Effect of Lower vs Higher Oxygen Saturation Targets on Survival to Hospital Discharge Among Patients Resuscitated After Out-of-Hospital Cardiac Arrest: The EXACT Randomized Clinical Trial.

Importance: The administration of a high fraction of oxygen following return of spontaneous circulation in out-of-hospital cardiac arrest may increase reperfusion brain injury. Objective: To determine whether targeting a lower oxygen saturation in the early phase of postresuscitation care for out-of-hospital cardiac arrest improves survival at hospital discharge. Design, Setting, and Participants: This multicenter, parallel-group, randomized clinical trial included unconscious adults with return of spontaneous circulation and a peripheral oxygen saturation (Spo2) of at least 95% while receiving 100% oxygen. The trial was conducted in 2 emergency medical services and 15 hospitals in Victoria and South Australia, Australia, between December 11, 2017, and August 11, 2020, with data collection from ambulance and hospital medical records (final follow-up date, August 25, 2021). The trial enrolled 428 of a planned 1416 patients. Interventions: Patients were randomized by paramedics to receive oxygen titration to achieve an oxygen saturation of either 90% to 94% (intervention; n = 216) or 98% to 100% (standard care; n = 212) until arrival in the intensive care unit. Main Outcomes and Measures: The primary outcome was survival to hospital discharge. There were 9 secondary outcomes collected, including hypoxic episodes (Spo2 <90%) and prespecified serious adverse events, which included hypoxia with rearrest. Results: The trial was stopped early due to the COVID-19 pandemic. Of the 428 patients who were randomized, 425 were included in the primary analysis (median age, 65.5 years; 100 [23.5%] women) and all completed the trial. Overall, 82 of 214 patients (38.3%) in the intervention group survived to hospital discharge compared with 101 of 211 (47.9%) in the standard care group (difference, -9.6% [95% CI, -18.9% to -0.2%]; unadjusted odds ratio, 0.68 [95% CI, 0.46-1.00]; P = .05). Of the 9 prespecified secondary outcomes collected during hospital stay, 8 showed no significant difference. A hypoxic episode prior to intensive care was observed in 31.3% (n = 67) of participants in the intervention group and 16.1% (n = 34) in the standard care group (difference, 15.2% [95% CI, 7.2%-23.1%]; OR, 2.37 [95% CI, 1.49-3.79]; P < .001). Conclusions and Relevance: Among patients achieving return of spontaneous circulation after out-of-hospital cardiac arrest, targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the intensive care unit did not significantly improve survival to hospital discharge. Although the trial is limited by early termination due to the COVID-19 pandemic, the findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest. Trial Registration: ClinicalTrials.gov Identifier: NCT03138005.

A protocol for the Heart Matters stepped wedge cluster randomised trial: The effectiveness of heart attack education in regions at highest-risk.

Aim: To describe the Heart Matters (HM) trial which aims to evaluate the effectiveness of a community heart attack education intervention in high-risk areas in Victoria, Australia. These local government areas (LGAs) have high rates of acute coronary syndrome (ACS), out-of-hospital cardiac arrest (OHCA), cardiovascular risk factors, and low rates of emergency medical service (EMS) use for ACS. Methods: The trial follows a stepped-wedge cluster randomised design, with eight clusters (high-risk LGAs) randomly assigned to transition from control to intervention every four months. Two pairs of LGAs will transition simultaneously due to their proximity. The intervention consists of a heart attack education program delivered by trained HM Coordinators, with additional support from opportunistic media and a geo-targeted social media campaign. The primary outcome measure is the proportion of residents from the eight LGAs who present to emergency departments by EMS during an ACS event. Secondary outcomes include prehospital delay time, rates of OHCA and heart attack awareness. The primary and secondary outcomes will be analysed at the patient/participant level using mixed-effects logistic regression models. A detailed program evaluation is also being conducted. The trial was registered on August 9, 2021 (NCT04995900). Results: The intervention was implemented between February 2022 and March 2023, and outcome data will be collected from administrative databases, registries, and surveys. Primary trial data is expected to be locked for analysis by October 31st 2023, with a follow-up planned until March 31st 2024. Conclusion: The results from this trial will provide high-level evidence the effectiveness of a community education intervention targeting regions at highest-risk of ACS and low EMS use.

