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A fast tracking system is demonstrated that is based on single laser illumination and a few single-pixel single photon avalanche diode (SPAD) detectors that improves on the previous tracking of non-line-of-sight motion by a factor of 300 in laser power. With an average illumination power of only 2 mW, a 15 cm ×15 cm object located up to 2.5 m away is tracked whilst outside of the direct line-of-sight and moving at approximately 6 cm/s.

Importance Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published. Objective To determine the effectiveness of omalizumab in treating severe atopic dermatitis in children. Design, Setting, and Participants The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) was a 24-week single-center, double-blind, placebo-controlled randomized clinical trial with a 24-week follow-up. Conducted from November 20, 2014, to August 31, 2017, at Guy’s and St Thomas’ Hospital NHS Foundation Trust and King’s College London in the United Kingdom, this trial recruited participants after a screening visit. Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index >40) that was unresponsive to optimum therapy. Statistical analysis was conducted using the intention-to-treat principle. Interventions Subcutaneous omalizumab or placebo for 24 weeks. The drug manufacturer’s dosing tables were used to determine the dosage based on total IgE (30-1500 IU/mL) and body weight (in kilograms) at randomization. Main Outcomes and Measures Objective SCORAD index after 24 weeks of treatment. Results In total, 62 children (mean [SD] age, 10.3 [4.2] years; 32 (52%) were male) were randomized to either omalizumab (n = 30) or placebo (n = 32). Five participants withdrew from treatment (4 [13%] from the placebo group, and 1 [3%] from the omalizumab group). Follow-up attendance was 97% at week 24 and 98% at week 48. After adjustment for baseline objective SCORAD index, age, and IgE level, the mean difference in objective SCORAD index improvement between groups at week 24 was −6.9 (95% CI, −12.2 to −1.5;P = .01), significantly favoring omalizumab therapy and reflecting the results in other assessments of atopic dermatitis severity. Improved quality-of-life scores were seen in the omalizumab group, as measured by the Children's Dermatology Life Quality Index/Dermatology Life Quality Index (−3.5; 95% CI, −6.4 to −0.5) and Pediatric Allergic Disease Quality of Life Questionnaire score (−0.5; 95% CI, −0.9 to −0.0). Improvements in disease severity occurred despite lower potent topical corticosteroid use in the omalizumab group compared with the placebo group (median [interquartile range (IQR)] percentage of body surface area covered, 16% [10%-46%] vs 31% [14%-55%]; median [IQR] number of days of use, 109 [34-164] days vs 161 [82-171] days). Conclusions and Relevance This randomized clinical trial found that omalizumab significantly reduced atopic dermatitis severity and improved quality of life in a pediatric population with atopy and severe eczema despite highly elevated total IgE levels at baseline. The result was associated with a potent topical corticosteroid sparing effect and may suggest that omalizumab is a treatment option for difficult-to-manage severe eczema in children with atopy. Trial Registration ClinicalTrials.gov identifier:NCT02300701

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BACKGROUND: Staphylococcus aureus has been implicated in the pathophysiology of eczema, allergic rhinitis, asthma, and food allergy. S aureus is a marker of more severe eczema, which is a risk factor for food sensitization/allergy. Therefore it might be that the association between S aureus and food allergy in eczematous patients is related to eczema severity.OBJECTIVE: We sought to investigate the association of S aureus colonization with specific IgE (sIgE) production to common food allergens and allergies in early childhood independent of eczema severity. We additionally determined the association of S aureus colonization with eczema severity and persistence.METHODS: In Learning Early About Peanut Allergy (LEAP) study participants eczema severity was assessed, and skin/nasal swabs were cultured for S aureus. Sensitization was identified by measuring sIgE levels. Peanut allergy was primarily determined by means of oral food challenge, and persistent egg allergy was primarily determined by using skin prick tests.RESULTS: Skin S aureus colonization was significantly associated with eczema severity across the LEAP study, whereas at 12 and 60 months of age, it was related to subsequent eczema deterioration. Skin S aureus colonization at any time point was associated with increased levels of hen's egg white and peanut sIgE independent of eczema severity. Participants with S aureus were more likely to have persistent egg allergy and peanut allergy at 60 and 72 months of age independent of eczema severity. All but one of the 9 LEAP study consumers with peanut allergy (9/312) were colonized at least once with S aureus.CONCLUSION: S aureus, independent of eczema severity, is associated with food sensitization and allergy and can impair tolerance to foods. This could be an important consideration in future interventions aimed at inducing and maintaining tolerance to food allergens in eczematous infants.

