Journal articles on the topic 'Nicola Dickson'

Dans cet article, Nicole Nolette explore le potentiel du concept de « différenciation solidaire » pour l’analyse intertextuelle entre les littératures francophones de l’Ontario et de l’Ouest canadien. Les grandes figures des « trois D » de l’Ontario français (Patrice Desbiens, Robert Dickson et Jean Marc Dalpé), rejetées par la génération de Louis Patrick Leroux, réapparaissent dans la dramaturgie de Marc Prescott au Manitoba et de Gilles Poulin-Denis, originaire de la Saskatchewan. Nicole Nolette identifie les traces des trois D dans la langue, la route, la ville minière et les animaux représentés par Prescott et Poulin-Denis pour montrer comment la solidarisation littéraire de l’Ouest et de l’Ontario francophones peut également signifier une différenciation régionale.

Abstract Background E. coli is the predominant uropathogen isolated in uncomplicated urinary tract infections (UTI). Surveillance data suggest increasing antimicrobial resistance (AMR), although recent data from the outpatient setting are limited. Treatment is typically empiric and should be guided by local resistance rates; however, this is challenging in the absence of routine culture and assessment of regional AMR. We characterized AMR trends for E. coli isolated from females with outpatient UTI in the US, from 2011 to 2019. Methods A retrospective multicenter cohort study of antimicrobial susceptibility using data from the BD Insights Research Database (Franklin Lakes, NJ) was conducted. The first E. coli urine culture isolates representing each distinct susceptibility pattern within 30 days of index urine from 2011–2019 were included from females ≥ 12 years old. E. coli isolates were identified as not-susceptible (NS) if intermediate or resistant to trimethoprim-sulfamethoxazole (TMP-SMX NS), fluoroquinolone (FQ NS), nitrofurantoin (NFT NS), ESBL+ (by commercial panels or intermediate/resistant to ceftriaxone, cefotaxime, ceftazidime or cefepime), and multi-drug resistant (MDR), defined as NS to ≥ 2 or ≥ 3 of FQ, TMP-SMX, NFT or ESBL+. Descriptive analyses characterized AMR (%) over time and generalized estimating equations were used to statistically assess AMR trends over time. Results A total of 1,513,882 E. coli isolates were tested at 106 to 295 US centers between 2011 and 2019. Over the study period, AMR remained persistently high (> 20%) for FQ and TMP-SMX and increased for the MDR (≥ 3 drugs) phenotype (from 3.1% to 4.0%) (Table). Prevalence of the ESBL+ phenotype increased year-on-year (from 4.1% to 7.3%). Modeling confirmed a significant increasing trend for the ESBL+ (7.7%/year) and MDR (≥ 3 drugs) phenotypes (2.7%/year) (P< 0.001), with decreasing or no trend change for NFT NS and other AMR phenotypes (Table). Table. Descriptive Statistics and Model-estimated Annual Change of AMR (count and % not-susceptible out of isolates tested) in E. coli among US Females (≥12 years of age) with Outpatient UTI Conclusion Characterization of AMR trends for E. coli over the last decade, in outpatient E. coli isolates in US females, shows persistently high AMR to FQ and TMP-SMX, and increasing AMR trends for the ESBL+ and MDR (≥ 3 drugs) phenotypes. Disclosures Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Aruni Mulgirigama, MBBS, GlaxoSmithKline plc. (Employee, Shareholder) Ashish V. Joshi, PhD, GlaxoSmithKline plc. (Employee, Shareholder) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) Kalvin Yu, MD, Becton, Dickinson and Company (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Gang Ye, PhD, Becton, Dickinson and Company (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc. (Employee, Shareholder)

Abstract Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, and is associated with an aggressive soft-tissue sarcoma, malignant peripheral nerve sheath tumours (MPNSTs), the greatest cause of mortality in people with NF1. The only potentially curative therapy involves en bloc resection with negative margins, which is not always appropriate. Even therapy with curative intent is associated with poor overall survival for both sporadic and NF1-related MPNSTs. The development of novel therapies has been largely hindered by a poor understanding of the molecular events underpinning MPNST pathogenesis. We report a comprehensive multi-omic study of MPNST evolution based on whole genome sequencing, transcriptomic and methylation profiling data on 95 tumors (64 NF1-related; 31 sporadic). In all cases, the early events in MPNST evolution involve biallelic inactivation of NF1 followed by inactivation of CDKN2A, as well as mutations in TP53 or PRC2 complex genes in a subset of cases. Analysis of the genomic architecture revealed distinct pathways of tumor evolution that can be identified through H3K27 trimethylation (H3K27me3) status. Integration of these data allows us to propose several mechanistic tumor evolution models. Tumors with H3K27me3 loss evolve through extensive copy number aberrations (CNAs) including haploidization followed by whole genome doubling and chromosome 8 amplifications, whereas tumors with H3K27me3 retention evolve through extensive chromosome instability and chromothripsis. Taken together, these genome-wide CNA profiles act as a surrogate for the loss of H3K27me3 status and correlate with prognosis, suggesting that CNA profiling of cell-free DNA could be incorporated in clinical decision-making. Citation Format: Isidro Cortes Ciriano, Chris D. Steele, Katherine Piculell, Alyaa Al-Ibraheemi, Vanessa Eulo, Marilyn M. Bui, Aikaterini Chatzipli, Brendan C. Dickson, Dana C. Borcherding, Alon Galor, Jesse Hart, Andrew Feber, Kevin B. Jones, Justin T. Jordan, Raymond H. Kim, Daniel Lindsay, Colin Miller, Yoshihiro Nishida, Jonathan Serrano, Nicole J. Ullrich, David Viskochil, Xia Wang, Matija Snuderl, Paula Proszek, Peter J. Park, Adrienne M. Flanagan, Angela C. Hirbe, Nischalan Pillay, David T. Miller, The Genomics of MPNST (GeM) Consortium. Recurrent genomic patterns of MPNST evolution correlate with clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6084.

