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The NOAA National Water Model (NWM) became operational in August 2016, producing the first ever real-time, distributed, continuous set of hydrologic forecasts over the continental United States (CONUS). This project uses integrated hydrometeorological assessment methods to investigate the utility of the NWM to predict catastrophic flooding associated with an extreme rainfall event that occurred in Ellicott City, Maryland, on 27–28 May 2018. Short-range forecasts (0–18-h lead time) from the NWM version 1.2 are explored, focusing on the quantitative precipitation forecast (QPF) forcing from the High-Resolution Rapid Refresh (HRRR) model and the corresponding NWM streamflow forecast. A comprehensive assessment of multiscale hydrometeorological processes are considered using a combination of object-based, grid-based, and hydrologic point-based verification. Results highlight the benefits and risks of using a distributed hydrologic modeling tool such as the NWM to connect operational CONUS-scale atmospheric forcings to local impact predictions. For the Ellicott City event, reasonably skillful QPF in several HRRR model forecast cycles produced NWM streamflow forecasts in the small Ellicott City basin that were suggestive of flash flood potential. In larger surrounding basins, the NWM streamflow response was more complex, and errors were found to be governed by both hydrologic process representation, as well as forcing errors. The integrated, hydrometeorological multiscale analysis method demonstrated here guides both research and ongoing model development efforts, along with providing user education and engagement to ultimately engender improved flash flood prediction.

The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients.

Objectives: Radiographers are key patient-facing healthcare professionals involved in many aspects of patient care. The working patterns and professional practice of the radiography workforce (RW) has been altered during the COVID-19 pandemic. This survey aimed to assess the impact of the pandemic on radiography practice in the United Kingdom (UK). Methods: An online cross-sectional survey of the UK RW was performed (March 25th to April 26th, 2020). The survey sought information regarding 1. Demographics 2. Impact of the pandemic on professional practice 3. Infection prevention/control and 4. COVID-19 related stress. Data collected was analysed using the Statistical Package for Social Sciences (v.26). Results: A total of 522 responses were received, comprising n = 412 (78.9%) diagnostic and n = 110 (21.1%) therapeutic RW categories from across the UK. 12.5% (65/522) of the respondents were redeployed. Redeployment did not appear to contribute (p = 0.31) to work-related stress. However, fear of contracting the infection and perceived inadequate personal protective equipment (PPE) were identified as key contributors to stress during the study period. Compared to the therapeutic RW, a significantly higher proportion of the diagnostic RW identified fear of being infected as a major stressor (166/412 (40.3%) vs 30/110 (27.3%), p = 0.01). Conclusion: This survey has demonstrated changes to clinical practice, in particular to working patterns, service delivery and infection prevention and control were key contributors to workplace-related stress during the pandemic. Advances in knowledge: Timely and adequate staff training and availability of PPE as well as psychosocial support during future pandemics would enhance quality patient and staff safety.

When extreme river levels are possible in a community, effective communication of weather and hydrologic forecasts is critical to protecting life and property. Residents, emergency personnel, and water resource managers need to make timely decisions about how and when to prepare. Uncertainty in forecasting is a critical component of this decision-making, but often poses a confounding factor for public and professional understanding of forecast products. A new suite of products from the National Weather Service’s Hydrologic Ensemble Forecast System (HEFS) provides short- and long-range forecasts, ranging from 6 h to 1 yr, and shows uncertainty in hydrologic forecasts. To understand how various audiences use and interpret ensemble forecasts showing a range of hydrologic forecast possibilities, a research project was conducted using scenario-based focus groups and surveys with community residents, emergency managers, and water resource managers in West Virginia and Maryland. The research assessed the utility of the HEFS products, identified barriers to proper understanding of the products, and suggested modifications to product design that could improve the understandability and accessibility for a range of users. There was a difference between the residential users’ reactions to the HEFS compared to the emergency managers and water resource managers, with the public reacting less favorably to all versions. The emergency managers preferred the revised HEFS products but had suggestions for additional changes, which were incorporated. Features such as interactive text boxes and forecaster’s notes further enhanced the utility and understandability of the products.

A noninvasive topical ocular therapy for the treatment of neovascular or “wet” age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.

Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures.

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.

