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This paper reports on the implementation and assessment of a wall-modeled large-eddy simulation (WMLES) methodology in an unstructured-grid, node-centered flow solver, FUN3D, that is developed and supported at the NASA Langley Research Center. Finite-volume (FV) and finite-element (FE) discretization schemes considered in the study provide formal second-order spatial accuracy. Large-eddy simulations (LES) resolve large-scale turbulent-flow features, and small-scale effects are modeled using the Vreman subgrid-scale model. At solid-wall boundaries, a shear-stress model is employed to provide a proper boundary-flux closure. The nonlinear equations are integrated in time using either an optimized backward difference formula or an implicit multistage Runge-Kutta temporal scheme. The implicit equations at each time step are solved by strong nonlinear iteration schemes. WMLES demonstrations are shown for two high-lift configurations, namely, the McDonnell Douglas 30P30N multi-element airfoil and a NASA High-Lift Common Research Model. Results show that the WMLES approaches implemented in the FV and FE discretization methods produce consistent solutions and are capable of capturing key aerodynamic characteristics and flow structures for high-lift configurations at a wide range of angles of attack, including maximum-lift conditions. In the 30P30N example, correct trends in the variations of integrated aerodynamic forces and moments, surface pressure distributions, and boundary-layer profiles are captured as the Reynolds number is increased. [ABSTRACT FROM AUTHOR]

Background: Tissue stimulations greatly affect cell growth, phenotype, and function, and they play an important role in modeling tissue physiology. With the goal of understanding the cellular mechanisms underlying the response of tissues to external stimulations, in vitro models of tissue stimulation have been developed in hopes of recapitulating in vivo tissue function. Methods: Herein we review the efforts to create and validate tissue stimulators responsive to electrical or mechanical stimulation including tensile, compression, torsion, and shear. Results: Engineered tissue platforms have been designed to allow tissues to be subjected to selected types of mechanical stimulation from simple uniaxial to humanoid robotic stain through equal‐biaxial strain. Similarly, electrical stimulators have been developed to apply selected electrical signal shapes, amplitudes, and load cycles to tissues, lending to usage in stem cell‐derived tissue development, tissue maturation, and tissue functional regeneration. Some stimulators also allow for the observation of tissue morphology in real‐time while cells undergo stimulation. Discussion on the challenges and limitations of tissue simulator development is provided. Conclusions: Despite advances in the development of useful tissue stimulators, opportunities for improvement remain to better reproduce physiological functions by accounting for complex loading cycles, electrical and mechanical induction coupled with biological stimuli, and changes in strain affected by applied inputs. [ABSTRACT FROM AUTHOR]

Bermudagrass (Cynodon dactylon (L.) Pers.) is one of the primary perennial forages in the southeastern USA. Newer hybrid cultivars have superior production and nutritive value compared to common ecotypes. However, there are many challenges facing bermudagrass production in the region. First, the bermudagrass stem maggot (BSM; Atherigona reversura Villeneuve) has severely damaged bermudagrass throughout the region. Strategically timed pyrethroid applications significantly reduce adult BSM populations, but efforts are needed to develop integrated pest management plans. Second, an increasing number of producers are noting challenges with green‐up following winter dormancy. This may be attributed to disease, unbalanced soil fertility, and weed pressure. Perhaps one of the most limiting factors for continued production is the deficit of sprigs and trained personnel to sprig hybrid bermudagrasses. This research is critically important as the need for cold‐tolerant bermudagrass is increasing as tall fescue (Lolium arundinaceum (Schreb.) S. J. Darbyshire) is declining due to changes in temperature and precipitation throughout the northern parts of the region. Plant breeders are investigating hybrid bermudagrass at latitudes >35° with respect to freeze or cold tolerance. Despite the many challenges facing hybrid bermudagrass in the southeastern USA, researchers are working to ensure its persistence, productivity, and availability for the future. [ABSTRACT FROM AUTHOR]

Myopia, including pathologic myopia, has seen a significant increase in prevalence in recent years. It is a significant cause of irreversible vision loss worldwide and prediction models demonstrate the substantial future impact on the population. With increased awareness and research, it is possible to prevent blindness on a large scale in the younger, productive age group affected by myopic maculopathy (MM). The vision-threatening manifestations of pathologic myopia include myopic choroidal neovascularization, macular atrophy, maculoschisis, macular hole, and retinal detachment. Myopic traction maculopathy (MTM) is a progressive manifestation of pathologic myopia and its treatment includes pars plana vitrectomy, macular buckle, or a combination. In this article we aim to review the diagnosis, clinical characteristics, and treatment of MM with an emphasis on recent developments in the surgical management of MTM. We discuss commercially available macular buckles, along with potential advantages to the use of macular buckle in MM. We review the new MTM staging system and its role in determining surgical management of these complex cases. [ABSTRACT FROM AUTHOR]

This document is a note celebrating the career of Evgeni Fedorovich, the former Editor-in-Chief of Boundary-Layer Meteorology. It highlights his scientific achievements, career milestones, and impacts on the field of boundary-layer meteorology. Evgeni is known for his research on various topics, including entrainment in convective boundary layers, contaminant dispersal in urban settings, and turbulence in slope flows. He has published numerous articles and monographs and has been recognized for his contributions through awards and invitations to collaborate and lead in research and academic communities. Evgeni's career spanned several institutions, including the University of Oklahoma, where he mentored students and conducted research. The authors of the note express their gratitude to Evgeni and wish him a happy retirement. [Extracted from the article]

To analyze multivariate outcomes in clinical trials, several authors have suggested generalizations of the univariate Mann–Whitney test. As the Mann–Whitney statistic compares the subjects' outcome pairwise, the multivariate generalizations are known as generalized pairwise comparisons (GPC) statistics. For GPC statistics such as the net treatment benefit, the win ratio, and the win odds, asymptotic based or re-sampling tests have been suggested in the literature. However, asymptotic methods require a sufficiently high sample size to be accurate, and re-sampling methods come with a high computational burden. We use graph theory notation to obtain closed-form formulas for the expectation and the variance of the permutation and bootstrap sampling distribution of the GPC statistics, which can be utilized to develop fast and accurate inferential tests for each of the GPC statistics. A simple example and a simulation study demonstrate the accuracy of the exact permutation and bootstrap methods, even in very small samples. As the time complexity is O (N 2) , where N is the total number of patients, the exact methods are fast. In situations where asymptotic methods have been used to obtain these variance matrices, the new methods will be more accurate and equally fast. In situations where bootstrap has been used, the new methods will be both more accurate and much faster. [ABSTRACT FROM AUTHOR]

