A non-randomized controlled study to assess the impact of the "Appui Parental", an early and intensive support programme for vulnerable families: Study protocol.

INTRODUCTION: Early home visit programmes have been developed to help parents build an adequate relationship with their baby and to prevent child developmental delays and affective disorders. The "Appui Parental" programme is an intervention carried out by nursery nurses to provide intensive parental support to vulnerable families. Before extending this programme, it seemed necessary to evaluate its impact objectively. OBJECTIVES: The main aim is to determine the impact of the "Appui Parental" programme on the change in the child's symptoms. The secondary objectives are to evaluate its effects on mother-child interactions, self-assessed parental competence, perception of social support, primary caregiver's anxiety-depression symptoms, alliance with the nursery nurse, frequency of out-of-home placements, and nursery nurses' stress. METHOD: This non-randomized prospective multicentre study would include 44 families who receive the "Appui Parental" intervention for a one to 20-month-old child (intervention group) and 44 families with the same vulnerability criteria who receive care as usual by the maternal and child protection services (control group). The child, parents, mother-child interaction, nursery nurse-mother alliance, and nursery nurse's stress will be assessed at month one and month 18 after inclusion. Comparisons between groups will be performed. CONCLUSION: This study should provide the public authorities with objective data on this programme's impact and allow them to pursue its generalization. For professionals, the study should confirm the interest in close early parental support through home visits or should lead to rethinking some aspects of the programme.

Human plasma cells express granzyme B.

While studying the plasma cell (PC) compartment in human tonsils, we identified that immunoglobulin kappa or lambda chain-expressing PCs are the main cells expressing granzyme B (GrzB). In vitro studies revealed that activated B cells differentiated into GrzB-expressing PCs when co-cultured with macrophages and follicular helper T cells. This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner. Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins. The precise role of GrzB in PC biology remains to be understood and studies in mice will not help as their PCs do not express GrzB.

Residual HIV-1 replication may impact immune recovery in patients on first-line lopinavir/ritonavir monotherapy.

BACKGROUND: Antiretroviral combination therapy raises issues of long-term adherence and toxicity. Initial treatment simplification based on single-drug therapy was investigated in the MONARK trial, which compared first-line lopinavir/ritonavir monotherapy (arm A) with first-line lopinavir/ritonavir + zidovudine/lamivudine tritherapy (arm B). The MONARK trial is registered as a randomized trial at clinical trials.gov under identifier NCT 00234923. PATIENTS AND METHODS: Immune recovery was compared in patients with undetectable plasma virus (<50 copies/mL) after 60 weeks of treatment (arm A, n = 21; arm B, n = 13). RESULTS: The week 60 CD4 T cell count and CD4 T cell subset distribution did not differ significantly between the treatment arms. Memory CD4 T cell responses to HIV and recall antigens were better with triple therapy than with monotherapy. The frequencies of activated CD8 T cells and anti-HIV CD8 T cell effector responses were similar in the two arms. However, the repertoire of CD8 T cell effector responses was broader and persistent residual viraemia more frequent (by ultrasensitive PCR) in the monotherapy arm. CONCLUSIONS: While viral control can be achieved with first-line lopinavir/ritonavir monotherapy, the quality of immune recovery is inferior to that obtained with triple therapy, possibly owing to a higher level of residual viral replication. Thus, the benefits of first-line lopinavir/ritonavir monotherapy in terms of toxicity and adherence might be offset by an increased risk of residual viral replication, which may also fuel latent viral reservoirs.

Immunological hallmarks of JC virus replication in multiple sclerosis patients on long-term natalizumab therapy.

Progressive multifocal leukoencephalopathy (PML) is the main adverse effect of natalizumab. Detectable JC virus-specific effector memory T-cell (TEM) responses may indicate ongoing JCV replication. We detected JCV-specific TEM responses in blood of patients with multiple sclerosis (MS) treated with natalizumab, including 2 patients with PML. The frequency of detection of these responses increased with the time on natalizumab. Thus, a subset of MS patients exhibit immunological hallmarks of JCV replication during prolonged natalizumab therapy.

Frequent detection of IFN-gamma -producing memory effector and effector T cells in patients with progressive multifocal leukoencephalopathy.

Introduction: Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis. Methods: Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood. Results: This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML). Discussion: The results show this assay's frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.

NK and T cell repertoire is established early after allogeneic HSCT and is profoundly imprinted by CMV reactivation.