Abstract Background The 2019 CDC Threats Report lists extended spectrum β-lactamase (ESBL) producing Enterobacterales as a serious health threat. While the clinical epidemiology of uncomplicated urinary tract infection (uUTI) has remained stable, there has been a notable increase in antimicrobial resistance (AMR) among community-acquired uUTIs. Urine cultures are seldom ordered for uUTI as treatment is often empiric; local surveillance data may therefore be lacking. The study objective was to determine the prevalence and geographic distribution of AMR in urine E. coli isolates from females in the US outpatient setting. Methods A retrospective cross-sectional study of E. coli ambulatory urine isolates identified from females (≥ 12 years of age) at 296 facilities, with ≥ 1 quarter of data in 2019 (BD Insights Research Database, Franklin Lakes, NJ). Initial isolates representing each distinct susceptibility pattern within 30 days of index urine were included. E. coli isolates were identified as not-susceptible (NS) if intermediate/resistant to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolone (FQ), nitrofurantoin (NFT), ESBL+ (by commercial panels or intermediate/resistant to ceftriaxone, cefotaxime, ceftazidime or cefepime), and multi-drug resistant, defined as NS to ≥ 2 or ≥ 3 of FQ, TMP-SMX, NFT or ESBL+. Logistic regression models were used to evaluate resistance prevalence and variation across US census regions. Results Of 267,524 non-duplicate E. coli isolates evaluated, 25.1% (67,189) were TMP-SMX NS, 20.3% (54,359) were FQ NS, 7.3% (19,576) were ESBL+, 3.5% (9,453) were NFT NS, 14.0% (37,328) were NS to ≥ 2 drugs and 4.0% (10,814) were NS to ≥ 3 drugs. For all phenotypes, there was significant variation in resistance across census regions (all P< 0.001) with the highest in the East South Central region and lowest in the New England region of the US (Table). The figure shows regional prevalence of ESBL+ E. coli in 2019. Table. Antimicrobial resistance data from 30-day non-duplicate urine E. coli isolates in females ≥12 years old in 2019, by US census region. Figure. Heat map of the overall US geographic distribution of ESBL+ E. coli (30-day non-duplicate urine isolates) from females across 296 acute care facilities in 2019. Conclusion The 2019 prevalence of AMR in non-duplicate ambulatory E. coli urine isolates was notable: TMP-SMX NS and FQ NS were > 20%. In addition, there were significant regional differences in resistance, with the highest in the East South Central region of the US, for all NS phenotypes. These analyses inform, and may optimize, empiric treatment of uUTI and patient outcomes. Disclosures Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Aruni Mulgirigama, MBBS, GlaxoSmithKline plc. (Employee, Shareholder) Ashish V. Joshi, PhD, GlaxoSmithKline plc. (Employee, Shareholder) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) Kalvin Yu, MD, Becton, Dickinson and Company (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Anthony Boyles, MSc, Becton, Dickinson and Company (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc. (Employee, Shareholder)

Abstract Background An estimated 12% of women experience ≥ 1 episode of urinary tract infection (UTI) annually. Incidence is bimodal, with peaks occurring in young, sexually active women (18–24 years) and in post-menopausal women. Previous studies suggest the prevalence of antimicrobial resistance (AMR) in UTI is rising; however recent AMR data for community-acquired UTI are lacking. We estimated the prevalence of AMR among US females with outpatient UTI in 2011–2019, stratified by age. Methods A retrospective, multicenter, cohort study of AMR among non-duplicate urine isolates in US females (≥ 12 years of age) from 296 institutions from 2011–2019 (BD Insights Research Database, Franklin Lakes, NJ). Phenotypes examined for Enterobacterales (ENT) were: extended spectrum β-lactamase positive (ESBL+; determined by commercial panels or intermediate/resistant to ceftriaxone, cefotaxime, ceftazidime or cefepime); nitrofurantoin (NFT) not-susceptible (NS); fluoroquinolone (FQ) NS; trimethoprim-sulfamethoxazole (TMP-SMX) NS; and NS to ≥ 2 or ≥ 3 drug classes (including ESBL+). Gram-positive phenotypes were, methicillin resistant S. aureus and S. saprophyticus and vancomycin-resistant Enterococcus. Isolates were stratified by patient age (≥ 12 to < 18, ≥ 18 to < 55, ≥ 55 to < 65, ≥ 65 to < 75, ≥ 75 years). Chi-square tests were used to evaluate AMR difference between groups. Results In total, urine isolates were collected from 106 to 296 (2011–2019) US sites. Overall, the prevalence of antimicrobial NS increased with age for all E. coli phenotypes (all P< 0.001; Table 1), and for non-E. coli ENT (all P< 0.001), except NFT NS, which decreased from 70.6% to 59.7% (P=0.002; Table 2). The greatest difference between age groups in prevalence of resistance was observed for FQ NS E.coli: 5.8% (≥ 12 to < 18 years) vs 34.5% (≥ 75 years). For the multi-drug resistant E. coli phenotypes, resistance increased with age, ranging from 4.8–22.4% and 0.9–6.5% for ≥ 2 and ≥ 3 drug NS, respectively. Overall, the prevalence of resistance for Gram-positive phenotypes increased with age (all P< 0.001; Table 3). Table 1. Prevalence of antimicrobial resistance among E. coli isolates in US females with outpatient UTI by age group. Table 2. Prevalence of antimicrobial resistance among non-E. coli ENT isolates in US females with outpatient UTI by age group. Table 3. Prevalence of antimicrobial resistance among Gram-positive isolates in US females with outpatient UTI by age group. Conclusion The prevalence of AMR in E. coli and non-E. coli ENT increased with age among US females presenting for care in the outpatient setting overall. A similar trend increase by age is also seen in Gram-positive isolates. Disclosures Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Aruni Mulgirigama, MBBS, GlaxoSmithKline plc. (Employee, Shareholder) Ashish V. Joshi, PhD, GlaxoSmithKline plc. (Employee, Shareholder) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) Kalvin Yu, MD, Becton, Dickinson and Company (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Gang Ye, PhD, Becton, Dickinson and Company (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc. (Employee, Shareholder)

