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The nonclinical safety assessments for gene therapies are evolving, leveraging over 20 years of experimental and clinical experience. Despite the growing experience with these therapeutics, there are no approved harmonized global regulatory documents for developing gene therapies with only the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) S12 guidance on nonclinical biodistribution currently under discussion. Several health authorities have issued guidance over the last 15 years on the nonclinical safety aspects for gene therapy products, but many of the recommendations are limited to high-level concepts on nonclinical safety aspects or altogether silent on key topics. Historically, this approach was appropriately vague given our relatively small dataset of nonclinical experience, where a comprehensive and detailed regulatory guidance approach was unlikely to be appropriate to address all scenarios. However, harmonization of key considerations and assumptions can provide a consistent basis for developing the appropriate nonclinical safety development plans for individual programs, reducing uncertainty across regulatory regions and unnecessary animal use. Several key areas of nonclinical safety testing are nearing maturation for a harmonized approach, including species selection, certain aspects of study design, study duration, and unintended genomic integration risks. Furthermore, several emerging topics are unaddressed in current regulatory guidance for gene therapy products, which will become key areas of differentiation for the next generation of therapeutics. These topics include redosing, juvenile/pediatric safety, and reproductive/developmental safety testing, where relevant experience from other modalities can be applied. The rationale and potential study design considerations for these topics will be proposed, acknowledging that certain aspects of gene therapy development are not considered appropriate for harmonization. This article provides an overview of the current nonclinical safety regulatory landscape, summarizes typical nonclinical safety study designs, highlights areas of uncertainty, and discusses emerging topics that warrant consideration. Specific recommendations and perspectives are provided to inform future regulatory discussions and harmonization efforts.

The term hydrospatial first emerged in the early 2000’s in the UK. Since February 2020, the term hydrospatial has been reenergized, promoted and mentioned in many fora such as: International Hydrographic Conferences virtual and in person; and in international publications including the International Hydrographic Review (IHR) in its six last volumes. This note is intended to provide an update on where this term stands with respect to its usage, endorsement and meaning.

CSF and serum levels of 21 cytokines and chemokines measured before and at indicated days after adoptive CD20 CAR T cell transfer.

Antibodies and reagents used in Materials and Methods.

Supp Figures S1 to S6 and Supp Tables S1 to S2

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190–202. ©2017 AACR.

Estimar temperaturas internas horárias de edificações ocupadas com métodos relativamente simples permite avaliar seu desempenho térmico e estimar o consumo energético. No entanto, o tema ainda é pouco explorado. Esta pesquisa teve como objetivo verificar a aplicabilidade do método de regressão linear para a estimativa de temperaturas internas em um apartamento ocupado na cidade de Curitiba. Para isso, foram monitoradas as temperaturas internas e externas do ar por 41 dias e calibradas equações para três situações do clima local. Os resultados mostraram que contextos não contemplados pelo período de calibração representaram um obstáculo para a precisão das estimativas.

Modelos preditivos de temperatura do ar podem ser usados para melhorar a qualidade térmica em ambientes internos e o desempenho térmico do edifício. Este estudo avaliou um método simples de previsão de temperatura do ar no qual a temperatura do ar é estimada considerando a média móvel das temperaturas externas das horas anteriores através da implementação de regressão linear. Uma moradia naturalmente ventilada foi monitorada por 89 dias em Aracati/CE, localizada em clima semiárido. As estimativas foram avaliadas considerando a raiz quadrática média das diferenças e a diferença de viés médio. Por fim, observou-se um bom ajuste do método avaliado.

