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Background The Long-ter M O U tcomes after the Multisystem Inflammatory S yndrome I n C hildren (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood. Methods This multicenter observational cohort study will enroll at least 600 patients Conclusion The MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

The Indiana O’Brien Center for Advanced Microscopic Analysis is a National Institutes of Health (NIH) P30-funded research center dedicated to the development and dissemination of advanced methods of optical microscopy to support renal researchers throughout the world. The Indiana O’Brien Center was founded in 2002 as an NIH P-50 project with the original goal of helping researchers realize the potential of intravital multiphoton microscopy as a tool for understanding renal physiology and pathophysiology. The center has since expanded into the development and implementation of large-scale, high-content tissue cytometry. The advanced imaging capabilities of the center are made available to renal researchers worldwide via collaborations and a unique fellowship program. Center outreach is accomplished through an enrichment core that oversees a seminar series, an informational website, and a biennial workshop featuring hands-on training from members of the Indiana O’Brien Center and imaging experts from around the world.

RATIONALE AND OBJECTIVE: The use of kidney histopathology for predicting kidney failure is not established. We hypothesized that use of histopathological features of kidney biopsy specimens would improve prediction of clinical outcomes made using demographic and clinical variables alone. STUDY DESIGN: Retrospective cohort study and development of a clinical prediction model. SETTING AND PARTICIPANTS: All 2720 individuals from the Biopsy Biobank Cohort of Indiana who underwent a kidney biopsy between 2002 and 2015 and had at least two years of follow-up. NEW PREDICTORS & ESTABLISHED PREDICTORS: Demographic variables, comorbidities, baseline clinical characteristics, and histopathological features. OUTCOMES: Time to kidney failure, defined as sustained estimated glomerular filtration rate

Objective Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low‐dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. Methods Patients 2‐ to 18‐years‐old with Dravet syndrome who had completed any of three randomized, placebo‐controlled clinical trials of fenfluramine were offered enrollment in this open‐label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. Results A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58‐634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. Significance Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.

Mycophenolic acid (MPA) is an immunosuppressant commonly used to prevent renal transplant rejection and treat glomerulonephritis. MPA inhibits IMPDH2 within stimulated lymphocytes, reducing guanosine synthesis. Despite the widespread use of MPA, interindividual variability in response remains with rates of allograft rejection up to 15% and approximately half of individuals fail to achieve complete remission to lupus nephritis. We sought to identify contributors to interindividual variability in MPA response, hypothesizing that the HPRT1 salvage guanosine synthesis contributes to variability. MPA sensitivity was measured in 40 healthy individuals using an ex vivo lymphocyte viability assay. Measurement of candidate gene expression (n ± 40) and single‐cell RNA‐sequencing (n ± 6) in lymphocytes was performed at baseline, poststimulation, and post‐MPA treatment. After stimulation, HPRT1 expression was 2.1‐fold higher in resistant individuals compared with sensitive individuals (P ± 0.049). Knockdown of HPRT1 increased MPA sensitivity (12%; P ± 0.003), consistent with higher expression levels in resistant individuals. Sensitive individuals had higher IMPDH2 expression and 132% greater stimulation. In lymphocyte subpopulations, differentially expressed genes between sensitive and resistant individuals included KLF2 and LTB. Knockdown of KLF2 and LTB aligned with the predicted direction of effect on proliferation. In sensitive individuals, more frequent receptor‐ligand interactions were observed after stimulation (P ± 0.0004), but fewer interactions remained after MPA treatment (P ± 0.0014). These data identify a polygenic transcriptomic signature in lymphocyte subpopulations predictive of MPA response. The degree of lymphocyte stimulation, HPRT1, KLF2, and LTB expression may serve as markers of MPA efficacy.

The nitrogen (N) fertilizer application rate (kg ha−1 year−1) in pastoral dairy systems affects the flow of N through the soil, plant and animal pools of the system. With better understanding of the magnitude of these pools and their fluxes, dairy systems could be managed to improve N use efficiency, therefore reducing losses to the environment. A study with three levels of N fertilizer, 0 (N0), 150 (N150) and 300 (N300) kg N ha−1 year−1, was conducted in the Canterbury region of New Zealand from 1 June 2017 till 31 May 2018. Farm measurements, e.g. pasture and milk production, were used to calibrate three different farm-scale models, DairyNZ’s Whole Farm Model, DairyMod, and Overseer®. The models were used to extrapolate periodic farm measurements to predictions of carbon (C) and N pools and fluxes on an annual basis. Pasture and milk production per hectare increased from N0 to N300 by 70 and 58%, respectively. There was a concomitant increase in farm-gate N surplus (input–output) of 43%, resulting in predicted increases in N leaching and greenhouse gas emissions of 72 and 67%, respectively. By increasing N fertilizer from 0 to 300 kg N ha−1 year−1, 53% more feed N flowed through the dairy herd with surplus N deposited as urinary N increasing by 49%. Plant uptake and soil immobilization increased by 58 and 343%, respectively, but not enough to avoid substantial increases in leaching and emission losses. Carbon flux through the soil system increased through increased litter and faecal deposition, but with very little C sequestration because of accelerated microbial respiration rates.

We compared cardiac findings in patients with multisystem inflammatory syndrome in children and Kawasaki disease in the first 6 months of the 2020 coronavirus disease pandemic to patients with Kawasaki disease during 2016-2019. We saw a high rate of coronary aneurysms in 2020, with a similar rate of coronary involvement but greater volume and incidence of cardiac dysfunction compared with previous years.