Light Detection and Ranging (LIDAR) applications pose extremely challenging dynamic range (DR) requirements on optical time-of-flight (ToF) receivers due to laser returns affected by the inverse square law over 2-3 decades of distance, diverse target reflectivity, and high solar background [1]. Integrated CMOS SPADs have a native DR exceeding 140dB, typically extending from the noise floor of few cps to 100’s Mcps peak rate. To deliver this DR to downstream DSP, large SPAD time-resolved imaging arrays must count and time billions of single photon events per second demanding massively parallel on-chip pixel processing to achieve practical I/O power consumption and data rates. Hybrid Cu-Cu bonding offers a mass-manufacturable platform to implement these sensors by providing high-fill-factor SPADs optimised for NIR stacked on dense nanoscale digital processors [2]. Stacked sensor architectures involving pixel-level histogramming, on-chip peak detection and TDC/processor resource sharing are now being investigated [3–5].

Background: Terminally ill patients at the end-of-life do transit between care settings due to their complex care needs. Problems of care fragmentation could result in poor quality of care. Aim: We aimed to evaluate the impact of an integrated hospice home care programme on acute care service usage and on the share of home deaths. Settings/participants: The retrospective study cohort comprised patients who were diagnosed with cancer, had an expected prognosis of 1 year or less, and were referred to a home hospice. The intervention group comprised deceased patients enrolled in the integrated hospice home care programme between September 2012 and June 2014. The historical comparison group comprised deceased patients who were referred to other home hospices between January 2007 and January 2011. Results: There were 321 cases and 593 comparator subjects. Relative to the comparator group, the share of hospital deaths was significantly lower for programme participants (12.1% versus 42.7%). After adjusting for differences at baseline, the intervention group had statistically significantly lower emergency department visits at 30 days (incidence rate ratio: 0.38; 95% confidence interval: 0.31–0.47), 60 days (incidence rate ratio: 0.61; 95% confidence interval: 0.54–0.69) and 90 days (incidence rate ratio: 0.69; 95% confidence interval: 0.62–0.77) prior to death. Similar results held for the number of hospitalisations at 30 days (incidence rate ratio: 0.48; 95% confidence interval: 0.40–0.58), 60 days (incidence rate ratio: 0.71; 95% confidence interval: 0.62–0.82) and 90 days (incidence rate ratio: 0.77; 95% confidence interval: 0.68–0.88) prior to death. Conclusion: Our results demonstrated that by integrating services between acute care and home hospice care, a reduction in acute care service usage could occur.

The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation.

Imaging systems with temporal resolution play a vital role in a diverse range of scientific, industrial, and consumer applications, e.g., fluorescent lifetime imaging in microscopy and time-of-flight (ToF) depth sensing in autonomous vehicles. In recent years, single-photon avalanche diode (SPAD) arrays with picosecond timing capabilities have emerged as a key technology driving these systems forward. Here we report a high-speed 3D imaging system enabled by a state-of-the-art SPAD sensor used in a hybrid imaging mode that can perform multi-event histogramming. The hybrid imaging modality alternates between photon counting and timing frames at rates exceeding 1000 frames per second, enabling guided upscaling of depth data from a native resolution of 64 × 32 to 256 × 128 . The combination of hardware and processing allows us to demonstrate high-speed ToF 3D imaging in outdoor conditions and with low latency. The results indicate potential in a range of applications where real-time, high throughput data are necessary. One such example is improving the accuracy and speed of situational awareness in autonomous systems and robotics.

Specific IgE performed better than SPT to predict reactivity to milk and egg during challenges with 50% positive predictive value cut-offs being useful to support the decision of whether to challenge to baked milk and egg to assess for tolerance.

