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Dabigatran Reversal Agent – Idarucizumab
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Thanks to Rob MacSweeney's fantastic Critical Care Reviews I learned of Idarucizumab, a monoclonal antibody fragment that binds the (pesky) anticoagulant dabigatran. Two industry-supported studies this week show rapid, complete reversal of anticoagulation in healthy volunteers(1) and patients who were either bleeding or undergoing procedures(2). The dose given to patients was 5g intravenously.
An accompanying editorial(3) highlights that the clinical study did not have a control group, and these patients had a high mortality. Further controlled studies examining patient-orientated outcomes will be helpful.
Of interest, another editorialist(4) lists other potential antidotes for Non-vitamin-K antagonist oral anticoagulants (NOACs) that have been or are being tested: an antidote against all oral direct factor Xa inhibitors called andexanet alpha (a recombinant activated factor X that binds direct factor Xa inhibitors), and a modified thrombin has been shown to be effective in vitro and in animals for reversal of dabigatran and potentially also other direct thrombin inhibitors.
1. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial
The Lancet Volume 386, No. 9994, p680–690, 15 August 2015
BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study.
METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m2 into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830.
FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.
INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress.
2. Idarucizumab for Dabigatran Reversal
N Engl J Med. 2015 Aug 6;373(6):511-20
BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran.
METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis.
RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.
CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).
3. Targeted Anti-Anticoagulants
N Engl J Med. 2015 Aug 6;373(6):569-71
4. Antidotes for anticoagulants: a long way to go
The Lancet Volume 386, No. 9994, p634–636, 15 August 2015
Esmolol for refractory VF
Already well publicised on social media, the team at Hennepin County published a retrospective comparison between patients with refractory VF who received esmolol with those who did not(1). The results are impressive and I look forward to further studies on this.
I work in an ED in a hospital with no cath lab and no access to extracorporeal life support, limiting our options for patients who remain in shockable rhythms despite ACLS interventions. We now have esmolol available in our resus room. You might want to keep it in your list of options for ACLS-refractory VF, which might also include double sequential external defibrillation(2) and even stellate ganglion block.
The dose of esmolol used was: loading dose 500 mcg/kg, followed by infusions of 0, 50, or 100 mcg/kg/min
An important point to note in the esmolol study is that almost all patients received high-quality mechanical CPR with the combined use of an impedence threshold device to augment venous return and cardiac output. The authors "speculate that this additional hemodynamic support may be essential given the hypotensive effects of esmolol."
1. Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation
Resuscitation. 2014 Oct;85(10):1337-41
INTRODUCTION: We compare the outcomes for patients who received esmolol to those who did not receive esmolol during refractory ventricular fibrillation (RVF) in the emergency department (ED).
METHODS: A retrospective investigation in an urban academic ED of patients between January 2011 and January 2014 of patients with out-of-hospital or ED cardiac arrest (CA) with an initial rhythm of ventricular fibrillation (VF) or ventricular tachycardia (VT) who received at least three defibrillation attempts, 300mg of amiodarone, and 3mg of adrenaline, and who remained in CA upon ED arrival. Patients who received esmolol during CA were compared to those who did not.
RESULTS: 90 patients had CA with an initial rhythm of VF or VT; 65 patients were excluded, leaving 25 for analysis. Six patients received esmolol during cardiac arrest, and nineteen did not. All patients had ventricular dysrhythmias refractory to many defibrillation attempts, including defibrillation after administration of standard ACLS medications. Most received high doses of adrenaline, amiodarone, and sodium bicarbonate. Comparing the patients that received esmolol to those that did not: 67% and 42% had temporary return of spontaneous circulation (ROSC); 67% and 32% had sustained ROSC; 66% and 32% survived to intensive care unit admission; 50% and 16% survived to hospital discharge; and 50% and 11% survived to discharge with a favorable neurologic outcome, respectively.
CONCLUSION: Beta-blockade should be considered in patients with RVF in the ED prior to cessation of resuscitative efforts.
2. Double Sequential External Defibrillation in Out-of-Hospital Refractory Ventricular Fibrillation: A Report of Ten Cases.
Prehosp Emerg Care. 2015 January-March;19(1):126-130
Background. Ventricular fibrillation (VF) is considered the out-of-hospital cardiac arrest (OOHCA) rhythm with the highest likelihood of neurologically intact survival. Unfortunately, there are occasions when VF does not respond to standard defibrillatory shocks. Current American Heart Association (AHA) guidelines acknowledge that the data are insufficient in determining the optimal pad placement, waveform, or energy level that produce the best conversion rates from OOHCA with VF.
Objective. To describe a technique of double sequential external defibrillation (DSED) for cases of refractory VF (RVF) during OOHCA resuscitation.
Methods. A retrospective case series was performed in an urban/suburban emergency medical services (EMS) system with advanced life support care and a population of 900,000. Included were all adult OOHCAs having RVF during resuscitation efforts by EMS providers. RVF was defined as persistent VF following at least 5 unsuccessful single shocks, epinephrine administration, and a dose of antiarrhythmic medication. Once the patient was in RVF, EMS personnel applied a second set of pads and utilized a second defibrillator for single defibrillation with the new monitor/pad placement. If VF continued, EMS personnel then utilized the original and second monitor/defibrillator charged to maximum energy, and shocks were delivered from both machines simultaneously. Data were collected from electronic dispatch and patient care reports for descriptive analysis.
Results. From 01/07/2008 to 12/31/2010, a total of 10 patients were treated with DSED. The median age was 76.5 (IQR: 65-82), with median resuscitation time of 51minutes (IQR: 45-62). The median number of single shocks was 6.5 (IQR: 6-11), with a median of 2 (IQR: 1-3) DSED shocks delivered. VF broke after DSED in 7 cases (70%). Only 3 patients (30%) had ROSC in the field, and none survived to discharge.
Conclusion. This case series demonstrates that DSED may be a feasible technique as part of an aggressive treatment plan for RVF in the out-of-hospital setting. In this series, RVF was terminated 70% of the time, but no patient survived to discharge. Further research is needed to better understand the characteristics of and treatment strategies for RVF.
Atropine for Paediatric RSI?
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In some areas it has been traditional to pre-medicate or co-medicate with atropine when intubating infants and children, despite a lack of any evidence showing benefit. It is apparently still in the American Pediatric Advanced Life Support (PALS) Provider Manual when age is less than 1 year or age is 1–5 years and receiving succinylcholine. However it is not recommended with rapid sequence intubation in the British and Australasian Advanced Paediatric Life Support manual and course.
