One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic ß-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic ß-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the ß-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

NCI Imaging Data Commons.

The National Cancer Institute (NCI) Cancer Research Data Commons (CRDC) aims to establish a national cloud-based data science infrastructure. Imaging Data Commons (IDC) is a new component of CRDC supported by the Cancer Moonshot. The goal of IDC is to enable a broad spectrum of cancer researchers, with and without imaging expertise, to easily access and explore the value of deidentified imaging data and to support integrated analyses with nonimaging data. We achieve this goal by colocating versatile imaging collections with cloud-based computing resources and data exploration, visualization, and analysis tools. The IDC pilot was released in October 2020 and is being continuously populated with radiology and histopathology collections. IDC provides access to curated imaging collections, accompanied by documentation, a user forum, and a growing number of analysis use cases that aim to demonstrate the value of a data commons framework applied to cancer imaging research. SIGNIFICANCE: This study introduces NCI Imaging Data Commons, a new repository of the NCI Cancer Research Data Commons, which will support cancer imaging research on the cloud.

Health-based ingestion exposure guidelines for Vibrio cholerae: Technical basis for water reuse applications.

U.S. military and allied contingency operations are increasingly occurring in locations with limited, unstable or compromised fresh water supplies. Non-potable graywater reuse is currently under assessment as a viable means to increase mission sustainability while significantly reducing the resources, logistics and attack vulnerabilities posed by transport of fresh water. Development of health-based (non-potable) exposure guidelines for the potential microbial components of graywater would provide a logical and consistent human-health basis for water reuse strategies. Such health-based strategies will support not only improved water security for contingency operations, but also sustainable military operations. Dose-response assessment of Vibrio cholerae based on adult human oral exposure data were coupled with operational water exposure scenario parameters common to numerous military activities, and then used to derive health risk-based water concentrations. The microbial risk assessment approach utilized oral human exposure V. cholerae dose studies in open literature. Selected studies focused on gastrointestinal illness associated with experimental infection by specific V. cholerae serogroups most often associated with epidemics and pandemics (O1 and O139). Nonlinear dose-response model analyses estimated V. cholerae effective doses (EDs) aligned with gastrointestinal illness severity categories characterized by diarrheal purge volume. The EDs and water exposure assumptions were used to derive Risk-Based Water Concentrations (CFU/100mL) for mission-critical illness severity levels over a range of water use activities common to military operations. Human dose-response studies, data and analyses indicate that ingestion exposures at the estimated ED1 (50CFU) are unlikely to be associated with diarrheal illness while ingestion exposures at the lower limit (200CFU) of the estimated ED10 are not expected to result in a level of diarrheal illness associated with degraded individual capability. The current analysis indicates that the estimated ED20 (approximately 1000CFU) represents initiation of a more advanced stage of diarrheal illness associated with clinical care.

Microbial inhibitors of the fungus Pseudogymnoascus destructans, the causal agent of white-nose syndrome in bats.

Pseudogymnoascus destructans, the fungus that causes white-nose syndrome in hibernating bats, has spread across eastern North America over the past decade and decimated bat populations. The saprotrophic growth of P. destructans may help to perpetuate the white-nose syndrome epidemic, and recent model predictions suggest that sufficiently reducing the environmental growth of P. destructans could help mitigate or prevent white-nose syndrome-associated bat colony collapse. In this study, we screened 301 microbes from diverse environmental samples for their ability to inhibit the growth of P. destructans. We identified 145 antagonistic isolates, 53 of which completely or nearly completely inhibited the growth of P. destructans in co-culture. Further analysis of our best antagonists indicated that these microbes have different modes of action and may have some specificity in inhibiting P. destructans. The results suggest that naturally-occurring microbes and/or their metabolites may be considered further as candidates to ameliorate bat colony collapse due to P. destructans.

Total CAD/CAM Supported Method for Manufacturing Removable Complete Dentures.

