Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex.

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate, and adaptive immunity. We have employed two orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins down-regulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterized, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.

Cardiac glycosides inhibit early and late vaccinia virus protein expression.

Cardiac glycosides (CGs) are natural steroid glycosides, which act as inhibitors of the cellular sodium-potassium ATPase pump. Although traditionally considered toxic to human cells, CGs are widely used as drugs for the treatment of cardiovascular-related medical conditions. More recently, CGs have been explored as potential anti-viral drugs and inhibit replication of a range of RNA and DNA viruses. Previously, a compound screen identified CGs that inhibited vaccinia virus (VACV) infection. However, no further investigation of the inhibitory potential of these compounds was performed, nor was there investigation of the stage(s) of the poxvirus lifecycle they impacted. Here, we investigated the anti-poxvirus activity of a broad panel of CGs. We found that all CGs tested were potent inhibitors of VACV replication. Our virological experiments showed that CGs did not impact virus infectivity, binding, or entry. Rather, experiments using recombinant viruses expressing reporter proteins controlled by VACV promoters and arabinoside release assays demonstrated that CGs inhibited early and late VACV protein expression at different concentrations. Lack of virus assembly in the presence of CGs was confirmed using electron microscopy. Thus, we expand our understanding of compounds with anti-poxvirus activity and highlight a yet unrecognized mechanism by which poxvirus replication can be inhibited.

Strain-Dependent Restriction of Human Cytomegalovirus by Zinc Finger Antiviral Proteins.

Cellular antiviral factors that recognize viral nucleic acid can inhibit virus replication. These include the zinc finger antiviral protein (ZAP), which recognizes high CpG dinucleotide content in viral RNA. Here, we investigated the ability of ZAP to inhibit the replication of human cytomegalovirus (HCMV). Depletion of ZAP or its cofactor KHNYN increased the titer of the high-passage HCMV strain AD169 but had little effect on the titer of the low-passage strain Merlin. We found no obvious difference in expression of several viral proteins between AD169 and Merlin in ZAP knockdown cells, but observed a larger increase in infectious virus in AD169 compared to Merlin in the absence of ZAP, suggesting that ZAP inhibited events late in AD169 replication. In addition, there was no clear difference in the CpG abundance of AD169 and Merlin RNAs, indicating that genomic content of the two virus strains was unlikely to be responsible for differences in their sensitivity to ZAP. Instead, we observed less ZAP expression in Merlin-infected cells late in replication compared to AD169-infected cells, which may be related to different abilities of the two virus strains to regulate interferon signaling. Therefore, there are strain-dependent differences in the sensitivity of HCMV to ZAP, and the ability of low-passage HCMV strain Merlin to evade inhibition by ZAP is likely related to its ability to regulate interferon signaling, not the CpG content of RNAs produced from its genome. IMPORTANCE Determining the function of cellular antiviral factors can inform our understanding of virus replication. The zinc finger antiviral protein (ZAP) can inhibit the replication of diverse viruses. Here, we examined ZAP interaction with the DNA virus human cytomegalovirus (HCMV). We found HCMV strain-dependent differences in the ability of ZAP to influence HCMV replication, which may be related to the interaction of HCMV strains with the type I interferon system. These observations affect our current understanding of how ZAP restricts HCMV and how HCMV interacts with the type I interferon system.

Inhibition of human cytomegalovirus replication by interferon alpha can involve multiple anti-viral factors.

The shortcomings of current direct-acting anti-viral therapy against human cytomegalovirus (HCMV) has led to interest in host-directed therapy. Here we re-examine the use of interferon proteins to inhibit HCMV replication utilizing both high and low passage strains of HCMV. Pre-treatment of cells with interferon alpha (IFNα) was required for robust and prolonged inhibition of both low and high passage HCMV strains, with no obvious toxicity, and was associated with an increased anti-viral state in HCMV-infected cells. Pre-treatment of cells with IFNα led to poor expression of HCMV immediate-early proteins from both high and low passage strains, which was associated with the presence of the anti-viral factor SUMO-PML. Inhibition of HCMV replication in the presence of IFNα involving ZAP proteins was HCMV strain-dependent, wherein a high passage HCMV strain was obviously restricted by ZAP and a low passage strain was not. This suggested that strain-specific combinations of anti-viral factors were involved in inhibition of HCMV replication in the presence of IFNα. Overall, this work further supports the development of strategies involving IFNα that may be useful to inhibit HCMV replication and highlights the complexity of the anti-viral response to HCMV in the presence of IFNα.