A French non-randomised observational study compares intubations with and without atropine in the neonatal and paediatric critical care setting. Atropine use was associated with significant acceleration of heart rate, and no atropine use was associated with a higher incidence of new dysrhythmia, the most common being junctional rhythm, but with none appearing to be clinically significant.
The incidence of the most important peri-intubation cause of bradycardia – hypoxia – is not reported. It is also not clear how many intubation attempts were required. The authors admit:
"it is not possible using our methodology to deduce whether bradycardia was due to hypoxia, laryngoscopy, or sedation drugs."
Actual rapid sequence was rarely employed – their use of muscle relaxants was low – making this difficult to extrapolate to modern emergency medicine / critical care practice.
My take home message here is that this study provides no argument whatsoever for the addition of atropine in routine RSI in the critically ill child. Why complicate a procedure with an unnecessary tachycardia-causing drug when the focus should be on no desat / no hypotension / first look laryngoscopy?
The Effect of Atropine on Rhythm and Conduction Disturbances During 322 Critical Care Intubations
Pediatr Crit Care Med. 2013 Jul;14(6):e289-97
OBJECTIVES: Our objectives were to describe the prevalence of arrhythmia and conduction abnormalities before critical care intubation and to test the hypothesis that atropine had no effect on their prevalence during intubation.
DESIGN: Prospective, observational study.
SETTING: PICU and pediatric/neonatal intensive care transport.
SUBJECTS: All children of age less than 8 years intubated September 2007-2009. Subgroups of intubations with and without atropine were analyzed.
INTERVENTION: None.
MEASUREMENT AND MAIN RESULTS: A total of 414 intubations were performed in the study period of which 327 were available for analysis (79%). Five children (1.5%) had arrhythmias prior to intubation and were excluded from the atropine analysis. Atropine was used in 47% (152/322) of intubations and resulted in significant acceleration of heart rate without provoking ventricular arrhythmias. New arrhythmias during intubation were related to bradycardia and were less common with atropine use (odds ratio, 0.14 [95% CI, 0.06-0.35], p < 0.001). The most common new arrhythmia was junctional rhythm. Acute bundle branch block was observed during three intubations; one Mobitz type 2 rhythm and five ventricular escape rhythms occurred in the no-atropine group (n = 170). Only one ventricular escape rhythm occurred in the atropine group (n = 152) in a child with an abnormal heart. One child died during intubation who had not received atropine.
CONCLUSIONS: Atropine significantly reduced the prevalence of new arrhythmias during intubation particularly for children over 1 month of age, did not convert sinus tachycardia to ventricular tachycardia or fibrillation, and may contribute to the safety of intubation.
Etomidate – there is always a downside
January 14, 2014 by Viking One
Filed under All Updates, ICU
By Norwegian intensivist/anaesthetist/HEMS Physician Dr Per Bredmose.
[Warning – Rant level: Viking]
Etomidate has for a long time been known in some countries as the "drug of choice" for RSI in unstable/fragile patients. This is due to the fact that induction with etomidate is fairly cardiovascularly stable. However, there is a down side: a subsequent suppression of adrenal function. This was initially discovered after etomidate was used for sedation infusions on ICU.
It has for a long time been debated whether this is a side effect with clinical implications after a single dose induction… and yes it has.
A recent Japanese study demonstrates this(1). This is a large propensity based study. Now, propensity based statistics are pretty complex to explain. In short, it is an advanced method to strengthen the statistics when comparing groups in non-cross over studies.
In this study 2616 patients receiving etomidate for induction and a volatile agent for maintenance are included.
This showed an increased OR for 30-days mortality with a factor of 2.5 and 1.5 times greater chance for a major cardiovascular event in hospital. Interestingly enough, there were no significant differences in either perioperative vasopressor use or infections complications during hospital stay.
What does this mean?
In my mind and experience, it strengthens the fact that there is no wonder drug. And also that there seems to be a reason for why etomidate is de-registered in many countries.
Also, it tells me that for a safe prehospital RSI we need physicians capable of clinical judgment and "decision making" to tailor an (any) induction agent to the specific individual patient. In my mind, there is no room for an etomidate-only (dose / weight) induction protocol!
1. Komatsu R, You J, Mascha EJ, Sessler DI, Kasuya Y, Turan A.
Anesthetic induction with etomidate, rather than propofol, is associated with increased 30-day mortality and cardiovascular morbidity after noncardiac surgery.
Anesth Analg. 2013 Dec;117(6):1329-37
Beta blockers potentially beneficial in septic shock
November 17, 2013 by Cliff
Filed under Acute Med, All Updates, ICU, Resus
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Counterintuitive as it sounds, this is pretty cool. I blogged about these guys before when they published their findings on microcirculatory flow in septic patients given beta blockers.
It's a small study – 77 patients with septic shock and a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of at least 65 mm Hg were randomised to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay. 77 patients received standard treatment. It should be noted the primary outcome (target heart rate) was not a patient-oriented endpoint. Interestingly though, there were no increased adverse events in the beta blocker group, which demonstrated improved left ventricular stroke work, lower lactate levels, decreased noradrenaline and fluid requirements, improved oxygenation, and a lower mortality.
Caution is appropriate here though: this study was a small, single-centre open-label trial. It will be very interesting to see if these effects are reproduced and whether they will ultimately translate to meaningful outcome benefits.
Read more about the study at the PulmCCM site.
There is also a great critical appraisal of the study at Emergency Medicine Literature of Note/a>.
Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial
JAMA. 2013 Oct 23;310(16):1683-91
IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects.
OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock.
DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher.
INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment.
MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization.
RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001).
CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
Beta blockade in sepsis
September 4, 2013 by Cliff
Filed under Acute Med, All Updates, ICU, Resus
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What do septic patients need if they remain shocked after fluid resuscitation? Catecholamines right? Let's stimulate some adrenoceptors and support that circulation!
Sydney's Prof Myburgh has told us why adrenaline (epinephrine) and noradrenaline (norepinephrine) are the go-to vasoactive choices, and Prof Singer from London likes to remind us about the detrimental effects of these drugs – the pros and cons are listed here. Tachycardia is associated with worse outcomes in sepsis, and the balance of oxygen supply and demand can be difficult to achieve. Beta blocking drugs could reduce tachycardia, but there does seem to be something counter-intuitive about giving both beta-blockers and catecholamines in the same patient. You might expect that beta blockers would cause fall in cardiac output and worsen tissue perfusion.
A small study previously showed possible helpful effects of beta blockers in children with burns. The potential benefits may extend beyond control of heart rate to anti-inflammatory / anti-catabolic effects. A recent publication evaluated beta blockers in adult patients with septic shock, which appears to be a pilot study for an ongoing randomised controlled trial.
