High-frequency (20–80 MHz) ultrasound was used to evaluate 77 lymph nodes from 38 patients to identify metastatic breast cancer. Lymph nodes were resected during routine breast conserving surgery. Through-transmission point measurements were collected from the resected nodes immediately following surgery using two single-element transducers (50-MHz center frequency, 6.35-mm diameter), a high-frequency ultrasonic pulser-receiver,and a 1-GHz digital oscilloscope. Attenuation and two spectral parameters—peak density and tortuosity—were calculated from the ultrasonic waveforms and power spectra, respectively. Fisher’s exact test was used to optimize the sensitivity and specificity for each parameter separately and for multivariate analyses. A multivariate analysis of peak density versus tortuosity with a cube-root decision boundary produced the most significant results, with an 89.6% accuracy, 100% sensitivity, 88.4% specificity, and p-value of 6.12 × 10−7. Computer simulations and phantom experiments showed that the sensitivity of the spectral parameters to tissue malignancy arises from ultrasonic Mie scattering from cell nuclei and nuclear pleomorphism. The results demonstrate that ultrasonic spectroscopy at 20–80 MHz provides high sensitivity and specificity for malignant lymph nodes in the breast, and has promise as a rapid, intraoperative, and potentially in vivo diagnostic tool for surgeons and a wide range of soft tissue cancers.

ID 20618 Poster Board 400 Paclitaxel, standard-of-care first-line chemotherapy for epithelial ovarian cancer and triple negative breast cancer, was shown to impair learning and memory functions in >50% of cancer survivors. Underpinning mechanisms of this major neurotoxicity are still mostly unknown, and there are no FDA-approved interventions. We developed a mouse model of paclitaxel-induced cognitive impairment whose cumulative dose is comparable to the total dose per cycle used in breast cancer patients. Paclitaxel-treated mice showed significant cognitive impairment in different hippocampal tests (T-maze, Novel Object Place Recognition test, NOPRT). Learning and memory functions were improved by co-administration of the selective A3 adenosine receptor (A3AR) agonist, MRS5980, without adversely affecting anxiety-like behavior and locomotor activity. Noteworthy, A3AR agonists possess anticancer activity and enhance the antitumor effects of paclitaxel. Moreover, we previously shown that targeting A3AR successfully improved neurocognitive functions after cisplatin, another widely used chemotherapeutic. Our previous studies in chemotherapy-induced peripheral neuropathy showed that Paclitaxel treatment caused a strong neuroinflammation in the central nervous system through the dysregulation of adenosine signaling. Adenosine kinase (ADK) is a key regulator of the adenosine signaling at its receptors. Here we demonstrated that the ADK inhibitor, ABT-702, attenuated paclitaxel-induced cognitive dysfunctions in mice. Mechanistically, these data suggest that paclitaxel-induced ADK dysregulation leads to a reduction of adenosine signaling at the A3AR and it is functionally linked to the development of cognitive dysfunctions. Collectively, the A3AR is emerging as an exciting novel approach in the treatment of a major chemotherapy-induced neurotoxicity. Keywords: Chemotherapy-induced cognitive impairment; A3 Adenosine receptor (A3AR); hippocampus; Paclitaxel; MRS5980. Fundings: This study was funded by the National Institutes of Health Grant RO1CA230512 (NIH) to Daniela Salvemini. Daniela Salvemini is a co-founder of BioIntervene Inc. All other authors claim no conflicts of interest.