Contains fulltext : 214790.pdf (Publisher’s version ) (Closed access) The aim of the current study was to compare levels of oxytocin, cortisol, and testosterone in adolescents with either autism spectrum disorder (ASD), or oppositional defiant disorder (ODD)/conduct disorder (CD), and in typically developing individuals (TDI), and relate hormone levels to severity and subtype of aggression and callous-unemotional (CU) traits. Saliva concentrations of oxytocin, cortisol, and testosterone were assessed in 114 male participants (N = 49 ASD, N = 37 ODD/CD, N = 28 TDI,) aged 12-19 years (M = 15.4 years, SD = 1.9). The ASD and the ODD/CD groups had significantly lower levels of oxytocin than the TDI group, and the ODD/CD group had significantly higher levels of testosterone than the ASD group. There were no group effects on cortisol levels. Group differences remained for oxytocin after correcting for the influence of CU traits, but were not significant after controlling for aggression. Results for testosterone became non-significant after correction for either CU traits or aggression. Across groups, higher levels of CU traits were related to higher levels of cortisol and testosterone, however, proactive and reactive aggression were unrelated to all three hormonal levels. The current findings show that, regardless of cognitive ability or comorbid disorders, the diagnostic groups (ASD, ODD/CD) differ from each other by their hormonal levels, with the ASD group characterized by relative low level of oxytocin, and the ODD/CD group by a relative low level of oxytocin and high level of testosterone. These group effects were partly driven by differences in CU traits between the groups. 15 p.

Fluorescence lifetime imaging microscopy (FLIM) systems are limited by their slow processing speed, low signal-to-noise ratio (SNR), and expensive and challenging hardware setups. In this work, we demonstrate applying a denoising convolutional network to improve FLIM SNR. The network will be integrated with an instant FLIM system with fast data acquisition based on analog signal processing, high SNR using high-efficiency pulse-modulation, and cost-effective implementation utilizing off-the-shelf radio-frequency components. Our instant FLIM system simultaneously provides the intensity, lifetime, and phasor plots \textit{in vivo} and \textit{ex vivo}. By integrating image denoising using the trained deep learning model on the FLIM data, provide accurate FLIM phasor measurements are obtained. The enhanced phasor is then passed through the K-means clustering segmentation method, an unbiased and unsupervised machine learning technique to separate different fluorophores accurately. Our experimental \textit{in vivo} mouse kidney results indicate that introducing the deep learning image denoising model before the segmentation effectively removes the noise in the phasor compared to existing methods and provides clearer segments. Hence, the proposed deep learning-based workflow provides fast and accurate automatic segmentation of fluorescence images using instant FLIM. The denoising operation is effective for the segmentation if the FLIM measurements are noisy. The clustering can effectively enhance the detection of biological structures of interest in biomedical imaging applications., Comment: SPIE Proceedings Volume 11648, Multiphoton Microscopy in the Biomedical Sciences XXI; 116481C (2021)

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living kidney donor biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomics analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for ten years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We previously demonstrated that systemic Tamm-Horsfall Protein (THP, uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we show that the kidney increases circulating THP by enhancing basolateral release of THP from medullary thick ascending limb cells. In sepsis patients, changes in circulating THP are positively associated with critical illness. THP is also found de novo in injured lungs. Genetic ablation of THP in mice leads to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo leads macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis and chemotaxis and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improves survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function and systemic THP has therapeutic potential in sepsis.Significance StatementSepsis is a significant contributor to kidney injury as well as morbidity and mortality worldwide. Specific therapies to improve outcomes in sepsis with kidney injury have largely been limited to symptom management and infectious agent control, in part because it is unclear how kidney injury increases sepsis mortality. This paper describes the identification of Tamm-Horsfall protein, previously known to protect in ischemic models of AKI, as protective in preclinical models of sepsis. It demonstrates how the loss of THP leads to decreased mononuclear phagocyte function and diversity, increased pathogen burden and decreased survival. THP also increases in sepsis without severe kidney injury and concentrates in injured organs. Further study of THP in sepsis could lead to novel sepsis therapeutics.

One of the more challenging areas in the echocardiographic evaluation of congenital heart disease (CHD) is the analysis of cardiac malpositions and heterotaxy. This is in large measure due to the fact that cardiac malpositions can occur with many different types of CHD. While abnormalities of cardiac position do tend to be seen more frequently with certain forms of CHD, the possibilities are numerous and varied, and one cannot draw any preliminary conclusions of the underlying cardiac anatomy/physiology based upon the position and orientation of the heart in the thorax. Instead, one must maintain an open mind to the various possibilities, guided by the segmental approach to CHD. This chapter provides an overview to the transesophageal echocardiographic evaluation of cardiac malpositions, including dextrocardia. In addition, the topic of heterotaxy (isomerism) will be discussed. Heterotaxy is a disorder of laterality that results in structural abnormalities affecting many organs in the body including the lungs, abdominal viscera, and heart. Patients with heterotaxy frequently have prominent cardiac abnormalities involving many levels of the heart. A significant proportion of these patients will also have a cardiac malposition, but even if they do not, most will still have multiple congenital cardiac defects that require a careful and systematic approach to evaluation. Therefore, the same fundamental diagnostic echocardiographic approach should be utilized to evaluate both cardiac malpositions and heterotaxy.

For anyone seeking to achieve proficiency in transesophageal echocardiography, it is important to have a solid understanding of the underlying science of ultrasound, along with knowledge of the instrumentation and equipment utilized for cardiac imaging. This chapter provides a review of all of these topics, particularly as they apply to echocardiography. Basic principles of sound will first be discussed, followed by the process of ultrasonic two-dimensional image formation. Principles of Doppler echocardiography (and its applications) will then be presented. Finally, echocardiography instrumentation, echocardiographic artifacts, and digital archiving/networking of echocardiographic studies will be discussed. Familiarity with the information in this chapter will provide readers a greater understanding of the many technical aspects of echocardiography, enabling them to optimize their cardiac ultrasound platforms so that the best possible information can be obtained.