The incorporation of computer-aided design/computer-aided manufacturing (CAD/CAM) technology into complete denture fabrication brings about several advantages to the fabrication process, providing better predictability of the desired outcomes and high accuracy of denture fit, mainly because the milling of prepolymerized acrylic resin eliminates the shrinkage of the acrylic base. Also, there is a decrease in the porosity when compared to a conventionally processed denture, and consequently there is a decrease in the retention of Candida albicans on the denture base. The presented workflow for complete denture fabrication presents a totally wax-free manufacturing process, combining rapid prototyping (RP) and rapid milling. With the presented technique, the maxillomandibular relation (MMR) and the ideal setup of the tooth arrangement are developed by using occlusion rims and trial setup made with RP. For the definitive final denture, the denture base and the basal surfaces of the conventional denture teeth were milled according to the individual clinical situation. Posteriorly, the teeth were adapted and bonded into the milled sockets of the milled base.

Evaluation of the safety and tolerability of rivaroxaban in dogs with presumed primary immune-mediated hemolytic anemia.

OBJECTIVE: To evaluate the safety and tolerability of rivaroxaban (RIV), an oral direct factor Xa inhibitory drug, in dogs with presumed primary immune-mediated hemolytic anemia (pIMHA). DESIGN: Prospective, multicenter, positive-controlled, unblinded clinical trial. Client-owned dogs were enrolled between October 2012 and March 2014. SETTING: Private referral centers. ANIMALS: Twenty-four client-owned dogs with pIMHA. Enrolled dogs were randomized in 2 treatment groups to receive by mouth RIV or clopidogrel (CL) and low-dose aspirin (LDA). All dogs were monitored for 90 days from the enrollment in the study. INTERVENTIONS: Enrolled dogs were given a standardized immunosuppressive protocol and RIV or CL and LDA. MEASUREMENTS AND MAIN RESULTS: There was no identifiable adverse drug reaction, evidence of hemorrhage, significant prolongation of prothrombin time or activated partial thromboplastin time, or increase in transfusion requirements associated with RIV therapy compared to CL and LDA in dogs with pIMHA. There was no significant difference between treatment groups with respect to thrombotic events, survival rates to discharge, at 1 month and 3 months from diagnosis. CONCLUSIONS: This study suggests that RIV at a median dose of 0.89 mg/kg by mouth once daily was safe and well tolerated in a small group of dogs with presumed pIMHA able to tolerate oral medications and treated with a standardized immunosuppressive treatment protocol. Conclusions regarding the relative efficacy of RIV as compared to CL and LDA cannot be made due to the small size of the treatment groups and because pharmacodynamic effects were not assessed.

Treatment of the edentulous patient.

For decades the edentulous population has been unrecognized in its need to be treated in an effective manner. The debilitating condition affects quality of life. Implants have provided a strategy for developing a standard of care. The McGill consensus statement provided evidence that 2 implants supporting a mandibular overdenture should be the first choice in the treatment of edentulism. Success in implementing this standard of care into an institution's curriculum depends on a close collaboration between the surgeon and the restoring dentist and an understanding of biomechanics and bone biology.

CANDO and the infinite drug discovery frontier.

The Computational Analysis of Novel Drug Opportunities (CANDO) platform (http://protinfo.org/cando) uses similarity of compound-proteome interaction signatures to infer homology of compound/drug behavior. We constructed interaction signatures for 3733 human ingestible compounds covering 48,278 protein structures mapping to 2030 indications based on basic science methodologies to predict and analyze protein structure, function, and interactions developed by us and others. Our signature comparison and ranking approach yielded benchmarking accuracies of 12-25% for 1439 indications with at least two approved compounds. We prospectively validated 49/82 'high value' predictions from nine studies covering seven indications, with comparable or better activity to existing drugs, which serve as novel repurposed therapeutics. Our approach may be generalized to compounds beyond those approved by the FDA, and can also consider mutations in protein structures to enable personalization. Our platform provides a holistic multiscale modeling framework of complex atomic, molecular, and physiological systems with broader applications in medicine and engineering.

