Quantum-limited optical time transfer for future geosynchronous links.

The combination of optical time transfer and optical clocks opens up the possibility of large-scale free-space networks that connect both ground-based optical clocks and future space-based optical clocks. Such networks promise better tests of general relativity1-3, dark-matter searches4 and gravitational-wave detection5. The ability to connect optical clocks to a distant satellite could enable space-based very long baseline interferometry6,7, advanced satellite navigation8, clock-based geodesy2,9,10 and thousandfold improvements in intercontinental time dissemination11,12. Thus far, only optical clocks have pushed towards quantum-limited performance13. By contrast, optical time transfer has not operated at the analogous quantum limit set by the number of received photons. Here we demonstrate time transfer with near quantum-limited acquisition and timing at 10,000 times lower received power than previous approaches14-24. Over 300 km between mountaintops in Hawaii with launched powers as low as 40 µW, distant sites are synchronized to 320 attoseconds. This nearly quantum-limited operation is critical for long-distance free-space links in which photons are few and amplification costly: at 4.0 mW transmit power, this approach can support 102 dB link loss, more than sufficient for future time transfer to geosynchronous orbits.

The time-programmable frequency comb and its use in quantum-limited ranging.

Two decades after its invention, the classic self-referenced frequency comb laser is an unrivalled ruler for frequency, time and distance metrology owing to the rigid spacing of its optical output1,2. As a consequence, it is now used in numerous sensing applications that require a combination of high bandwidth and high precision3-5. Many of these applications, however, are limited by the trade-offs inherent in the rigidity of the comb output and operate far from quantum-limited sensitivity. Here we demonstrate an agile programmable frequency comb where the pulse time and phase are digitally controlled with ±2-attosecond accuracy. This agility enables quantum-limited sensitivity in sensing applications as the programmable comb can be configured to coherently track weak returning pulse trains at the shot-noise limit. To highlight its capabilities, we use this programmable comb in a ranging system, reducing the required power to reach a given precision by about 5,000-fold compared with a conventional dual-comb system. This enables ranging at a mean photon per pulse number of 1/77 while retaining the full accuracy and precision of a rigid frequency comb. Beyond ranging and imaging6-12, applications in time and frequency metrology1,2,5,13-23, comb-based spectroscopy24-32, pump-probe experiments33 and compressive sensing34,35 should benefit from coherent control of the comb-pulse time and phase.

Optical timing jitter due to atmospheric turbulence: comparison of frequency comb measurements to predictions from micrometeorological sensors.

During propagation through atmospheric turbulence, variations in the refractive index of air cause fluctuations in the time-of-flight of laser light. These timing jitter fluctuations are a major noise source for precision laser ranging, optical time transfer, and long-baseline interferometry. While there exist models that estimate the turbulence-induced timing jitter power spectra using parameters obtainable from conventional micrometeorological instruments, a direct and independent comparison of these models to measured timing jitter data has not been done. Here we perform this comparison, measuring turbulence-induced optical pulse timing jitter over a horizontal, near-ground path using frequency comb lasers while independently characterizing the turbulence along the path using a suite of micrometeorological sensors. We compare the power spectra of measured optical pulse timing jitter to predictions based on the measured micrometeorological data and standard turbulence theory. To further quantitatively compare the frequency comb data to the micrometeorological measurements, we extract and compare the refractive index structure parameter, Cn2, from both systems and find agreement to within a factor of 5 for wind speed >1 m/s, and further improvement is possible as wind speed increases. These results validate the use of conventional micrometeorological instruments in predicting optical timing jitter statistics over co-located laser beam paths.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

BACKGROUND: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. RESULTS: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.

Audible Coronary Artery Stenosis.

OBJECTIVE: Hemodynamically significant coronary artery stenoses generate turbulent blood flow patterns that manifest as intracoronary murmurs. This study aims to evaluate the performance of modern acoustic detection of these murmurs by acoustic signals captured from patients undergoing gold standard comparative coronary angiography. METHODS: We prospectively studied 156 patients undergoing elective coronary angiography, excluding those with acute coronary syndrome, prior chest surgery, or significant valvular disease. Acoustic signals were captured before arterial access. Angiographic degree of stenosis in each coronary artery was graded blinded to clinical and acoustic data. Acoustic data were analyzed blinded to clinical and angiographic data, categorizing subjects as "normal," "diseased," or "inconclusive." Of 156 patients examined, 123 generated analyzable data. RESULTS: Angiographically significant stenosis (≥50%) prevalence was 52% (18%, 23%, 11% with 1-, 2-, 3-vessel disease, respectively). Acoustic detection sensitivity and specificity for stenosis ≥50% in any vessel were 0.70 and 0.80, respectively (negative predictive value, 0.71; positive predictive value, 0.79). Acoustic detection optimally identified stenosis ≥50% with an area under the curve of 0.75. For stenosis ≥50% in major vessels only (left main, proximal-mid left anterior descending, proximal-mid circumflex, proximal-mid right coronary), prevalence was 46%; sensitivity and specificity were 0.72 and 0.76, respectively (negative predictive value, 0.76; positive predictive value, 0.72; area under the curve, 0.76). CONCLUSIONS: Acoustic signal patterns and modern analysis techniques may be used to identify intracoronary murmurs generated by hemodynamically significant coronary artery stenoses in all major vessels. Further investigation is warranted to compare the clinical performance of this modality with current noninvasive approaches that evaluate patients at risk for atherosclerotic and obstructive coronary artery disease.

Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol.

BACKGROUND: In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis-St. Paul. METHODS AND RESULTS: Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07-3.72], P=0.03). CONCLUSIONS: Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.

Early coronary revascularization improves 24h survival and neurological function after ischemic cardiac arrest. A randomized animal study.

BACKGROUND: Survival after out-of-hospital cardiac arrest (OHCA) remains poor. Acute coronary obstruction is a major cause of OHCA. We hypothesize that early coronary reperfusion will improve 24h-survival and neurological outcomes. METHODS: Total occlusion of the mid LAD was induced by balloon inflation in 27 pigs. After 5min, VF was induced and left untreated for 8min. If return of spontaneous circulation (ROSC) was achieved within 15min (21/27 animals) of cardiopulmonary resuscitation (CPR), animals were randomized to a total of either 45min (group A) or 4h (group B) of LAD occlusion. Animals without ROSC after 15min of CPR were classified as refractory VF (group C). In those pigs, CPR was continued up to 45min of total LAD occlusion at which point reperfusion was achieved. CPR was continued until ROSC or another 10min of CPR had been performed. Primary endpoints for groups A and B were 24-h survival and cerebral performance category (CPC). Primary endpoint for group C was ROSC before or after reperfusion. RESULTS: Early compared to late reperfusion improved survival (10/11 versus 4/10, p=0.02), mean CPC (1.4±0.7 versus 2.5±0.6, p=0.017), LVEF (43±13 versus 32±9%, p=0.01), troponin I (37±28 versus 99±12, p=0.005) and CK-MB (11±4 versus 20.1±5, p=0.031) at 24-h after ROSC. ROSC was achieved in 4/6 animals only after reperfusion in group C. CONCLUSIONS: Early reperfusion after ischemic cardiac arrest improved 24h survival rate and neurological function. In animals with refractory VF, reperfusion was necessary to achieve ROSC.

Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation.

AIM OF THE STUDY: We investigated the effects of ischemic postconditioning (IPC) with and without cardioprotective vasodilatory therapy (CVT) at the initiation of cardiopulmonary resuscitation (CPR) on cardio-cerebral function and 48-h survival. METHODS: Prospective randomized animal study. Following 15 min of ventricular fibrillation, 42 Yorkshire farm pigs weighing an average of 34 ± 2 kg were randomized to receive standard CPR (SCPR, n=12), SCPR+IPC (n=10), SCPR+IPC+CVT (n=10), or SCPR+CVT (n=10). IPC was delivered during the first 3 min of CPR with 4 cycles of 20s of chest compressions followed by 20-s pauses. CVT consisted of intravenous sodium nitroprusside (2mg) and adenosine (24 mg) during the first minute of CPR. Epinephrine was given in all groups per standard protocol. A transthoracic echocardiogram was obtained on all survivors 1 and 4h post-ROSC. The brains were extracted after euthanasia at least 24h later to assess ischemic injury in 7 regions. Ischemic injury was graded on a 0-4 scale with (0=no injury to 4 ≥ 50% neural injury). The sum of the regional scores was reported as cerebral histological score (CHS). 48 h survival was reported. RESULTS: Post-resuscitation left ventricular ejection (LVEF) fraction improved in SCPR+CVT, SCPR+IPC+CVT and SCPR+IPC groups compared to SCPR (59% ± 9%, 52% ± 14%, 52% ± 14% vs. 35% ± 11%, respectively, p<0.05). Only SCPR+IPC and SCPR+IPC+CVT, but not SCPR+CVT, had lower mean CHS compared to SCPR (5.8 ± 2.6, 2.8 ± 1.8 vs. 10 ± 2.1, respectively, p<0.01). The 48-h survival among SCPR+IPC, SCPR+CVT, SCPR+IPC+CVT and SCPR was 6/10, 3/10, 5/10 and 1/12, respectively (Cox regression p<0.01). CONCLUSIONS: IPC and CVT during standard CPR improved post-resuscitation LVEF but only IPC was independently neuroprotective and improved 48-h survival after 15 min of untreated cardiac arrest in pigs.

Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation.

OBJECTIVES: Ischemic postconditioning (PC) with "stuttering" reintroduction of blood flow after prolonged ischemia has been shown to offer protection from ischemia reperfusion injury to the myocardium and brain. We hypothesized that four 20-s pauses during the first 3 min of standard CPR would improve post resuscitation cardiac and neurological function, in a porcine model of prolonged untreated cardiac arrest. METHODS: 18 female farm pigs, intubated and isoflurane anesthetized had 15 min of untreated ventricular fibrillation followed by standard CPR (SCPR). Nine animals were randomized to receive PC with four, controlled, 20-s pauses, during the first 3 min of CPR (SCPR+PC). Resuscitated animals had echocardiographic evaluation of their ejection fraction after 1 and 4 h and a blinded neurological assessment with a cerebral performance category (CPC) score assigned at 24 and 48 h. All animals received 12 h of post resuscitation mild therapeutic hypothermia. RESULTS: SCPR+PC animals had significant improvement in left ventricular ejection fraction at 1 and 4 h compared to SCPR (59±11% vs. 35±7% and 55±8% vs. 31±13% respectively, p<0.01). Neurological function at 24h significantly improved with SCPR+PC compared to SCPR alone (CPC: 2.7±0.4 vs. 3.8±0.4 respectively, p=0.003). Neurological function significantly improved in the SCPR+PC group at 48 h and the mean CPC score of that group decreased from 2.7±0.4 to 1.7±0.4 (p<0.00001). CONCLUSIONS: Ischemic postconditioning with four 20-s pauses during the first 3 min of SCPR improved post resuscitation cardiac function and facilitated neurological recovery after 15 min of untreated cardiac arrest in pigs.

Sodium nitroprusside enhanced cardiopulmonary resuscitation (SNPeCPR) improves vital organ perfusion pressures and carotid blood flow in a porcine model of cardiac arrest.

PURPOSE OF THE STUDY: To describe a new method of CPR that optimizes vital organ perfusion pressures and carotid blood flow. We tested the hypothesis that a combination of high dose sodium nitroprusside (SNP) as well as non-invasive devices and techniques known independently to enhance circulation would significantly improve carotid blood flow (CBF) and return of spontaneous circulation (ROSC) rates in a porcine model of cardiac arrest. METHODS: 15 isofluorane anesthetized pigs (30±1 kg), after 6 min of untreated ventricular fibrillation, were subsequently randomized to receive either 15 min of standard CPR (S-CPR) (8 animals) or 5 min epochs of S-CPR followed by active compression-decompression (ACD)+inspiratory impedance threshold device (ITD) CPR followed by ACD+ITD+abdominal binding (AB) with 1mg of SNP administered at minutes 2, 7, 12 of CPR (7 animals). Primary endpoints were CBF and ROSC rates. ANOVA and Fisher's exact test were used for comparisons. RESULTS/CONCLUSION: There was significant improvement in the hemodynamic parameters in the SNP animals. ROSC was achieved in 7/7 animals that received SNP and in 2/8 in the S-CPR (p=0.007). CBF and end tidal CO(2) (ETCO(2)) were significantly higher in the ACD+ITD+AB+SNP (SNPeCPR) animals during CPR. Bolus doses of SNP, when used in conjunction with ACD+ITD+AB CPR, significantly improve CBF and ROSC rates compared to S-CPR.

Sodium nitroprusside-enhanced cardiopulmonary resuscitation improves resuscitation rates after prolonged untreated cardiac arrest in two porcine models.

