Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation.

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

2,6-Bis(pyrazol-1-yl)pyridine (1-bpp) as a General Ligand for the Negishi Alkylation of Alkylpyridinium Salts.

A Ni/1-bpp catalyst was demonstrated to be effective in the Negishi alkylation with multiple classes of alkylpyridinium salts, including α-primary and α-secondary. These conditions are also effective for benzylic pyridinium salts, demonstrating the successful Negishi alkylation of benzylic pyridinium salts for the first time. Further, 14 derivatives of 1-bpp were prepared with a variety of steric and electronic properties to study how these changes impact the success of the Negishi alkylation.

Canadian Association of Radiologists Musculoskeletal System Diagnostic Imaging Referral Guideline.

The Canadian Association of Radiologists (CAR) Musculoskeletal System Expert Panel consists of musculoskeletal radiologists, a family physician, a sports and exercise medicine physician, emergency medicine physicians, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 25 musculoskeletal clinical/diagnostic scenarios, a systematic rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for 1 or more of these clinical/diagnostic scenarios. Recommendations from 41 guidelines (50 publications) and contextualization criteria in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for guidelines framework were used to develop 124 recommendation statements across the 25 scenarios related to the evaluation of the musculoskeletal system. This guideline presents the methods of development and the recommendations for imaging in the context of musculoskeletal pain, infection, tumors, arthropathies, metabolic bone disease, stress injuries, orthopedic hardware, avascular necrosis/bone infarction, and complex regional pain syndrome.

Overcoming the Naphthyl Requirement in Stereospecific Cross-Couplings to Form Quaternary Stereocenters.

The use of a simple stilbene ligand has enabled a stereospecific Suzuki-Miyaura cross-coupling of tertiary benzylic carboxylates, including those lacking naphthyl substituents. This method installs challenging all-carbon diaryl quaternary stereocenters in good yield and ee and represents an important breakthrough in the "naphthyl requirement" that pervades stereospecific cross-couplings involving enantioenriched electrophiles.

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids.

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N-alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2-pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative Alkyl-Alkyl Cross-Couplings.

A Negishi cross-coupling of alkylpyridinium salts and alkylzinc halides has been developed. This is the first example of alkyl-alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkylpyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the noncanonical transformation of NH2 groups into a wide range of alkyl substituents with broad functional group tolerance.

Superconditioning TMS for examining upper motor neuron function in MND.

We used transcranial magnetic stimulation (TMS) of motor cortex, including a novel four-pulse superconditioning (TMSsc) paradigm, in repeated examinations of motor-evoked potentials (MEPs) in eight subjects with motor neuron disease (MND), including seven with amyotrophic lateral sclerosis (ALS). The goals were: (1) to look for evidence of cortical hyperexcitability, including a reduction in short-interval intracortical inhibition (SICI); and (2) to examine the utility of using TMSsc for quantifying upper motor neuron function during MND progression. Testing of abductor pollicis brevis (APB) and tibialis anterior (TA) muscles bilaterally was carried out every 3 months in MND subjects for up to 2 years; results were compared to those from a cohort of 15 control subjects. Measures of SICI were not significantly different between control and MND subjects for either APB or TA muscles. Other measures of cortical excitability, including TMS threshold and MEP amplitude, were consistent with lowered cortical excitability in MND subjects. Certain combinations of superconditioning TMS were capable of causing stronger inhibition or facilitation of MEPs compared to dual-pulse TMS, for both APB and TA target muscles. Moreover, there were multiple cases in which target muscles unresponsive to strong single-pulse TMS, whether at rest or when tested with an active contraction, showed an MEP in response to TMSsc optimized for facilitation. Our findings suggest that a multi-faceted neurophysiologic protocol for examining upper motor neuron function in MND subjects might benefit from inclusion of TMSsc testing.

Pediatric continuous renal replacement therapy: have practice changes changed outcomes? A large single-center ten-year retrospective evaluation.