A systematic review and meta-analysis of the prevalence of human cytomegalovirus shedding in seropositive pregnant women.

The detection of human cytomegalovirus (HCMV) in an individual's bodily fluid by culture techniques or through HCMV DNA detection by polymerase chain reaction, is known as HCMV shedding. Human cytomegalovirus shedding has the potential to transmit HCMV infection, where an individual can become infected with HCMV through contact with the bodily fluid of another individual containing HCMV. Human cytomegalovirus shedding can occur in primary infection and in non-primary infection for individuals with prior infection (HCMV seropositive). Human cytomegalovirus infection causes few or no symptoms in a pregnant woman, but can cause significant harm to her foetus if congenital CMV (cCMV) infection occurs. The association between HCMV shedding in HCMV seropositive pregnant women and the vertical transmission of HCMV to result in cCMV infection is poorly investigated, challenged by a limited understanding of the distribution of HCMV shedding in HCMV seropositive pregnant women. We systematically reviewed the published literature to describe the prevalence of HCMV shedding in HCMV seropositive women during pregnancy up to delivery. This analysis identified nine studies that met our eligibility criteria. In these studies, the prevalence of HCMV shedding in any bodily fluid of HCMV seropositive women during pregnancy and at delivery ranged from 0% to 42.5%. A meta-analysis, performed on six of the nine studies with suitable sample sizes, estimated a pooled prevalence of 21.5% [95% CI 12.7%,30.3%]. To our knowledge, this is the first review to systematically search the literature to summarise the prevalence of HCMV shedding in HCMV seropositive pregnant women. These estimates can help in the development of disease burden models and therapeutic or preventative strategies against cCMV infection in the context of non-primary maternal HCMV infection.

Dry matter intake and feed efficiency of heifers from 4 dairy breed types grazing organic grass and grass-birdsfoot trefoil mixed pastures.

Insufficient dry matter intake (DMI) of pasture by dairy cattle is a major factor limiting growth and milk production; however, it has been hypothesized that some dairy breeds may be more efficient grazers than others. This study was conducted to determine whether dairy breed types differ in DMI and feed efficiency when grazing either grass monoculture or grass-legume mixed pastures. The experiment compared 4 different dairy breed types (Jersey, Holstein, Holstein-Jersey crossbreds, and Montbéliarde-Swedish Red-Holstein 3-breed crossbreds) and 2 levels of pasture type [grass monoculture (MONO) and grass-birdsfoot trefoil (BFT) mixture (MX)] for a total of 8 treatments. Pastures were rotationally stocked with groups of 4 prepubertal heifers for 105 d for 3 yr, and DMI was determined from herbage disappearance. Feed conversion efficiency (FCE) and residual feed intake (RFI) were then derived from DMI, and heifer body weights (BW) and normalized to animal units (AU) as 40% metabolic mature BW of the corresponding dairy breed type to account for inherent differences in size and growth rates. We observed differences in DMI and feed efficiency among breed types and between pasture types. On average, Holsteins had the greatest overall DMI (4.4 kg/AU), followed by intermediate DMI by the crossbreds (4.0 kg/AU), and Jerseys had the least DMI (3.6 kg/AU). Heifers grazing MX pastures had on average 22% greater DMI than those grazing MONO, but heifers on grass monocultures were more efficient in converting DMI to BW gain (i.e., RFI/AU of 0.27 and -0.27, respectively; more negative RFI numbers indicate less DMI to achieve the expected gains). Overall, Jerseys had the most favorable feed efficiency; however, ranking of Holsteins and crossbreds depended upon the feed efficiency metric. This study is one of the first to compare the interaction of dairy breed and pasture quality on grazing efficiency. However, the lack of a breed type × pasture type interaction for DMI, FCE, or RFI indicated that none of these dairy breed types were better adapted than another breed type to pastures with contrasting levels of nutritive value.

Toward inhibition of human cytomegalovirus replication with compounds targeting cellular proteins.