They included patients who had been fluid resuscitated and who required noradrenaline, and treated them with a titrated esmolol infusion commenced at 25 mg/hr, with an upper dose limit of 2,000 mg/hr, to maintain a predefined HR range between 80 and 94 beats per minute. Esmolol was chosen because of its half-life of approximately 2 min, so any adverse effects could be rapidly reversed. They examined the macrocirculation using pulmonary artery catheterisation and the microcirculation using sublingual microvascular blood flow imaging.
Most of the patients had pneumonia, and interestingly, all patients received intravenous hydrocortisone (200mg/d) as a continuous infusion.
In this small cohort of patients, they found that titrating the heart rate to less than 95 bpm was associated with maintenance of stroke volume and preservation of microvascular blood flow. Although cardiac output fell because of the lower HR, stroke volume, MAP, and lactate levels were unchanged while noradrenaline requirements were reduced.
- blockade of a peripheral β2-mediated vasodilatory effect of noradrenaline
- decreased clearance of infused noradrenaline
- a centrally mediated effect on reflex activity
- inhibition of vascular endothelial nitric oxide synthase activity
Microvascular Effects of Heart Rate Control With Esmolol in Patients With Septic Shock: A Pilot Study
Crit Care Med. 2013 Sep;41(9):2162-2168
OBJECTIVE: β-blocker therapy may control heart rate and attenuate the deleterious effects of β-stimulating catecholamines in septic shock. However, their negative chronotropy and inotropy may potentially lead to an inappropriately low cardiac output, with a subsequent compromise of microvascular blood flow. The purpose of the present pilot study was to investigate the effects of reducing heart rate to less than 95 beats per minute in patients with septic shock using the β-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation.
DESIGN: Prospective, observational clinical study.
SETTING: Multidisciplinary ICU at a university hospital.
MEASUREMENTS AND MAIN RESULTS: After 24 hours of initial hemodynamic optimization, 25 septic shock patients with a heart rate greater than or equal to 95 beats per minute and requiring norepinephrine to maintain mean arterial pressure greater than or equal to 65 mm Hg received a titrated esmolol infusion to maintain heart rate less than 95 beats per minute. Sublingual microcirculatory blood flow was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 24 hours after esmolol administration. Heart rates targeted between 80 and 94 beats per minute were achieved in all patients. Whereas cardiac index decreased (4.0 [3.5; 5.3] vs 3.1 [2.6; 3.9] L/min/m; p < 0.001), stroke volume remained unchanged (34 [37; 47] vs 40 [31; 46] mL/beat/m; p = 0.32). Microcirculatory blood flow in small vessels increased (2.8 [2.6; 3.0] vs 3.0 [3.0; 3.0]; p = 0.002), while the heterogeneity index decreased (median 0.06 [interquartile range 0; 0.21] vs 0 [0; 0]; p = 0.002). PaO2 and pH increased while PaCO2 decreased (all p < 0.05). Of note, norepinephrine requirements were significantly reduced by selective β-1 blocker therapy (0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p = 0.03).
CONCLUSIONS: This pilot study demonstrated that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.
Xenon – no bull?
August 31, 2013 by Cliff
Filed under All Updates, ICU
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Xenon, an inert 'noble' gas with proven anaesthetic properties, has possible neuroprotective properties and appears to be also cardioprotective in this small study of post-cardiac arrest patients. Its high viscosity affects airway resistance, resulting in higher peak pressures and the need for a strategy to avoid gas trapping (ie. longer expiratory times as with asthma). Apparently it's expensive, but these results suggest further study is warranted.
Feasibility and Cardiac Safety of Inhaled Xenon in Combination With Therapeutic Hypothermia Following Out-of-Hospital Cardiac Arrest
Crit Care Med. 2013 Sep;41(9):2116-24
OBJECTIVES: Preclinical studies reveal the neuroprotective properties of xenon, especially when combined with hypothermia. The purpose of this study was to investigate the feasibility and cardiac safety of inhaled xenon treatment combined with therapeutic hypothermia in out-of-hospital cardiac arrest patients.
DESIGN: An open controlled and randomized single-centre clinical drug trial (clinicaltrials.gov NCT00879892).
SETTING: A multipurpose ICU in university hospital.
PATIENTS: Thirty-six adult out-of-hospital cardiac arrest patients (18-80 years old) with ventricular fibrillation or pulseless ventricular tachycardia as initial cardiac rhythm.
INTERVENTIONS: Patients were randomly assigned to receive either mild therapeutic hypothermia treatment with target temperature of 33°C (mild therapeutic hypothermia group, n = 18) alone or in combination with xenon by inhalation, to achieve a target concentration of at least 40% (Xenon + mild therapeutic hypothermia group, n = 18) for 24 hours. Thirty-three patients were evaluable (mild therapeutic hypothermia group, n = 17; Xenon + mild therapeutic hypothermia group, n = 16).
MEASUREMENTS AND MAIN RESULTS: Patients were treated and monitored according to the Utstein protocol. The release of troponin-T was determined at arrival to hospital and at 24, 48, and 72 hours after out-of-hospital cardiac arrest. The median end-tidal xenon concentration was 47% and duration of the xenon inhalation was 25.5 hours. The frequency of serious adverse events, including inhospital mortality, status epilepticus, and acute kidney injury, was similar in both groups and there were no unexpected serious adverse reactions to xenon during hospital stay. In addition, xenon did not induce significant conduction, repolarization, or rhythm abnormalities. Median dose of norepinephrine during hypothermia was lower in xenon-treated patients (mild therapeutic hypothermia group = 5.30 mg vs Xenon + mild therapeutic hypothermia group = 2.95 mg, p = 0.06). Heart rate was significantly lower in Xenon + mild therapeutic hypothermia patients during hypothermia (p = 0.04). Postarrival incremental change in troponin-T at 72 hours was significantly less in the Xenon + mild therapeutic hypothermia group (p = 0.04).
CONCLUSIONS: Xenon treatment in combination with hypothermia is feasible and has favorable cardiac features in survivors of out-of-hospital cardiac arrest.
Clopidogrel and aspirin for TIA
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A large Chinese trial compared aspirin alone with combination aspirin / clopidogrel in patients who had had a TIA in the previous 24 hours. 90-day stroke outcome was reduced in the combination therapy group without an apparent increase in haemorrhage.
Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack
N Engl J Med. 2013 Jul 4;369(1):11-19
Background Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.
Methods In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.
Results Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.
Conclusions Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.