A reflection on Dionne Brand's A Map to the Door of No Return, originally presented at A Map to the Door of No Return at 20: A Gathering. [ABSTRACT FROM AUTHOR]

The impact of a dilated left ventricular (LV) on right ventricular (RV) diastolic function has not been investigated. We hypothesized that in patients with a patent ductus arteriosus (PDA), LV dilation causes elevation of the RV end-diastolic pressure (RVEDP) through ventricular-ventricular interaction. We identified patients' ages 6 months to 18 years who underwent transcatheter PDA closure at our center from 2010 to 2019. One hundred and thirteen patients were included with a median age of 3 years (0.5-18). The median LV end-diastolic dimension (LVEDD) Z-score was 1.6 (-1.4-6.3). RVEDP was positively associated with RV systolic pressure (0.38, P < 0.01), ratio of pulmonary artery/aortic systolic pressure (0.4, P < 0.01), and pulmonary capillary wedge pressure (0.71, P < 0.01). RVEDP was not associated with LVEDD Z-score (0.03, P = 0.74). In children with a PDA, RVEDP was not associated with LV dilation, but was positively associated with RV systolic pressure. [ABSTRACT FROM AUTHOR]

Mesenchymal lesions of the breast are a heterogeneous range of entities with diverse clinical, histological, and molecular features, as well as biological behaviour. Their morphologic overlap with non‐mesenchymal lesions (such as metaplastic carcinoma and phyllodes tumour) and relative rarity also pose significant diagnostic challenges. In this review, we summarize the salient features of selected mesenchymal lesions of the breast, emphasizing those that are the most common and problematic. Vascular, fibroblastic/myofibroblastic, adipocytic, and smooth muscle lesions are each covered with regard to their clinicopathological features and differential diagnosis, while recent advances and the role of immunohistochemistry and molecular tests are also highlighted. [ABSTRACT FROM AUTHOR]

The Organisation of Economic Co-operation and Development (OECD) is proposing a dramatic shift to international corporate taxation that both sets a floor for corporate tax rates across the globe and transforms how countries obtain taxing rights over large multinational corporations. This Note focuses on the proposed framework for re-allocating taxing rights over corporations away from the traditional requirement of a physical presence in a country to mere revenues in a country. This Note identifies problems with the proposal as it relates to artificially altering corporate incentives and structures, as well as the proposal's incompatibility with theories of taxation-- including Adam Smith's views on the necessity and evaluation of taxes. To resolve these problems, this Note suggests modifying the OECD proposal by removing the segmentation rule for companies that would not otherwise qualify for Pillar One taxation and allocating taxing rights to countries based on jurisdiction-specific profits, not revenues. While the OECD proposal will face obstacles, these suggestions should reduce the obstacles by limiting the proposal's disruptive impact on US corporations and addressing legislators' concerns about disproportionate impact on the United States. [ABSTRACT FROM AUTHOR]

Aims. Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare aggressive renal malignancy associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Tumors exhibiting heterogeneous (ie, patchy) FH loss by immunohistochemistry have rarely been described, may be diagnostically challenging, and have never been the focus of a study. We aimed to investigate the FH mutational status of FH-deficient RCC with heterogeneous versus complete FH loss, to characterize additional genetic drivers, and to evaluate 2SC immunohistochemistry in this setting. Methods and Results. We studied FH-deficient RCC with heterogeneous (n = 3) and complete (n = 4) FH loss. Targeted next-generation sequencing (NGS) was performed on all tumors. No patients had a known history of HLRCC. All tumors had histological features within the morphologic spectrum described for FH-deficient RCC. All 7 tumors were immunoreactive for 2SC. Molecularly, all 7 tumors revealed multiple hits involving the FH locus resulting in complete loss of wild-type alleles. All tumors with heterogeneous FH loss harbored FH missense variants within domain 2 of the protein, and each had concomitant copy neutral loss of heterozygosity (CN-LOH). In complete FH loss tumors, FH alterations included splice variants with concomitant loss of heterozygosity (n = 2) and homozygous gene deletions (n = 2). Other non-recurrent alterations included biallelic alterations of TP53, NF2, SMAD4 and activation of PIK3CA. Conclusions. Our series highlights how heterogeneous FH loss (patchy positive staining) is an important staining pattern to recognize since it is compatible with a diagnosis of FH-deficient RCC and should prompt additional ancillary studies (confirmatory 2SC immunohistochemistry and/or molecular testing) and genetic evaluation. [ABSTRACT FROM AUTHOR]

Aims: Malignant mesothelioma (MM) of the tunica vaginalis (TV) is a rare and aggressive tumour, and the molecular features and staining profile with contemporary immunohistochemical (IHC) biomarkers are largely unexplored. We characterise the clinicopathological, molecular and IHC features of MM (n = 13) and mesothelial neoplasms of uncertain malignant potential (MUMP) (n = 4). Methods and results: Targeted next‐generation sequencing was performed on seven MMs and two MUMPs. IHC was performed for methylthioadenosine phosphorylase (MTAP), BRCA1‐associated protein 1 (BAP1) and SRY‐box transcription factor 6 (SOX6). Thirteen adenomatoid tumours were also assessed with SOX6. MM were epithelioid (seven of 13) or biphasic (six of 13). In MM, NF2 (five of seven; 71%), CDKN2A (three of seven; 43%) and BAP1 (two of seven; 29%) were most frequently altered. Non‐recurrent driver events were identified in PTCH1 and TSC1. In contrast, none of these alterations were identified in MUMPs; however, one MUMP harboured a TRAF7 missense mutation. By IHC, loss of MTAP (two of 12; 17%) and BAP1 (two of nine; 22%) was infrequent in MM, whereas both were retained in the MUMPs. SOX6 was positive in nine of 11 (82%) MMs and negative in all MUMPs and adenomatoid tumours. Conclusions: Testicular MM exhibit a similar mutational profile to those of the pleura/peritoneum; however, alterations in CDKN2A and BAP1 are less common. These findings suggest that although MTAP and BAP1 IHC are specific for MM, their sensitivity in testicular MMs appears lower. In addition, rare tumours may harbour targetable alterations in driver genes (PTCH1 and TSC1) that are unusual in MMs at other anatomical sites. SOX6 is sensitive for MM; accordingly, the presence of SOX6 expression argues against a benign neoplastic process. [ABSTRACT FROM AUTHOR]