Antiviral therapy for human cytomegalovirus (HCMV) currently relies upon direct-acting antiviral drugs. However, it is now well known that these drugs have shortcomings, which limit their use. Here I review the identification and investigation of compounds targeting cellular proteins that have anti-HCMV activity and could supersede those anti-HCMV drugs currently in use. This includes discussion of drug repurposing, for example the use of artemisinin compounds, and discussion of new directions to identify compounds that target cellular factors in HCMV-infected cells, for example screening of kinase inhibitors. In addition, I highlight developing areas such as the use of machine learning and emphasize how interaction with fields outside virology will be critical for development of anti-HCMV compounds.

Care of Sexual and Gender Minorities in the Emergency Department: A Scoping Review.

STUDY OBJECTIVE: This scoping review was conducted to collate and summarize the published research literature addressing sexual and gender minority care in the emergency department (ED). METHODS: Using PRISMA-ScR criteria, an electronic search was conducted of CINAHL, Embase, Ovid Medline, and Web of Science for all studies that were published after 1995 involving sexual and gender minorities, throughout all life stages, presenting to an ED. We excluded non-US and Canadian studies and editorials. Titles and abstracts were screened, and full-text review was performed independently with 4 reviewers. Abstraction focused on study design, demographics, and outcomes, and the resulting data were analyzed using an ad hoc iterative thematic analysis. RESULTS: We found 972 unique articles and excluded 743 after title and abstract screening. The remaining 229 articles underwent full-text review, and 160 articles were included. Themes identified were HIV in sexual and gender minorities (n=61), population health (n=46), provider training (n=29), ED avoidance or barriers (n=23), ED use (n=21), and sexual orientation/gender identity information collection (n=9). CONCLUSION: The current literature encompassing ED sexual and gender minority care cluster into 6 themes. There are considerable gaps to be addressed in optimizing culturally competent and equitable care in the ED for this population. Future research to address these gaps should include substantial patient stakeholder engagement in all aspects of the research process to ensure patient-focused outcomes congruent with sexual and gender minority values and preferences.

Cross-Reactivity with Self-Antigen Tunes the Functional Potential of Naive B Cells Specific for Foreign Antigens.

Upon Ag exposure, naive B cells expressing BCR able to bind Ag can undergo robust proliferation and differentiation that can result in the production of Ab-secreting and memory B cells. The factors determining whether an individual naive B cell will proliferate following Ag encounter remains unclear. In this study, we found that polyclonal naive murine B cell populations specific for a variety of foreign Ags express high levels of the orphan nuclear receptor Nur77, which is known to be upregulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naive human B cells specific for clinically-relevant Ags derived from respiratory syncytial virus and HIV-1 also exhibited an IgMLOW IgD+ phenotype, which is associated with self-antigen cross-reactivity. Functionally, naive B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following Ag injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naive B cells specific for foreign Ags and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following Ag exposure.

Public awareness and knowledge of sepsis: a cross-sectional survey of adults in Canada.

BACKGROUND: Sepsis is a life-threatening complication of the body's response to infection. The financial, medical, and psychological costs of sepsis to individuals and to the healthcare system are high. Most sepsis cases originate in the community, making public awareness of sepsis essential to early diagnosis and treatment. There has been no comprehensive examination of adult's sepsis knowledge in Canada. METHODS: We administered an online structured survey to English- or French-literate adults in Canada. The questionnaire comprised 28 questions in three domains: awareness, knowledge, and information access. Sampling was stratified by age, sex, and geography and weighted to 2016 census data. We used descriptive statistics to summarize responses; demographic differences were tested using the Rao-Scott correction for weighted chi-squared tests and associations using multiple variable regression. RESULTS: Sixty-one percent of 3200 adults sampled had heard of sepsis. Awareness differed by respondent's residential region, sex, education, and ethnic group (p < 0.001, all). The odds of having heard of sepsis were higher for females, older adults, respondents with some or completed college/university education, and respondents who self-identified as Black, White, or of mixed ethnicity (p < 0.01, all). Respondent's knowledge of sepsis definitions, symptoms, risk factors, and prevention measures was generally low (53.0%, 31.5%, 16.5%, and 36.3%, respectively). Only 25% of respondents recognized vaccination as a preventive strategy. The strongest predictors of sepsis knowledge were previous exposure to sepsis, healthcare employment, female sex, and a college/university education (p < 0.001, all). Respondents most frequently reported hearing about sepsis through television (27.7%) and preferred to learn about sepsis from healthcare providers (53.1%). CONCLUSIONS: Sepsis can quickly cause life-altering physical and psychological effects and 39% of adults sampled in Canada have not heard of it. Critically, a minority (32%) knew about signs, risk factors, and strategies to lower risk. Education initiatives should focus messaging on infection prevention, employ broad media strategies, and use primary healthcare providers to disseminate evidence-based information. Future work could explore whether efforts to raise public awareness of sepsis might be bolstered or hindered by current discourse around COVID-19, particularly those centered on vaccination.

