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Background Sotrovimab is a human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike (S) protein. COMET-PEAK was a 3-part, phase 2 study that evaluated intravenous (500 mg) and intramuscular (500 mg and 250 mg) administration of sotrovimab in outpatients (n=353) with mild-to-moderate COVID-19. We assessed amino acid substitutions in the SARS-CoV-2 S protein and circulating variants of concern/interest (VOC/VOI) in COMET-PEAK participants (enrolled Feb–July 2021). Methods Mid-turbinate (Part A) or nasopharyngeal (Part B/C) samples were obtained from all participants at Baseline and Post-Baseline visits. Next generation sequencing of the SARS-CoV-2 S gene was conducted using Illumina MiSeq with a ≥5% allelic frequency cut-off for samples with a viral load above 3.0 log10 copies/mL. Baseline, post-baseline and treatment-emergent (TE) substitutions were assessed, and prevalence of VOC/VOI was evaluated. Phenotypic analyses of epitope substitutions were conducted using a pseudotyped virus assay. Results In total, 282/353 participants had sequencing results for ≥1 visit (253 baseline, 248 post-baseline), and 219 had paired baseline and post-baseline sequences; among these, 149 (68%) had TE substitutions in the S protein (26 [12%] in the epitope). E340K was the predominant TE substitution in the epitope (15 [7%]). Across all arms 92/245 (38%) experienced virologic rebound, 8 of whom (Part A: 2; Part B: 2; Part C: 4) had TE substitutions in the epitope; none had evidence of clinical progression to severe disease. Prevalence of VOC/VOI or single amino acid substitutions of concern was 94% (266/282); the most frequent were Alpha (Part A: 8/16 [50%]; Part B: 75/128 [59%]) and Delta (Part C: 99/122 [81%]). Of 7 participants with evidence of clinical progression, none had S protein substitutions in the epitope and all had VOC/VOI (3 Alpha, 3 Delta, 1 Gamma). Sotrovimab effectively neutralized most epitope substitutions tested in vitro; P337L and E340A/K/V conferred significantly reduced susceptibility. Conclusion There was no evidence that sotrovimab epitope substitutions were associated with clinical progression or virologic rebound. These data are consistent with those from the COMET-ICE study. Funding Vir Biotechnology/GSK (NCT04779879). Disclosures Phillip J Yates, PhD, GlaxoSmithKline: Employee Jennifer Moore, MD, GlaxoSmithKline: Employee Jennifer Han, MD, GlaxoSmithKline: Employee Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Jill Walker, PhD, GlaxoSmithKline: Employee.

Background There is a continued need for therapeutics for the treatment of COVID-19, including intramuscular (IM) agents, which will enable broader use across a variety of healthcare delivery settings. Methods COMET-PEAK (NCT04779879) is a 3-part study evaluating the safety, tolerability, pharmacokinetics (Part A), and viral pharmacodynamics (PD) of sotrovimab as treatment in adults ≥ 18 years with early mild/moderate COVID-19. In Parts B and C, the safety, tolerability and viral PD of sotrovimab administered as a 500 mg intravenous (IV) infusion or as a 500 mg or 250 mg IM injection, respectively, was evaluated. The primary objective for Parts B and C was to compare the virologic response of sotrovimab IM to IV, with an endpoint of mean area under the curve (AUC) of SARS-CoV-2 viral load as measured by qRT-PCR from Day 1 to Day 8 (AUCD1-8) in nasopharyngeal swabs and predefined 90% confidence interval (CI) limits of 0.5-2.0 indicating equivalence. Results A total of 167 and 157 participants were enrolled in Part B and C, respectively, from February-July 2021. The median age of participants was 47 and 42 years in Part B and C, respectively, and ∼50% had ≥ 1 risk factor for progression to severe disease. The viral load at baseline and through Day 29 of follow-up for each arm is shown in Table 1 and Figure 1. The primary objective was met for both study parts: the ratio of the least square geometric mean viral load AUC(D1-8) of sotrovimab IM vs IV was 1.04 (90% CI, 0.98, 1.09) and 1.02 (90% CI, 0.94, 1.11), for Part B and C, respectively. Through Day 29 of follow-up, the most common adverse event was injection site reactions (ISRs) in the IM arms. A total of 10 (12%) participants in the 500 mg IM group and 4 (5%) participants in the 250 mg IM group experienced an ISR, all Grade 1. Serious adverse events were uncommon, and related to COVID-19 progression, including one death in the 250 mg IM arm (Table 2). ISRs aside, there were few treatment-related AEs (2/84 IV, 1/82 IM) in Part B, none serious. Conclusion IM administration of sotrovimab 500 mg and 250 mg each demonstrated equivalence to 500 mg sotrovimab IV in viral load assessments. Overall, there were no treatment-related serious AEs and sotrovimab was well tolerated. An 500 mg IM formulation will allow for expanded treatment potential with sotrovimab. Funding Vir/GSK (NCT04779879). Disclosures Anil K. Gupta, MD, Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support|Vir Biotechnology: Speaker Moti Ramgopal, MD, FACP, FIDSA, AbbVie: Grant/Research Support|Gilead Sciences Inc.: Advisor/Consultant|Gilead Sciences Inc.: Grant/Research Support|Gilead Sciences Inc.: Honoraria|Gilead Sciences Inc.: Stocks/Bonds|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|GlaxoSmithKline: Honoraria|GlaxoSmithKline: Stocks/Bonds|Janssen Research & Development LLC: Advisor/Consultant|Janssen Research & Development LLC: Grant/Research Support|Janssen Research & Development LLC: Honoraria|Janssen Research & Development LLC: Stocks/Bonds|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Merck: Stocks/Bonds|Shionogi: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Jennifer Han, MD, GlaxoSmithKline: Employee Jennifer Moore, MD, GlaxoSmithKline: Employee Rudrani Banerjee, PhD, GSK: Employee|GSK: Stocks/Bonds Phillip Yates, PhD, GSK: Employee during conduct of this research|GSK: Stocks/Bonds Jill Walker, PhD, GlaxoSmithKline: Employee Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Mary Beth Connolly, PharmD, GSK: Employee|GSK: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Varsha Imber, MSc, GSK: Employee|GSK: Stocks/Bonds Rabia Anselm, n/a, GSK: Employee|GSK: Stocks/Bonds Lindsay Winograd, MSc, GSK: Employee|GSK: Stocks/Bonds Nancy Haeusser, n/a, GSK: Employee|GSK: Stocks/Bonds Scott Segal, MD, GSK: Employee|GSK: Stocks/Bonds Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds.

