ABSTRACT
BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.
Subject(s)
Receptors, OX40 , Animals , Humans , Mice , Receptors, OX40/agonists , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Neoplasms/drug therapy , Neoplasms/immunology , Cell Line, Tumor , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/drug effects , Disease Models, AnimalABSTRACT
The International Liaison Committee on Resuscitation engages in a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation and first aid science. Draft Consensus on Science With Treatment Recommendations are posted online throughout the year, and this annual summary provides more concise versions of the final Consensus on Science With Treatment Recommendations from all task forces for the year. Topics addressed by systematic reviews this year include resuscitation of cardiac arrest from drowning, extracorporeal cardiopulmonary resuscitation for adults and children, calcium during cardiac arrest, double sequential defibrillation, neuroprognostication after cardiac arrest for adults and children, maintaining normal temperature after preterm birth, heart rate monitoring methods for diagnostics in neonates, detection of exhaled carbon dioxide in neonates, family presence during resuscitation of adults, and a stepwise approach to resuscitation skills training. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, using Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces list priority knowledge gaps for further research. Additional topics are addressed with scoping reviews and evidence updates.
Subject(s)
Cardiopulmonary Resuscitation , Emergency Medical Services , Out-of-Hospital Cardiac Arrest , Premature Birth , Adult , Female , Child , Infant, Newborn , Humans , First Aid , Consensus , Out-of-Hospital Cardiac Arrest/therapy , Cardiopulmonary Resuscitation/methodsABSTRACT
The International Liaison Committee on Resuscitation engages in a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation and first aid science. Draft Consensus on Science With Treatment Recommendations are posted online throughout the year, and this annual summary provides more concise versions of the final Consensus on Science With Treatment Recommendations from all task forces for the year. Topics addressed by systematic reviews this year include resuscitation of cardiac arrest from drowning, extracorporeal cardiopulmonary resuscitation for adults and children, calcium during cardiac arrest, double sequential defibrillation, neuroprognostication after cardiac arrest for adults and children, maintaining normal temperature after preterm birth, heart rate monitoring methods for diagnostics in neonates, detection of exhaled carbon dioxide in neonates, family presence during resuscitation of adults, and a stepwise approach to resuscitation skills training. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, using Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces list priority knowledge gaps for further research. Additional topics are addressed with scoping reviews and evidence updates.
Subject(s)
Cardiopulmonary Resuscitation , Emergency Medical Services , Out-of-Hospital Cardiac Arrest , Premature Birth , Adult , Female , Child , Infant, Newborn , Humans , First Aid , Consensus , Out-of-Hospital Cardiac Arrest/diagnosis , Out-of-Hospital Cardiac Arrest/therapyABSTRACT
Background: Training schoolchildren in cardiopulmonary resuscitation (CPR) can increase the number of qualified people in the community, which in turn can improve survival rates of out-of-hospital cardiac arrests (OHCA). Medical students could be a valuable resource for providing the training. This systematic review aims to determine the outcomes of medical students providing CPR training to schoolchildren, aged 13-18 (who are thought to have the strength for effective chest compression), specifically CPR skills for both and non-technical skills such as communication and leadership for medical students. Methods: A literature search of academic databases was conducted on 5 July 2023 using the following keywords: cardiopulmonary resuscitation, basic life support, medical students and high/middle/secondary school students. For the purpose of this review, "schoolchildren" refer to those aged 13-18. Studies were included where the primary focus was medical students teaching CPR to schoolchildren. The studies were critically appraised using the Medical Education Research Study Quality Instrument (MERSQI) tool and outcomes categorised by Kirkpatrick's Levels. Results: Eleven studies were included, six randomised controlled trials and five cohort studies, with 1670 schoolchildren and 355 medical students as participants. Eight studies examined outcomes targeting schoolchildren, two examined outcomes for medical students and one examined both. Four of the eleven studies used validated outcome measures. Only outcomes at Kirkpatrick Level 1 and 2 were found, and all outcomes for both schoolchildren and medical students were positive. Schoolchildren showed improvements in theoretical and practical elements of CPR post-training, while medical students demonstrated improved professional practice skills such as leadership and mentorship as well as improvements in their own CPR skills post-teaching. Conclusions: Schoolchildren can effectively acquire CPR skills through being trained by medical students, who themselves also benefit from improved CPR and professional practice skills after teaching. Further studies with robust methodology such as multi-site randomised controlled trials, the use of consistent and validated outcome measures, and the measurement of outcomes at higher Kirkpatrick levels to determine the impact on bystander CPR rates and community OHCA survival rates, are needed.