Reeve, Alison J., Anthony H. Dickenson, and Nicola C. Kerr. Spinal effects of bicuculline: modulation of an allodynia-like state by an A1-receptor agonist, morphine, and an NMDA-receptor antagonist. J. Neurophysiol. 79: 1494–1507, 1998. Single-unit recordings were made in the intact anesthetized rat of the responses of dorsal horn neurons to C-, Aδ-, and Aβ-fiber stimulation. The postdischarge and windup responses of the same cells along with responses to innocuous stimuli, prod and brush, also were measured. The effects of (−)-bicuculline-methobromide (0.5, 5, 50, and 250 μg) were observed on these neuronal responses. The C- and Aδ-fiber–evoked responses were facilitated significantly in a dose-dependent manner. The input was facilitated, but as the final overall response was not increased by the same factor, windup appeared to be reduced. However, postdischarge, resulting from the increase in the excitability produced by windup, tended to be facilitated. After doses of ≥5 μg bicuculline, stimulation at suprathreshold Aβ-fiber–evoked activity caused enhanced firing, mainly at later latencies corresponding to Aδ-fiber–evoked activity in normal animals. Few cells responded consistently to brush and so no significant change was observed. Responses evoked by innocuous pressure (prod) always were observed in cells that concurrently responded to electrical stimulation with a C-fiber response. This tactile response was facilitated significantly by bicuculline. The effects of N6-cyclopentyladenosine (N6-CPA), an adenosine A1-receptor agonist, was observed after pretreatment with 50 μg bicuculline, as were the effects of morphine and 7-chlorokynurenate (7-CK). N6-CPA inhibited prod, C- and Aδ-fiber–evoked responses as well as the initial and overall final response to the train of C-fiber strength stimuli. Inhibitions were reversed with 8(p-sulphophenyl) theophylline. Morphine, the mu-receptor agonist, also inhibited the postbicuculline responses to prod, C-, and Aδ-fiber responses and initial and final responses to a train of stimuli. Inhibitory effects of morphine were reversed partly by naloxone. 7-CK, an antagonist at the glycine site on the N-methyl-d-aspartate-receptor complex, inhibited the responses to C- and Aδ-fiber–evoked activity as well as prod. The postdischarges were inhibited by this drug. Again both the initial and overall responses of the cell were inhibited. To conclude, bicuculline caused an increase in the responses of deep dorsal horn cells to prod, Aδ-fiber–evoked activity, increased C-fiber input onto these cells along with the appearance of responses at latencies normally associated with Aδ fibers, but evoked by suprathreshold Aβ-fiber stimulation. These alterations may be responsible for some aspects of the clinical phenomenon of allodynia and hyperalgesia. These altered and enhanced responses were modulated by the three separate classes of drugs, the order of effectiveness being 7-CK, N6-CPA, and then morphine.

Background:EULAR/ACR 2019 SLE Classification Criteria were validated in an international cohort.Objectives:To evaluate performance characteristics of SLE classification systems in sex, race/ethnicity, and disease duration subsets.Methods:Sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated in the validation cohort.Results:The cohort consisted of female (n=1098), male (n=172), Asian (n=118), Black (n=68), Hispanic (n=124) and White (n=941) patients; and patients with an SLE duration of 1-3 years (n=196), 3-5 years (n=157), and ≥5 years (n=879). Among patients with 1-3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% (95%CI 92-99%) vs 81% (95%CI 72-88%). The new criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). The new criteria had better sensitivity than the ACR criteria in White (95% vs 83%), Hispanic (100% vs 86%) and Asian patients (97% vs 77%).Conclusion:The EULAR/ACR 2019 criteria perform well in patients with early disease, and across sexes and ethnicities.Disclosure of Interests:Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Ralph Brinks: None declared, Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca, David Daikh: None declared, Marta Mosca: None declared, Rosalind Ramsey-Goldman: None declared, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche – grant/research support, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – consultant, Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – speaker, David Wofsy: None declared, Dimitrios Boumpas Grant/research support from: Unrestricted grant support from various pharmaceutical companies, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Ricard Cervera: None declared, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institution, Betty Diamond: None declared, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Bevra H. Hahn Grant/research support from: Janssen Research & Development, LLC, Falk Hiepe: None declared, Soren Jacobsen: None declared, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Kirsten Lerstrom: None declared, Elena Massarotti: None declared, William Joseph McCune: None declared, Guillermo Ruiz-Irastorza: None declared, Jorge Sanchez-Guerrero: None declared, Matthias Schneider: None declared, Murray B Urowitz: None declared, George Bertsias Grant/research support from: GSK, Consultant of: Novartis, Bimba F. Hoyer: None declared, Nicolai Leuchten: None declared, Chiara Tani: None declared, Sara Tedeschi: None declared, Zahi Touma: None declared, Gabriela Schmajuk Grant/research support from: Pfizer, Branimir Anic: None declared, Florence Assan: None declared, Tak Chan: None declared, Ann E Clarke: None declared, Mary K. Crow: None declared, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Winfried Graninger: None declared, Bernadett Halda-Kiss: None declared, Sarfaraz Hasni: None declared, Peter Izmirly: None declared, Michelle Jung: None declared, Gabor Kumanovics Consultant of: Boehringer, Teva, Speakers bureau: Roche, Lilly, Novartis, Xavier Mariette: None declared, Ivan Padjen: None declared, Jose M Pego-Reigosa: None declared, Juanita Romero-Diaz Consultant of: Biogen, Iñigo Rua-Figueroa: None declared, Raphaèle Seror Consultant of: BMS, Medimmune, Novartis, Pfizer, GSK, Lilly, Georg Stummvoll: None declared, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Maria Tektonidou Grant/research support from: AbbVie, MSD, Novartis and Pfizer, Consultant of: AbbVie, MSD, Novartis and Pfizer, Carlos Vasconcelos: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Daniel J Wallace: None declared, Sule Yavuz: None declared, Pier Luigi Meroni: None declared, Marvin Fritzler: None declared, Raymond Naden: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche

Abstract Background Over the past decade, extended spectrum β-lactamase producing Enterobacterales (ESBL) and multidrug resistance has risen among community-acquired uncomplicated urinary tract infections (uUTIs). This study was conducted to determine co-resistance among Klebsiella pneumoniae (K. pneumoniae) isolates in urine from female outpatients in the United States (US). Methods This was a retrospective, cross-sectional study of 30-day non-duplicate K. pneumoniae urine isolates from female outpatients (≥ 12 years of age) at 304 US facilities, with ≥ 3 months of data from 2011–2019 (Becton, Dickinson and Company [BD] Insights Research Database). K. pneumoniae isolates were defined as those that were ESBL-positive (ESBL+) (by commercial panel or not susceptible [NS] to ceftriaxone, cefotaxime, ceftazidime or cefepime), or NS if intermediate/resistant to any of the following: fluoroquinolones (FQs), trimethoprim/sulfamethoxazole (SXT), nitrofurantoin (NFT). Co-resistance phenotypes were characterized in isolates NS to ≥ 2 of the 4 resistance phenotypes assessed. Results Among 250,719 non-duplicate K. pneumoniae isolates evaluated, 11,065 were ESBL+ (Table). Co-resistance among ESBL+ isolates was observed as follows: 54.9% to FQ; 65.7% to SXT; 75.5% to NFT; and 38.2% to all 4 resistance phenotypes. Of 10,962 isolates NS to FQ, co-resistance was observed as follows: 55.4% were ESBL+; 65.7% to SXT; 79.6% to NFT; and 38.6% to all 4 resistance phenotypes. Of 141,545 isolates NS to NFT, co-resistance was observed as follows: 5.9% were ESBL+; 6.2% to FQ; 11.8% to SXT; and 3.0% to all 4 resistance phenotypes. Among 23,887 isolates NS to SXT, co-resistance was observed as follows: 30.4% were ESBL+; 30.1% to FQ; 69.7% to NFT; and 17.7.% to all 4 resistance phenotypes. Table.Co-resistance phenotype combinations observed among Klebsiella pneumoniae isolates in urine from 2011–2019In total, 250,719 non-duplicate (30-day) Klebsiella pneumoniae isolates were evaluated.Note: Some isolates had overlapping susceptibilities/antimicrobial resistance types, hence individual phenotype totals do not reflect total number of isolates evaluated.Abbreviations: ESBL+, extended spectrum β-lactamase-producing or not susceptible to ceftriaxone, cefotaxime, ceftazidime or cefepime; FQ, fluoroquinolone; NFT, nitrofurantoin; NS, not susceptible; SXT, trimethoprim/sulfamethoxazole. Conclusion The high prevalence of co-resistance in 30-day non-duplicate outpatient K. pneumoniae urinary isolates, particularly towards NFT (70–80% of isolates), limits the effective oral treatment options for uUTI. These analyses may help inform and optimize appropriate empiric treatment of female outpatients with uUTI in the US. Disclosures Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|GlaxoSmithKline plc.: Receiving symposia honoraria|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502|Merck: Advisor/Consultant|qpex: Advisor/Consultant|Shionogi: Grant/Research Support|Spero: Advisor/Consultant Vikas Gupta, PharmD, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Aruni Mulgirigama, MBBS, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Ashish V. Joshi, PhD, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study Nicole E. Scangarella-Oman, MS, GlaxoSmithKline plc.: Employee and shareholder Kalvin Yu, MD, FIDSA, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Janet Watts, PhD, Becton, Dickinson and Company: Employee of Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502.

Abstract Background In the past 10 years, there has been a substantial increase in antimicrobial resistance among uropathogens in community-acquired uncomplicated urinary tract infections (uUTIs), including extended spectrum β-lactamase producing (ESBL+) Enterobacterales and multidrug resistance. This study examined urine isolates from female outpatients in the United States (US) for co-resistance among Escherichia coli (E. coli). Methods This was a retrospective, cross-sectional study of 30-day non-duplicate E. coli urine isolates (first isolates collected within a 30-day period) from female outpatients (≥ 12 years of age) at 304 US facilities. Included patients had ≥ 3 months of data from 2011 to 2019 (Becton, Dickinson and Company [BD] Insights Research Database). Urine-isolated E. coli were defined as ESBL+ by 1) commercial panel or 2) not susceptible (NS; intermediate/resistant) to ceftriaxone, cefotaxime, ceftazidime, or cefepime), or NS to any of: fluoroquinolones (FQs), trimethoprim/sulfamethoxazole (SXT), or nitrofurantoin (NFT). Microbiological co-resistance phenotypes were characterized in isolates NS to ≥ 2 of the 4 resistance phenotypes assessed. Results In total, 856,918 unique isolates were evaluated. Co-resistance data are shown in the Table. Of ESBL+ isolates (96,306), 72.4% were co-resistant to FQ, 56.7% to SXT, and 11.9% to NFT; 6.8% had all 4 phenotypes. For FQ NS isolates (319,354), 21.8% were also ESBL+, 51.6% were co-resistant to SXT, 8.0% were co-resistant to NFT, and 2.0% had all 4 phenotypes. Among SXT NS isolates (384,304), 14.2% were also ESBL+, 42.9% were co-resistant to FQ, 6.8% were co-resistant to NFT, and 1.7% had all 4 phenotypes. Finally, for NFT NS isolates (56,954), 20.1% were ESBL+, 44.7% were co-resistant to FQ, 46.0% were co-resistant to SXT, and 11.5% had all 4 phenotypes. Table.Co-resistance phenotype combinations among urine-isolated Escherichia coli (2011–2019)In total, 856,918 non-duplicate (30-day) Escherichia coli isolates were evaluated.Note: Some isolates had overlapping susceptibilities/antimicrobial resistance types, hence individual phenotype totals do not reflect total number of isolates evaluated.Abbreviations: ESBL+, extended spectrum β-lactamase-producing (by commercial panel or not susceptible to ceftriaxone, cefotaxime, ceftazidime or cefepime); FQ, fluoroquinolone; NFT, nitrofurantoin; NS, not susceptible; SXT, trimethoprim/sulfamethoxazole. Conclusion Among urine-isolated E. coli, there was a high prevalence of co-resistance, particularly for ESBL+ isolates where co-resistance to FQ was > 70%. The availability of effective oral treatments for uUTI is limited by uropathogen antibiotic resistance. These data may help inform appropriate empiric prescribing practices to optimize the treatment of uUTI, mitigate multiple drug exposure for a uUTI event, and potentially influence long-term resistance patterns among E. coli. Disclosures Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|GlaxoSmithKline plc.: Receiving symposia honoraria|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502|Merck: Advisor/Consultant|qpex: Advisor/Consultant|Shionogi: Grant/Research Support|Spero: Advisor/Consultant Vikas Gupta, PharmD, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Aruni Mulgirigama, MBBS, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Ashish V. Joshi, PhD, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study Nicole E. Scangarella-Oman, MS, GlaxoSmithKline plc.: Employee and shareholder Kalvin Yu, MD, FIDSA, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Janet Watts, PhD, Becton, Dickinson and Company: Employee of Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502.

