Borylation directed borylation of N-alkyl anilines using iodine activated pyrazaboles.

Doubly electrophilic pyrazabole derivatives (pyrazabole = [H2B(µ-C3N2H3)]2) combined with one equiv. of base effect the ortho-borylation of N-alkyl anilines. Initial studies found that the bis(trifluoromethane)sulfonimide ([NTf2]-) pyrazabole derivative, [H(NTf2)B(µ-C3N2H3)]2, is highly effective for ortho-borylation, with this process proceeding through N-H borylation and then ortho C-H borylation. The activation of pyrazabole by I2 was developed as a cheaper and simpler alternative to using HNTf2 as the activator. The addition of I2 forms mono or ditopic pyrazabole electrophiles dependent on stoichiometry. The ditopic electrophile [H(I)B(µ-C3N2H3)]2 was also effective for the ortho-borylation of N-alkyl-anilines, with the primary C-H borylation products readily transformed into pinacol boronate esters (BPin) derivatives. Comparison of borylation reactions using the di-NTf2-and the diiodo-pyrazabole congeners revealed that more forcing conditions are required with the latter. Furthermore, the presence of iodide leads to competitive formation of side products, including [HB(µ-C3N2H3)3BH]+, which are not active for C-H borylation. Using [H(I)B(µ-C3N2H3)]2 and 0.2 equiv. of [Et3NH][NTf2] combines the higher yields of the NTf2 system with the ease of handling and lower cost of the iodide system generating an attractive process applicable to a range of N-alkyl-anilines. This methodology represents a metal free and transiently directed C-H borylation approach to form N-alkyl-2-BPin-aniline derivatives.

Survival and variability over time from out of hospital cardiac arrest across large geographically diverse communities participating in the Resuscitation Outcomes Consortium.

BACKGROUND: The Resuscitation Outcomes Consortium (ROC)epidemiological registry (Epistry) provides opportunities to assess trends in out-of-hospital cardiac arrest treatment and outcomes. METHODS: Patient, event, system, treatment, and outcome data from adult (≥18 years) out-of-hospital cardiac arrest (OHCA) from 10 geographically diverse North American ROC sites over four 12-month epochs, from July 1, 2011 to June 30, 2015, were assessed. Descriptive statistics were used to characterize the sample and logistic regression assessed the association of study epoch and key covariates on survival. RESULTS: Overall, 85,553 patients were assessed by Emergency Medical Services (EMS) and 45,516 (53.2%, site range 30.4%-69.9%) had resuscitation attempted by EMS. Patient and event characteristics were consistent except for increases in bystander CPR (41.3%-44.9%) and bystander AED application (3.9%-5.2%). EMS CPR depth and compression fraction increased while pre-shock pause interval decreased. Targeted temperature management was performed in 51.1% of admitted patients and early coronary angiography in 30.2%. Survival to hospital discharge improved (from 10.9% to 11.3% across epochs) with epoch significantly associated with survival (p < 0.001) showing an increasing trend in survival over time. (p = 0.02). Marked site variation in survival persisted within and across epochs (overall site range: 4.2%-19.8%). Patients with an initially shockable rhythm (VT/VF) had an overall survival of 32.2% (site range: 11.9%-47.1%) while survival in bystander witnessed VT/VF was 35.8% (site range: 12.9%-53.1%). CONCLUSIONS: Survival from adult OHCA in multiple large geographically-separate sites improved over the study period. Marked site differences in survival persist and addressing this variation is essential to improve outcomes from OHCA across North America.

A randomized controlled clinical trial on the effectiveness of cinnamon tea in reducing menopausal symptoms among perimenopausal women / The Health Sciences Journal

INTRODUCTION@#Women in the perimenopausal period experience the height of menopausal symptoms due to the fluctuating levels of hormones because of ovarian dysfunction. This study aimed to determine the effect of cinnamon tea on menopausal symptoms among perimenopausal women.@*METHODS@#Perimenopausal women from Cainta, Rizal were recruited using cluster sampling and were randomly allocated into cinnamon tea or black tea groups. All participants were instructed to consume one tea bag once a day for 28 days. A response survey was conducted by the researchers using the Menopausal Rating Scale questionnaire every 2 weeks during the 28-day period to assess the number and severity of symptoms associated with perimenopausal stage.@*RESULTS@#The Menopausal Rating Scale scores of both cinnamon and placebo groups showed a statistically significant decrease in the number and severity of symptoms over time within groups. However, there was greater decrease in symptom number and severity among the cinnamon tea group and the difference was significant.@*CONCLUSION@#Cinnamon tea resulted in a decrease in the severity of perimenopausal symptoms and maybe an effective, economical and accessible alternative treatment for perimenopausal symptoms.