It is well-known that echocardiographic evaluation of congenital heart disease (CHD) can present challenges due to a number of factors: the multiplicity of the different forms of CHD, the variations in anatomy and physiology associated with each class of cardiac lesion, and the complex (and unique) three-dimensional anatomy seen with many of the individual cardiac defects. These challenges have been well documented with transthoracic and fetal echocardiography, and they are equally daunting, if not more so, with transesophageal echocardiography (TEE) due to the limited availability of echocardiographic windows afforded by the esophageal location of the probe. Nonetheless, in most patients with CHD, a comprehensive TEE study can be performed using a variety of probe manipulations and views, as well as a systematic evaluation. The goal of this chapter is to discuss the general aspects of TEE structural evaluation of the cardiovascular system, focusing upon pediatric patients with heart disease as well as any patient with CHD. The TEE views and probe manipulations from the 2019 Guidelines for Performing a Comprehensive Transesophageal Echocardiographic Examination in Children and All Patients with Congenital Heart Disease: Recommendations from the American Society of Echocardiography (ASE) will be detailed, along with their specific application (and modifications), especially as applies to CHD evaluation. Throughout this textbook, the terminology and techniques defined in this chapter will be used to describe the TEE assessment of the various cardiac defects. This chapter also presents a suggested methodology for a comprehensive, systematic, and segmental approach to the TEE evaluation of the cardiovascular system—one that is particularly applicable for the evaluation of a patient with known or suspected CHD.

Sepsis is a dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single-cell RNA-sequencing in a murine endotoxemia model revealed the involvement of various cell populations to be temporally organized and highly orchestrated. Endothelial and stromal cells were the first responders. At later time points, epithelial cells upregulated immune-related pathways while concomitantly downregulating physiological functions such as solute homeostasis. Sixteen hours after endotoxin, there was global cell–cell communication failure and organ shutdown. Despite this apparent organ paralysis, upstream regulatory analysis showed significant activity in pathways involved in healing and recovery. This rigorous spatial and temporal definition of murine endotoxemia will uncover precise biomarkers and targets that can help stage and treat human sepsis.

Over the past two decades, real-time three-dimensional echocardiography has emerged as an important new technique in echocardiography for the diagnosis and evaluation of both acquired and congenital heart disease. In recent years, three-dimensional transesophageal echocardiography (3D TEE) probes have become available. While these probes were designed primarily for use in the adult age group, they have also been utilized effectively in older children and adolescents. These probes are capable of real-time 3D TEE imaging and color flow Doppler, providing excellent spatial detail of selected acquired and congenital heart defects. Thus, 3D TEE serves an important and ever-increasing role for preoperative diagnostic evaluation, interventional cardiology procedures, and cardiac surgery. This chapter describes the technique of 3D TEE imaging as well as some of its most common applications for congenital heart disease evaluation.

Agriculture in West Africa is constrained by several yield-limiting factors, such as poor soil fertility, erratic rainfall distributions and low input systems. Projected changes in climate, thus, pose a threat since crop production is mainly rain-fed. The impact of climate change and its variation on the productivity of cereals in smallholder settings under future production systems in Navrongo, Ghana and Nioro du Rip, Senegal was assessed in this study. Data on management practices obtained from household surveys and projected agricultural development pathways (through stakeholder engagements), soil data, weather data (historical: 1980–2009 and five General Circulation Models, mid-century time slice 2040–2069 for two Representative Concentration Pathways, 4.5 and 8.5) were used for the impact assessment, employing a crop simulation model. Ensemble maize yield changes under the sustainable agricultural development pathway (SDP) were −13 and −16%, while under the unsustainable development pathway (USDP), yield changes were −19 and −20% in Navrongo and Nioro du Rip, respectively. The impact on sorghum and millet were lower than that on maize. Variations in climate change impact among smallholders were high with relative standard deviations (RSD) of between 14% and 60% across the cereals with variability being higher under the USDP, except for millet. Agricultural production systems with higher intensification but with less emphasis on soil conservation (USDP) will be more negatively impacted by climate change compared to relatively sustainable ones (SDP).

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is thought to be a delayed reaction to SARS-CoV-2 exposure. Coronary artery aneurysms (CAA) have been described in the MIS-C diagnostic criteria, with many symptoms mimicking Kawasaki disease (KD). Our institution has seen a significant rise in KD-like illness during the current COVID-19 pandemic. Objectives: We sought to describe the variation in coronary artery (CA) involvement between traditional KD and post-COVID-19 pandemic KD/MIS-C cases. Methods: We identified children admitted to our center with KD from April to June 2016 - 2017 and those with MIS-C/KD from April 1 - June 6, 2020, with review of clinical and echocardiogram data. Presence of CAA (any CA z-score ≥ +2.5), z-scores of the left main (LMCA), left anterior descending (LAD), and right coronary artery (RCA), and presence of cardiac and valvar dysfunction were evaluated. Nonparametric Wilcoxon rank sum test was used to compare the groups. Results: There were 26 patients in the 2016-17 KD group and 24 in the 2020 KD/MIS-C group; results are shown in Table 1. The groups had similar median age, and 2016-17 KD patients were more likely to be male. 2020 KD/MIS-C patients were more likely to have CAA than 2016-17 KD patients (54% vs 26%, p=0.05). The LAD had larger median z-score in 2020 KD/MIS-C than KD (p=0.017). RCA and LMCA z-scores of 2020 KD/MIS-C patients tended to be larger than 2016-17 KD but did not reach statistical significance (p=0.097, p=0.07 respectively). More 2020 KD/MIS-C patients had cardiac dysfunction, not statistically significant (13% vs 0%, p=NS), with no differences in valve function or effusion. Conclusions: Our spring 2020 cohort of MIS-C/KD patients had higher incidence of CAA, particularly larger LAD z-scores than those with KD pre-COVID-19 pandemic. Coronary arteries should be thoroughly assessed in patients presenting with MIS-C symptoms. Future studies are needed to determine long term outcomes in this cohort.

Introduction: The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle (SV) function in this cohort has not been studied. Methods: Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline in indices of SV systolic, diastolic and global function, atrioventricular valve (AVV) regurgitation and mean Fontan fenestration gradient in the udenafil cohort vs placebo, controlling for ventricular morphology (LV vs. RV/other). Effects of ventricular morphology on echo measures and its interaction over time was also evaluated. Difficult imaging windows limited consistent capture of all measures. Results: The 191 udenafil participants had significantly improved myocardial performance index (p=0.03), AVV inflow peak E and A velocities (p = 0.007 and 0.03), and annular DTI-derived peak e’ velocity (p = 0.008) compared to 195 placebo participants (Table). There were no significant differences in change in SV size, systolic function, AVV regurgitation severity or mean fenestration gradient. Although LV morphology participants had significantly more favorable indices of SV size and function (lower volumes and areas, E/e’ ratio, systolic:diastolic time and AVV regurgitation, and higher annular s’ and e’ velocity) at baseline, there was no differential effect of udenafil by ventricular morphology at 26 weeks. Conclusions: FUEL participants who received udenafil demonstrated a significant improvement in global and diastolic echo indices. The changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular relaxation, which may help explain improved exercise performance in that cohort.