BACKGROUND: Due to the ongoing opioid epidemic in the United States, deceased organ donors increasingly have a history of injection drug use (IDU), raising concerns about infectious risks to solid organ transplant (SOT) recipients. We sought to determine how recent IDU among deceased organ donors impacted donor culture results and recipient outcomes. METHODS: A retrospective cohort study was performed at three transplant centers. Exposed donors were those with “recent IDU” (in the prior 12 months). Primary outcomes included (1) positive donor cultures for bacteria or Candida species, (2) recipient bacterial or Candida infection within 3 months posttransplant, and (3) recipient graft failure or death within 12 months posttransplant. Mixed effects multivariable regression models were used to evaluate the relationship between recent donor IDU and each outcome. RESULTS: A total of 658 SOT recipients who received organs from 394 donors were included. Sixty-six (17%) donors had a history of recent IDU. Recent IDU in donors was associated with a significantly increased odds of donor culture positivity (aOR 3.65, 95% CI 1.06–12.60, p = .04) but was not associated with SOT recipient infection (aHR 0.98, 95% CI 0.71–1.36, p = .92) or graft failure or death (aHR 0.67, 95% CI 0.29–1.51, p = .33). CONCLUSION: Donors with recent IDU are more likely to have positive cultures, but their recipients’ outcomes are unaffected, suggesting organs from donors with recent IDU may be safely utilized.

Introduction Mild parkinsonian signs (MPS) are associated with morbidity. Identification of MPS progression markers may be vital for preventive management, yet has not been pursued. This study aimed to ascertain clinical/neuroimaging features predictive of MPS progression. Methods 205 participants in the Health ABC Study were included. MPS was defined using published guidelines. MPS progression was evaluated by determining UPDRS-III change between baseline and follow-up ≥2 years later. Standard brain MRI and DTI were obtained at baseline. Correlation coefficients between demographics, vascular risk factors, imaging markers, and UPDRS-III change were adjusted for follow-up time. Linear regression was used to adjust for possible confounders in the relationship between imaging markers and MPS progression. Results 30% of participants had baseline MPS. Demographics and risk factors did not differ significantly between participants with MPS (MPS+) and without MPS (MPS-). Mean follow-up time was 3.8±0.8 years. Older age, male gender, diabetes were associated with faster rate of UPDRS-III change in MPS- but not MPS+ participants. Among MPS- participants, the only imaging marker associated with faster UPDRS-III progression was higher gray matter mean diffusivity (MD), widespread in various cortico-subcortical bihemispheric regions, independent of age, gender, diabetes. No imaging features were associated with UPDRS-III change among MPS+ participants. Conclusions Lower gray matter integrity predicted MPS progression in those who did not have baseline MPS. Microstructural imaging may capture early changes related to MPS development, prior to macrostructural change. Any future management promoting gray matter preservation may inhibit MPS development.

Intro: IV-tPA was approved for the treatment of acute ischemic stroke in 1996. IV-tPA administration in the setting of trauma can propagate hemorrhagic complications, such as Disseminated Intravascular Coagulation, which can be difficult to reverse especially in the elderly. Robust data on outcomes in patients with undiagnosed traumatic fracture receiving IV-tPA for acute ischemic stroke is lacking. Our study investigates the safety of IV-tPA in patients with occult trauma. Methods: We reviewed our database over a three-year period, August 2018 to August 2021, for complications of reperfusion therapy as defined and reported to GWTG registry. These charts were retrospectively reviewed for patients who were determined to have presented with acute traumatic fracture. Results: IV-tPA was administered 329 times. 18 total hemorrhagic complications were discovered. Four of these patients presented with occult acute traumatic fracture - three had rib fractures; one had pelvic fracture. Hypovolemic shock was attributed to the respective traumatic fracture in all cases. All required blood products and intravenous fluid resuscitation. Three patients underwent invasive treatment in an attempt to abort or alleviate hemorrhagic complication including intercostal artery embolization, video-assisted thoracoscopic surgery, thoracentesis, and internal iliac artery branch embolization. Two patients developed a severe consumptive coagulopathy and suffered in-hospital death. All four patients were elderly, age range 83-90, median 87.5. All had presented with Emergent Large Vessel Occlusion (ELVO) and underwent Mechanical Thrombectomy (MT). Conclusion: Elderly patients with occult trauma may be at high-risk for serious hemorrhagic complication after receiving IV-tPA. Our findings suggest increased caution in administering IV-tPA to elderly with stigmata of trauma who may have underlying traumatic fracture. Our findings are relevant as alternatives to IV-tPA become available and as rapid advanced imaging enables individualized precision medicine - in elderly patients presenting with concomitant trauma and ELVO who are candidates for MT, the risk versus benefit of IV-tPA may be questioned. Larger studies are needed to validate our findings.

