Genomic Profiling of Rare Undifferentiated Sarcomatoid Subtypes of Pancreatic Carcinomas: In Search of Therapeutic Targets.

PURPOSE: The highly aggressive undifferentiated sarcomatoid carcinoma (USC) subtype of pancreatic ductal adenocarcinoma (PDAC) remains poorly characterized because of its rarity. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy, but the prevalence of established predictive biomarkers of response is largely unknown. The objective of this study was to leverage comprehensive genomic profiling of USC PDAC tumors to determine the prevalence of biomarkers associated with potential response to targeted therapies. METHODS: USC tumors (n = 20) underwent central pathology review by a board-certified gastrointestinal pathologist to confirm the diagnosis. These samples were compared with non-USC PDAC tumors (N = 5,562). Retrospective analysis of DNA and RNA next-generation sequencing data was performed. RESULTS: USC PDACs were more frequently PD-L1+ by immunohistochemistry than non-USC PDAC (63% v 16%, respectively, P < .001). Furthermore, USC PDAC had an increase in neutrophils (8.99% v 5.55%, P = .005) and dendritic cells (1.08% v 0.00%, q = 0.022) and an increased expression of PDCD1LG2 (4.6% v 1.3%, q = 0.001), PDCD1 (2.0% v 0.8%, q = 0.060), and HAVCR2 (45.9% v 21.7%, q = 0.107) than non-USC PDAC. Similar to non-USC PDAC, KRAS was the most commonly mutated gene (86% v 90%, respectively, P = 1). CONCLUSION: To our knowledge, this work represents the largest molecular analysis of USC tumors to date and showed an increased expression of immune checkpoint genes in USC tumors. These findings provide evidence for further investigation into immune checkpoint inhibitors in USC tumors.

Evaluating the Role of Competency-Based Behavioral Interviewing in Holistic Medical School Admissions.

PROBLEM: Holistic review is a multifaceted concept that aims to increase diversity and applicant fit with program needs by complementing traditional academic requirements with appraisal of a wider range of personal characteristics and experiences. Behavioral interviewing has been practiced and studied in human resources, business, and organizational psychology for over 50 years. Its premise is that future performance can be anticipated from past actions. However, many of the interview approaches within the holistic framework are resource intensive and logistically challenging. APPROACH: The Vanderbilt University School of Medicine instituted a competency-based behavioral interview (CBBI) to augment the selection process in 2012. Behavioral interviews are based on key competencies needed for entering students and require applicants to reflect on their actual experiences and what they learned from them. The authors reviewed 5 years of experience (2015-2019) to evaluate how CBBI scores contributed to the overall assessment of applicants for admission. OUTCOMES: The final admission committee decision for each applicant was determined by reviewing multiple factors, with no single assessment determining the final score. The CBBI and summary interview scores showed a strong association (P < .005), suggesting that the summary interviewer, who had access to the full applicant file, and the CBBI interviewer, who did not, assessed similar strengths despite the 2 different approaches, or that the strengths assessed tracked in the same direction. Students whose 2 interview scores were not aligned were less likely to be accepted to the school. NEXT STEPS: The review raised awareness about the cultural aspects of interpreting the competencies and the need to expand our cultural framework throughout interviewer training. Findings indicate that CBBIs have the potential to reduce bias related to over-reliance on standardized metrics; however, additional innovation and research are needed.

Association between First-pass Intubation Success and Enhanced PPE Use during the COVID-19 Pandemic.

OBJECTIVES: We evaluated first-pass endotracheal intubation (ETI) success within the critical care transport (CCT) environment using a natural experiment created by the COVID-19 pandemic. Our primary objective was to evaluate if the use of personal protective equipment (PPE) or the COVID-19 time period was associated with differences in first-pass success rates of ETI within a large CCT system with a high baseline ETI first-pass success rate. We hypothesized that pandemic-related challenges would be associated with decreased first-pass success rates. METHODS: We performed a retrospective before-after cohort study of airway management by CCT personnel relative to the COVID-19 pandemic. We used a mixed effects logistic regression to evaluate the association between enhanced PPE (N95 mask, eye protection) use and the pandemic time period on first-pass intubation success, while controlling for other factors potentially associated with intubation success. Variables in the final model included patient demographics (age, sex, and race), body mass index, medical category (trauma versus non-trauma), interfacility or scene response, blade size (Macintosh 3 versus 4), use of face mask, use of eye protection, and crew member length of service. RESULTS: We identified 1279 cases involving intubation attempts on adult patients during the study period. A total of 1133 cases were included in the final analysis, with an overall first-pass success rate of 95.7% (96.4% pre-COVID-19 and 94.8% during COVID-19). In our final mixed effects logistic regression model, enhanced PPE use and the COVID-19 time period were not associated with first-pass intubation success rate. CONCLUSION: In a large regional CCT system with a high ETI first-pass success rate, neither PPE use nor the COVID-19 time period were associated with differences in ETI first-pass success while controlling for relevant patient and operational factors. Other emergency medical services (EMS) systems may have encountered different effects of pandemic-related PPE use on intubation success rates. Further studies are needed to evaluate the influence of sustained use of enhanced PPE or changes in training or procedural experience on post-pandemic ETI first-pass success rates for non-CCT EMS clinicians.