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate three-dimensional (3-D) molecular atlases of healthy and diseased kidney biopsies by using multiple state-of-the-art omics and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single-cell level or in 3-D space is a significant challenge that can be a futile exercise if not well controlled. We describe a “follow the tissue” pipeline for generating a reliable and authentic single-cell/region 3-D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation, and harmonization across different omics and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis, and sharing. We established benchmarks for quality control, rigor, reproducibility, and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before their being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multiomics and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

Background Previous studies have identified the presence of trace valvular regurgitation; however, these studies are typically cross-sectional assessments at a single point in time and provide no information regarding the natural history of trace aortic or mitral regurgitation (AR, MR). To our knowledge no study has assessed valve function in growing children with longitudinal echocardiogram (ECHO) assessments. Purpose To monitor cardiac valve function with regular, standardized ECHOs in patients with Dravet syndrome (DS) treated with fenfluramine for up to 3 years. Methods Patients with DS who completed either of two double-blind Phase 3 clinical trials were eligible to enroll in the open label extension (OLE) study. Patients were to be excluded from entry into the double-blind trials if they exhibited any degree of AR or MR, including trace; or pulmonary artery hypertension (PAH). However, trace MR or AR were not exclusion criteria for continuation into the OLE study. All patients had an ECHO prior to initiation of treatment in the double-blind study, after 6 to 8 weeks of treatment, and at the end of that study. In the OLE study, ECHOs were performed at study week 4, 5, or 6, and every 3 months thereafter. Valve morphology was also examined. Results As of September 1, 2019 a total of 330 patients had enrolled in the OLE study and received at least one dose of fenfluramine. The average age of patients at enrollment was 9.0±4.6 years, 27.6% were Conclusions In this long-term longitudinal ECHO study in DS children treated with fenfluramine, we identified that trace MR and AR were intermittent and not predictive of future valve disease. In all cases trace reverted to absent regurgitation at subsequent ECHOs. No valve morphological changes were seen. The intermittent and transient nature of trace regurgitation observed in this study is consistent with current ECHO guidelines, which consider trace regurgitation to be a normal physiologic phenomenon. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Zogenix, Inc.

Retinal degenerations are the leading causes of visual impairment in aging populations. Advances in retinal stem cell biology provide an avenue for studying and treating these diseases. Remarkably, retinal tissues are self-organizing, which simplifies the challenge of creating three-dimensional culture models. The problem that confronts the investigator is that current models are small, multilayered spheres, which limits experimental access to both sides of the multilayer. Furthermore, for grafting into a diseased retina, these neurospheres must be dissociated with the hope that they will reorganize into a multilayered sheet in the environment of the diseased retina. This chapter discusses the scaffolds under investigation that can promote formation of a planar, multilayered model of the retina. Such a tissue would allow investigators to study the mechanisms of retinal diseases, identify therapeutic targets, develop therapeutic agents, and serve as an engraftable tissue.

Background Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN). Methods All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed. Results ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10−6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10−6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN. Conclusions Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.

Clinical sepsis is a highly dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single cell RNA sequencing revealed the involvement of various cell populations in injury and repair to be temporally organized and highly orchestrated. We identified key changes in gene expression that altered cellular functions and can explain features of clinical sepsis. These changes converged towards a remarkable global cell-cell communication failure and organ shutdown at a well-defined point in the sepsis timeline. Importantly, this time point was also a transition towards the emergence of recovery pathways. This rigorous spatial and temporal definition of murine sepsis will uncover precise biomarkers and targets that can help stage and treat human sepsis.

In Mali's cotton belt, spatial variability in management practices, soil fertility and rainfall strongly impact crop productivity and the livelihoods of smallholder farmers. To identify crop growth conditions and hence improve food security, accurate assessment of local crop production is key. However, production estimates in heterogeneous smallholder farming systems often rely on labor-intensive surveys that are not easily scalable, nor exhaustive. Recent advances in high-resolution earth observation (EO) open up new possibilities to work in heterogeneous smallholder systems. This paper develops a method to estimate individual crop production at farm-to-community scales using high-resolution Sentinel-2 time series and ground data in the commune of Koningue, Mali. Our estimation of agricultural production relies on (i) a supervised, pixel-based crop type classification inside an existing cropland mask, (ii) a comparison of yield estimators based on spectral indices and derived leaf area index (LAI), and (iii) a Monte Carlo approach combining the resulting unbiased crop area estimate and the uncertainty on the associated yield estimate. Results show that crop types can be mapped from Sentinel-2 data with 80% overall accuracy (OA), with best performances observed for cotton (Fscore 94%), maize (88%) and millet (83%), while peanut (71%) and sorghum (46%) achieve less. Incorporation of parcel limits extracted from very high-resolution imagery is shown to increase OA to 85%. Obtained through inverse radiative transfer modeling, Sen2-Agri estimates of LAI achieve better prediction of final grain yield than various vegetation indices, reaching R2 of 0.68, 0.62, 0.8 and 0.48 for cotton, maize, millet and sorghum respectively. The uncertainty of Monte Carlo production estimates does not exceed 0.3% of the total production for each crop type.