Lithium (Li) carbonate has been established as a mood stabilizer and an efficacious treatment for bipolar disorder since its discovery by Dr. John Cade in 1948. Li interacts significantly with organ systems and endocrine pathways. One of the most challenging side effects of Li to manage is its effect on the parathyroid glands. Dysregulation of parathyroid signaling due to Li results in hypercalcemia due to increased vitamin D3 generation, increased calcium absorption from the gut, and bone resorption, occasionally resulting in concomitant hypercalciuria. However, hypercalciuria is not a definitive feature for hyperparathyroidism, and normal calcium excretion might be seen in these patients. Hypercalcemia may also result from volume contraction and decreased renal clearance, which are commonly seen in these patients. Anatomically the parathyroid abnormalities can present as single or multiglandular disease. We report 3 cases where the patients developed multiple side effects of Li therapy as well as hypercalcemia due to hyperparathyroidism. The literature is reviewed with regard to medical and surgical management of Li-associated hyperparathyroidism in the context of these 3 presented cases.

Entomopathogenic fungi show great promise as pesticides in terms of their relatively high target specificity, low non-target toxicity, and low residual effects in agricultural fields and the environment. However, they also frequently have characteristics that limit their use, especially concerning tolerances to temperature, ultraviolet radiation, or other abiotic factors. The devastating ectoparasite of honey bees, Varroa destructor, is susceptible to entomopathogenic fungi, but the relatively warm temperatures inside honey bee hives have prevented these fungi from becoming effective control measures. Using a combination of traditional selection and directed evolution techniques developed for this system, new strains of Metarhizium brunneum were created that survived, germinated, and grew better at bee hive temperatures (35 °C). Field tests with full-sized honey bee colonies confirmed that the new strain JH1078 is more virulent against Varroa mites and controls the pest comparable to current treatments. These results indicate that entomopathogenic fungi are evolutionarily labile and capable of playing a larger role in modern pest management practices.

Background Colistin resistance in CRKP presents a serious clinical challenge for patients of LTACHs. However, risk factors for colistin-resistant CRKP have not been previously characterized in this population. Here, we determined risk factors for colistin resistance among CRKP isolates from a network of LTACHs. Methods CRKP clinical cultures were collected from 21 Kindred Healthcare LTACHs in 4 US states (California, Texas, Florida, Kentucky) from 8/1/14-7/25/15. Cultures collected within 30 days of a prior CRKP culture from the same patient were excluded. Colistin resistance (minimum inhibitory concentration ≥4) was determined using a custom SensititreTM broth microdilution assay (ThermoFisher Scientific, Waltham, MA). Multivariate logistic regression was performed to evaluate candidate risk factors of age, sex, cirrhosis, chronic kidney disease, culture source, length of stay, indwelling line or tracheostomy, and antibiotic exposure (colistin, fluoroquinolones, 3rd-5th generation cephalosporins, piperacillin-tazobactam, carbapenems, and aminoglycosides) for ≥48 hours in the prior 30 days. Results Among 430 CRKP cultures (237 respiratory, 145 urine, 38 blood, 10 wound) from 375 patients, 144 (33.5%) were colistin-resistant. In multivariate analysis, colistin resistance was associated with prior colistin exposure (odds ratio [OR] = 5.9, 95% CI = 2.5-14.0) and culture source (Wald test for joint significance, p=0.03), with higher odds of colistin resistance among respiratory (OR = 2.9, 95% CI = 1.2-7.2), urine (OR = 1.6, 95% CI = 0.7-4.1), or wound (OR = 2.2, 95% CI = 0.4-11.5) compared to blood cultures. Conclusion In this sample of CRKP from LTACHs, colistin resistance was associated with prior colistin exposure and respiratory culture source. Other patient factors such as co-morbidities, indwelling devices or tracheostomy, or exposure to other antibiotics/antibiotic classes were not associated with colistin resistance in CRKP. These findings will help inform strategies to reduce colistin resistance and identify LTACH patients at risk of colistin-resistant CRKP. Disclosures Jennifer Han, MD, MSCE, GlaxoSmithKline (Employee, Shareholder) Ebbing Lautenbach, MD, MPH, MSCE, Merck (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB))

