Organocatalytic synthesis of ß-enaminyl radicals as single-electron donors for phenyliodine(III) dicarboxylates: direct one-pot alkylation-aminoxidation of styrenes.

A direct one-pot alkylation-aminoxidation of styrene derivatives was achieved using in situ-generated alkyl and N-oxyl radicals. The corresponding O-alkylated hydroxylamine derivatives were obtained in moderate to good yields. The reaction features the generation of the alkyl radicals from phenyliodine(III) dicarboxylates via an organocatalytic process, the use of phenyliodine(III) dicarboxylates as the source of the alkyl radicals and oxidants for the generation of N-oxyl radicals, and the first generation of the ß-enaminyl radicals via a HAT process and their use as single-electron donors.

Use of a Lightweight Portable Fluoroscopy Device for Obtaining Weightbearing Ankle Images.

Portable fluoroscopy devices provide point-of-care imaging in emergency and out-patient clinics. In this prospective study, we compared weightbearing images of syndesmosis obtained using a novel lightweight portable battery-powered fluoroscopy device with those obtained with a conventional radiography device. Eleven healthy participants underwent bilateral 3-view weightbearing imaging of both ankles using a radiography (X-ray group) device and a portable fluoroscopy system (LPF group). Anteroposterior, mortise, and lateral views were compared between the 2 techniques. Radiographic measurements were done by 2 observers. These measurements included talar tilt, tibiofibular clear space, tibiofibular overlap, plafond malleolar angle, medial distal tibial angle, medial clear space, lateral distal tibial angle, anterior and posterior tibiofibular distance were measured using the appropriate view. Data were compared between the 2 techniques; the interobserver agreement was calculated within each group. P < .05 was considered statistically significant. Comparing the 2 imaging modalities, there was no significant difference between the measurements in LPF and X-ray groups except plafond malleolar angle. The overall interobserver agreement was excellent between the 2 observers. There was no significant difference between the measures by the 2 observers and between the bilateral ankles. Fluoroscopy was associated with about 50% extra radiation exposure, although the absolute amount of radiation was not clinically significant. These results support the use of weightbearing images using portable fluoroscopy device as an alternative for the conventional radiography systems.

Arthroscopic assessment of syndesmotic instability: Are we pulling correctly in the coronal plane?

BACKGROUND: While the lateral hook test (LHT) has been widely used to arthroscopically evaluate syndesmotic instability in the coronal plane, it is unclear whether the angulation of the applied force has any impact on the degree of instability. We aimed to determine if changing the direction of the force applied while performing the LHT impacts the amount of coronal diastasis observed in subtle syndesmotic injuries. METHODS: In 10 cadaveric specimens, arthroscopic evaluation of the syndesmotic joint was performed by measuring anterior and posterior-third coronal plane diastasis in the intact state, and repeated after sequential transection of the 1) anterior inferior tibiofibular ligament (AITFL), 2) interosseous ligament (IOL), and 3) posterior inferior tibiofibular ligament (PITFL). In all scenarios, LHT was performed under 100 N of laterally directed force. Additionally, LHT was also performed under: 1) anterior inclination of 15 degrees and 2) posterior inclination of 15 degrees in intact and AITFL+IOL deficient state. RESULTS: Compared to the intact state, the syndesmosis became unstable after AITFL +IOL transection under laterally directed force with no angulation (p = 0.029 and 0.025 for anterior and posterior-third diastasis, respectively), which worsened with subsequent PITFL transection (p = <0.001). Moreover, there was no statistical difference in anterior and posterior-third coronal diastasis in both intact and AITFL+IOL deficient states under neutral, anterior, and posteriorly directed force (p-values ranging from 0.816 to 0.993 and 0.396-0.80, respectively). However, in AITFL+IOL transected state, posteriorly directed forces resulted in greater diastasis than neutral or anteriorly directed forces. CONCLUSIONS: Angulation of the applied force ranging from 15 degrees anteriorly to 15 degrees posteriorly during intraoperative LHT has no effect on coronal plane measurements in patients with subtle syndesmotic instability. On the other hand, posteriorly directed forces result in more sizable diastasis, potentially increasing their sensitivity. CLINICAL RELEVANCE: When arthroscopically evaluating subtle syndesmotic instability, clinicians should assess coronal diastasis with the hook angled 15 degrees posteriorly.

