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Analysing the fitness cost of antibiotic resistance to identify targets for combination antimicrobials

Rasouly, Aviram; Shamovsky, Yosef; Epshtein, Vitaly; Tam, Kayan; Vasilyev, Nikita; Hao, Zhitai; Quarta, Giulio; Pani, Bibhusita; Li, Lingting; Vallin, Carmen; Shamovsky, Ilya; Krishnamurthy, Shankarling; Shtilerman, Aaron; Vantine, Samantha; Torres, Victor J; Nudler, Evgeny
Mutations in the rifampicin (Rif)-binding site of RNA polymerase (RNAP) confer antibiotic resistance and often have global effects on transcription that compromise fitness and stress tolerance of resistant mutants. We suggested that the non-essential genome, through its impact on the bacterial transcription cycle, may represent an untapped source of targets for combination antimicrobial therapies. Using transposon sequencing, we carried out a genome-wide analysis of fitness cost in a clinically common rpoB H526Y mutant. We find that genes whose products enable increased transcription elongation rates compound the fitness costs of resistance whereas genes whose products function in cell wall synthesis and division mitigate it. We validate our findings by showing that the cell wall synthesis and division defects of rpoB H526Y result from an increased transcription elongation rate that is further exacerbated by the activity of the uracil salvage pathway and unresponsiveness of the mutant RNAP to the alarmone ppGpp. We applied our findings to identify drugs that inhibit more readily rpoB H526Y and other RifR alleles from the same phenotypic class. Thus, genome-wide analysis of fitness cost of antibiotic-resistant mutants should expedite the discovery of new combination therapies and delineate cellular pathways that underlie the molecular mechanisms of cost.
PMID: 34697460
ISSN: 2058-5276
CID: 5042332

In the case of an esophageal food impaction, does the time between symptom onset and endoscopy start time influence the duration and difficulty of esophagogastroduodenoscopy? [Meeting Abstract]

Zenger, C; Quarta, G; DiLeo, D A
Introduction: Esophageal food impaction is considered a medical emergency and its incidence has increased in recent years. Potential complications of the condition are myriad: ulcers, lacerations, erosions, and esophageal perforation have all been documented in the literature. For this reason, the American Society for Gastrointestinal Endoscopy recommends removal of an esophageal impaction within 24 hours as delay decreases the likelihood of successful removal and increases the risk of complications. Other factors, such as duration of impaction and size of the ingested food bolus have also been independently associated with esophageal complications. We sought to identify the elements that most affected the duration and success of EGD procedures for treatment of esophageal food impaction.
Method(s): We carried out a retrospective cohort study via review of the EHR for all adults treated for food impaction (n=230) in an academic medical center between 2010 to 2020. Information on individual demographics, clinical variables, and timelines from symptom onset to procedure conclusion was collected.
Result(s): Our data showed multiple items associated with increased EGD duration time for treatment of esophageal food impaction. A longer time-to-procedure following symptom onset was correlated (Spearman R 50.1836) with increased procedure duration. There was a similar positive correlation between the duration of the procedure and number of instruments used (R = 0.583). Types of pathology also affected procedure times. In patients with achalasia, the mean procedure duration was almost 54 minutes, while cases without identifiable underlying pathology took 21 minutes on average (p < 0.001). Types of pathology also affected which instruments were used. Endoscopists were much more likely to successfully remove the impaction with the rat tooth forceps in eosinophilic esophagitis than in other conditions studied.
Conclusion(s): Knowledge of the factors most strongly associated with prolonged EGD procedure times for treatment of food impaction is highly advantageous for clinicians. For example, cognizance of the inherent complexity of treating an impaction in patients with achalasia may prompt the operator to place an overtube or to recommend general anesthesia in anticipation of the expected difficulty of the procedure. Likewise, understanding which instruments would be most useful in treating an impaction depending on etiology can reduce medical waste and minimize procedure time. (Table Presented)
ISSN: 1572-0241
CID: 5083782

Endovascular Intervention in Patients with Gastric Variceal Hemorrhage Is Associated with Improved Short-Term Hepatic Function in the Presence of Splenorenal Shunt Compared to Absence of Splenorenal Shunt [Meeting Abstract]