Background Multidrug-resistant (MDR) Gram-negative (GN) bloodstream infections (BSI) are a major cause of morbidity and mortality among solid organ transplant recipients (SOTR). We determined risk factors associated with subsequent MDR-GN BSI following an initial Enterobacterales (EB) BSI among SOTRs. Methods A retrospective cohort study was performed. All SOTR with an EB BSI at the Hospital of the University of Pennsylvania and University of Maryland Medical Center between 1 Jan 2007 and 30 June 2018 and The Johns Hopkins Hospital between 1 Jan 2005 and 31 Dec 2015 were included. The primary outcome was any MDR-GN BSI within 60 days of the EB BSI, including MDR-EB (defined by ceftriaxone MIC ≥8μg/mL), and MDR-Pseudomonas and Acinetobacter (defined by resistance to three or more antibiotic classes). Unadjusted analyses were performed to identify possible risk factors, using a Fisher’s exact or χ 2 test for categorical and Student’s t-test for continuous variables. Results Of 988 SOTR with an EB BSI, 138 (14%) had a MDR-GN BSI within 60 days. In unadjusted analyses, possible risk factors for a subsequent MDR-GN BSI (Table 1) included: (1) an index BSI due to extended-spectrum beta-lactamase (ESBL)-producing EB (compared to a susceptible index EB BSI); (2) a carbapenem-resistant EB (CRE) index BSI (compared to a susceptible index EB BSI); (3) exposure to piperacillin-tazobactam or carbapenems in the 6 months prior to the index EB BSI; (4) prior liver transplantation; and (5) need for reoperation within four weeks of the original transplantation. There was no significant association between recurrent MDR-GN BSI and immunosuppression at time of infection, induction immunosuppression history, acute rejection history, or primary graft dysfunction. Table 1. Risk factors for subsequent MDR-GN BSI following EB BSI among SOTR. Data are presented as numbers (percentages) except where noted. Abbreviations: BSI, bloodstream infection; CRE, carbapenem-resistant Enterobacterales; EB, Enterobacterales; ESBL, extended-spectrum beta-lactamase; GN, Gram-negative; IQR, interquartile range; MDR, multidrug-resistant Conclusion This study shows that liver transplantation, reoperation following transplantation, an index ESBL-EB or CRE BSI, and recent exposure to broad-spectrum beta-lactam antibiotics are associated with an increased odds of subsequent MDR-GN BSI in SOTR, and underscores the need for future studies aimed at preventing emergence of MDR-GN infections in this vulnerable population. Disclosures Jennifer Han, MD, MSCE, GlaxoSmithKline (Employee, Shareholder) Ebbing Lautenbach, MD, MPH, MSCE, Merck (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB)) Pranita Tamma, MD, MHS, Nothing to disclose Emily Blumberg, MD, Amplyx (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB))Hologic (Research Grant or Support)Merck (Grant/Research Support, Other Financial or Material Support, Member of Scientific Advisory Committee)Takeda (Research Grant or Support, Other Financial or Material Support, Member of Scientific Advisory Committee) Judith A. Anesi, MD, MSCE, Nothing to disclose

Purpose Descriptions of large series of accessory atrioventricular pathway (AP) ablations in adults and adolescents have been limited to referral centers and published over 20 years ago. We aimed to characterize contemporary accessory AP distribution and features in a large community-based population that influence ablation outcomes. Methods Retrospective analysis of 289 patients (age 14–81) who underwent AP ablation from 2015–2019 was performed. Pathways were categorized into anteroseptal (AS), left freewall (LFW), posteroseptal (PS), and right freewall (RFW) locations. We analyzed patient and pathway features to identify factors associated with prolonged procedure time parameters. Results Initial ablation success rate was 94.7% with long-term success rate of 93.4% and median follow-up of 931 days. APs were in LFW (61.6%), PS (24.6%), RFW (9.6%), and AS (4.3%) locations. Procedure outcome was dependent on pathway location. Acute success was highest for LFW pathways (97.1%) with lowest case times (144 ± 68 minutes) and fluoroscopy times (15 ± 19 minutes). Longest procedure time parameters were seen with AS, left anterolateral, epicardial-coronary sinus, and right anterolateral pathway ablations. A novel ECG algorithm was developed to predicts AP locations and further guide procedure planning. Conclusion In this community-based population, majority of APs are located in the left freewall and posteroseptal region, with only retrograde conduction, and can be ablated using traditional approaches with short time parameters and high success. Using a novel ECG algorithm for pathway localization, we can predict cases with longer procedure times, higher fluoroscopy exposure, and lower acute and long-term success for manifest pathways.

Sex chromosome evolution results in the disparity in gene content between heterogametic sex chromosomes and creates the need for dosage compensation to counteract the effects of gene dose imbalance of sex chromosomes in males and females. It is not known at which stage of sex chromosome evolution dosage compensation would evolve. We used global gene expression profiling in male and female papayas to assess gene expression patterns of sex-linked genes on the papaya sex chromosomes. By analyzing expression ratios of sex-linked genes to autosomal genes and sex-linked genes in males relative to females, our results showed that dosage compensation was regulated on a gene-by-gene level rather than whole sex-linked region in papaya. Seven genes on the papaya X chromosome exhibited dosage compensation. We further compared gene expression ratios in the two evolutionary strata. Y alleles in the older evolutionary stratum showed reduced expression compared to X alleles, while Y alleles in the younger evolutionary stratum showed elevated expression compared to X alleles. Reduced expression of Y alleles in the older evolutionary stratum might be caused by accumulation of deleterious mutations in regulatory regions or transposable element-mediated methylation spreading. Most X-hemizygous genes exhibited either no or very low expression, suggesting that gene silencing might play a role in maintaining transcriptional balance between females and males.