Natural and man-made obscurants like fog, cloud, smoke and dust are an impediment to the conduct of military operations, preventing effective pilotage, denying the ability to carry out surveillance and reconnaissance, and restricting situational awareness. Additionally, there is a growing interest in the ability to penetrate haze and fog for the safe navigation of autonomous vehicle applications. There are several electro-optic technologies that offer improved ability to image through obscurants [1,2]. In this study the authors assessed 4 different active imaging technologies in the presence of an artificial smoke, and obtained 3D imagery of targets at ranges of 100m out to 1400m. The four systems tested were: • a scanned time-correlated single photon counting (TCSPC) sensor using a InGaAs/InP single-photon avalanche diode (SPAD) detector operating at  ~ 1.55 µm [2]; • a 32  32 InGaAs/InP SPAD array using TCSPC at  ~ 1.55 µm; • a coherent frequency modulated continuous wave (FMCW) scanned lidar system  ~ 1.55 µm , [1]; • a CMOS SPAD array camera operating as a time gated imager operating at  ~ 670nm. The selection of sensors enables comparisons to be drawn between scanning and staring systems and direct detection and coherent detection, and between short-wave infrared and visible wavelengths. Three-dimensional structured targets were placed at ranges of 100 – 150m and smoke was introduced between the targets and the sensors. The smoke transmission was measured with a separate laser device to correlate the imagery with the level of attenuation presented by the smoke and thereby relate the image quality to the degree of optical loss in the system. For the coherent lidar system, long range 3D images were obtained out to a distance of 1400m, and imaging through smoke of a target at 900m was achieved. Under the test conditions at least 2 of the systems have demonstrated the ability to obtain images through greater than 4 attenuation lengths of obscurant between transceiver and target, and work is progressing on image processing approaches to reconstruct images at greater levels of loss. Imagery from the systems will be presented, the relative merits of the different techniques discussed, and the prospects for future practical systems will be explored. [1] “Demonstration of frequency modulated continuous wave (FMCW) eye-safe, coherent LIDAR to See Through Clouds”, M.Silver, P.Feneyrou, L.Leviander, A.Martin and J Parsons, Optro, Jan 2018. [2] “Depth imaging through obscurants using time-correlated single-photon counting”, R.Tobin, A.Halimi, A.McCarthy, M.Laurenzis, F.Christnacher and G.S.Buller, SPIE Vol 10659, April 2018

The ability to measure and record high-resolution depth images at long stand-off distances is important for a wide range of applications, including connected and automotive vehicles, defense and security, and agriculture and mining. In LIDAR (light detection and ranging) applications, single-photon sensitive detection is an emerging approach, offering high sensitivity to light and picosecond temporal resolution, and consequently excellent surface-to-surface resolution. The use of large format CMOS (complementary metal-oxide semiconductor) single-photon detector arrays provides high spatial resolution and allows the timing information to be acquired simultaneously across many pixels. In this work, we combine state-of-the-art single-photon detector array technology with non-local data fusion to generate high resolution three-dimensional depth information of long-range targets. The system is based on a visible pulsed illumination system at a wavelength of 670 nm and a 240 × 320 array sensor, achieving sub-centimeter precision in all three spatial dimensions at a distance of 150 meters. The non-local data fusion combines information from an optical image with sparse sampling of the single-photon array data, providing accurate depth information at low signature regions of the target.

International audience; Basophils have been recently recognized to play important roles in type 2 immune responses during allergies and parasitic infection, largely due to the development of novel tools for the in vivo study of these cells. As such, the genetically-engineered MCPT8DTR mouse line has been used to specifically deplete basophils following treatment with diphtheria toxin (DT). In this study, we showed that DT-injected MCPT8DTR mice exhibited a striking decrease of eosinophils and neutrophils in skin when subjected to a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) experimental protocol. Unexpectedly, we found that loss of skin eosinophils and neutrophils was not due to a lack of basophil-mediated recruitment, as DT injection caused a systemic reduction of eosinophils and neutrophils in MCPT8DTR mice in a time-dependent manner. Furthermore, we found that hematopoietic stem-cell-derived granulocyte-macrophage progenitors (GMPs) expressed MCPT8 gene, and that these cells were depleted upon DT injection. Finally, we optimized a protocol in which a low-dose DT achieved a better specificity for depleting basophils, but not GMPs, in MCPT8DTR mice, and demonstrate that basophils do not play a major role in recruiting eosinophils and neutrophils to ACD skin. These data provide new and valuable information about functional studies of basophils.

