Tissue-Based Predictors of Impaired Right Ventricular Strain in Coronary Artery Disease: A Multicenter Stress Perfusion Study.

BACKGROUND: Right ventricular (RV) dysfunction is known to impact prognosis, but its determinants in coronary artery disease are poorly understood. Stress cardiac magnetic resonance (CMR) has been used to assess ischemia and infarction in relation to the left ventricle (LV); the impact of myocardial tissue properties on RV function is unknown. METHODS: Vasodilator stress CMR was performed in patients with known coronary artery disease at 7 sites between May 2005 and October 2018. Myocardial infarction was identified on late gadolinium enhancement-CMR, and infarct transmurality was graded on a per-segment basis. Ischemia was assessed on stress CMR based on first-pass perfusion and localized by using segment partitions corresponding to cine and late gadolinium enhancement analyses. RV function was evaluated by CMR-feature tracking for primary analysis with a global longitudinal strain threshold of 20% used to define impaired RV strain (RVIS); secondary functional analysis via RV ejection fraction was also performed. RESULTS: A total of 2604 patients were studied, among whom RVIS was present in 461 patients (18%). The presence and magnitude of RVIS were strongly associated with LV dysfunction, irrespective of whether measured by LV ejection fraction or wall motion score (P<0.001 for all). Regarding tissue substrate, regions of ischemic and dysfunctional myocardium (ie, hibernating myocardium) and infarct size were each independently associated with RVIS (both P<0.001). During follow-up (median, 4.62 [interquartile range, 2.15-7.67] years), 555 deaths (21%) occurred. Kaplan-Meier analysis for patients stratified by presence and magnitude of RV dysfunction by global longitudinal strain and RV ejection fraction each demonstrated strong prognostic utility for all-cause mortality (P<0.001). RVIS conferred increased mortality risk (hazard ratio, 1.35 [95% CI, 1.11-1.66]; P=0.003) even after controlling for LV function, infarction, and ischemia. CONCLUSIONS: RVIS in patients with known coronary artery disease is associated with potentially reversible LV processes, including LV functional impairment due to ischemic and predominantly viable myocardium, which confers increased mortality risk independent of LV function and tissue substrate.

Use of Integrated Metabolic Maps as a Framework for Teaching Biochemical Pathways in the Pre-clinical Medical Curriculum.

Introduction: The Larner College of Medicine has steadily transitioned to primarily active learning-based instruction. Although evaluations praise session formats, students often highlight difficulties in synthesizing preparatory materials to integrate biochemical pathways. A student/faculty collaboration led to the development of interactive metabolic maps that illustrate pathways and link to a broader framework of metabolism. Methods: A review of the session materials identified relevant biochemical pathways, and for each pathway, we created a fillable visual diagram to highlight the interactions between all substrates, enzymes, and cofactors. Implementation of the metabolic maps began for first-year medical students in fall 2022. Evaluation data included standard student session evaluations (Likert scale and qualitative comments) and a survey specific to the metabolic maps. Results: After implementing the maps, student ratings of biochemistry/metabolism session materials significantly improved (3.2 ± 1.04 to 4.3 ± 0.87, p < 0.001), and students made positive comments about their effectiveness. Most students (77.8%) used the metabolic maps to aid in studying biochemistry content for exams and found the metabolic maps important for integrating information about metabolic pathways. The median performance on metabolism-specific questions was higher, although not statistically significant (69.23 to 77.28, ns). Discussion: The implementation of integrated metabolic maps improved student satisfaction of biochemistry/metabolism session materials. Limitations include confounding factors related to student population differences and other simultaneous curriculum changes. Implementing interactive visual aids to integrate metabolism pathways and concepts is applicable to any medical curriculum, and other longitudinal topics may benefit from this type of curricular framework. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-024-02073-1.

Pediatric head and neck trauma in the United States: Trends, risk factors and outcomes using the National Trauma Data Bank.