Georgia, located in the Southeastern USA, has been historically dominated by two perennial forage grass production systems. Tall fescue (Lolium arundinaceum [Schreb.] S.J. Darbyshire) is more prevalent in the northern parts of the state, while bermudagrass [Cynodon dactylon (L.) Pers.] is ubiquitous to the southern portion. Climatologists have documented notable changes in temperature and precipitation patterns in the state that have contributed to an invasion of warm‐season species in the northern portion of the state. In the transition zones between warm‐season and‐cool‐season perennial grass‐dominated regions of North America, C4 grasses can maintain productivity at high temperatures while C3 grasses are transitioning to a reproductive stage with minimal vegetative growth during summer. For this reason, warm‐season grasses could replace a portion of the grasslands at latitudes greater than 35°. This manuscript documents the expansion of warm‐season bermudagrass into northern Georgia, explores the climatic factors driving this transition, and highlights previous and on‐going research. We specifically focus on evaluating freeze or cold tolerance of bermudagrass germplasm. The C. dactylon cultivars exhibit more cold tolerance than C. nlemfuënsis (stargrass) since they are more rhizomatous and rely less on above‐ground stolons for regrowth and winter survival. Conversely, these cultivars tend to have poor nutritive value and are highly susceptible to insect damage. On‐going research is identifying germplasm that provides adequate cold tolerance to meet the needs of farmers transitioning to warm‐season production systems in the lower transition zone. [ABSTRACT FROM AUTHOR]

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and clinically aggressive RCC subtype that is commonly associated with the hereditary leiomyomatosis and renal cell carcinoma syndrome. The diagnostic hallmark of FH-deficient RCC is a high-grade microscopic appearance with prominent inclusion-like eosinophilic nucleoli and perinucleolar halos. Herein we report a case of an FH-deficient RCC in a 30-year-old female that exhibited low-grade nuclei and abundant eosinophilic cytoplasm, reminiscent of the clinically more indolent succinate dehydrogenase-deficient RCC subtype and the newly described eintity, eosinophilic, solid and cystic RCC. This case illustrates that FH-deficient RCC can have a wide spectrum of microscopic appearances, including low-grade eosinophilic RCC. In addition, it highlights that a low threshold to perform the immunohistochemical stains for FH and S-(2-succino) cysteine is warranted in RCC cases with unusual and even low-grade eosinophilic morphology. [ABSTRACT FROM AUTHOR]

Aims: Large cell calcifying Sertoli cell tumour (LCCSCT) is a rare testicular sex cord‐stromal tumour that primarily affects young patients and is associated with Carney complex. We sought to characterise the clinicopathological features of a series of LCCSCT and evaluate the diagnostic utility of PRKAR1A immunohistochemistry (IHC). Methods and results: The LCCSCT cohort (n = 15) had a median age of 16 years (range = 2–30 years). Four patients were known to have Carney complex. PRKAR1A IHC was performed in each case. For comparison, PRKAR1A IHC was also assessed in other sex cord‐stromal tumours, including Sertoli cell tumour, not otherwise specified (SCT, NOS; n = 10), intratubular large cell hyalinising Sertoli cell tumour (n = 1) and Leydig cell tumour (n = 23). Loss of cytoplasmic PRKAR1A expression was observed in all but one LCCSCT (14 of 15; 93%). PRKAR1A expression was retained in all SCTs, NOS (10 of 10; 100%), the majority of Leydig cell tumours (22 of 23; 96%) and an intratubular large cell hyalinising Sertoli cell tumour (1 of 1; 100%). One Leydig cell tumour showed equivocal staining (multifocal weak expression). Conclusions: Overall, PRKAR1A loss is both sensitive (93%) and highly specific (97%) for the diagnosis of LCCSCT. PRKAR1A loss may aid its diagnosis, particularly in sporadic cases and those that are the first presentation of Carney complex. [ABSTRACT FROM AUTHOR]

The role of biomarkers in risk-based early detection of lung cancer may enable screening to become cost effective and widely accessible. EarlyCDT-Lung is an example of such a blood-based autoantibody biomarker which may improve accessibility to Low dose Computed Tomography (LDCT) screening for those at highest risk. We randomized 12 208 individuals aged 50–75 at high risk of developing lung cancer to either the test or to standard clinical care. Outcomes were ascertained from Register of Deaths and Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio of the rate of deaths from all causes and lung cancer. Additional analyses were performed for cases of lung cancer diagnosed within two years of the initial test. After 5 years 326 lung cancers were detected (2.7% of those enrolled). The total number of deaths reported from all causes in the intervention group was 344 compared to 388 in the control group. There were 73 lung cancer deaths in the intervention arm and 90 in the controls (Adjusted HR 0.789 (0.636, 0.978). An analysis of cases of lung cancer detected within 2 years of randomization in the intervention group showed that there were 34 deaths from all causes and 29 from lung cancer. In the control group there were 56 deaths with 49 from lung cancer. In those diagnosed with lung cancer within 2 years of randomization the hazard ratio for all cause mortality was 0.615 (0.401,0.942) and for lung cancer 0.598 (0.378, 0.946). Further large-scale studies of the role of biomarkers to target lung cancer screening, in addition to LDCT, are likely to provide additional value. [ABSTRACT FROM AUTHOR]

Reduced-order models of time-dependent partial differential equations (PDEs) where the solution is assumed as a linear combination of prescribed modes are rooted in a well-developed theory. However, more general models where the reduced solutions depend nonlinearly on time varying parameters have thus far been derived in an ad hoc manner. Here, we introduce reducedorder nonlinear solutions (RONS): a unified framework for deriving reduced-order models that depend nonlinearly on a set of time-dependent parameters. The set of all possible reduced-order solutions are viewed as a manifold immersed in the function space of the PDE. The parameters are evolved such that the instantaneous discrepancy between reduced dynamics and the full PDE dynamics is minimized. This results in a set of explicit ordinary differential equations on the tangent bundle of the manifold. In the special case of linear parameter dependence, our reduced equations coincide with the standard Galerkin projection. Furthermore, any number of conserved quantities of the PDE can readily be enforced in our framework. Since RONS does not assume an underlying variational formulation for the PDE, it is applicable to a broad class of problems. We demonstrate the efficacy of RONS on three examples: an advection-diffusion equation, the nonlinear Schrödinger equation, and Euler's equation for ideal fluids. [ABSTRACT FROM AUTHOR]

