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.

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.

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.

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.

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.

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.

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.

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.

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.

Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy After Prolonged CTLA4 Therapy.

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy-induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery.

Probing a Device's Active Atoms.

Materials science and device studies have, when implemented jointly as "operando" studies, better revealed the causal link between the properties of the device's materials and its operation, with applications ranging from gas sensing to information and energy technologies. Here, as a further step that maximizes this causal link, the paper focuses on the electronic properties of those atoms that drive a device's operation by using it to read out the materials property. It is demonstrated how this method can reveal insight into the operation of a macroscale, industrial-grade microelectronic device on the atomic level. A magnetic tunnel junction's (MTJ's) current, which involves charge transport across different atomic species and interfaces, is measured while these atoms absorb soft X-rays with synchrotron-grade brilliance. X-ray absorption is found to affect magnetotransport when the photon energy and linear polarization are tuned to excite FeO bonds parallel to the MTJ's interfaces. This explicit link between the device's spintronic performance and these FeO bonds, although predicted, challenges conventional wisdom on their detrimental spintronic impact. The technique opens interdisciplinary possibilities to directly probe the role of different atomic species on device operation, and shall considerably simplify the materials science iterations within device research.

The Henri Mondor Procedure of Morbidity and Mortality Review Meetings: Prospective Registration of Clinical, Dosimetric, and Individual Radiosensitivity Data of Patients With Severe Radiation Toxicity.

PURPOSE: After radiation therapy (RT), various radiation-induced toxicities can develop in about one-fourth of patients. An international interest in using morbidity and mortality rates to monitor the quality of care and integrate morbidity and mortality review (MMR) meetings into organizations' governance processes has arisen. We report the first results of patients included in our MMR procedure that included biological assays for individual intrinsic radiosensitivity (IIRS). METHODS AND MATERIALS: Twenty-three patients were prospectively included in the MMR database. Twenty-two were evaluable for IIRS. Prostate (n=10) and breast (n=8) cancers were the most frequent disease types. The total dose delivered, determined according to the type of disease, ranged from 30 to 74 Gy. Our MMR procedure requires strict criteria: patients with unresolved toxicity of grade 3 or higher with availability of clinical (photographic) data, IIRS results obtained from skin biopsy assays, treatment modalities, and follow-up data. The RT technique and dosimetry were reviewed. RESULTS: Our prospective registration of toxicities showed mainly rectitis, occurring in 7 cases, and skin toxicities, occurring in 9. Of the 7 patients with rectitis, 5 received 66 Gy of post-prostatectomy RT with V50 (rectum volume receiving 50 Gy) ranging from 45% to 75% and a mean maximal dose of 66.5 Gy. For dermatitis and cystitis, the mean maximal doses were in the range of classical constraints without any overdosage or dose heterogeneity. No errors were found in the review of treatment planning and positioning. Conversely, all the patients were considered biologically as radiosensitive with genomic instability and ATM (ataxia telangiectasia mutated)-dependent DNA double-strand break repair impairments. CONCLUSIONS: The MMR review of files allowed clear answers for patients on the relationship between clinical events and their IIRS. Our procedure has allowed education of all our staff to monitor, identify, and document clinical, physical, and biological aspects of radiation-induced toxicities. Thus we recommend the introduction of the MMR procedure in RT departments.

B cells and progressive multifocal leukoencephalopathy: search for the missing link.

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients with severe immunodepression, and cases have recently been linked to therapeutic monoclonal antibodies such as natalizumab and also rituximab, which depletes B cells. B cells appear to play a complex role in the pathogenesis of PML. They may act as a viral reservoir and as a vector for viral dissemination in the central nervous system. Anti-JCV antibody responses appear to have a limited effect on JCV replication in the brain. However, accumulating evidence suggests that B cells may considerably influence T cell responses through their cytokine secretion. This immunomodulatory function of B cells may play an important role in the control of JCV infection and in the pathogenesis of PML, including rituximab-induced PML.

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.

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.

Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy.

In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

Tissue competence imprinting and tissue residency of CD8 T cells.

T cell immunity is characterized by striking tissue specialization. Tissue-specificity imprinting starts during priming by tissue-derived migratory dendritic cells in the non-random, specialized micro-anatomical area of the draining lymph node and is influenced by constitutive and induced cues from local environment. Besides tissue-specific effectors, memory cells also exhibit a tissue-specificity. Long-lived tissue-resident memory T cells likely play a considerable role in preventing pathogen invasion. Understanding of the mechanisms of tissue specialization of T cells is of major importance for the design of optimal vaccination strategies and therapeutic interventions in tissue/organ-specific inflammatory diseases. The present review summarizes our current knowledge and hypothesis about tissue-specificity imprinting and tissue residency of T cells.