Abstract Background Recently approved β-lactamase inhibitor combinations (BLIs), such as ceftazidime-avibactam (CAZ-AVI) and meropenem-vaborbactam (MEM-VAB), have demonstrated a broad spectrum of activity against carbapenem-resistant Enterobacterales (CRE) from US hospitals, but resistance may emerge with the increasing use of these compounds. Aztreonam-avibactam (ATM-AVI) has shown potent activity against CRE, including MBL producers, and is under clinical development. We evaluated the activity of ATM-AVI and comparators against CREs from US hospitals. Methods 45,497 Enterobacterales (ENT) isolates were consecutively collected from 79 US medical centers (36 states) and susceptibility tested by CLSI broth microdilution. ATM-AVI was tested with AVI at a fixed 4 mg/L and a susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. CRE isolates were screened for carbapenemase (CPE) by whole genome sequencing. Results ATM-AVI inhibited > 99.9% of ENT at ≤4 mg/L and only 4 isolates (< 0.01%) showed ATM-AVI MICs > 8 mg/L. CAZ-AVI (MIC50/90, 0.12/0.25 mg/L) and MEM-VAB (MIC50/90, 0.03/0.06 mg/L) were active against 99.9% and 99.8% of ENT isolates, respectively. CRE rates varied from 0.2% (New England [NE]) to 2.4% (Middle Atlantic; Table). ATM-AVI was active (MIC ≤ 8 mg/L) against 99.5% (412/414) of CREs, whereas susceptibility to CAZ-AVI and MEM-VAB were lowest in the Mountain [MO] division (67.7% and 74.2%, respectively) and highest (100.0%) in West North Central. ATM-AVI retained activity against ENT non-S to CAZ-AVI and/or MEM-VAB (n=73; MIC50/90, 0.25/2 mg/L; 98.6% inhibited at ≤8 mg/L). KPC was the most common CPE (65.5% of CREs), followed by NDM (8.2%) and OXA-48–like (3.6%). A CPE gene was not observed in 20.8% of CREs. The occurrence of KPC among CREs varied from 14.3% (1/7; NE) to 77.8% (14/18; East South Central [ESC]); whereas the frequency of metallo-β-lactamases (MBLs) ranged from ≤ 3.0% (South Atlantic, East North Central, ESC and Pacific) to 19.4% (6/31) in MO and 42.9% (3/7) in NE. Conclusion ATM-AVI showed potent activity against CRE, including MBL producers, from all US Census Divisions. Resistance to CAZ-AVI and MEM-VAB among CRE was observed in the NE and MO Census Divisions due to increasing occurrence of MBL-producing isolates. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

Neuropathic pain is a debilitating chronic condition that remains difficult to treat. There is a high priority to identify novel non‐opioid‐based therapeutic targets as long‐term use of opioids is problematic due to its severe side effects and strong abuse potential. Our lab recently discovered G‐protein coupled receptor 160 (GPR160) has a role in neuropathic pain. Gpr160 was upregulated in the dorsal horn of the spinal cord (DH‐SC) on the side of nerve injury relative to the uninjured side in mice. Blocking GPR160 using siRNA or a neutralizing antibody (Ab) reversed and prevented pain hypersensitivity. In addition, our lab deorphanized GPR160 as the receptor for cocaine‐ and amphetamine‐regulated transcript peptide (CARTp). We showed that an intrathecal (i.th.) injection of CARTp in naive mice caused mechano‐hypersensitivity that was dependent on GPR160. CARTp‐induced gene expression is relatively unexplored and the mechanism by which CARTp/GPR160 signaling promotes chronic pain is not well known. Therefore, our objective was to perform an unbiased RNA transcriptomics analysis to identify which genes were altered at the time of CARTp‐mediated peak pain in the DH‐SC. We found that Nucleotide‐binding oligomerization domain‐containing protein 2 (Nod2) expression was increased upon i.th. injection of CARTp and its expression decreased after CARTp was co‐administered with GPR160 Ab, pointing to a potential interaction between CARTp/GPR160 and NOD2. NOD2 is a cytosolic pattern recognition receptor that is involved in activating the immune system in response to pathogens. Moreover, a recent study linked NOD2 to the development of neuropathic pain. This led to our hypothesis that CARTp/GPR160 causes mechano‐hypersensitivity through NOD2 and NOD2 has a functional role in neuropathic pain. C57BL/6 (WT) and NOD2‐/‐ mice received an i.th. injection of CARTp and mechano‐allodynia was assessed. The WT mice developed mechano‐allodynia by 30min and persisted for 5hrs. In contrast, mechano‐allodynia was attenuated for 4hrs in NOD2‐/‐ mice, suggesting CARTp/GPR160 induces mechano‐hypersensitivity through NOD2. Furthermore, we found that NOD2 has a functional role in a chronic constriction injury (CCI) model of neuropathic pain. WT mice started developing mechano‐allodynia on day 3 (D3) after CCI, reached a maximum by D7, and persisted until D14. However, NOD2‐/‐ mice did not develop mechano‐allodynia until D10, indicating that NOD2 is involved in the development of CCI neuropathic pain. Overall, our results provide a potential mechanistic insight on how CARTp causes mechano‐sensitivity and NOD2 has a functional role in CCI‐mediated neuropathic pain.