Aims: Spermatocytic tumour (ST) is a rare testicular germ cell neoplasm with few confirmatory biomarkers that can be challenging to diagnose. Like normal spermatogonia, STs are known to express SSX proteins. Recently, a novel SSX antibody directed against a conserved C‐terminal region of SSX1, SSX2 and SSX4 (SSX_CT) has emerged as a reliable biomarker for these SSX proteins and synovial sarcoma. However, SSX_CT immunostaining has not been demonstrated in ST. The aim of this study was to assess the diagnostic utility of SSX_CT immunohistochemistry in ST and other tumours in the differential diagnosis with ST. Methods and results: SSX_CT, OCT3/4 and c‐KIT immunohistochemistry was performed on 15 STs, 38 seminomas, 13 embryonal carcinomas, 12 yolk sac tumours, six choriocarcinomas, four teratomas, seven Sertoli cell tumours, and six lymphomas. Staining was scored as negative, rare, focal, or diffuse. SSX_CT was positive in all (15/15) STs, and diffusely positive in 14 of 15 (93%). SSX_CT was positive in 22 of 38 (58%) seminomas; however, only two cases showed diffuse expression. SSX_CT was negative in all other tumours. OCT3/4 was negative in all STs, but positive in all seminomas and embryonal carcinomas. c‐KIT was frequently positive in both STs (12/15; 80%) and seminomas (33/38; 87%). OCT3/4 and c‐KIT were negative in all other tumours. Conclusions: SSX_CT is a valuable and highly sensitive biomarker that supports the diagnosis of ST. Diffuse expression of SSX‐CT in STs is also highly specific for ST. Nevertheless, SSX_CT is best used in combination with OCT3/4 when ST is in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell (hiPSC)- derived neurons offer the possibility of studying human-specific neuronal behaviors in physiologic and pathologic states in vitro. It is unclear whether cultured neurons can achieve the fundamental network behaviors required to process information in the brain. Investigating neuronal oscillations and their interactions, as occurs in cross-frequency coupling (CFC), addresses this question. We examined whether networks of two-dimensional (2D) cultured hiPSC-derived cortical neurons grown with hiPSC-derived astrocytes on microelectrode array plates recapitulate the CFC that is present in vivo. We employed the modulation index method for detecting phase-amplitude coupling (PAC) and used offline spike sorting to analyze the contribution of single neuron spiking to network behavior. We found that PAC is present, the degree of PAC is specific to network structure, and it is modulated by external stimulation with bicuculline administration. Modulation of PAC is not driven by single neurons, but by network-level interactions. PAC has been demonstrated in multiple regions of the human cortex as well as in organoids. This is the first report of analysis demonstrating the presence of coupling in 2D cultures. CFC in the form of PAC analysis explores communication and integration between groups of neurons and dynamical changes across networks. In vitro PAC analysis has the potential to elucidate the underlying mechanisms as well as capture the effects of chemical, electrical, or ultrasound stimulation; providing insight into modulation of neural networks to treat nervous system disorders in vivo. • Phase amplitude coupling (PAC) is present in 2-dimensional human cultures. • In vitro PAC, suggests that PAC is a fundamental property of neural networks. • 2D cultures offer a model to understand the biology of PAC. [ABSTRACT FROM AUTHOR]

Aims: Perivascular epithelioid cell tumours (PEComas) of the appendix have been reported very rarely. In this study, we describe three cases of a distinctive micronodular proliferation in the appendix consistent with a variant of PEComa. Although known as 'granular degeneration of smooth muscle' in prior reports, we reappraise its clinicopathological, immunohistochemical and ultrastructural features which support a change in classification. Methods and results: Patients were two females (aged 33 and 41 years) and one male (aged 41). None had a history of tuberous sclerosis. Histologically, each case demonstrated a multifocal nodular proliferation towards the distal tip of the appendix, composed of epithelioid cells with abundant granular eosinophilic to clear cytoplasm. By immunohistochemistry, the lesional cells were positive for muscle markers [smooth muscle actin (SMA) and desmin], melanocytic markers (HMB45, melan A), cathepsin K and the lysosomal marker NKI‐C3 in each case. MITF was positive in two of three cases. None expressed S100 protein. Electron microscopy in one case revealed striated electron‐dense structures consistent with pre‐melanosomes. Follow‐up, available in one case, showed no recurrence at 5 years. Conclusions: We propose the term 'micronodular PEComa' for this appendiceal lesion to reflect more accurately its histological and immunohistochemical characteristics, which include consistent positivity for both muscle and melanocytic markers. Micronodular PEComa seems to follow an indolent course, consistent with its uniformly low‐grade histological features, and appears to be unassociated with tuberous sclerosis. [ABSTRACT FROM AUTHOR]

Objectives: Rapid delivery of antibiotics is a cornerstone of sepsis therapy, although time targets for specific components of antibiotic delivery are unknown. We quantified time intervals comprising the task of antibiotic delivery and evaluated the association between interval delays and hospital mortality among patients treated in the emergency department for suspected sepsis.Design: Retrospective cohort.Setting: Twelve hospitals in Southeastern United States from 2014 to 2017.Patients: Twenty-four thousand ninety-three encounters among 20,026 adults with suspected sepsis in 12 emergency departments.Measurements and Main Results: We divided antibiotic administration into two intervals: time from emergency department triage to antibiotic order (recognition delay) and time from antibiotic order to infusion (administration delay). We used generalized linear mixed models to evaluate associations between these intervals and hospital mortality. Median time from emergency department triage to antibiotic administration was 3.4 hours (interquartile range, 2.0-6.0 hr), separated into a median recognition delay (time from emergency department triage to antibiotic order) of 2.7 hours(interquartile range, 1.5-4.7 hr) and median administration delay (time from antibiotic order to infusion) of 0.6 hours (0.3-1.2 hr). Adjusting for other risk factors, both recognition delay and administration delay were associated with mortality, but pairwise comparison with a no-delay reference group was not significant for up to 6 hours of recognition delay or up to 1.5 hours of administration delay.Conclusions: Both recognition delays and administration delays were associated with increased hospital mortality, but only for longer delays. These results suggest that both metrics may be important to measure and improve for patients with suspected sepsis but do not support targets less than 1 hour. [ABSTRACT FROM AUTHOR]

