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While loss-of-function variants in the WAS gene are associated with Wiskott-Aldrich syndrome and lead to microthrombocytopenia, gain-of-function variants of WAS are associated with X-linked neutropenia (XLN) and the absence of microthrombocytopenia. Only a few XLN families have been reported so far, and their platelet phenotype was not described in detail. To date, no renal involvement was described in XLN. In the present study, we report exome sequencing of individuals from 3 generations of a family with a dominant disease combining neutropenia, macrothrombocytopenia, and renal failure. We identified a heterozygous missense gain-of-function variant in the WAS gene (c.881T>C, p.I294T) that segregates with the disease and is already known to cause XLN. There was no pathogenic variant in MYH9, TUBB1, or ACTN1. This is the first report of a WAS gain-of-function variant associated with both the hematological phenotype of XLN (neutropenia, macrothrombocytopenia) and renal disease (proteinuria, renal failure) with glomerular tip lesion hyalinosis and actin condensations in effaced podocytes foot processes.

Supplemental Digital Content is available in the text., Background. Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in kidney transplant recipients (KTRs) remain rare. We sought to shed further light on this issue by conducting a single-center study in a kidney transplant center located in one of the France’s highest risk zone (Grand Est) for coronavirus disease 2019 (Covid-19) during the initial disease outbreak. Methods. To this aim, we used a survey approach coupled with systematic investigation of SARS-CoV-2 serology in a cohort of 1390 KTRs. Results. SARS-CoV-2 serologies were available for 780 survey respondents, among whom 48 had anti-SARS-CoV-2 antibodies (total seroprevalence: 6.2%). Thirty-five of the 48 seropositive KTRs had previously received a diagnosis of Covid-19, whereas the remaining 13 patients were not known to be infected (8 asymptomatic cases). Specifically, 18.7% of seropositive KTRs and 1.1% of the entire cohort were asymptomatic. Household exposure was found to markedly increase the risk of SARS-CoV-2 transmission. Conclusions. Our findings demonstrate that the overall SARS-CoV-2 seroprevalence in KTRs living in one of the France’s highest risk zone for Covid-19 during the first French lockdown was as low as 6.3%. Rapid and strict implementation of protective measures could have significantly mitigated virus spread even in an area of high virus circulation.

Kidney transplant recipients (KTR) are at increased risk of fractures. Total urinary hydroxyproline excretion used to be a marker for bone resorption (BR) but faded into the background when more specific markers like Beta-CrossLaps (CTX) became available. Proteomic studies identified numerous hydroxyproline-containing urinary collagen peptides but their origin remains unknown. We followed the hypothesis that some of the urinary collagen peptides are associated with BR and are markers for pathophysiological changes in bone metabolism of KTR. Clinical and laboratory data including serum levels of CTX in 96 KTR from two French centers (Strasbourg, n=38; Paris-Necker, n=58) were correlated with the signal intensity of urinary peptides identified by capillary electrophoresis (CE) coupled to mass spectrometry (MS) and tandem-MS. The effect of oral bisphosphonates on urinary peptides was studied in an independent group of 11 KTR. Eighty-two urinary peptides were identified to be significantly correlated with serum CTX levels in both cohorts. Statistical association with parameters other than BR markers were not significant. Collagen α-1(I) chain (COL1A1) was the most frequently identified peptide source. COL1A1 peptides associated with BR were significantly more hydroxylated than those showing no association (55.9% versus 45,2%, p2-test). From the 82 urinary peptides correlated to CTX, 17 were significantly associated with bisphosphonate treatment. All of these 17 peptides showed a marked reduction in their excretion levels after 410 ± 344 days of bisphosphonate treatment compared to baseline levels. We studied the cleavage sites of these COL1A1 peptides and observed a signature of Cathepsin K and Matrix Metallopeptidase 9. This study provides strong evidence for the occurrence of collagen peptides in the urine of KTR that are associated with BR and that are sensitive to bisphosphonate treatment. Their assessment might become a valuable tool to monitor bone status in KTR.