Abstract Background Resistance to recently approved β-lactamase inhibitor combinations, such as ceftazidime-avibactam (CAZ-AVI) and meropenem-vaborbactam (MEM-VAB), appears to be increasing among carbapenem-resistant Enterobacterales (CRE) in some US hospitals. We evaluated the frequency and antimicrobial susceptibility of Gram-negative bacteria (GNB) causing pneumonia in US hospitals. Methods Bacterial isolates were consecutively collected (1/patient) from patients hospitalized with pneumonia and the susceptibility of GNBs (3,911 Enterobacterales [ENT] and 2,753 non-fermenters) was evaluated by broth microdilution. Isolates were collected in 69 medical centers in 2020–2022. Susceptibility testing was performed by CLSI broth microdilution in a monitoring laboratory. Aztreonam-avibactam (ATM-AVI) was tested with AVI at fixed 4 mg/L and a pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. CRE isolates were screened for carbapenemases (CPE) by whole genome sequencing. Results GNB represented 71.1% of organisms. The most common GNB species were P. aeruginosa (22.4% of organisms), K. pneumoniae (8.6%), E. coli (6.6%), S. marcescens (6.2%), S. maltophilia (4.9%), and E. cloacae complex (4.8%). ATM-AVI inhibited 100.0% of ENT at ≤ 8 mg/L and 99.9% at ≤ 4 mg/L and showed potent activity against CRE (MIC50/90, 0.25/1 mg/L; Table). CAZ-AVI and MEM-VAB were active against 89.4% and 88.5% of CREs, respectively. ATM-AVI retained activity against ENT non-S to CAZ-AVI and/or MEM-VAB (n=19; MIC50/90, 0.25/4 mg/L). The most common CPEs were KPC (69.2% of CREs), NDM (9.6%), and SME (4.8%). A CPE gene was not observed in 16.3% of CREs. CAZ-AVI and MEM-VAB were highly active against KPC and SME producers but showed limited activity against MBL producers. The most active comparators against CRE were tigecycline (95.2%S), amikacin (73.1%S), and gentamicin (60.6%S). Among P. aeruginosa, 79.1% were inhibited at ≤8 mg/L of ATM-AVI, 77.2% were MEM-S, and 77.2% were piperacillin-tazobactam-S. ATM-AVI was highly active against S. maltophilia, inhibiting 99.5% of isolates at ≤ 8 mg/L. Conclusion ATM-AVI demonstrated potent in vitro activity against the GNB most isolated from patients with pneumonia in US hospitals. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