BACKGROUND: Early introduction of dietary peanut in high-risk infants with severe eczema, egg allergy, or both prevented peanut allergy at 5 years of age in the Learning Early About Peanut Allergy (LEAP) study. The protective effect persisted after 12 months of avoiding peanuts in the 12-month extension of the LEAP study (LEAP-On). It is unclear whether this benefit is allergen and allergic disease specific.OBJECTIVE: We sought to assess the effect of early introduction of peanut on the development of allergic disease, food sensitization, and aeroallergen sensitization.METHODS: Asthma, eczema, and rhinoconjunctivitis were diagnosed based on clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food allergens and aeroallergens was determined by means of skin prick testing and specific IgE measurement.RESULTS: A high and increasing burden of food allergen and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least 1 allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts, with levels being higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants and was not affected by peanut consumption.CONCLUSION: Early consumption of peanut in infants at high risk of peanut allergy is allergen specific and does not prevent the development of other allergic disease, sensitization to other food allergens and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy.

Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFβ function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFβ activation, suggesting that Ikaros is an upstream negative regulator of the TGFβ pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with γ-secretase inhibitors, which affects both TGFβ-dependent and -independent pathways, but is Notch-independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity., Author summary Dendritic cells (DCs) are an important component of the immune system, and exist as two major subtypes: conventional DCs (cDCs) which present antigen via major histocompatibility class II molecules, and plasmacytoid DCs (pDCs) which act mainly as producers of type-I interferon in response to viral infections. Both types of DCs derive from a common dendritic progenitor (CDP), but the genetic pathways that influence their development are not completely understood. A better understanding of these pathways is important, which may lead to protocols for generating specific DCs in culture, depending on the need. In this study, we have discovered important roles for the Ikaros transcription factor in DC development. We found that: (i) Ikaros cooperates with the Notch pathway to promote the development or homeostasis of CDPs; (ii) Ikaros controls pDC differentiation from CDPs through a γ-secretase sensitive pathway; and (iii) Ikaros antagonizes the TGFβ pathway to inhibit cDC differentiation. Our results thus identify Ikaros as a key player in the early steps of DC development.

Basophils have been recently recognized to play important roles in type 2 immune responses during allergies and parasitic infection, largely due to the development of novel tools for the in vivo study of these cells. As such, the genetically-engineered MCPT8

This review is of the ‘Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel’. We aim to summarise the key recommendations for the prevention of peanut allergy (PA) for general paediatricians to use in their day-to-day practice. The prevalence of PA has risen significantly across the developed world over the past few decades, with a recent estimate of around 2% among UK children.1 Severe reactions to peanut are rare, but PA remains a leading cause of fatal food-related anaphylaxis. While there have been important advances in peanut desensitisation, primary prevention remains the most attractive strategy for addressing this rise. The guideline outlines current recommendations on the prevention of PA in infants at various risk levels in the USA. The guideline was developed by the National Institute of Allergy and Infectious Diseases alongside 25 professional organisations, federal agencies and patient advocacy groups and was overseen by an expert panel of 26 members. It was published in September 2016 following a landmark clinical trial suggesting that early introduction of peanut to infants can help prevent the development of PA2 (box 1).Box 1 ### Resources 1. http://www.jacionline.org/article/S0091-6749(16)31222-2/fulltext Link to full guideline: Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel 2. Learning Early About Peanut (LEAP) study 3. Enquiring About Tolerance (EAT) study A previous national guideline for the diagnosis and management of food allergy in the USA was published in December 2010.3 This guideline did not offer any specific strategies for the prevention of food allergies due to a lack of evidence from studies at the time. It did state that …

A remote-sensing system that can determine the position of hidden objects has applications in many critical real-life scenarios, such as search and rescue missions and safe autonomous driving. Previous work has shown the ability to range and image objects hidden from the direct line of sight, employing advanced optical imaging technologies aimed at small objects at short range. In this work we demonstrate a long-range tracking system based on single laser illumination and single-pixel single-photon detection. This enables us to track one or more people hidden from view at a stand-off distance of over 50 m. These results pave the way towards next generation LiDAR systems that will reconstruct not only the direct-view scene but also the main elements hidden behind walls or corners.

The Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT) is a trial to determine the clinical efficacy and safety of omalizumab for children with severe atopic eczema. This article describes the detailed statistical analysis plan for the ADAPT as an update to the published protocol and is submitted prior to knowing all outcomes. The ADAPT is a randomised, double-blind, placebo-controlled trial with a primary objective to determine whether anti-IgE reduces eczema severity as assessed by the validated eczema score (objective SCORAD) after 24 weeks of treatment in children with severe eczema. This articles outline the overall analysis principles including considerations on sample definition in each analysis, missing data, and adjusted covariates. Comparability and representativeness of the randomised groups, primary and sensitivity analyses of the primary and secondary outcomes as well as subgroup analysis are described. This prespecified statistical analysis plan has been developed to comply with international guidelines which will increase the transparency of the data analysis for the ADAPT. ISRCTN, identifier: ISRCTN15090567 . Registered on 3 December 2014; EU Clinical Trials Register, EudraCT Number: 2010-020841-29 . Registered on 14 May 2010. The first participant was enrolled on 15 January 2015.