Introduction: Pediatric head and neck (HN) trauma is an important contributor to pediatric morbidity, resulting in significant downstream consequences. Few studies provide epidemiological predictors of pediatric HN trauma on a national scale. The present study aims to identify risk factors of HN injury and mortality in the pediatric population. Methods: A retrospective cohort study was conducted for patients (age <18 years) using the US National Trauma Data Bank (NTDB 2007-2019). Demographic, injury, and physiologic outcome data were analyzed. HN injury was defined as a head or neck Abbreviated Injury Scale (AIS) >0. Logistic regression identified independent predictors of mortality following HN trauma. Results: Of the 1.42 million pediatric patients analyzed, 44.05% had HN injury. In patients aged 0-4, the most common mechanism was falls (47.67% in this age group) while in ages 14-17, motor vehicle/transport accidents (MVTs) were the most common mechanism (56.06%). Controlling for demographics, comorbidities, and injury severity, HN injury was associated with increased odds of mortality (OR 2.404, 95% CI 1.530-3.778). HN injury mortality was strongly predicted by firearm exposure (OR 11.28, 95% CI 6.074-20.95), age <4 (OR 1.179, 95% CI 1.071-1.299), and self-insured status (OR 1.977, 95% CI 1.811-2.157). Conclusion: NTDB data demonstrate that the percentage of pediatric patients with HN trauma has decreased over the past 12 years although is associated with increased odds of mortality. Age and insurance status predicted mortality from HN trauma, with falls and MVTs being the most common mechanisms of injury. These data have implications for future public health efforts in this patient population. Level of Evidence: 3.

GWAS reveals Genetic Susceptibility to Air Pollution-Related Asthma Exacerbations in Children of African Ancestry.

Background: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, mitigation efforts have yielded mixed results, potentially due to genetic variability in the response to AAP. We hypothesize that common single nucleotide polymorphisms (SNPs) are linked to AAP sensitivity and test this through a Genome Wide Association Study (GWAS). Methods: We selected a cohort of pediatric asthma patients frequently exposed to AAP. Patients experiencing exacerbations immediately following AAP spikes were deemed sensitive. A GWAS compared sensitive versus non-sensitive patients. Findings were validated using data from the All of Us program. Results: Our study included 6,023 pediatric asthma patients. Due to the association between AAP exposure and race, GWAS analysis was feasible only in the African ancestry cohort. Seven risk loci reached genome-wide significance, including four non-intergenic variants. Two variants were validated: rs111970601 associated with sensitivity to CO (odds ratio [OR], 6.58; PL=L1.63L×L10-8; 95% CI, 3.42-12.66) and rs9836522 to PM2.5 sensitivity (OR 0.75; PL=L3,87 ×L10-9; 95% CI, 0.62-0.91). Interpretation: While genetic variants have been previously linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. The identified variants implicate genes with a known role in asthma and established links to AAP. Future research should explore how clinical interventions interact with genetic risk to mitigate the effects of AAP, particularly to enhance health equity for vulnerable populations. What is already known on this topic: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, efforts to mitigate the impact of AAP on children with asthma have yielded mixed results, potentially due to genetic variability in response to AAP. What this study adds: Using publicly available AAP data, we identify which children with asthma experience exacerbations immediately following spikes in AAP. We then conduct a Genome Wide Association Study (GWAS) comparing these patients with those who have no temporal association between AAP spikes and asthma exacerbations, identifying several Single Nucleotide Polymorphisms (SNPs) significantly associated with AAP sensitivity. How this study might affect research practice or policy: While genetic variants have previously been linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. This creates a framework for identifying children especially at risk when exposed to AAP. These children should be targeted with policy interventions to reduce exposure and may require specific treatments to mitigate the effects of ongoing AAP exposure in the interim.

Identifying diversity of patient anatomy through automated image analysis of clinical ultrasounds.

PURPOSE: Central venous catheterization (CVC) carries inherent risks which can be mitigated through the use of appropriate ultrasound-guidance during needle insertion. This study aims to comprehensively understand patient anatomy as it is visualized during CVC by employing a semi-automated image analysis method to track the internal jugular vein and carotid artery throughout recorded ultrasound videos. METHODS: The ultrasound visualization of 50 CVC procedures were recorded at Penn State Health Milton S. Hershey Medical Center. The developed algorithm was used to detect the vessel edges, calculating metrics such as area, position, and eccentricity. RESULTS: Results show typical anatomical variations of the vein and artery, with the artery being more circular and posterior to the vein in most cases. Notably, two cases revealed atypical artery positions, emphasizing the algorithm's precision in detecting anomalies. Additionally, dynamic vessel properties were analyzed, with the vein compressing on average to 13.4% of its original size and the artery expanding by 13.2%. CONCLUSION: This study provides valuable insights which can be used to increase the accuracy of training simulations, thus enhancing medical education and procedural expertise. Furthermore, the novel approach of employing automated data analysis techniques to clinical recordings showcases the potential for continual assessment of patient anatomy, which could be useful in future advancements.

Prevalence and Genetic Diversity of Adenovirus 40/41, Astrovirus, and Sapovirus in Children with Acute Gastroenteritis in Kansas City 2011-2016.