BACKGROUND: To evaluate changes in population characteristics and outcomes in a large single-center pediatric patient cohort treated with continuous renal replacement therapy (CRRT) over a 10 year course, coincident with multiple institutional practice changes in CRRT delivery. METHODS: A retrospective cohort study with comparative analysis of all patients treated from 2004 to 2013 with CRRT in the neonatal, pediatric, and cardiovascular intensive care units within a free-standing pediatric tertiary care hospital. RESULTS: Three hundred eleven total patients were identified, 38 of whom received concurrent treatment with extracorporeal membrane oxygenation. 273 patients received CRRT only and were compared in two study eras (2004-2008 n = 129; 2009-2013 n = 144). Across eras, mean patient age decreased (9.2 vs 7.7 years, p = 0.08), and the most common principal diagnosis changed from cardiac to liver disease. There was an increase in patients treated with continuous renal replacement therapy between cohorts for acute kidney injury of multi factorial etiology (44% vs 56%) and a decrease in treated patients with sepsis (21% vs 11%, p = 0.04). There was no significant difference in survival to hospital discharge between eras (47% vs 49%). Improvement in outpatient follow-up after discharge amongst survivors was seen between study eras (33% vs 54%). CONCLUSIONS: Despite multiple institutional practice changes in provision of CRRT, few changes were seen regarding patient demographics, diseases treated, indications for therapy, and survival over 10 years at a single tertiary care. Recognition of need for follow-up nephrology care following CRRT is improving. Ongoing assessment of the patient population in a changing landscape of care for critically ill pediatric patients remains important.

Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation.

We developed a strategy to harness alkyl amines as alkylating agents via C-N bond activation. This Suzuki-Miyaura cross coupling of alkylpyridinium salts, readily formed from primary amines, is the first example of a metal-catalyzed cross coupling via C-N bond activation of an amine with an unactivated alkyl group. This reaction enjoys broad scope and functional group tolerance. Primary and secondary alkyl groups can be installed. Preliminary studies suggest a NiI/NiIII catalytic cycle.

Accessing Both Retention and Inversion Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates.

We have developed a stereospecific, nickel-catalyzed Miyaura borylation of allylic pivalates, which delivers highly enantioenriched α-stereogenic γ-aryl allylboronates with good yields and regioselectivities. Our complementary sets of conditions enable access to either enantiomer of allylboronate product from a single enantiomer of readily prepared allylic pivalate substrate. Excellent functional group tolerance, yields, regioselectivities, and stereochemical fidelities are observed. The stereochemical switch from stereoretention to stereoinversion largely depends upon solvent and can be explained by competitive pathways for the oxidative addition step. Our mechanistic investigations support a stereoretentive pathway stemming from a directed oxidative addition and a stereoinvertive pathway that is dominant when MeCN blocks coordination of the directing group by binding the nickel catalyst.

Stereospecific Cross Couplings To Set Benzylic, All-Carbon Quaternary Stereocenters in High Enantiopurity.

Asymmetric preparation of all-carbon quaternary stereocenters is an important goal. Despite advances in formation of highly enantioenriched products with quaternary stereocenters proximal to a functional group, methods to install quaternary stereocenters isolated from functional groups are limited. Transition metal catalysis offers a potential solution, but prior cross couplings are limited to allylic substrates or deliver little to no enantiomeric enrichment. We report a stereospecific, nickel-catalyzed Suzuki-Miyaura arylation of tertiary benzylic acetates to deliver products with diaryl and triaryl quaternary stereocenters in high yields and ee's. This reaction employs an inexpensive, air-stable Ni(II) salt and commercially available phosphine ligand to transform tertiary alcohol derivatives, which are easily available in exceptional ee, into valuable products with stereoretention.

Involving patients in clinical research: the Telescot Patient Panel.