Deformable mirrors (DMs) are an essential part of any coronagraphic, high contrast instrument. They mitigate optical aberrations in the system and can even be used to generate contrast for the coronagraph. MEMS DMs from Boston Micromachines have been selected as the baseline for two flagship space telescopes proposed to the 2020 Decadal Survey. Although MEMS DMs have over a decade of heritage on ground-based telescopes and in in-air testbeds around the globe, they have not been tested in vacuum down to the ∼10−10 contrast level needed to image terrestrial exoplanets. In this paper, we describe vacuum tests of MEMS DMs in the Decadal Survey Testbed at the Jet Propulsion Laboratory. The first challenge was a bright, temporally incoherent signal, which was identified as electronics noise and removed with a low-pass filter. After that, the contrast has been limited in broadband light by the strong print-through on the DM surfaces. We performed numerical simulations to confirm that conclusion and to characterize the improvements needed to the MEMS DM surfaces and the testbed layout to attain our goal of 10−10 contrast. Keywords: deformable mirror, coronagraph

The Phase-Induced Amplitude Apodization Complex Mask Coronagraph (PIAACMC) is a coronagraph architecture for the next generation of large space telescopes optimized for habitable exoplanet imaging that can achieve attractive theoretical performance with high throughput at small inner working angles (IWA). PIAACMC designs are compatible with large, on-axis, segmented apertures such as the Large UV / Optical/ Infrared A (LUVOIRA) concept currently being considered by the decadal survey review which would greatly enhance the possibility to achieve statistically significant scientific yields and signal quality for direct imaging exoplanet surveys. A PIAACMC design has been recently created for LUVOIR-A and is currently being tested in vacuum at JPL’s High-Contrast Imaging Testbed (HCIT). In this work, we review the theoretical performance of the PIAACMC instrument designed to meet a 1e-9 raw contrast goal in 10% broadband light in a region from 2-8 λ/D both before and after the wavefront control loop. We use empirical measurements from the vacuum testbed to verify the instrument model and its performance including line-of-sight errors, instrument alignment, and fabricated components. In particular, the model verification includes measured sags of the manufactured PIAA mirrors by NuTek. The CMC mask was manufactured at JPL’s Microdevices Laboratory and we include surface profile characterization measurement. We assess the impact on performance of the different manufacturing and alignment errors.

The phase-induced amplitude apodization complex mask coronagraph (PIAACMC) provides high throughput and small inner working angle with little loss in image quality. Coronagraph compatibility with segmented apertures is essential for the success of habitable planet characterization with future large aperture space telescopes, such as the Large UV/Optical/Infrared (LUVOIR) and HabEx telescope mission concepts. The PIAACMC designs are compatible with such segmented telescope apertures with little loss of performance. We report the contrast and other performance results of a PIAACMC coronagraph with a LUVOIR-like pupil mask assembled and tested in a vacuum chamber at the JPL high contrast imaging testbed (HCIT). As the success of electric field conjugation (EFC) to achieve best contrast on the testbed is dependent upon a diffraction model of the coronagraph, we will also discuss variations of the testbed and its diffraction model with the PIAACMC design, including suspected sources of knowledge error in the EFC diffraction model.

Within health care, the Just Culture is model of workplace justice intended to create fairness for providers and create better outcome for patients. It is about creating a common language to evaluate provider conduct. A Just Culture helps create an open reporting culture. To create better patient safety outcomes, a Just Culture shifts the focus from errors and outcomes to system design and the facilitation of good behavioral choices.