5 days of steroids for COPD exacerbation
July 8, 2013 by Cliff
Filed under Acute Med, All Updates, EMS, Resus
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A randomised trial showed 5 days of oral steroid therapy (40 mg prednisone) was non-inferior to 14 days' duration in delaying the next exacerbation.
Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial
JAMA. 2013 Jun 5;309(21):2223-31
IMPORTANCE: International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown.
OBJECTIVE: To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids.
DESIGN, SETTING, AND PATIENTS: REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011.
INTERVENTIONS: Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%.
MAIN OUTCOME AND MEASURE: Time to next exacerbation within 180 days.
RESULTS: Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.
CONCLUSIONS AND RELEVANCE: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.
Potential new therapy for acute heart failure
July 6, 2013 by Cliff
Filed under Acute Med, All Updates, ICU, Resus
Comments Off on Potential new therapy for acute heart failure
Interesting new drug to know about: Serelaxin, recombinant human relaxin-2. It's hard to assess the clinical significance of the statistically significant findings. Let's see if a benefit is replicated in future studies. It's hard to imagine a normotensive patient that can't be fixed with existing therapies though.
Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.
Lancet. 2013 Jan 5;381(9860):29-39
BACKGROUND: Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.
METHODS: RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.
FINDINGS: 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019).
INTERPRETATION: Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality


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Hillah Shriners News
2016 Circus
This year we welcome the Jordan World Circus again at 4 different locations: Douglas County, Josephine County, Jackson County and Klamath Falls.
For times, dates and pricing open the flyer below.
Hope to see you all out there!
2016 Donkey Basketball
Coming up on February 5th, 2016 is Hillah's Annual Donkey Basketball game!
Come on out and join us at the Jackson County Fairgrounds (Expo) for a fun filled game.
1 Peninger Road
Central Point, OR
Doors open at 4:30pm
Game starts at 6pm
$8 per attendee
Children 3 & under are free
*Proceeds are for the benefit of Hillah Shriners and are not tax deductible as a charitable contribution
Fall Ceremonial 2015
Coming up on November 6th & 7th is the Hillah Shriner's Fall Ceremonial.
Attached are copies of the Registration Form, Schedule and information on the Stated Meeting taking place on November 6th.
Deadline for Registration is November 2nd.
If you have any questions, contact:
Noble Don Wetzel (541) 840-5777
Noble Tom Shine (541) 297-0086
Kay at the office (541) 774-1305
East-West Football Game Sponsors
Future Sponsor:
For the past 62 years the Shriners number 1 fundraisers to benefit the Portland Shrine Hospital for children has been and continues today to be the East West Shrine All-Star Football Game. The game is held on August 1, 2015 at the Baker City High School Stadium in Baker City, Oregon.
The game is made possible from donations from individual people and business like you. All the personnel working to make this game possible are volunteers. There are no expense accounts paid from your donations. The net proceeds go directly to the hospital.
The teams are made up of high school seniors throughout the state. There is certain criteria to be consider for selection each player must meet.
This is an ideal time to show your support for these young people. I have enclosed sponsorship packages for both the ad book and air time, a complete list of the schools the players will be representing and material that will allow you to review the scope of the Shriners Hospitals and the work they do.
Please feel free to call IS Jack Adams, Secretary Josephine County Shrine Club or email him at anytime if you have any questions.
Phone: (541) 761-0322
Email: email@example.com
Please submit your charitable donation made out to
"East-West Game Baker City 2015"
and send to:
Josephine Count Shrine Club
PO Box 631
Grants Pass, OR
The deadline for ads and/or Air Time is June 1, 2015.
On behalf of the Shriners and the Shrine Hospitals, I wish to thank you in advance for you charitable donation.
Noble Michael Harder
President of Josephine County Shrine Club
*For more information open the file below.
Burn Awareness Week
2015 Shrine Circus
Donkey Basketball
The doors will open at 12:00 Noon. Game time is 2:00 PM. Plan on attending for a really good time. Food and soft drinks will be available to purchase.
There will be four (4) teams participating; with two main events between two eager teams. Those winners will play a third game for championship rights and a unique trophy.
Wolf Performance will be one of the teams participating. They took home the trophy last year and plan on winning another trophy this year. A couple of other competitors are the Jackson County Sheriff's Department, and The Medford Police Department. A fourth team is still to be selected.
Each team will have four (4) donkey riders with a fifth player on the floor. That person is restricted to about a 4' circle in the center of the court. To score the player has to be on a Donkeys back and somewhat in control of their animal. It is a lot of fun to watch, so come out and cheer for your favorite team.
For more information please contact:
Noble Don Wetzel
Assistant Rabban
(541) 840- 5777 - Cell
Medford Armory
1701 S. Pacific Hwy.
Medford 97501
February 14th, 2015 at 2:00 PM
Fundraiser for Medford Shrine Center
2015 Installation of Officers
Click the file below to print out a copy of the 2015 Installation flyer.
Hillah Annual Meeting - January 9, 2015
Hillah Annual Meeting
January 9, 2015
Where: Scottish Rite Center – Medford, Or.
Oasis: 6:00 PM
Annual (Stated) Meeting: 7:00 PM
Free Chili Dinner after meeting:
Chili, Cornbread, Salad, Dessert & Coffee
Note: This is our Annual Meeting to finish the 2014 business year before the start of the 2015 year.
(The Chili dinner will be after the Meeting.)
Note: Installation of 2015 Officers will be
Saturday January 10, 2015.
Your attendance is requested as we will be voting on the acceptance of the 2015 Operating Budget submitted at the last Stated Meeting (December 5, 2014)
Please RSVP by January 5, 2015 to the Hillah Office at: 541-774-1305 or
e-mail: firstname.lastname@example.com so we can
determine how many to prepare for.
From the Potentate – January 2015
The 2014 year is finishing and the 2015 year is about to start. This is my last monthly article as your Potentate as Potentate-elect Walt Hager and the 2015 Divan will be installed on January 10, 2015. I wish them well in the ensuing year.
I would like to take this time to thank all the Nobles and Ladies that have supported the events and activities of Hillah Shriners this past year. Your support and participation was essential to make these events a success. I hope that you enjoyed the themed dinners we presented this past year as we tried to have some fun at our social gatherings.
I would also like to thank all the Past Potentates that have helped me this past year. First of all, I would like to give a big thank you to my Chief Potentates Aid IS Bill Wirch and Lady Nanci for their help and assistance to Lady Laura and myself throughout the past year. Many other Past Potentates deserve special mention:
IS Steve Pomerleau our Ceremonial Master for the Fall Ceremonial in Brookings; IS Jim Westerfield our Hospital Transportation Chairman for his excellent service with the Hospital Transportation Representatives and arranging the out of state transportation of our patients; IS Bob Mallory for his excellent work as our Membership Chairman and all of his efforts in that respect; IS Irv Urie for his assistance on multiple occasions to many to mention; IS Jack Adams for his making distribution of event notices and getting information distributed via e-mails. These Past Potentates have assisted me whenever necessary and I am very grateful for their experienced guidance and support.