Advances in LIDAR-based methods have enabled the detection and reconstruction of images of static objects hidden from the direct line-of-sight [1, 2]. One of the drawbacks to the technology used in these demonstrations is the requirement for long acquisition times. More recently, Gariepy et al. have shown that it is possible to detect and track a moving hidden object, albeit with no information of the object’s form [3]. Applications of this include, but are not limited to, search and rescue, and hazard detection. We present a real-time tracking system that enables the detection of moving objects that are outside the direct line-of-sight. Our active imaging system is a single-pixel variant of the technology reported by Gariepy et al. It replaces the single-photon avalanche diode (SPAD) camera of 1024 pixels with a number of SPAD detectors to detect light back-scattered from the hidden object. The flexibility of the single-pixel detectors provides an increased field of view, allowing us to detect and simultaneously track with better precision with respect to a SPAD array. The use of single-pixel detectors also has the advantage of a high detection efficiency. We perform two proof-of-concept experiments using three pixels and a single pulsed laser to interrogate a “room” for a hidden object. In the first experiment, we demonstrate that we can accurately locate the position of a hidden object. In the second experiment, we use the same system and demonstrate that we can accurately track the motion of a hidden object in real time. The “room” is a purpose-built box measuring 102×102×77 cm. Optical access is provided by a 28×12 cm window. The target object is a 15×15 cm textured viewing screen that we move along a designated ground track outside the line-of- sight of our system. In our experiments, we send a train of light pulses through the window to the back of the room. The pulses scatter off the wall as a spherical wavefront that propagates in all directions. Some of this light reaches our hidden object and is scattered back again towards the rear wall where we image our three SPAD pixels. The SPAD detectors are capable of picosecond temporal resolutions. Our time-correlated single-photon counting system measures the photon arrival times (64 ps resolution) for the signal returning to each detector. A histogram is built up in one second of acquisition time over 80 million pulses. We use this temporal information in our target position retrieval of the hidden object. We place the object at 11 positions in turn in a seven minute experiment, and localise its position. We then perform real-time tracking and move the object around the hidden scene for approximately one minute, processing the target position retrieval every 1.5 s.

Background The evidence for systemic treatments for severe childhood eczema is limited and largely based on extrapolation of data from adult studies. Current therapies are often immunosuppressant and may be associated with both short- and long-term side effects. There is increasing in vitro and murine-model evidence for the role of IgE in the immunopathogenesis of atopic eczema. The aim of the study is to assess whether anti-IgE treatment (omalizumab) improves eczema, compared to placebo. Methods/design The Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT) is a randomised, double-blind, placebo-controlled study assessing the role of anti-IgE in the management of severe paediatric eczema. Children with severe atopic eczema, with an objective SCORing Atopic Dermatitis (SCORAD) score of over 40 will be recruited. These children are candidates for systemic therapy, have failed systemic therapy or have experienced side effects from systemic therapy. Sixty-two patients aged between 4 and 19 years will receive anti-IgE for 6 months. The primary outcome measure will be the validated eczema score, the objective SCORAD at 24 weeks. This study has 90% power to detect a 33% relative reduction in SCORAD between active and placebo groups, with 5% significance. Discussion IgE may have a role to play in eczema, particularly in childhood. This forms the basis for the hypothesis that anti-IgE may be an effective treatment in this patient population. This will be the largest study to evaluate the efficacy of anti-IgE (omalizumab) versus placebo in children with severe eczema. The findings will help to clarify the role of anti-IgE as a potential treatment option in patients with severe childhood eczema. Trial registration European Clinical Trials Database (EudraCT) Number: 2010-020841-29. Assigned on 14 May 2010. ISRCTN Registry, Identifier: ISRCTN15090567. Retrospectively assigned on 3 December 2014. ClinicalTrials.gov, Identifier: NCT02300701. First received 21 November 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1809-7) contains supplementary material, which is available to authorized users.