ABSTRACT
BACKGROUND: Basic life support education for schoolchildren has become a key initiative to increase bystander cardiopulmonary resuscitation rates. Our objective was to review the existing literature on teaching schoolchildren basic life support to identify the best practices to provide basic life support training in schoolchildren. METHODS: After topics and subgroups were defined, a comprehensive literature search was conducted. Systematic reviews and controlled and uncontrolled prospective and retrospective studies containing data on students <20 years of age were included. RESULTS: Schoolchildren are highly motivated to learn basic life support. The CHECK-CALL-COMPRESS algorithm is recommended for all schoolchildren. Regular training in basic life support regardless of age consolidates long-term skills. Young children from 4 years of age are able to assess the first links in the chain of survival. By 10 to 12 years of age, effective chest compression depths and ventilation volumes can be achieved on training manikins. A combination of theoretical and practical training is recommended. Schoolteachers serve as effective basic life support instructors. Schoolchildren also serve as multipliers by passing on basic life support skills to others. The use of age-appropriate social media tools for teaching is a promising approach for schoolchildren of all ages. CONCLUSIONS: Schoolchildren basic life support training has the potential to educate whole generations to respond to cardiac arrest and to increase survival after out-of-hospital cardiac arrest. Comprehensive legislation, curricula, and scientific assessment are crucial to further develop the education of schoolchildren in basic life support.
Subject(s)
Cardiopulmonary Resuscitation , Out-of-Hospital Cardiac Arrest , Child , Humans , Child, Preschool , Retrospective Studies , Prospective Studies , Cardiopulmonary Resuscitation/education , Educational Status , Out-of-Hospital Cardiac Arrest/therapyABSTRACT
BACKGROUND: Basic life support education for schoolchildren has become a key initiative to increase bystander cardiopulmonary resuscitation rates. Our objective was to review the existing literature on teaching schoolchildren basic life support to identify the best practices to provide basic life support training in schoolchildren. METHODS: After topics and subgroups were defined, a comprehensive literature search was conducted. Systematic reviews and controlled and uncontrolled prospective and retrospective studies containing data on students <20 years of age were included. RESULTS: Schoolchildren are highly motivated to learn basic life support. The CHECK-CALL-COMPRESS algorithm is recommended for all schoolchildren. Regular training in basic life support regardless of age consolidates long-term skills. Young children from 4 years of age are able to assess the first links in the chain of survival. By 10 to 12 years of age, effective chest compression depths and ventilation volumes can be achieved on training manikins. A combination of theoretical and practical training is recommended. Schoolteachers serve as effective basic life support instructors. Schoolchildren also serve as multipliers by passing on basic life support skills to others. The use of age-appropriate social media tools for teaching is a promising approach for schoolchildren of all ages. CONCLUSIONS: Schoolchildren basic life support training has the potential to educate whole generations to respond to cardiac arrest and to increase survival after out-of-hospital cardiac arrest. Comprehensive legislation, curricula, and scientific assessment are crucial to further develop the education of schoolchildren in basic life support.
Subject(s)
Cardiopulmonary Resuscitation , Out-of-Hospital Cardiac Arrest , Child , Humans , Child, Preschool , Retrospective Studies , Prospective Studies , Cardiopulmonary Resuscitation/education , Educational StatusABSTRACT
This is the sixth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. This summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. Topics covered by systematic reviews include cardiopulmonary resuscitation during transport; approach to resuscitation after drowning; passive ventilation; minimizing pauses during cardiopulmonary resuscitation; temperature management after cardiac arrest; use of diagnostic point-of-care ultrasound during cardiac arrest; use of vasopressin and corticosteroids during cardiac arrest; coronary angiography after cardiac arrest; public-access defibrillation devices for children; pediatric early warning systems; maintaining normal temperature immediately after birth; suctioning of amniotic fluid at birth; tactile stimulation for resuscitation immediately after birth; use of continuous positive airway pressure for respiratory distress at term birth; respiratory and heart rate monitoring in the delivery room; supraglottic airway use in neonates; prearrest prediction of in-hospital cardiac arrest mortality; basic life support training for likely rescuers of high-risk populations; effect of resuscitation team training; blended learning for life support training; training and recertification for resuscitation instructors; and recovery position for maintenance of breathing and prevention of cardiac arrest. Members from 6 task forces have assessed, discussed, and debated the quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria and generated consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections, and priority knowledge gaps for future research are listed.
