A promiscuous T cell epitope-based HIV vaccine providing redundant population coverage of the HLA class II elicits broad, polyfunctional T cell responses in nonhuman primates.

Over the last few decades, several emerging or reemerging viral diseases with no readily available vaccines have ravaged the world. A platform to fastly generate vaccines inducing potent and durable neutralizing antibody and T cell responses is sorely needed. Bioinformatically identified epitope-based vaccines can focus on immunodominant T cell epitopes and induce more potent immune responses than a whole antigen vaccine and may be deployed more rapidly and less costly than whole-gene vaccines. Increasing evidence has shown the importance of the CD4+ T cell response in protection against HIV and other viral infections. The previously described DNA vaccine HIVBr18 encodes 18 conserved, promiscuous epitopes binding to multiple HLA-DR-binding HIV epitopes amply recognized by HIV-1-infected patients. HIVBr18 elicited broad, polyfunctional, and durable CD4+and CD8+ T cell responses in BALB/c and mice transgenic to HLA class II alleles, showing cross-species promiscuity. To fully delineate the promiscuity of the HLA class II vaccine epitopes, we assessed their binding to 34 human class II (HLA-DR, DQ, and -DP) molecules, and immunized nonhuman primates. Results ascertained redundant 100% coverage of the human population for multiple peptides. We then immunized Rhesus macaques with HIVBr18 under in vivo electroporation. The immunization induced strong, predominantly polyfunctional CD4+ T cell responses in all animals to 13 out of the 18 epitopes; T cells from each animal recognized 7-11 epitopes. Our results provide a preliminary proof of concept that immunization with a vaccine encoding epitopes with high and redundant coverage of the human population can elicit potent T cell responses to multiple epitopes, across species and MHC barriers. This approach may facilitate the rapid deployment of immunogens eliciting cellular immunity against emerging infectious diseases, such as COVID-19.

The RCA ReCAst: A Root Cause Analysis Simulation for the Interprofessional Clinical Learning Environment.

PROBLEM: The Accreditation Council for Graduate Medical Education calls for resident participation in real or simulated interprofessional analysis of a patient safety event. There are far more residents who must participate in these investigations than available institutional root cause analyses (RCAs) to accommodate them. To correct this imbalance, the authors developed an institutionally sponsored, interprofessional RCA simulation program and implemented it across all graduate medical education (GME) residency programs at the Hospital of the University of Pennsylvania. APPROACH: The authors developed RCA simulations based upon authentic adverse events experienced at their institution. To provide relevance to all GME programs, RCA simulation cases varied widely and included examples of errors involving high-risk medications, communication, invasive procedures, and specimen labeling. Each simulation included residents and other health care professionals such as nurses or pharmacists whose disciplines were involved in the actual event. Participants adopted the role of RCA investigation team, and in small groups systematically progressed through the RCA process. OUTCOMES: A total of 289 individuals from 18 residency programs participated in an RCA simulation in 2019-2020. This included 84 interns (29%), 123 residents (43%), 20 attending physicians (7%), and 62 (21%) other health care professionals. There was an increase in ability of GME trainees to correctly identify factors required for an RCA investigation (62% pre vs 80% post, P = .02) and an increase in intent to "always report" for each adverse event category (3% pre vs 37% post, P < .001) following the simulation. NEXT STEPS: The authors plan to expand the RCA simulation program to other GME clinical sites while striving to involve all GME learners in this educational experience at least once during training. Additionally, by collaborating with health system patient safety leaders, they will annually review all new RCAs to identify cases suitable for simulation adaptation.

Fostering belonging in academic anaesthesiology: faculty and department chair perspectives on supporting women anaesthesiologists.

An increasing number of global initiatives aim to address the disconnection between the increasing number of women entering medicine and the persistence of gender imbalance in the physician anaesthesiologist workforce. This commentary complements the global movement's efforts to increase women's representation in academic anaesthesiology by presenting considerations for fostering inclusion for women in academic anaesthesiology from both the faculty and departmental leadership perspectives in a US academic anaesthesiology department.

The Year in Vascular Anesthesia: Selected Highlights From 2018.

This special article is the second in an annual series for the Journal of Cardiothoracic and Vascular Anesthesia that is specifically dedicated to highlights in vascular anesthesiology published in 2018. This review begins with 2 updates in preoperative medicine in the vascular surgery population, including recent publications regarding the management of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers and antiplatelet medications in the perioperative period. The next section focuses on complications related to thoracic endovascular aortic surgery, particularly as technology advances allow for endovascular repair of more complex anatomy. The final section focuses on quality in vascular surgery and evaluates recent publications that examine the safety and feasibility of fast-track endovascular aortic surgery. Even though this is only a sampling of the literature published in 2018 relevant to the cardiovascular anesthesiologist, these themes represent some of the topics most clinically relevant to the perioperative period.

Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms.

Aging impairs the activation of stress signaling pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here, we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient Caenorhabditis elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Quality Improvement in Anesthesiology - Leveraging Data and Analytics to Optimize Outcomes.

Quality improvement is at the heart of practice of anesthesiology. Objective data are critical for any quality improvement initiative; when possible, a combination of process, outcome, and balancing metrics should be evaluated to gauge the value of an intervention. Quality improvement is an ongoing process; iterative reevaluation of data is required to maintain interventions, ensure continued effectiveness, and continually improve. Dashboards can facilitate rapid analysis of data and drive decision making. Large data sets can be useful to establish benchmarks and compare performance against other providers, practices, or institutions. Audit and feedback strategies are effective in facilitating positive change.

Differential Sensitivity of Target Genes to Translational Repression by miR-17~92.

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5'UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes.

Breastfeeding after Anesthesia: A Review for Anesthesia Providers Regarding the Transfer of Medications into Breast Milk.

Doctors, nurses, and midwives often inform mothers to "pump and dump" their breast milk for 24 hours after receiving anesthesia to avoid passing medications to the infant. This advice, though cautious, is probably outdated. This review highlights the more recent literature regarding common anesthesia medications, their passage into breast milk, and medication effects observed in breastfed infants. We suggest continuing breastfeeding after anesthesia when the mother is awake, alert, and able to hold her infant. We recommend multiple types of medications for pain relief while minimizing sedating medications. Few medications can have sedating effects to the infant, but those medications are specifically outlined. For additional safety, anesthesia providers and patients may screen medications using the National Institute of Health' LactMed database.