Distal effect of amino acid substitutions in CYP2C9 polymorphic variants causes differences in interatomic interactions against (S)-warfarin.

Cytochrome P450 2C9 (CYP2C9) is crucial in excretion of commonly prescribed drugs. However, changes in metabolic activity caused by CYP2C9 polymorphisms inevitably result in adverse drug effects. CYP2C9*2 and *3 are prevalent in Caucasian populations whereas CYP2C9*13 is remarkable in Asian populations. Single amino acid substitutions caused by these mutations are located outside catalytic cavity but affect kinetic activities of mutants compared to wild-type enzyme. To relate distal effects of these mutations and defective drug metabolisms, simulations of CYP2C9 binding to anti-coagulant (S)-warfarin were performed as a system model. Representative (S)-warfarin-bound forms of wild-type and mutants were sorted and assessed through knowledge-based scoring function. Interatomic interactions towards (S)-warfarin were predicted to be less favorable in mutant structures in correlation with larger distance between hydroxylation site of (S)-warfarin and reactive oxyferryl heme than wild-type structure. Using computational approach could delineate complication of CYP polymorphism in management of drug therapy.

Mechanisms of injury and emergency care of acute spinal cord injury in dogs and cats.

OBJECTIVES: To review the literature in regards to the pathophysiology of acute spinal cord injury, and to describe current concepts in regards to patient assessment, diagnostic, and therapeutic measures with a special emphasis on emergency and critical care considerations. ETIOLOGY: Acute spinal cord injury occurs in 2 phases. The primary injury occurs at the time of initial injury and may include intervertebral disk herniation, vertebral fracture or luxation, penetrating injury, and vascular anomalies such as fibrocartilaginous embolic myelopathy. Secondary injury occurs following primary injury and is multifactorial encompassing numerous biochemical and vascular events that result in progression of injury. DIAGNOSIS: The diagnosis is based on history and physical examination findings. A neurologic examination should be performed following initial patient assessment and stabilization. Further diagnostics to characterize acute spinal injury include radiographs and advanced imaging modalities such as myelography, computed tomography, or magnetic resonance imaging. THERAPY: Initial treatment should focus on addressing the patient's cardiovascular and respiratory system. Supportive measures to support systemic perfusion are vital to minimizing secondary injury. Specific therapy toward minimizing secondary injury in veterinary medicine remains controversial, especially in regards to the utilization of methylprednisolone. Other therapies are either in need of additional research or have failed to document clinical difference. PROGNOSIS: The prognosis for acute spinal injury is varied and is dependent upon the presence of concurrent trauma, location, and type of primary injury sustained, and extent of neurologic impairment at the time of initial presentation. The etiology of the underlying trauma is of great importance in determining prognosis and outcome. Loss of deep pain is generally accepted as a poor prognostic indicator; however, even these patients can recover depending on their response to treatment.

Flapless CAD/CAM-guided surgery for staged transition from failing dentition to complete arch implant rehabilitation: a 3-year clinical report.

The transition of patients from failing dentition to complete arch implant rehabilitation often requires that the patient be rendered edentulous and has to wear a complete removable dental prosthesis for varying periods of time. This is objectionable to many patients. A staged treatment approach allows a fixed interim restoration, patient comfort, and prosthodontic control throughout the rehabilitation process. CAD/CAM-guided flapless implant surgery has the advantage of prosthetically driven implant placement and minimal postoperative sequelae. A patient with a failing dentition was treated with this combined protocol and was followed up for 3 years after loading. Implant and prosthesis survival rates were 100%, with no technical complications encountered up to the last recall. The purpose of this clinical report is to describe a combination of CAD/CAM-guided flapless surgery and a staged treatment approach, thereby giving the patient a tooth-supported or implant-supported fixed interim prosthesis during the entire rehabilitation process. The various surgical, laboratory, and prosthetic stages are illustrated for the complete arch prosthetic rehabilitation, and the 3-year follow-up outcome is reported.

