged 5–7 years, 553 could be traced and analysed (274 in the LPV/r and 279 in the 3TC groups). Growth, clinical and neuropsychological outcomes did not differ between treatment groups. At school age, children exposed to LPV/r and 3TC at birth for 1 year had comparable growth and neuropsychological outcomes without evidence of long-term side-effects of LPV/r. It provides reassuring data on clinical outcomes for all HIV-infected children treated with this antiretroviral drug in early life.

Single nucleotide polymorphism (SNP) arrays, also named « SNP chips », enable very large numbers of individuals to be genotyped at a targeted set of thousands of genome-wide identified markers. We used preexisting variant datasets from USDA, a French commercial line and 30X-coverage whole genome sequencing of INRAE isogenic lines to develop an Affymetrix 665 K SNP array (HD chip) for rainbow trout. In total, we identified 32,372,492 SNPs that were polymorphic in the USDA or INRAE databases. A subset of identified SNPs were selected for inclusion on the chip, prioritizing SNPs whose flanking sequence uniquely aligned to the Swanson reference genome, with homogenous repartition over the genome and the highest Minimum Allele Frequency in both USDA and French databases. Of the 664,531 SNPs which passed the Affymetrix quality filters and were manufactured on the HD chip, 65.3% and 60.9% passed filtering metrics and were polymorphic in two other distinct French commercial populations in which, respectively, 288 and 175 sampled fish were genotyped. Only 576,118 SNPs mapped uniquely on both Swanson and Arlee reference genomes, and 12,071 SNPs did not map at all on the Arlee reference genome. Among those 576,118 SNPs, 38,948 SNPs were kept from the commercially available medium-density 57 K SNP chip. We demonstrate the utility of the HD chip by describing the high rates of linkage disequilibrium at 2–10 kb in the rainbow trout genome in comparison to the linkage disequilibrium observed at 50–100 kb which are usual distances between markers of the medium-density chip.

Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2–12.8 years according to the number of MDEs, making this group more prone to age-related diseases.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Because of their wide network of interactions, miRNAs have become the focus of many studies over the past decade, particularly in animal species. To streamline the number of potential wet lab experiments, the use of miRNA target prediction tools is currently the first step undertaken. However, the predictions made may vary considerably depending on the tool used, which is mostly due to the complex and still not fully understood mechanism of action of miRNAs. The discrepancies complicate the choice of the tool for miRNA target prediction. To provide a comprehensive view of this issue, we highlight in this review the main characteristics of miRNA-target interactions in bilaterian animals, describe the prediction models currently used, and provide some insights for the evaluation of predictor performance.

Abstract Background Ibrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged, whether related or not to BTK mutations. Patterns of CLL evolution under ibrutinib therapy are well characterized for the leukemic cells but not for their microenvironment. Methods Here, we addressed this question at the single cell level of both transcriptome and immune-phenotype. The PBMCs from a CLL patient were monitored during ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology. Results This unveiled that the short clinical relapse of this patient driven by BTK mutation is associated with intraclonal heterogeneity in B leukemic cells and up-regulation of common signaling pathways induced by ibrutinib in both B leukemic cells and immune cells. This approach also pinpointed a subset of leukemic cells present before treatment and highly enriched during progression under ibrutinib. These latter exhibit an original gene signature including up-regulated BCR, MYC-activated, and other targetable pathways. Meanwhile, although ibrutinib differentially affected the exhaustion of T lymphocytes, this treatment enhanced the T cell cytotoxicity even during disease progression. Conclusions These results could open new alternative of therapeutic strategies for ibrutinib-refractory CLL patients, based on immunotherapy or targeting B leukemic cells themselves.