Use of antibiotics inevitably leads to antimicrobial resistance. Selection for resistance occurs primarily within the gut of humans and animals as well as in the environment through natural resistance and residual antibiotics in streams and soil. We evaluated antimicrobial resistance in Gram negative bacteria from a river system in a rural community in Bahia, Brazil. Water was collected from the Jiquiriçá and Brejões rivers and the piped water supply. Additionally, stools were collected from a random sample of residents, cows, pigs and horses near the river. The samples were screened for bacteria resistant to ciprofloxacin, cefotaxime, and meropenem and identified biochemically at the genus and species levels. Microbial source tracking demonstrated that ruminant and human fecal contamination increased as the rivers neared the village center and decreased after the last residence. Antibiotic bacteria were identified from all samples (n = 32). No bacteria were resistant to carbapenems, but the majority of the enterobacteria were resistant to ciprofloxacin, even though this class of antibiotics is not commonly used in food animals in this region. Considering these facts, together with the pattern of human fecal contamination, a human source was considered most likely for these resistant isolates. Resumo O uso de antibióticos inevitavelmente leva à resistência antimicrobiana. A seleção para resistência antimicrobiana ocorre principalmente no intestino de seres humanos e animais, bem como no meio ambiente, através da resistência natural e resíduos de antibióticos nos esgotos e no solo. Avaliamos a resistência antimicrobiana em bactérias Gram-negativas de um sistema fluvial em uma comunidade rural da Bahia, Brasil. A água foi coletada nos rios Jiquiriçá e Brejões e no abastecimento de água encanada. Além disso, foram coletadas amostras randomizadas de fezes de moradores, vacas, porcos e cavalos próximos ao rio. As amostras foram triadas para bactérias resistentes à ciprofloxacina, cefotaxima e meropenem e identificadas bioquimicamente nos níveis de gênero e espécie. O rastreamento de fontes microbianas demonstrou que a contaminação fecal de ruminantes e humanos aumentou à medida que os rios se aproximavam do centro da vila e diminuía após a última residência. Bactérias resistentes a antibióticos foram identificadas em todas as amostras (n = 32). Nenhuma bactéria demonstrou ser resistente aos carbapenêmicos testados, contudo, foi encontrado enterobactérias resistentes à ciprofloxacina, ainda que essa classe de antibióticos não seja comumente usada na medicina veterinária dos animais dessa região. Considerando esses fatos, juntamente com o padrão de contaminação fecal avaliado, a fonte de contaminação humana foi considerada a mais provável na interação desses isolados resistentes.

INTRODUCTION: Inadequate wastewater treatment and fecal contamination have a strong environmental impact on antimicrobial resistance (AMR). This study evaluated the profile of AMR enterobacteria and fecal contamination from four surface waters: Jiquiriça-Brejões River and Cabrito, Tororó, and Abaeté Lagoons. METHODS: We analyzed AMR β-lactamase genes using the polymerase chain reaction method and fecal contamination using Coliscan®. RESULTS: We found high levels of fecal contamination, β-lactamase producers, and AMR genes (blaOXA-48, blaSPM, and blaVIM) in all waterbodies. CONCLUSIONS: Poor sanitation evidenced by fecal contamination and human activities around these surface waters contributed to the distribution and increase in AMR enterobacteria.

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.

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The use of immunotherapy in the treatment of chronic inflammatory conditions has demonstrated important clinical utility across a range of conditions including organ allograft maintenance and autoimmune disorders. However, the observation of increased cancer risk with broadly active immune suppression and concern about increased cancer risk with more targeted immune modulation remain as persistent challenges for clinicians, patients, and regulators. A strong relationship between immune status and cancer outcomes in human populations has been established based on the accumulated epidemiology findings in humans with immune deficiencies, clinical observational and biomarker data from patients, and mechanistic/experimental data. These data have refined our understanding of the role of the immune system in either promoting or suppressing tumor development and growth, and the reciprocal effects on the immune system driven by the tumor. The integration of the epidemiological, clinical and mechanistic data have given rise to several modern conceptual paradigms that capture the complex interactions between tumors and the immune system. Under the Immunoediting Model, tumors and the host immune system co-evolve, and the selective pressure of the immune system can either eliminate the cancer, establish a state of equilibrium, or lead to tumor variants that escape immune surveillance. The Inflammation Model captures the role of chronic inflammation in promoting tumor growth in association with certain cancers. The observation of increased B cell malignancies in patients with either immune deficiencies or chronic immune activation likely results from the unique sensitivity of chronically activated B cells to genetic injury (B cell Lymphoma Model). Finally, because a viral etiology has been identified for a number of cancers, alterations in immune-mediated viral surveillance may underlie cancer risk in humans (Oncogenic Virus Model). The models described above demonstrate formidable complexity when trying to understand the potential risks associated with alterations in immune status that arise from use of therapeutic immunomodulators. These models can be used to guide our assessments when assessing or predicting the risk of cancer associated with immunomodulation, and can be used to guide mechanistic experiments to understand the role of specific components of immunity in regulating or contributing to cancer risk.