Abstract Background Infections caused by extended spectrum β-lactamase producing Enterobacterales (ESBLs), as well as antimicrobial resistance (AMR) and multi-drug resistance among uncomplicated urinary tract infections (uUTIs) in outpatients have risen in the past decade. The study objective was to determine the prevalence and geographic distribution of AMR among Klebsiella pneumoniae (K. pneumoniae) isolates in urine from female outpatients in the United States (US). Methods A retrospective, cross-sectional study of non-duplicate urine isolates from female outpatients (≥ 12 years of age) at 304 facilities, with ≥ 3 months of data, including initial isolates with distinct susceptibility patterns within 30 days of index urine samples, were used to assess regional AMR in 2019, and AMR trends from 2011 to 2019 (BD Insights Research Database, Franklin Lakes, NJ). K. pneumoniae isolates were identified as ESBL-positive (ESBL+) (confirmed by commercial panel or not susceptible [NS] to ceftriaxone, cefotaxime, ceftazidime, or cefepime), or NS if intermediate/resistant to any of the following: nitrofurantoin (NFT), trimethoprim/sulfamethoxazole (SXT), or fluoroquinolones (FQs). AMR prevalence and variation across US census regions was evaluated using logistic regression (with covariate adjustment) and generalized estimating equations. Results 44,056 non-duplicate K. pneumoniae isolates were evaluated in 2019 (Figure). For all microbiological phenotypes, there was significant variation in resistance for K. pneumoniae across all US census regions (p< 0.0001). Among 250,719 isolates evaluated from 2011 to 2019, AMR prevalence increased for all studied antimicrobials except for NFT NS (all p< 0.0041; Table). There was an increase in adjusted AMR rates by age groups with higher AMR rates for females ≥ 55 versus < 55, except for NFT, which showed the highest resistance in those aged < 55. Figure.Prevalence of antimicrobial resistance in Klebsiella pneumoniae isolates in 2019Abbreviations: ESBL+, extended spectrum β-lactamase-positive or not susceptible to ceftriaxone, cefotaxime, ceftazidime, or cefepime; FQ, fluoroquinolone; FQ, fluoroquinolone; NFT, nitrofurantoin; NS, not susceptible; SXT, trimethoprim/sulfamethoxazole.Table.Klebsiella pneumoniae: model-estimated trends of relative average annual percentage change of antimicrobial resistance over time (2011 to 2019), by patient age, and by census region (N=250,719 isolates)All p values were p< 0.0001 apart from NFT trend over years, which was p=0.0041.*Relative average annual percentage change in resistance rate.Abbreviations: CDC, Centers for Disease Control and Prevention; CI, confidence interval; ESBL+, extended spectrum β-lactamase-positive or not susceptible to ceftriaxone, cefotaxime, ceftazidime, or cefepime; FQ, fluoroquinolone; NFT, nitrofurantoin; NS, not susceptible; SXT, trimethoprim/sulfamethoxazole. Conclusion AMR prevalence in 2019 among non-duplicate K. pneumoniae isolates from urine in outpatients was notable. There were significant regional differences in resistance rates, which were higher in those aged ≥ 55 years, except for NFT. These analyses inform, and may be used to optimize, empiric treatment of uUTI. Disclosures Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|GlaxoSmithKline plc.: Receiving symposia honoraria|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502|Merck: Advisor/Consultant|qpex: Advisor/Consultant|Shionogi: Grant/Research Support|Spero: Advisor/Consultant Vikas Gupta, PharmD, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Aruni Mulgirigama, MBBS, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Ashish V. Joshi, PhD, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study Nicole E. Scangarella-Oman, MS, GlaxoSmithKline plc.: Employee and shareholder Kalvin Yu, MD, FIDSA, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Gang Ye, PhD, Becton, Dickinson and Company: Employee of Becton, Dickinson and Company, and received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc.: Employee and shareholder|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502.

Abstract Background The aims of the study were to 1) evaluate the prevalence of multidrug resistant (MDR) /Extensively drug resistant (XDR) strains among hospitalized adults with Pseudomonas aeruginosa (PA) infections, and 2) examine whether antimicrobial resistance in PA infections is associated with worsening functional status and higher health care resource utilization (HCRU). Methods This multicenter prospective study was conducted in 9 large Italian teaching hospitals between June 2018-February 2020. We included patients aged ≥18 years with a diagnosis of nosocomial pneumonia (NP), complicated urinary tract infections (cUTI) or complicated intra-abdominal infections (cIAI) due to PA as confirmed by local evaluation of microbiological results. MDR PA was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories. XDR PA was defined as acquired non-susceptibility to at least one agent in all but two or fewer antimicrobial categories. HCRU metrics evaluated included hospital length of stay (LOS) and intensive care unit (ICU) LOS. Results A total of 95 patients with a nosocomial infection due to PA were enrolled. The main baseline characteristics of overall patients were reported in Table 1. Almost one-third of patients (28.4%) reported either MDR or XDR PA infection, with more patients experiencing MDR (Table 1). Health care resource use stratified by patients with and without MDR/XDR status are reported in Table 2. Overall, in our study population, median hospital LOS and ICU LOS were 42.0 (IQR=39.0) and 15.5 (IQR=37.0) days, respectively. There was a statistically significant longer median hospital LOS for patients with MDR/XDR infections compared to non MDR/XDR PA infections (53.0 vs. 36.5 days, p=0.04). ICU LOS also trended towards being longer for patients with MDR/XDR infections compared to those with non-MDR/XDR infections (25.5 vs. 13.5 days, p=0.10). Conclusion MDR/XDR isolates were prevalent among patients with nosocomial infections due to PA, particularly in those with cIAI. Overall, the present study may suggest a positive correlation between having MDR-XDR PA nosocomial infections (NP, cUTI, and cIAI) and increased HCRU that require further attention from a disease management perspective. Disclosures Matteo Bassetti, PhD, Angelini: Advisor/Consultant|Astellas: Grant/Research Support|Bayer: Advisor/Consultant|Bayer: Honoraria|BioMe ́ rieux: Advisor/Consultant|BioMe ́ rieux: Honoraria|Cidara: Advisor/Consultant|Cidara: Honoraria|Cipla: Advisor/Consultant|Cipla: Honoraria|Gilead: Advisor/Consultant|Gilead: Honoraria|Menarini: Advisor/Consultant|Menarini: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|Tetraphase: Advisor/Consultant Francesco Menichetti, n/a, Aneglini: Advisor/Consultant|Aneglini: Board Member|Aneglini: Grant/Research Support|Aneglini: Honoraria|Astellas: Advisor/Consultant|Astellas: Honoraria|Becton: Advisor/Consultant|Becton: Honoraria|bioMérieux: Advisor/Consultant|bioMérieux: Honoraria|Biotest: Advisor/Consultant|Biotest: Board Member|Biotest: Honoraria|Bristol-Myers Squibb: Advisor/Consultant|Bristol-Myers Squibb: Honoraria|Correvio: Advisor/Consultant|Correvio: Speaker honoraria|Dickinson: Advisor/Consultant|Dickinson: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Speaker honoraria|Nordic pharma: Board Member|Nordic pharma: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria Nicola Petrosillo, n/a, Becton & Dickinson,: Honoraria|MSD: Honoraria|ohnson & Johnson: Honoraria|Pfizer: Honoraria|Shionogi: Honoraria.