Non-equilibrium cobalt(iii) "click" capsules.

Cobalt(iii) tetrahedral capsules have been prepared using an assembly-followed-by-oxidation protocol from a cobalt(ii) precursor and a readily derivatizable pyridyl-triazole ligand system. Experiments designed to probe the constitutional dynamics show that these architectures are in a non-equilibrium state. A preliminary investigation into the host-guest chemistry of a water-soluble derivative shows it can bind and differentiate a range of different neutral organic molecules. The stability of this ensemble also permits the study of guest-binding at high salt concentrations.

On coenrollment in clinical resuscitation studies: review and experience from randomized trials.

CONTEXT: Patients with acute life-threatening illness are candidates for enrollment in multiple trials. Whether patients are enrolled in multiple trials has implications for patient safety, trial enrollment duration, and study validity. OBJECTIVE: We review issues related to coenrollment and propose guidelines for when it should be allowed. RESULTS: There is no regulatory prohibition on coenrollment of patients in more than one study. Randomized trials of interventions for a variety of clinical conditions have allowed coenrollment without any reported deleterious impact on either study. Guidelines for coenrollment are proposed.

Patterns of analgesic and anti-inflammatory medicine use by Australian veterans.

BACKGROUND: We examined analgesic and anti-inflammatory medicine use by Australian veterans before and after the introduction of selective Cox-2 inhibitors. METHODS: We studied cohorts of Gold Card-holding veterans using prescription data held by the Department of Veterans' Affairs for the period 1 July 1998 to 30 June 2004. Outcomes were volume dispensed, average daily quantity and cumulative incidence of use of paracetamol-containing and aspirin-containing medicines, non-selective and Cox-2-selective non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and dextropropoxyphene. RESULTS: Overall, we found high levels of use of analgesic and anti-inflammatory medicines, which increased by 43% over the study period. Use of paracetamol-containing medicines was overtaken by NSAIDs in 1999/2000, corresponding to the introduction of the Cox-2-selective agents. Between 12 and 17% of Cox-2-selective medicine recipients were supplied amounts indicative of continuous use in relatively high doses and 51% of veterans received at least one relatively Cox-2-selective medicine (celecoxib, rofecoxib, meloxicam, diclofenac) by the end of the study period. Dextropropoxyphene use declined during the study and tramadol use increased 10-fold. CONCLUSION: This study shows very high levels of Cox-2 inhibitor use during the 6-year period. Cox-2-selective agents were more likely to be taken continuously and at higher doses than non-selective NSAIDs. This is relevant in view of the cardiovascular toxicity of this group of medicines. The study shows the value of using unit record dispensing data to assess drug use patterns. Linking dispensing records to hospital separation and mortality data will further enhance our ability to monitor drug safety.

CCS/CAR/CANM/CNCS/CanSCMR joint position statement on advanced noninvasive cardiac imaging using positron emission tomography, magnetic resonance imaging and multidetector computed tomographic angiography in the diagnosis and evaluation of ischemic heart disease--executive summary.

BACKGROUND: Over the past few decades, advanced imaging modalities with excellent diagnostic capabilities have emerged. The aim of the present position statement was to systematically review existing literature to define Canadian recommendations for their clinical use. METHODS: A systematic literature review to 2005 was conducted for positron emission tomography (PET), multidetector computed tomographic angiography and magnetic resonance imaging (MRI) in ischemic heart disease. Papers that met the criteria were reviewed for accuracy, prognosis data and study quality. Recommendations were presented to primary and secondary panels of experts, and consensus was achieved. RESULTS: Indications for PET include detection of coronary artery disease (CAD) with perfusion imaging, and defining viability using fluorodeoxyglucose to determine left ventricular function recovery and/or prognosis after revascularization (class I). Detection of CAD in patients, vessel segments and grafts using computed tomographic angiography was considered class IIa at the time of the literature review. Dobutamine MRI is class I for CAD detection and, along with late gadolinium enhancement MRI, class I for viability detection to predict left ventricular function recovery. Imaging must be performed at institutions and interpreted by physicians with adequate experience and training. CONCLUSIONS: Cardiac imaging using advanced modalities (PET, multidetector computed tomographic angiography and MRI) is useful for CAD detection, viability definition and, in some cases, prognosis. These modalities complement the more widespread single photon emission computed tomography and echocardiography. Given the rapid evolution of technology, initial guidelines for clinical use will require regular updates. Evaluation of their integration in clinical practice should be ongoing; optimal use will require proper training. A joint effort among specialties is recommended to achieve these goals.