Besides genetic influences, non-genetic factors such as graft-versus-host disease (GvHD) and viral infections have been shown as important shapers of the immune reconstitution and diversification processes after hematopoietic stem cell transplantation (HSCT). However, the differential susceptibility to immune modulation by non-genetic factors is not fully understood. We determined to follow the reconstitution of the T cell receptor (TCR) repertoire through immune-sequencing, of natural killer (NK) cells using a 35-marker spectral flow cytometry panel, and in relation to clinical events. Longitudinal investigation was performed on samples derived from 54 HSCT recipients during the first-year post-HSCT. We confirmed a significant contraction in TCR repertoire diversity with a remarkable stability over time. CMV reactivation had the ability to significantly change TCR repertoire clonality and composition, with a long-lasting imprint. Our data further revealed skewing of NK cell reconstitution in CMV reactivated recipients, with an increased frequency of KIR2DL2L3S2+ adaptive, cytolytic and functional CD107a+ NK cells concomitant with a reduced pool of NKG2A+ NK cells. We provided support that CMV might act as one of the more important driver of peripheral homeostatic proliferation of circulating specific T and NK cells, which can be viewed as a compensatory mechanism to establish a new peripheral repertoire.

QTL meta-analysis provides a comprehensive view of loci controlling partial resistance to Aphanomyces euteiches in four sources of resistance in pea.

BACKGROUND: Development of durable plant genetic resistance to pathogens through strategies of QTL pyramiding and diversification requires in depth knowledge of polygenic resistance within the available germplasm. Polygenic partial resistance to Aphanomyces root rot, caused by Aphanomyces euteiches, one of the most damaging pathogens of pea worldwide, was previously dissected in individual mapping populations. However, there are no data available regarding the diversity of the resistance QTL across a broader collection of pea germplasm. In this study, we performed a meta-analysis of Aphanomyces root rot resistance QTL in the four main sources of resistance in pea and compared their genomic localization with genes/QTL controlling morphological or phenological traits and with putative candidate genes. RESULTS: Meta-analysis, conducted using 244 individual QTL reported previously in three mapping populations (Puget x 90-2079, Baccara x PI180693 and Baccara x 552) and in a fourth mapping population in this study (DSP x 90-2131), resulted in the identification of 27 meta-QTL for resistance to A. euteiches. Confidence intervals of meta-QTL were, on average, reduced four-fold compared to mean confidence intervals of individual QTL. Eleven consistent meta-QTL, which highlight seven highly consistent genomic regions, were identified. Few meta-QTL specificities were observed among mapping populations, suggesting that sources of resistance are not independent. Seven resistance meta-QTL, including six of the highly consistent genomic regions, co-localized with six of the meta-QTL identified in this study for earliness and plant height and with three morphological genes (Af, A, R). Alleles contributing to the resistance were often associated with undesirable alleles for dry pea breeding. Candidate genes underlying six main meta-QTL regions were identified using colinearity between the pea and Medicago truncatula genomes. CONCLUSIONS: QTL meta-analysis provided an overview of the moderately low diversity of loci controlling partial resistance to A. euteiches in four main sources of resistance in pea. Seven highly consistent genomic regions with potential use in marker-assisted-selection were identified. Confidence intervals at several main QTL regions were reduced and co-segregation among resistance and morphological/phenological alleles was identified. Further work will be required to identify the best combinations of QTL for durably increasing partial resistance to A. euteiches.

Direct CD4 help provision following interaction of memory CD4 and CD8 T cells with distinct antigen-presenting dendritic cells.

Accumulating evidence suggests that CD4 help is needed at the memory stage to mount effective secondary CD8 T cell responses. In this paper, we report that memory CD4 T cells can provide efficient help to memory CD8 T cells after interaction of the two lymphocytes with distinct dendritic cells. Provision of help to CD8 T cells required direct cell-cell contact and involved both IL-2 and CD40 ligation, within a CD4-CD8 T cell synapse. Thus, following antigenic interaction with APCs, activated memory CD4 and CD8 T cells appear to separate from their respective APCs before meeting each other for help provision, regardless of their Ag specificity. CD4 help for memory CD8 T cells therefore appears to be conditioned primarily not by Ag specificity but by activation status.

When Immunity Kills: The Lessons of SARS-CoV-2 Outbreak.

