The aggregation of the amyloidogenic polypeptide IAPP (Islet Amyloid Polypeptide, amylin) is believed to play a direct role in the death of pancreatic β-islet cells in type II diabetes. Preventing the initial aggregation event of IAPP is one strategy for slowing, and possibly preventing, the progression of this disease. Here, we investigate myricetin’s potential as an inhibitor of IAPP aggregation. We show that myricetin prevented thioflavin T binding in a concentration dependent manner. Atomic force microscopy revealed that myricetin prevented fiber formation under rigorous conditions conducive to forming IAPP aggregates. Using an IAPP-EGFP (Enhanced Green Fluorescent Protein) protein construct, we find that high concentrations of myricetin slowed the in vivo aggregation of IAPP-EGFP. Myricetin was also found to rescue living mammalian cells from the toxic effects of IAPP. These results indicate that myricetin is a strong inhibitor of IAPP amyloid aggregation and a potential lead molecule for the development of an amyloid inhibiting therapeutic.

Background Pneumonia is a significant cause of morbidity and mortality, with increasing interest in the detection and clinical significance of co-infection. However, the impact of methodology to obtain lower respiratory samples along with the utility of various microbiological diagnostic testing remains unclear. Methods A single-center retrospective analysis was performed on bronchoalveolar lavage (BAL) samples obtained from mechanically ventilated adults treated in critical care units from August 2012 to December 2017. BAL methodology (bronchoscopic vs blinded), microbiological diagnostic testing, and outcomes measures were obtained. Associations between categorical variables were assessed using Chi-Square or Fisher’s exact tests. Kruskal Wallace tests analyzed differences in distributions of measures between categories based on number of organism types detected. SAS software version 9.4 (SAS Institute Inc., Cary, NC). Results Analysis of the 803 samples that met inclusion criteria found a significant linear association between mortality and number of organism types detected by BAL, with 30 day mortality rates of 43.0%, 47.8%, and 58.3% among those with zero, one, and two or more organisms respectively (p = 0.003). Comparing BALs with at least one organism isolated, the detection of viruses specifically was associated with increased mortality, with the presence and absence of viral organisms corresponding to 56.3% and 46.5% mortality at thirty days (p = 0.03). No association was found between mortality and isolation of acid-fast bacilli, bacteria, or fungi. Co-infection was detected more frequently among bronchoscopic BALs than blinded BALs (26.3% vs 8.6%, p < 0.0001), with more viruses detected bronchoscopic BALs (41.9% vs 13.1%, p < 0.0001), and more bacteria in blinded BALs (41.8% vs 33.0%, p = 0.01). 30 Day Mortality vs Isolation of Specific Organism Types from BAL Number of Organism Types Isolated from BAL Compared to BAL Methodology BAL Methodology vs Isolation of Specific Organism Types Conclusion Co-infection in mechanically ventilated adult patients with pneumonia appears to be a significant risk factor for mortality, with the detection of viral organisms potentially playing an independent role. Within this population, bronchoscopic BALs may have a valuable diagnostic and prognostic methodology. Disclosures All Authors: No reported disclosures

BackgroundThe understanding of pneumonia epidemiology has been evolving in recent years with an increased awareness of viral respiratory pathogens since the introduction of respiratory pathogen panels. However, epidemiological and clinical data on pneumonia due to co-infection are lacking.MethodsA single-center retrospective analysis of mechanically ventilated adult patients treated in critical care units from January to October 2018 was performed on patients with one or more pathogen identified via microbiological testing of a bronchoalveolar lavage (BAL) sample. SOFA and APACHE II scores at the time of admission to the critical care unit and SOFA the day the of BAL were obtained, along with ICU length of stay, duration of ventilation, and pathogens. Associations between categorical variables and co-infection status were assessed using Chi-Square tests, Fisher exact tests, and t-tests. Differences in counts of days between coinfection status groups were analyzed by generalized linear models.Results140 bronchoalveolar lavage samples met inclusion criteria, of which 31 were determined to have co-infection with two or more pathogens identified. Of the two methods used to obtain BAL samples, co-infection was found in a higher proportion of patients undergoing bronchoscopic BAL as compared with blinded (35.6% vs. 7.5%; P < 0.0001). Patients with co-infection were determined to be statistically more likely to require a longer duration of mechanical ventilation (P = 0.03); however, there was no difference overall seen in 30 day mortality rate (23.4% vs. 19.57%; P = 0.61).ConclusionCo-infection is a significant risk factor for a prolonged duration of mechanical ventilation compared with patients with single pathogen pneumonia. In addition, the use of bronchoscopic BAL appears to be a significant factor in identifying higher rates of co-infection compared with blinded. Although our study failed to demonstrate a significant difference in mortality rates, this could have occurred due to the small sample size. Disclosures All authors: No reported disclosures.