© The Author(s)., Here, we unravel the mechanism of action of the Ikaros family zinc finger protein Helios (He) during the development of striatal medium spiny neurons (MSNs). He regulates the second wave of striatal neurogenesis involved in the generation of striatopallidal neurons, which express dopamine 2 receptor and enkephalin. To exert this effect, He is expressed in neural progenitor cells (NPCs) keeping them in the G1/G0 phase of the cell cycle. Thus, a lack of He results in an increase of S-phase entry and S-phase length of NPCs, which in turn impairs striatal neurogenesis and produces an accumulation of the number of cycling NPCs in the germinal zone (GZ), which end up dying at postnatal stages. Therefore, He−/− mice show a reduction in the number of dorso-medial striatal MSNs in the adult that produces deficits in motor skills acquisition. In addition, overexpression of He in NPCs induces misexpression of DARPP-32 when transplanted in mouse striatum. These findings demonstrate that He is involved in the correct development of a subset of striatopallidal MSNs and reveal new cellular mechanisms for neuronal development., This study was supported by grants from the Ministerio de Economıa y ́ Competitividad (BFU2010-19630 to C.V.-A.; SAF 2014-57160-R, to J. A.; SAF2015- 66505-R to J.M.C.), and Instituto de Salud Carlos III-Subdirección General de Evaluación, and European Regional Development Fund (ERDF) [CIBERNED, to J. A and C.V.-A.; and RETICS (RD12/0019/0002; Red de Terapia Celular), to J.M.C.], Spain; Generalitat de Catalunya (2014SGR-968 to J.A.); Fundació la Marató de TV3 (20140130/1 to J.A.); and CHDI Foundation (A-7332 to J.M.C.). M.P. was a fellow from the Generalitat de Catalunya, Spain and E.C. was a fellow of the Ministerio de Economía y Competitividad, Spain

International audience; Objective: The role of plasmacytoid dendritic cells (PDCs) and type I interferons (IFNs) in rheumatoid arthritis (RA) remains a subject of controversy. This study was undertaken to explore the contribution of PDCs and type I IFNs to RA pathogenesis using various animal models of PDC depletion and to monitor the effect of localized PDC recruitment and activation on joint inflammation and bone damage.Methods: Mice with K/BxN serum-induced arthritis, collagen-induced arthritis, and human tumor necrosis factor transgene insertion were studied. Symptoms were evaluated by visual scoring, quantification of paw swelling, determination of cytokine levels by enzyme-linked immunosorbent assay, and histologic analysis. Imiquimod-dependent therapeutic effects were monitored by transcriptome analysis (using quantitative reverse transcriptase-polymerase chain reaction) and flow cytometric analysis of the periarticular tissue.Results: PDC-deficient mice showed exacerbation of inflammatory and arthritis symptoms after arthritogenic serum transfer. In contrast, enhancing PDC recruitment and activation to arthritic joints by topical application of the Toll-like receptor 7 (TLR-7) agonist imiquimod significantly ameliorated arthritis in various mouse models. Imiquimod induced an IFN signature and led to reduced infiltration of inflammatory cells.Conclusion: The therapeutic effects of imiquimod on joint inflammation and bone destruction are dependent on TLR-7 sensing by PDCs and type I IFN signaling. Our findings indicate that local recruitment and activation of PDCs represents an attractive therapeutic opportunity for RA patients.

Ikaros is essential for pre-BCR down-regulation, Igκ germline transcription, Ig light chain recombination, and pre-B cell differentiation, in part by antagonizing IL-7–dependent gene regulation., Pre-B cell receptor (pre-BCR) signaling and migration from IL-7–rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C′ stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Igκ germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7–dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C′ and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development.

The recent development of 2D arrays of single-photon avalanche diodes (SPAD) has driven the development of applications based on the ability to capture light in motion. Such arrays are composed typically of 32x32 SPAD detectors, each having the ability to detect single photons and measure their time of arrival with a resolution of about 100 ps. Thanks to the single-photon sensitivity and the high temporal resolution of these detectors, it is now possible to image light as it is travelling on a centimetre scale. This opens the door for the direct observation and study of dynamics evolving over picoseconds and nanoseconds timescales such as laser propagation in air, laser-induced plasma and laser propagation in optical fibres. Another interesting application enabled by the ability to image light in motion is the detection of objects hidden from view, based on the recording of scattered waves originating from objects hidden by an obstacle. Similarly to LIDAR systems, the temporal information acquired at every pixel of a SPAD array, combined with the spatial information it provides, allows to pinpoint the position of an object located outside the line-of-sight of the detector. A non-line-of-sight tracking can be a valuable asset in many scenarios, including for search and rescue mission and safer autonomous driving.