Abstract Background In vitro-in vivo discordance in the activity of β-lactams against MBL-producing Enterobacterales has been described. This discordance is likely attributed to the supra-physiologic zinc level in the in vitro testing media, which facilitates the bicyclic β-lactam ring hydrolysis. In this study, we compared the outcome of empirical non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam plus aztreonam) among patients with bloodstream infections due to NDM-producing Klebsiella pneumoniae. Validation of the efficacy of carbapenem in a murine septicemia model was conducted. In vitro susceptibility testing conditions were altered to better predict the in vivo outcome. Methods A retrospective observational study of patients admitted to hospitals in Italy. The primary outcome was 14-day all-cause mortality. Cox regression analysis was performed to evaluate primary outcome. Kaplan Meier survival and log-rank test were used to compare 14-day mortality between patient’s cohorts. Septicemia was induced in mice via intraperitoneal inoculation with the isolates retrieved from the patients then clinical exposure of meropenem (MEM; 2 g q8h 3h infusion) was given for 2 days. Survival was recorded for 4 days and compared with sham controls. Unbound zinc levels were measured in human and infected mice plasma. MEM MICs were determined in Mueller Hinton Broth (MHB) and MHB adjusted to the physiologic zinc levels. Results Of the patients identified, 29 received empirical non-MBL-active β-lactams for median duration 4 days while 29 received MBL-active β-lactams. The 14-day mortality rate was 21% in the non-MBL-active group vs 14% in the MBL-active group (P = 0.73) and survival patterns were not significantly different (Fig. 1). Cox regression showed that use of non-MBL-active therapy was not associated with significantly increased 14-day mortality (hazard ratio = 1.45; P = 0.57). MEM treatment resulted in protection from mortality in mice (Fig. 2). MEM MICs in zinc-adjusted MHB were 1- to > 16-fold lowered relative to MICs in MHB ( ≥ 64 mg/L). Conclusion Our data provide foundational support to help establish PK/PD relationships using MICs derived in physiologic zinc levels which may better predict β-lactam therapy outcome. Disclosures Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support Christian M. Gill, PharmD, Everest Medicines, Shionogi, Cepheid: Grant/Research Support Matthew Gethers, PhD, Thermo Fisher: Employee Marco Falcone, MD, PhD, GILEAD: Grant/Research Support|GSK: Honoraria|MENARINI: Advisor/Consultant|MENARINI: Grant/Research Support|MSD: Honoraria|PFIZER: Honoraria|SHIONOGI: Grant/Research Support Francesco Menichetti, n/a, Aneglini: Advisor/Consultant|Aneglini: Board Member|Aneglini: Grant/Research Support|Aneglini: Honoraria|Astellas: Advisor/Consultant|Astellas: Honoraria|Becton: Advisor/Consultant|Becton: Honoraria|bioMérieux: Advisor/Consultant|bioMérieux: Honoraria|Biotest: Advisor/Consultant|Biotest: Board Member|Biotest: Honoraria|Bristol-Myers Squibb: Advisor/Consultant|Bristol-Myers Squibb: Honoraria|Correvio: Advisor/Consultant|Correvio: Speaker honoraria|Dickinson: Advisor/Consultant|Dickinson: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Speaker honoraria|Nordic pharma: Board Member|Nordic pharma: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria David P. Nicolau, PharmD, Shionogi: Grant/Research Support.

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There is an expression, in recent Marvel superhero films, of a social anxiety about genetic science that, in part, replaces the social anxieties about nuclear weapons that can be detected in the comic books on which these films are based (Rutherford). Much of the analysis of superhero comics – and the films on which they are based – has focussed its attention on the anxieties contained within them about gender, sexuality, race, politics, and the nation. Surprisingly little direct critique is applied to the most obvious point of difference within those texts, namely the acquisition, display, and use of extra-ordinary abilities. These superhero films represent some of the ways that audiences come to understand genetics. I am interested in this essay in considering how the representation of genetic mutation, as an error in a bio-chemical code, is a key narrative device. Moreover, mutation is central to the way the films explore the social exclusion of characters who acquire super-abilities. My contention is that, in these Marvel comic films, extra-ordinary ability, and the anxieties expressed about those abilities, parallels some of the social and cultural beliefs about the disabled body. The impaired body thus becomes a larger trope for any deviation from the “normal” body and gives rise to the anxieties about deviation and deviance explored in these films. Impairment and illness have historically been represented as either a blessing or a curse – the source of revelation and discovery, or the site of ignominy. As Western culture developed, the confluence of Greek and Judeo-Christian stories about original sin and inherited punishment for parental digression resulted in the entrenchment of beliefs about bent and broken bodies as the locus of moral questions (and answers) about the abilities and use of the human body (Sontag 47). I want to explore, firstly, in the film adaptations of the Marvel comics X-Men, Spiderman, Fantastic Four, and The Hulk, the representation of changes to the body as the effect of invisible bio-chemical states and processes. It has been impossible to see DNA, whether with the human eye or with technical aid; the science of genetics is largely based on inference from other observations. In these superhero films, the graphic display of DNA and genetic restructuring is strikingly large. This overemphasis suggests both that the genetic is a key narrative impetus of the films and that there is something uncertain or disturbing about genetic science. One such concern about genetic science is identifying the sources of oppression that might underlie the, at times understandable, desire to eliminate disease and congenital defect through changes to the genetic code or elimination of genetic error. As Adrienne Asch states, this urge to eliminate disease and impairment is problematic: Why should it be acceptable to avoid some characteristics and not others? How can the society make lists of acceptable and unacceptable tests and still maintain that only disabling traits, and not people who live with those traits, are to be avoided? (339) Asch’s questioning ends with the return to the moral concerns that have always circulated around the body, and in particular a body that deviates from a norm. The maxim “hate the sin, not the sinner” is replaced by “eradicate the impairment, not the impaired”: it is some kind of lack of effort or resourcefulness on the part of the impaired that is detectable in the presence of the impairment. This replacement of sin by science is yet another example of the trace of the body as the site of moral arguments. As Bryan Turner argues, categories of disease, and by association impairment, are intrinsic to the political discourse of Western societies about otherness and exclusion (Turner 216). It is not surprising then, that characters that experience physical changes caused by genetic mutation may take on for themselves the social shame that is part of the exclusion process. As genetic science has increasingly infiltrated the popular imagination and thus finds expression in cinema, so too has this concern of shame and guilt become key to the narrative tension