The link between carotid artery stenosis and outcomes in patients with refractory out-of-hospital cardiac arrest.

BACKGROUND: Mortality of out-of-hospital cardiac arrest (OHCA) remains high. Extracorporeal cardiopulmonary resuscitation (ECPR) has revolutionized OHCA treatment, but our understanding of the ECPR responder's clinical profile is incomplete. Carotid artery stenosis (CAS) is a well-established cardiovascular disease risk factor. The impact of CAS on OHCA outcomes remains unelucidated. OBJECTIVE: To assess whether CAS burden affects the outcomes of OHCA patients treated with ECPR. METHODS: This study included patients with OHCA admitted for ECPR consideration, who had carotid ultrasonography performed. A numeric scale was applied to the plaque to create a CAS burden numeric scale. The primary outcome of the study was survival at discharge, compared among the different degrees of CAS. Neurologically intact survival and surrogate markers of neurologic injury were the secondary study endpoints. To assess the independent effect of CAS burden on survival to hospital discharge, we conducted a logistic regression analysis. RESULTS: Between 2019 and 2023, carotid ultrasonography was performed on 163 patients who were admitted for refractory OHCA. CAS burden was equally distributed between the right and left carotid arteries. Logistic regression analysis indicated that the CAS burden was significantly associated with both overall and neurologically intact survival at discharge (p = 0.004). A linear relationship between the CAS burden and neuron-specific and S-100 levels was identified. Patients with normal carotids were significantly less likely to have encephalopathy on electroencephalograms. CONCLUSION: CAS burden independently predicts the risk for worse survival and neurologic outcomes in patients suffering refractory OHCA who are treated with ECPR.

The DNA Methyltransferase DMAP1 is Required for Tissue Maintenance and Planarian Regeneration.

The precise regulation of transcription is required for embryonic development, adult tissue turnover, and regeneration. Epigenetic modifications play a crucial role in orchestrating and regulating the transcription of genes. These modifications are important in the transition of pluripotent stem cells and their progeny. Methylation, a key epigenetic modification, influences gene expression through changes in histone tails and direct DNA methylation. Work in different organisms has shown that the DNA methyltransferase-1-associated protein (DMAP1) may associate with other molecules to repress transcription through DNA methylation. Thus, DMAP1 is a versatile protein implicated in a myriad of events, including pluripotency maintenance, DNA damage repair, and tumor suppression. While DMAP1 has been extensively studied in vitro, its complex regulation in the context of the adult organism remains unclear. To gain insights into the possible roles of DMAP1 at the organismal level, we used planarian flatworms that possess remarkable regenerative capabilities driven by pluripotent stem cells called neoblast. Our findings demonstrate the evolutionary conservation of DMAP1 in the planarian Schmidtea mediterranea. Functional disruption of DMAP1 through RNA interference revealed its critical role in tissue maintenance, neoblast differentiation, and regeneration in S. mediterranea. Moreover, our analysis unveiled a novel function for DMAP1 in regulating cell death in response to DNA damage and influencing the expression of axial polarity markers. Our findings provide a simplified paradigm for studying DMAP1's epigenetic regulation in adult tissues.

The association of regional cerebral oximetry and neurologically intact survival in a porcine model of cardiac arrest.

Background: The objective of this study was to determine if regional cerebral oximetry (rSO2) assessed during CPR would be predictive of survival with favorable neurological function in a prolonged model of porcine cardiac arrest. This study also examined the relative predictive value of rSO2 and end-tidal carbon dioxide (ETCO2), separately and together. Methods: This study is a post-hoc analysis of data from a previously published study that compared conventional CPR (C-CPR) and automated head-up positioning CPR (AHUP-CPR). Following 10 min of untreated ventricular fibrillation, 14 pigs were treated with either C-CPR (C-CPR) or AHUP-CPR. rSO2, ETCO2, and other hemodynamic parameters were measured continuously. Pigs were defibrillated after 19 min of CPR. Neurological function was assessed 24 h later. Results: There were 7 pigs in the neurologically intact group and 7 pigs in the poor outcomes group. Within 6 min of starting CPR, the mean difference in rSO2 by 95% confidence intervals between the groups became statistically significant (p < 0.05). The receiver operating curve for rSO2 to predict survival with favorable neurological function reached a maximal area under the curve value after 6 min of CPR (1.0). The correlation coefficient between rSO2 and ETCO2 during CPR increased towards 1.0 over time. The combined predictive value of both parameters was similar to either parameter alone. Conclusion: Significantly higher rSO2 values were observed within less than 6 min after starting CPR in the pigs that survived versus those that died. rSO2 values were highly predictive of survival with favorable neurological function.

