Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates.

The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules. In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation of two distinct catalysts--multimetallic catalysis--can be used instead. Many important reactions rely on multimetallic catalysis, such as the Wacker oxidation of olefins and the Sonogashira coupling of alkynes with aryl halides, but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition. Here, we demonstrate that cooperativity between two group 10 metal catalysts--(bipyridine)nickel and (1,3-bis(diphenylphosphino)propane)palladium--enables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles). Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon-hydrogen bonds that is required for direct arylation methods. Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino)propane)palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine)nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents, and lead to the discovery of new multimetallic reactions.

Seat belt use among patients in motor vehicle collisions: Clinical and demographic factors.

OBJECTIVE: Proper use of automobile seat belt in a motor vehicle crash is associated with reduced morbidity and mortality, shorter hospital stays, reduced resource utilization, and fewer missed work days. Seatbelt compliance nationwide is 86%. This study was undertaken to identify factors associated with noncompliance with seatbelt use among admitted patients following a motor vehicle crash. METHODS: This study was a retrospective analysis of motor vehicle crashes at an Urban Level 1 Trauma Center. Eligible subjects included patients age 18 and over, who were admitted by the Trauma Service following a motor vehicle crash from January to December 2017. RESULTS: Among 766 participants, the overall rate of seatbelt noncompliance was 32% (N = 245). Some participants met the legal limit of intoxication (80 mg/dl) (N = 119 patients; 22%). Drug use was high among this population, including THC (30%), opiates (29%), benzodiazepines (24%), cocaine (10%), and methamphetamine (10%). Patients who did not wear seat belts were more likely to be male (62.4% no seat belt vs. 51.8% seat belt), intoxicated (30.5% vs. 17.0%), screen positive for cocaine (18.2% vs. 4.7%), THC (37.7% vs. 24.2%), and methamphetamine (15.6% vs. 5.9%). We did not detect significant differences by seat belt use with respect to ethnicity, mode of arrival, day of week, opiate use, or benzodiazepine use. CONCLUSIONS: In this study, 32% of patients in motor vehicle crashes were not compliant with seat belt use. Noncompliance with seat belt use was higher among patients who were male, younger age, intoxicated, or who had positive screens for cocaine, THC, or methamphetamine.

Use of a contact force-sensing ablation catheter with advanced catheter location significantly reduces fluoroscopy time and radiation dose in catheter ablation of atrial fibrillation.

AIMS: The aim of this study was to evaluate the 'real-world' impact of a novel contact force (CF)-sensing (SmartTouch™, Biosense Webster, Diamond Bar, CA, USA) catheter coupled with an advanced catheter location (ACL) system on fluoroscopy time and fluoroscopy dose during atrial fibrillation (AF) ablation. METHODS AND RESULTS: This was a retrospective observational cohort study of prospectively collected data of 1515 consecutive patients undergoing paroxysmal AF (PAF) and persistent AF (PerAF) ablation at a single institution between 2009 and 2014. Patients undergoing AF ablation with the SmartTouch catheter and the ACL system (SmartTouch group, n = 510) were compared with those undergoing AF ablation without this technology (control group, n = 1005). The primary outcomes were total fluoroscopy time (min) and fluoroscopy dose as measured by the dose-area product (mGy cm(2)). Secondary endpoints included total procedure time, total ablation time, and major cardiac complications (tamponade, pericardial effusion, and urgent cardiac surgery). The SmartTouch group had significantly lower fluoroscopy times (9.5 vs. 41 min, P < 0.001), radiation doses (1044 vs. 3571 mGy cm(2), P < 0.001), and shorter procedural time (195 vs. 240 min, P < 0.001) when compared with the control group. This was statistically significant for both PAF and PerAF ablations and for both de novo and redo AF procedures. After a learning curve, a median fluoroscopy time of 3.5 min (interquartile range 6) for all AF ablations was achieved. There was no difference in the rate of cardiac complications (∼ 1.5%). CONCLUSION: SmartTouch™ CF-sensing catheter use with ACL™ during AF ablation significantly reduces fluoroscopy times by 77%, radiation dose by 71%, and procedural time by 19% but does not improve overall safety or the risk of cardiac complications.