I would also like to say how appreciative I am for the excellent work performed by our Noble Treasurer Reg Powell; his professional and extremely competent approach to the financial affairs of Hillah Shriners was outstanding. Working with Hillah's financial advisor Noble Joe Spurgeon and the Finance Committee, our financial accounts were handled successfully, profitably and in the best interests of Hillah Shriners. To all the above mentioned Nobles; well done!
Last but certainly not least, I am thankful for my Lady Laura who has supported me throughout my journey through the Divan and this last year as your Potentate. I could not have made this journey without her understanding, patience and assistance. She was instrumental in making the themed dinners fun and highly successful. I know how many hours she has spent on getting all the arrangements for these events prepared and constructed. I am most proud of her efforts with her First Ladies Project of raising a donation for the Northern California Shrine Hospital for Children which I had the pleasure to present at the Divan Days last November. Again, we would not have had so much success without the support of the Nobles and Ladies of Hillah Shriners. Thank you all for making 2014 a fun and very successful year. To all I wish; Es selamu aleikum.
IS Bruce Kundert
Potentate 2014
Hillah Shriners


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|VERACIOUS ENTROPY LLC Patent applications
|Patent application number
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What does volatile mean?
What does volatile mean?
4 Answers
Having a high degree of volatility; i.e. characterized by large price movements; for example, a high-flyer. opposite of stable
Volatile means changing or changeable. Its noun form is volatility, which refers to any of several measures of instability.
Explosive, having the ability to become hot and spew like a volcano. In large price movments you can see this.
In finance, volatility most frequently refers to the standard deviation of the continuously compounded returns of a financial instrument within a specific time horizon. It is used to quantify the risk of the financial instrument over the specified time period. ...en.wikipedia.org/wiki/Volatile_(economics)


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Diplomatic Activity With Middle East
Mr. Goshko discussed the goal of the United States to diffuse problems in the Middle East.
People in this video
- John Goshko Correspondent Washington Post
- Bruce Collins Host C-SPAN
Hosting Organization
Related Video
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Elaine Shannon discussed United States relations with Israel and the risks of a nuclear war.
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Mr. Knickerbocker discussed cutting the defense spending budget.
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Mary Beth Franklin discussed the federal deficit and the need to increase taxes.
United States Relations with Syria
Mr. Smith discussed the United States relations with Syria and its importance to resolving affairs in…


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The Rise of Electronic Cigarettes
New brands such as bluCigs, Green Smoke and NJOY have emerged recently. Unlike traditional cigarettes, e-cigs advertise on the radio and television and flaunt nicotine cartridges in a spectrum of flavors from chocolate to bubble gum. E-cigs are likely to appeal to kids and can easily be purchased online. Of high-school students who smoke in the U.S., 10.5 percent are African-American. (Photo: Spencer Platt/Getty Images)
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June 27 Is National HIV Testing Day06/27/2015
The Danger Behind Butt Injections06/04/2015
Major Slim Downs: Stars Who Underwent Weight Loss Surgery05/14/2015
Mother's Day Yoga With Faith Hunter05/10/2015
Nine Ways to Mentally Cope With Racial Injustice04/28/2015
Running a 5K: What You Need to Know04/24/2015
Health Rewind: 1,000 People Sent to Hospital Over Fake Weed04/21/2015
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Medical Racism: What You Need to Know04/16/2015
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Did Johns Hopkins Infect Study Participants With STDs?04/10/2015
Lessons From the Red Carpet: How Celebs Stay Healthy04/10/2015
The 411 on Young People and HIV/AIDS04/10/2015
The Todd Family: When Carbon Monoxide Kills04/08/2015
That Ain't True: 8 Myths About Autism04/07/2015
That Ain't True! Debunking 8 STD Myths04/03/2015
Processed Foods and What You Need to Know04/01/2015
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Obamacare Turns Five03/23/2015
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text:
|ISSN 1088-6826(online) ISSN 0002-9939(print)
Difference randomness
Abstract | References | Similar Articles | Additional Information
Abstract: In this paper, we define new notions of randomness based on the difference hierarchy. We consider various ways in which a real can avoid all effectively given tests consisting of -r.e. sets for some given . In each case, the -r.e. randomness hierarchy collapses for . In one case, we call the resulting notion difference randomness and show that it results in a class of random reals that is a strict subclass of the Martin-Löf random reals and a proper superclass of both the Demuth random and weakly 2-random reals. In particular, we are able to characterize the difference random reals as the Turing incomplete Martin-Löf random reals. We also provide a martingale characterization for difference randomness.
Retrieve articles in Proceedings of the American Mathematical Society with MSC (2010): 03D32
Retrieve articles in all journals with MSC (2010): 03D32
Additional Information


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©2012-2016 JillAuville
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2015 Participating Financial Institutions
|Abington Bank
Avidia Bank
Bank of Canton
Bay State Savings Bank
BayCoast Bank
Belmont Savings Bank
Boston Private Bank & Trust Company
Braintree Cooperative Bank
Canton Co-operative Bank
Cape Ann Savings Bank
Century Bank
Commerce Bank
Commonwealth Utilities Employees Credit Union
Country Bank
DCU - Digital Federal Credit Union
Dedham Institution for Savings
East Cambridge Savings Bank
Eastern Bank
Easthampton Savings Bank
Energy Credit Union
Equitable Co-operative Bank
Family Federal Savings, F.A.
