Although resilient youth provide an important model of successful adaptation to adversity, we know relatively little about the origins of their positive outcomes, particularly the role of biological mechanisms. The current study employed a series of methylome-wide association studies to identify methylomic biomarkers of resilience in a unique sample of 276 twins within 141 families residing in disadvantaged neighborhoods. Results revealed methylome-wide significant differentially methylated probes (DMPs) for social and academic resilience and suggestive DMPs for psychological resilience and resilience across domains. Pathway analyses informed our understanding of the biological underpinnings of significant differentially methylated probes. Monozygotic twin difference analyses were then employed to narrow in on DMPs that were specifically environmental in origin. Our findings suggest that alterations in the DNA methylome may be implicated in youth resilience to neighborhood adversity and that some of the suggestive DMPs may be environmentally engendered. Importantly, our ability to replicate our findings in a well-powered sample was hindered by the scarcity of twin samples with youth exposed to moderate to substantial levels of adversity. Thus, although preliminary, the present study is the first to identify DNA methylation biomarkers of academic and social resilience.

Background: Asymptomatic bacteriuria (ASB) is often treated with antibiotics despite recommendations against screening for and treating ASB in most populations. Some providers cite concern for progression of ASB to a symptomatic urinary tract infection (UTI) as the jultification for antibiotic use. While the 2019 Infectious Diseases Society of America (IDSA) ASB guidelines refute this concern, most evidence is derived from studies done in females, potentially limiting external validity. The purpose of this study is to compare the outcomes of patients with ASB who received antibiotic treatment versus those who did not in a primarily male population. Methods: This is a multi-center, retrospective, cohort study conducted by the 5 sites within the Veterans Affairs MidSouth Healthcare Network. Patients with a positive urine culture (defined as cultures with a colony forming unit count >100,000) collected from January 1, 2021 through December 31, 2021 were identified. ASB was determined via chart review using pre-determined criteria (positive culture in the absence of reported or documented signs or symptoms attributable to UTI as defined by the 2019 IDSA ASB guidelines). Additional data collected included antibiotic use, clinic visits and hospital admissions related to UTI or sepsis from a UTI. The primary outcome was the comparison of UTI incidence at 30 days, 6 months, and 1 year in those untreated versus treated with antibiotics. Secondary outcomes included a comparison of admissions with sepsis from UTI and adverse drug reactions (ADRs) between the cohorts. Continuous data were analyzed using a Student’s t-test. Discrete data were analyzed using either a Chi-squared or Fisher’s exact test. Results: The study population was primarily elderly (73 years, range 27-99 years) and male (79.7%). Of the 281 patients with ASB, 127 (45.2%) and 154 (54.8%) were untreated and treated, respectively. The incidence of UTI was 3% versus 1% (p = 0.41) at 30 days, 10% versus 12% (p = 0.61) at 6 months and 11% versus 12% (p = 0.94) at 12 months in the untreated and treated cohorts, respectively. There was no difference in admissions for UTI, sepsis from UTI or ADRs at 30 days. Conclusion: This study found no difference in the development of symptomatic UTI in veterans with untreated ASB compared to those treated with antibiotics. These findings align with current ASB guideline recommendations and support avoidance of unnecessary antibiotic use in the veteran population.

Background: Data regarding the effects of the SARS-COV-2 (COVID-19) pandemic on healthcare-associated infections (HAIs) in Canadian acute-care hospitals are limited. We examined the impact of the COVID-19 pandemic on HAIs and antimicrobial resistant organisms in hospitals participating in the Canadian Nosocomial Infection Surveillance Program. Methods: We analyzed 13,406 HAIs including adult mixed intensive care unit (ICU) central-line–associated bloodstream infections (CLABSIs), and healthcare-associated (HA) Clostridioides difficile infection (CDI), methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), vancomycin-resistant Enterococcus (VRE) BSI, and carbapenemase-producing Enterobacterales (CPE) infections collected using standardized case definitions and questionnaires from 29–64 hospitals participating in the Canadian Nosocomial Infection Surveillance Program (CNISP) from January 2018 to December 2021. We used a generalized linear mixed model with quasi-Poisson distribution to assess step and slope changes in monthly HAI rates between the pre–COVID-19 pandemic period (January 1, 2018–February 29, 2020; 26 time points) and the COVID-19 pandemic period (March 1, 2020–December 31, 2021; 22 time points). Results were reported as incidence rate ratios (IRRs) with 95% confidence intervals (CIs) and adjusted for seasonality, hospital clustering, and hospital characteristics of interest. Results: In the CNISP network, 7,352 (55%) HAIs were reported in the prepandemic period and 6,054 (45%) in the pandemic period. Median age was significantly younger during the pandemic period compared to the prepandemic period among patients with HA-CDI, HA-MRSA BSI, and adult mixed ICU CLABSIs, and more than half of cases among all reported HAIs were male (range, 52%–65%). The 30-day all-cause in-hospital mortality rate did not significantly change between the prepandemic and pandemic periods for all reported HAIs and was highest among HA-VRE BSIs (34%). Modeling results indicated that the COVID-19 pandemic was associated with an immediate increase in HA-CDI and adult mixed ICU CLABSI rates whereas HA-MRSA BSI, HA-CPE and HA-VRE BSI rates immediately decreased. However, pandemic status did not have a statistically significant lasting impact on monthly rate trends for all reported HAIs after adjusting for seasonality, clustering, and hospital covariates (Fig. 1 and 2). Adjusted IRRs for all HAIs ranged from 1.00 to 1.01 (95% CI, 0.94–0.99 to 1.01–1.05).