Point-by-Point Radiofrequency Ablation Versus the Cryoballoon or a Novel Combined Approach: A Randomized Trial Comparing 3 Methods of Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation (The Cryo Versus RF Trial).

INTRODUCTION: Catheter ablation of paroxysmal AF using the Cryoballoon (CRYO) has yielded similar success rates to conventional wide encirclement using radiofrequency catheter ablation (RFCA), but randomized data are lacking. Pilot data suggested a high success rate with a combined approach (COMBINED) using wide encirclement with RFCA followed by 2 CRYO applications to each vein. We compared these 3 strategies in a randomized controlled trial. METHODS AND RESULTS: Patients undergoing first time paroxysmal AF ablation were randomized to RFCA, CRYO, or COMBINED. Patients were followed up at 3, 6, and 12 months with 7 days of ambulatory ECG monitoring. Success was defined as freedom from arrhythmia without antiarrhythmic drugs after a single procedure. A total of 237 patients were randomized. Success at 1 year was achieved in 47% in the RFCA group, 67% in the CRYO group, and 76% in the COMBINED group (P < 0.001 for RFCA vs. CRYO, P<0.001 for RFCA vs. COMBINED, and P = 0.220 for CRYO vs. COMBINED). Procedure time was 211 (IQR 174-256) minutes for RFCA compared to 167 (136-202) minutes for CRYO and 278 (243-327) minutes for COMBINED (P < 0.001 for RFCA vs. COMBINED, RFCA vs. CRYO, and CRYO vs. COMBINED groups). CONCLUSIONS: Pulmonary vein isolation for paroxysmal AF is faster with CRYO and results in a higher single procedure success rate than conventional point by point RFCA. The COMBINED approach was not superior to CRYO alone.

Diagnosis and Management of Intra-articular Causes of Pain After Total Knee Arthroplasty.

Total knee arthroplasty (TKA) is an effective procedure for decreasing pain, improving functional capability, and increasing the overall quality of life for thousands of people with chronic knee osteoarthritis. Although patient outcomes and satisfaction remain high, a substantial percentage of patients report residual pain after TKA. Sources of postoperative pain include intra- and extra-articular etiologies as well as factors unrelated to the implants themselves. A patient-centered approach to the painful TKA may aid clinicians in diagnosing and treating patients with intra-articular causes of pain after TKA. A thorough understanding of the mechanisms involved may lead to improved preoperative planning and patient selection, ultimately decreasing the number of patients with less than optimal postoperative outcomes.

Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin.

BACKGROUND: Catheter ablation is an effective treatment for symptomatic individuals with atrial fibrillation (AF) but is associated with a risk of periprocedual stroke. Recent data suggest that this risk may be abolished if catheter ablation is performed with uninterrupted warfarin (UW). We sought to compare the incidence, severity and timing of periprocedural stroke between 2 periprocedural anticoagulation protocols: bridging low-molecular-weight heparin (LMWH) and UW. METHODS AND RESULTS: Periprocedural stroke (≤14 days) was assessed in 2,855 ablations performed in 1,813 patients. Thromboembolic stroke occurred in 11/1,653 (0.7%) procedures with bridging LMWH and in 5/1,202 (0.4%) procedures on UW (P = 0.5). Four of the 5 strokes (80%) on UW occurred despite a therapeutic INR and a mean activated clotting time of ≥300 seconds and 4/5 strokes (80%) occurred in patients with a CHADS2 score of 0. Eleven of 16 (69%) strokes overall occurred within 24 hours of the procedure. All 4 strokes resulting in major neurological deficit occurred in the LMWH group. Major bleeding complications occurred in 6.0% of patients in the bridging LMWH group compared to 4.0% in the UW group (P = 0.02). CONCLUSIONS: In contrast to existing data, periprocedural stroke still occurs despite therapeutic anticoagulation throughout the operative period. The optimal strategy to protect patients against thromboembolic stroke remains unclear.

Republished review: Cardiac stem cell therapy: progress from the bench to bedside.

In the rush to assess the role of stem cell therapy for cardiovascular disease the details of translation are easily overlooked. This review summarises the progress to date in translating the exciting preclinical results of cardiac repair into man and considers the questions that this area of research has stimulated about the challenges of moving from bench to bedside.

Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase.

Reduction of nitrite (NO(2)(-)) provides a major source of nitric oxide (NO) in the circulation, especially in hypoxemic conditions. Our previous studies suggest that xanthine oxidoreductase (XOR) is an important nitrite reductase in the heart and kidney. Herein, we have demonstrated that conversion of nitrite to NO by blood vessels and RBCs was enhanced in the presence of the XOR substrate xanthine (10 micromol/L) and attenuated by the XOR inhibitor allopurinol (100 micromol/L) in acidic and hypoxic conditions only. Whereas endothelial nitric oxide synthase (eNOS) inhibition had no effect on vascular nitrite reductase activity, in RBCs L-NAME, L-NMMA, and L-arginine inhibited nitrite-derived NO production by >50% (P<0.01) at pH 7.4 and 6.8 under hypoxic conditions. Western blot and immunohistochemical analysis of RBC membranes confirmed the presence of eNOS and abundant XOR on whole RBCs. Thus, XOR and eNOS are ideally situated on the membranes of RBCs and blood vessels to generate intravascular vasodilator NO from nitrite during ischemic episodes. In addition to the proposed role of deoxyhemoglobin, our findings suggest that the nitrite reductase activity within the circulation, under hypoxic conditions (at physiological pH), is mediated by eNOS; however, as acidosis develops, a substantial role for XOR becomes evident.

Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells.

BACKGROUND & AIMS: How mutations are established and spread through the human stomach is unclear because the clonal structure of gastric mucosal units is unknown. Here we investigate, using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion, the clonality of the gastric unit and show how mutations expand in normal mucosa and gastric mucosa showing intestinal metaplasia. This has important implications in gastric carcinogenesis. METHODS: Mutated units were identified by a histochemical method to detect activity of cytochrome c oxidase. Negative units were laser-capture microdissected, and mutations were identified by polymerase chain reaction sequencing. Differentiated epithelial cells were identified by immunohistochemistry for lineage markers. RESULTS: We show that mtDNA mutations establish themselves in stem cells within normal human gastric body units, and are passed on to all their differentiated progeny, thereby providing evidence for clonal conversion to a new stem cell-derived unit-monoclonal conversion, encompassing all gastric epithelial lineages. The presence of partially mutated units indicates that more than one stem cell is present in each unit. Mutated units can divide by fission to form patches, with each unit sharing an indentical, mutant mtDNA genotype. Furthermore, we show that intestinal metaplastic crypts are clonal, possess multiple stem cells, and that fission is a mechanism by which intestinal metaplasia spreads. CONCLUSIONS: These data show that human gastric body units are clonal, contain multiple multipotential stem cells, and provide definitive evidence for how mutations spread within the human stomach, and show how field cancerization develops.

Neuromuscular disease as the cause of late clubfoot relapses: report of 4 cases.

Following correction with the Ponseti method some idiopathic clubfeet still will relapse even after six years of age. A better understanding of the cause for these late relapses will greatly help in the management of this condition. We evaluated a consecutive case-series from 1948 through December 1984 including 209 patients (321 clubfeet). Patients were treated following the Ponseti method. Initial number of casts, age at relapse, neurological evaluation, and final treatment for the late-relapses were recorded. There were 12 patients (6%) having a relapse after the seventh birthday. In 4 of these patients (6 clubfeet) a neuromuscular disease was diagnosed, representing 33% of the late relapses. These patients were initially treated with an average of 4 casts (range: 2-6) with 2 requiring an Achilles tenotomy. Patients used the brace for an average of 4 years. The average age at the relapse prior to the suspicion of neuromuscular disease was 9 years (range: 8-11 years). Two patients had family history of neuromuscular disease (myotonic dystrophy and multiple core disease). In the other two cases (Charcot-Marie-Tooth Disease type IA and myasthenia gravis) neuromuscular disease was not suspected. All four patients required an anterior tibialis transfer, three had a plantar fasciotomy, and two had peroneus longus to brevis transfers. One patient required a subsequent posterior tibialis transfer and another patient a triple arthrodesis (myotonic dystrophy). In conclusion, late relapses in patients with idiopathic clubfoot may represent the onset of a previously undiagnosed neuromuscular disease, and should be thoroughly evaluated.