of films that link changes in the genetic code to the acquisition of super-ability. In the X-Men franchise, the young female character Rogue (Anna Paquin), acquires the ability to absorb another’s life force (and abilities), and she seeks to have her genetic code resequenced in order to be able to touch others, and thus by implication have a “normal” life. In X2 (Bryan Singer, 2003), Rogue’s boyfriend, Iceman (Shawn Ashmore), who has been largely excluded from her touch, returns home with other mutants. After having hidden his mutant abilities from his family, he finally confesses to them the truth about himself. His shocked mother turns to him and asks: “Have you tried not being a mutant?” Whilst this moment has been read as an expression of anxiety about homosexuality (“Pop Culture: Out Is In”; Vary), it also marks a wider social concern about otherness, including disability, and its attendant social exclusion. Moreover, this moment reasserts the paradigm of effort that underlies anxieties about deviations from the norm: Iceman could have been normal if only he had tried harder, had a different girlfriend, remained at home, sought more knowledge, or had better counsel. Science, and more specifically genetic science, is suggested in many of these films as the site of bad counsel. The narratives of these superhero stories, almost without exception, begin or hinge on some kind of mistake by scientists – the escaped spider, the accident in the laboratory, the experiment that gets out of control. The classic image of the mad scientist or Doctor Frankenstein type, locked away in his laboratory is reflected in the various scenes in all these films, in which the scientists are separated from wider society. In Fantastic 4 (Tim Story, 2005), the villain, Dr Von Doom (Julian McMahon), is located at the top of a large multi-story building, as too are the heroes. Their separation from the rest of society is made even more dramatic by placing the site of their exposure to cosmic radiation, the source of the genetic mutation, in a space station that is empty of anyone else except the five main characters whose bodies will be altered. In Spiderman (Sam Raimi, 2002), the villain is a scientist whose experiments are kept secret by the military, emphasising the danger inherent in his work. The mad-scientist imagery dominates the representation of Bruce Bannor’s father in Hulk (Ang Lee, 2003), whose experiments have altered his genetic code, and that alteration in genetic structure has subsequently been passed onto his son. The Fantastic 4 storyline returns several times to the link between genetic mutation and the exposure to cosmic radiation. Indeed, it is made explicit that human existence – and by implication the human body and abilities – is predicated on this cosmic radiation as the source of transformations that formed the human genetic code. The science of early biology thus posits this cosmic radiation as the source of what is “normal,” and it is this appeal to the cosmos – derived from the Greek kosmos meaning “order” – that provides, in part, the basis on which to value the current human genetic code. This link to the cosmic is also made in the opening sequence of X-Men in which the following voice-over is heard as we see a ball of light form. This light show is both a reminder of the Big Bang (the supposed beginning of the universe which unleased vast amounts of radiation) and the intertwining of chromosomes seen inside biological nuclei: Mutation, it is the key to our evolution. It has enabled us to evolve from a single celled organism to the dominant species on the planet. This process is slow, normally taking thousands and thousands of years. But every few hundred millennia evolution leaps forward. Whilst mutation may be key to human evolution and the basis for the dramatic narratives of these superhero films, it is also the source of social anxiety. Mutation, whilst derived from the Latin for “change,” has come to take on the connotation of an error or mistake. Richard Dawkins, in his celebrated book The Selfish Gene, compares mutation to “an error corresponding to a single misprinted letter in a book” (31). The language of science is intended to be without the moral overtones that such words as “error” and “misprint” attract. Nevertheless, in the films under consideration, the negative connotations of mutation as error or mistake, are, therefore, the source of the many narrative crises as characters seek to rid themselves of their abilities. Norman Osborn (Willem Dafoe), the villain of Spiderman, is spurred on by his belief that human beings have not achieved their potential, and the implication here is that the presence of physical weakness, illness, and impairment is the supporting evidence. The desire to return the bodies of these superheroes to a “normal” state is best expressed in_ Hulk_, when Banner’s father says: “So you wanna know what’s wrong with him. So you can fix him, cure him, change him.” The link between a mistake in the genetic code and the disablement of the these characters is made explicit when Banner demands from his father an explanation for his transformation into the Hulk – the genetic change is explicitly named a deformity. These films all gesture towards the key question of just what is the normal human genetic code, particularly given the way mutation, as error, is a fundamental tenet in the formation of that code. The films’ focus on extra-ordinary ability can be taken as a sign of the extent of the anxiety about what we might consider normal. Normal is represented, in part, by the supporting characters, named and unnamed, and the narrative turns towards rehabilitating the altered bodies of the main characters. The narratives of social exclusion caused by such radical deviations from the normal human body suggest the lack of a script or language for being able to talk about deviation, except in terms of disability. In Spiderman, Peter Parker (Tobey Maguire) is doubly excluded in the narrative. Beginning as a classic weedy, glasses-wearing, nerdy individual, unable to “get the girl,” he is exposed to numerous acts of humiliation at the commencement of the film. On being bitten by a genetically altered spider, he acquires its speed and agility, and in a moment of “revenge” he confronts one of his tormentors. His super-ability marks him as a social outcast; his tormentors mock him saying “You are a freak” – the emphasis in speech implying that Parker has never left a freakish mode. The film emphasises the physical transformation that occurs after Parker is bitten, by showing his emaciated (and ill) body then cutting to a graphic depiction of genes being spliced into Parker’s DNA. Finally revealing his newly formed, muscular body, the framing provides the visual cues as to the verbal alignment of these bodies – the extraordinary and the impaired bodies are both sources of social disablement. The extreme transformation that occurs to Ben Grimm (Michael Chiklis), in Fantastic 4, can be read as a disability, buying into the long history of the disabled body as freak, and is reinforced by his being named “The Thing.” Socially, facial disfigurement may be regarded as one of the most isolating impairments; for example, films such as The Man without a Face (Mel Gibson, 1993) explicitly explore this theme. As the only character with a pre-existing relationship, Grimm’s social exclusion is reinforced by the rejection of his girlfriend when she sees his face. The isolation in naming Ben Grimm as “The Thing” is also expressed in the naming of Bruce Banner’s (Eric Bana) alter ego “Hulk.” They