Saini, S; Quarta, G; Feldman, D M
INTRODUCTION: Variceal hemorrhage represents a major life threatening event in patients with decompensated cirrhosis. In comparison to esophageal varices, gastric variceal hemorrhage has a worse prognosis with higher rates of morbidity, mortality, and rebleeding. Gastric varices (GV) are currently classified based on anatomical location, but this approach fails to distinguish between different vascular compensatory mechanisms that develop in portal hypertension. Unlike esophageal variceal bleeds where endoscopic management is largely successful, endovascular approaches including transjugular intrahepatic portosystemic shunt (TIPS) and balloon-occluded retrograde transvenous obliteration (BRTO) play a more crucial role. We performed a retrospective review of patients with GV hemorrhage with and without splenorenal shunt (SRS) who underwent TIPS or BRTO to document outcomes that would help further our understanding of this disease process.
METHOD(S): A retrospective chart review of patients at NYU Langone Health with ICD-9/10 codes for GV was performed. We extracted data for the presence of GV on endoscopy (i.e. Sarin Classification) and radiographic findings from contrast-enhanced imaging to determine the presence or absence of vascular shunt. Analysis was performed on patients with GV hemorrhage who underwent either TIPS or BRTO.
RESULT(S): Thirteen patients with GV bleeds were included in our analysis; 5 with SRS and 8 without SRS shunt. We found that hepatic encephalopathy, as well as 30-day and 1-year readmissions were higher in the TIPS group, compared with patients who underwent BRTO (Table 1). Average MELD-Na score and platelets after a GV bleed trended toward improvement in patients with SRS who underwent either BRTO or TIPS (Table 2, P . 0.05) after an average of 47 days. This trend was not seen in patients without SRS.
CONCLUSION(S): Our data suggest that patients who presented with GV hemorrhage with underlying SRS trended toward improved hepatic function (based on MELD-Na and platelets) 2 weeks after intervention compared to patients without SRS. We propose that mapping of gastrointestinal vas-culature early in the course of GV hemorrhage has a role in determining prognosis and treatment. In the presence of a splenorenal shunt, BRTO should be highly considered if technically feasible irrespective of Sarin classification. Further understanding of the vascular anatomy and pathogenesis of shunt formation may assist in future management of GV hemorrhage
ISSN: 1572-0241
CID: 4718892

A Theory-based Educational Pamphlet With Low-residue Diet Improves Colonoscopy Attendance and Bowel Preparation Quality

Gausman, Valerie; Quarta, Giulio; Lee, Michelle H; Chtourmine, Natalia; Ganotisi, Carmelita; Nanton-Gonzalez, Frances; Ng, Chui Ling; Jun, Jungwon; Perez, Leslie; Dominitz, Jason A; Sherman, Scott E; Poles, Michael A; Liang, Peter S
GOALS/BACKGROUND/OBJECTIVE:Patients who "no-show" for colonoscopy or present with poor bowel preparation waste endoscopic resources and do not receive adequate examinations for colorectal cancer (CRC) screening. Using the Health Belief Model, we modified an existing patient education pamphlet and evaluated its effect on nonattendance rates and bowel preparation quality. STUDY/METHODS:We implemented a color patient education pamphlet to target individual perceptions about CRC and changed bowel preparation instructions to include a low-residue diet instead of the previous clear liquid diet. We compared the nonattendance rate over a 2-month period before and after the introduction of the pamphlet, allowing for a washout period during which pamphlet use was inconsistent. We compared the Boston Bowel Preparation Scale (BBPS) in 100 consecutive patients who underwent colonoscopy during each of the 2 periods. RESULTS:Baseline characteristics between the 2 groups were similar, although patients who received the pamphlet were younger (P=0.03). The nonattendance rate was significantly lower in patients who received the pamphlet (13% vs. 21%, P=0.01). The percentage of patients with adequate bowel preparation increased from 82% to 86% after introduction of the pamphlet, although this was not statistically significant (P=0.44). The proportion of patients with a BBPS score of 9 was significantly higher in the pamphlet group (41% vs. 27%, P=0.03). There was no difference in adenoma and sessile serrated adenoma detection rates before and after pamphlet implementation. CONCLUSIONS:After implementing a theory-based patient education intervention with a low-residue diet, our absolute rate for colonoscopy nonattendance decreased by 8% and the proportion of patients with a BBPS score of 9 increased by 14%. The Health Belief Model appears to be a useful construct for CRC screening interventions.
PMID: 30439762
ISSN: 1539-2031
CID: 3457682