Domino Michael/Michael reaction catalyzed by switchable modularly designed organocatalysts.

The domino Michael/Michael reaction between (E)-7-aryl-7-oxohept-5-enals and trans-cinnamaldehydes was investigated by using modularly designed organocatalysts (MDOs). It was found that both the enamine and iminium catalytic modes of the MDOs are switchable and can be individually switched on and off by using appropriate combinations of the precatalyst modules and the reaction conditions. When both the enamine and iminium catalysis modes of the MDOs are switched on, the desired domino reaction products can be obtained in good yields and stereoselectivities under optimized conditions.

Diastereodivergent Synthesis of Hexahydro-6H-benzo[c]chromen-6-one Derivatives Catalyzed by Modularly Designed Organocatalysts.

The diastereodivergent synthesis of hexahydro-6H-benzo[c]chromen-6-one derivatives with good to high diastereoselectivities (up to 98:2 d.r.) and enantioselectivities (up to >99 % ee) has been achieved by using a domino Michael/Michael/hemiacetalization reaction between trans-2-hydroxy-ß-nitrostyrenes and trans-7-oxo-5-heptenals followed by oxidation. With use of appropriate modularly designed organocatalysts (MDOs) that are self-assembled in situ from amino acid derivatives and cinchona alkaloid derivatives, two different diastereomers of the desired hexahydro-6H-benzo[c]chromen-6-ones are obtained from the same substrates.

Stereoselective Synthesis of 3-Oxabicyclo[3.3.1]nonan-2-ones via a Domino Reaction Catalyzed by Modularly Designed Organocatalysts.

A highly stereoselective method for the synthesis of functionalized 3-oxabicyclo[3.3.1]nonan-2-one derivatives with four contiguous stereogenic centers, including one tetrasubstituted stereogenic center, was realized through an organocatalytic domino Michael-hemiacetalization-Michael reaction of (E)-3-aryl-2-nitroprop-2-enols and (E)-7-aryl-7-oxohept-5-enals followed by a PCC oxidation. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good yields (up to 84%), excellent diastereoselectivities (> 99:1 dr), and high enantioselectivities (up to 96% ee).

Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy.

Preclinical investigations support the concept that donor cells more oriented towards a cardiovascular phenotype favor repair. In light of this philosophy, we previously identified HDAC1 as a mediator of cardiac mesenchymal cell (CMC) cardiomyogenic lineage commitment and paracrine signaling potency in vitro-suggesting HDAC1 as a potential therapeutically exploitable target to enhance CMC cardiac reparative capacity. In the current study, we examined the effects of pharmacologic HDAC1 inhibition, using the benzamide class 1 isoform-selective HDAC inhibitor entinostat (MS-275), on CMC cardiomyogenic lineage commitment and CMC-mediated myocardial repair in vivo. Human CMCs pre-treated with entinostat or DMSO diluent control were delivered intramyocardially in an athymic nude rat model of chronic ischemic cardiomyopathy 30 days after a reperfused myocardial infarction. Indices of cardiac function were assessed by echocardiography and left ventricular (LV) Millar conductance catheterization 35 days after treatment. Compared with naïve CMCs, entinostat-treated CMCs exhibited heightened capacity for myocyte-like differentiation in vitro and superior ability to attenuate LV remodeling and systolic dysfunction in vivo. The improvement in CMC therapeutic efficacy observed with entinostat pre-treatment was not associated with enhanced donor cell engraftment, cardiomyogenesis, or vasculogenesis, but instead with more efficient inhibition of myocardial fibrosis and greater increase in myocyte size. These results suggest that HDAC inhibition enhances the reparative capacity of CMCs, likely via a paracrine mechanism that improves ventricular compliance and contraction and augments myocyte growth and function.