The fifth edition of the World Health Organization (WHO) classification of soft tissue and bone tumours was published in May 2020. This 'Blue Book', which is also available digitally for the first time, incorporates an array of new information on these tumours, amassed in the 7 years since the previous edition. Major advances in molecular characterisation have driven further refinements in classification and the development of ancillary diagnostic tests, and have improved our understanding of disease pathogenesis. Several new entities are also included. This review summarises the main changes introduced in the 2020 WHO classification for each subcategory of soft tissue and bone tumours. [ABSTRACT FROM AUTHOR]

The Mars 2020 rover will land in Jezero crater, characterize the local geology, and collect samples to send back to Earth. Ionizing radiation at the Martian surface degrades the complex organic molecules sought by this mission, making it critical to mission success that samples be selected from recently eroded strata minimally exposed to surface radiation. We used numerical modeling to identify sites near the rover landing area potentially eroded by recent winds. Large‐eddy simulation of turbulent airflow over topography was coupled with interpretations of the surface geology to (1) establish a baseline estimate of local grain mobility and (2) characterize potential wind‐driven erosion across the Jezero crater delta deposit. We discuss sediment sources with respect to abrasion and rover trafficability at several locations. Our results identify several locations that provide optimal sites for sample collection. These results offer a baseline for comparing theory and observations collected by the rover. Plain Language Summary: The Mars 2020 rover will land in Jezero crater and collect samples that will eventually be returned to Earth. Rocks exposed at the surface of Mars become damaged by radiation, therefore, the best samples to collect will be those that have recently been exposed to the surface. On Mars, surface erosion is mostly caused by wind. In this work, we use numerical modeling of wind over the terrain in the Mars 2020 landing area to predict where the landscape has most recently been eroded and identify potential locations for optimal sample collection. We discuss several specific sites in terms of the sand available to cause erosion and how that sand might limit rover trafficability. Further, the results of this work are based on theoretical predictions of sand motion and can be compared with future rover observations. Key Points: Large‐eddy simulation was used to model wind‐driven surface stress, a proxy for eolian erosion, across the Jezero crater western deltaBased on two interpreted wind regimes, locations of recently exposed strata are interpreted and discussed as potential sampling sitesEstimates of sand size across the domain provide a baseline for comparison with future rover observations [ABSTRACT FROM AUTHOR]

Brolucizumab is the newest anti-vascular endothelial growth factor (anti-VEGF) drug approved for use. The aim of this review is to review the HAWK/HARRIER clinical trials, examine post-marketing experience with the drug, and evaluate the packaging/procedural differences with brolucizumab. Brolucizumab is a more potent and longer lasting anti-VEGF agent, and is an important agent that may be used in the treatment of neovascular age-related macular degeneration. Retinal vasculitis is a rare but very serious complication of brolucizumab that the patient and physician must be aware of. [ABSTRACT FROM AUTHOR]

Atmospheric boundary-layer dynamics over heterogeneous surfaces is significant to a wide array of geophysical and engineering applications. Yet, despite over five decades of intense efforts by the research community, numerous open research questions remain. This underlines the complexity of the physical processes that are excited by heterogeneity, the multitude of patterns and manifestations that it can display, and the importance of the implications to research in the atmospheric sciences and beyond. Here, existing knowledge is reviewed and a path forward for research is proposed, starting with the smaller scales near a surface transition and proceeding to the influence on large-scale dynamics and their forecasting. [ABSTRACT FROM AUTHOR]

Sand transport initiation and cessation occurs when the surface shear velocity exceeds a fluid threshold and falls below an impact threshold, respectively. Even when average shear velocity is below fluid threshold, turbulent fluctuations can initiate saltation, leading to turbulence‐driven transport intermittency. We leveraged the dynamic properties of large‐eddy simulation to recover a shear velocity time series due to atmospheric turbulence and recover a probability density function for saltation based on the frequency of events where wind has previously exceeded fluid threshold but not yet dropped below impact threshold. By conditionally sampling, we can quantitatively predict the frequency of intermediate saltation. Results show that a compensated, subthreshold shear velocity exhibits linear dependence upon the actual shear velocity. This compensated shear velocity compares favorably against field data. Model performance under terrestrial and Mars conditions is also shown. Plain Language Summary: Windblown sand transport occurs due to aerodynamic drag imposed by the aloft atmosphere. Models for sand mass flux make use of a nonlinear dependence upon the so‐called shear velocity, which is derived from aerodynamic drag: Sand transport begins and ends when the shear velocity exceeds a fluid threshold and falls below an impact threshold, respectively. Using sand transport and wind data from two high‐frequency field campaigns, and from a relatively lower‐frequency field campaign encompassing nine months of continuous measurements, systematic correlation is recovered in the nature of "subthreshold" transport. Using computational fluid dynamics simulation of wind turbulence, stress statistics are studied and an accompanying prognostic model is recovered. The model performs well against the field data. The implications for this on Earth and Mars are shown. Key Points: Aeolian sand transport responds to turbulent fluctuations in the atmosphere that can be accounted for probabilisticallyConditionally sampled shear velocity scales linearly with actual time‐averaged shear velocity for subthreshold transportThe proposed aeolian transport model can be readily generalized to Mars, where subthreshold transport is significant [ABSTRACT FROM AUTHOR]

The Fokker–Planck equation describes the evolution of the probability density associated with a stochastic differential equation. As the dimension of the system grows, solving this partial differential equation (PDE) using conventional numerical methods becomes computationally prohibitive. Here, we introduce a fast, scalable, and interpretable method for solving the Fokker–Planck equation which is applicable in higher dimensions. This method approximates the solution as a linear combination of shape-morphing Gaussians with time-dependent means and covariances. These parameters evolve according to the method of reduced-order nonlinear solutions (RONS) which ensures that the approximate solution stays close to the true solution of the PDE for all times. As such, the proposed method approximates the transient dynamics as well as the equilibrium density, when the latter exists. Our approximate solutions can be viewed as an evolution on a finite-dimensional statistical manifold embedded in the space of probability densities. We show that the metric tensor in RONS coincides with the Fisher information matrix on this manifold. We also discuss the interpretation of our method as a shallow neural network with Gaussian activation functions and time-varying parameters. In contrast to existing deep learning methods, our method is interpretable, requires no training, and automatically ensures that the approximate solution satisfies all properties of a probability density. • Develop shape-morphing modes as a fast and interpretable method for solving the Fokker-Planck equation in higher dimensions. • Analysis of the computational complexity of the method. • Connection between shape-morphing modes and Fisher information. • Connection between shape-morphing modes and shallow neural networks. • Application of the proposed method to four numerical examples. [ABSTRACT FROM AUTHOR]