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models. Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses. Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy. Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190–202. ©2017 AACR.

Resumen: La recuperación del patrimonio local es una pieza clave para el desarrollo de cualquier municipio, más aún si esté se encuentra afectado por procesos de despoblación. En el caso de Utiel, desde 2015 se ha logrado iniciar toda una serie de acciones destinadas a la recuperación del patrimonio cultural tangible e intangible, gracias a la apuesta por dichos elementos por parte de la administración local y de diversos colectivos sociales. Así, se dispone de un renovado stock de recursos turísticos, como por ejemplo lo son las bodegas del casco histórico, diversas recreaciones culturales e históricas, y distintos edificios y espacios urbanos. Todos estos elementos constituyen un valor único para el proceso de identidad y arraigo que el municipio de Utiel está experimentando en los últimos años, vectores sin duda de un desarrollo territorial mucho más amplio y duradero. Palabras clave: Turismo, participación cívica, bodegas, identidad local, regeneración urbana.

Pensamiento crítico-complejo-innovador es el modo de pensar, que corresponde a las actuales condiciones del desarrollo de las fuerzas productivas y tecnológicas, su complejidad y cambios que subyacen en la multidimensionalidad de los sistemas. Es el pensar crítico, propositivo, del ser bío, psíquico, histórico, antropológico y cultural que se adapta a las condiciones de movimiento y de la complejidad del desarrollo de la ciencia y el cambio de paradigma. La filosofía de la educación y las ciencias pedagógicas tienen la responsabilidad de asimilar estas modificaciones sistémicas y el desarrollo vertiginoso de la ciencia y la tecnología, para incorporarlos en un sistema educativo superior. Estas nuevas condiciones deben ser reconocidas por el maestro en la aplicación de estrategias participativas en el aula.

In recent years Ecuador has grown a very vital underground cinema industry that relies on three key factors for its current success: First, its strong independence from the traditional and centralized film industry and the exclusiveness of education and means for filmmaking since the production of these underground films is in most of the cases run by non-professional crews (from script writing and direction to acting and post-production). Second, these films have placed their production and reception arena out of the economic and political centers of Quito and Guayaquil, giving space to “lo local” to be represented, but also to be watched on the screen by the same people in their own space of projection. This is due the use of mostly local, legal and pirate, distribution channels. Finally, as we analyze this movement, we propose that what is behind the success of the new “Cine Bajo Tierra” is a vigorous response to, and sometimes a critique of, the disastrous consequences of the application of neoliberal policies in Ecuador. Boasting titles such as Sicarios manabitas [Hitmen from Manabí], Doble trampa [Double trap], El regreso del llanero vengador [The return of the avenging cowboy], Drogas: el comienzo del fin [Drugs: the beginning of the end], Avaricia [Greed], and El ángel de los sicarios [The hitmen’s angel], these films depict scenarios of crude violence, poverty, and merciless surviving behaviors that have found an “appreciation” from their local viewers as a dialectical relationship of self-awareness between filmmakers and audiences who ultimately have suffered the same under the long neoliberal night.