are grossly enlarged bodies that are seen as grotesque mutations of the “normal” human body – not human, but “thing-like.” The theme of social exclusion is played alongside the idea that those with extra-ordinary ability are also emblematic of the evolutionary dominance of a superior species of which science is an example of human dominance. The Human Genome Project, begun in 1990, and completed in 2003, was in many ways the culmination of a century and a half of work in biochemistry, announcing that science had now completely mapped the human genome: that is, provided the complete sequence of genes on each of the 46 chromosomes in human cells. The announcement of the completed sequencing of the human genome led to, what may be more broadly called, “genomania” in the international press (Lombardo 193). But arguably also, the continued announcements throughout the life of the Project maintained interest in, and raised significant social, legal, and ethical questions about genetics and its use and abuse. I suggest that in these superhero films, whose narratives centre on genetic mutation, that the social exclusion of the characters is based in part on fears about genetics as the source of disability. In these films deviation becomes deviance. It is not my intention to reduce the important political aims of the disability movement by equating the acquisition of super-ability and physical impairment. Rather, I suggest that in the expression of the extraordinary in terms of the genetic within the films, we can detect wider social anxieties about genetic science, particularly as the representations of that science focus the audience’s attention on mutation of the genome. An earlier film, not concerned with superheroes but with the perfectibility of the human body, might prove useful here. Gattaca (Andrew Nicol, 1997), which explores the slippery moral slope of basing the value of the human body in genetic terms (the letters of the title recall the chemicals that structure DNA, abbreviated to G, A, T, C), is a powerful tale of the social consequences of the primacy of genetic perfectibility and reflects the social and ethical issues raised by the Human Genome Project. In a coda to the film, that was not included in the theatrical release, we read: We have now evolved to the point where we can direct our own evolution. Had we acquired this knowledge sooner, the following people may never have been born. The screen then reveals a list of significant people who were either born with or acquired physical or psychological impairments: for example, Abraham Lincoln/Marfan Syndrome, Jackie Joyner-Kersee/Asthma, Emily Dickinson/Manic Depression. The audience is then given the stark reminder of the message of the film: “Of course the other birth that may never have taken place is your own.” The social order of Gattaca is based on “genoism” – discrimination based on one’s genetic profile – which forces characters to either alter or hide their genetic code in order to gain social and economic benefit. The film is an example of what the editors of the special issue of the Florida State University Law Journal on genetics and disability note: how we look at genetic conditions and their relationship to health and disability, or to notions of “normalcy” and “deviance,” is not strictly or even primarily a legal matter. Instead, the issues raised in this context involve ethical considerations and require an understanding of the social contexts in which those issues appear. (Crossley and Shepherd xi) Implicit in these commentators’ concern is the way an ideal body is assumed as the basis from which a deviation in form or ability is measured. These superhero films demonstrate that, in order to talk about super-ability as a deviation from a normal body, they rely on disability scripts as the language of deviation. Scholars in disability studies have identified a variety of ways of talking about disability. The medical model associates impairment or illness with a medical tragedy, something that must be cured. In medical terms an error is any deviation from the norm that needs to be rectified by medical intervention. By contrast, in the social constructivist model, the source of disablement is environmental, political, cultural, or economic factors. Proponents of the social model do not regard impairment as equal to inability (Karpf 80) and argue that the discourses of disability are “inevitably informed by normative beliefs about what it is proper for people’s bodies and minds to be like” (Cumberbatch and Negrine 5). Deviations from the normal body are classification errors, mistakes in social categorisation. In these films aspects of both the medical tragedy and social construction of disability can be detected. These films come at a time when disability remains a site of social and political debate. The return to these superheroes, and their experiences of exclusion, in recent films is an indicator of social anxiety about the functionality of the human body. And as the science of genetics gains increasing public representation, the idea of ability – and disability – that is, what is regarded as “proper” for bodies and minds, is increasingly related to how we regard the genetic code. As the twenty first century began, new insights into the genetic origins of disease and congenital impairments offered the possibility that the previous uncertainty about the provenance of these illnesses and impairments may be eliminated. But new uncertainties have arisen around the value of human bodies in terms of ability and function. This essay has explored the way representations of extra-ordinary ability, as a mutation of the genetic code, trace some of the experiences of disablement. A study of these superhero films suggests that the popular dissemination of genetics has not resulted in an understanding of ability and form as purely bio-chemical, but that thinking about the body as a bio-chemical code occurs within already present moral discourses of the body’s value. References Asch, Adrienne. “Disability Equality and Prenatal Testing: Contradictory or Compatible?” Florida State University Law Review 30.2 (2003): 315-42. Crossley, Mary, and Lois Shepherd. “Genes and Disability: Questions at the Crossroads.” Florida State University Law Review 30.2 (2003): xi-xxiii. Cumberbatch, Guy, and Ralph Negrine. Images of Disability on Television. London: Routledge, 1992. Dawkins, Richard. The Selfish Gene. 30th Anniversary ed. Oxford: Oxford UP, 2006. Karpf, A. “Crippling Images.” Framed: Interrogating Disability in the Media. Eds. A. Pointon and C. Davies. London: British Film Institute, 1997. 79-83. Lombardo, Paul A. “Taking Eugenics Seriously: Three Generations Of ??? Are Enough.” Florida State University Law Review 30.2 (2003): 191-218. “Pop Culture: Out Is In.” Contemporary Sexuality 37.7 (2003): 9. Rutherford, Adam. “Return of the Mutants.” Nature 423.6936 (2003): 119. Sontag, Susan. Illness as Metaphor. London: Penguin, 1988. Turner, Bryan S. Regulating Bodies. London: Routledge, 1992. Vary, Adam B. “Mutant Is the New Gay.” Advocate 23 May 2006: 44-45. Citation reference for this article MLA Style Mantle, Martin. "“Have You Tried Not Being a Mutant?”: Genetic Mutation and the Acquisition of Extra-ordinary Ability." M/C Journal 10.5 (2007). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0710/10-mantle.php>. APA Style Mantle, M. (Oct. 2007) "“Have You Tried Not Being a Mutant?”: Genetic Mutation and the Acquisition of Extra-ordinary Ability," M/C Journal, 10(5). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0710/10-mantle.php>.