Modern sugarcanes are polyploid interspecific hybrids, combining high sugar content from Saccharum officinarum with hardiness, disease resistance and ratooning of Saccharum spontaneum. Sequencing of a haploid S. spontaneum, AP85-441, facilitated the assembly of 32 pseudo-chromosomes comprising 8 homologous groups of 4 members each, bearing 35,525 genes with alleles defined. The reduction of basic chromosome number from 10 to 8 in S. spontaneum was caused by fissions of 2 ancestral chromosomes followed by translocations to 4 chromosomes. Surprisingly, 80% of nucleotide binding site-encoding genes associated with disease resistance are located in 4 rearranged chromosomes and 51% of those in rearranged regions. Resequencing of 64 S. spontaneum genomes identified balancing selection in rearranged regions, maintaining their diversity. Introgressed S. spontaneum chromosomes in modern sugarcanes are randomly distributed in AP85-441 genome, indicating random recombination among homologs in different S. spontaneum accessions. The allele-defined Saccharum genome offers new knowledge and resources to accelerate sugarcane improvement.

Background With the ongoing opioid epidemic in the US, there has been an increase in the proportion of deceased organ donors with a history of injection drug use (IDU), raising concern for additional infectious risks to transplantation.We sought to determine how recent IDU among deceased organ donors impacted donor culture results. Methods A retrospective cohort study was conducted at four transplant centers in Philadelphia between 1/1/2015 and 6/30/2016. All deceased organ donors who donated ≥ 1 organ to one of the centers were included. Exposed donors were those with a recent history of IDU (defined by use in the prior 12 months based on donor chart review). Unexposed donors were those with no recent history of IDU. The primary outcome was any positive donor culture (taken during the terminal hospitalization or at the time of organ procurement) for bacteria or Candida. Multivariable logistic regression was used to determine the association between recent IDU and donor culture positivity. Secondarily, the association between donor IDU and isolation of (1) a multidrug-resistant organism (MDRO) on culture, (2) Staphylococcus aureus on culture, (3) Candida on non-respiratory culture, and (4) bacteria or Candida on blood culture were determined. Results Of 394 total donors, 66 (17%) had a history of recent IDU and 343 (87%) had at least one positive donor culture. On multivariable analysis, recent IDU was associated with significantly increased odds of having at least one positive donor culture (aOR 3.6, 95% CI 1.1-11.9, P=0.04) and Candida on non-respiratory culture (aOR 2.6, 95% CI 1.1-6.2, P=0.03). However, recent IDU was not significantly associated with increased odds of MDRO on culture (OR 0.90, 95% CI 0.41-1.93, P=0.79), S. aureus on culture (OR 1.35, 95% CI 0.79-2.28, P=0.27), or positive blood culture (OR 0.79, 95% CI 0.32-1.95, P=0.60). Conclusion Donors with a recent history of IDU are more likely to have bacteria or Candida identified on cultures taken during their terminal hospitalization or at organ procurement. This increase does not appear to be driven by MDROs, S. aureus, or bloodstream infections but rather by Candida isolated from non-respiratory sites, potentially alleviating some fears surrounding the acceptance of solid organs from donors with a history of recent IDU. Disclosures Ebbing Lautenbach, MD, MPH, MSCE, Merck (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB)) Emily Blumberg, MD, Amplyx (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB))Hologic (Research Grant or Support)Merck (Grant/Research Support, Other Financial or Material Support, Member of Scientific Advisory Committee)Takeda (Research Grant or Support, Other Financial or Material Support, Member of Scientific Advisory Committee) Jennifer Han, MD, MSCE, GlaxoSmithKline (Employee, Shareholder) Judith A. Anesi, MD, MSCE, Nothing to disclose

