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.

A novel online training program for sexual and gender minority health increases allyship in cisgender, heterosexual paramedics.

Introduction: Sexual and gender minorities (SGM) make up 4% of the Canadian population. Due to existing barriers to care in the community, SGM patients may seek more help and be sicker at presentation to hospital. Paramedics occupy a unique role and can remove or decrease these barriers. There are no existing evaluations of training programs in SGM health for prehospital providers. A training program to develop better allyship in paramedics toward SGM populations was developed and assessed. Methods: A 70- to 90-min mandatory, asynchronous, online training module in SGM health in the prehospital environment was developed and delivered via the emergency medical service (EMS) system's learning management system. A before-and-after study of cisgender, heterosexual, frontline paramedics was performed to measure the impact of the training module on the care of SGM patients. The validated Ally Identity Measure (AIM) tool was used to identify success of training and includes subscales of knowledge and skills, openness and support, and oppression awareness. Demographics and satisfaction scores were collected in the posttraining survey. Matched and unmatched pairs of surveys and demographic associations were analyzed using nonparametric statistics. Results: Of 609 paramedics, 571 completed the training, and 239 surveys were completed before and 105 (n = 344) surveys after the training; 60 surveys were paired. Overall AIM scores of matched pairs (n = 60) improved by 12% (p < 0.001), with knowledge and skills accounting for most of the increase (21%, p < 0.001). Unmatched pairs (n = 344) were similar in demographics and scores. Rural paramedics also had significantly lower pretraining oppression awareness scores and had lower posttraining AIM scores compared to suburban paramedics (6% difference). Satisfaction scores rated the training as relevant and applicable (87% and 82%, respectively). Conclusions: A novel prehospital training program in the care of SGM patients resulted in a statistically significant increase in allyship in cisgender, heterosexual-identified frontline paramedics.

Gender, Socioeconomic Status, Race, and Ethnic Disparities in Bystander Cardiopulmonary Resuscitation and Education-A Scoping Review.

BACKGROUND: Social determinants are associated with survival from out-of-hospital sudden cardiac arrest (SCA). Because prompt delivery of bystander CPR (B-CPR) doubles survival and B-CPR rates are low, we sought to assess whether gender, socioeconomic status (SES), race, and ethnicity are associated with lower rates of B-CPR and CPR training. METHODS: This scoping review was conducted as part of the continuous evidence evaluation process for the 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care as part of the Resuscitation Education Science section. We searched PubMed and excluded citations that were abstracts only, letters or editorials, and pediatric studies. RESULTS: We reviewed 762 manuscripts and identified 24 as relevant; 4 explored gender disparities; 12 explored SES; 11 explored race and ethnicity; and 3 had overlapping themes, all of which examined B-CPR or CPR training. Females were less likely to receive B-CPR than males in public locations. Observed gender disparities in B-CPR may be associated with individuals fearing accusations of inappropriate touching or injuring female victims. Studies demonstrated that low-SES neighborhoods were associated with lower rates of B-CPR and CPR training. In the US, predominantly Black and Hispanic neighborhoods were associated with lower rates of B-CPR and CPR training. Language barriers were associated with lack of CPR training. CONCLUSION: Gender, SES, race, and ethnicity impact receiving B-CPR and obtaining CPR training. The impact of this is that these populations are less likely to receive B-CPR, which decreases their odds of surviving SCA. These health disparities must be addressed. Our work can inform future research, education, and public health initiatives to promote equity in B-CPR knowledge and provision. As an immediate next step, organizations that develop and deliver CPR curricula to potential bystanders should engage affected communities to determine how best to improve training and delivery of B-CPR.

Adjuvanted Vaccine Induces Functional Antibodies against Pseudomonas aeruginosa Filamentous Bacteriophages.

Pseudomonas aeruginosa (Pa), a WHO priority 1 pathogen, resulted in approximately 559,000 deaths globally in 2019. Pa has a multitude of host-immune evasion strategies that enhance Pa virulence. Most clinical isolates of Pa are infected by a phage called Pf that has the ability to misdirect the host-immune response and provide structural integrity to biofilms. Previous studies demonstrate that vaccination against the coat protein (CoaB) of Pf4 virions can assist in the clearance of Pa from the dorsal wound model in mice. Here, a consensus peptide was derived from CoaB and conjugated to cross-reacting material 197 (CRM197). This conjugate was adjuvanted with a novel synthetic Toll-like receptor agonist (TLR) 4 agonist, INI-2002, and used to vaccinate mice. Mice vaccinated with CoaB-CRM conjugate and INI-2002 developed high anti-CoaB peptide-specific IgG antibody titers. Direct binding of the peptide-specific antibodies to whole-phage virus particles was demonstrated by ELISA. Furthermore, a functional assay demonstrated that antibodies generated from vaccinated mice disrupted the replicative cycle of Pf phages. The use of an adjuvanted phage vaccine targeting Pa is an innovative vaccine strategy with the potential to become a new tool targeting multi-drug-resistant Pa infections in high-risk populations.

Bisbenzimide compounds inhibit the replication of prototype and pandemic potential poxviruses.