Abstract Background β-lactamase (BL) –producing isolates are widespread and threaten the use of β-lactams. We evaluated the activity of ceftazidime-avibactam (CAZ-AVI) and aztreonam-avibactam (ATM-AVI) and comparators against common BLs detected in US hospitals. Methods A total of 21,853 Enterobacterales (ENT) isolates collected during 2020–2021 were susceptibility (S) tested by reference broth microdilution methods. Isolates submitted to whole genome sequencing were: (1) Escherichia coli (EC; n=1,013) and Klebsiella pneumoniae (KPN; n=621) displaying MIC values ≥ 2 mg/L for at least 2 of the following: ceftazidime, ceftriaxone, aztreonam, or cefepime; (2) Enterobacter cloacae (n=452) and Citrobacter spp. (n=169) displaying MIC values ≥ 16 mg/L for ceftazidime and/or ≥ 2 mg/L for cefepime; and (3) ENT (n=240) displaying elevated carbapenem (meropenem and/or imipenem) MIC results at > 1 mg/L. Results CAZ-AVI inhibited all ESBL-producers (n=1,446; without carbapenemases) including EC, KPN, and isolates producing CTX-M enzymes (Table). Meropenem-vaborbactam (MEV) inhibited 99.8–100% and ceftolozane-tazobactam (CT) inhibited 67–93.6% of these isolates. ATM-AVI inhibited > 99.4% (using an aztreonam alone breakpoint) of the isolates regardless of the ESBL type or organism. Meropenem S rates against ESBLs ranged from 97.8 to 99.7%. Among other classes, amikacin and tigecycline were the most active agents, inhibiting 78.1% and 97.7% of the ESBL-producing isolates. A total of 97.7% of the isolates had intermediate colistin MIC values. All isolates carrying transferrable AmpC genes were S to CAZ-AVI, ATM-AVI, and MEV and 99.1% were susceptible to meropenem, but only 79.1% were S to CT. These included 82 CMY-producers. Among carbapenemase producers (n=165), CAZ-AVI, ATM-AVI, and MEV susceptibility rates were 81.2%, 98.8% and 80.6%. The only comparator displaying activity against these isolates was tigecycline (93.3% susceptible). Conclusion Avibactam combinations were active against common BL-producing isolates from US hospitals, including carbapenemase-producing isolates for which therapeutic options are limited. ATM-AVI was the most active agent against carbapenemase-producers when applying the aztreonam breakpoints for comparison. Disclosures Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

TNP-2198, a stable conjugate of a rifamycin pharmacophore and a nitroimidazole pharmacophore, has been designed, synthesized, and evaluated as a novel dual-targeted antibacterial agent for the treatment of microaerophilic and anaerobic bacterial infections. TNP-2198 exhibits greater activity than a 1:1 molar mixture of the parent drugs and exhibits activity against strains resistant to both rifamycins and nitroimidazoles. A crystal structure of TNP-2198 bound to a Mycobacterium tuberculosis RNA polymerase transcription initiation complex reveals that the rifamycin portion of TNP-2198 binds to the rifamycin binding site on RNAP and the nitroimidazole portion of TNP-2198 interacts directly with the DNA template-strand in the RNAP active-center cleft, forming a hydrogen bond with a base of the DNA template strand. TNP-2198 is currently in Phase 2 clinical development for the treatment of Helicobacter pylori infection, Clostridioides difficile infection, and bacterial vaginosis.

Ceftibuten is an oral cephalosporin approved by the US Food and Drug Administration in 1995 that is in early clinical development to be combined with an oral prodrug of avibactam. We evaluated the activity of ceftibuten-avibactam against molecularly characterized Enterobacterales that produced clinically relevant β-lactamases and assessed the best avibactam concentration to be combined with ceftibuten for susceptibility testing. Resistance mechanisms were evaluated by whole genome sequencing. MIC values were determined by broth microdilution of ceftibuten, avibactam, and ceftibuten combined with fixed concentrations (2, 4, and 8 mg/L) and ratios (1:1 and 2:1) of avibactam. The organism collection (n = 71) included Enterobacterales producing ESBLs, KPC, metallo-β-lactamases, AmpC, K-1, OXA-48, and SME, as well as isolates with porin alterations. The ceftibuten-avibactam combination that best separated isolates with β-lactamases inhibited by avibactam from isolates with resistance mechanisms that are not affected by avibactam was the combination with avibactam at a fixed concentration of 4 mg/L.