Panoramic characterization of endocardial left atrial activation during human persistent AF: Insights from non-contact mapping.

BACKGROUND: The relative importance of focal drivers, multiple wavelets, rotors and endocardial-epicardial circuits in the maintenance of persistent AF remains unclear. Our objective was to characterize AF wavefront (WF) dynamics during persistent AF. METHODS: The Ensite 3000 (St Jude Medical) non-contact mapping system was used to map the LA of 15 patients with persistent AF. Wavefronts were classified into planar WFs, rotors or focal WFs. For each new WF the site of origin, the unipolar electrogram, and propagation patterns were determined. RESULTS: AF was characterized by highly unstable patterns of activation with random combinations of 1-2 propagating planar wavefronts alternating with focal activations in a dynamic process. Stable reentry circuits and rotors were never seen. A total of 499 wavefront patterns were analyzed in this study (416 planar wavefronts and 83 focal wavefronts). In an individual patient planar WFs accounted for 67±35% of activations with lifespans of 98±86ms. Focal activations accounted for 29.7±33.5% of activations with lifespans of 76±95ms. The most common sites for new WF generation were the PVs (33%), LA roof (23%), anterior LA (15%), LAA (11%), and posterior LA (8%). The most common unipolar electrogram morphologies observed were QS pattern (34%), rS (29%), CFAE (26%), QR (7%) and Rs (4%), suggesting that WFs may originate from both the endocardial and epicardial surfaces. CONCLUSION: Human persistent AF is characterized by the formation of highly unstable WFs consisting of various combinations of one to two planar WFs and brief focal activations without any evidence of rotors or sustained focal sources.

Stem cell plasticity and tumour formation.

Stem cell plasticity refers to the ability of certain stem cells to switch lineage determination and generate unexpected cell types. This review applies largely to bone marrow cells (BMCs), which appear to contribute positively to the regeneration of several damaged non-haematopoietic tissues. This beneficial effect on regeneration may be a direct result of BMCs giving rise to organ parenchymal cells. Alternatively, it could be due to BMCs fusing with existing parenchymal cells, or providing paracrine growth factor support, or contributing to neovascularisation. In the context of oncology, BMC derivation of the tumour stroma and vasculature has profound biological and therapeutic implications, and there are several examples of carcinomas seemingly being derived from BMCs.

Mechanisms of disease: from stem cells to colorectal cancer.

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of beta-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass beta-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression.

Patient location strategies for pediatric long-term follow-up studies.

BACKGROUND: Poor follow-up rates greatly diminish the validity of prospective and long-term studies. Therefore, locating patients is of critical importance. This is especially true in populations treated during childhood because addresses will change several times in intervening years. Recent publications have reported new strategies for patient location. The purpose of this study is to test an algorithm proposed by King et al., as well as other search methods, using a cohort of patients treated for clubfoot in childhood METHODS: The study population included 126 patients with clubfeet treated between 1950 and 1967. We followed the search algorithm proposed by King et al. In addition, we used state driver's license records, Reunitetonight.com, and Intelius.com. Patients were considered to be found when they returned a postage-paid reply letter or were contacted by phone. RESULTS: Using web pages recommended by King et al. we located 26 of 126 (21 percent) patients. Operator directory assistance failed to locate any patients not located by free internet sources. Additional websites had varied results. State driver's license records found 25 patients. Reunitetonight.com found none with thirty attempted. The best search engine was Intelius.com which located 68 out of 126 (54 percent) patients. CONCLUSION: The algorithm proposed by King et al. is not effective for long-term follow-up studies of pediatric populations. Intelius.com is worth the small fee charged (dollar 22.45) as it was the most effective method of locating patients.

Complications after therapeutic trauma laparotomy.