Background Early introduction of peanut is an effective strategy to prevent peanut allergy in high-risk infants; however, feasibility and effects on growth and nutritional intake are unknown. Objective We sought to evaluate the feasibility of introducing peanut in infancy and explore effects on growth and nutritional intake up to age 60 months. Methods In the Learning Early About Peanut Allergy trial, 640 atopic infants aged 4 to 11 months were randomly assigned to consume (6 g peanut protein per week) or avoid peanut until age 60 months. Peanut consumption and early feeding practices were assessed by questionnaire. Dietary intake was evaluated with prospective food diaries. Anthropometric measurements were taken at all study visits. Results Peanut was successfully introduced and consumed until 60 months, with median peanut protein intake of 7.5 g/wk (interquartile range, 6.0-9.0 g/wk) in the consumption group compared with 0 g in the avoidance group. Introduction of peanut in breast-feeding infants did not affect the duration of breast-feeding. There were no differences in anthropometric measurements or energy intakes between groups at any visits. Regular peanut consumption led to differences in dietary intakes. Consumers had higher intakes of fat and avoiders had higher carbohydrate intakes; differences were greatest at the upper quartiles of peanut consumption. Protein intakes remained consistent between groups. Conclusions Introduction of peanut proved feasible in infants at high risk of peanut allergy and did not affect the duration of breast-feeding nor impact negatively on growth or nutrition. Energy balance was achieved in both groups through variations in intakes from fat and carbohydrate while protein homeostasis was maintained.

Wnt signaling is important for T-cell differentiation at the early CD4(-)CD8(-) stage and is subsequently downregulated with maturation. To assess the importance of this downregulation, we generated a mouse line (R26-βcat) in which high levels of active β-catenin are maintained throughout T-cell development. Young R26-βcat mice show a differentiation block at the CD4(+)CD8(+) double-positive (DP) stage. These DP cells exhibit impaired apoptosis upon irradiation or dexamethasone treatment. All R26-βcat mice develop T-cell leukemias at 5 to 6 months of age. R26-βcat leukemias remain dependent on β-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because β-catenin activation and Myc translocations were previously found in murine T-cell acute lymphoblastic leukemias (T-ALLs) deficient for Pten, our results suggest that activation of the canonical Wnt pathway is associated with a subtype of Notch-independent T-ALLs that bear Myc gene rearrangements and Pten mutations.

Group 3 innate lymphoid cells (ILC3s) expressing the transcription factor (TF) RORγt are important for the defense and homeostasis of host intestinal tissues. The zinc finger TF Ikaros encoded by Ikzf1 is essential for RORγt+ fetal lymphoid tissue inducer (LTi) cell development and lymphoid organogenesis, but its role in postnatal ILC3s is unknown. Here, we showed that small intestinal ILC3s had the lowest expression of Ikaros compared to ILC precursors and other ILC subsets. Ikaros inhibited ILC3s in a cell-intrinsic manner through zinc finger-dependent inhibition of transcriptional activity of the aryl hydrocarbon receptor, a key regulator of ILC3 maintenance and function. Ablation of Ikzf1 in RORγt+ ILC3s resulted in increased expansion and cytokine production of intestinal ILC3s and protection against infection and colitis. Therefore, in contrast to its requirement for LTi development, Ikaros inhibits postnatal ILC3 development and function to regulate gut immune responses at steady state and in disease.

The ability to detect motion and to track a moving object that is hidden around a corner or behind a wall provides a crucial advantage when physically going around the obstacle is impossible or dangerous. One recently demonstrated approach to achieving this goal makes use of non-line-of-sight picosecond pulse laser ranging. This approach has recently become interesting due to the availability of single-photon avalanche diode (SPAD) receivers with picosecond time resolution. We present a time-resolved non-sequential ray-tracing model and its application to indirect line-of-sight detection of moving targets. The model makes use of the Zemax optical design programme's capabilities in stray light analysis where it traces large numbers of rays through multiple random scattering events in a 3D non-sequential environment. Our model then reconstructs the generated multi-segment ray paths and adds temporal analysis. Validation of this model against experimental results is shown. We then exercise the model to explore the limits placed on system design by available laser sources and detectors. In particular we detail the requirements on the laser's pulse energy, duration and repetition rate, and on the receiver's temporal response and sensitivity. These are discussed in terms of the resulting implications for achievable range, resolution and measurement time while retaining eye-safety with this technique. Finally, the model is used to examine potential extensions to the experimental system that may allow for increased localisation of the position of the detected moving object, such as the inclusion of multiple detectors and/or multiple emitters.