Abstract Background The acquisition of mutations is the main driver of β-lactam resistance in Pseudomonas aeruginosa isolates. New BL/BLIs, such as ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C/T), and imipenem-relebactam (IMI-REL), are active against most P. aeruginosa isolates from US hospitals, but the ability of these agents to induce resistance have not been explored. We subjected 8 P. aeruginosa isolates, including ATCC 27853 and 7 clinical isolates, to a 10-day serial passage with 6 antipseudomonal agents to evaluate resistance levels and mechanisms in terminal mutant strains. Fold change in MIC results from parent isolate to terminal mutant Methods Serial passaging was performed in broth microdilution (BMD) for CAZ-AVI, IMI-REL, C/T, meropenem (MEM), cefepime (FEP), and piperacillin-tazobactam (P/T). The MIC of the terminal mutants was determined after 2X passaging on drug-free agar. Parent strains and terminal mutants were subjected to short-read whole genome sequencing (WGS) at 100X coverage. Parent isolates were sequenced using long-read WGS and the data was combined with short-reading sequencing for single nucleotide polymorphism (SNP) analysis. Results Overall, IMI-REL (1- to 4-fold) and CAZ-AVI (2- to 8-fold) displayed lower fold increases in MIC values when compared to other agents tested (Figure). Of the CAZ-AVI terminal mutants, 3 displayed a nalD regulator alteration, and 1 of these had a clpA chaperone missense substitution. FEP terminal mutants exhibited alterations in ampD, mexB, and the TetR family transcriptional regulator AmrR. C/T mutants had ampG and ftsI missense alterations. MEM mutants had nalC, ftsI, and phoP missense alterations. Mutations in merR, nalC, and ampD were observed in the P/T terminal mutants. Among 2 IMI-REL terminal mutants displaying a SNP alteration, 1 displayed a nonsense mutation in pilF, a pilus forming protein. Many terminal mutants displayed alterations in genes not commonly associated to β-lactam resistance. Conclusion MEM, FEP, and P/T terminal mutants displayed high MIC values compared to those obtained after exposure to C/T, CAZ-AVI, and IMI-REL. This data might indicate a benefit of using these newer agents to prevent the emergence of high-level resistance. Disclosures Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Jill Lindley, BS, AbbVie: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support Jessica Ewald, PhD, AbbVie: Grant/Research Support Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support.

Objective: To estimate risk of SARS-CoV-2 infection in pregnancy and assess adverse maternal and perinatal outcomes. Design: A population-based, retrospective cohort. Setting: Florida, USA. Population: All pregnancies with a live birth or fetal death from March 1, 2020 to April 30, 2021. Methods: COVID-19 case reports were matched to vital registries. Modified Poisson and multinomial logistic regression models were used to derive relative risk estimates. Main Outcome Measures: Infection in pregnancy, preterm birth, maternal or neonatal admission to and intensive care unit (ICU), fetal death. Results: Of 234,492 women with a live birth or fetal death during the study period, 12,976 (5.5%) were identified with COVID-19 during pregnancy. Risk factors for COVID-19 in pregnancy included Hispanic ethnicity (relative risk [RR]=1.89), Black race (RR=1.34), being unmarried (RR=1.04), and being overweight or obese pre-pregnancy (RR=1.08-1.32). COVID-19 during pregnancy was associated with preterm birth (RR=1.31), Cesarean delivery (RR=1.04), and neonatal (RR=1.17) and maternal (RR=3.10) ICU admission, but no association was found with increased risk of perinatal (RR=0.72) or fetal death (RR=0.86). Women infected during any trimester showed increased risk of preterm birth compared to women without COVID-19. Thirteen maternal deaths were identified among COVID-19 cases; of those who died, 11 were obese. The death rate was 20.53 per 10,000 among obese and 1.22 per 10,000 among non-obese gravida with COVID-19 during pregnancy (RR=16.88, P=0.001). Conclusions: Obesity is a risk factor for SARS-CoV-2 infection in pregnancy and for more severe COVID-19 illness among pregnant women. SARS-CoV-2 infection is associated with preterm birth.

Due to sporadic transmission, human contact with Rift Valley Fever Virus (RVFV) is difficult to ascertain at a population level. Detection of antibodies against RVFV antigens assist in estimating exposure as antibodies remain in the host long after the virus has been cleared.