Foxboro Federal Savings
Georgetown Bank
Greenfield Co-operative Bank
Hampden Bank
Haverhill Bank
Hometown Bank, A Cooperative Bank
Industrial Credit Union
Jeanne D'Arc Credit Union
Leader Bank
Lee Bank
Lowell Five Bank
Marblehead Bank
Mechanics Cooperative Bank
|Meetinghouse Bank
Melrose Cooperative Bank
Merrimac Savings Bank
Middlesex Savings Bank
Milford Federal Savings and Loan Association
Millbury Savings Bank
Monson Savings Bank
MountainOne Bank
Mutual Bank
MutualOne Bank
Newburyport Five Cents Savings Bank
North Cambridge Co-operative Bank
North Easton Savings Bank
Northmark Bank
NorthShore Bank
Norwood Bank
Patriot Community Bank
Peoples Federal Savings Bank
Pilgrim Bank
Rockland Trust Company
Salem Five Bank
Savers Bank
Seaman's Bank
Southbridge Savings Bank
STCU Credit Union
StonehamBank - A Co=operative Bank
Stoughton Co-Operative Bank
The Cape Cod Five Cents Savings Bank
The Pittsfield Cooperative Bank
The Provident Bank
The Village Bank
Wakefield Co-operative Bank
Walpole Co-operative Bank
Washington Savings Bank
Watertown Savings Bank
Wellesley Bank
Winchester Co-operative Bank
Winchester Savings Bank
Winter Hill Bank
Wrentham Co-operative Bank
The 76 financial institutions listed above qualify for Basic Banking for Massachusetts by providing both checking and savings accounts that meet the Basic Banking for Massachusetts guidelines. In addition, 26 other financial institutions provide either a checking or savings account that meet Basic Banking for Massachusetts guidelines. They are:
Attleboro Municipal Employees Federal Credit Union
Bank of Easton
Bridgewater Savings Bank
Brookline Bank
Charles River Bank
Colonial Federal Savings Bank
Commerce Bank
Commonwealth Cooperative Bank
Community Credit Union
Eagle Bank
Everett Co-operative Bank
Florence Savings Bank
GFA Federal Credit Union
Mansfield Bank
Metro Credit Union
Mills42 Federal Credit Union
Northern Bank & Trust Company
People's United Bank
Rollstone Bank & Trust
The Cooperative Bank
The Savings Bank
Westfield Bank
Weymouth Bank
Workers' Credit Union
Beverly Bank


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text:
1 John 1New American Standard Bible (NASB)
Introduction, The Incarnate Word
1 What was from the beginning, what we have heard, what we have seen with our eyes, what we have looked at and touched with our hands, concerning the Word of Life— 2 and the life was manifested, and we have seen and testify and proclaim to you the eternal life, which was with the Father and was manifested to us— 3 what we have seen and heard we proclaim to you also, so that you too may have fellowship with us; and indeed our fellowship is with the Father, and with His Son Jesus Christ. 4 These things we write, so that our joy may be made complete.
God Is Light
5 This is the message we have heard from Him and announce to you, that God is Light, and in Him there is no darkness at all. 6 If we say that we have fellowship with Him and yet walk in the darkness, we lie and do not practice the truth; 7 but if we walk in the Light as He Himself is in the Light, we have fellowship with one another, and the blood of Jesus His Son cleanses us from all sin. 8 If we say that we have no sin, we are deceiving ourselves and the truth is not in us. 9 If we confess our sins, He is faithful and righteous to forgive us our sins and to cleanse us from all unrighteousness. 10 If we say that we have not sinned, we make Him a liar and His word is not in us.
Cross references:
New American Standard Bible (NASB)
Copyright © 1960, 1962, 1963, 1968, 1971, 1972, 1973, 1975, 1977, 1995 by The Lockman Foundation
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and Publications
and Events
Conferences & Events
Annual Conference
EDUCAUSE Connect Events
EDUCAUSE Institute Programs
ELI Annual Meeting
ECAR Annual Meeting
NERCOMP Annual Conference
Security Professionals Conference
Enterprise IT Summit
Online Events
Webinars/Online Events Calendar
Event Resources
Fellowship/Scholarship Program
Presenter Concierge
EDUCAUSE On Campus
Other Higher Ed Event Calendar
Events for all Levels and Interests
Whether you're looking for a conference to attend face-to-face to connect with peers, or for an online event for team professional development, see what's upcoming.Stay
Career Center
EDUCAUSE Institute
Leadership and Management Programs
Project Management
Fellowships and Awards
Getting Involved
Jump Start Your Career Growth
Explore EDUCAUSE professional development opportunities that match your career aspirations and desired level of time investment through our interactive online guide.Stay
Focus Areas
and Initiatives
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The Black Cauldron
Based on the popular children's book series, The Prydain Chronicles, by Lloyd Alexander, The Black Cauldron follows the adventures of Taran (voice of Grant Bardsley), a young, assistant pig herder who cares for a prophetic porker sought after by the ill-intentioned Horned King (voice of Arthur Malet).
|MPAA Rating
|PG for some scary images.
|Theatrical Release
|July 24, 1985
|Jack Hannah, Richard Rich, Ted Berman
|Grant Bardsley, Freddie Jones, Susan Sheridan, June Foray, Clarence Nash
|Run Time
|1985 Walt DIsney Home Entertainment
|Official Movie Website
Full Review
Why did we give The Black Cauldron an overall grade of B? Read our full movie review for parents.
Content Details
Why is The Black Cauldron rated PG?
The Black Cauldron has a grade of B for sex, A- for language and B for violence. Find out why...
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[This post was originally published April 2013. It was completely updated and republished in October 2013. Most recent update: October 11, 2013.]
The impending retirement of Windows XP and Office 2003 shouldn't come as a surprise to anyone. As I've noted before, Microsoft has a well-established support lifecycle for its software products. It's basically an agreement that the company makes with everyone who commits to Windows. The terms of that agreement don't change often, which is an important assurance for business customers who tend to be conservative in their approach to upgrades.
For the next six months and counting, Microsoft will officially offer support for five versions of Windows for desktop and notebook PCs. Here's the rundown, starting with the newest member of the family:
Windows 8.1
Microsoft's official Windows 8.1 Support Lifecycle Policy treats this update as if it were a service pack for Windows 8. That means the lifecycle calculations start when Windows 8 shipped, in 2012.
This version is currently available only for Microsoft's volume licensing customers, MSDN and TechNet subscribers, and hardware OEM partners. It will be available to the public as a free update and in retail packages on October 18, 2013.
Mainstream support ends: January 9, 2018
Extended support ends: January 10, 2023
Windows 8
Windows 8 is fully supported today, but you need to update to Windows 8.1 to remain supported under the Windows 8 lifecycle. The deadline is "two years after the General Availability of the Windows 8.1 update," or October 18, 2015.
The same policy applies to Windows Server 2012 and 2012 R2 (equivalent to Windows 8.1).
Mainstream support ends: see Windows 8.1
Extended support ends: see Windows 8.1
Windows 7 Service Pack 1
This is currently the most popular release of Windows, and promises to hold that top spot for a long, long time. The following support dates require that you install Service Pack 1 (Windows 7 RTM support ended in April 2009).
Note that these dates are identical for Windows Server 2008 R2.