Subject(s)
Cardiopulmonary Resuscitation , Emergency Medical Services , Out-of-Hospital Cardiac Arrest , Infant, Newborn , Child , Humans , First Aid , Consensus , Out-of-Hospital Cardiac Arrest/therapy , Emergency TreatmentABSTRACT
This is the sixth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. This summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. Topics covered by systematic reviews include cardiopulmonary resuscitation during transport; approach to resuscitation after drowning; passive ventilation; minimising pauses during cardiopulmonary resuscitation; temperature management after cardiac arrest; use of diagnostic point-of-care ultrasound during cardiac arrest; use of vasopressin and corticosteroids during cardiac arrest; coronary angiography after cardiac arrest; public-access defibrillation devices for children; pediatric early warning systems; maintaining normal temperature immediately after birth; suctioning of amniotic fluid at birth; tactile stimulation for resuscitation immediately after birth; use of continuous positive airway pressure for respiratory distress at term birth; respiratory and heart rate monitoring in the delivery room; supraglottic airway use in neonates; prearrest prediction of in-hospital cardiac arrest mortality; basic life support training for likely rescuers of high-risk populations; effect of resuscitation team training; blended learning for life support training; training and recertification for resuscitation instructors; and recovery position for maintenance of breathing and prevention of cardiac arrest. Members from 6 task forces have assessed, discussed, and debated the quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria and generated consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections, and priority knowledge gaps for future research are listed.
Subject(s)
Cardiopulmonary Resuscitation , Emergency Medical Services , Out-of-Hospital Cardiac Arrest , Infant, Newborn , Child , Humans , Out-of-Hospital Cardiac Arrest/therapy , First Aid , ConsensusABSTRACT
This is the sixth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. This summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. Topics covered by systematic reviews include cardiopulmonary resuscitation during transport; approach to resuscitation after drowning; passive ventilation; minimizing pauses during cardiopulmonary resuscitation; temperature management after cardiac arrest; use of diagnostic point-of-care ultrasound during cardiac arrest; use of vasopressin and corticosteroids during cardiac arrest; coronary angiography after cardiac arrest; public-access defibrillation devices for children; pediatric early warning systems; maintaining normal temperature immediately after birth; suctioning of amniotic fluid at birth; tactile stimulation for resuscitation immediately after birth; use of continuous positive airway pressure for respiratory distress at term birth; respiratory and heart rate monitoring in the delivery room; supraglottic airway use in neonates; prearrest prediction of in-hospital cardiac arrest mortality; basic life support training for likely rescuers of high-risk populations; effect of resuscitation team training; blended learning for life support training; training and recertification for resuscitation instructors; and recovery position for maintenance of breathing and prevention of cardiac arrest. Members from 6 task forces have assessed, discussed, and debated the quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria and generated consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections, and priority knowledge gaps for future research are listed.
Subject(s)
Cardiopulmonary Resuscitation , Emergency Medical Services , Out-of-Hospital Cardiac Arrest , Infant, Newborn , Child , Humans , First Aid , Consensus , Out-of-Hospital Cardiac Arrest/therapy , Emergency TreatmentABSTRACT
Many therapeutic antibodies deplete target cells and elicit immunotherapy by engaging activating Fc gamma receptors (FcγRs) on host effector cells. These antibodies are negatively regulated by the inhibitory FcγRIIB (CD32B). Dogma suggests inhibition is mediated through the FcγRIIB immunoreceptor tyrosine-based inhibition motif (ITIM), negatively regulating immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling from activating FcγR. To assess this, we generated experimental models expressing human (h)FcγRIIB on targets or effectors, lacking or retaining ITIM signaling capacity. We demonstrate that signaling through the hFcγRIIB ITIM is dispensable for impairing monoclonal antibody (mAb)-mediated depletion of normal and malignant murine target cells through three therapeutically relevant surface receptors (CD20, CD25, and OX40) affecting immunotherapy. We demonstrate that hFcγRIIB competition with activating FcγRs for antibody Fc, rather than ITIM signaling, is sufficient to impair activating FcγR engagement, inhibiting effector function and immunotherapy.
Subject(s)
Antibodies, Monoclonal , Receptors, IgG/immunology , Animals , Humans , Immunotherapy , Mice , Receptors, IgG/metabolism , Signal TransductionABSTRACT
PURPOSE OF REVIEW: The purpose of this review is to provide an update for critical care clinicians and providers on the recent developments in patient and healthcare professional (HCP) resuscitation education. RECENT FINDINGS: The family members of patients at high-risk of cardiac arrest need to be provided with access to basic life support (BLS) training. Many low-cost methods are now available to provide BLS training beyond attending a traditional BLS instructor-led cardiopulmonary resuscitation (CPR) class. Hybrid-blended learning formats provide new opportunities to receive individualized CPR-training in a flexible and convenient format. HCPs' participation in accredited advanced life support courses improves patient outcomes. Monitoring HCPs exposure to resuscitation and supplementing with frequent simulation is recommended. Training should include human factors and nontechnical skills. Volunteering for first responder programs when off-duty provides a great opportunity for HCP's to improve out-of-hospital cardiac arrest survival and increase exposure to resuscitation. SUMMARY: Frequent resuscitation education and training is critical to improving cardiac arrest patient outcomes. Recent evidence shows the effectiveness of technological developments to improve access to training and outcomes.