Repeated treatments with praziquantel reduce schistosomiasis prevalence and morbidity, but transmission persists and populations often recover within a few years. To identify factors associated with persistence, we surveyed and treated all identified Schistosoma mansoni infections in two rural Brazilian communities (Jenipapo and Volta do Rio) in 2009, 2012 and 2013. Eggs were collected from all infected individuals and genotyped with 11 microsatellite markers to evaluate parasite differentiation and diversity. After successive rounds of community-wide treatment, prevalence decreased from 45% to 24% then 16%. Intensity of infection decreased by 57% over this period, and the number of eggs transmitted to the environment decreased by 92%. During all time periods the majority of eggs were excreted by those >15 years of age. The incidence was 23% in 2012 and 15% in 2013, consistent with a decrease in transmission. There was little immigration or gene flow over a distance of 6 km. On reinfection, infrapopulations were moderately differentiated indicating that pretreatment multilocus genotypes were not fully reacquired. The effective population size responded to census population decline more rapidly than differentiation. Reinfection was concentrated in the downstream portion of Jenipapo, consistent with the observed increased human fecal contamination. At this scale and in this area S. mansoni infections exist on a fragmented landscape with a highly focal pattern of transmission that may facilitate future elimination.

Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed.

This qualitative study explored the social experiences and HIV-related sexual practices of 30 young gay and bisexual men who moved to New York City in the past 3 years from other countries or elsewhere in the United States. For many migrants, a key basis of vulnerability to HIV was their engagement with New York City's unfamiliar sexual culture. Many recent arrivals migrated from places with small gay communities and low HIV prevalence, and some came with a practice of limited condom use. Participants described encountering an abundance of sexual opportunity in New York City, accessible to even the newest arrivals through internet sex sites. Some migrants expressed surprise that few men they met were interested in dating or establishing trust before having sex. Although frequent HIV testing was common, HIV status, testing history, and condom use were seldom discussed with sex partners for some men even with new partners or before sex without condoms. International and in-country migrants who are beginning to navigate New York City's gay sexual culture may be more vulnerable to HIV infection than established residents if they are inexperienced in encountering vast sexual opportunity, are less practiced in local norms of sexual communication, or if their lack of economic resources or social connections encourages them to have sex for money or shelter. This article suggests HIV prevention interventions for urban migrants and other men who have sex with men.

Tumor necrosis factor (TNF) is a highly pleiotropic cytokine with multiple activities other than its originally discovered role of tumor necrosis in rodents. TNF is now understood to play a contextual role in driving either tumor elimination or promotion. Using both animal and human data, this review examines the role of TNF in cancer development and the effect of TNF and TNF inhibitors (TNFis) on malignancy risk.A literature review was performed using relevant search terms for TNF and malignancy.Although administration of TNF can cause tumor regression in specific rodent tumor models, human expression polymorphisms suggest that TNF can be a tumor-promoting cytokine, whereas blocking the TNF pathway in a variety of tumor models inhibits tumor growth. In addition to direct effects of TNF on tumors, TNF can variously affect immunity and the tumor microenvironment. Whereas TNF can promote immune surveillance designed to eliminate tumors, it can also drive chronic inflammation, autoimmunity, angiogenesis, and other processes that promote tumor initiation, growth, and spread. Key players in TNF signaling that shape this response include NF-κB and JNK, and malignant-inflammatory cell interactions, each of which may have different responses to TNF signaling. Focusing on rheumatoid arthritis (RA) patients, where clinical experience is most extensive, a review of the clinical literature shows no increased risk of overall malignancy or solid tumors such as breast and lung cancers with exposure to TNFis. Lymphoma rates are not increased with use of TNFis. Conflicting data exist regarding the risks of melanoma and nonmelanoma skin cancer. Data regarding the risk of recurrent malignancy are limited.Overall, the available data indicate that elevated TNF is a risk factor for cancer, whereas its inhibition in RA patients is not generally associated with an increased cancer risk. In particular, TNF inhibition is not associated with cancers linked to immune suppression. A better understanding of the tumor microenvironment, molecular events underlying specific tumors, and epidemiologic studies of malignancies within specific disease indications should enable more focused pharmacovigilance studies and a better understanding of the potential risks of TNFis.