This study was designed to investigate the acute and subacute toxicity of the aqueous extract from colocasia esculenta (CE) leaves infected by Phytophthora colocsiae (PC) in rats. Toxicity of the aqueous extract was evaluated in both male and female wistar rats after a single administration (Acute model) and during 21 days (subacute model). Acute administration of the extract up to a dose 4000 mg/kg did not induce treatment related signs of toxicity or mortality of any rat tested. Therefore, LD50 was estimated to be more than 4000 mg/kg. In the subacute treatment, 3 days before the end of treatment, the male rats treated with the infected Colocasia esculenta leaves extract at doses of 800 mg/kg presented some signs of toxicity such as spiky hair, breathing, paralysis and death. Hematological analysis revealed a significant decrease (p

Innovation platforms have emerged as a way of enhancing the resilience of agricultural and food systems in the face of environmental change. Consequently, a great deal of theoretical reflection and empirical research have been devoted to the goal of understanding the factors that enhance and constrain their functionality. In this article, we further examine this enquiry by applying the concept of institutional embeddedness, understood as encompassing elements of platform design, structure, and functions as well as aspects of the broader historical, political, and social context to which platforms are connected. We present a case study of sub-national platforms established in three districts of the climatically-stressed Upper West Region of Ghana and charged with facilitating climate change responses at the local level and channelling community priorities into national climate change policy. A different kind of organization − the traditional chief council, the agricultural extension service, and a local NGO − was chosen by members to convene and coordinate the platform in each district. We examine platform members’ accounts of the platform formation and selection of facilitating agent, their vision for platform roles, and their understandings of platform agenda and impacts. We analyse these narratives through the lens of institutional embeddedness, as expressed mostly, but not solely, by the choice of facilitating agents. We illustrate how the organizational position − and related vested interests − of facilitating agents contribute to shaping platform agendas, functions, and outcomes. This process hinges on the deployment of legitimacy claims, which may appeal to cultural tradition, technical expertise, community engagement, and dominant scientific narratives on climate change. Iinstitutional embeddedness is thereby shown to be a critical aspect of agency in multi-actor processes, contributing to framing local understandings of the climate change and to channelling collective efforts towards select response strategies. In conclusion, we stress that the institutional identity of facilitating agents and their relationship to members of the platform and to powerholders in the broader context provides a useful diagnostic lens to analyse the processes that shape the platform’s ability to achieve its goals.

Kidney biopsy remains the gold standard for uncovering the pathogenesis of acute and chronic kidney diseases. However, the ability to perform high resolution, quantitative, molecular and cellular interrogation of this precious tissue is still at a developing stage compared to other fields such as oncology. Here, we discuss recent advances in performing large-scale, three-dimensional (3D), multi-fluorescence imaging of kidney biopsies and quantitative analysis referred to as 3D tissue cytometry. This approach allows the accurate measurement of specific cell types and their spatial distribution in a thick section spanning the entire length of the biopsy. By uncovering specific disease signatures, including rare occurrences, and linking them to the biology in situ, this approach will enhance our understanding of disease pathogenesis. Furthermore, by providing accurate quantitation of cellular events, 3D cytometry may improve the accuracy of prognosticating the clinical course and response to therapy. Therefore, large-scale 3D imaging and cytometry of kidney biopsy is poised to become a bridge towards personalized medicine for patients with kidney disease.

Preconditioning with a low dose of endotoxin confers unparalleled protection against otherwise lethal models of sepsis. The mechanisms of preconditioning have been investigated extensively in isolated immune cells such as macrophages. However, the role of tissue in mediating the protective response generated by preconditioning remains unknown. Here, using the kidney as a model organ, we investigated cell type–specific responses to preconditioning. Compared with preadministration of vehicle, endotoxin preconditioning in the cecal ligation and puncture mouse model of sepsis led to significantly enhanced survival and reduced bacterial load in several organs. Furthermore, endotoxin preconditioning reduced serum levels of proinflammatory cytokines, upregulated molecular pathways involved in phagocytosis, and prevented the renal function decline and injury induced in mice by a toxic dose of endotoxin. The protective phenotype involved the clustering of macrophages around S1 segments of proximal tubules, and full renal protection required both macrophages and renal tubular cells. Using unbiased S1 transcriptomic and tissue metabolomic approaches, we identified multiple protective molecules that were operative in preconditioned animals, including molecules involved in antibacterial defense, redox balance, and tissue healing. We conclude that preconditioning reprograms macrophages and tubules to generate a protective environment, in which tissue health is preserved and immunity is controlled yet effective. Endotoxin preconditioning can thus be used as a discovery platform, and understanding the role and participation of both tissue and macrophages will help refine targeted therapies for sepsis.

Elucidation of the networks of physical (functional) interactions present in cells and tissues is fundamental for understanding the molecular organization of biological systems, the mechanistic basis of essential and disease-related processes, and for functional annotation of previously uncharacterized proteins (via guilt-by-association or -correlation). After a decade in the field, we felt it timely to document our own experiences in the systematic analysis of protein interaction networks. Areas covered: Researchers worldwide have contributed innovative experimental and computational approaches that have driven the rapidly evolving field of 'functional proteomics'. These include mass spectrometry-based methods to characterize macromolecular complexes on a global-scale and sophisticated data analysis tools - most notably machine learning - that allow for the generation of high-quality protein association maps. Expert commentary: Here, we recount some key lessons learned, with an emphasis on successful workflows, and challenges, arising from our own and other groups' ongoing efforts to generate, interpret and report proteome-scale interaction networks in increasingly diverse biological contexts.

Two-photon intravital microscopy is a powerful tool that allows the examination of dynamic cellular processes in the live animal with unprecedented resolution. Indeed, it offers the ability to address unique biological questions that may not be solved by other means. While two-photon intravital microscopy has been successfully applied to study many organs, the kidney presents its own unique challenges that need to be overcome in order to optimize and validate imaging data. For kidney imaging, the complexity of renal architecture and salient autofluorescence merit special considerations as these elements directly impact image acquisition and data interpretation. Here, using illustrative cases, we provide practical guides and discuss issues that may arise during two-photon live imaging of the rodent kidney.

Projections indicate that climate change may exacerbate existing challenges to the productivity of New Zealand dairy farming systems. To assess the importance of these projections and understand adaptation challenges at farm level, detailed farm-scale model simulations of climate change impacts were undertaken for six representative pasture-based dairy farms located in the major dairying regions of New Zealand. The analysis suggested that without adaptation, climate change is likely to have a negative impact in most of the study locations. However, the level and type of impact depends to a large degree on regional climate variability as well as on the management practices of each farm. Under current management, responses to projected climate changes ranged from no change to an 18% decrease in average annual pasture production. A number of modelled adaptations demonstrated the potential to reduce climate change impacts under current management. The modelling work, together with farmers' responses, showed the adaptations' potential to provide both benefits and management challenges across different regions and climate conditions. In particular, it highlighted the need for the results of farm systems modelling under climate change scenarios to be considered in the context of their specific and localised climatic and management challenges.