Since its emergence at the end of 2019, SARS-CoV-2 has spread worldwide at a very rapid pace. While most infected individuals have an asymptomatic or mild disease, a minority, mainly the elderly, develop a severe disease that may lead to a fatal acute respiratory distress syndrome (ARDS). ARDS results from a highly inflammatory immunopathology process that includes systemic manifestations and massive alveolar damages that impair gas exchange. The present review summarizes our current knowledge in the rapidly evolving field of SARS-CoV-2 immunopathology, emphasizing the role of specific T cell responses. Indeed, accumulating evidence suggest that while T-cell response directed against SARS-CoV-2 likely plays a crucial role in virus clearance, it may also participate in the immunopathology process that leads to ARDS.

Heterospecific CD4 help to rescue CD8 T cell killers.

Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.

Hemostatic radiotherapy for bladder cancer-related hematuria in patients unfit for surgery: is there any impact of fractionation schedule?

PURPOSE: The optimal schedule for palliative external beam radiotherapy (EBRT) in patients with bladder tumors with hematuria unfit for surgery remains undefined. This study aimed to assess the clinical hemostatic efficacy and safety of two EBRT hypofractionated schedules. METHODS: From February 2008 to October 2017, 31 patients were referred to our department for palliative hemostatic bladder irradiation. EBRT consisted of two schedules: "continuous" treatment (CRT) was delivered following consecutive 3-10 weekdays (3-6Gy/fraction (fr), to a total dose of 18-30Gy) (n=14); the "discontinuous" schedule (DRT) consisted of 23Gy in 4fr (6.5Gy/fr on days 1 and 3, followed by 5Gy/fr on days 15 and 17; n=12). The primary endpoint was the rate of hemostatic control (HC) at the end of the radiation course. Other endpoints included mid-term HC, toxicities and overall survival. Comparative analyses were performed by exact Fisher test with a cut-off of 0.05 for statistical significance. RESULTS: The rate of HC at the end of EBRT was 92% (n=24) with no differences between CRT and DRT (100% vs 86%; p=0.48). The median follow-up was 6 months, HC was achieved in 15/26 (58%) patients at the last follow-up, without meaningful differences between CRT and DRT (50% vs 67%; p=0.45). Three and two patients developed acute grade ≤2 diarrhea in CRT and DRT groups, respectively. CONCLUSION: Our study suggests that both hypofractionated "continuous" and "discontinuous" EBRT are well tolerated and represent acceptable schedules for patients with limited life expectancy. DRT schedule could be preferred for departments' organization to increase the slots for the treatment of other referred patients for radiotherapy.

Axillary nodal irradiation practice in the sentinel lymph node biopsy era: Comparison of the contemporary available 3D and IMRT techniques.

OBJECTIVE: Our study aimed to compare regional node coverage and doses to the organ at risk (OAR) using conventional technique (CT) vs "AMAROS" (AT) vs intensity-modulated radiation therapy (IMRT) techniques in patients receiving regional nodal irradiation (RNI) for breast cancer (BC). METHODS: We included 30 consecutive patients with BC who received RNI including axillary nodes. Two independent and blinded dosimetric RNI plans were generated for all patients. For target volume coverage, we analyzed the V95%, the D95%, the mean and the minimal dose within the nodal station. For hotspots within nodal target volume, we used the V105%, the V108% and the maximal doses. For OAR, lung V20, mean lung and heart doses, the maximal dose to the brachial plexus and the axillary-lateral thoracic vessel junction region were compared between the three techniques. RESULTS: Target volume coverage and hotspots: Mean V95% in stations I, II, III and IV were 35.8% and 75% respectively with CV, 22.59 and 59.9% respectively with AT technique and 45.58 and 99.6% respectively with IMRT with statistically significant differences (p < 0.001). Mean V105% (cc) in axillary and supraclavicular stations were 21.3 and 6.4 respectively with CV, 1.2 and 0.02 respectively with AT technique and 0.5 and 0.4 respectively with IMRT with statistically significant differences (p < 0.001)..OARs: The mean ipsilateral lung V20 was 16.9%, 16.4 and 13.3% with CT, AT and IMRT respectively. The mean heart dose (Gy) was 0.3, 0.2 and 0.2 with CT, AT and IMRT respectively. The maximal dose to the plexus brachial (Gy) was 50.3, 46.3 and 47.3 with CT, AT and IMRT respectively. The maximal dose to the axillary-lateral thoracic vessel junction (Gy) was 52.3, 47.3 and 47.6 with CT, AT and IMRT respectively. The differences were statistically significant for all OAR (p < 0.001). CONCLUSION: AT is a valuable technique for RNI including axilla in patients with limited sentinel lymph node biopsy involvement without additional axillary lymph node dissection since it decreases hotspots in the target volume and lowers the radiation exposure of the OAR. For more advanced tumors or patients who did not respond to primary systemic therapy, CT or IMRT should be considered because of their better coverage of the potentially residual nodal disease. IMRT combines several advantages of offering high conformal plans, limited hotspots and protection of main OAR. The clinical impact of these dosimetric differences need to be addressed. ADVANCES IN KNOWLEDGE: This study is to our knowledge the first to compare conventional three-dimensional and IMRT techniques for regional nodal irradiation for each nodal station in breast cancer in a context of increasing utilization of axillary irradiation.