Abstract Rainbow trout has a male heterogametic (XY) sex determination system controlled by a major sex-determining gene, sdY. Unexpectedly, a few phenotypically masculinised fish are regularly observed in all-female farmed trout stocks. To better understand the genetic determinism underlying spontaneous maleness in XX-rainbow trout, we recorded the phenotypic sex of 20,210 XX-rainbow trout from a French farm population at 10 and 15 months post-hatching. The overall masculinisation rate was 1.45%. We performed two genome-wide association studies (GWAS) on a subsample of 1139 individuals classified as females, intersex or males using either medium-throughput genotyping (31,811 SNPs) or whole-genome sequencing (WGS, 8.7 million SNPs). The genomic heritability of maleness ranged between 0.48 and 0.62 depending on the method and the number of SNPs used for the estimation. At the 31K SNPs level, we detected four QTL on three chromosomes (Omy1, Omy12 and Omy20). Using WGS information, we narrowed down the positions of the two QTL detected on Omy1 to 96 kb and 347 kb respectively, with the second QTL explaining up to 14% of the total genetic variance of maleness. Within this QTL, we detected three putative candidate genes, fgfa8, cyp17a1 and an uncharacterised protein (LOC110527930), which might be involved in spontaneous maleness of XX-female rainbow trout.

Summary: Background: Access to psychiatric care for people who inject drugs (PWID) is limited/absent and stigmatized in most low-middle-income countries (LMICs). Innovative interventions are needed. We aimed to describe and assess the impact of a community-based psychiatric intervention among PWID in Hai Phong, Vietnam Methods: In a cohort study with one year psychiatric follow-up, PWID diagnosed with a psychotic disorder, a major depressive episode, or suicide risk, were recruited from the wider Drug-Related Infections in ViEtnam (DRIVE) project in the city of Hai Phong. The community-based psychiatric intervention included specialized follow-up (free consultations with psychiatrists, free medication, referral to mental health department for hospitalization when necessary) and support from community-based organisations (case management, harm reduction, administrative support, linkage to HIV care, methadone maintenance treatment and mental health support). The main outcome was reduction/remission of symptoms. Access to and retention in psychiatric care, quality-of-life and stigmatization were also measured pre and post-intervention. Findings: Among the 1212 participants screened from March to May 2019, 271 met the inclusion criteria, 233 (86.3%) accepted the intervention and 170 completed the follow-up (72.9%). At inclusion, 80.6% were diagnosed with current depression, 44.7% with psychotic disorder and 42.4% with suicide risk. After a one-year follow-up, these proportions dropped to 15.9%, 21.8%, and 22.9% respectively. Quality-of-life and perceived stigma related to mental health were also significantly improved, while drug use decreased only marginally. Interpretation: Community-based psychiatric interventions are both feasible and efficient in the Vietnamese context. Similar interventions should be implemented and evaluated in other, different LMICs. Funding: This work was supported by grants from NIDA (US) (#DA041978) and ANRS (France) (#13353). The funding agencies had no role in designing the research, data analyses, or preparation of the report.

ABSTRACT Viruses exert diverse ecosystem impacts by controlling their host community through lytic predator-prey dynamics. However, the mechanisms by which lysogenic viruses influence their host-microbial community are less clear. In hot springs, lysogeny is considered an active lifestyle, yet it has not been systematically studied in all habitats, with phototrophic microbial mats (PMMs) being particularly not studied. We carried out viral metagenomics following in situ mitomycin C induction experiments in PMMs from Porcelana hot spring (Northern Patagonia, Chile). The compositional changes of viral communities at two different sites were analyzed at the genomic and gene levels. Furthermore, the presence of integrated prophage sequences in environmental metagenome-assembled genomes from published Porcelana PMM metagenomes was analyzed. Our results suggest that virus-specific replicative cycles (lytic and lysogenic) were associated with specific host taxa with different metabolic capacities. One of the most abundant lytic viral groups corresponded to cyanophages, which would infect the cyanobacteria Fischerella, the most active and dominant primary producer in thermophilic PMMs. Likewise, lysogenic viruses were related exclusively to chemoheterotrophic bacteria from the phyla Proteobacteria, Firmicutes, and Actinobacteria. These temperate viruses possess accessory genes to sense or control stress-related processes in their hosts, such as sporulation and biofilm formation. Taken together, these observations suggest a nexus between the ecological role of the host (metabolism) and the type of viral lifestyle in thermophilic PMMs. This has direct implications in viral ecology, where the lysogenic-lytic switch is determined by nutrient abundance and microbial density but also by the metabolism type that prevails in the host community. IMPORTANCE Hot springs harbor microbial communities dominated by a limited variety of microorganisms and, as such, have become a model for studying community ecology and understanding how biotic and abiotic interactions shape their structure. Viruses in hot springs are shown to be ubiquitous, numerous, and active components of these communities. However, lytic and lysogenic viral communities of thermophilic phototrophic microbial mats (PMMs) remain largely unexplored. In this work, we use the power of viral metagenomics to reveal changes in the viral community following a mitomycin C induction experiment in PMMs. The importance of our research is that it will improve our understanding of viral lifestyles in PMMs via exploring the differences in the composition of natural and induced viral communities at the genome and gene levels. This novel information will contribute to deciphering which biotic and abiotic factors may control the transitions between lytic and lysogenic cycles in these extreme environments.