We previously identified the bisbenzimide Hoechst 33342 (H42) as a potent multi-stage inhibitor of the prototypic poxvirus, the vaccinia virus (VACV), and several parapoxviruses. A recent report showed that novel bisbenzimide compounds similar in structure to H42 could prevent human cytomegalovirus replication. Here, we assessed whether these compounds could also serve as poxvirus inhibitors. Using virological assays, we show that these bisbenzimide compounds inhibit VACV spread, plaque formation, and the production of infectious progeny VACV with relatively low cell toxicity. Further analysis of the VACV lifecycle indicated that the effective bisbenzimide compounds had little impact on VACV early gene expression but inhibited VACV late gene expression and truncated the formation of VACV replication sites. Additionally, we found that bisbenzimide compounds, including H42, can inhibit both monkeypox and a VACV mutant resistant to the widely used anti-poxvirus drug TPOXX (Tecovirimat). Therefore, the tested bisbenzimide compounds were inhibitors of both prototypic and pandemic potential poxviruses and could be developed for use in situations where anti-poxvirus drug resistance may occur. Additionally, these data suggest that bisbenzimide compounds may serve as broad-activity antiviral compounds, targeting diverse DNA viruses such as poxviruses and betaherpesviruses.IMPORTANCEThe 2022 mpox (monkeypox) outbreak served as a stark reminder that due to the cessation of smallpox vaccination over 40 years ago, most of the human population remains susceptible to poxvirus infection. With only two antivirals approved for the treatment of smallpox infection in humans, the need for additional anti-poxvirus compounds is evident. Having shown that the bisbenzimide H33342 is a potent inhibitor of poxvirus gene expression and DNA replication, here we extend these findings to include a set of novel bisbenzimide compounds that show anti-viral activity against mpox and a drug-resistant prototype poxvirus mutant. These results suggest that further development of bisbenzimides for the treatment of pandemic potential poxviruses is warranted.

Systematic Review, Quality Assessment, and Synthesis of Guidelines for Emergency Department Care of Transgender and Gender-diverse People: Recommendations for Immediate Action to Improve Care.

Introduction: We conducted this systematic review to identify emergency department (ED) relevant recommendations in current guidelines for care of transgender and gender-diverse (TGD) people internationally. Methods: Using PRISMA criteria, we did a systematic search of Ovid Medline, EMBASE, and CINAHL and a hand search of gray literature for clinical practice guidelines (CPG) or best practice statements (BPS) published until June 31, 2021. Articles were included if they were in English, included medical or paramedical care of TGD populations of any age, in any setting, region or nation, and were national or international in scope. Exclusion criteria included primary research studies, review articles, narrative reviews or otherwise non-CPG or BPS, editorials, or letters to the editor, articles of regional or individual hospital scope, non-medical articles, articles not in English, or if a more recent version of the guideline existed. Recommendations relevant to ED care were identified, recorded, and assessed for quality using the AGREE-II and AGREE-REX criteria. We performed interclass correlation coefficient for interrater reliability. Recommendations were coded for the relevant point of care while in the ED (triage, registration, rooming, investigations, etc.). Results: We screened 1,658 unique articles, and 1,555 were excluded. Of the remaining 103 articles included, seven had recommendations relevant to care in the ED, comprising a total of 10 recommendations. Four guidelines and eight recommendations were of high quality. They included recommendations for testing, prevention, referral, and provision of post-exposure prophylaxis for HIV, and culturally competent care of TGD people. Conclusions: This is the most comprehensive review to date of guidelines and best practices statements offering recommendations for care of ED TGD patients, and several are immediately actionable. There are also many opportunities to build community-led research programs to synthesize and inform a comprehensive dedicated guideline for care of TGD people in emergency settings.

Considerations on the Use of Neonatal and Pediatric Resuscitation Guidelines for Hospitalized Neonates and Infants: On Behalf of the American Heart Association Emergency Cardiovascular Care Committee and the American Academy of Pediatrics.

Between 0.25% and 3% of admissions to the NICU, PICU, and PCICU receive cardiopulmonary resuscitation (CPR). Most CPR events occur in patients <1 year old. The incidence of CPR is 10 times higher in the NICU than at birth. Therefore, optimizing the approach to CPR in hospitalized neonates and infants is important. At birth, the resuscitation of newborns is performed according to neonatal resuscitation guidelines. In older infants and children, resuscitation is performed according to pediatric resuscitation guidelines. Neonatal and pediatric guidelines differ in several important ways. There are no published recommendations to guide the transition from neonatal to pediatric guidelines. Therefore, hospitalized neonates and infants can be resuscitated using neonatal guidelines, pediatric guidelines, or a hybrid approach. This report summarizes the current neonatal and pediatric resuscitation guidelines, considers how to apply them to hospitalized neonates and infants, and identifies knowledge gaps and future priorities. The lack of strong scientific data makes it impossible to provide definitive recommendations on when to transition from neonatal to pediatric resuscitation guidelines. Therefore, it is up to health care teams and institutions to decide if neonatal or pediatric guidelines are the best choice in a given location or situation, considering local circumstances, health care team preferences, and resource limitations.