Radiation Therapy Department Reorganization during the Coronavirus Disease 2019 (COVID-19) Outbreak: Keys to Securing Staff and Patients During the First Weeks of the Crisis and Impact on Radiation Therapy Practice from a Single Institution Experience.

PURPOSE: During the first weeks of the coronavirus disease 2019 (COVID-19) outbreak in France, it was necessary to clearly define organizational priorities in the radiation therapy (RT) departments. In this report, we focus on the urgent measures taken to reduce risk for both our staff and patients by reducing the number of patients receiving treatment. METHODS AND MATERIALS: We reviewed the fractionation schemes for all patients in our department, including those receiving treatment and those soon to start treatment. Our goals were to (1) decrease the number of patients coming daily to the hospital for RT, (2) adapt our human resources to continue patients' care in the department, and (3) help to cover understaffed COVID-19 sectors of the hospital. RESULTS: We identified 50 patients who were receiving treatment (n = 6), were going to start radiation after CT scan simulation (n = 41), or for whom the CT scan was pending (n = 3). The majority were women (64%) treated for breast cancer (54%). RT was delayed for 22 (44%) patients. The majority were offered hormone therapy as "waiting therapy." Hypofractionation was considered in 21 (42%) patients mainly with breast cancer (18 of 21, 86%). The number of courses initially planned and replanned as a result of the COVID-19 outbreak during the period of March 15 to May 31, 2020, were 1383 and 683, respectively, which represented a reduction of 50% (including delayed sessions) that allowed our reorganization process. CONCLUSIONS: To conserve resources during the pandemic, we successfully reduced the number of patients receiving treatment in a proactive fashion and adapted our organization to minimize the risk of COVID-19 contamination. Departments across the world may benefit from this same approach.

Towards Laterally Resolved Ferromagnetic Resonance with Spin-Polarized Scanning Tunneling Microscopy.

We used a homodyne detection to investigate the gyration of magnetic vortex cores in Fe islands on W(110) with spin-polarized scanning tunneling microscopy at liquid helium temperatures. The technique aims at local detection of the spin precession as a function of frequency using a radio-frequency (rf) modulation of the tunneling bias voltage. The gyration was excited by the resulting spin-polarized rf current in the tunneling junction. A theoretical analysis of different contributions to the frequency-dependent signals expected in this technique is given. These include, besides the ferromagnetic resonance signal, also signals caused by the non-linearity of the I ( U ) characteristics. The vortex gyration was modeled with micromagnetic finite element methods using realistic parameters for the tunneling current, its spin polarization, and the island shape, and simulations were compared with the experimental results. The observed signals are presented and critically analyzed.

Follicular CD4 T Cells Tutor CD8 Early Memory Precursors: An Initiatory Journey to the Frontier of B Cell Territory.

The early events of CD8 memory generation remain largely unknown. Here we report that as early as 2 days after antigen priming, very early memory precursors can be identified by their expression of the chemokine receptor CXCR5. These early precursors, which have an effector phenotype, expand and temporarily migrate to the T-B cell zone junction where they interact with follicular CD4+ T cells (Tfh). Remarkably, this interaction with Tfh, hitherto considered as exclusive B cell helpers, is required for CD8 memory precursors to become highly competent memory cells. CD40 and interleukin-21 signaling are involved in the help provided to CXCR5+CD8 memory precursors. This study thus unveils critical early steps in the generation of CD8 memory, identifies CXCR5 as the earliest known marker of CD8 memory precursors, suggests a major helper role for Tfh, and points to possible coordination between the pathways of CD8 and B cell memory generation at the T-B-cell zone junction.

Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression.