International audience; This paper investigates the problem of localizing a sound source in a heated flow using a microphone array. Applications are found in studies dealing with the identification of sound sources in hot turbulent jets, or with the sound radiation from installed turbofans. Two configurations have been investigated: a shear layer flow (wind-tunnel type) and a jet flow. In the present study acoustic data are generated using a simulation based on the Linearized Euler Equations. For heated flows, refraction by temperature gradients is superimposed with refraction by velocity gradients, and the objective of this study is to assess whether this effect is important and how it can be accounted for in different source localisation methods. For this purpose, a time-reversal-based imaging method has been compared with a beamforming-based method in which the time-delays are computed based on ray tracing. For the shear flow, the results show that for high subsonic Mach numbers and steep thermal gradients, the thermal stratification must be taken into account to ensure a satisfactory precision of localisation for both methods. However, including the gradients of velocity and temperature is less crucial for imaging sound sources in the jet flow. The results indicate also that the localisation error is lower with the beamforming and ray-tracing technique than with the time-reversal technique, the latter being more sensitive to the limited array aperture.

To create a high contrast field of view with a shaped pupil coronagraph (SPC), the telescope pupil is imaged onto the shaped pupil mask, the shaped pupil mask is designed and fabricated through a design optimization based on a given pupil wavefront, and deformable mirrors (DM) in the coronagraph are modulated according to a nonlinear optimization procedure. Both the mask design optimization and the DM optimization require accurate knowledge of the image of the pupil at the shaped pupil plane for the calculation of Jacobians, and the evaluation of alignment tolerances. The shaped pupil coronagraphs demonstrated in the high contrast imaging testbed (HCIT) at JPL has heretofore assumed perfect imaging of the pupil onto the shaped pupil mask. Similarly, the design and performance modeling of the WFIRST CGI instrument makes the same assumption. In this paper we estimate and compare the image of the pupil mask at the shaped pupil plane in the case of the coronagraph testbed, and the image of the telescope pupil at the shaped pupil plane for the WFIRST CGI instrument. The estimated pupil images include field curvature and aberrations resulting from the layout of the parabolic mirror imaging system, which is optimized for the source image, not the image of the pupil. We also show the results of direct measurement of the image of the pupil mask at the shaped pupil plane in the coronagraph testbed.

Objectives: Suicides of hospitalized patients present rare but very serious adverse events in healthcare settings. The aim of this article is to describe and analyse the facilities and material equipment of acute psychiatric settings in the Czech Republic and contrast these with recommendations for effective prevention of suicidal behaviour. Since there are currently no universally accepted protocols for risk assessment and prevention of suicides in hospital settings in the Czech Republic, these recommendations draw on international guidelines. Based on the outcomes of our study we provide recommendations for risk management and effective prevention of suicidal behaviour of patients hospitalized in acute care settings. Methods: In order to describe and analyse the environment of acute psychiatric wards in the Czech Republic we have developed a questionnaire based on international recommendations for risk management and prevention of suicidal behaviour. We also collected data on the prevalence of attempted and completed suicides and their respective methods in these hospitals. Results: We have established that acute psychiatric wards in the Czech Republic operate within insufficient safety regimes, especially with respect to the prevention of suicide by hanging and the accessibility of objects for cutting. Our findings demonstrate that only 75% of the wards are equipped with safety glass, and only 50% of the wards with safety mirrors. Only just over 40% of hospitals have safety door handles and shower heads. Conclusion: While it is impossible to entirely eliminate the risk of suicidal behaviour it is possible to manage it. The risk reduction is attainable by providing a safe-proofed environment and minimizing opportunities of suicide attempts by hanging and cutting. In order to effectively prevent suicides, it is essential to increase the awareness of the possibilities of safe proofing of the environment as well as standardization of risk assessment of potential suicidal behaviour of patients.