Stereoselective synthesis of chromane derivatives via a domino reaction catalyzed by modularly designed organocatalysts.

A highly enantio- and diastereoselective method for the synthesis of functionalized chroman-2-ones and chromanes was achieved by using an organocatalytic domino Michael/hemiacetalization reaction of aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols followed by a PCC oxidation and dehydroxylation, respectively. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good to high yields (up to 97%) and excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 99% ee).

Enantioselective anti-Mannich reaction catalyzed by modularly designed organocatalysts.

A highly stereoselective method for achieving the anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate was realized using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and (A)-pyrrolidien-3-carboxylic acid in the reaction media. The desired anti-Mannich products were obtained in good to excellent yields (up to 93%), excellent diastereoselectivities (up to 99:1 dr), and good to high enantioselectivities (up to 99% ee).

The Epigenetic Regulator HDAC1 Modulates Transcription of a Core Cardiogenic Program in Human Cardiac Mesenchymal Stromal Cells Through a p53-Dependent Mechanism.

Histone deacetylase (HDAC) regulation is an essential process in myogenic differentiation. Inhibitors targeting the activity of specific HDAC family members have been shown to enhance the cardiogenic differentiation capacity of discrete progenitor cell types; a key property of donor cell populations contributing to their afforded benefits in cardiac cell therapy applications. The influence of HDAC inhibition on cardiac-derived mesenchymal stromal cell (CMC) transdifferentiation or the role of specific HDAC family members in dictating cardiovascular cell lineage specification has not been investigated. In the current study, the consequences of HDAC inhibition on patient-derived CMC proliferation, cardiogenic program activation, and cardiovascular differentiation/cell lineage specification were investigated using pharmacologic and genetic targeting approaches. Here, CMCs exposed to the pan-HDAC inhibitor sodium butyrate exhibited induction of a cardiogenic transcriptional program and heightened expression of myocyte and endothelial lineage-specific markers when coaxed to differentiate in vitro. Further, shRNA knockdown screens revealed CMCs depleted of HDAC1 to promote the induction of a cardiogenic transcriptional program characterized by enhanced expression of cardiomyogenic- and vasculogenic-specific markers, a finding which depended on and correlated with enhanced acetylation and stabilization of p53. Cardiogenic gene activation and elevated p53 expression levels observed in HDAC1-depleted CMCs were associated with improved aptitude to assume a cardiomyogenic/vasculogenic cell-like fate in vitro. These results suggest that HDAC1 depletion-induced p53 expression alters CMC cell fate decisions and identify HDAC1 as a potential exploitable target to facilitate CMC-mediated myocardial repair in ischemic cardiomyopathy. Stem Cells 2016;34:2916-2929.

Utility of the HAS-BLED Score in Risk Stratifying Patients on Dual Antiplatelet Therapy Post 12 Months After Drug-Eluting Stent Placement.