Part 7: Systems of Care: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Survival after cardiac arrest requires an integrated system of people, training, equipment, and organizations working together to achieve a common goal. Part 7 of the 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care focuses on systems of care, with an emphasis on elements that are relevant to a broad range of resuscitation situations. Previous systems of care guidelines have identified a Chain of Survival, beginning with prevention and early identification of cardiac arrest and proceeding through resuscitation to post-cardiac arrest care. This concept is reinforced by the addition of recovery as an important stage in cardiac arrest survival. Debriefing and other quality improvement strategies were previously mentioned and are now emphasized. Specific to out-of-hospital cardiac arrest, this Part contains recommendations about community initiatives to promote cardiac arrest recognition, cardiopulmonary resuscitation, public access defibrillation, mobile phone technologies to summon first responders, and an enhanced role for emergency telecommunicators. Germane to in-hospital cardiac arrest are recommendations about the recognition and stabilization of hospital patients at risk for developing cardiac arrest. This Part also includes recommendations about clinical debriefing, transport to specialized cardiac arrest centers, organ donation, and performance measurement across the continuum of resuscitation situations.

Education, Implementation, and Teams: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.

For this 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, the Education, Implementation, and Teams Task Force applied the population, intervention, comparator, outcome, study design, time frame format and performed 15 systematic reviews, applying the Grading of Recommendations, Assessment, Development, and Evaluation guidance. Furthermore, 4 scoping reviews and 7 evidence updates assessed any new evidence to determine if a change in any existing treatment recommendation was required. The topics covered included training for the treatment of opioid overdose; basic life support, including automated external defibrillator training; measuring implementation and performance in communities, and cardiac arrest centers; advanced life support training, including team and leadership training and rapid response teams; measuring cardiopulmonary resuscitation performance, feedback devices, and debriefing; and the use of social media to improve cardiopulmonary resuscitation application.

Metagenomic profiling of placental tissue suggests DNA virus infection of the placenta is rare.

It is widely recognized that pathogens can be transmitted across the placenta from mother to foetus. Recent re-evaluation of metagenomic studies indicates that the placenta has no unique microbiome of commensal bacteria. However, viral transmission across the placenta, including transmission of DNA viruses such as the human herpesviruses, is possible. A fuller understanding of which DNA virus sequence can be found in the placenta is required. We employed a metagenomic analysis to identify viral DNA sequences in placental metagenomes from full-term births (20 births), pre-term births (13 births), births from pregnancies associated with antenatal infections (12 births) or pre-term births with antenatal infections (three births). Our analysis found only a small number of DNA sequences corresponding to the genomes of human herpesviruses in four of the 48 metagenomes analysed. Therefore, our data suggest that DNA virus infection of the placenta is rare and support the concept that the placenta is largely free of pathogen infection.

Limited replication of human cytomegalovirus in a trophoblast cell line.

Several viruses, including human cytomegalovirus (HCMV), are thought to replicate in the placenta. However, there is little understanding of the molecular mechanisms involved in HCMV replication in this tissue. We investigated replication of HCMV in the extravillous trophoblast cell line SGHPL-4, a commonly used model of HCMV replication in the placenta. We found limited HCMV protein expression and virus replication in SGHPL-4 cells. This was associated with a lack of trophoblast progenitor cell protein markers in SGHPL-4 cells, suggesting a relationship between trophoblast differentiation and limited HCMV replication. We proposed that limited HCMV replication in trophoblast cells is advantageous to vertical transmission of HCMV, as there is a greater opportunity for vertical transmission when the placenta is intact and functional. Furthermore, when we investigated the replication of other vertically transmitted viruses in SGHPL-4 cells we found some limitation to replication of Zika virus, but not herpes simplex virus. Thus, limited replication of some, but not all, vertically transmitted viruses may be a feature of trophoblast cells.

Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication.

The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of bioactive compounds and identified a range of compounds with the potential to inhibit HCMV replication. Of these compounds, we selected bisbenzimide compound RO-90-7501 for further study. We generated analogues of RO-90-7501 and found that one compound, MRT00210423, had increased anti-HCMV activity compared to RO-90-7501. Using a combination of compound analogues, microscopy and biochemical assays we found RO-90-7501 and MRT00210423 interacted with DNA. In single molecule microscopy experiments we found RO-90-7501, but not MRT00210423, was able to compact DNA, suggesting that compaction of DNA was non-obligatory for anti-HCMV effects. Using bioinformatics analysis, we found that there were many putative bisbenzimide binding sites in the HCMV DNA genome. However, using western blotting, quantitative PCR and electron microscopy, we found that at a concentration able to inhibit HCMV replication our compounds had little or no effect on production of certain HCMV proteins or DNA synthesis, but did have a notable inhibitory effect on HCMV capsid production. We reasoned that these effects may have involved binding of our compounds to the HCMV genome and/or host cell chromatin. Therefore, our data expand our understanding of compounds with anti-HCMV activity and suggest targeting of DNA with bisbenzimide compounds may be a useful anti-HCMV strategy.

The effects of organic grass and grass-birdsfoot trefoil pastures on Jersey heifer development: Herbage characteristics affecting intake.

Low dietary energy and decreased intake of herbage have been attributed to the reduced performance of grazing dairy cattle. We hypothesized that grasses with inherently greater energy would interact in a complementary way with condensed tannins (CT) in birdsfoot trefoil to increase herbage intake by grazing dairy heifers. Eight pasture treatments comprising high-sugar perennial ryegrass (Lolium perenne L.), orchardgrass (Dactylis glomerata L.), meadow bromegrass (Bromus riparius Rehmann), and tall fescue [Schendonorus arundinaceus (Schreb.) Dumort] were established in Lewiston, Utah as monocultures and binary mixtures with birdsfoot trefoil (Lotus corniculatus L.; BFT). Pasture treatments were rotationally stocked by Jersey heifers for 105 d in 2017 and 2018, and herbage samples were collected pre- and postgrazing for each 7-d grazing period and analyzed for herbage mass, nutritive value, and apparent herbage intake. We observed differences among pasture treatments in herbage quantity and nutritive value, as well as differences in herbage intake by grazing Jersey heifers. On average, grass-BFT mixtures had greater herbage intake than grass monocultures, and every grass-BFT treatment individually had greater herbage intake than their respective grass monocultures. Using multivariate analyses, we determined that approximately 50% of the variation in herbage intake was due to nutritive and physical herbage characteristics, with the most explanatory being characteristics related to fiber and energy, followed by those related to the percent of BFT in the herbage. Grass monocultures exhibited a range of inherent dietary energy, but there was indication that an imbalance of energy to crude protein (e.g., protein deficient) reduced intake of grass monocultures. Moreover, there was some evidence of a complementary effect between increased dietary energy and CT; however, low CT levels made it impossible to determine the effect of CT on herbage intake per se. This study confirmed that chemical and physical characteristics inherent to different pasture species have a large effect on herbage intake by grazing cattle. Pastures planted to binary mixtures of nutritious grasses and birdsfoot trefoil increase herbage intake of temperate pastures by grazing Jersey heifers.

The effects of organic grass and grass-birdsfoot trefoil pastures on Jersey heifer development: Heifer growth, performance, and economic impact.