Higher-order genome organization in platypus and chicken sperm and repositioning of sex chromosomes during mammalian evolution.

In mammals, chromosomes occupy defined positions in sperm, whereas previous work in chicken showed random chromosome distribution. Monotremes (platypus and echidnas) are the most basal group of living mammals. They have elongated sperm like chicken and a complex sex chromosome system with homology to chicken sex chromosomes. We used platypus and chicken genomic clones to investigate genome organization in sperm. In chicken sperm, about half of the chromosomes investigated are organized non-randomly, whereas in platypus chromosome organization in sperm is almost entirely non-random. The use of genomic clones allowed us to determine chromosome orientation and chromatin compaction in sperm. We found that in both species chromosomes maintain orientation of chromosomes in sperm independent of random or non-random positioning along the sperm nucleus. The distance of loci correlated with the total length of sperm nuclei, suggesting that chromatin extension depends on sperm elongation. In platypus, most sex chromosomes cluster in the posterior region of the sperm nucleus, presumably the result of postmeiotic association of sex chromosomes. Chicken and platypus autosomes sharing homology with the human X chromosome located centrally in both species suggesting that this is the ancestral position. This suggests that in some therian mammals a more anterior position of the X chromosome has evolved independently.

A novel role for gamma-secretase in the formation of primitive streak-like intermediates from ES cells in culture.

gamma-Secretase is a membrane-associated protease with multiple intracellular targets, a number of which have been shown to influence embryonic development and embryonic stem (ES) cell differentiation. This paper describes the use of the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) to evaluate the role of gamma-secretase in the differentiation of pluripotent stem cells to the germ lineages. The addition of DAPT did not prevent the formation of primitive ectoderm-like cells from ES cells in culture. In contrast, the addition of DAPT during primitive ectoderm-like cell differentiation interfered with the ability of both serum and BMP4 to induce a primitive streak-like intermediate and resulted in the preferential formation of neurectoderm. Similarly, DAPT reduced the formation of primitive streak-like intermediates from differentiating human ES cells; the culture conditions used resulted in a population enriched in human surface ectoderm. These data suggest that gamma-secretase may form part of the general pathway by which mesoderm is specified within the primitive streak. The addition of an E-cadherin neutralizing antibody was able to partially reverse the effect of DAPT, suggesting that DAPT may be preventing the formation of primitive streak-like intermediates and promoting neurectoderm differentiation by stabilizing E-cadherin and preventing its proteolysis.

The EXACT protocol: A multi-centre, single-blind, randomised, parallel-group, controlled trial to determine whether early oxygen titration improves survival to hospital discharge in adult OHCA patients.

BACKGROUND: Experimental and observational research suggests hyperoxia following resuscitation from cardiac arrest is associated with neurological injury and worse clinical outcomes. This paper describes the rationale and design of the EXACT trial. EXACT aims to determine whether reducing oxygen in the acute phase of post-resuscitation care for out-of-hospital cardiac arrest (OHCA) improves survival. METHODS: EXACT is a multi-centre, randomised (1:1), single-blind, parallel trial. Presumed cardiac OHCA cases who achieve a return of spontaneous circulation will be eligible if they are comatose, with an advanced airway and have an oxygen saturation (SpO2) ≥95% on >10 L/min (or 100% oxygen). Paramedics will randomise 1416 eligible cases to receive oxygen therapy targeting an SpO2 of 90-94% (intervention) or 98-100% (control). Study treatment will continue until admission to an intensive care unit or hospital ward. The primary outcome is survival to hospital discharge. Secondary outcomes include 12-month survival and quality of life. RESULTS: The study has commenced in the Australian states of Victoria and South Australia, and has enrolled 167 eligible cases to date (80 intervention and 87 control). Further sites are due to commence in 2019, recruitment is expected to take three years. CONCLUSION: This study will determine if early reduction of oxygen leads to improved outcomes in OHCA. Such a finding may potentially change clinical practice with implications on future OHCA survival outcomes. TRIAL REGISTRATION NUMBER: NCT03138005.