Connecting the branches of multistable non-Euclidean origami by crease stretching.

Non-Euclidean origami is a promising technique for designing multistable deployable structures folded from nonplanar developable surfaces. The impossibility of flat foldability inherent to non-Euclidean origami results in two disconnected solution branches each with the same angular deficiency but opposite handedness. We show that these regions can be connected via "crease stretching," wherein the creases exhibit extensibility in addition to torsional stiffness. We further reveal that crease stretching acts as an energy storage method capable of passive deployment and control. Specifically, we show that in a Miura-Ori system with a single stretchable crease, this is achieved via two unique, easy to realize, equilibrium folding pathways for a certain wide set of parameters. In particular, we demonstrate that this connection mostly preserves the stable states of the non-Euclidean system, while resulting in a third stable state enabled only by the interaction of crease torsion and stretching. Finally, we show that this simplified model can be used as an efficient and robust tool for inverse design of multistable origami based on closed-form predictions that yield the system parameters required to attain multiple, desired stable shapes. This facilitates the implementation of multistable origami for applications in architecture materials, robotics, and deployable structures.

Analysis of DNA Double-Stranded Breaks Using the Comet Assay in Planarians.

Comet assay provides the opportunity to detect and characterize DNA strand breaks. Cellular lysing followed by embedding in agarose slide is used to visualize under an electrical current migration patterns corresponding to DNA fragments of different sizes. Here we describe the process of detecting and characterizing DNA damage by Comet assay on planarians, which is a model organism commonly used to understand the process of whole-body regeneration, stem cell regulation, and adult tissue maintenance.

Restoration of DNA integrity and the cell cycle by electric stimulation in planarian tissues damaged by ionizing radiation.

Exposure to high levels of ionizing γ radiation leads to irreversible DNA damage and cell death. Here, we establish that exogenous application of electric stimulation enables cellular plasticity and the re-establishment of stem cell activity in tissues damaged by ionizing radiation. We show that subthreshold direct current stimulation (DCS) rapidly restores pluripotent stem cell populations previously eliminated by lethally γ-irradiated tissues of the planarian flatworm Schmidtea mediterranea. Our findings reveal that DCS enhances DNA repair, transcriptional activity, and cell cycle entry in post-mitotic cells. These responses involve rapid increases in cytosolic Ca2+ concentration through the activation of L-type Cav channels and intracellular Ca2+ stores, leading to the activation of immediate early genes and ectopic expression of stem cell markers in post-mitotic cells. Overall, we show the potential of electric current stimulation to reverse the damaging effects of high-dose γ radiation in adult tissues. Furthermore, our results provide mechanistic insights describing how electric stimulation effectively translates into molecular responses capable of regulating fundamental cellular functions without the need for genetic or pharmacological intervention.

Faster time to automated elevation of the head and thorax during cardiopulmonary resuscitation increases the probability of return of spontaneous circulation.