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.

Learning from the experiences of pregnant women participating in a research study investigating human cytomegalovirus shedding: A qualitative study.

Transmission of human cytomegalovirus (CMV), from a pregnant woman to her fetus can cause congenital CMV infection, with life-long problems in some infected children. The presence of CMV in an infected individual's bodily fluid is known as shedding. An individual can become infected with CMV through contact with another individual who is shedding CMV in their bodily fluid, and the avoidance of contact with infected fluids may reduce the risk of infection. We explored the experiences of pregnant women taking part in a study investigating CMV shedding, to identify the potential facilitators and barriers towards engaging pregnant women with CMV risk-reduction measures. Twenty pregnant women participated in semi-structured, end-of-study, telephone interviews, analysed using thematic analysis. They participated in an observational study investigating CMV shedding in pregnant women previously infected with CMV living with young children. Participating women considered that CMV testing of themselves and their newborns was a benefit of participation, without raising additional concerns. They identified that their participation was contingent on a balance of convenience and inconvenience, and benefits and risks. Participation increased their awareness of their hygiene-based practices, leading to behavioural modifications that put them in contact with urine and saliva of their children without instructions to do so. These behavioural modifications might interfere with household routines. However, they recognised it to be a time-limited risk-reduction measure, and felt empowered by the knowledge they had gained through study participation and the support they had received from their partners. Participating women gained an increased awareness of their behaviour, resulting in behavioural modification without instructions to do this, in line with previous findings that trial participation can impact on participants' thinking about their behaviour with a possibility to influence change. Maternal research and risk-reduction measures should be centred around being informative, convenient, empowering, and supportive.

Exploring a case for education about sexual and gender minorities in postgraduate emergency medicine training: forming recommendations for change.

Social medicine and health advocacy curricula are known to be uncommon in postgraduate medical education. As justice movements work to unveil the systemic barriers experienced by sexual and gender minority (SGM) populations, it is imperative that the emergency medicine (EM) community progress in its efforts to provide equitable, accessible, and competent care for these vulnerable groups. Given the paucity of literature on this subject in the context of EM in Canada, this commentary borrows evidence from other specialties across North America. Trainees across specialties and of all stages are caring for an increasing number of SGM patients. Lack of education at all levels of training is identified as a significant barrier to adequately caring for these populations, thereby precipitating significant health disparities. Cultural competency is often mistakenly attributed to a willingness to treat rather than the provision of quality care. However, positive attitudes do not necessarily correlate with trainee knowledge. Barriers to creating and implementing culturally competent curricula are plentiful, yet facilitating policies and resources are rare. While international bodies continuously publish position statements and calls to action, concrete change is seldom made. The scarcity of SGM curricula can be attributed to the universal absence of formal acknowledgment of SGM health as a required competency by accreditation boards and professional membership associations. This commentary synthesizes hand-picked literature in an attempt to inform healthcare professionals on their journey toward developing culturally competent postgraduate medical education. By thematically organizing evidence into a stepwise approach, the goal of this article is to borrow ideas across medical and surgical specialties to inform the creation of recommendations and make a case for an SGM curriculum for EM programs in Canada.

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.

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.

Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons.

BACKGROUND: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold. METHODS: To dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. RESULTS: In iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation. CONCLUSIONS: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.

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.

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.

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.

Monckeberg calcification of coronary arteries: a string of pearls.

Coronary artery calcium scores are derived from cardiac-gated noncontrast computed tomography scans that are used in cardiac risk stratification. However, an elevated calcium score does not always translate to coronary artery luminal obstruction. Our case demonstrates an extremely high coronary artery calcium score despite nonobstructive coronaries on angiogram.

The simulated newsroom: A novel educational innovation to teach advocacy skills to resident physicians.

Need for Innovation: Advocacy is a key competency of Canadian residency education, yet physicians seldom engage with supraclinical advocacy efforts upon completion of training. Objective of innovation: The objective was to equip participants with the knowledge and skills required to engage as physician-advocates in their communities using opinion writing as a tool. Developmental process: We used Kern's six-step framework to leverage a common medical training method, simulation, to teach journalistic skills related to advocacy in our novel "simulated newsroom." Two emergency physicians with journalism training and workplace experience developed simulated newsroom workshops. The simulated newsroom consisted of participants acting as journalists and the expert facilitator acting as a news editor over two workshops. The participants were encouraged to write and workshop an article with colleagues. Evaluation: Participants were invited to participate in a semistructured focus group and to submit their article for qualitative analysis. Focus group transcripts and written work were qualitatively analyzed to understand acceptability and feasibility and how participants might engage as future health advocates. Outcomes: Twelve participants registered for the workshops and six attended. All six participated in the focus group; four submitted written work. The innovation bolstered participants' confidence in advocacy through the popular press and provided demonstrable skills in opinion writing. Participants valued the workshop as a voluntary component of residency education led by physicians with journalism expertise. Discussion: The simulated newsroom may be an effective mechanism for increasing confidence and competence in advocacy writing.

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.