Aims: Classification of renal neoplasms on small tissue biopsies is in increasing demand, and maintaining broad differential diagnostic considerations in this setting is necessary. When evaluating a renal or perirenal tumour biopsy with sarcomatoid morphology, together with sarcomatoid renal cell carcinoma and sarcomatoid urothelial carcinoma as top diagnostic considerations, it is vital to additionally consider the possibility of well‐differentiated and de‐differentiated liposarcoma. Methods and results: This study reports a series of 30 biopsy samples from sites in or around the kidney collected from four institutions in which the correct diagnosis was either well‐differentiated or de‐differentiated liposarcoma. The majority (26 of 30, 87%) of lesions were accurately diagnosed on biopsy sampling, all of which incorporated testing for MDM2 by immunohistochemistry (IHC), fluorescence in‐situ hybridisation (FISH) or a combination of the two as part of the diagnostic work‐up. Tumour expression of MDM2 by IHC without confirmatory FISH analysis was sometimes (30%) sufficient to reach a diagnosis, but demonstration of MDM2 amplification by FISH was ascertained in the majority (57%) of biopsy samples. A diagnosis of de‐differentiated liposarcoma was not definitively established until resection in four (13%) patients, as no MDM2 testing was performed on the corresponding pre‐operative biopsies. Conclusions: When a retroperitoneal tumour is not clinically suspected, histological consideration of a liposarcoma diagnosis may be overlooked. Implementation of ancillary immunohistochemical and cytogenetic testing can ultimately lead to a definitive diagnosis in this potentially misleading anatomical location. [ABSTRACT FROM AUTHOR]

Strategies to control the risk domain of NHLBI EPR-3 (National Heart, Lung, and Blood Institute Expert Panel Report-3) asthma guidelines, which includes exacerbations requiring systemic corticosteroids, reduction in lung growth, and progressive loss of lung function, and treatment-related adverse effects, are evolving in children and adolescents. Increasing evidence demonstrates that children and adolescents with asthma are at risk of a reduction in lung growth, leading to lower lung function and potentially chronic obstructive pulmonary disease as adults. Readily available clinical biomarkers for atopy, including aeroallergen testing, total serum IgE, blood eosinophilia, and spirometry, are being utilized to phenotype difficult-to-treat pediatric patients, to assess risk for seasonal exacerbations, and to predict response to controller therapies. The Composite Asthma Severity Index is a novel, freely available scoring system to define asthma control, incorporating NHLBI EPR-3 risk and impairment domains. As new asthma controller therapies, such as tiotropium, are introduced for pediatric use, the safety of established controller therapies including inhaled corticosteroid and long-acting beta-agonist are being reexamined. Macrolide antibiotics may be an oral corticosteroid sparing alternative for the treatment of severe respiratory tract infection in preschool-aged children. Seasonally directed courses of omalizumab may provide an alternative approach to prevent fall asthma exacerbations in children. Combining these pharmaceuticals and biomarker-directed therapies provide potential new options and personalized approaches to gain asthma control in pediatric patients failing current management. [ABSTRACT FROM AUTHOR]

• Ag/Fe 2 O 3 /ZnO heterostructure was prepared via precipitation method. • 76.4% CPX was degraded with Ag/Fe 2 O 3 /ZnO after 210 min of solar illumination. • CPX degradation largely succeeded by defluorination, hydroxylation and cleavage of piperazine ring. • Heterostructure exhibited antibacterial characteristics against Escherichia coli. This paper reports on the multitasking potential of a silver/iron oxide/zinc oxide (Ag/Fe 2 O 3 /ZnO) heterostructure, which was used for the photocatalytic decomposition of ciprofloxacin (CPX) and bacterial disinfection. The Ag/Fe 2 O 3 /ZnO heterostructure was successfully prepared using a facile precipitation method, and characterization results showed interesting structural, morphological, compositional and luminescent properties. The morphological results of the prepared heterostructure confirmed the deposition of Ag nanoparticles onto the surface of ZnO nanoplates and Fe 2 O 3 nanorods. Treatment studies showed that the Ag/Fe 2 O 3 /ZnO heterostructure had superior solar light driven photocatalytic activity towards CPX degradation (76.4%) compared to bare Fe 2 O 3 nanorods (43.2%) and ZnO nanoplates (63.1%), Ag/Fe 2 O 3 (28.2%) and Ag/ZnO (64.5%) under optimized conditions (initial CPX concentration: 10 mg/L; pH 4; catalyst loading: 0.3 g/L). Reactive species study confirmed the roles of e−, h+, OH and O 2 − in the photocatalytic degradation process. This photocatalytic behaviour of the Ag/Fe 2 O 3 /ZnO heterostructure could be attributed to the improved full solar spectrum harvesting capacity, separation of charge carriers and migration of e−/h+ across the heterostructure interface. In addition, the Ag/Fe 2 O 3 /ZnO heterostructure also showed good antibacterial activity against Escherichia coli (E. coli) under both dark and visible light conditions. This might be due to generation of reactive oxygen species during the reaction. To the best of our knowledge, this is the first study till date on the utilization of Ag/Fe 2 O 3 /ZnO heterostructure for the photocatalytic degradation of CPX and E. coli bacteria disinfection. Therefore, this work offers an attractive path to design ZnO-based ternary heterostructures for solar-driven applications in wastewater remediation. [ABSTRACT FROM AUTHOR]