Background CRKP infection is common among LTACH patients. However, CRKP antimicrobial susceptibility testing (AST) with newer antibiotics has not been described in this population. In this study, we performed AST on CRKP in LTACHs. Methods CRKP clinical cultures were collected from 21 Kindred Healthcare LTACHs (12 southern California, 6 Texas, 2 Florida, 1 Kentucky) from 8/1/14-7/25/15. AST was performed using a custom SensititreTM broth microdilution panel (ThermoFisher Scientific, Waltham, MA). 2021 Clinical & Laboratory Standards Institute interpretive criteria were used for all agents except plazomicin (PLZ), for which US Food and Drug Administration breakpoints were used. Results 459 CRKP clinical isolates were collected, including 254 (55.5%) respiratory, 155 (33.8%) urine, 39 (8.5%) blood, and 10 (2.2%) wound cultures. Most (419, 91.0%) were from southern California. 151 (32.9%) were colistin-resistant. 42 (9.2%) isolates were non-susceptible to meropenem-vaborbactam (MVB), 16 (8.9%) to imipenem-relebactam (IPR), 4 (0.9%) to ceftazidime-avibactam (CZA), and 3 (0.7%) to PLZ. Cross-resistance patterns are shown in Table 1. Among southern California facilities, there was significant inter-facility variation in MVB non-susceptibility (Pearson’s chi-squared test, p=0.005) but not in CZA, IPR, or PLZ non-susceptibility. Table 1. Cross-resistance to antimicrobials among carbapenem-resistant Klebsiella pneumoniae isolates from 21 Kindred long-term acute care facilities, August 1, 2014 – July 25, 2015 (N=459). Number of isolates and column percentages reported. 2021 Clinical & Laboratory Standards Institute interpretive criteria are used for all agents except for PLZ, for which US Food and Drug Administration breakpoints are used. Abbreviations: CST = colistin. CZA = ceftazidime-avibactam. I = intermediate. IPR = imipenem-relebactam. MIC = minimum inhibitory concentration. MVB = meropenem-vaborbactam. PLZ = plazomicin. R = resistant. S = susceptible. Conclusion In this sample of CRKP isolates from LTACHs in 2014-2015, nearly 10% of isolates were non-susceptible to MVB or IPR, respectively, despite neither agent being commercially available at the time. In contrast, there was a low prevalence of non-susceptibility to CZA, which received initial US Food and Drug Association approval in 2/2015, and PLZ, which was not commercially available during the study period. Cross-resistance between CZA and carbapenem/beta-lactamase combination antibiotics was uncommon. Future studies should evaluate CRKP susceptibilities to new agents in post-marketing cohorts and identify risk factors for resistance. Disclosures Jennifer Han, MD, MSCE, GlaxoSmithKline (Employee, Shareholder) Ebbing Lautenbach, MD, MPH, MSCE, Merck (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB))

Background: Treatment options, together with guidelines, for pts with CLL have evolved and expanded with the introduction of novel agents. The informCLLTM registry is the largest US-based prospective, observational registry of pts who received treatment for CLL/SLL in the post-novel agent era. This prospective real-world registry is uniquely positioned to examine the impact of the dynamic treatment landscape, treatment practices, and outcomes in routine clinical setting. Here we present baseline characteristics, prognostic biomarker testing, and treatment patterns for the fully enrolled pt population. Methods: From Oct 2015 to June 2019, informCLL (PCYC-1134; NCT02582879) enrolled eligible pts with CLL/SLL who were ≥18 years (y), initiated FDA-approved treatment for CLL/SLL within ±45 days of enrollment and provided consent. Pts were classified into 5 groups based on treatment received at enrollment (index): ibrutinib (single agent or combination), chemoimmunotherapy (CIT), chemotherapy (CT), immunotherapy (IT), and other novel agents. Descriptive analyses are presented. Results: The registry fully enrolled with 1461 pts: 855 (59%) previously untreated and 606 (41%) relapsed/refractory (R/R) pts. Community-based practices enrolled 93% of pts. The median age was 71 y (33% ≥75 y), the majority were male (64%), and 88% had ECOG performance status of 0/1. For pts with staging performed at enrollment (n=852), 51% had Rai stage III/IV. Median (range) time from diagnosis to initial treatment on study was 18.6 months (mos, FISH testing was performed in 28% (n=415) of pts and was more frequent in previously untreated vs R/R pts (33% vs 21%). TP53 mutation testing was performed in 11% (n=162) of pts (previously untreated: 13%; R/R: 9%). IGHV mutational status testing was performed in 12% (n=171) of pts (previously untreated: 13%; R/R 10%). Of pts with prognostic biomarker testing, 24% (100/415) had del(17p), 27% (43/162) had TP53 mutation, and 71% (121/171) had unmutated IGHV. Prognostic biomarker testing by treatment group is shown in Figure 1. Table 1 shows the distribution of pts receiving different treatments on study. Across lines of therapy, the most common treatment was ibrutinib (46%); the majority (87%) started ibrutinib treatment at the recommended daily dose of 420 mg, and pts continuing ibrutinib therapy largely did not require dose modifications (75%). At 12 or 24 mos, 77% (307/401) and 68% (126/184) of pts continued on ibrutinib treatment, respectively. For pts who completed the most common CIT regimens (bendamustine + rituximab [BR] and fludarabine + cyclophosphamide + rituximab), 80% and 85%, respectively, received Conclusions: The informCLL registry provides an opportunity to prospectively assess CLL treatment patterns in the era of novel agents. The most common index treatment was ibrutinib and the majority of ibrutinib-treated pts remained on therapy at 2 y follow-up; CIT (primarily BR) was also used for one-third of patients. Prognostic biomarker testing rates were poor, especially for TP53 and IGHV mutational status. Data from informCLL also indicate a 'knowledge gap' in terms of prognostic marker testing and selection of therapies for pts with high-risk disease. Data from the now complete pt population and with continued follow up will allow for the ongoing evaluation of real-world treatment decisions and pt care that cannot be addressed by data from randomized clinical trials. Disclosures Mato: Janssen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding. Barrientos:Janssen: Honoraria; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Brander:BeiGene: Other, Research Funding; MEI Pharma: Other, Research Funding; DTRM: Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Ascentage: Other, Research Funding; Teva: Consultancy, Honoraria; Tolero: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding. Kadish:Bluebird Bio: Current equity holder in publicly-traded company; Blueprint Medicines: Current equity holder in publicly-traded company; Teva Pharmaceutical: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Editas Medicine: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; Sarepta Therapeutics: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company, Speakers Bureau; Takeda: Speakers Bureau. Arango-Hisijara:Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Upasani:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment; Protagonist Therapeutics: Current Employment. Han:Johnson and Johnson: Current equity holder in publicly-traded company; Janssen: Current Employment, Other: Travel expenses. Huang:Janssen Scientific Affairs, LLC: Current Employment; Johnson & Johnson: Current equity holder in publicly-traded company. Iyengar:Express Scripts: Patents & Royalties; AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Ghosh:Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding.