OBJECTIVES: Resuscitation in the Head Up position improves outcomes in animals treated with active compression decompression cardiopulmonary resuscitation and an impedance threshold device (ACD + ITD CPR).We assessed impact of time to deployment of an automated Head Up position (AHUP) based bundle of care after out-of-hospital cardiac arrest on return of spontaneous circulation (ROSC). METHODS: Observational data were analyzed from a patient registry. Patients received treatment with 1) ACD + and/or automated CPR 2) an ITD and 3) an AHUP device. Probability of ROSC (ROSCprob) from the 9-1-1 call to AHUP device placement was assessed with a restricted cubic spline model and linear regression. RESULTS: Of 11 sites, 6 recorded the interval from 9-1-1 to AHUP device (n = 227). ROSCprobfor all rhythms was 34%(77/227). Median age (range) was 66 years (19-101) and 68% men. TheROSCprobfor shockable rhythms was 47%(18/38). Minutes from 9-1-1 to AHUP device (median, range) varied between sites: 1) 6.4(4,15), 2) 8.0(5,19), 3) 9.9(4, 12), 4) 14.1(6, 36), 5) 15.9(6, 34), 6) 19.0(8, 38),(p = 0.0001).ROSCprobalso varied; 1) 55.1%(16/29), 2) 60%(3/5), 3) 50%(3/6), 4) 22.7%(17/75), 5) 26.4%(9/34), and 6) 37.1%(29/78), (p = 0.019). For all rhythms between 4 and 12 min (n = 85),ROSCprobdeclined 5.6% for every minute elapsed (p = 0.024). For shockable rhythms, between 6 and 15 min (n = 23),ROSCprobdeclined 9.0% for every minute elapsed (p = 0.006). CONCLUSIONS: Faster time to deployment of an AHUP based bundle of care is associated with higher incidence of ROSC. This must be considered when evaluating and implementing this bundle.

Can neural signals override cellular decisions in the presence of DNA damage?

Cells within an organism are in constant crosstalk with their surrounding environment. Short and long-range signals influence cellular behavior associated with division, differentiation, and death. This crosstalk among cells underlies tissue renewal to guarantee faithful replacement of old or damaged cells over many years. Renewing tissues also offer recurrent opportunities for DNA damage and cellular transformation that tend to occur with aging. Most cells with extensive DNA damage have limited options such as halting cell cycle to repair DNA, undergo senescence, or programmed cell death. However, in some cases cells carrying toxic forms of DNA damage survive and proliferate. The underlying factors driving survival and proliferation of cells with DNA damage remain unknown. Here we discuss potential roles the nervous system may play in influencing the fate of cells with DNA damage. We present a brief survey highlighting the implications the nervous system has in regeneration, regulation of stem cells, modulation of the immune system, and its contribution to cancer progression. Finally, we propose the use of planarian flatworms as a convenient model organism to molecularly dissect the influence of neural signals over cellular fate regulation in the presence of DNA damage.

Improving post-cardiac arrest cerebral perfusion pressure by elevating the head and thorax.

AIM: The optimal head and thorax position after return of spontaneous circulation (ROSC) following cardiac arrest (CA) is unknown. This study examined whether head and thorax elevation post-ROSC is beneficial, in a porcine model. METHODS: Protocol A: 40 kg anesthetized pigs were positioned flat, after 7.75 min of untreated CA the heart and head were elevated 8 and 12 cm, respectively, above the horizontal plane, automated active compression decompression (ACD) plus impedance threshold device (ITD) CPR was started, and 2 min later the heart and head were elevated 10 and 22 cm, respectively, over 2 min to the highest head up position (HUP). After 30 min of CPR pigs were defibrillated and randomized 10 min later to four 5-min epochs of HUP or flat position. Multiple physiological parameters were measured. In Protocol B, after 6 min of untreated VF, pigs received 6 min of conventional CPR flat, and after ROSC were randomized HUP versus Flat as in Protocol A. The primary endpoint was cerebral perfusion pressure (CerPP). Multivariate analysis-of-variance (MANOVA) for repeated measures was used. Data were reported as mean ±â€¯SD. RESULTS: In Protocol A, intracranial pressure (ICP) (mmHg) was significantly lower post-ROSC with HUP (9.1 ±â€¯5.5) versus Flat (18.5 ±â€¯5.1) (p < 0.001). Conversely, CerPP was higher with HUP (62.5 ±â€¯19.9) versus Flat (53.2 ±â€¯19.1) (p = 0.004), respectively. Protocol A and B results comparing HUP versus Flat were similar. CONCLUSION: Post-ROSC head and thorax elevation in a porcine model of cardiac arrest resulted in higher CerPP and lower ICP values, regardless of VF duration or CPR method. IACUC PROTOCOL NUMBER: 19-09.

Controlled sequential elevation of the head and thorax combined with active compression decompression cardiopulmonary resuscitation and an impedance threshold device improves neurological survival in a porcine model of cardiac arrest.

