Sequential multicomponent C-H bond addition is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. In this approach, C-H bonds are typically added ...across π-bonds or π-bond isosteres, followed by subsequent coupling to another type of functionality, thereby forming two -bonds in a single reaction sequence. Many sequential C-H bond addition reactions have been developed to date, including additions across both conjugated and isolated π-systems followed by coupling with reactants such as carbonyl compounds, cyanating reagents, aminating reagents, halogenating reagents, oxygenating reagents, and alkylating reagents. These atom-economical reactions transform ubiquitous C-H bonds under mild conditions to more complex structures with a high level of regiochemical and stereochemical control. Surprising connectivities and diverse mechanisms have been elucidated in the development of these reactions. Given the large number of possible combinations of coupling partners, there are enormous opportunities for the discovery of new sequential C-H bond addition reactions.
Sequential multicomponent C-H bond addition is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction.
A three-component method is described for the preparation of syn-1,2-disubstituted bridged bicyclic compounds. The reaction was demonstrated for readily available aromatic and heteroaromatic C–H bond ...substrates with tertiary and secondary amide, lactam, pyrazole, and triazole directing groups and a variety of bridged bicyclic alkenes, including norbornene, benzonorbornadiene, oxygen- and nitrogen-bridged analogs, and an unsaturated tropinone. A broad dioxazolone scope was also observed. The use of a chiral Cp-derived RhIII catalyst enables asymmetric synthesis of products.
Efficient syntheses of α-branched amines by three- and four-component C–H functionalization employing a diversifiable hydrazone directing group have been developed. The hydrazone in the α-branched ...amine products has been readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using diverse heterolytic chemistry and homolytic transition metal- or photoredox-catalyzed processes. This study represents the first example of a four-component C–H functionalization reaction.
1. This account presents information on all aspects of the biology of Ambrosia artemisiifolia L. (Common ragweed) that are relevant to understanding its ecology. The main topics are presented within ...the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, and history, conservation, impacts and management. 2. Ambrosia artemisiifolia is a monoecious, wind-pollinated, annual herb native to North America whose height varies from 10 cm to 2.5 m, according to environmental conditions. It has erect, branched stems and pinnately lobed leaves. Spike-like racemes of male capitula composed of staminate (male) florets terminate the stems, while cyme-like clusters of pistillate (female) florets are arranged in groups in the axils of main and lateral stem leaves. 3. Seeds require prolonged chilling to break dormancy. Following seedling emergence in spring, the rate of vegetative growth depends on temperature, but development occurs over a wide thermal range. In temperate European climates, male and female flowers are produced from summer to early autumn (July to October). 4. Ambrosia artemisiifolia is sensitive to freezing. Late spring frosts kill seedlings and the first autumn frosts terminate the growing season. It has a preference for dry soils of intermediate to rich nutrient level. 5. Ambrosia artemisiifolia was introduced into Europe with seed imports from North America in the 19th century. Since World War II, it has become widespread in temperate regions of Europe and is now abundant in open, disturbed habitats as a ruderal and agricultural weed. 6. Recently, the North American ragweed leaf beetle (Ophraella communa) has been detected in southern Switzerland and northern Italy. This species appears to have the capacity to substantially reduce growth and seed production of A. artemisiifolia. 7. In heavily infested regions of Europe, A. artemisiifolia causes substantial crop-yield losses and its copious, highly allergenic pollen creates considerable public health problems. There is a consensus among models that climate change will allow its northward and uphill spread in Europe.
A three-component method is described for the preparation of
-1,2-disubstituted bridged bicyclic compounds. The reaction was demonstrated for readily available aromatic and heteroaromatic C-H bond ...substrates with tertiary and secondary amide, lactam, pyrazole, and triazole directing groups and a variety of bridged bicyclic alkenes, including norbornene, benzonorbornadiene, oxygen- and nitrogen-bridged analogs, and an unsaturated tropinone. A broad dioxazolone scope was also observed. The use of a chiral Cp-derived Rh
catalyst enables asymmetric synthesis of products.
Most known methods to access δ-lactams with stereogenic centers at the α- and β-positions are highly selective for the contra-thermodynamic syn diastereomer, typically via hydrogenation of the ...corresponding pyridinones or quinolinones. We describe here the development of a photoredox-mediated hydrogen atom transfer approach for the epimerization of δ-lactams to access the more stable anti diastereomers from the contra-thermodynamic syn isomers. The reaction displays broad functional group compatibility, including acid, ester, 1°, 2°, and 3° amide, carbamate, and pyridyl groups, and was effective for a range of differently substituted monocyclic and bicyclic lactams. Experimentally observed diastereoselectivities are consistent with the calculated relative stabilities of lactam diastereomers. Convergence to the same diastereomer ratio from the syn- and anti-diastereomers establishes that reversible epimerization provides an equilibrium mixture of diastereomers. Additionally, deuterium labeling and luminescence quenching studies shed further light on the mechanism of the reaction.
Purpose
To facilitate surveillance and evaluate interventions addressing opioid‐related overdoses, algorithms are needed for use in large health care databases to identify and differentiate ...community‐occurring opioid‐related overdoses from inpatient‐occurring opioid‐related overdose/oversedation.
Methods
Data were from Kaiser Permanente Northwest (KPNW), a large integrated health plan. We iteratively developed and evaluated an algorithm for electronically identifying inpatient overdose/oversedation in KPNW hospitals from 1 January 2008 to 31 December 2014. Chart audits assessed accuracy; data sources included administrative and clinical records.