Neuropathic pain arises from injuries to the nervous system. It affects 20% of the adult US population and poses a major socioeconomic burden yet remains exceedingly difficult to treat. Current therapeutic approaches have limited efficacy and a large side effect profile that impedes their ability to treat neuropathic pain effectively. Preclinical research over the last 30 yr has established the critical role that pro-inflammatory neuro-immune cell interactions have in the development and maintenance of neuropathic pain arising from various etiologies. Pro-inflammatory neuro-immune cell interactions also underlie the development of adverse side effects of opioids and the loss of their efficacy to treat pain. Evidence from work in our lab and others in preclinical animal models have shown that signaling from the bioactive sphingolipid, sphingosine-1-phosphate (S1P), through the S1P receptor subtype 1 (S1PR1) modulates neuro-immune cell interactions. Here, we discuss how targeting S1P/S1PR1 signaling with S1PR1 antagonists already Food and Drug Administration-approved or in clinical trials for multiple sclerosis can provide a viable pharmacotherapeutic approach to reduce neuro-immune cell inflammatory signaling and potentially treat patients suffering neuropathic pain and the adverse effects of opioids.

Abstract Background CRE isolates are considered a threat to human health. Until recently, the treatment options for CRE were limited. New BL/BLIs, such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MVB), and imipenem-relebactam (IMI-REL), are active against most of these isolates, but these agents display some variation in activity. In this study, we evaluated the activity of these new BL/BLIs and comparator agents against CRE isolates collected in US hospitals. Methods A total of 27,834 Enterobacterales isolates were collected in 74 US hospitals and susceptibility tested by reference broth microdilution methods. CLSI breakpoints were applied. CRE isolates resistant to imipenem or meropenem were submitted to whole genome sequencing and data analysis for the detection of β-lactamases. Results CRE comprised 0.9% (261) of the isolates. An increase in CRE prevalence was noted in 2021 (1.1%) compared to 2019 (0.8%) and 2020 (0.9%; p=0.06). This increase was noted in isolates from bloodstream infections and among patients hospitalized with pneumonia; a slight decrease was observed among urinary tract infections. Among the CREs, an increase in E. cloacae, K. aerogenes, and less common Enterobacterales species was observed. CRE isolates included 8 species in 2019/2020 and 12 species in 2021. Most CRE isolates produced KPC enzymes, mainly KPC-2 and KPC-3, but a decline was noted over time, from 73.8% in 2019 to 67. 5% in 2020 and 54.1% in 2021. Conversely, MBLs increased from 3.8% in 2019 to 18.4% in 2021. MBLs were mainly NDM-1/-5, but also IMP-27 and IMP-4. OXA-48-like enzymes without NDM were detected among 8 isolates. Overall, CAZ-AVI inhibited 86.6% of CRE isolates. When comparing the activity of 3 new BL/BLIs tested against 2021 isolates, CAZ-AVI was active against 78.6% of the CRE isolates whereas MVB inhibited 76.5% and IMI-REL inhibited 73.3%. Conclusion An increase in CREs driven by an increase in MBL-producing isolates was noted in 2021. This increase is worrisome since there are no effective therapeutic options against MBL producers. CAZ-AVI was the most active agent against CREs, but the increase in MBLs should be closely monitored. New therapies against these isolates are urgently needed. Disclosures Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support.

After detection of cases of COVID-19 in Florida in March 2020, the governor declared a state of emergency on March 9,* and all school districts in the state suspended in-person instruction by March 20. Most kindergarten through grade 12 (K-12) public and private schools in Florida reopened for in-person learning during August 2020, with varying options for remote learning offered by school districts. During August 10-December 21, 2020, a total of 63,654 COVID-19 cases were reported in school-aged children; an estimated 60% of these cases were not school-related. Fewer than 1% of registered students were identified as having school-related COVID-19 and <11% of K-12 schools reported outbreaks. District incidences among students correlated with the background disease incidence in the county; resumption of in-person education was not associated with a proportionate increase in COVID-19 among school-aged children. Higher rates among students were observed in smaller districts, districts without mandatory mask-use policies, and districts with a lower proportion of students participating in remote learning. These findings highlight the importance of implementing both community-level and school-based strategies to reduce the spread of COVID-19 and suggest that school reopening can be achieved without resulting in widespread illness among students in K-12 school settings.