Future development pathways for irrigated dairy farms in Canterbury operating under stricter nitrogen (N) loss limits were compared in two farmlets over four years. One represented the traditional pathway of intensification via higher inputs of N fertiliser and supplementary feed (‘higher input-high efficiency’, HI-HE), while the other represented a lower input pathway using half the amount of N fertiliser and one quarter the amount of supplementary feed (‘lower input-high efficiency’, LI-HE). The stocking rate of both systems was matched to feed supply to achieve high utilisation (∼90%) of the pasture grown. Mean total annual N surplus and estimated nitrate-N leaching were lower in LI-HE than HI-HE, by 46% and 25% respectively. Milk production was lower for LI-HE (1,700 kg versus 2,240 kg milk fat + protein per ha/year). Estimated profit was the same for both systems at a milk price of $6.46/kg fat + protein, below which LI-HE was more profitable than HI-HE and vice-versa. Compared with the benchmark high-performing Lincoln University Demonstration Dairy Farm (LUDF) through the same period, LI-HE was 2% less profitable, but estimated N leaching was ∼30% lower. Subsequent adoption of the LI-HE system by LUDF demonstrated that the system is scalable, and profitable.

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and therapies tailored to the disease of each patient. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3-dimensional (3D) space is a significant challenge that can be a futile exercise if not well controlled. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3D molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. We describe a pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney with emphasis on quality assurance, quality control, validation and harmonization across different OMICS and imaging methods. Our “follow the tissue” approach encompasses sample procurement to data generation, analysis, data sharing, while standardizing, and harmonizing procedures at sample collection, processing, storage and shipping. We provide key features of preanalytical parameters, bioassays, post analyses, reference standards and data depositions. A pilot experiment from a common source tissue processed and analyzed at different institutions was executed to identify potential sources of variation, feasibility of multimodal analyses and unique and redundant features of the macromolecules being characterized by each technology. An important outcome was identification of limitations and strengths of the different technologies, and how composite information can be leveraged for clinical application. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before granting approval to work on clinical biopsy specimens. This unique pipeline establishes a process that economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and which can serve as a model for similar personalized medicine projects. Author Contributions MTE, RM, BBL, TS, TA, AS, SP, CRA, DD, EAO, SW, GZ, MJ and KD performed the ground work for the quality control group, wrote the KPMP TIS manual of procedures and generated figures. HH, JZ, RS, RM, TS, EAO, MTE, TME, PH, SP, MK, ZL and SJ generated the initial working reference marker list. CEA, TME, JBH, JL, MK and SJ led the Pilot 1 protocol. TME, VD, LB, JG, CEA, ZL, SJ and JBH developed the pathology QC tissue qualification and tissue processing criteria. JBH organized and executed the Pilot tissue collection and distribution. JC designed the SpecTrack system. CP prepared and organized the TIS manual of procedures and performed data organization services. YH led ontology development for QC metadata and knowledge standardization. BS and EA organized data integration efforts and data authentication in the data hub. KS and MS led the OMICS discussion group. SJ led the quality control group. TME and CEA led the tissue processing group. MTE and SJ led the Molecular and Pathology Integration group. MTE and SJ conceived and led the TISAC process. RI, OGT KZ, ZL, PH, BR, PCD, KS, MS, JBH, CEA, LB, JG, TME, MK and SJ conceived the integrated TIS pipeline and QC vision. TME and SJ wrote the initial draft of the paper. All authors contributed to the writing and editing of the manuscript.

Reasoning about complex and abstract ideas is greatly influenced by the choice of metaphors through which they are represented. In this paper we consider the framing effect in military doctrine of considering cyberspace as a domain of action, parallel to the traditional domains of land, sea, air, and space. By means of the well-known Victorian science-fiction novella Flatland, we offer a critique of this dominant cyber metaphor. In Flatland, the problems of lower-dimensional beings comprehending additional dimensions are explored at some length. Inspired by Flatland, our suggested alternate metaphor for cyber is an additional (fourth) dimension. We then propose three common characteristics between the world of Spaceland as experienced by Flatland natives and that of Cyberland as experienced by humans, and finally explore some possible new insights suggested by the Flatland dimensional metaphor.

Many predictive cyber analytics assume, implicitly or explicitly, that the underlying statistical processes they treat have simple properties. Often statistics predicated on Wiener processes are used, but even if not, assumptions on statistical stationarity, ergodicity, and memorylessness are often present. We present here empirical observations of several common network time series, and demonstrate that these assumptions are false; the series are non-stationary, non-ergodic, and possess complicated correlation structures. We compute several statistical tests, borrowed from other disciplines, for the evaluation of network time series. We discuss the implications of these results on the larger goal of constructing a meaningful cyber baseline of a network or host, intended to establish the bounds of “normal” behavior. For many common network observables used in defensive cyber operations, it may prove to be unrealistic to establish such a baseline, or detect significant deviations from it.

Fluorescence lifetime imaging microscopy (FLIM) provides additional contrast for fluorophores with overlapping emission spectra. The phasor approach to FLIM greatly reduces the complexity of FLIM analysis and enables a useful image segmentation technique by selecting adjacent phasor points and labeling their corresponding pixels with different colors. This phasor labeling process, however, is empirical and could lead to biased results. In this Letter, we present a novel and unbiased approach to automate the phasor labeling process using an unsupervised machine learning technique, i.e., K-means clustering. In addition, we provide an open-source, user-friendly program that enables users to easily employ the proposed approach. We demonstrate successful image segmentation on 2D and 3D FLIM images of fixed cells and living animals acquired with two different FLIM systems. Finally, we evaluate how different parameters affect the segmentation result and provide a guideline for users to achieve optimal performance.