Characterizing Air Medical Transport Experiences in Emergency Medicine Residency Training Programs.

OBJECTIVE: Air medical transportation (AMT) of patients plays a critical role in the prehospital care of the ill patient. Despite its importance, there is no requirement in emergency medicine training programs to have direct experience or education on the topic, and data detailing current AMT experiences across programs are limited. METHODS: A survey detailing program characteristics, AMT experience characteristics, and curriculum factors relating to AMT experience was sent to all 275 credentialed emergency medicine residency training programs in the United States. Our outcomes were to describe the characteristics of AMT and non-AMT programs (proportions) and to evaluate associations (odds ratios with 95% confidence intervals) between program characteristics and 1) AMT experience opportunity and 2) level of resident participation among AMT programs. RESULTS: Two hundred (73%) programs responded, with 135 of 200 (68%) offering some type of AMT experience. The majority of programs offering AMT were 3 years (113 [84%]), university based (63 [47%]), and located in small urban areas (57 [42%]). When AMT was offered, most programs reported that the overall resident participation was low (≤ 20%). Programs that did not offer shift reduction or additional pay for participation in AMT were significantly more likely to have low participation than those with incentives (odds ratio = 4.8; 95% confidence interval, 1.8-15.3). Around one third of AMT experiences allowed for direct patient care. Less than half of the responding programs reported a dedicated AMT curriculum. CONCLUSION: The majority of emergency medicine residency training programs offer an AMT experience, but this experience is highly variable, and overall participation by residents is low. Given the importance of AMT in the care of emergency patients, standardization and increased access to AMT experience and education should be considered by emergency medicine training programs moving forward.

Control of white mold (Sclerotinia sclerotiorum) through plant-mediated RNA interference.

The causative agent of white mold, Sclerotinia sclerotiorum, is capable of infecting over 600 plant species and is responsible for significant crop losses across the globe. Control is currently dependent on broad-spectrum chemical agents that can negatively impact the agroecological environment, presenting a need to develop alternative control measures. In this study, we developed transgenic Arabidopsis thaliana (AT1703) expressing hairpin (hp)RNA to silence S. sclerotiorum ABHYDROLASE-3 and slow infection through host induced gene silencing (HIGS). Leaf infection assays show reduced S. sclerotiorum lesion size, fungal load, and ABHYDROLASE-3 transcript abundance in AT1703 compared to wild-type Col-0. To better understand how HIGS influences host-pathogen interactions, we performed global RNA sequencing on AT1703 and wild-type Col-0 directly at the site of S. sclerotiorum infection. RNA sequencing data reveals enrichment of the salicylic acid (SA)-mediated systemic acquired resistance (SAR) pathway, as well as transcription factors predicted to regulate plant immunity. Using RT-qPCR, we identified predicted interacting partners of ABHYDROLASE-3 in the polyamine synthesis pathway of S. sclerotiorum that demonstrate co-reduction with ABHYDROLASE-3 transcript levels during infection. Together, these results demonstrate the utility of HIGS technology in slowing S. sclerotiorum infection and provide insight into the role of ABHYDROLASE-3 in the A. thaliana-S. sclerotiorum pathosystem.

Using Technology to Facilitate Evidence-Based Practice During the COVID-19 Pandemic.

The COVID-19 pandemic brought many challenges to the health care workforce. A novel infectious disease, COVID-19 uncovered information gaps that were essential for frontline staff, including nurses, to care for patients and themselves. The authors developed a Web-based solution consisting of saved searches from PubMed on clinically relevant topics specific to nurses' information needs. This article discusses the objectives, development, content, and usage of this Internet resource and also provides tips for hospitals of all sizes to implement similar tools to evidence-based practice during infectious disease outbreaks.