informCLL is the first United States-based registry of patients with chronic lymphocytic leukemia that initiated enrollment after approval of novel targeted agents. Prognostic/predictive testing rates and chronic lymphocytic leukemia treatment selection with availability of novel agents have not been previously investigated in clinical practice. Results from this interim analysis demonstrate that prognostic/predictive testing was infrequently used to guide treatment selection, potentially inhibiting beneficial outcomes for patients. Introduction: The therapeutic landscape for chronic lymphocytic leukemia (CLL) has significantly shifted with the approval of novel agents. Understanding current prognostic testing and treatment practices in this new era is critical. Beginning enrollment in 2015, informCLL is the first United States-based real-world, prospective, observational registry that initiated enrollment after approval of novel agents. Patients and Methods: Eligible patients were age ≥ 18 years, started CLL treatment within 30 days of enrollment, and provided consent. For this planned interim analysis, treatments were classified into 5 groups: ibrutinib, chemoimmunotherapy, chemotherapy, immunotherapy, and other novel agents. Results: Frequency of prognostic testing and treatment patterns are reported among 840 patients (459 previously untreated; 381 relapsed/refractory), enrolled largely (96%) from community practice settings. Testing for chromosomal abnormalities by fluorescence in situ hybridization, TP53 mutation, or IGHV mutation status occurred infrequently among all patients (31%, 11%, and 11%, respectively). Chemoimmunotherapy was the most common treatment in previously untreated patients (42%), whereas ibrutinib was the most common treatment among relapsed/ refractory patients (51%). Of patients who tested positive for del(17p) or TP53 mutation, 34% and 26% received chemoimmunotherapy, respectively. Among patients who did not have fluorescence in situ hybridization or TP53 mutation testing prior to enrollment, 33% and 32% received chemoimmunotherapy, respectively. Conclusion: Our findings indicate that prognostic testing rates were poor, and approximately one-third of high-risk patients (del[17p] and TP53) received chemoimmunotherapy, which is not aligned with current CLL treatment recommendations. This represents an opportunity to educate and alert health care professionals about the necessity of prognostic testing to guide optimal CLL treatment decisions.

Waves of highly infectious viruses sweeping through global honey bee populations have contributed to recent declines in honey bee health. Bees have been observed foraging on mushroom mycelium, suggesting that they may be deriving medicinal or nutritional value from fungi. Fungi are known to produce a wide array of chemicals with antimicrobial activity, including compounds active against bacteria, other fungi, or viruses. We tested extracts from the mycelium of multiple polypore fungal species known to have antiviral properties. Extracts from amadou (Fomes) and reishi (Ganoderma) fungi reduced the levels of honey bee deformed wing virus (DWV) and Lake Sinai virus (LSV) in a dose-dependent manner. In field trials, colonies fed Ganoderma resinaceum extract exhibited a 79-fold reduction in DWV and a 45,000-fold reduction in LSV compared to control colonies. These findings indicate honey bees may gain health benefits from fungi and their antimicrobial compounds.

At a time of resurgence in injection drug use and injection-attributable infections, needle stick injury (NSI) risk and its correlates among police remain understudied. In the context of occupational safety training, a convenience sample of 771 Baltimore city police officers responded to a self-administered survey. Domains included NSI experience, protective behaviors, and attitudes towards syringe exchange programs. Sixty officers (8%) reported lifetime NSI. Officers identifying as Latino or other race were almost three times more likely (aOR 2.58, 95% CI 1.12-5.96) to have experienced NSI compared to whites, after adjusting for potential confounders. Findings highlight disparate burdens of NSIs among officers of color, elevating risk of hepatitis, HIV, and trauma. Training, equipment, and other measures to improve occupational safety are critical to attracting and safeguarding police, especially minority officers.

Expertise in the broader impacts of scientific research is an increasingly important aspect of professional development, particularly because federal grant proposals are commonly reviewed using both the Intellectual Merit and the Broader Impacts Criteria. Unfortunately, training in broader impacts, such as science communication and outreach, is not typically part of undergraduate or graduate curricula. We initiated one of the first graduate-level biology courses on broader impacts, focusing on giving graduate students firsthand, authentic experiences with grant writing, science communication, and educational outreach. Students in this interdisciplinary course learned from experts, wrote for a broad audience about their own research, and proposed and implemented outreach in collaboration with local organizations. We outline our approach, discuss outcomes from each activity, assess our impact, and finally consider how future programs might expand on this model.