Accuracy of implant casts generated with splinted and non-splinted impression techniques for edentulous patients: an optical scanning study.

BACKGROUND: The accuracy of implant casts generated with various impression techniques was mainly investigated in vitro resulting in limited clinical data. PURPOSE: (1) To compare the three-dimensional (3-D) accuracy of splinted and non-splinted impression techniques to the control casts (verification jigs) that had been used for actual patient treatment; and (2) to determine the maximum level of clinically undetectable misfit. The null hypothesis was that there would be no significant difference in the accuracy of casts generated with different impression techniques. MATERIALS AND METHODS: The implant casts used for the prosthetic rehabilitation of 12 edentulous jaws with CAD/CAM zirconia, implant-fixed complete dental prosthesis (IFCDP) were included in this study. Intraoral acrylic jigs were used to fabricate index casts. Splinted and non-splinted, open-tray techniques were used to generate two casts. Optical scanning acquisition of the x-coordinates, y-coordinates and z-coordinates of the implant positions for each individual cast was performed. The "best fit" algorithm was used with computer software to superimpose the scanning datasets. Group I (n=12) included casts from the splinted impression technique vs. acrylic jig casts, and group II (n=12) included casts from non-splinted technique vs. jig casts. RESULTS: The paired t-test and Wilcoxon's signed ranks test were used to compare the 3-D discrepancies within and between groups I (splinted vs. jig) and II (non-splinted vs. jig), respectively. Significant difference was found at the x-axis, y-axis and 3-D between groups I and II (P<0.05), but not in the vertical z-axis (P>0.05). Within subject, global 3-D discrepancies between groups I and II were significantly different (P<0.05), corroborated by in vivo observations of clinical fit. Implant position in the arch affected the 3-D accuracy of casts for both anterior and posterior implants (P<0.05). CONCLUSION: The splinted technique generated more accurate master casts than the non-splinted technique for one-piece IFCDPs in edentulous jaws and the null hypothesis was rejected. These clinical implications demonstrate improved accuracy of splinted impression techniques compared with the non-splinted technique. For the external connection, the implant system used in this study, a 3-D misfit ranging from 59 to 72 µm, may be considered the maximum discrepancy resulting in an acceptable clinical fit with one-piece IFCDPs.

Effect of splinted and nonsplinted impression techniques on the accuracy of fit of fixed implant prostheses in edentulous patients: a comparative study.

PURPOSE: The effect of different implant impression techniques on the accuracy of casts has been investigated mostly in vitro, and clinically relevant evidence is scarce. The purpose of this study was to investigate the effect of implant impression techniques--specifically, splinted versus nonsplinted--on the accuracy of fit of fixed implant prostheses in edentulous patients. MATERIALS AND METHODS: This clinical study included 12 edentulous patients (13 edentulous arches). All patients had undergone computer-guided, prosthetically driven implant surgery. Splinted (with acrylic resin) and nonsplinted pickup implant impression techniques were used to generate two different casts. Intraoral verification jigs were made to fabricate a third index cast (prosthesis fabrication cast); these made up a control group. All patients were definitively rehabilitated with one-piece zirconia prostheses. The accuracy of fit of each prosthesis was evaluated indirectly by examining them clinically and radiographically while they were fit on the generated casts. RESULTS: Of the 13 splinted casts, 12 presented with accurate clinical fit when the zirconia prosthesis was seated on its respective cast. Only 6 of the 13 nonsplinted casts showed accurate clinical fit. The zirconia prostheses fit accurately on all respective casts of the control group (prosthesis fabrication cast) as well as intraorally. The differences between the test groups and between the nonsplinted and control groups were statistically significant. No statistically significant differences were found between the splinted and control groups. CONCLUSION: There is clinical evidence that the splinted impression technique generates more accurate implant impressions and master casts than the nonsplinted technique for complete-arch, one-piece fixed prostheses.