BACKGROUND Data on coronavirus disease 2019 (COVID-19) in immunocompromised kidney transplant recipients (KTR) remain scanty. Although markers of inflammation, cardiac injury, and coagulopathy have been previously associated with mortality in the general population of patients with COVID-19, their prognostic impact amongst KTR with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has not been specifically investigated. METHODS We conducted a cohort study of 49 KTR who presented with COVID-19. Clinical and laboratory risk factors for severe disease and mortality were prospectively collected and analyzed with respect to outcomes. The study participants were divided into 3 groups: (1) mild disease manageable in an outpatient setting (n = 8), (2) nonsevere disease requiring hospitalization (n = 21), and (3) severe disease (n = 20). RESULTS Gastrointestinal manifestations were common at diagnosis. The 30-day mortality rate in hospitalized patients was 19.5%. Early elevations of C-reactive protein (>100 mg/L) and interleukin-6 (>65 ng/L) followed by increases in high-sensitivity troponin I (>30 ng/L) and D-dimer (>960 ng/mL) were significantly associated with severe disease and mortality. Viral load did not have prognostic significance in our sample, suggesting that outcomes were chiefly driven by a cytokine release syndrome (CRS). CONCLUSIONS Regular monitoring of CRS biomarkers in KTR with COVID-19 is paramount to improve clinical outcomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via reverse transcription-polymerase chain reaction and SARS-CoV-2 serology via enzyme-linked immunosorbent assay and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study, we examined hospitalized kidney transplant recipients with nonsevere (n = 21) and severe (n = 19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (P = .010) and mortality (P = .010). All patients harbored antibodies during the second week after symptom onset that persisted for 2 months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via RT-PCR and SARS-CoV-2 serology via ELISA and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study we examined hospitalized kidney transplant recipients with non-severe (n = 21) and severe (n =19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (p=0.0087) and mortality (p=0.024). All patients harbored antibodies the second week after symptom onset that persisted for two months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.

Background and Aims BK virus-associated nephropathy (BKvN) is an important complication occurring after kidney transplantation. Its treatment mainly relies on lowering immune suppression. BKvN’s histological aspect can mimic T cell-mediated rejection (TCMR) and other inflammatory conditions featuring tubulitis and interstitial infiltrate. At present, the screening strategy consists of measuring urinary and blood viral loads of BKv. Upon rising BK viremia, BKvN diagnosis is established by a graft biopsy. Biopsies are invasive and are not suitable for repeated screening. Therefore, the aim of this case-control study was to establish a urinary proteome-based test for BKvN diagnosis. Method Urine was obtained from 700 allograft recipients prior to either protocol or „for cause“ biopsies during the first year of post-transplantation surveillance. Aside from normal biopsy findings (N=294), the histological diagnoses included BKvN (N=50), IFTA II-III (N=145), glomerulonephritis (N=17) and T cell-mediated, antibody-mediated, mixed or borderline rejection episodes (N=194). From all patients, relevant clinical and demographic data including Banff classification scores, HLA mismatches and the presence of donor-specific antibodies was collected at the date of sample collection and in further clinical follow-up. BKvN cases were defined as having SV40-positive immunostaining on allograft biopsy. BKvN patients were considered as cases and all other recipients were considered as controls. Patient’s urinary peptide profiles were generated using capillary electrophoresis coupled to mass spectrometry consisting of 9430 different peptides in the mass range of 0.8 to 20 kDa. Results The CE-MS peptide profiles of randomly selected 30 BKvN cases and 307 kidney allograft controls (one sample per patient) were statistically analyzed to identify the most discriminative peptide markers for BKvN. In total, there were 117 peptides detected to have significantly different urinary excretion rates between both patient groups after false discovery rate adjustment for multiple testing. Thirty-two of these peptides were selected by cross-validated variable selection to establish a Support Vector Machine-based multi-marker model. Applying the 32-peptide marker model to an independent validation cohort consisting of 20 BKvN cases and 343 controls resulted in an area under the receiver operating characteristic curve of 0.86 and a 95% confidence interval from 0.82 to 0.89 with the p-value below 0.0001 and sensitivities and specificities for BKvN diagnosis of 85 and 76 %, respectively. Most notably, distribution of the classification values (figure 1) in the different patient groups of the validation set indicated specificities of the peptide marker model for TCMR/borderline of 85% (17 of 20 true negative classifications) and for viruria/viremia of 73% (8 of 11 true negative classifications) Conclusion In conclusion, the established urinary peptide marker model might serve as a non-invasive diagnostic test for BKvN and its differentiation from TCMR and states of isolated viruria or viremia.