International Resuscitation Network Registry: design, rationale and preliminary results.

There is a lack of high-quality information about the effectiveness of resuscitation interventions and international differences in structure, process and outcome after out-of-hospital cardiac arrest and cardiopulmonary resuscitation because data are not collected uniformly. An internet-based international registry could make such evaluations possible, and enable the conduct of large randomized controlled trials of resuscitation therapies. A prospective international cohort study was performed that included 571 infants, children and adults (a) who experienced cardiac arrest requiring chest compressions or external defibrillation, (b) outside the hospital in the study communities and (c) upon whom resuscitation was attempted by EMS personnel. Cardiac arrest was defined as lack of responsiveness, breathing or movement in individuals for whom the EMS system is activated for whom an arrest record is completed. All data were collated via a secure and confidential web-based method by using automated forms processing software with appropriate variable range checks, logic checks and skip rules. Median number of missing responses for each variable was 0 (interquartile range 0, 0). Twenty-seven percent of the patients had a first recorded rhythm of ventricular fibrillation or ventricular tachycardia, 60% had a witnessed arrest, and 34% received bystander CPR. Mean time from call to arrival on scene was 7.1+/-5.1 min. Six percent of the patients survived to hospital discharge. The resuscitation process was highly variable across centers, and survival and neurological outcome were also significantly and independently different across centers. This study shows that it is possible to collect data prospectively describing the structure, process and outcome associated with cardiac arrest in multiple international sites via the internet. Therefore, it is feasible to conduct adequately powered randomized trials of resuscitation therapies in international settings.

Impact of informed consent requirements on cardiac arrest research in the United States: exception from consent or from research?

INTRODUCTION: Research in patients with life-threatening illness such as cardiac arrest is challenging since they can not consent. The Food and Drug Administration addressed research under emergency conditions by publishing new criteria for exception from informed consent in 1996. We systematically reviewed randomized trials over a 10-year period to assess the impact of these regulations. METHODS: Case-control study of published trials for cardiac arrest (cases) and atrial fibrillation (controls.) Studies were identified by using structured searches of MEDLINE and EMBASE from 1992 to 2002. Included were studies using random allocation in humans with cardiac arrest or atrial fibrillation prior to enrollment. Excluded were duplicate publications. Number of American trials, foreign trials and proportion of trials of American origin were compared by using regression analysis. Changes in cardiac arrest versus atrial fibrillation trials were calculated as risk differences. RESULTS: Of 4982 identified cardiac arrest studies, 57 (1.1%) were randomized trials. The number of American cardiac arrest trials decreased by 15% (95% CI: 8, 22%) annually (P = 0.05). The proportion of cardiac arrest trials of American origin decreased by 16% (95% CI: 10, 22%) annually (P = 0.006). Of 5596 identified atrial fibrillation studies, 197 trials (3.5%) were randomized trials. The risk difference between cardiac arrest versus atrial fibrillation trials being of American origin decreased significantly (annual difference -5.8% (95% CI: -10, -0.1%), P = 0.03). INTERPRETATION: Fewer American cardiac arrest trials were published during the last decade, when federal consent requirements changed. Regulatory requirements for clinical trials may inhibit improvements in care and threaten public health.

Variation in outcome in studies of out-of-hospital cardiac arrest: a review of studies conforming to the Utstein guidelines.

The objective of this study was to systematically review studies on out-of-hospital cardiac arrest published according to the Utstein guidelines to describe the variability in factors of resuscitation and outcome. Articles that reported primary data on survival after out-of-hospital cardiac arrest in the Utstein style were included. Forty-seven articles were identified using Medline. Fourteen studies met our criteria for inclusion. The number of patients in whom resuscitation was attempted varied between 78 and 3,243. The proportion of bystander-witnessed cases varied between 38% and 89%; bystander CPR was performed in 21% to 56% of the cases. Patients with a bystander-witnessed cardiac arrest of cardiac etiology were discharged alive in 2% to 49% of the cases. Even when data are reported in a uniform way as suggested by the Utstein template, there is a tremendous variability in outcome. This did not appear to be entirely explained by variability in the traditional risk factors for a low chance of survival. One cannot exclude the possibility of other factors being of ultimate importance for the outcome.

Cost effectiveness of defibrillation by targeted responders in public settings.