Adapting military field water supplies to the asymmetric battlefield.

Army transformation to a brigade-centric force has created a distributed battlefield, challenging the surveillance and logistical supply of field water. The daily requirement of up to 15 gal of potable water per person per day from bulk water supplies has been achievable for many years using currently fielded ROWPUs. However, the need to reduce the transport of water and move towards a sustainable force has created a gap in materiel capable of producing safe water at the individual and unit level. While materiel development is slow, the PM community, tasked with doctrine development and battlefield oversight of field water, is beginning to address the requirements of field water on the changed battlefield. In addition to materiel gaps, the transformed battlefield has created a lack of trained personnel for water production and oversight. Without trained operators and PM oversight, to what level of health risk are consumers of this water exposing themselves? Currently PM is unable to answer this question but is working diligently with the RDT&E community to develop materiel solutions, and with the medical community to provide interim guidance to reduce the potential health risks to using such equipment.

Standardized ultrasound protocol, trained sonographers and digital system for carotid atherosclerosis screening.

BACKGROUND AND PURPOSE: Carotid intima-media thickness (IMT), a valid measure of atherosclerotic disease, has been proposed to be included in the algorithms for cardiovascular risk stratification. However, assessment of carotid IMT is still not easily performed in an office setting. In the present study, we evaluated the reproducibility of a standardized protocol for carotid artery atherosclerosis screening. METHODS: Carotid arteries of 30 patients were scanned twice (interval 1-10 days) by six trained sonographers, using portable ultrasound systems. A screening protocol was adapted from methods used in clinical trials in which carotid IMT was the primary outcome measure. To test the reproducibility of the method, variability between the two scans was analyzed. RESULTS: A high level of agreement was found between the scans for measurement of mean common carotid IMT [mean difference S0.002, 95% confidence interval (CI) S0.011 to 0.006, PU0.435], maximum region common carotid IMT (mean difference S0.002, 95% CIS0.017 to 0.014, PU0.779) and mean maximum IMT including the common, bifurcation and internal carotid arteries (mean differences 0.021, 95% CI S0.006 to 0.047, PU0.166). No significant differences were found between scans with regard to the average number of carotid segments visualized, the number of atherosclerotic plaques or plaque burden. CONCLUSION: Reliable IMT measurements can be obtained using a standardized protocol performed by trained sonographers using a digital portable ultrasound system in an office setting.

Elevation of alanine transaminase and gallbladder wall abnormalities as biomarkers of anaphylaxis in canine hypersensitivity patients.

OBJECTIVE: The purpose of the study was to evaluate alanine transaminase (ALT) and gallbladder wall abnormalities as possible biomarkers for anaphylaxis in dogs presented for acute hypersensitivity reactions. DESIGN: Pilot study. SETTING: A private practice, small animal, 24-hour emergency and specialty hospital. ANIMALS: Ninety-six dogs presenting 101 times on an emergency basis for hypersensitivity reactions from March 2007 through March 2009. INTERVENTIONS: Veterinarians acquired a history, physical exam, serum chemistry panel, blood pressure, and ultrasound image of the gallbladder. MEASUREMENTS AND MAIN RESULTS: Dogs were then divided into 2 groups: dogs fulfilling the definition for anaphylaxis (moderate and severe systemic hypersensitivity) and dogs that did not fulfill the definition and were classified as allergic reactions (local hypersensitivity and mild systemic hypersensitivity). Elevated ALT was significantly associated with anaphylaxis (P<0.001). Increased gallbladder wall thickness and a striated wall pattern were significantly associated with anaphylaxis (P<0.001) and these changes were readily apparent to first-responder veterinarians. Decreased body temperature (P<0.001) and hypothermia (P=0.006) were significantly associated with anaphylaxis. There was no significant difference between groups regarding age, heart rate, or presence of respiratory signs. Lower blood pressure was significantly associated with anaphylaxis (P<0.001) but hypotension was not significantly different (P=0.09) between groups. Cutaneous signs were significantly associated with the allergic reactions group (P<0.001) and, when seen with anaphylaxis, were subtle. CONCLUSIONS: This study showed an elevated ALT and an abnormal gallbladder wall to be biomarkers significantly associated with anaphylaxis in dogs with acute hypersensitivity reactions.