The vegetative forms of male (XY), female (XX), and hermaphrodite (XYh) papaya (Carica papaya L.) plants are phenotypically identical. However, the flower and inflorescence morphology of each sex type is unique. Gynodioecious varieties SunUp, SunUp Diminutive mutant, and dioecious AU9 were used to test the response of papaya to gibberellic acid (GA3). Exogenous applications of GA3 on female and hermaphrodite flowers of papaya did not yield any sex reversal phenotype but caused a significant increase in peduncle elongation and inflorescence branch number in all treated plants. An increase in flower number was seen in females but not hermaphrodites or males. There was an increase in plant height for all treated plants except SunUp Diminutive mutant, suggesting that the mechanism causing the dwarf phenotype is independent of gibberellins. Gibberellin metabolism genes were identified in the papaya genome, none of which mapped to the sex-determining region of either the male- or hermaphrodite-specific region of papaya Y or Yh chromosome. We hypothesize that a transacting regulatory element that enhances gibberellin biosynthesis plays a role in the extreme length of the male papaya peduncle.

The papaya Y-linked region showed clear population structure, resulting in the detection of the ancestral male population that domesticated hermaphrodite papayas were selected from. The same populations were used to study nucleotide diversity and population structure in the X-linked region. Diversity is very low for all genes in the X-linked region in the wild dioecious population, with nucleotide diversity π syn = 0.00017, tenfold lower than the autosomal region (π syn = 0.0017) and 12-fold lower than the Y-linked region (π syn = 0.0021). Analysis of the X-linked sequences shows an undivided population, suggesting a geographically wide diversity-reducing event, whereas two subpopulations were observed in the autosomes separating gynodioecy and dioecy and three subpopulations in the Y-linked region separating three male populations. The extremely low diversity in the papaya X-linked region was probably caused by a recent, strong selective sweep before domestication, involving either the spread of a recessive mutation in an X-linked gene that is beneficial to males or a partially dominant mutation that benefitted females or both sexes. Nucleotide diversity in the domesticated X samples is about half that in the wild Xs, probably due to the bottleneck when hermaphrodites were selected during domestication. The extreme low nucleotide diversity in the papaya X-linked region is much greater than observed in humans, great apes, and the neo-X chromosome of Drosophila miranda, which show the expected pattern of Y-linked genes

Young women engaged in exotic dancing have a higher need for reproductive health services than women not in this profession, and many also use drugs or exchange sex for money or drugs. Few report receiving reproductive health services. We describe a public health, academic, and community partnership that provided reproductive health services on needle exchange mobile vans in the “red light district” in downtown Baltimore, Maryland. Women made 220 visits to the vans in the first 21 months of the program's operation, and 65% of these visits involved provision of contraception. Programmatic costs were feasible. Joint provision of needle exchange and reproductive health services targeting exotic dancers has the potential to reduce unintended pregnancies and link pregnant, substance-abusing women to reproductive care, and such programs should be implemented more widely.

X chromosomes have long been thought to conserve the structure and gene content of the ancestral autosome from which the sex chromosomes evolved. We compared the recently evolved papaya sex chromosomes with a homologous autosome of a close relative, the monoecious Vasconcellea monoica , to infer changes since recombination stopped between the papaya sex chromosomes. We sequenced 12 V. monoica bacterial artificial chromosomes, 11 corresponding to the papaya X-specific region, and 1 to a papaya autosomal region. The combined V. monoica X-orthologous sequences are much shorter (1.10 Mb) than the corresponding papaya region (2.56 Mb). Given that the V. monoica genome is 41% larger than that of papaya, this finding suggests considerable expansion of the papaya X; expansion is supported by a higher repetitive sequence content of the X compared with the papaya autosomal sequence. The alignable regions include 27 transcript-encoding sequences, only 6 of which are functional X/ V. monoica gene pairs. Sequence divergence from the V. monoica orthologs is almost identical for papaya X and Y alleles; the Carica - Vasconcellea split therefore occurred before the papaya sex chromosomes stopped recombining, making V. monoica a suitable outgroup for inferring changes in papaya sex chromosomes. The papaya X and the hermaphrodite-specific region of the Y h chromosome and V. monoica have all gained and lost genes, including a surprising amount of changes in the X.

In the version of this article originally published, the accession codes listed in the data availability section were incorrect and the section was incomplete. The text for this section should have read "The genome assembly and gene annotation have been deposited in the NCBI database under accession number QVOL00000000, BioProject number PRJNA483885 and BioSample number SAMN09753102. The data can also be downloaded from the following link: http://www.life.illinois.edu/ming/downloads/Spontaneum_genome/ ." The errors have been corrected in the HTML and PDF versions of the article.

A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.

Objectives. We piloted a monitoring mechanism to document police encounters around programs targeting people who inject drugs (PWID), and assessed their demographic predictors at 2 Baltimore, Maryland, needle exchange program (NEP) sites. Methods. In a brief survey, 308 clients quantified, characterized, and sited recent police encounters. Multivariate linear regression determined encounter predictors, and we used geocoordinate maps to illustrate clusters. Results. Within the past 6 months, clients reported a median of 3 stops near NEP sites (interquartile range [IQR] = 0–7.5) and a median of 1 arrest in any location (IQR = 0–2). Three respondents reported police referral to the NEP. Being younger (P = .009), being male (P = .033), and making frequent NEP visits (P = .02) were associated with reported police stops. Among clients reporting arrest or citation for syringe possession, Whites were significantly less likely than non-Whites to report being en route to or from an NEP (P Conclusions. Systematic surveillance of structural determinants of health for PWID proved feasible when integrated into service activities. Improved monitoring is critical to informing interventions to align policing with public health, especially among groups subject to disproportionate levels of drug law enforcement.