A survey of computable biomedical knowledge repositories.

Introduction: While data repositories are well-established in clinical and research enterprises, knowledge repositories with shareable computable biomedical knowledge (CBK) are relatively new entities to the digital health ecosystem. Trustworthy knowledge repositories are necessary for learning health systems, but the policies, standards, and practices to promote trustworthy CBK artifacts and methods to share, and safely and effectively use them are not well studied. Methods: We conducted an online survey of 24 organizations in the United States known to be involved in the development or deployment of CBK. The aim of the survey was to assess the current policies and practices governing these repositories and to identify best practices. Descriptive statistics methods were applied to data from 13 responding organizations, to identify common practices and policies instantiating the TRUST principles of Transparency, Responsibility, User Focus, Sustainability, and Technology. Results: All 13 respondents indicated to different degrees adherence to policies that convey TRUST. Transparency is conveyed by having policies pertaining to provenance, credentialed contributors, and provision of metadata. Repositories provide knowledge in machine-readable formats, include implementation guidelines, and adhere to standards to convey Responsibility. Repositories report having Technology functions that enable end-users to verify, search, and filter for knowledge products. Less common TRUST practices are User Focused procedures that enable consumers to know about user licensing requirements or query the use of knowledge artifacts. Related to Sustainability, less than a majority post describe their sustainability plans. Few organizations publicly describe whether patients play any role in their decision-making. Conclusion: It is essential that knowledge repositories identify and apply a baseline set of criteria to lay a robust foundation for their trustworthiness leading to optimum uptake, and safe, reliable, and effective use to promote sharing of CBK. Identifying current practices suggests a set of desiderata for the CBK ecosystem in its continued evolution.

Dual RNA-sequencing of Fusarium head blight resistance in winter wheat.

Fusarium head blight (FHB) is a devastating fungal disease responsible for significant yield losses in wheat and other cereal crops across the globe. FHB infection of wheat spikes results in grain contamination with mycotoxins, reducing both grain quality and yield. Breeding strategies have resulted in the production of FHB-resistant cultivars, however, the underlying molecular mechanisms of resistance in the majority of these cultivars are still poorly understood. To improve our understanding of FHB-resistance, we performed a transcriptomic analysis of FHB-resistant AC Emerson, FHB-moderately resistant AC Morley, and FHB-susceptible CDC Falcon in response to Fusarium graminearum. Wheat spikelets located directly below the point of inoculation were collected at 7-days post inoculation (dpi), where dual RNA-sequencing was performed to explore differential expression patterns between wheat cultivars in addition to the challenging pathogen. Differential expression analysis revealed distinct defense responses within FHB-resistant cultivars including the enrichment of physical defense through the lignin biosynthesis pathway, and DON detoxification through the activity of UDP-glycosyltransferases. Nucleotide sequence variants were also identified broadly between these cultivars with several variants being identified within differentially expressed putative defense genes. Further, F. graminearum demonstrated differential expression of mycotoxin biosynthesis pathways during infection, leading to the identification of putative pathogenicity factors.

Host induced gene silencing of the Sclerotinia sclerotiorum ABHYDROLASE-3 gene reduces disease severity in Brassica napus.

Sclerotinia sclerotiorum is a pathogenic fungus that infects hundreds of crop species, causing extensive yield loss every year. Chemical fungicides are used to control this phytopathogen, but with concerns about increasing resistance and impacts on non-target species, there is a need to develop alternative control measures. In the present study, we engineered Brassica napus to constitutively express a hairpin (hp)RNA molecule to silence ABHYRDOLASE-3 in S. sclerotiorum. We demonstrate the potential for Host Induced Gene Silencing (HIGS) to protect B. napus from S. sclerotiorum using leaf, stem and whole plant infection assays. The interaction between the transgenic host plant and invading pathogen was further characterized at the molecular level using dual-RNA sequencing and at the anatomical level through microscopy to understand the processes and possible mechanisms leading to increased tolerance to this damaging necrotroph. We observed significant shifts in the expression of genes relating to plant defense as well as cellular differences in the form of structural barriers around the site of infection in the HIGS-protected plants. Our results provide proof-of-concept that HIGS is an effective means of limiting damage caused by S. sclerotiorum to the plant and demonstrates the utility of this biotechnology in the development of resistance against fungal pathogens.

Tissue-specific mRNA profiling of the Brassica napus-Sclerotinia sclerotiorum interaction uncovers novel regulators of plant immunity.