AIM OF THE STUDY: Controlled sequential elevation of the head and thorax (CSE) during active compression decompression (ACD) cardiopulmonary resuscitation (CPR) with an impedance threshold device (ITD) has been shown to increase cerebral perfusion pressure and cerebral blood flow in previous animal studies as compared to the traditional supine position. The potential for this novel bundled treatment strategy to improve survival with intact neurological function is unknown. METHODS: Female farm pigs were sedated, intubated, and anesthetized. Central arterial and venous access were continuously monitored. Regional brain tissue perfusion (CerO2) was also measured transcutaneous. Ventricular fibrillation (VF) was induced and untreated for 10 min. Pigs were randomized to (1) Conventional CPR (C-CPR) flat or (2) ACD + ITD CSE CPR that included 2 min of ACD + ITD with the head and heart first elevated 10 and 8 cm, and then gradual elevation over 2 min to 22 and 9 cm, respectively. After 19 min of CPR, pigs were defibrillated and recovered. A veterinarian blinded to the intervention assessed cerebral performance category (CPC) at 24 h. A neurologically intact outcome was defined as a CPC score of 1 or 2. Categorical outcomes were analyzed by Fisher's exact test and continuous outcomes with an unpaired student's t-test. RESULTS: In 16 animals, return of spontaneous circulation rate was 8/8 (100%) with ACD + ITD CSE and 3/8 (25%) for C-CPR (p = 0.026). For the primary outcome of neurologically intact survival, 6/8 (75%) pigs had a CPC score 1 or 2 with ACD + ITD CSE versus 1/8 (12.5%) with C-CPR (p = 0.04). Coronary perfusion pressure (mmHg, mean ±â€¯SD) was higher with CSE at 18 min (41 ±â€¯24 versus 10 ±â€¯5, p = 0.004). rSO2 (%, mean ±â€¯SD) and ETCO2 (mmHg, mean ±â€¯SD) values were higher at 18 min with CSE (32 ±â€¯9 versus 17 ±â€¯2, p = 0.01, and 55 mmHg ±â€¯10 versus 21 mmHg ±â€¯4, p < 0.001), respectively. CONCLUSIONS: The novel bundled resuscitation approach of CSE with ACD + ITD CPR increased favorable neurological survival versus C-CPR in a swine model of cardiac arrest.

Rationale and Strategies for Development of an Optimal Bundle of Management for Cardiac Arrest.

OBJECTIVES: To construct a highly detailed yet practical, attainable roadmap for enhancing the likelihood of neurologically intact survival following sudden cardiac arrest. DESIGN SETTING AND PATIENTS: Population-based outcomes following out-of-hospital cardiac arrest were collated for 10 U.S. counties in Alaska, California, Florida, Ohio, Minnesota, Utah, and Washington. The 10 identified emergency medical services systems were those that had recently reported significant improvements in neurologically intact survival after introducing a more comprehensive approach involving citizens, hospitals, and evolving strategies for incorporating technology-based, highly choreographed care and training. Detailed inventories of in-common elements were collated from the ten 9-1-1 agencies and assimilated. For reference, combined averaged outcomes for out-of-hospital cardiac arrest occurring January 1, 2017, to February 28, 2018, were compared with concurrent U.S. outcomes reported by the well-established Cardiac Arrest Registry to Enhance Survival. INTERVENTIONS: Most commonly, interventions and components from the ten 9-1-1 systems consistently included extensive public cardiopulmonary resuscitation training, 9-1-1 system-connected smart phone applications, expedited dispatcher procedures, cardiopulmonary resuscitation quality monitoring, mechanical cardiopulmonary resuscitation, devices for enhancing negative intrathoracic pressure regulation, extracorporeal membrane oxygenation protocols, body temperature management procedures, rapid cardiac angiography, and intensive involvement of medical directors, operational and quality assurance officers, and training staff. MEASUREMENTS AND MAIN RESULTS: Compared with Cardiac Arrest Registry to Enhance Survival (n = 78,704), the cohorts from the 10 emergency medical services agencies examined (n = 2,911) demonstrated significantly increased likelihoods of return of spontaneous circulation (mean 37.4% vs 31.5%; p < 0.001) and neurologically favorable hospital discharge, particularly after witnessed collapses involving bystander cardiopulmonary resuscitation and shockable cardiac rhythms (mean 10.7% vs 8.4%; p < 0.001; and 41.6% vs 29.2%; p < 0.001, respectively). CONCLUSIONS: The likelihood of neurologically favorable survival following out-of-hospital cardiac arrest can improve substantially in communities that conscientiously and meticulously introduce a well-sequenced, highly choreographed, system-wide portfolio of both traditional and nonconventional approaches to training, technologies, and physiologic management. The commonalities found in the analyzed systems create a compelling case that other communities can also improve out-of-hospital cardiac arrest outcomes significantly by conscientiously exploring and adopting similar bundles of system organization and care.