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis. Significance: We provide the first immunologically relevant, nonhuman primate model of B cell–directed CAR T-cell therapy–mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750–63. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663

Background The epidemiology of disseminated Mycobacterium avium complex (DMAC) infection in the United States is changing. Previously most DMAC occurred in adults with advanced AIDS. Since the development of effective antiretroviral therapy, the incidence of DMAC in AIDS has fallen more than 10-fold. Malignancy, immunosuppression, and tumor necrosis factor inhibitors are known risk factors for DMAC. We sought to describe the epidemiology of DMAC disease in HIV seronegative patients in the United States. Methods We performed a retrospective analysis of a commercial database (Explorys Inc., Cleveland, OH). This database contains an aggregate of Electronic Health Record data from 26 major integrated healthcare systems in the United States from 1999 to present. Explorys contains de-identified information from over 50 million patients, 360 hospitals, and over 317,000 providers. We identified a total of 571 persons diagnosed with DMAC, based on Systemized Nomenclature of Medicine-Clinical Terms. We excluded 80 HIV-infected and identified association of the infection with known risk factors. Results Of 570 patients, 491 HIV-uninfected patients with DMAC were studied. Underlying structural pulmonary diseases were COPD and bronchiectasis (51% and 47%, respectively). Two hundred ten patients had concomitant malignancy of which lung cancer was the most frequent (43%). Seventy-nine percent were receiving corticosteroids and 10 patients (2%) were on TNF inhibitors (2%). Conclusion In this study, majority of patients with DMAC are HIV-uninfected. Larger studies should focus on identifying the prevalence and risk factors of DMAC in the post-AIDS era. Table: Distribution of the Sample According to Associated Conditions N = 490 (%) Age, years Senior (>65) 330 (67%) Adult (18–65) 160 (33%) Female 310 (63) Smoking history 420 (86) Bronchiectasis 230 (47) Previous pulmonary tuberculosis 40 (8) COPD 250 (51) HTN 310 (63) Diabetes mellitus 130 (27) Chronic kidney disease 110 (22) Interstitial lung disease 90 (18) Inflammatory bowel disease 20 (4) Concomitant malignancy 210 (43) Lung 60 (28) GI 50 (23) Head and neck 40 (19) Hematological 40 (19) Renal 30 (14) Chronic oral corticosteroid treatment 390 (79) Tumor necrosis factor alpha inhibitor therapy 10 (2) COPD; chronic obstructive pulmonary disease, HTN; hypertension, GI gastrointestinal. Disclosures All authors: No reported disclosures.

Background Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) were described first in relation to hospital-acquired infections. However, infections by these organisms acquired in the community have become a public health problem. There are no well-known risk factors for acquisition of these bacteria in the community. Surface waters and sanitation conditions may serve as reservoir and transmission. Methods We conducted a retrospective study over 12 months of patients who had positive cultures with ESBL-PE in our laboratory. We excluded patients with hospitalization in the previous 3 months, those in skilled nursing facilities, and those whose culture was taken 3 or more days after hospitalization. Geographic Information System analysis was performed based on patient’s residence, population, and sewer overflow public data. Results Among 485 patients with cultures positive for ESBL-PE in 2018, 64 were included in the study. Mean age was 54, and 68.7% were females. Organisms isolated were E. coli (78.2%) and K. pneumoniae ESBL (21.8%). These were isolated from urine 47 (73.4%), blood 5 (7.8%), abscess 6 (9.3%), ulcers 5 (7.8%), and sputum 1 (1.5%). Antibiotic exposure in the preceding 3 months was noted in 12 patients (18.7%). Spatial distribution of patients in the community was not random based on nearest neighbor analysis (Z score = −2.6). Kernel density estimation showed clustering of cases. Infection rates were calculated per census tracts. There was poor correlation between infection rate and mean family income (R2 = 0.18, P = 0.017). Analysis of Kernel density estimations showed that sewer overflow distribution explained over 50% of the variance of distribution of cases with ESBL-PE (R2 = 0.51, P < 0.001). Conclusion Patients presenting with infections due to ESBL-PE acquired in the community did not have a random spatial distribution. Other factors besides prior antibiotic use and financial status should be investigated. Proximity to sanitary sewer overflows may be a contributing factor. Location of residence within a community may aid in identifying patients at risk for acquisition of ESBL-PE. Disclosures All Authors: No reported Disclosures.