White mold is caused by the fungal pathogen Sclerotinia sclerotiorum and leads to rapid and significant loss in plant yield. Among its many brassicaceous hosts, including Brassica napus (canola) and Arabidopsis, the response of individual tissue layers directly at the site of infection has yet to be explored. Using laser microdissection coupled with RNA sequencing, we profiled the epidermis, mesophyll, and vascular leaf tissue layers of B. napus in response to S. sclerotiorum. High-throughput tissue-specific mRNA sequencing increased the total number of detected transcripts compared with whole-leaf assessments and provided novel insight into the conserved and specific roles of ontogenetically distinct leaf tissue layers in response to infection. When subjected to pathogen infection, the epidermis, mesophyll, and vasculature activate both specific and shared gene sets. Putative defense genes identified through transcription factor network analysis were then screened for susceptibility against necrotrophic, hemi-biotrophic, and biotrophic pathogens. Arabidopsis deficient in PR5-like RECEPTOR KINASE (PR5K) mRNA levels were universally susceptible to all pathogens tested and were further characterized to identify putative interacting partners involved in the PR5K signaling pathway. Together, these data provide insight into the complexity of the plant defense response directly at the site of infection.

Seamens' Sign: a novel electrocardiogram prediction tool for left ventricular hypertrophy.

Introduction: Patients with left ventricular hypertrophy (LVH) diagnosed by electrocardiogram (ECG) have increased mortality and higher risk for life-threatening cardiovascular disease. ECGs offer an opportunity to identify patients with increased risk for potential risk-modifying therapy. We developed a novel, quick, easy to use ECG screening criterion (Seamens' Sign) for LVH. This new criterion was defined as the presence of QRS complexes touching or overlapping in two contiguous precordial leads. Methods: This study was a retrospective chart review of 2,184 patient records of patients who had an ECG performed in the emergency department and a transthoracic echocardiogram performed within 90 days. The primary outcome was whether Seamens' Sign was noninferior in confirming LVH compared to other common diagnostic criteria. Test characteristics were calculated for each of the LVH criteria. Inter-rater agreement was assessed on a random sample using Cohen's Kappa. Results: Median age was 63, 52% of patients were male and there was a 35% prevalence of LVH by transthoracic echocardiogram (TTE). Nine percent were positive for LVH on ECG based on Seamens' Sign. Seamens' Sign had a specificity of 0.92. Tests assessing noninferiority indicated Seamens' Sign was non-inferior to all criteria (p < 0.001) except for Cornell criterion for women (p = 0.98). Seamens' Sign had 90% (0.81-1.00) inter-rater agreement, the highest of all criteria in this study. Conclusion: When compared to both the Sokolow-Lyon criteria and the Cornell criterion for men, Seamens' Sign is noninferior in ruling in LVH on ECG. Additionally, Seamens' Sign has higher inter-rater agreement compared to both Sokolow-Lyon criteria as well as the Cornell criteria for men and women, perhaps related to its ease of use.

Treatment of Malignant Hyperthermia During Interfacility Transport of a Patient With Methamphetamine Toxicity.

Malignant hyperthermia (MH) is a rare disorder that leads to a hypermetabolic response; if unrecognized, it can quickly lead to serious morbidity and mortality. It is imperative that critical care transport providers are able to recognize and initiate treatment for MH. A 33-year-old man presented to the emergency department with seizures and altered mental status after ingesting methamphetamine. The patient was intubated in the emergency department with succinylcholine and propofol. After intubation, the patient became tetanic, hyperthermic, and hypercarbic. Given the concern for MH, the patient was treated with dantrolene and transported by helicopter air ambulance to the affiliated quaternary care center where he progressed to multiorgan failure and died. MH is a genetic disorder that manifests after exposure to certain stimuli, most notably inhaled anesthetics and succinylcholine. The hypermetabolic response is triggered by unregulated release of intracellular calcium secondary to a dysfunctional calcium channel. MH is often diagnosed clinically. Early clinical manifestations of MH include an increase in end-tidal carbon dioxide, tachycardia, muscle rigidity, and hyperthermia. For prehospital clinicians, the most likely offending agent is succinylcholine. The pharmacologic treatment of MH is dantrolene. Prompt recognition and treatment of MH can decrease morbidity and mortality.

Development of a bayesian toxo-equivalence model between docetaxel and paclitaxel.