We use a femtosecond laser and a single-photon avalanche diode (SPAD) camera to develop a system that is able to locate objects hidden from view and track their motion.

We demonstrate tracking of an object hidden from the direct line-of-sight. We reconstruct its position in real-time using a single laser spot and three individual single pixel single-photon detectors.

[This corrects the article DOI: 10.1371/journal.pone.0157767.].

Objective The aim of this study was to examine the knowledge, attitudes and perceptions of advance care planning (ACP) in caregivers of patients with advanced illness in Singapore. Methods Family caregivers of patients within the palliative care unit in a hospital and a hospice were purposively recruited and interviewed. Qualitative content analysis was carried out exploring key themes and subthemes emerging from the data. Results Between May 2009 and May 2010, 18 participants were interviewed. All participants interviewed had low awareness of ACP and the Advance Medical Directive but felt that ACP is important. Perceived benefits of ACP were that it respects autonomy, guides patients and families, and reduces burden of decision-making near the end-of-life. Barriers to ACP include non-disclosure of diagnosis as well as uncertainty of when and how ACP should be broached. There was a reticence to talk openly about issues surrounding end-of-life care as a result of cultural taboo and a fear that doing so will destroy hope. While all participants would consider ACP for themselves, some were ambivalent about discussing ACP for their loved ones, especially when their loved ones were of an older generation. Involvement of the family unit and physicians in ACP were viewed as important. Conclusion This study highlights the need for public education on the benefits and process of ACP in Singapore. In formulating an approach to ACP, there is a need to take into account cultural sensitivities towards ACP discussions and the importance of closely involving the family unit in the process.

The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.

The IKZF1 gene encodes the Ikaros transcription factor, a key regulator of lymphocyte differentiation.1 IKZF1 is mutated in 20–30% of B-cell acute lymphoblastic leukemia (B-ALL) mostly by genomic deletions.2, 3, 4 Several reports have shown that IKZF1 deletions are associated with an adverse prognosis, especially in pediatric patients.3, 4, 5, 6, 7, 8, 9, 10 Ikaros mutations fall mainly into three types: (a) deletions of exons 4–7 (Δ4–7), which lead to the synthesis of the Ikaros-6 (Ik6) dominant-negative isoform; (b) deletions of exons 2–7 (Δ2–7), which delete the initiation codon and lead to haploinsufficiency; and (c) larger deletions of various sizes, which affect the coding exons (referred to below as ‘complete’ deletions). Thus, IKZF1 mutations have until now been separated into dominant-negative and haploinsufficient groups. Here we report that about 20% of B-ALL patients with IKZF1 mutations present two distinct deletions. These deletions are biallelic, leading to a complete loss of Ikaros function, or biclonal, marking distinct clones within the leukemia. These results highlight a more complex picture of IKZF1 loss of function in B-ALL than thought previously.

Point mutations that trigger ligand-independent proteolysis of the Notch1 ectodomain occur frequently in human T-cell acute lymphoblastic leukemia (T-ALL) but are rare in murine T-ALL, suggesting that other mechanisms account for Notch1 activation in murine tumors. Here we show that most murine T-ALLs harbor Notch1 deletions that fall into 2 types, both leading to ligand-independent Notch1 activation. Type 1 deletions remove exon 1 and the proximal promoter, appear to be RAG-mediated, and are associated with mRNA transcripts that initiate from 3′ regions of Notch1. In line with the RAG dependency of these rearrangements, RAG2 binds to the 5′ end of Notch1 in normal thymocytes near the deletion breakpoints. Type 2 deletions remove sequences between exon 1 and exons 26 to 28 of Notch1, appear to be RAG-independent, and are associated with transcripts in which exon 1 is spliced out of frame to 3′ Notch1 exons. Translation of both types of transcripts initiates at a conserved methionine residue, M1727, which lies within the Notch1 transmembrane domain. Polypeptides initiating at M1727 insert into membranes and are subject to constitutive cleavage by γ-secretase. Thus, like human T-ALL, murine T-ALL is often associated with acquired mutations that cause ligand-independent Notch1 activation.