BackgroundPneumonia epidemiology is increasingly showing the presence of co-infection due to the utilization of emerging diagnostic testing modalities such as multiplex polymerase chain reaction (PCR) panels. However, the prevalence and clinical significance of co-infection with respect to host immune status remain unclear.MethodsA single-center retrospective analysis of mechanically ventilated adult patients treated in critical care units from January to October 2018 was performed on those with positive microbiological analysis of a bronchoalveolar lavage (BAL) sample. Host immune status and microbiological analyses were obtained including PCR and culture testing. Categorical variables and co-infection or immunocompetent status were assessed using Chi-Square, Fisher exact tests, or t-tests. REDCap was utilized for data abstraction and SAS software version 9.4 was used to perform all analysis.ResultsOf the 139 BAL samples that met inclusion criteria, 107 and 32 were obtained from immunocompetent and immunocompromised hosts, respectively. There was no statistical difference found between the frequency of co-infection detected by BAL culture with respect to host immune status. Immunocompetent patients had a higher proportion of positive bacterial cultures compared with immunocompromised (76.7% vs. 43.8% respectively, P = 0.0004). There was no significant difference seen with frequency of fungal or acid fast bacilli cultures between the two groups. Analysis of the microbiologic data obtained (figures) revealed different pathogens according to host immune status.ConclusionPneumonia due to co-infection in critically ill, mechanically ventilated immunocompromised hosts occurs at a similar frequency regardless of host immune status, however different microbiological patterns emerge. Interestingly, patients who were not immunocompromised had a higher proportion of positive bacterial cultures compared with those who were immunocompromised. Comparative analysis of the other pathogen types may also reveal differences in detection rates if sample size is increased. Clinically, this may help guide efficient use of microbiological testing among patients based on immune status. Disclosures All authors: No reported disclosures.

OBJECTIVES: Pneumonia remains a significant cause of morbidity and mortality, with increasing interest in the detection and clinical significance of coinfection. Further investigation into the impact of bronchoalveolar lavage (BAL) sampling methodology and efficient clinical utilization of microbiological analyses is needed to guide the management of lower respiratory tract infection in the ICU. DESIGN: Retrospective observational study. SETTING: ICUs at a single center between August 1, 2012, and January 1, 2018. PATIENTS: Mechanically ventilated adult patients who underwent BAL testing during an ICU admission were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: BAL methodology (bronchoscopic vs nonbronchoscopic), microbiological diagnostic testing, and clinical outcomes measures were obtained. Chi-square or Fisher exact tests assessed associations between categorical variables, whereas Kruskal-Wallis tests analyzed differences in distributions of measures. BAL samples from 803 patients met inclusion criteria. Coinfection was detected more frequently via bronchoscopic BAL compared with nonbronchoscopic BAL (26% vs 9%; p < 0.001). Viruses were detected more frequently in bronchoscopic (42% vs 13%; p < 0.001) and bacteria in nonbronchoscopic (42% vs 33%; p = 0.011) BALs. A positive correlation between mortality and the number of organisms isolated was identified, with 43%, 48%, and 58% 30-day mortality among those with 0, 1, and more than 2 organisms, respectively (p = 0.003). Viral organism detection was associated with increased 30-day mortality (56% vs 46%; p = 0.033). CONCLUSIONS: Even in the setting of standardized institutional techniques, retrospective evaluation of bronchoscopic and nonbronchoscopic BAL methodologies did not reveal similar microbiologic yield in critically ill patients, though bronchoscopic BAL overall yielded more organisms, and occurrence of multiple organisms in BAL was associated with worse outcome. Prospective data are needed for direct comparison of both methods to develop more standardized approaches for use in different patient groups.