BACKGROUND: Most U.S. acute gastroenteritis (AGE) episodes in children are attributed to norovirus, whereas very little information is available on adenovirus 40/41 (AdV40/41), astrovirus or sapovirus. The New Vaccine Surveillance Network (NVSN) conducted prospective, active, population-based AGE surveillance in young children. METHODS: We tested and typed stool specimens collected between December 2011 to June 2016 from one NVSN site in Kansas City for the three viruses, and calculated hospitalization and emergency department (ED) detection rate. RESULTS: Of 3,205 collected specimens, 2,453 (76.5%) were from AGE patients (339 inpatients and 2,114 ED patients) and 752 (23.5%) were from healthy controls (HC). In AGE patients, astrovirus was detected in 94 (3.8%), sapovirus in 252 (10.3%) and AdV40/41 in 101 (4.5%) of 2249 patients. In HC, astrovirus was detected in 13 (1.7%) and sapovirus in 15 (2.0%) specimens. Astrovirus type 1 (37.7%) and genogroup I sapoviruses (59.3%) were most prevalent.Hospitalization rates were 5 (AdV40/41), 4 (astrovirus) and 8 (sapovirus) per 100,000 children <11 years old, whereas ED rates were 2.4 (AdV40/41), 1.9 (astrovirus) and 5.3 (sapovirus) per 1000 children <5 years old. CONCLUSIONS: Overall, AdV40/41, astrovirus, and sapovirus were detected in 18.6% of AGE in a large pediatric hospital in Kansas City.

Effects of Preoperative Glucocorticoid Use on Patients Undergoing Single-Level Lumbar Fusions: A Retrospective Propensity Score-Matched Registry Study.

Objective Spinal fusions are gaining popularity as a means of treating spinal deformity and instability from a range of pathologies. The prevalence of glucocorticoid use has also increased in recent decades, and their systemic effects are well-documented. Although commonly used in the preoperative period, the effects of steroids on outcomes among patients undergoing spinal fusions are inadequately described. This study compares the odds of developing complications among patients who underwent single-level lumbar fusions with and without preoperative glucocorticoid use in hopes of establishing more evidence-based parameters for guiding preoperative steroid use. Methods The TriNetX multi-institutional electronic health record database was used to perform a retrospective, propensity score-matched analysis of clinical outcomes of two cohorts of patients who underwent posterior or posterolateral single-level lumbar fusions with and without interbody fusion, those who used glucocorticoids for at least one week within a year of fusion and those who did not. The outcomes of interest were examined within 30 days of the operation and included death, reoperation, deep or superficial surgical site infection (SSI), pneumonia, reintubation, ventilator dependence, tracheostomy, acute kidney injury (AKI), renal insufficiency, pulmonary embolism (PE) or deep venous thrombosis (DVT), urinary tract infection (UTI), emergency department (ED) visit, sepsis, and myocardial infarction (MI). Results The odds of developing pneumonia within 30 days of spinal fusion in the cohort that used glucocorticoids within one year of operation compared to the cohort without glucocorticoid use was 0.67 (p≤0.001, 95% CI: 0.59-0.69). The odds of requiring a tracheostomy within 30 days of spinal fusion in the cohort that used glucocorticoids within one year of operation compared to the cohort without glucocorticoid use was 0.39 (p≤0.001, 95% CI: 0.26-0.60). The odds of reoperation, deep and superficial SSI, and ED visits within 30 days of operation were significantly higher for the same glucocorticoid-receiving cohort, with odds ratios of 1.4 (p=0.003, 95% CI: 1.11-1.65), 1.86 (p≤0.001, 95% CI: 1.31-2.63), 2.28 (p≤0.001, 95% CI: 1.57-3.31), and 1.25 (p≤0.001, 95% CI: 1.17-1.33), respectively. After propensity score-matching, there was no significant difference between the odds of death, DVT, PE, MI, UTI, AKI, sepsis, reintubation, and ventilator dependence between the two cohorts. Conclusion In support of much of the current literature regarding preoperative glucocorticoid use and rates of complications, patients who underwent a single-level lumbar fusion and have used glucocorticoids for at least a week within a year of operation experienced significantly higher odds of reoperation, deep and superficial SSI, and ED visits. However, these patients using glucocorticoids were also found to have lower odds of developing pneumonia, renal insufficiency, and tracheostomy requirement than those who did not use steroids within a year of surgery.

Treatment of Organophosphorus Poisoning with 6-Alkoxypyridin-3-ol Quinone Methide Precursors: Resurrection of Methylphosphonate-Aged Acetylcholinesterase.

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 µM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.

Disordered proteins interact with the chemical environment to tune their protective function during drying.

The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins combined with the exposure of their residues accounts for this sensitivity. One context in which IDPs play important roles that is concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family, synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet, the mechanisms underlying this synergy differ between IDP families.