Mainstream support ends: January 13, 2015
Extended support ends: January 14, 2020
Windows Vista Service Pack 2
Fun fact: As of October 2013 the much-reviled Windows Vista was still in use on more computers than any version of OS X. The mainstream support phase ended in 2012, but extended support will continue for a few more years.
Mainstream support ends: No longer supported
Extended support ends: April 11, 2017
Windows XP Service Pack 3
Windows XP is more than 12 years old. It's midway through a year-long farewell tour , counting down to April 8, 2014, when Microsoft officially ends its support. XP lived longer than any version of Windows ever, getting multiple extensions on its retirement date to placate customers who said no to Vista. But April 2014 is the end of the road. XP will not get a last-minute reprieve.
Mainstream support ends: No longer supported
Extended support ends: April 8, 2014
Let me say that again: Microsoft will not extend the support deadline for XP. If you're still relying on XP, you should have a plan to switch to a supported platform, whether it's from Microsoft or someone else.
April 8, 2014 is a deadline. It's not a death sentence. PCs running XP will not stop working when the clock runs out. In fact, XP diehards won't notice anything different except an eerie quiet on the second Tuesday of each month. Newer versions, including Windows Vista, Windows 7, and Windows 8, will continue to get security patches and bug fixes via Windows Update, but not XP. When the extended support period ends, so do those updates. (Large enterprise customers who have custom support agreements with Microsoft and who are willing to pay a very steep price for the privilege might be able to get custom updates after the official end of support. But consumers and small businesses will not have that option.)
Meanwhile, it's become obvious that Windows 7 is the new Long Term Support version. If you're concerned that Microsoft is going to try to kill off Windows 7, you can relax. It's not time to start a "Save Windows 7" movement yet. You've got many years to ponder what comes next.
A couple of footnotes:
Windows RT doesn't exactly fit in the support policy, because it's sold only in combination with ARM-based hardware. Updates to both the operating system and the included Office 2013 programs are delivered through Windows Update. It cannot be upgraded to a different operating system. After a full year on the market, Microsoft's official Windows RT Product Support Lifecycle Policy FAQ still doesn't list any support lifecycle dates. Instead, it simply says:
Microsoft will make software updates, including security updates, available for Windows RT. Additional information regarding the Windows RT lifecycle policy will be communicated as available.
Microsoft has committed to a four-year support lifecycle for Surface RT, which is currently the only Windows RT device on the market.
And if you're curious about Server versions, the clock isn't ticking yet, but it's time to get just a little bit nervous. Extended support for Windows Server 2003 ends on July 14, 2015. That's less than two years away.
Next page: Office support dates and how the Support Lifecycle works
[For details about Windows support dates, see the previous page.]
Office support dates
The Office support lifecycle works just like Windows. Here are the support dates for each current member of the Office family:
Office 2013
This is the current release of Office, with a schedule that goes roughly three months past that of Windows 8. Mainstream support ends on April 10, 2018, with extended support continuing until April 11, 2023. (As a side note: the subscription-based Office 365 automatically updates itself to the most recent release, so it has no support lifecycle.)
Office 2010 Service Pack 2
Support for Service Pack 1 ends on October 14, 2014. But once you install Service Pack 2, you'll find this version is in its prime, with end of support dates that are 6 months after those of Windows 7. Mainstream support ends October 13, 2015, and the end date for extended support is not until October 13, 2020.
Office 2007 Service Pack 3
Earlier service pack release are no longer supported, and this group of products has already passed the end of mainstream support. Extended support ends on October 10, 2017.
Office 2003 Service Pack 3
This old-timer is on the same calendar as Windows XP, with mainstream support already ended and extended support slated to end on April 8, 2014.
How the support lifecycle works
For all versions of Windows and Office, Microsoft provides at least five years of mainstream support, followed by another five years of extended support. These lifecycles apply equally to business and home versions of Windows and Office. Service packs have separate end-of-support dates. For example, beginning next week you'll need to be running Service Pack 1 to get support for Windows 7. (There's an exhaustive FAQ if you want to dig deeper into this stuff.)
Generally, "supported" means you have access to at least one type of assisted support option (possibly paid) and no-charge security updates through channels like Windows Update and the Download Center.
The calculations start with the general availability (GA) date for each product. The official date of retirement for support is the second Tuesday in the first month of the quarter following that anniversary (which also happens to be Patch Tuesday). That grace period typically means a few weeks or months of extra support tacked on at the end of the five- and ten-year support cycles for each product.
For Windows 7, you can do the math yourself. The GA date for all Windows 7 editions was October 22, 2009. Five years after that date is October 22, 2014. The next calendar quarter begins in January, 2015, and the second Tuesday of that month is January 13. So, that's when mainstream support is scheduled to end. Extended support for business all editions goes an extra five years, until January 14, 2020, which happens to be the second Tuesday of that month. (Those calculations don't work for Windows XP, whose end-of-life date was extended artificially.)
To find the end-of-support date for any Microsoft product, use the Microsoft Product Lifecycle Search page, the product family index, or the full A-Z product index to get the official answer. When you find the entry for a specific product, you can see the general availability date, the retirement dates for mainstream and extended support, and retirement dates for service packs.


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Much has been made about Section 3.3.1 of the new iPhone developer's agreement: Applications may only use Documented APIs in the manner prescribed by Apple and must not use or call any private APIs. Applications must be originally written in Objective-C, C, C++, or JavaScript as executed by the iPhone OS WebKit engine, and only code written in C, C++, … Read More
iPhone OS 4.0 Jailbreak Confirmed (Video)
We reported yesterday that iPhone OS 4.0 had either been jailbroken already, or was on the verge of being jailbroken : [touchreviews.net] Well overnight iPhone Dev Team member MuscleNerd (@MuscleNerd) managed to complete the jailbreak, and released a video online of his exploits: In the video we can see a VNC server running on the new iPhone OS 4.0 Developer … Read More
Twitter acquires Tweetie: Renames it "Twitter for iPhone" makes it free
Tweetie were very late to update their app when the iPad was launched. Well, they didn't actually launch one. That made a few people curious. Now we know why. Twitter has just bought Atebits, the company who makes Tweetie for the iPhone. Tweetie will now be renamed as "Twitter for iPhone", and Tweetie's author, Loren Brichter, will be joining the … Read More
iPhone OS 4 SDK Hints At Improved Hardware
We have the iPad and iPhone OS 4.0. The only major item of speculation left for this year is the new iPhone. It is widely expected new iPhone hardware will be introduced at the Apple Worldwide Developer's Conference (WWDC) some time this summer. Thanks to some digging by MacRumors and TUAW it now appears a bit more of the new … Read More
iPhone OS 4.0 Initial analysis and Developers perspective
The next major iteration of Apple's strongest facet in it's increasing domination of the mobile marketplace is upon us, in the form of iPhone OS 4.0 Of course this is just a "sneak peak" of an OS which Apple promises boasts more than 100 new user features, and over 1500 new APIs for developers… Let's take a look at the … Read More
Tetris for iPad Game Review
Tetris Rating: EA Bring Tetris into the 21st Century With All the Fun of the Original & More! I'll confess, I've been a fan of Tetris ever since I got my very first GameBoy, I would play for hours in the hope of reaching the Holy Grail of the Space Shuttle launch. The great thing about it is its simplicity, … Read More
35% of iPad Apps are games: Report
Distimo, from their own About page, is an "innovative app store analytics company built to solve the challenges created by a widely fragmented app store marketplace filled with equally fragmented information and statistics." They offer a free service for Developers who are interested in monitoring the mobile app ecosystem. They also offer free analytics tools for developers so they can … Read More
iPhone OS 4.0 already Jailbroken?