Relationship between hemodynamic parameters and cerebral blood flow during cardiopulmonary resuscitation.

INTRODUCTION: Cerebral blood flow during cardiopulmonary resuscitation (CPR) is a major neuroprognostic factor although not clinically feasible for routine assessment and monitoring. In this context, a surrogate marker for cerebral perfusion during CPR is highly desirable. Yet, cerebral blood flow hemodynamic determinants remain poorly understood and their significance might be altered by changes in head positioning such as flat, head up, and head down during CPR. HYPOTHESIS: We hypothesized that routinely measured hemodynamic parameters would correlate with cerebral brain flow during CPR, independently of the head position. METHODS: Associations between cerebral blood flow, measured using microsphere techniques, and hemodynamic parameters were studied from two prior publications. Eight pigs receiving CPR with an automated device and an impedance threshold device in the flat or supine, whole body head down and whole body head up tilt positions were analysed for the derivation sample. Relevant associations were examined for consistency in an external validation sample consisting of 18 pigs randomized to supine position versus head and torso elevation. RESULTS: After adjusting for position, arterial blood pressure and cerebral perfusion pressure during decompression were significantly associated with cerebral blood flow, in the derivation and the external validation samples. No significant associations were found between cerebral blood flow during CPR and right atrial pressure, intracranial pressure, end tidal CO2, carotid blood flow, and coronary perfusion pressure in the derivation sample. CONCLUSION: Decompression arterial blood pressure and cerebral perfusion pressure are relevant candidate surrogate markers for cerebral blood flow during CPR, independently of head position.

Controlled progressive elevation rather than an optimal angle maximizes cerebral perfusion pressure during head up CPR in a swine model of cardiac arrest.

AIM OF THE STUDY: Elevation of the head and thorax (HUP) during cardiopulmonary resuscitation (CPR) has been shown to double brain blood flow with increased cerebral perfusion pressures (CerPP) after active compression-decompression (ACD) CPR with an impedance threshold device (ITD). However, the optimal angle for HUP CPR is unknown. METHODS: In Study A, different angles were assessed (20°, 30°, 40°), each randomized over 5-min periods of ACD + ITD CPR, after 8 min of untreated ventricular fibrillation in an anesthetized swine model. Based upon Study A, Study B was performed, where animals were randomized to 1 of 2 sequences: 20°, 30°, 40° or 40°, 30°, 20° with a similar protocol. The primary endpoint was CerPP for both studies. RESULTS: In Study A, no optimal HUP angle was observed in 18 pigs. CerPPs for 30° and 40° (mmHg, mean ±â€¯SD) were equivalent (44 ±â€¯22 and 47 ±â€¯26, p = 0.18). However, CerPP appeared higher when 40° HUP was performed during the last 5-min of CPR, suggestive of a sequence effect. For Study B, after 17 min of CPR, CerPP (mmHg) were higher with the 20°, 30°, 40° sequence: 60 ±â€¯17 versus 33 ±â€¯18 (p = 0.035). CONCLUSIONS: No optimal HUP CPR angle was observed. However, controlled progressive elevation of the head and thorax during CPR is more beneficial than an absolute angle or height to maximize CerPP. Further studies are needed to determine the optimal rate of rise during HUP ACD + ITD CPR. INSTITUTIONAL PROTOCOL NUMBER: 17-06.

Effect of controlled sequential elevation timing of the head and thorax during cardiopulmonary resuscitation on cerebral perfusion pressures in a porcine model of cardiac arrest.