Tumor growth requires the development and remodeling of the vascular system, involving paracrine signaling between various growth factors and endothelial receptors. Vascular endothelial growth factor (VEGF) is a key regulator of developmental, physiological and pathological neovascularization, especially involved in tumor growth. Recent studies indicate that 17beta-estradiol (E2) modulates VEGF expression in breast cancer cells through transcriptional activation. We have investigated both the molecular mechanisms of E2-induction of VEGF expression and of VEGF control of breast cancer angiogenesis. In transient transfection assays using the VEGF promoter-luciferase construct, E2 increased VEGF transcriptional activity in MCF-7 cells and in MDA-MB-231 cotransfected with estrogen receptor (ERalpha or ERbeta). The positive effect was abolished when MCF-7 cells were treated with the pure antiestrogen ICI 182,780 or the agonist/antagonist tamoxifen. We further identified an imperfect estrogen responsive element (ERE1520) in the VEGF promoter, which formed a complex with ERalpha or ERbeta proteins in gel shift assay using MCF-7 or MDA-MB-231 nuclear extracts; the ERE sequence is involved in the transcriptional regulation of VEGF in our experimental conditions. These results demonstrate that in breast cancer (BC) cells VEGF is a target gene for ERalpha or ERbeta. To determine the role of VEGF in the progression of human breast carcinoma, we generated stable human breast carcinoma cells (MCF-7) overexpressing VEGF165 (V165 clones). Cells or control vector clones were implanted subcutaneously in athymic mice. Our in vivo findings show that overexpression of VEGF significantly decreased tumor uptake and increased tumor growth and angiogenesis in a murine model of BC.

Does the portal of entry determine our view? Interfaces between dyadic and three-way assessment of a clinical family transitioning to parenthood.

The purpose of this interface was to explore the influences of dyadic and three-way observation on clinical assessment of young families. Three independent clinicians observed a clinically referred family using semistructured play paradigms, each with only a limited view of the family. One had only the data on dyadic interactions, the second only had data on the family triad, and the third observed both the dyads and the triad. Interactions were scored using standardized measures as well as the clinical impressions of the three practitioners. The various ports of entry yielded similar impressions in some instances, but each port also provided a richness of information not available from the other portal. Clinical implications are discussed, including not only the benefits of each port for assessment but also the implications for therapy in this case example.

Publisher Correction: Stabilizing spin spirals and isolated skyrmions at low magnetic field exploiting vanishing magnetic anisotropy.

The original version of this Article had an incorrect Received date of 21 November 2016; it should have been 21 November 2017. This has been corrected in the PDF and HTML versions of the Article.

Stabilizing spin spirals and isolated skyrmions at low magnetic field exploiting vanishing magnetic anisotropy.

Skyrmions are topologically protected non-collinear magnetic structures. Their stability is ideally suited to carry information in, e.g., racetrack memories. The success of such a memory critically depends on the ability to stabilize and manipulate skyrmions at low magnetic fields. The non-collinear Dzyaloshinskii-Moriya interaction originating from spin-orbit coupling drives skyrmion formation. It competes with Heisenberg exchange and magnetic anisotropy favoring collinear states. Isolated skyrmions in ultra-thin films so far required magnetic fields as high as several Tesla. Here, we show that isolated skyrmions in a monolayer of Co/Ru(0001) can be stabilized down to vanishing fields. Even with the weak spin-orbit coupling of the 4d element Ru, homochiral spin spirals and isolated skyrmions were detected with spin-sensitive scanning tunneling microscopy. Density functional theory calculations explain the stability of the chiral magnetic features by the absence of magnetic anisotropy energy.

Linking Electronic Transport through a Spin Crossover Thin Film to the Molecular Spin State Using X-ray Absorption Spectroscopy Operando Techniques.

One promising route toward encoding information is to utilize the two stable electronic states of a spin crossover molecule. Although this property is clearly manifested in transport across single molecule junctions, evidence linking charge transport across a solid-state device to the molecular film's spin state has thus far remained indirect. To establish this link, we deploy materials-centric and device-centric operando experiments involving X-ray absorption spectroscopy. We find a correlation between the temperature dependencies of the junction resistance and the Fe spin state within the device's [Fe(H2B(pz)2)2(NH2-phen)] molecular film. We also factually observe that the Fe molecular site mediates charge transport. Our dual operando studies reveal that transport involves a subset of molecules within an electronically heterogeneous spin crossover film. Our work confers an insight that substantially improves the state-of-the-art regarding spin crossover-based devices, thanks to a methodology that can benefit device studies of other next-generation molecular compounds.