INTRODUCTION: Current guidelines recommend continuation of dual anti-platelet therapy (DAPT) for 12 months after percutaneous coronary intervention (PCI). Recent studies have shown benefit in continuing DAPT beyond 12 months but at the risk of increase bleeding. To date, there has been little data on risk stratifying patients to determine who can continue DAPT beyond 12 months at minimal bleeding risk. METHODS: All patients who underwent drug-eluting stent (DES) placement from January 1, 2013 to September 30, 2014 were reviewed. Patients who had follow-up for at least 12 months, placement of 2nd generation everolimus-coated DES, and were on DAPT for at least 12 months were included. Patients with a history of atrial fibrillation, follow-up time less than 12 months, or were on concurrent oral anticoagulation therapy were excluded. RESULTS: Five hundred thirty-one patients were analyzed as described above. Two hundred two patients included in our study with 7 patients in the bleeding cohort and 195 patients in no-bleed cohort. The HAS-BLED score in patients who had a bleeding episode vs. those who did not was 3.29 vs. 2.24 (P value of 0.0009). Although not statistically significant, patients who had a bleeding episode were more likely to have renal dysfunction, alcohol use, be on prasugrel, and be on 325mg of aspirin. CONCLUSION: The study shows that the HAS-BLED score can be of utility in risk stratifying patients in determining who can continue DAPT beyond 12 months. Furthermore, a HAS-BLED score of less than 2 may help guide extended DAPT beyond 12 months at minimal bleeding risk. © 2016 Wiley Periodicals, Inc.

Stereoselective synthesis of spirooxindole derivatives using an organocatalyzed tandem Michael-Michael reaction.

A highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with three stereogenic centers was realized through an organocatalytic tandem Michael-Michael reaction. By employing (S)-α,α-diphenylprolinol trimethylsilyl ether as the catalyst and N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea as the cocatalyst, the reaction between N-tritylisatylidenemalononitriles and (E)-7-alkyl-7-oxohept-5-enals yields the desired spirooxindole products in good yields (76-95%) and with excellent diastereoselectivities (up to 97 : 3 dr) and enantioselectivities (up to 98% ee), which can be stereoselectively converted into the spiro[indoline-3,8'-isoquinoline] derivative through an intramolecular reductive amination reaction.

The Impact of Collagenase Clostridium histolyticum Introduction on Dupuytren Treatment Patterns in the United States.

PURPOSE: The U.S. Food and Drug Administration approved the use of collagenase Clostridium histolyticum (CCH) in the United States in February 2010. This study addresses the impact of that approval on the number of Dupuytren contracture (DC) encounters and treatment patterns in the United States. METHODS: Using the Intercontinental Marketing Services Health Office-Based Medical Claims database, we identified the monthly number of DC encounters and DC procedures between January 2007 and December 2013. Collagenase Clostridium histolyticum usage data from March 2010 to December 2013 was derived from the U.S. CCH manufacturer's data warehouse. Using the combined data, the yearly increasing trends in DC encounters and treatment volume were compared before and after the introduction of CCH. Time trends in the relative procedure frequencies were then examined. Finally, the presence of seasonal variation was tested for in each treatment type. RESULTS: Dupuytren contracture encounters increased on average by 19,015 per year between 2007 and 2009, whereas between 2011 and 2013, DC encounters increased on average by 34,940 per year. In terms of absolute procedure counts, the surgery trend line began decreasing in 2010 with the release of CCH. Meanwhile, CCH continuously increased between 2010 and 2013, and needle aponeurotomy (NA) remained relatively stable. By the year 2013, minimally invasive techniques (NA and CCH) comprised 39% of all treatment, compared with only 14% in 2007. Lastly, there was a statistically significant seasonal increase in the number of surgical procedures during the wintertime but no seasonal variation in NA or CCH. CONCLUSIONS: After the introduction of CCH, the number of Dupuytren encounters increased at a greater annual rate. The introduction and growth of CCH coincided with a decrease in surgery. The number of NA procedures remained steady throughout the study period. The number of open surgery cases followed a predictable seasonal variation with more procedures during the winter months, but this seasonal variation was not seen with less invasive techniques. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic/Decision Analysis II.

Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis- and trans-Fused Pyrano[2,3-b]pyrans.

Both enantiomers of cis- and trans-fused 3,4,4a,8a-tetrahydro-2H,5H-pyrano[2,3-b]pyran-7-carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse-electron-demand hetero-Diels-Alder/oxa-Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self-assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives.

Organocatalyzed asymmetric aldol reactions of ketones and ß,γ-unsaturated α-ketoesters and phenylglyoxal hydrates.