BACKGROUND: Out-of-hospital cardiac arrest is frequent and has poor outcomes. Defibrillation by trained targeted nontraditional responders improves survival versus historical controls, but it is unclear whether such defibrillation is a good value for the money. Therefore, this study estimated the incremental cost effectiveness of defibrillation by targeted nontraditional responders in public settings by using decision analysis. METHODS AND RESULTS: A Markov model evaluated the potential cost effectiveness of standard emergency medical services (EMS) versus targeted nontraditional responders. Standard EMS included first-responder defibrillation followed by advanced life support. Targeted nontraditional responders included standard EMS supplemented by defibrillation by trained lay responders. The analysis adopted a US societal perspective. Input data were derived from published or publicly available data. Future costs and effects were discounted at 3%. Monte Carlo simulation and sensitivity analyses assessed the robustness of results. Standard EMS had a median of 0.47 (interquartile range [IQR]=0.32 to 0.69) quality-adjusted life years and a median of 14 100 dollars (IQR=8600 dollars to 21 900 dollars) costs per arrest. Targeted nontraditional responders in casinos had an incremental cost of a median 56 700 dollars (IQR=44 100 dollars to 77 200 dollars) per additional quality-adjusted life year. The results were sensitive to changes in time to defibrillation, incidence of arrest, and number of devices required to implement rapid defibrillation. CONCLUSIONS: Where cardiac arrest is frequent and response time intervals are short, rapid defibrillation by targeted nontraditional responders may be a good value for the money compared with standard EMS. The incidence of arrest should be considered when choosing locations to implement public access defibrillation.

Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation.

OBJECTIVE: To conduct a meta-analysis of randomised controlled trials to estimate the effectiveness of antiarrhythmic drugs at promoting sinus rhythm in patients with atrial fibrillation. DESIGN: Articles were identified by using a comprehensive search of English language papers indexed in Medline from 1966 to August 2001. For the outcomes of sinus rhythm and death, a random effects model was used to model repeated assessments within a study at different time points. SETTING: Emergency departments and ambulatory clinics. PATIENTS: Patients with atrial fibrillation. INTERVENTIONS: Antiarrhythmic agents grouped according to their Vaughan-Williams class. MAIN OUTCOME MEASURES: Sinus rhythm and mortality. RESULTS: 91 articles met a priori criteria for inclusion in the analysis. Median duration of follow up was one day (range 0.04-1096, mean (SD) 46 (136) days). The median proportion of patients in sinus rhythm at follow up was 55% (range 0-100%) and 32% (range 0-90%) receiving active treatment and placebo, respectively. Median survival was 99% (range 55-100%) and 99% (range 55-100%). Compared with placebo, the following drug classes were associated with increased sinus rhythm at follow up: IA (treatment difference 21.5%, 95% confidence interval (CI) 16.3% to 26.8%); IC (treatment difference 33.1%, 95% CI 23.3% to 42.9%); and III (treatment difference 17.4%, 95% CI 11.5% to 23.3%). Class IC drugs were associated with increased sinus rhythm at follow up compared with class IV drugs (treatment difference 43.2%, 95% CI 11.5% to 75.0%). There was no significant difference in mortality between any drug classes. CONCLUSIONS: Class IA, IC, and III drugs are associated with increased sinus rhythm at follow up compared with placebo. It is unclear whether any antiarrhythmic drug class is associated with increased or decreased mortality.

The effect of perioperative aspirin therapy in peripheral vascular surgery: a decision analysis.

Patients who undergo infrainguinal revascularization surgery are at increased risk for perioperative thrombotic complications. Aspirin decreases thrombotic events in the nonoperative setting; however, aspirin is often discontinued to avoid perioperative hemorrhagic complications. We used a decision analysis to determine whether aspirin should be discontinued before infrainguinal revascularization surgery. Two strategies were compared: aspirin cessation 2 wk before surgery and aspirin continuation throughout the perioperative period. Clinical events examined included myocardial infarction, thrombotic cerebrovascular accident, hemorrhagic cerebrovascular accident, gastrointestinal hemorrhage, and incisional hemorrhagic complications. Event rates and effect of aspirin were obtained by using MEDLINE. The outcomes were perioperative mortality, life expectancy, and quality-adjusted life expectancy. According to the model, continued aspirin use decreased perioperative mortality rates from 2.78% to 2.05%. Continued aspirin use increased life expectancy from 14.83 to 14.89 yr and increased quality-adjusted life expectancy from 14.72 to 14.79 yr. Aspirin increased the number of hemorrhagic complications by 2.46%, primarily because of an increased incidence of non-life-threatening complications.