BACKGROUND: To date, patient involvement in the development of clinical research work has been limited. In 2011, the Telescot research team commenced work on a feasibility trial to investigate home telemonitoring of blood pressure for people who have experienced stroke or transient ischaemic attack (TIA). The team decided to involve patients in the development of the research. OBJECTIVES: To improve research design through patient involvement. METHOD OF PATIENT INVOLVEMENT: A modified form of the 'Scrutiny Panel' approach was used to involve people who had stroke in the research project. RESULTS: The Patient Panel supported the research in three key ways: it informed patient communication; it presented patient perspectives on the applicability and usability of the intervention; and it guided the development of the qualitative study. DISCUSSION: The initiative was considered a positive experience for all. However, challenges were identified in terms of the time and cost implications of undertaking patient involvement. IMPLICATION FOR RESEARCH PRACTICE: Importance is attached to adequate project planning and development, partnership working with community-based organizations and the necessity for clear role delineation between patients and professionals to enable effective collaborative working. CONCLUSIONS: The Telescot Patient Panel was beneficial in supporting the development of the feasibility trial. The Panel approach was considered transferable to other clinical research contexts.

Enantioselective copper-catalyzed alkynylation of benzopyranyl oxocarbenium ions.

We have developed highly enantioselective, copper-catalyzed alkynylations of benzopyranyl acetals. By using a copper(I) catalyst equipped with a chiral bis(oxazoline) ligand, high yields and enantioselectivities are achieved in the alkynylation of widely available, racemic isochroman and chromene acetals to deliver α-chiral oxygen heterocycles. This method demonstrates that chiral organometallic nucleophiles can be successfully used in enantioselective additions to oxocarbenium ions.

Emergency Procedural Sedation With Propofol in Older Teenagers: Any Cause for Concern?

INTRODUCTION: Propofol is a standard for adult emergency department procedural sedation (EDPS). Use in pediatric patients remains controversial. Our primary objective was to investigate whether adverse events occurred more frequently in teenage pediatric patients receiving propofol for EDPS. METHODS: This retrospective study examines records from the Halifax Procedural Sedation Registry, collected between January 1, 2006 and May 31, 2013. Patients undergoing EDPS using propofol were divided into those aged 16 to 19 years (teenagers), 20 to 65 years (adults), and older than 65 years (seniors). The primary outcomes were the incidences of hypotension and hypoxia. RESULTS: Four thousand sixty-three EDPSs were included in the analysis, of which 230 involved teenagers, 2853 adults (mean age, 43.0 years), and 980 seniors (mean age, 77.1). The teenage group was significantly less likely to develop hypotension or hypoxia. These differences were confirmed on multivariate analysis. Patients in the teenage group received higher doses of propofol per kilogram/minute than the other groups. No other differences met statistical significance. CONCLUSIONS: Teenage patients receiving EDPS with propofol had a lower incidence of adverse events, and both received and tolerated larger adjusted doses of medication than older patients. Satisfaction and duration of EDPS were similar. Concerns about propofol use in younger patients have not been supported by this study. We believe that these findings support the use of propofol for EDPS in older teenagers.

Enantioselective Copper(I)-Catalyzed Alkynylation of Oxocarbenium Ions to Set Diaryl Tetrasubstituted Stereocenters.

An enantioselective, copper(I)-catalyzed addition of terminal alkynes to isochroman ketals to set diaryl, tetrasubstituted stereocenters has been developed. The success of this reaction relies on identification of a Cu/PyBox catalyst capable of distinguishing the faces of the diaryl-substituted oxocarbenium ion. This challenging transformation enables efficient conversion of readily available, racemic ketals into high-value enantioenriched isochroman products with fully substituted stereogenic centers. High yields and enantiomeric excesses are observed for various isochroman ketals and an array of alkynes.

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions.

The development of enantioselective, copper-catalyzed alkynylations of cyclic iminium and oxocarbenium ions is reviewed. The use of chiral copper-based catalysts has enabled high yields and enantioselectivites in the formation of nitrogen- and oxygen-containing heterocycles with α-stereogenic centers. This review highlights both the accomplishments and the future work needed in this important area.