Within the context of a growing aquaculture production coupled with a plateau of the production in the main components of aquafeeds (fish oil and fishmeal), recent studies have typically focused on replacing these feedstuffs with terrestrial plant ingredients for cultured carnivorous aquatic species, such as rainbow trout (Oncorhynchus mykiss). Substitution rates without adverse effects have, however, reached their limit. One potential way forward would be to take advantage of the genetic variability that exists in the salmonid population. However, to date, little is known about the underlying molecular mechanisms responsible for this genetic variability. The aim of the present research was to understand why some genotypes are better able to utilize plant-based diets devoid of marine resources. In this regard, three isogenic lines of rainbow trout (R23h, AB1h, and A22h), with similar growth when fed marine resources-based diets and which differ greatly in their responses to a plant-based diet, were fed with either a complete plant-based diet (V diet) or a marine resources-based diet (M diet) since first-feeding. Fish traits and the hepatic transcriptome of these three genotypes were compared after 5 months of feeding. First, differences in the ability to grow with the V diet observed amongst genotypes was not due to higher feed intake, but instead due to differences in feed efficiency. The comparison of transcriptome profiles revealed 575 (R23h vs. AB1h), 1,770 (R23h vs. A22h), and 2,973 (AB1h vs. A22h) probes differentially expressed amongst the three genotypes when fed the V diet. Interestingly, R23h and AB1h fish, which were the least affected by the V diet, exhibited the highest growth. These results demonstrate that these fish were able to maintain a high level of energy production and protein synthesis. Moreover, these genotypes were also able to activate pathways linked to lipid and cholesterol metabolisms, such as the biosynthesis of long-chain polyunsaturated fatty acids. Finally, as previously, immunity seems to also play an important role in the ability of fish to use the V diet, and further studies are needed to understand the mechanisms by which immunity interacts with growth.

Abstract Background Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers. Methods We assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event. Results Multivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm3 (HR, 3.30, p

Abstract Background Selective breeding is a relatively recent practice in aquaculture species compared to terrestrial livestock. Nevertheless, the genetic variability of farmed salmonid lines, which have been selected for several generations, should be assessed. Indeed, a significant decrease in genetic variability due to high selection intensity could have occurred, potentially jeopardizing the long-term genetic progress as well as the adaptive capacities of populations facing change(s) in the environment. Thus, it is important to evaluate the impact of selection practices on genetic diversity to limit future inbreeding. The current study presents an analysis of genetic diversity within and between six French rainbow trout (Oncorhynchus mykiss) experimental or commercial lines based on a medium-density single nucleotide polymorphism (SNP) chip and various molecular genetic indicators: fixation index (F ST), linkage disequilibrium (LD), effective population size (N e ) and inbreeding coefficient derived from runs of homozygosity (ROH). Results Our results showed a moderate level of genetic differentiation between selected lines (F ST ranging from 0.08 to 0.15). LD declined rapidly over the first 100 kb, but then remained quite high at long distances, leading to low estimates of N e in the last generation ranging from 24 to 68 depending on the line and methodology considered. These results were consistent with inbreeding estimates that varied from 10.0% in an unselected experimental line to 19.5% in a commercial line, and which are clearly higher than corresponding estimates in ruminants or pigs. In addition, strong variations in LD and inbreeding were observed along the genome that may be due to differences in local rates of recombination or due to key genes that tended to have fixed favorable alleles for domestication or production. Conclusions This is the first report on ROH for any aquaculture species. Inbreeding appeared to be moderate to high in the six French rainbow trout lines, due to founder effects at the start of the breeding programs, but also likely to sweepstakes reproductive success in addition to selection for the selected lines. Efficient management of inbreeding is a major goal in breeding programs to ensure that populations can adapt to future breeding objectives and SNP information can be used to manage the rate at which inbreeding builds up in the fish genome.