Since its 2010 discovery in southern Georgia, the bermudagrass stem maggot (BSM, Atherigona reversura Villenueve) has spread throughout the southeastern United States, damaging bermudagrass [Cynodon dactylon (L.) Pers.] hayfields and pastures. The objective of this research was to quantify the damage potential of the BSM in terms of forage accumulation, nutritive value, and economic returns from five bermudagrass varieties grown in Tifton, GA. The BSM significantly reduced accumulated forage only from late July to September in each year of this study. This would generally correspond to the third, fourth, and/or fifth harvest of the year for bermudagrass hay producers in the states of the Deep South. When BSM damage affected accumulated forage, crude protein increased while other nutritive value parameters decreased in plots not treated with insecticide. The results indicate that spraying prior to every harvest is not an economical management strategy. Instead, insecticide applications should only be made when significant forage loss is expected (generally from late July to September). Producers should create and implement a strategic integrated pest management plan to manage BSM populations on their farms to ensure positive economic returns and slow the potential resistance of the BSM to pyrethroids by preventing their overuse. [ABSTRACT FROM AUTHOR]

It is useful to have analytic expressions for important functions in the equations of state of materials. The Debye model has been quite successful in approximating the thermal energy properties of a variety of solids, but is nonanalytic. Existing approximations suffer from various shortcomings, the most common being lack of applicability over some temperature range. A new analytic and integrable functional form that closely approximates the Debye model for the heat capacity is presented. This form, based on the mean of two Einstein heat capacity functions with a low temperature correction, exhibits deviations from the Debye model smaller than typical experimental scatter in heat capacity data. [ABSTRACT FROM AUTHOR]

A multifidelity framework oriented toward efficient modeling of combustion dynamics that integrates a reduced-order model (ROM) for the combustion response into the Euler equations is proposed. The ROM is developed from computational fluid dynamics (CFD) simulations of a combusting flow that is periodically forced at the boundaries of a reduced domain. Galerkin's method is used to reduce the high-order partial differential equations to a low-order ordinary differential equation system via proper orthogonal decomposition eigenbases generated from a reduced-domain dataset. Evaluations of the framework are performed based on parametric studies of a simplified test problem for a model combustor showing distinguishable combustion instability behavior. Two-way information transfer between the ROM and Euler solutions is accomplished by interface matching at the boundaries of the reduced domain. It is shown that accurate predictions require the use of multiple ROMs to account for both upstream- and downstream-traveling perturbations. Characteristic boundary conditions are required at both reduced-domain boundaries to minimize wave reflections and preclude generic unstable responses in the multifidelity model predictions. Comparisons with CFD solutions show the multifidelity model is capable of capturing overall instability trends. [ABSTRACT FROM AUTHOR]

The Great Lakes and St. Lawrence binational region is one of the most significant concentrations of industrial production on earth and contains the most active corridors for goods movements in the Canada‐United States trade relationship. The history of industrial development in this region involves the exploitation of coal and iron ore for steel production, the development of the railroads and the expansion of commercial agriculture, and the growth of the automotive and other high value‐added manufacturing industries. Canadian and American industrial complexes became increasingly integrated with the support of trade agreements in the latter decades of the 20th century. Development of cross‐border supply chains led to massive international flows of intermediate goods. In this context, the performance of a few key border crossings is of critical economic importance. New information drawn from very large datasets of Global Positioning System records generated by cross‐border truck movements sheds new light on both the spatial patterns of cross‐border goods movement and the performance of border crossings. Key Messages: The history of industrial development in the Great Lakes and St. Lawrence region involves steel production, the development of railroads, and the expansion of key industries.Canada‐US trade agreements led to very large volumes of cross‐border trade at Great Lakes crossings, characterized by integrated cross‐border supply chains.GPS data from trucks provide a new opportunity to study the spatial patterns of Canada‐US trade and the performance of border crossings. [ABSTRACT FROM AUTHOR]

Napier grass (Pennisetum purpureum Schum.) is one of the highest-yielding feedstocks for bio-based products and biofuel in semi-tropical areas of the USA and the world. Thirty genetically diverse Napier grass accessions were selected from a germplasm nursery in Tifton, GA and analyzed for fiber, ash, nitrogen (N) concentration, and biochemical conversion to ethanol. A near-infrared reflectance spectroscopy (NIRS) calibration was developed from this material to predict ethanol production, xylans, N concentration, and ash by separating leaves and stems and correlating with wet chemistry analyses. The high diversity of material from dwarf material with high leaf and stem digestibility to taller and more productive Napier grass cultivars resulted in high correlations with predicted results for in vitro dry matter digestibility (2 = 0.93), neutral detergent fiber (r2 = 0.83), acid detergent fiber (r2 = 0.95), ethanol (r2 = 0.90), nitrogen (r2 = 0.99), and ash (r2 = 0.98). This information will allow faster evaluation of Napier grass biomass for use by industry or geneticists. [ABSTRACT FROM AUTHOR]

We have observed a strong two-photon absorption in the B 2Σ+←X 2Σ+(3,0) band of CN by means of a resonant enhancement through the A 2Πi, v’=4 level. Many lines are seen in the two-photon spectrum due to multiple single-photon near resonances in the A 2Πi←X 2Σ+(4,0) band. The detuning of the laser from these resonances varies from less than one to hundreds of wave numbers, producing unusually large intensity variations in the two-photon spectrum. This effect is not observed in two-photon transitions far from resonance. Resonant enhancement is observed over a range from N=5 to 20. We know of no other molecular two-photon transition in which a near resonance produces such dramatically varying intensities over a short range of rotational levels. A calculation of the line strengths for these transitions reproduces the major features of the spectrum. [ABSTRACT FROM AUTHOR]

Fluorescence in the A 2A1-X 2B1 system of the NH2 radical has been excited in NH3/N2O/N2, H2/N2O/N2, and CH4/N2O/N2 flames using the 6471 Å line of a krypton ion laser. Rotationally resolved fluorescence spectra indicate that the laser simultaneously pumps two rotational lines in the (0,11,0)–(0,2,0)∑ vibrational hot band of the radical. The placement of the laser line relative to the two molecular transitions has been inferred from intensities in the fluroescence spectrum. Rotational and vibrational energy transfer in the excited state were observed to be very slow in comparison to electronic quenching by the flame molecules. An NH2 density profile in a rich H2/N2O/N2 flame is given. Also, a method for the calculation of Einstein coefficients and oscillator strengths for nonperturbed, main-branch transitions is presented. [ABSTRACT FROM AUTHOR]