A high prevalence of obstructive sleep apnea (OSA) has been reported in Down syndrome (DS) owing to the coexistence of multiple predisposing factors related to its genetic abnormality, posing a challenge for the management of OSA. We hypothesized that DS mice recapitulate craniofacial abnormalities and upper airway obstruction of human DS and can serve as an experimental platform for OSA research. This study, thus, aimed to quantitatively characterize the upper airway as well as craniofacial abnormalities in Dp(16)1Yey (Dp16) mice. Dp16 mice demonstrated craniofacial hypoplasia, especially in the ventral part of the skull and the mandible, and rostrally positioned hyoid. These changes were accompanied with a shorter length and smaller cross-sectional area of the upper airway, resulting in a significantly reduced upper airway volume in Dp16 mice. Our non-invasive approach, a combination of computational fluid dynamics and high-resolution micro-CT imaging, revealed a higher negative pressure inside the airway of Dp16 mice compared to wild-type littermates, showing the potential risk of upper airway collapse. Our study indicated that Dp16 mice can be a useful model to examine the pathophysiology of increased upper airway collapsibility of DS and to evaluate the efficacy of therapeutic interventions for breathing and sleep anomalies.

A major aim in the surgical management of soft tissue cancers is to detect and remove all cancerous tissues while ensuring noncancerous tissue remains intact. Breast-conserving surgery provides a prime illustration of this aim, since remaining cancer in breast margins results in multiple surgeries, while removal of too much unaffected tissue often has undesirable cosmetic effects. Similarly, resection of benign lymph nodes during sentinel lymph node biopsy can cause deleterious health outcomes. The objective of this study was to create an intraoperative, in vivo device to address these challenges. Instant diagnostic information generated by this device could allow surgeons to precisely and completely remove all malignant tissue during the first surgery. Surgical forceps based on Martin forceps were instrumented at the tips with high-frequency ultrasonic transducers composed of polyvinylidene difluoride, a thickness-sensing rotary potentiometer at the base, and a spring to provide the appropriate restoring force. Transducer wires within the forceps were connected to an external high-frequency pulser-receiver, activating the forceps' transmitting transducer at 50 MHz and amplifying through-transmission signals from the receiving transducer. The forceps were tested with tissue-mimicking agarose phantoms embedded with 58-550 mu m polyethylene microspheres to simulate various stages of cancer progression and to provide a range of measurement values. Results were compared with measurements from standard 50 MHz immersion transducers. The results showed that the forceps displayed similar sensitivity for attenuation and increased accuracy for wave speed. The forceps could also be extended to endoscopes and laparoscopes.

Chronic neuropathic pain affects millions of people in the United States today. Opioids are currently the frontline agent for the treatment of neuropathic pain; however, as their use continues to grow, serious side effects can arise including addiction and death. The need for a safer alternative to opioids is becoming increasingly more urgent. GPR183 (Ebstein‐Barr induced gene 2, EBI2) is a G‐protein coupled receptor (GPCR) that binds to 7a,25‐dihydroxycholesterol (7a,25‐OHC). A homology model for GPR183 was constructed and a pharmacophore hypothesis was built around the binding of other known ligands to the receptor. Over 5 million compounds were screened in silico for their similarity to our pharmacophore hypothesis and the top 20k hits were funneled into a high‐throughput docking protocol. Several compounds showed strong inhibition of 7a,25‐OHC calcium mobilization with nanomolar potency. Intrathecal injections of these GPR183 antagonists reversed CCI‐induced mechano‐allodynia in mice when given at peak neuropathic pain. These results identify a prominent and functional role for GPR183 in the spinal cord in the maintenance of neuropathic pain. A preliminary structure‐activity relationship study of one of these compounds is being performed to study the pharmacology and medicinal properties of this new class of compounds.Support or Funding InformationWe would like to acknowledge Dr. Dale Dorsett and the Saint Louis University Genomics Core Facility for their assistance with the RNA‐Sequencing. This research was supported by funds from Dr. Salvemini and Dr. Arnatt and T32 GM008306‐01 training grant (KB). Dr. Salvemini and Dr. Arnatt have filed a patent describing the intellectual property generated at SLU. All other authors claim no conflict of interest.