AIM: Controlled sequential elevation of the head and thorax (CSE) during active compression-decompression (ACD) CPR with an impedance threshold device (ITD) augments cerebral (CerPP) and coronary (CorPP) perfusion pressures. The optimal CSE is unknown. METHODS: After 8 minutes of untreated VF, 40 kg anesthetized female pigs were positioned on a customized head and thorax elevation device (CED). After 2 min of automated ACD + ITD-16 CPR to 'prime the system', 12 pigs were randomized to CSE to the highest CED position over 4-min or 10-min. The primary outcome was CerPP after 7 minutes of CPR. Secondarily, 24-sec (without a priming step) and 2-min CSE times were similarly tested (n = 6 group) in a non-randomized order. Values expressed as mean ±â€¯SD. RESULTS: After 7 min of CPR, CerPPs were significantly higher in the 4-min vs 10-min CSE groups (53 ±â€¯14.4 vs 38.5 ±â€¯3.6 mmHg respectively, p = 0.03) whereas CorPP trended higher. The 4-min CSE group achieved 50% of baseline (50% BL) CerPP faster than the 10-min group (2.5 ±â€¯1.2 vs 6 ±â€¯3.1 minutes, p = 0.03). CerPP values in the 2-min and 4-min CSE groups were significantly higher than in the 24-sec group. With CSE, CerPPs and CorPPs increased over time in all groups. CONCLUSIONS: By optimizing controlled sequential elevation timing, CerPP values achieved 50% of baseline within less than 2.5 minutes and >80% of baseline after 7 minutes of CPR. This novel CPR approach rapidly restored CerPPs to near normal values non-invasively and without vasopressors.

Supraglottic airway devices variably develop negative intrathoracic pressures: A prospective cross-over study of cardiopulmonary resuscitation in human cadavers.

AIM OF THE STUDY: Negative intrathoracic pressure (ITP) during the decompression phase of cardiopulmonary resuscitation (CPR) is essential to refill the heart, increase cardiac output, maintain cerebral and coronary perfusion pressures, and improve survival. In order to generate negative ITP, an airway seal is necessary. We tested the hypothesis that some supraglottic airway (SGA) devices do not seal the airway as well the standard endotracheal tube (ETT). METHODS: Airway pressures (AP) were measured as a surrogate for ITP in seven recently deceased human cadavers of varying body habitus. Conventional manual, automated, and active compression-decompression CPR were performed with and without an impedance threshold device (ITD) in supine and Head Up positions. Positive pressure ventilation was delivered by an ETT and 5 SGA devices tested in a randomized order in this prospective cross-over designed study. The primary outcome was comparisons of decompression AP between all groups. RESULTS: An ITD was required to generate significantly lower negative ITP during the decompression phase of all methods of CPR. SGAs varied in their ability to support negative ITP. CONCLUSION: In a human cadaver model, the ability to generate negative intrathoracic pressures varied with different SGAs and an ITD regardless of the body position or CPR method. Differences in SGAs devices should be strongly considered when trying to optimize cardiac arrest outcomes, as some SGAs do not consistently develop a seal or negative intrathoracic pressure with multiple different CPR methods and devices.

Captive breeding of the barndoor skate (Dipturus laevis) at the Montreal Biodome, with comparison notes on two other captive-bred skate species.

In 1997, the Montreal Biodome obtained five barndoor skates (Dipturus laevis) from the waters off Boston, Massachusetts. Six years later, those specimens began reproducing, and the first egg case was collected in November 2003. Since then, 73 hatchlings have been born and raised. Egg cases were observed year round, and annual fecundity was measured for the first time: one female laid 69 eggs in 2005, 85 in 2006 and 115 in 2007. Egg incubation was longer than believed previously, ranging from 342 to 494 days. Hatching occurred throughout the year. Hatchlings averaged 193 mm total length and 128 mm disk width and weighed 32 g. They were fed krill and diced fish. All but one survived the first month. A photo identification system was useful in recognizing two groups of 10 specimens during their first year, and transponders could be inserted in the wing muscles of 1-year-old skates. Total lengths at birth and at age 2 were similar to the data reported from the wild, suggesting a similar growth pattern in captivity. The reproduction characteristics of the barndoor skate were compared with those of two other skate species currently bred at the Montreal Biodome, the winter skate (Leucoraja ocellata) and the thorny skate (Amblyraja radiata). Zoo Biol 27:145-153, 2008. (c) 2008 Wiley-Liss, Inc.