Dairy heifers developed in certified organic programs, especially those utilizing pasture-based management schemes, have lower rates of gain than heifers raised in nonorganic confinement production systems in temperate climates, such as in the Intermountain West region of the United States. This study investigates the effects that different forages in a rotational grazing system have on development of organically raised Jersey heifers. Over 3 years, 210 yearling Jersey heifers were randomly assigned to one of 9 treatments, including a conventional confinement control where animals were fed a total mixed ration or one of 8 pasture treatments: Cache Meadow bromegrass (Bromus riparius Rehmann), QuickDraw orchard grass (Dactylis glomerata L.), Amazon perennial ryegrass (Lolium perenne L.), or Fawn tall fescue (Schendonorus arundinaceus [Schreb.] Dumort) and each individual grass interseeded with birdsfoot trefoil (Lotus corniculatus L., BFT). Each treatment had 3 blocks/yr over the 3-yr period, with each block having a 0.4 ha pasture of each treatment. Every 35 d, over a 105-d period, heifers were weighed and measured for hip height, and blood samples were collected to determine serum insulin-like growth factor-1 and blood urea nitrogen concentrations. Fecal egg counts were also assessed. Heifer body weight (BW), blood urea nitrogen, and insulin-like growth factor-1 concentrations were affected by treatment when analyzed over time. Heifers on grass-BFT pastures had increased BW compared with heifers on monoculture grass pastures. Heifers receiving a total mixed ration or perennial ryegrass+BFT had increased BW gain over the 105-d period compared with heifers grazing tall fescue+BFT, orchard grass, perennial ryegrass, meadow bromegrass, or tall fescue. Individually for all grass species, heifers grazing +BFT pastures had greater ending BW and weight gain than heifers grazing the respective grass monocultures. Furthermore, weight gain for heifers on perennial ryegrass+BFT, meadow bromegrass+BFT, and orchard grass+BFT were not different from those on a total mixed ration. Heifers grazing grass-BFT pastures had increased blood urea nitrogen compared with heifers grazing monoculture grass pastures. Heifer hip height and fecal egg counts were not affected by treatment. These results show that the addition of BFT to organic pasture improves growth of grazing replacement heifers. Economic analyses also demonstrate that interseeding grass pastures with BFT results in an increased economic return compared with grazing monoculture grass pastures. Grass pastures interseeded with BFT may be a sustainable option to achieve adequate growth of Jersey heifers raised in an organic pasture scenario in a temperate climate.

If we could turn back time: Imagining time-variable, competency-based medical education in the context of COVID-19.

The COVID-19 pandemic has exposed a paradox in historical models of medical education: organizations responsible for applying consistent standards for progression have needed to adapt to training environments marked by inconsistency and change. Although some institutions have maintained their traditional requirements, others have accelerated their programs to rush nearly graduated trainees to the front lines. One interpretation of the unplanned shortening of the duration of training programs during a crisis is that standards have been lowered. But it is also possible that these trainees were examined according to the same standards as usual and were judged to have already met them. This paper discusses the impacts of the COVID-19 pandemic on the current workforce, provides an analysis of how competency-based medical education (CBME) in the context of the pandemic might have mitigated wide-scale disruption, and identifies structural barriers to achieving an ideal state. The paper further calls upon universities, health centres, governments, certifying bodies, regulatory authorities, and health care professionals to work collectively on a truly time-variable model of CBME. The pandemic has made clear that time variability in medical education already exists and should be adopted widely and formally. If our systems today had used a framework of outcome competencies, sequenced progression, tailored learning, focused instruction, and programmatic assessment, we may have been even more nimble in changing our systems to care for our patients with COVID-19.

2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the 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. The task forces also listed priority knowledge gaps for further research.

2017 American Heart Association Focused Update on Pediatric Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This focused update to the American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care follows the Pediatric Task Force of the International Liaison Committee on Resuscitation evidence review. It aligns with the International Liaison Committee on Resuscitation's continuous evidence review process, and updates are published when the International Liaison Committee on Resuscitation completes a literature review based on new science. This update provides the evidence review and treatment recommendation for chest compression-only CPR versus CPR using chest compressions with rescue breaths for children <18 years of age. Four large database studies were available for review, including 2 published after the "2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care." Two demonstrated worse 30-day outcomes with chest compression-only CPR for children 1 through 18 years of age, whereas 2 studies documented no difference between chest compression-only CPR and CPR using chest compressions with rescue breaths. When the results were analyzed for infants <1 year of age, CPR using chest compressions with rescue breaths was better than no CPR but was no different from chest compression-only CPR in 1 study, whereas another study observed no differences among chest compression-only CPR, CPR using chest compressions with rescue breaths, and no CPR. CPR using chest compressions with rescue breaths should be provided for infants and children in cardiac arrest. If bystanders are unwilling or unable to deliver rescue breaths, we recommend that rescuers provide chest compressions for infants and children.