People who inject drugs (PWID) are a population exposed to many genotoxicants and with a high prevalence of HCV infection. Direct-acting antiviral (DAA) regimens are now widely used to treat chronic HCV infection. Although side effects to treatment are currently rare, the long-term effects such as suspicions of de novo hepatocellular carcinoma (HCC) occurrence or HCC recurrence and cardiac defects are still up for debate. Given the structure of DAAs, the molecules have a potential mitochondrial DNA (mtDNA) genotoxicity. We have previously reported acute mtDNA toxicity of three DAA regimens among PWID with a strong impact on the rate of mtDNA deletion, less on the quantity of mtDNA copy per cell at sustained viral response at 12 weeks (SVR12). Herein, we report the mtDNA parameters nine months after drug discontinuation. We observed that the percentage of the deleted mtDNA genome increased over time. No exposure to any other genotoxicants during this period was associated with a high deletion percentage, suggesting that the replicative advantage of the deleted molecules outweighed their elimination processes. Such observation calls for longer-term follow-up and may contribute to the molecular basis of subclinical side effects of DAA treatments.

High-definition transcriptomic studies through single-cell RNA sequencing (scRNA-Seq) have revealed the heterogeneity and functionality of the various microenvironments across numerous solid tumors. Those pioneer studies have highlighted different cellular signatures correlated with clinical response to immune checkpoint inhibitors. scRNA-Seq offers also a unique opportunity to unravel the intimate heterogeneity of the ecosystems across different lymphoma entities. In this review, we will first cover the basics and future developments of the technology, and we will discuss its input in the field of translational lymphoma research, from determination of cell-of-origin and functional diversity, to monitoring of anti-cancer targeted drugs response and toxicities, and how new improvements in both data collection and interpretation will further foster precision medicine in the upcoming years.

Aims To describe the use of large-scale respondent driven sampling (RDS) surveys to demonstrate the “end of an HIV epidemic” (HIV incidence < 0.5/100 person-years) among persons who inject drugs (PWID) in a middle-income country. Large sample sizes are needed to convincingly demonstrate very low incidence rates. Methods 4 large surveys (Ns approximately 1500 each) were conducted among PWID in Hai Phong, Vietnam in 2016–2019. Respondent driven sampling (RDS) with a modification to add snowball sampling was used for recruiting participants. HIV incidence was measured through recency testing, repeat participants across multiple surveys and in a cohort study of PWID recruited from the surveys. RDS analytics (time to equilibria and homophilies for major variables) were used to assess similarities/differences in RDS only versus RDS plus snowball recruiting. Characteristics were compared among respondents recruited through standard RDS recruitment versus through snowball sampling. An overall assessment of the robustness of RDS to modification was made when adding a snowball sampling recruitment. Results RDS recruiting was very efficient in the first 5 weeks of each survey with approximately 180 respondents recruited per week. Recruiting then slowed considerably, and snowball sampling (permitting an individual respondent to recruit large numbers of new respondents) was added to the existing RDS recruiting. This led to recruiting within 13–14 weeks of 1383, 1451, 1444 and 1268 respondents, close to the target of 1500 respondents/survey. Comparisons of participants recruited through standard RDS method and respondents recruited through snowball methods showed very few significant differences. RDS analytics (quickly reaching equilibria, low homophilies) were favorable for both RDS recruited and total numbers of participants in each survey. DRug use and Infections in ViEtnam (DRIVE) methods have now been officially adopted in other provinces. Conclusions RDS appears to be quite robust with respect to adding a modest number of participants recruited through snowball sampling. Large sample sizes can provide compelling evidence for “ending an HIV epidemic” to policy makers in a PWID population in a middle income country setting.

γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor’s blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.

Introduction In Vietnam, people who inject drugs (PWID), who are the major population infected by hepatitis C virus (HCV), remain largely undiagnosed and unlinked to HCV prevention and care despite recommended universal hepatitis C treatment. The data on the outcomes of HCV treatment among PWID also remain limited in resource-limited settings. The DRug use & Infections in ViEtnam–hepatitis C (DRIVE-C) study examines the effectiveness of a model of hepatitis C screening and integrated care targeting PWID that largely uses community-based organisations (CBO) in Hai Phong, Vietnam. In a wider perspective, this model may have the potential to eliminate HCV among PWID in this city.Methods and analysis The model of care comprises large community-based mass screening, simplified treatment with direct-acting antivirals (DAAs) and major involvement of CBO for PWID reaching out, linkage to care, treatment adherence and prevention of reinfection. The effectiveness of DAA care strategy among PWID, the potential obstacles to widespread implementation and its impact at population level will be assessed. A cost-effectiveness analysis is planned to further inform policy-makers. The enrolment target is 1050 PWID, recruited from the DRIVE study in Hai Phong. After initiation of pan-genotypic treatment consisting of sofosbuvir and daclatasvir administrated for 12 weeks, with ribavirin added in cases of cirrhosis, participants are followed-up for 48 weeks. The primary outcome is the proportion of patients with sustained virological response at week 48, that will be compared with a theoretical expected rate of 70%.Ethics and dissemination The study was approved by Haiphong University of Medicine and Pharmacy's Ethics Review Board and the Vietnamese Ministry of Health. The sponsor and the investigators are committed to conducting this study in accordance with ethics principles contained in the World Medical Association's Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects). Informed consent is obtained before study enrolment. The data are anonymised and stored in a secure database. The study is ongoing. Results will be presented at international conferences and submitted to international peer-review journals.Trial registration number NCT03537196.

Infectious diseases represent a major threat for the sustainable development of fish farming. Efficient vaccines are not available against all diseases, and growing antibiotics resistance limits the use of antimicrobial drugs in aquaculture. It is therefore important to understand the basis of fish natural resistance to infections to help genetic selection and to develop new approaches against infectious diseases. However, the identification of the main mechanisms determining the resistance or susceptibility of a host to a pathogenic microbe is challenging, integrating the complexity of the variation of host genetics, the variability of pathogens, and their capacity of fast evolution and adaptation. Multiple approaches have been used for this purpose: (i) genetic approaches, QTL (quantitative trait loci) mapping or GWAS (genome-wide association study) analysis, to dissect the genetic architecture of disease resistance, and (ii) transcriptomics and functional assays to link the genetic constitution of a fish to the molecular mechanisms involved in its interactions with pathogens. To date, many studies in a wide range of fish species have investigated the genetic determinism of resistance to many diseases using QTL mapping or GWAS analyses. A few of these studies pointed mainly toward adaptive mechanisms of resistance/susceptibility to infections; others pointed toward innate or intrinsic mechanisms. However, in the majority of studies, underlying mechanisms remain unknown. By comparing gene expression profiles between resistant and susceptible genetic backgrounds, transcriptomics studies have contributed to build a framework of gene pathways determining fish responsiveness to a number of pathogens. Adding functional assays to expression and genetic approaches has led to a better understanding of resistance mechanisms in some cases. The development of knock-out approaches will complement these analyses and help to validate putative candidate genes critical for resistance to infections. In this review, we highlight fish isogenic lines as a unique biological material to unravel the complexity of host response to different pathogens. In the future, combining multiple approaches will lead to a better understanding of the dynamics of interaction between the pathogen and the host immune response, and contribute to the identification of potential targets of selection for improved resistance.