SUMMARY: Magnetic particle imaging is an emerging tomographic technique with the potential for simultaneous high-resolution, high-sensitivity, and real-time imaging. Magnetic particle imaging is based on the unique behavior of superparamagnetic iron oxide nanoparticles modeled by the Langevin theory, with the ability to track and quantify nanoparticle concentrations without tissue background noise. It is a promising new imaging technique for multiple applications, including vascular and perfusion imaging, oncology imaging, cell tracking, inflammation imaging, and trauma imaging. In particular, many neuroimaging applications may be enabled and enhanced with magnetic particle imaging. In this review, we will provide an overview of magnetic particle imaging principles and implementation, current applications, promising neuroimaging applications, and practical considerations.

In 2007, South Africa (SA) launched a field epidemiology training program (SAFETP) to enhance its capacity to prevent, detect, and respond to public health threats through training in field epidemiology. The SAFETP began as a collaboration between the SA National Department of Health (NDOH), National Institute for Communicable Diseases (NICD), and the University of Pretoria (UP), with technical and financial support from the U.S. Centers for Disease Control and Prevention (CDC). In 2010, the CDC in collaboration with the NICD, established a Global Disease Detection (GDD) Center in SA, and the SAFETP became a core activity of the GDD center. Similar to other FETPs globally, the SAFETP is a 2-year, competency-based, applied epidemiology training program, following an apprenticeship model of learn by doing'. SAFETP residents spend approximately 25% of the training in classroom-based didactic learning activities, and 75% in field activities to attain core competencies in epidemiology, biostatistics, outbreak investigation, scientific communication, surveillance evaluation, teaching others, and public health leadership. Residents earn a Master's in Public Health (MPH) degree from UP upon successfully completing a planned research study that serves as a mini-dissertation.Since 2007, SAFETP has enrolled an average of 10 residents each year and, in 2017, enrolled its 11th cohort. During the first 10years of the program, 98 residents have been enrolled, 89% completed the 2-year program, and of these, 76 (87%) earned an MPH degree. Of those completing the program, 88% are employed in the public health sector, and work at NICD, NDOH, Provincial Health Departments, foreign health institutions, or non-governmental organizations. In the first 10years of the program, the combined outputs of trainees included over 130 outbreak investigations, more than 150 abstracts presented at national and international scientific conferences, more than 80 surveillance system evaluations, and more than 45 manuscripts published in peer-reviewed scientific journals. The SAFETP is having an impact in building epidemiology capacity for public health in South Africa. Developing methods to directly link and measure the impact of the program is planned for the future.

Two high-frequency (10–100 MHz) ultrasound studies were conducted at the Huntsman Cancer Institute (Salt Lake City, Utah) on breast cancer margin and lymph node specimens from 90 patients, and produced sensitivities and specificities as high as 87.5% and 82.9%. The method used through-transmission measurements and a new parameter that correlated not only to malignant versus benign tissue, but also to various breast cancer types and other pathologies. This parameter, peak density, measures the number of peaks in the ultrasonic spectrum. The data indicated that peak density increased successively for atypical pathologies, ductal carcinomas, and lobular carcinomas as compared to normal tissue. Additional correlations were found between the distribution of peaks in the spectra and the above pathologies. This study’s objective was to test the hypothesis that peak density measures the nuclear diameter of the cells in the tested tissue. A computer model of Mie scattering from a single, nucleated cell was used to calculate ultrasonic spectral peaks in the 10-100 MHz band as a function of nuclear diameter. Experiments were also conducted with agarose tissue phantoms containing polyethylene microspheres having diameters of 10-102 μm. The model and phantom results confirmed the hypothesis that peak density directly correlates to nuclear diameter.