Background Heart size and function in children with single right ventricle (RV) anomalies may be influenced by shunt type at the Norwood procedure. We sought to identify shunt-related differences during early childhood after staged surgical palliations using echocardiography. Methods We compared echocardiographic indices of RV, neoaortic, and tricuspid valve size and function at 14 months, pre-Fontan, and 6 years in 241 subjects randomized to a Norwood procedure using either the modified Blalock-Taussig shunt or RV-to-pulmonary-artery shunt. Results At 6 years, the shunt groups did not differ significantly in any measure except for increased indexed neoaortic area in the modified Blalock-Taussig shunt. RV ejection fraction improved between pre-Fontan and 6 years in the RV-to-pulmonary artery shunt group but was stable in the modified Blalock-Taussig shunt group. For the entire cohort, RV diastolic and systolic size and functional indices were improved at 6 years compared with earlier measurements, and indexed tricuspid and neoaortic annular area decreased from 14 months to 6 years. The prevalence of ≥moderate tricuspid and neoaortic regurgitation was uncommon and did not vary by group or time period. Diminished RV ejection fraction at the 14-month study was predictive of late death/transplant; the hazard of late death/transplant when RV ejection fraction was Conclusions By 6 years after staged palliation, shunt type has not impacted RV size and function, and RV and valvar size and function show beneficial remodeling. Poor RV systolic function at 14 months predicts worse late survival independent of the initial shunt type. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00115934.

Discriminatory programs that favor local and small firms in government procurement are common in many countries. This paper studies the long-run impact of procurement discrimination on market structure and future competition in industries where learning-by-doing makes incumbent firms more efficient over time. We consider a sequential procurement design problem in which local and global firms compete for public good provision. Both firms benefit from learning-by-doing if they provide the public good in the previous period but global firms only may be able to transfer learning-by-doing from different markets. We find that the optimal procurement has to be biased in favor of the local firm even when all firms are symmetric with respect to their initial cost distribution. This bias fosters future competition and reduces intertemporal expected transfers to providers.

Automotive, Artificial Intelligence/Machine Learning and blockchain generation are imposing increasing demanding specs for Dynamic Random Access Memory (DRAM) memories. Wider memory bandwidth can be achieved by using conventional planar SiO2 MOSFET and different interfaces but at the expense of required energy per bit. Advantages of High-K/Metal Gate versus SiO2/SiON planar DRAM periphery devices compatible with DRAM memory fabrication have been demonstrated in literature. More recently, the power performance benefit of FinFET for DRAM peri devices have been discussed. In this paper we provide a detailed analysis and additional insights in the first experimental validation of a thermally stable, reliable and cost effective tall fins platform (65 and 80 nm fin height). Power performance benefit versus fin height and expected area advantages on Sense Amp area are presented.

This study was conducted to survey US pediatric specialists about administration of respiratory syncytial virus (RSV) immunoprophylaxis, communication patterns among physicians and parents, and barriers to access. Separate surveys were sent to neonatologists, pediatricians, pediatric pulmonologists, and pediatric cardiologists. Most physicians (≥93.5%) routinely recommended immunoprophylaxis to high-risk children. Most respondents (≥71.8%) reported that >50.0% of eligible infants and young children received each monthly dose throughout the RSV season, with the first dose most commonly administered before discharge from the birth hospitalization. To ensure receipt of subsequent doses, specialists frequently scheduled a follow-up visit at the end of the current appointment. All specialists reported insurance denials as the biggest obstacle to the administration of immunoprophylaxis to high-risk children. These findings may be used to improve adherence to immunoprophylaxis by enhancing education and physician-parent communications about severe RSV disease prevention, and by reducing known barriers to use of this preventive therapy.

Farmers face complex decisions at the time to feed animals, trying to achieve production goals while contemplating social and environmental constraints. Our purpose was to facilitate such decision making for pastoral dairy farmers, aiming to reduce urinary N (UN) and methane emissions (CH4), while maintaining or increasing milk production (MP). There is a number of feeds the farmers can choose from and combine. We used 50 feeds (forages and grains) combined systematically in different proportions producing 11,526 binary diets. Diets were screened, using an a posteriori approach and a Pareto front (PF) analysis of model (Molly) outputs. The objective was to identify combinations with the best possible compromise (i.e. frontier) between UN, CH4, and MP. Using high MP and low UN as objective functions, PF included 10, 14, 12 and 50 diets, for non-lactating, early-, mid- and late-lactation periods, with cereals and beets featuring strongly. Using the same objective functions, but including ryegrass as dietary base PF included 2, 4, 8 and 4 diets for those periods. Therefore, from a wide range of diets, farmers could choose from few feeds combined into binary diets to reduce UN while maintaining or increasing MP. If the intention is maintaining pasture-based systems, there are fewer suitable options. Reducing UN will simply require dilution of N supplied by pasture by supplementing low N conserved forages. The results also evidence the risk of pollution swapping, reaching the frontier means arriving at a point where trade-off decisions need to be made. Any further reduction in UN implies an increment in CH4, or reduction in CH4 emissions increases UN. There is no perfect diet to optimize all objectives simultaneously; but if the current diet is not in the frontier some options can offset pollution swapping. The choice is with the farmers and conditioned by their context.

The floating body retention time is investigated on fully depleted SOI devices with UTBOX. The retention is occurring through the junctions and strongly assisted by defects in the junction space charge region during the holding state at a negative gate voltage. For standard devices with a gate overlap, the junction field is high and the dominant mechanism in this case is the generation by band-to-band tunneling. For optimized extensionless devices with lower junction field, the Shockley–Read–Hall generation enhanced by the field and Poole–Frenkel mechanism takes over the band-to-band tunneling. Therefore, reducing the concentration of Si impurities closer to the junctions is the key to approach an ideal retention time only due to band-to-band tunneling with the Si bandgap as the energy barrier for tunneling.