BACKGROUND: Therapeutic trauma laparotomy (TTL) is a common emergency procedure after traumatic abdominal injury, but it can lead to complications and even death. We explored the role of the time from emergency department (ED) arrival to surgical intervention as a predictor of complications and mortality from TTL. STUDY DESIGN: This is a retrospective study of 175 patients receiving TTL between July 1997 and October 2003 in a Level I teaching hospital serving a primarily rural population. Mortality after TTL and complications, both general and abdominal, were the main outcomes. Time from ED arrival to operation was the primary exposure. Confounders, including time from injury to ED arrival, age, gender, injury severity, and patient status, were controlled in logistic models. RESULTS: Of the 175 TTL patients, 23 (13.1%) died, 102 (58.3%) had abdominal complications, and 119 (68.0%) had general complications. Controlling for confounders, patients whose operation began more than 1 hour after ED arrival were 11.3 (95% CI=2.2 to 58.8) times more likely to die and 3.1 (95% CI=1.44 to 6.60) times more likely to have complications. CONCLUSIONS: The traumatologist has little control over patient treatment and transfer before ED arrival. After arrival the traumatologist can reduce negative outcomes by reducing the time for patient assessment and start of TTL, when warranted.

Impact of diabetes mellitus and renal insufficiency on 5-year mortality following coronary artery bypass graft surgery: a cohort study of 4869 UK patients.

OBJECTIVES: Diabetes mellitus (DM) and renal impairment (RI) are both independent predictors of mortality after coronary artery bypass graft surgery (CABG). The two conditions often coexist, yet the impact on long-term prognosis after CABG of each factor relative to the other and the two in combination is uncertain. METHODS: We undertook a prospective cohort study of 4869 patients who underwent CABG between 2003 and 2007. The cohort was divided into four groups according to preoperative diabetic status and renal function: patients without either DM or RI (reference group), patients with DM alone, patients with RI alone and patients with both DM and RI. Clinical outcomes were compared between groups. Patients receiving renal replacement therapy were excluded. The primary outcome was 5-year all-cause mortality. RESULTS: The crude 5-year all-cause mortality rate was 9.0% for patients in the reference group, 11.1% for patients with DM alone, 20.3% for patients with RI alone and 28.5% for patients with both DM and RI (P < 0.0001). Five-year survival adjusted for potential confounding factors was significantly worse for patients with DM (hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.06-1.59), patients with RI (HR 1.32; 95% CI 1.08-1.61) and patients with both DM and RI (HR 2.04; 95% CI 1.65-2.53) when compared with patients with neither condition. CONCLUSIONS: Preoperative DM and RI were important predictors of 5-year mortality after CABG. Patients with RI alone had a higher mortality rate than patients with DM alone, but this difference was largely accounted for by age and other comorbidities. The combination of DM and RI doubled the 5-year mortality rate after CABG independently of potential confounding factors.

The impact of acute kidney injury on midterm outcomes after coronary artery bypass graft surgery: a matched propensity score analysis.

BACKGROUND: The development of acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with increased short- and long-term mortality. Whether AKI has a causal relationship with subsequent mortality or whether the development of AKI simply occurs in patients with more comorbidity undergoing more complex procedures remains unresolved. METHODS AND RESULTS: This was an observational cohort study of prospectively collected data from 4694 patients discharged from the hospital after first-time CABG surgery at a tertiary cardiac center between 2003 and 2008. AKI was defined using the Risk, Injury, Failure, Loss, and End stage (RIFLE) criteria, which require at least a 50% increase in serum creatinine. The primary outcome measure was all-cause mortality determined via UK Office of National Statistics. A total of 562 (12.0%) of patients developed AKI after CABG surgery. Patients who developed AKI were older, more likely to be female, and had more comorbidity than patients who did not develop AKI. In a Cox multivariable analysis, the development of AKI was an independent predictor of midterm mortality (hazard ratio, 1.80; 95% confidence interval, 1.50-2.16). Subsequently, a comparison of 562 patients who sustained AKI with 562 propensity score-matched patients who did not sustain AKI was undertaken. After propensity matching, baseline clinical and operative characteristics were similar between both groups. After Cox multivariable analysis of the propensity-matched cohort, AKI remained an independent predictor of midterm mortality (hazard ratio, 1.52; 95% confidence interval, 1.19-1.93). CONCLUSIONS: The development of AKI after CABG is a serious event associated with worse midterm survival. This excess mortality cannot be explained simply by coexisting comorbidity and surgical complexity.