The role of tissue factor and tissue factor pathway inhibitor in health and disease states.

OBJECTIVE: To review the veterinary and human literature on the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in health and disease states. DATA SOURCES: Original research articles and scientific reviews from both human and veterinary literature were searched for relevance to TF and TFPI. HUMAN DATA SYNTHESIS: Interest in both TF and TFPI has grown widely over the last several years. The impact TF plays in coagulation, inflammation, angiogenesis, tumor metastasis, and cellular signaling has become apparent. Treatment with TFPI for severe sepsis has been examined and is still currently under investigation. Inhibition of the TF pathway is being studied as an aid in the treatment of neoplasia. The important physiologic and pathophysiologic role these molecules play has only begun to be understood. VETERINARY DATA SYNTHESIS: There is a paucity of publications that discuss the importance of TF and TFPI in veterinary medicine. An enhanced understanding of the TF pathway in human medicine, in experimental animal models treating sepsis with TFPI, and in animal models demonstrating the proangiogenic properties of TF provides relevance to veterinary medicine. CONCLUSION: It is apparent that TF and TFPI are important in health and disease. An enhanced understanding of the physiologic and pathophysiologic roles of these factors provides better insight into coagulation, inflammation, angiogenesis, disseminated intravascular coagulation, and tumor metastasis. This greater understanding may provide for the development of therapeutics for sepsis, disseminated intravascular coagulation, and neoplasia.

In vitro fertilization availability and utilization in the United States: a study of demographic, social, and economic factors.

OBJECTIVE: To characterize the demographic correlates of IVF availability and utilization. DESIGN: Demographic analysis of public data. SETTING: Each of the 50 states in the United States was used as a unit of analysis. PATIENT(S): Patients undergoing IVF, as demographically estimated. INTERVENTION(S): Publicly available data were collected through the Society for Assisted Reproductive Technology and the Centers for Disease Control. The US Census Bureau data were collected by using software available from the Centers for Disease Control. MAIN OUTCOME MEASURE(S): The number of physicians performing IVF and the number of IVF cycles per 100,000 reproductive-age women were used to estimate IVF availability and utilization. RESULT(S): In 2005, 1,031 providers performed 98,242 fresh IVF cycles in 430 centers. Overall availability was 2.5 IVF physicians per 100,000, and utilization was 236 IVF cycles per 100,000. Availability and utilization of IVF were highly correlated. Mean IVF availability and utilization were significantly higher in states with IVF insurance coverage. In adjusted analyses, IVF availability correlated positively with mandated insurance coverage, percentage of single persons, and median income. Utilization of IVF correlated with IVF availability, percentage urbanization, and percentage of individuals >or=25 years of age who had a bachelor's degree. CONCLUSION(S): Lower rates of IVF utilization in some states are correlated with a lack of insurance coverage and decreased availability of physicians providing this service.

Principals' attitudes regarding inclusion of children with autism in Pennsylvania public schools.

This study sought to identify the attitudes that principals held regarding the inclusion of students with disabilities, and the relationship between their attitudes and their placement recommendations for children with autism and to identify the relationship between specific demographic factors and attitudes toward inclusion and placement. A stratified random sample was drawn from the active list of 3,070 principals in the Pennsylvania public schools. From 1,500 surveys, 571 principal responses were received. The most significant factor in predicting both a positive attitude toward inclusion of children with disabilities and higher recommendations of placements for children with autism was the principal's belief that children with autism could be included in a regular education classroom.