The productivity of smallholder farming systems is held back by poor soil fertility, low input levels and erratic rainfall distribution in the sorghum-based cropping systems of the Sudano-Sahelian zone of West Africa. We assessed the sensitivity of current agricultural practices to climate change and to improved management practices: (i) increased fertilizer application combined with increased plant populations and (ii) use of improved sorghum varieties. We applied the Decision Support Systems for Agro-Technological Transfer (DSSAT) Cropping Systems Model, and the Agricultural Production Systems sIMulator (APSIM), for a multiple-farm assessment (i.e. diverse types of management and soils) in Koutiala (Mali) and Navrongo (Ghana), which are representative sites for West African sorghum production systems. Baseline climate data from observed weather (1980–2009) and future climates from five Global Circulation Models (GCMs: 2040–2069) in two Representative Concentration Pathways (RCP 4.5 and 8.5) were used as inputs for crop models. In Navrongo, under current management, sorghum yields either decreased or increased compared to the baseline, depending on the crop models and the GCMs; changes in management options induced a yield increase of up to 256%. The addition of genetic improvement resulted in further yield increases (24%). In Koutiala, sorghum yield changes for future climates ranged from −38 to +8% assuming current management. Shifting to an improved cultivar had a marginal effect on grain yields, while increased fertilizer rates resulted in grain yield increases ranging of 20% and 153% for DSSAT and APSIM, respectively, assuming the current climate. We conclude that in the Sudano-Sahelian zone of West Africa sorghum, as it is cultivated today, appears moderately vulnerable to climate change, while doubling fertilizer inputs with an adjusted planting density, in the current climate, would more than double yields. However, by exploring farm diversity we established that, under certain conditions, the effect of the future climate might be as important as the effect of management changes in the current climate, hinting at the importance of locally-relevant management practices.

Background Adolescents with acute psychiatric disorders are typically treated with long-term clinical admission. However, long term admission may be associated with a variety of negative outcomes. This pilot study presents a new model of care, that is, the combined application of intensive home treatment and the possibility of short term stay at a psychiatric high & intensive care. Methods In total 112 referred adolescents with mixed diagnoses participated in this longitudinal observational design. Clinical outcome was measured by the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) which measures the severity of multiple mental health problems. The HoNOSCA was clinician-rated at intake, after two months and after four months at discharge. Change in HoNOSCA total score was analysed with paired t-tests. Outcome moderators were gender, age, primary diagnosis, clinical admission, home treatment-time, medication and additional therapies. Follow up data were completed for 62 patients after two months and for 53 after four months. Results Participants aged between 11 and 18 years (M = 14.8 years, SD = 0.3; 52% female). Mean HoNOSCA total score at intake was 18.8 (SD = 5.2), after two months 13.0 (SD = 5.0); after four months resulting in a score of 9.3 (SD = 5.2). None of the moderators tested showed a significant effect on HoNOSCA scores. However, a control group could not be used because of the severe psychopathology and high risk for suicidality and the lack of an effective treatment intervention for a comparable study group. Conclusion With a symptom decrease of over 50% within four months as measured by the HoNOSCA, including less risk for hospitalization, this new model appears promising and of clinical relevance. Nevertheless, further research regarding stability of treatment outcome is warranted and evaluation of long-term effects of this model in follow-up studies is needed.

International audience; The convergence of new EO data flows, new methodological developments and cloud computing infrastructure calls for a paradigm shift in operational agriculture monitoring. The Copernicus Sentinel-2 mission providing a systematic 5-day revisit cycle and free data access opens a completely new avenue for near real-time crop specific monitoring at parcel level over large countries. This research investigated the feasibility to propose methods and to develop an open source system able to generate, at national scale, cloud-free composites, dynamic cropland masks, crop type maps and vegetation status indicators suitable for most cropping systems. The so-called Sen2-Agri system automatically ingests and processes Sentinel-2 and Landsat 8 time series in a seamless way to derive these four products, thanks to streamlined processes based on machine learning algorithms and quality controlled in situ data. It embeds a set of key principles proposed to address the new challenges arising from countrywide 10 m resolution agriculture monitoring. The full-scale demonstration of this system for three entire countries (Ukraine, Mali, South Africa) and five local sites distributed across the world was a major challenge met successfully despite the availability of only one Sentinel-2 satellite in orbit. In situ data were collected for calibration and validation in a timely manner allowing the production of the four Sen2-Agri products over all the demonstration sites. The independent validation of the monthly cropland masks provided for most sites overall accuracy values higher than 90%, and already higher than 80% as early as the mid-season. The crop type maps depicting the 5 main crops for the considered study sites were also successfully validated: overall accuracy values higher than 80% and F1 Scores of the different crop type classes were most often higher than 0.65. These respective results pave the way for countrywide crop specific monitoring system at parcel level bridging the gap between parcel visits and national scale assessment. These full-scale demonstration results clearly highlight the operational agriculture monitoring capacity of the Sen2-Agri system to exploit in near real-time the observation acquired by the Sentinel-2 mission over very large areas. Scaling this open source system on cloud computing infrastructure becomes instrumental to support market transparency while building national monitoring capacity as requested by the AMIS and GEOGLAM G-20 initiatives.

Grazing land models can assess the provisioning and trade-offs among ecosystem services attributable to grazing management strategies. We reviewed 12 grazing land models used for evaluating forage and animal (meat and milk) production, soil C sequestration, greenhouse gas emission, and nitrogen leaching, under both current and projected climate conditions. Given the spatial and temporal variability that characterizes most rangelands and pastures in which animal, plant, and soil interact, none of the models currently have the capability to simulate a full suite of ecosystem services provided by grazing lands at different spatial scales and across multiple locations. A large number of model applications have focused on topics such as environmental impacts of grazing land management and sustainability of ecosystems. Additional model components are needed to address the spatial and temporal dynamics of animal foraging behavior and interactions with biophysical and ecological processes on grazing lands and their impacts on animal performance. In addition to identified knowledge gaps in simulating biophysical processes in grazing land ecosystems, our review suggests further improvements that could increase adoption of these models as decision support tools. Grazing land models need to increase user-friendliness by utilizing available big data to minimize model parameterization so that multiple models can be used to reduce simulation uncertainty. Efforts need to reduce inconsistencies among grazing land models in simulated ecosystem services and grazing management effects by carefully examining the underlying biophysical and ecological processes and their interactions in each model. Learning experiences among modelers, experimentalists, and stakeholders need to be strengthened by co-developing modeling objectives, approaches, and interpretation of simulation results.