The bicyclo[7.3.0]dodecadiyne core structure of the antitumor agents neocarzinostatin, kedarcidin, C-1027 and maduropeptin can be readily constructed by an intramolecular aldol reaction to form the C -8 C -9 bond only if the C-6,7 triple bond is complexed as its η 2 Co 2 (CO) 6 -acetylene adduct.

The advent of readily accessible, inexpensive Web-conferencing applications has opened the door for distance psychotherapy supervision, using video recordings of treated clients. Although relatively new, this method of supervision is advantageous given the ease of use and low cost of various Internet applications. This method allows periodic supervision from point to point around the world, with no travel costs and no long gaps between direct training contacts. Web-conferencing permits face-to-face training so that the learner and supervisor can read each other’s emotional responses while reviewing case material. It allows group learning from direct supervision to complement local peer-to-peer learning methods. In this article, we describe the relevant literature on this type of learning method, the practical points in its utilization, its limitations, and its benefits.

The bicyclo[7.3.0]dodecadiyne core structure of the antitumor agents neocarzinostatin, kedarcidin, C-1027 and maduropeptin can be readily constructed by an intramolecular aldol reaction to form the C -8 C -9 bond only if the C-6,7 triple bond is complexed as its η 2 Co 2 (CO) 6 -acetylene adduct.

Objective – To describe the patient population, disease severity, and outcome in dogs with immune-mediated hemolytic anemia (IMHA) that underwent splenectomy. To compare presurgical and postsurgical data. Design – Retrospective case series. Setting – Emergency clinic/referral hospital. Animals – Ten dogs diagnosed with IMHA. Interventions – Splenectomy in addition to standard medical management for IMHA. Measurements – Medical records of 10 dogs with IMHA, in which a splenectomy was performed were reviewed. The population was analyzed with regards to physical and clinicopathologic data, severity, treatment, and outcome. Outcome was defined as survival at 30 days, percentage of dogs on medications at 30 days, and number of relapses documented by 30 days. The presurgical and postsurgical PCV and transfusion requirements were documented and compared for each dog. Results – Nine of 10 dogs survived to 30 days. Four of the 9 that survived were not on any immunosuppressive medications. There were no relapses during the 30 days. The 3-day postsplenectomy PCVs were significantly higher than presplenectomy. The number of transfusions administered postsplenectomy was significantly less than those administered presplenectomy. Conclusion – The use of splenectomy may be associated with an improved outcome in dogs with IMHA.

AquaMOOSE 3D is a multi-user, graphical, constructionist environment to help children learn about mathematics and computer programming. In this paper, we present the system design, and results from our first round of formative evaluation.

Allylic rearrangement of substitued 2-hydroxyalk-3-en-1-yl(diphenyl)phosphine oxides to 4-hydroxyalk-2-en-1-yl(diphenyl)phosphine oxides can be performed with total regio- and reasonable stereochemical control. Alternatively, the reduction of substituted 4-diphenylphosphinoylbut-2-en-1 -ones shows remarkable 1,4-diastereoselectivity. All these reactions are directed by the diphenylphosphinoyl (Ph2PO) group.

2,5-Dimethylhex-4-en-3-one, E-6-methylhept-2-en-4-one, E-7-methyloct-4-en-3-one, ar-turmerone, and E-7-oxo-act-5-enoic acid were synthesized regiospecifically viaα-phenylthio ketones from bisphenylthio carbanions and aldehydes.

Reduction of ketones having an α-dibenzophosphoie-5-oxide group witin NaBH4, L-Selectride, or Superhydride gives threo Horner-Wittig intermediates and hence E -alkenes, while NaBH4/CeCl3 gives erythro intermediates and hence Z -alkenes.

Enones not available from aldol condensations may be synthesised regio-specifically via α-(phenylthio)ketones: the title compounds have been made by this route.

Reduction of α′-diphenylphosphinoyl enones (6) and crowded α-diphenylphosphinoyl ketones (4) with sodium borohydride in the presence of cerium chloride gives the otherwise difficult to obtain erythro -alcohols (5) and (7).

Fragmentation of the tetracyclic amine (5), initiated by a chloroformate to give the putative iminium ion (6) in the presence of an aromatic nucleophile, provides convenient access to model bis-alkaloids such as (7)–(15).