OBJECTIVE: Sodium nitroprusside-enhanced cardiopulmonary resuscitation consists of active compression-decompression, an impedance threshold device, abdominal binding, and large intravenous doses of sodium nitroprusside. We hypothesize that sodium nitroprusside-enhanced cardiopulmonary resuscitation will significantly increase carotid blood flow and return of spontaneous circulation compared to standard cardiopulmonary resuscitation after prolonged ventricular fibrillation and pulseless electrical activity cardiac arrest. DESIGN: Prospective randomized animal study. SETTING: Hennepin County Medical Center Animal Laboratory. SUBJECTS: Forty Yorkshire female farm-bred pigs weighing 32 ± 2 kg. INTERVENTIONS: In protocol A, 24 isoflurane-anesthetized pigs underwent 15 mins of untreated ventricular fibrillation and were subsequently randomized to receive standard cardiopulmonary resuscitation (n = 6), active compression-decompression cardiopulmonary resuscitation + impedance threshold device (n = 6), or sodium nitroprusside-enhanced cardiopulmonary resuscitation (n = 12) for up to 15 mins. First defibrillation was attempted at minute 6 of cardiopulmonary resuscitation. In protocol B, a separate group of 16 pigs underwent 10 mins of untreated ventricular fibrillation followed by 3 mins of chest compression only cardiopulmonary resuscitation followed by countershock-induced pulseless electrical activity, after which animals were randomized to standard cardiopulmonary resuscitation (n = 8) or sodium nitroprusside-enhanced cardiopulmonary resuscitation (n = 8). MEASUREMENTS AND MAIN RESULTS: The primary end point was carotid blood flow during cardiopulmonary resuscitation and return of spontaneous circulation. Secondary end points included end-tidal CO2 as well as coronary and cerebral perfusion pressure. After prolonged untreated ventricular fibrillation, sodium nitroprusside-enhanced cardiopulmonary resuscitation demonstrated superior rates of return of spontaneous circulation when compared to standard cardiopulmonary resuscitation and active compression-decompression cardiopulmonary resuscitation + impedance threshold device (12 of 12, 0 of 6, and 0 of 6 respectively, p < .01). In animals with pulseless electrical activity, sodium nitroprusside-enhanced cardiopulmonary resuscitation increased return of spontaneous circulation rates when compared to standard cardiopulmonary resuscitation. In both groups, carotid blood flow, coronary perfusion pressure, cerebral perfusion pressure, and end-tidal CO2 were increased with sodium nitroprusside-enhanced cardiopulmonary resuscitation. CONCLUSIONS: In pigs, sodium nitroprusside-enhanced cardiopulmonary resuscitation significantly increased return of spontaneous circulation rates, as well as carotid blood flow and end-tidal CO2, when compared to standard cardiopulmonary resuscitation or active compression-decompression cardiopulmonary resuscitation + impedance threshold device.

Cell therapy and satellite centers: the Cardiovascular Cell Therapy Research Network experience.

Due to the changing population in patients with myocardial infarction, recruiting patients in clinical trials continues to challenge clinical investigators. The Cardiovascular Cell Therapy Research Network (CCTRN) chose to expand the reach and power of its recruitment effort by incorporating both referral and treatment satellite centers. Eight treatment satellites were successfully identified and they screened patients over a two year period. The result of this effort was an increase in recruitment, with these treatment satellites contributing 30% of the patients to two of the three Network studies. The hurdles that these satellite treatment centers faced and how they surmounted them provide instruction to clinical research groups eager to expand to satellite systems and to health care practitioners who are interested in taking part in multicenter clinical trials.

Sodium nitroprusside enhanced cardiopulmonary resuscitation prevents post-resuscitation left ventricular dysfunction and improves 24-hour survival and neurological function in a porcine model of prolonged untreated ventricular fibrillation.

AIM OF STUDY: Sodium nitroprusside-enhanced CPR, or SNPeCPR, consists of active compression-decompression CPR with an impedance threshold device, abdominal compression, and intravenous sodium nitroprusside (SNP). We hypothesize that SNPeCPR will improve post resuscitation left ventricular function and neurological function compared to standard (S) CPR after 15 min of untreated ventricular fibrillation in a porcine model of cardiac arrest. METHODS: Pigs (n = 22) anesthetized with isoflurane underwent 15 min of untreated ventricular fibrillation, were then randomized to 6 min of S-CPR (n = 11) or SNPeCPR (n = 11) followed by defibrillation. The primary endpoints were neurologic function as measured by cerebral performance category (CPC) score and left ventricular ejection fraction. RESULTS: SNPeCPR increased 24-hour survival rates compared to S-CPR (10/11 versus 5/11, p = 0.03) and improved neurological function (CPC score 2.5 ± 1, versus 3.8 ± 0.4, respectively, p = 0.004). Left ventricular ejection fractions at 1, 4 and 24 hours after defibrillation were 72 ± 11, 57 ± 11.4 and 64 ± 11 with SNPeCPR versus 29 ± 10, 30 ± 17 and 39 ± 6 with S-CPR, respectively (p < 0.01 for all). CONCLUSIONS: In this pig model, after 15 min of untreated ventricular fibrillation, SNPeCPR significantly improved 24-hour survival rates, neurologic function and prevented post-resuscitation left ventricular dysfunction compared to S-CPR.