Members of the taxane class of chemotherapies, staples of cancer treatment since the 1990s, can induce chemotherapy-induced peripheral neuropathy (CIPN), a potentially irreversible outcome related to cumulative exposure. Switching between taxanes is often clinically necessary; however, different taxanes have different efficacies, toxicities, and dosing strategies, necessitating an evidence-based schema focused on toxicity. We performed a systematic review and meta-analysis of the literature on docetaxel and paclitaxel, extracting cumulative dose, rates of CIPN, and subject demographics, thereby establishing their dose-toxo-equivalence relationship through a Bayesian meta-analysis model, calculating doses of the two drugs that are expected to have comparable rates of CIPN, along with credible intervals. Our final model, based on 169 studies, produces credible interval widths that provide guidance within one treatment cycle. In practice, this model provides a framework under which oncologists can make treatment switching and dosing decisions, hopefully reducing patient risk of CIPN.

Balancing food acquisition and predation risk drives demographic changes in snowshoe hare population cycles.

Snowshoe hare cycles are one of the most prominent phenomena in ecology. Experimental studies point to predation as the dominant driving factor, but previous experiments combining food supplementation and predator removal produced unexplained multiplicative effects on density. We examined the potential interactive effects of food limitation and predation in causing hare cycles using an individual-based food-supplementation experiment over-winter across three cycle phases that naturally varied in predation risk. Supplementation doubled over-winter survival with the largest effects occurring in the late increase phase. Although the proximate cause of mortality was predation, supplemented hares significantly decreased foraging time and selected for conifer habitat, potentially reducing their predation risk. Supplemented hares also lost less body mass which resulted in the production of larger leverets. Our results establish a mechanistic link between how foraging time, mass loss and predation risk affect survival and reproduction, potentially driving demographic changes associated with hare cycles.

Efficacy of virtual and asynchronous teaching of computer-assisted diagnosis of genetic diseases seen in clinics.

We studied if clinicians could gain sufficient working knowledge of a computer-assisted diagnostic decision support system (DDSS) (SimulConsult), to make differential diagnoses (DDx) of genetic disorders. We hypothesized that virtual training could be convenient, asynchronous, and effective in teaching clinicians how to use a DDSS. We determined the efficacy of virtual, asynchronous teaching for clinicians to gain working knowledge to make computer-assisted DDx. Our study consisted of three surveys (Baseline, Training, and After Use) and a series of case problems sent to clinicians at Vanderbilt University Medical Center. All participants were able to generate computer-assisted DDx that achieved passing scores of the case problems. Between 75% and 92% agreed/completely agreed the DDSS was useful to their work and for clinical decision support and was easy to use. Participants' use of the DDSS resulted in statistically significant time savings in key tasks and in total time spent on clinical tasks. Our results indicate that virtual, asynchronous teaching can be an effective format to gain a working knowledge of a DDSS, and its clinical use could result in significant time savings across multiple tasks as well as facilitate synergistic interaction between clinicians and lab specialists. This approach is especially pertinent and offers value amid the COVID-19 pandemic.

The Never-Ending Evolutionary Saga of Assessing and Demonstrating the Value of Information Services in a Biomedical Library.

Demonstrating added value can be very challenging, yet it is becoming important in academic libraries. The current literature primarily discusses citation analysis and usage reports to demonstrate return on investment for collections or impact on scholarly activity. However, value is not only in our collections but also in the library staff who support the institutional mission. Vanderbilt University's Annette and Irwin Eskind Family Biomedical Library and Learning Center has been experimenting with several methods to supplement the collections data with services performed by the staff. This article discusses the project's four phases as part of the goal to strategically demonstrate the biomedical library's added value to the university and medical center.

The library's role in countering infodemics.

Internet and communication technologies enable the creation of tremendous amounts of textual, graphic, and pictorial information. User-generated content published through personal web pages, blogs, and social media platforms has not only increased the amount of information available, but also expanded its reach. However, this ubiquity of information and empowerment of its creators leads to potentially controversial, futile, and inaccurate content circulating throughout the world. In the case of the COVID-19 pandemic, this can create false hope, fear, anxiety, harm, and confusion amongst information stakeholders. The World Health Organization recently applied the term "infodemic" to the COVID-19 pandemic. This commentary briefly discusses the current infodemic, its potential consequences, and the role of libraries-specifically health sciences, biomedical, and medical libraries-to help counter the COVID-19 infodemic. The discussion also has relevance for infodemics relating to other health and non-health affairs.

Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort.

The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43-4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.