Conclusions: Although the COVID-19 pandemic placed a significant burden on the Canadian healthcare system, the immediate impact on monthly rates of HAIs in Canadian acute-care hospitals was not sustained over time. Understanding the epidemiological effects of the COVID-19 pandemic in the context of changing patient populations, and clinical and infection control practices, are essential to inform the continued management and prevention of HAIs in Canadian acute-care settings.

Disclosures: None

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

The coronavirus disease 2019 (COVID-19) pandemic has placed significant burden on healthcare systems. We compared Clostridioides difficile infection (CDI) epidemiology before and during the pandemic across 71 hospitals participating in the Canadian Nosocomial Infection Surveillance Program. Using an interrupted time series analysis, we showed that CDI rates significantly increased during the COVID-19 pandemic.

Cerebrospinal fluid shunt–associated surgical site infection surveillance for 3 months compared to 12 months after surgery captures 83% of cases with no significant differences in patient characteristics, surgery types, or pathogens. A shorter 3-month follow-up can reduce resource use and allow for more timely reporting of healthcare-associated infection rates for hospitals.

Background: Surgical site infection (SSI) after cerebrospinal fluids (CSF) shunt surgery is thought to be acquired intraoperatively. Biomaterial-associated infection can present up to 1 year after surgery, but many national systems have shortened follow-up to 90 days. We compared 3- versus 12-month follow-up periods to determine the nature of case ascertainment in the 2 periods. Methods: Participants of any age with placement of an internal CSF shunt or revision surgical manipulation of an existing internal shunt identified in the Canadian Nosocomial Infection Surveillance Program (CNISP) participating hospitals between 2006 and 2018 were eligible. We excluded patients with external shunting devices or culture-positive CSF at the time of surgery. Patients were followed for 12 months after surgery for the primary outcome of a CSF infection with a positive CSF culture by review of laboratory and health records. Patients were categorized as adult (aged ≥18 years) or pediatric (aged < 18 years). The infection rate was expressed as the number of CSF shunt-associated infections divided by the number of shunt surgeries per 100 procedures. Results: In total, 325 patients (53% female) met inclusion criteria in 14 hospitals from 7 provinces were identified. Overall, 46.1% of surgeries were shunt revisions and 90.3% of shunts were ventriculoperitoneal. For pediatric patients, the median age was 0.7 years (IQR, 0.2–7.0). For adult patients, the median age was 47.9 years (IQR, 29.6–64.6). The SSI rates per 100 procedures were 3.69 for adults and 3.65 for pediatrics. The overall SSI rates per 100 procedures at 3 and 12 months were 2.74 (n = 265) and 3.48 (n = 323), respectively. By 3 months (90 days), 82% of infection cases were identified (Fig. 1). The median time from procedure to SSI detection was 30 days (IQR, 10–65). No difference was found in the microbiology of the shunt infections at 3- and 12-month follow-ups. The most common pathogens were coagulase-negative Staphylococcus (43.6 %), followed by S. aureus (24.8 %) and Propionibacterium spp (6.5 %). No differences in age distribution, gender, surgery type (new or revision), shunt type, or infecting organisms were observed when 3- and 12-month periods were compared. Conclusions: CSF-SSI surveillance for 3 versus 12 months would capture 82.0% (95% CI, 77.5–86.0) of cases, with no significant differences in the patient characteristics, surgery types, or pathogens. A 3-month follow-up can reduce resources and allow for more timely reporting of infection rates.

Funding: None

Disclosures: None

A prospective study of norovirus outbreaks in Ireland was carried out over a 1-year period from 1 October 2004 to 30 September 2005. Epidemiological and molecular data on norovirus outbreaks in the Republic of Ireland (ROI) and Northern Ireland (NI) were collected and combined in real time in a common database. Most reported outbreaks occurred in hospitals and residential institutions and person-to-person spread was the predominant mode of transmission. The predominant circulating norovirus strain was the GII.4-2004 strain with a small number of outbreaks due to GII.2. This study represents the first time that enhanced epidemiological and virological data on norovirus outbreaks in Ireland have been described. The link established between the epidemiological and virological institutions during the course of this study has been continued and the data is being used as a source of data for the Foodborne Viruses in Europe Network (DIVINE-NET).