Intragastric balloon hyperinflation secondary to polymicrobial overgrowth associated with proton pump inhibitor use

Quarta, Giulio; Popov, Violeta B
PMID: 30935931
ISSN: 1097-6779
CID: 3783932

Corticosteroid use is not associated with decreased length of stay in patients hospitalized with crohn's associated small bowel obstruction [Meeting Abstract]

Quarta, G; Tanawala, S; Liu, Y; Chang, S; Malter, L; Dikman, A; Hudesman, D
Background: Nearly one-half of Crohn's disease patients require bowel resection within the frst 10 years of disease (1). Small bowel obstruction (SBO) is the most common indication for surgery in Crohn's patients, followed by abscess and presence of fstulizing disease (2). Tere are little data regarding pharmacologic treatment of Crohn's-associated SBO with corticosteroids. In particular, the safety and efcacy of corticosteroids in treating inflammation in the setting of acute Crohn's SBO remains unclear. METHODS: Our group performed a retrospective chart review of patients admitted with Crohn's-disease associated SBO to our institution. Key variables examined included use of corticosteroids, length of stay, infectious complications, and short-term requirement for surgery. Inclusion criteria included adults (>18 years) who were not pregnant and carried a known diagnosis of Crohn's disease. Using the i2b2 search engine, patients admitted with the ICD10 diagnoses for Crohn's disease and a primary diagnosis of SBO were included. Analysis of outcomes was performed comparing patients who received steroids versus those who did not using t-statistics and chi-square analysis. RESULTS: Between 2015 and 2017, ffy-seven patients met inclusion criteria. Te majority (n=32, 56%) received no corticosteroids for the preceding three months nor during the admission for SBO, while the minority (n=25, 44%) did receive steroids. Te mean age of patients (45+/-19 years vs 46+/-18 years, P=0.92), and duration of Crohn's disease (14+/-13 years vs 14+/-12 years, P=0.93) did not differ between groups. C-reactive peptide (CRP) on admission did not differ between groups (23.9+/-17 vs 46.6+/-78, P=0.49). Eleven patients (19%) required surgery related to Crohn's disease during or within the three months following admission. Tere was no difference in requirement for surgery between groups. In multivariable logistic regression, the only factor associated with requirement for surgery was duration of Crohn's disease (P<0.05). Tere was no difference in duration of nasogastric tube placement, time to PO challenge, or length of hospital stay. Tere were no mortalities in either group and no difference in infectious complications afer discharge. CONCLUSION(S): Tese results suggest that corticosteroids are not associated with improved outcomes in patients with Crohn's associated SBO. Length of stay is not decreased due to use of corticosteroids. Te study is limited by its retrospective design and small sample size. However, future case-control or randomized clinical trials can examine the use of corticosteroids during acute Crohn's-associated SBO
ISSN: 1572-0241
CID: 3113172

Metastatic Gastric Adenocarcinoma Diagnosed Following Spontaneous Bacterial Peritonitis: A Rare Complication of Malignant Ascites [Meeting Abstract]

Dornblaser, David W.; Torres, Christian; Quarta, Giulio; McCulloch, Denise
ISSN: 0002-9270
CID: 5526502

Intragastric Balloon Placement Hyperinflation Associated With Lipase Elevation, Candida Infection, and Abdominal Pain [Meeting Abstract]

Quarta, Giulio; Popov, Violeta
ISSN: 0002-9270
CID: 3242532

Portal Vein Thrombosis and Coagulopathy Are Independent Risk Factors for the Increase in Liver Transplantation for Autoimmune Hepatitis in the United States [Meeting Abstract]

Kilaru, Saikiran M.; Quarta, Giulio; Popov, Violeta
ISSN: 0002-9270
CID: 3242522

A Theory-Based Educational Booklet Improves Colonoscopy Attendance and Bowel Preparation Quality [Meeting Abstract]

Gausman, Valerie; Quarta, Giulio; Lee, Michelle H.; Chtourmine, Natalia; Ganotisi, Carmelita; Nanton-Gonzalez, Frances; Ng, Chui Ling; Jun, Jungwon; Perez, Leslie; Sherman, Scott E.; Poles, Michael A.; Liang, Peter S.
ISSN: 0002-9270
CID: 3242512