Results
The best‐performing algorithm used these rules: (1) Include events with opioids administered in an inpatient setting (including emergency department/urgent care) followed by naloxone administration within 275 hours of continuous inpatient stay; (2) exclude events with electroconvulsive therapy procedure codes; and (3) exclude events in which an opioid was administered prior to hospital discharge and followed by readmission with subsequent naloxone administration. Using this algorithm, we identified 870 suspect inpatient overdose/oversedation events and chart audited a random sample of 235. Of the random sample, 185 (78.7%) were deemed overdoses/oversedation, 37 (15.5%) were not, and 13 (5.5%) were possible cases. The number of hours between time of opioid and naloxone administration did not affect algorithm accuracy. When “possible” overdoses/oversedations were included with confirmed events, overall positive predictive value (PPV) was very good (PPV = 84.0%). Additionally, PPV was reasonable when evaluated specifically for hospital stays with emergency/urgent care admissions (PPV = 77.0%) and excellent for elective surgery admissions (PPV = 97.0%).
Conclusions
Algorithm performance was reasonable for identifying inpatient overdose/oversedation with best performance among elective surgery patients.
IMPROVING QPE AND VERY SHORT TERM QPF Vasiloff, Steven V.; Seo, Dong-Jun; Howard, Kenneth W. ...
Bulletin of the American Meteorological Society,
12/2007, Letnik:
88, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Accurate quantitative precipitation estimates (QPE) and very short term quantitative precipitation forecasts (VSTQPF) are critical to accurate monitoring and prediction of water-related hazards and ...water resources. While tremendous progress has been made in the last quarter-century in many areas of QPE and VSTQPF, significant gaps continue to exist in both knowledge and capabilities that are necessary to produce accurate high-resolution precipitation estimates at the national scale for a wide spectrum of users. Toward this goal, a national next-generation QPE and VSTQPF (Q2) workshop was held in Norman, Oklahoma, on 28–30 June 2005. Scientists, operational forecasters, water managers, and stakeholders from public and private sectors, including academia, presented and discussed a broad range of precipitation and forecasting topics and issues, and developed a list of science focus areas. To meet the nation's needs for the precipitation information effectively, the authors herein propose a community-wide integrated approach for precipitation information that fully capitalizes on recent advances in science and technology, and leverages the wide range of expertise and experience that exists in the research and operational communities. The concepts and recommendations from the workshop form the Q2 science plan and a suggested path to operations. Implementation of these concepts is expected to improve river forecasts and flood and flash flood watches and warnings, and to enhance various hydrologic and hydrometeorological services for a wide range of users and customers. In support of this initiative, the National Mosaic and Q2 (NMQ) system is being developed at the National Severe Storms Laboratory to serve as a community test bed for QPE and VSTQPF research and to facilitate the transition to operations of research applications. The NMQ system provides a real-time, around-the-clock data infusion and applications development and evaluation environment, and thus offers a community-wide platform for development and testing of advances in the focus areas.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody ...against the CGRP receptor, in patients with chronic migraine. Methods This was a phase 2, randomised, double-blind, placebo-controlled, multicentre study of erenumab for adults aged 18–65 years with chronic migraine, enrolled from 69 headache and clinical research centres in North America and Europe. Chronic migraine was defined as 15 or more headache days per month, of which eight or more were migraine days. Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, or erenumab 140 mg, given every 4 weeks for 12 weeks. Randomisation was centrally executed using an interactive voice or web response system. Patients, study investigators, and study sponsor personnel were masked to treatment assignment. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9–12). Safety endpoints were adverse events, clinical laboratory values, vital signs, and anti-erenumab antibodies. The efficacy analysis set included patients who received at least one dose of investigational product and completed at least one post-baseline monthly measurement. The safety analysis set included patients who received at least one dose of investigational product. The study is registered with ClinicalTrials.gov , number NCT02066415. Findings From April 3, 2014, to Dec 4, 2015, 667 patients were randomly assigned to receive placebo (n=286), erenumab 70 mg (n=191), or erenumab 140 mg (n=190). Erenumab 70 mg and 140 mg reduced monthly migraine days versus placebo (both doses −6·6 days vs placebo −4·2 days; difference −2·5, 95% CI −3·5 to −1·4, p<0·0001). Adverse events were reported in 110 (39%) of 282 patients, 83 (44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70 mg, and 140 mg groups, respectively. The most frequent adverse events were injection-site pain, upper respiratory tract infection, and nausea. Serious adverse events were reported by seven (2%), six (3%), and two (1%) patients, respectively; none were reported in more than one patient in any group or led to discontinuation. 11 patients in the 70 mg group and three in the 140 mg group had anti-erenumab binding antibodies; none had anti-erenumab neutralising antibodies. No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified. Of 667 patients randomly assigned to treatment, 637 completed treatment. Four withdrew because of adverse events, two each in the placebo and 140 mg groups. Interpretation In patients with chronic migraine, erenumab 70 mg and 140 mg reduced the number of monthly migraine days with a safety profile similar to placebo, providing evidence that erenumab could be a potential therapy for migraine prevention. Further research is needed to understand long-term efficacy and safety of erenumab, and the applicability of this study to real-world settings. Funding Amgen.
Background
Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is ...being evaluated for migraine prevention.
Methods
In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3.
Results
Patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% CI) treatment difference of −1.0 (−1.6, −0.5) (p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) (p = 0.010). Migraine-specific medication treatment days were reduced by −1.2 (erenumab) and −0.6 (placebo) days, a treatment difference of −0.6 (−1.0, −0.2) (p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary – Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) (p = 0.13) and in Migraine Physical Function Impact Diary – Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) (p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis.
Conclusions
As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen).
Trial registration
ClinicalTrials.gov, NCT02483585.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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