Laser induced fluorescence in the (0,0) band of the A 2Σ+–X 2π system of the PO radical (∼2470 Å) has been used to study the radiative properties of the A state. A laser excitation scan of the (0,0) band and a fluorescence scan of the emission are given. Fluorescence from the B 2Σ+ state to the X state was observed (∼3250 Å) when the A state was pumped by the laser. The branching ratio for emission from the A state to the lower B and X states was indirectly determined. The A state was found to have a very short free radiative lifetime, 9.68±0.47 ns. In the absence of quenching, the excited state decay is found to be primarily due to radiative processes. Upper limits were determined for the quenching rates of Ar and He carrier gases. Relative intensities of emission of the v’=0 progression in the A–X system were also measured. These intensities were used to determine the electronic transition moment function in the region of the equilibrium internuclear distance. [ABSTRACT FROM AUTHOR]

Pulsed laser excited fluorescence in the B 2Σ+ ← X 2π system of gas phase PO was used to measure the lifetime for v’=0 of the B state. Rotationally resolved measurements for a few selected J’ levels, at Ar or He carrier gas pressures of ∼2 Torr, reveal no dependence of the lifetime on the rotational level excited. Earlier measurements of relative fluorescence intensities in the v’=0 vibrational progression were reinterpreted to extract the dependence of the electronic transition moment on internuclear distance. Using this transition moment, no lifetime dependence on rotational level is to be expected, even at low pressures. Rate constants for quenching of the B state PO by N2, O2, CO2, and H2O, and upper limits thereof for He and Ar are reported. O2 was found to react with ground state PO. A crude measurement of the rate constant was performed. The result is compared to two other known measurements. The rate constant is in excellent agreement with the previous measurement, but in poor agreement with that of a concurrent study. Further work is required to determine the reason for the discrepancy. A cathode ray–vidicon type waveform digitizer was found to lend itself readily to the lifetime measurements, wherein a low repetition rate laser was used. Unfortunately, it was discovered that small nonlinearities (∼1% of full scale) in the digitizer response have a marked effect on the fits to the exponential lifetime decays and, especially, the quenching rate constants. We believe this problem is not commonly recognized. A simple method for calibration of this type of digitizer and removal of these effects is presented. [ABSTRACT FROM AUTHOR]

We develop fast and scalable methods for computing reduced-order nonlinear solutions (RONS). RONS was recently proposed as a framework for reduced-order modeling of time-dependent partial differential equations (PDEs), where the modes depend nonlinearly on a set of time-varying parameters. RONS uses a set of ordinary differential equations (ODEs) for the parameters to optimally evolve the shape of the modes to adapt to the PDE's solution. This method has already proven extremely effective in tackling challenging problems such as advection-dominated flows and high-dimensional PDEs. However, as the number of parameters grow, integrating the RONS equation and even its formation become computationally prohibitive. Here, we develop three separate methods to address these computational bottlenecks: symbolic RONS, collocation RONS and regularized RONS. We demonstrate the efficacy of these methods on two examples: Fokker–Planck equation in high dimensions and the Kuramoto–Sivashinsky equation. In both cases, we observe that the proposed methods lead to several orders of magnitude in speedup and accuracy. Our proposed methods extend the applicability of RONS beyond reduced-order modeling by making it possible to use RONS for accurate numerical solution of linear and nonlinear PDEs. Finally, as a special case of RONS, we discuss its application to problems where the PDE's solution is approximated by a neural network, with the time-dependent parameters being the weights and biases of the network. The RONS equations dictate the optimal evolution of the network's parameters without requiring any training. • Symbolic RONS uses symbolic computing to develop a scalable computational method for solving the RONS equations. • Collocation RONS introduces a collocation point approach to RONS. • Regularization of the RONS equations speeds up their time integration by addressing the stiffness issue. • Application to evolutional neural network is investigated and demonstrated on a numerical example. [ABSTRACT FROM AUTHOR]

Recent ground surveys in the Samtskhe-Javakheti region of southern Georgia have investigated a previously undocumented group of sites along a ridge overlooking the upper Kura river valley. Features and artefacts recorded at Varneti suggest long but episodic occupation from the Chalcolithic to the later medieval periods, with prominent phases in the Early to Middle Bronze Age and the Late Bronze Age to Early Iron Age. Varneti has the potential to contribute to understanding economic and strategic aspects of the long-term settlement pattern in the southern Caucasus, especially the interplay between lowland and highland zones. Its position in the landscape, at a transitional point between the river valley and the upland pasture (yayla), may explain its persistent use by agro-pastoral communities that operated in varied cultural situations. The survey results help us frame a series of questions regarding economic and social dynamics at a local and regional scale and the continuity and discontinuity of practice in highland environments through long timespans. [ABSTRACT FROM AUTHOR]

The article presents a prognostic roughness model for unresolved generations of turbulent flows in urban environments, taking into consideration an iterated function system, large-eddy simulation, the topography fractal dimension, and immersed-boundary methods.

Interest and focus on development of renewable biofuels has been increasing over the past decade leading to the introduction of a wide cadre of renewable feedstocks. As a result, numerous perennial warm-season grasses have been introduced and management practices evaluated to determine their suitability as biofuel feedstocks. “Merkeron” napier grass (Pennisetum purpureum) plots were established in 2010 and harvested during crop years 2011 through 2015 adjacent to an on-going peanut (Arachis hypogaea L.), corn (Zea mays L.), and cotton (Gossypium hirsutum L.) cropping systems study conducted at the USDA/ARS Multi-crop Irrigation Research Farm in Shellman, GA (84 36 W, 30 44 N) on a Greenville fine sandy loam (fine, kaolinitic, thermic Rhodic Kandiudults). Napier grass was produced in both non-irrigated and two irrigated levels with different levels of nitrogen and potassium fertilizers. Peanut, corn, and cotton were produced in non-irrigated and full irrigation regimes. Breakeven prices for napier grass ranged from $65 to $84 Mg−1 at variable and total costs. The breakeven napier grass price was estimated such that the net returns were equal between napier grass and peanut, cotton, corn cropping systems. At variable production cost, comparative breakeven napier grass prices for non-irrigated, 50% irrigated, and full irrigated regimes were $77, $117, and $112 Mg−1, respectively. Napier grass did not compete economically against traditional irrigated cropping systems. Depending on traditional crop prices and bioenergy feed stock prices, napier grass could offer economic opportunities in non-irrigated production environments, riparian buffer zone edges, or non-cropped marginal production areas. [ABSTRACT FROM AUTHOR]