Enantioselective aldol reactions of acetophenone with ß,γ-unsaturated α-ketoesters and cyclic ketones with phenylglyoxal hydrates were realized with cinchona alkaloid-derived thiourea catalysts. The corresponding aldol products were obtained in high yields and good to excellent diastereoselectivities and enantioselectivities (up to 95% ee).

A homochiral microporous hydrogen-bonded organic framework for highly enantioselective separation of secondary alcohols.

A homochiral microporous hydrogen-bonded organic framework (HOF-2) based on a BINOL derivative has been synthesized and structurally characterized to be a uninodal 6-connected {3(3)5(5)6(6)7} network. This new HOF exhibits not only a permanent porosity with the BET of 237.6 m(2) g(-1) but also, more importantly, a highly enantioselective separation of chiral secondary alcohols with ee value up to 92% for 1-phenylethanol.

Asymmetric Aldol Reaction of 3-Acetyl-2H-chromen-2-ones and Isatins Catalyzed by a Bifunctional Quinidine Urea Catalyst.

The asymmetric aldol reaction of 3-acetyl-2H-chromen-2-ones and isatins has been realized by using a bifunctional quinidine-derived urea as the catalyst. The corresponding 3-hydroxyoxindole derivatives containing a 2H-chromen-2-one moiety were obtained in good yields and high enantioselectivities. When (Z)-ethyl 2-benzylideneacetoacetate was used as the substrate, a mixture of two diastereomers (both Z and E) was obtained due to the isomerization of the double bond under the reaction conditions.

Highly diastereodivergent synthesis of tetrasubstituted cyclohexanes catalyzed by modularly designed organocatalysts.

A highly diastereodivergent synthesis of tetrasubstituted cyclohexanes has been achieved using modularly designed organocatalysts (MDOs) which are self-assembled in situ from amino acids and cinchona alkaloid derivatives. Diastereodivergence is realized through controlling the stereoselectivity of the individual steps of a tandem Michael/Michael reaction. Up to 8 of the 16 possible stereoisomers have been successfully obtained in high stereoselectivities using MDOs for the tandem reaction and an ensuing epimerization. The method was used in the enantioselective synthesis of the natural products (-)-α- and ß-lycoranes.

Visible Light-Assisted Ring-Opening of Cyclic Ethers with Carboxylic Acids Mediated by Triphenylphosphine and N-Halosuccinimides.

The ring-opening of cyclic ethers (epoxide, oxetane, THF, and THP) by carboxylic acids was achieved by using N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) and triphenylphosphine under blue light. The corresponding ω-haloalkyl carboxylates were obtained under mild reaction conditions. The reaction is believed to work through a halogen bond complex between NIS (or NBS) and triphenylphosphine, which, upon irradiation with blue light, produces the key phosphine radical cation intermediate that initiates the ring-opening reactions.

Long-Term Statistical Process Monitoring of an Ultrafiltration Water Treatment Process.

As water treatment technology has improved, the amount of available process data has substantially increased, making real-time, data-driven fault detection a reality. One shortcoming of the fault detection literature is that methods are usually evaluated by comparing their performance on hand-picked, short-term case studies, which yields no insight into long-term performance. In this work, we first evaluate multiple statistical and machine learning approaches for detrending process data. Then, we evaluate the performance of a PCA-based fault detection approach, applied to the detrended data, to monitor influent water quality, filtrate quality, and membrane fouling of an ultrafiltration membrane system for indirect potable reuse. Based on two short case studies, the adaptive lasso detrending method is selected, and the performance of the multivariate approach is evaluated over more than a year. The method is tested for different sets of three critical tuning parameters, and we find that for long-term, autonomous monitoring to be successful, these parameters should be carefully evaluated. However, in comparison with industry standards of simpler, univariate monitoring or daily pressure decay tests, multivariate monitoring produces substantial benefits in long-term testing.