Subject(s)
Cardiopulmonary Resuscitation , Out-of-Hospital Cardiac Arrest , Critical Care , Family , Humans , Out-of-Hospital Cardiac Arrest/therapyABSTRACT
The aim of these guidelines is to provide evidencebased guidance for temperature control in adults who are comatose after resuscitation from either in-hospital or out-of-hospital cardiac arrest, regardless of the underlying cardiac rhythm. These guidelines replace the recommendations on temperature management after cardiac arrest included in the 2021 post-resuscitation care guidelines co-issued by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). The guideline panel included thirteen international clinical experts who authored the 2021 ERC-ESICM guidelines and two methodologists who participated in the evidence review completed on behalf of the International Liaison Committee on Resuscitation (ILCOR) of whom ERC is a member society. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations. The panel provided suggestions on guideline implementation and identified priorities for future research. The certainty of evidence ranged from moderate to low. In patients who remain comatose after cardiac arrest, we recommend continuous monitoring of core temperature and actively preventing fever (defined as a temperatureâ¯>â¯37.7⯰C) for at least 72 hours. There was insufficient evidence to recommend for or against temperature control at 32-36⯰C or early cooling after cardiac arrest. We recommend not actively rewarming comatose patients with mild hypothermia after return of spontaneous circulation (ROSC) to achieve normothermia. We recommend not using prehospital cooling with rapid infusion of large volumes of cold intravenous fluids immediately after ROSC.
Subject(s)
Cardiopulmonary Resuscitation , Hypothermia, Induced , Out-of-Hospital Cardiac Arrest , Adult , Critical Care , Humans , Out-of-Hospital Cardiac Arrest/therapy , Resuscitation , TemperatureABSTRACT
The aim of these guidelines is to provide evidencebased guidance for temperature control in adults who are comatose after resuscitation from either in-hospital or out-of-hospital cardiac arrest, regardless of the underlying cardiac rhythm. These guidelines replace the recommendations on temperature management after cardiac arrest included in the 2021 post-resuscitation care guidelines co-issued by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). The guideline panel included thirteen international clinical experts who authored the 2021 ERC-ESICM guidelines and two methodologists who participated in the evidence review completed on behalf of the International Liaison Committee on Resuscitation (ILCOR) of whom ERC is a member society. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations. The panel provided suggestions on guideline implementation and identified priorities for future research. The certainty of evidence ranged from moderate to low. In patients who remain comatose after cardiac arrest, we recommend continuous monitoring of core temperature and actively preventing fever (defined as a temperature > 37.7 °C) for at least 72 h. There was insufficient evidence to recommend for or against temperature control at 32-36 °C or early cooling after cardiac arrest. We recommend not actively rewarming comatose patients with mild hypothermia after return of spontaneous circulation (ROSC) to achieve normothermia. We recommend not using prehospital cooling with rapid infusion of large volumes of cold intravenous fluids immediately after ROSC.
Subject(s)
Cardiopulmonary Resuscitation , Hypothermia, Induced , Out-of-Hospital Cardiac Arrest , Adult , Critical Care , Humans , Out-of-Hospital Cardiac Arrest/therapy , TemperatureABSTRACT
BACKGROUND: Peer teaching involves learners at the same level in their academic career aiding each other's education. In medical education, it has had success in clinical and procedural skills; we set out to design a pharmacology peer teaching initiative and evaluate its acceptability and value as a learning tool. APPROACH: Second-year medical students (n = 62) were invited to participate in a peer-led pharmacology educational initiative over 2 months. Students created PowerPoint presentations on medications using Pecha Kucha principles (automatic slide advancement that emphasises concision through time and content limitations to sustain the audience's attention). Presentations occurred over eight, 1-hour sessions, facilitated by senior academics. EVALUATION: The evaluation consisted of an anonymous questionnaire with 10 Likert-scale questions and two open-ended questions on the learners' perceptions of feasibility, acceptability and effectiveness in improving knowledge, teaching and independent learning skills. Fifty-three students presented at well-attended sessions. Twenty-nine students completed the Kirkpatrick Level 1 evaluation with largely positive perceptions, including improved pharmacology knowledge (n = 21, 72%), teaching skills (n = 23, 79%) and independent learning skills (n = 22, 76%). Satisfaction with both the quality of peer teaching (n = 21, 72%) and presence of expert facilitators (97%, n = 28) was high. Three found the initiative burdensome, and 23 reported information overload. Nevertheless, 23 deemed the experience valuable. Facilitator reflections were also positive. IMPLICATIONS: Our peer teaching initiative appeared useful to our learners, but in this process, we gained valuable information to improve the next iteration. We plan to use this format either for revision material or reduce session length and increase interval time between sessions to address the perceived information overload.