iPhone OS 4.0 Jailbreak! As you probably know iPhone OS 4.0 was unveiled in the US yesterday, and was made available for download immediately as a Developer Preview. If you want to have a go then you need to sign up as an Apple Developer, pay $99 and then you're good to go. I have it installed on my 3G … Read More
Download iPhone OS 4 Keynote Event
Apple has updated their website with information about the upcoming iPhone OS update for iPhone, iPod touch and iPad. In the iPhone OS 4 event Apple gave us a sneak peek into the future of iPhone OS. The update will bring many highly anticipated features. If you missed our live coverage here, you can read our event roudup here. You can also … Read More
Apple iPhone OS 4.0 Keynote Event Roundup
Apple has certainly been on a streak lately. The public release of the iPad has been a complete success and now the details of the much anticipated iPhone OS 4.0. The new operating system has been the main object of speculation and rumor since the unveiling of the Apple tablet in January. Today's announcement finally threw back the curtain and … Read More
Apple patents "peer to peer financial transactions"
Could peer to peer financial transactions be part of the iPhone OS 4.0 sneak peek? Seems strange that it should suddenly pop up online now. I find the whole US patent thing a bit strange. It appears that anyone can patent anything, and then it's a big free for all in court where the lawyers make out like bandits. In … Read More
Live Coverage. Apple iPhone OS 4.0 Sneak Peek Keynote Event
With less than a week after a major product launch Apple's announcement of iPhone OS 4.0 event was quite unexpected. Apple will give us a sneak peek into the future of iPhone OS later today. The event will be live at Apple's Infinite Loop campus in Cupertino. There have been many rumors suggesting different features which could possibly be announced today. The … Read More
Apple to restrict multitasking in iPhone OS 4.0? (Speculation)
Some tech sites have started to hint at information they have that Apple will restrict multitasking in iPhone OS 4.0. We still don't know if Apple will even announce it tomorrow. But I do think it is probably the only other definite thing (other than iAds) that Apple could announce. Having said that it is a no-brainer in my opinion … Read More
Apple iPad Criticism and The Experience
Much of the criticism surrounding the iPad has been focused on the technical characteristics of the device. Its inability to run Flash, its lack of video conferencing capabilities, its non-existent USB ports, its closed system. Its interesting no one is attacking the iPad where it counts; squarely in the usage experience. A lot of tablet manufacturers are about to find … Read More
Accordéon iPad Music App Review
Accordéon Rating: Writing the review for this application is possibly one of the most difficult reviews that I've ever had to write. Actually, let me rephrase that. Most difficult I've had to score. I'll write my review and then perhaps you'll see what I mean. Accordéon is exactly that, it's an accordéon simulator for the iPad and in that it … Read More


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Corvallis 104.3 FM • Hood River 91.9 FM • Portland 90.7 FM
dr. zomb hosted and jason ulrick spun vinyl this is what he played:
ok success dungeni 7" shungu
segenya river jazz masela obado 7" papadisco
orch. mabonza minga A 7" afridisco
sandwidi pierre musso gwe lp kouri
akaba man okhou no mose lp ja ja
stanley murphy saint a tout a l'heure lp ?
miki jaga vbenosawenmuwenmwighaye s/t lp akpolla
This week's show is hosted by Dr. Zomb and he'll be joined by local collector and musician Jason Urick. He'll bring a selection of late '70's - early '80's juju, high life, and afrobeat for our listening pleasure. Check him out at http://jasonurick.com. Thanks to Karen from Mississippi Records for bringing us together.
Don't miss the 3 Hour THIEVERY CORPORATION Pledge Drive Special
Tuesday 10/11/2011 from 7-10pm
Dr. J will be Blending and Remixing the music of Thievery Corporation live in the studio for 3 hours focusing on the new album Culture of Fear as well as past Collaborations, Classics and Rarities. We will be offering offering a variety of Thank You Gifts including the new album "Culture of Fear", the Thievery Corporation DVD "Live @ Club 9:30" and the "Babylon Central" DVD directed by Eric Hilton of Thievery Corporation, where they provide the soundtrack and give you a view into the music scene of their DC home.
A Fall Membership Drive special edition of "Paula's Picks" from me to YOU!
Thank you for support during the Drive & every 1st & 3rd Thursday of the month. More importantly, thank YOU for supporting KBOO 90.7 FM!
This week's host Dr. Zomb will be joined in the air room by Eric Isaacson of Mississippi Records (Portland) and hopefully Hisham Mayet of Sublime Frequencies (Seattle). Both labels are resonsible for some of the best releases of obscure international music in the last several years or more. We will either feature African selections from their catalogs or maybe just play some of what they are listening to these days from the continent of Africa...
It will be the first day of KBOO's fall pledge drive and both labels have generously donated some cds and lps for us to use as thank-you gifts for you listeners who call in to subscribe during the show so tune in and support Africa O-YE! and KBOO!
Latest newsletter: January 2016
Past newsletters
The next regular monthly Board meeting will be Monday, February 22nd (the fourth Monday) at 6 pm at KBOO - 20 SE 8th Ave. Portland, and is open to the public
KBOO is seeking new board members! Please click here to find out more!
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541 by intelkuritsaWatch
©2012-2016 intelkuritsa
by Nikolay Lukianchikov
Your simple pictures (without makeup and so on) just stunningly beautiful.
Some women, just don't need stuff like that.
Some women, just don't need stuff like that.
true beauty
your expression is amazing and your eyes perfect...nice portrait...
Beautiful, classic portrait.
Stunning portrait!
...and each face, each woman, so full of emotion and mystery...
Beautiful, intense look!
Very strong portrait.
hello beauty, merry christmas