Background. Previous studies of personality characteristics in women with eating disorders primarily have focused on women who are acutely ill. This study compares personality characteristics among women who are ill with eating disorders, recovered from eating disorders, and those without eating or other Axis I disorder pathology.

Method. Female participants were assessed for personality characteristics using the Temperament and Character Inventory (TCI): 122 with anorexia nervosa (AN; 77 ill, 45 recovered), 279 with bulimia nervosa (BN; 194 ill, 85 recovered), 267 with lifetime histories of both anorexia and bulimia nervosa (AN+BN; 194 ill, 73 recovered), 63 with eating disorder not otherwise specified (EDNOS; 31 ill, 32 recovered), and 507 without eating or Axis I disorder pathology.

Results. Women ill with all types of eating disorders exhibited several TCI score differences from control women, particularly in the areas of novelty-seeking, harm avoidance, self-directedness, and cooperativeness. Interestingly, women recovered from eating disorders reported higher levels of harm avoidance and lower self-directedness and cooperativeness scores than did normal control women.

Conclusions. Women with eating disorders in both the ill and recovered state show higher levels of harm avoidance and lower self-directedness and cooperativeness scores than normal control women. Although findings suggest that disturbances may be trait-related and contribute to the disorders' pathogenesis, additional research with more representative community controls, rather than our pre-screened, normal controls, is needed to confirm these impressions.

Sixty-six patients were assessed clinically, psychologically and physiologically before operation, at six weeks and at a mean of 16 months following stereotactic limbic leucotomy. Seventy-three per cent were clinically improved at six weeks and 76 per cent at 16 months. In obsessional neurosis, 89 per cent of patients showed definite clinical improvement at 16 months; in chronic anxiety, 66 per cent were improved; in depression, 78 per cent; and in the small number of schizophrenics treated the improvement rate was over 80 per cent. Self-assessment and observer-assessment questionnaires and scales measuring Depression, Anxiety, Neuroticism, Hysterical symptoms and Obsessional symptoms and traits all showed highly significant reductions of mean scores at 16 months. There was no fall-off in intelligence, and adverse effects were minimal. Limbic leucotomy, with its enhanced accuracy and safety, compares very favourably with similarly assessed, more extensive ‘free-hand’ procedures, and in obsessional neurosis and chronic anxiety the results are superior.

The neurophysiological aspects and operative technique of stereotactic limbic leucotomy have been described in a previous paper (Kelly, Richardson and Mitchell-Heggs, 1973). The present investigation is a prospective study designed to assess the results of such surgery in a group of 40 severely ill psychiatric patients, who had failed to respond satisfactorily to every other type of treatment. The results have been assessed clinically, psychologically and physiologically, in a very detailed way, at six weeks; a similar follow-up at one year is in progress. A comparison is made between the results of the present series and those of a previous: study (Kelly et al., 1972), in which more extensive leucotomy operations were carried out, and similar means of assessment were employed.

Psychosurgery has always been, and is likely to remain, a controversial subject. Blind operations lack precision and can lead to adverse personality changes or other serious side-effects. Open surgery is becoming less acceptable because of the difficulties of accurately assessing the extent of a lesion and its exact location. The introduction of stereotactic techniques enables far smaller lesions to be placed with a high degree of accuracy, and increased knowledge of the limbic system has contributed to advances in this field.

After more than thirty years the operation of leucotomy still remains a controversial treatment, and its value is questioned by many. This scepticism, and the advent of new surgical techniques, have emphasized the need for careful appraisal of the results of psychosurgery. In a previous prospective study 40 patients were assessed six weeks after modified leucotomy, and 75 per cent of these patients were found to be clinically improved (Kelly, Walter and Sargant, 1966). They were less neurotic on the M.P.I., had lower Taylor Manifest Anxiety scores and rated themselves as less anxious; a good clinical outcome was associated with diminution of physiological arousal as measured by forearm blood flow and heart rate. This group has now been followed-up and reassessed 18 months after operation, and a further group of 38 patients has been examined before, and again six weeks after, leucotomy. The data from the two groups have been combined to determine the immediate outcome for various diagnostic categories, and a multiple regression has been performed to elicit which of the pre-operative factors predict a favourable post-operative result.

Anxiety neurosis has been the subject of intensive study during the past ten years. Renewed interest in this syndrome has arisen both from the stimulus of new methods of treatment and from attempts to classify anxiety more accurately. Recently Pitts and McClure (1967) reported that anxiety symptoms and anxiety attacks could be produced by a specific biochemical stimulus: sodium lactate. This work was prompted by the finding that 'standard exercise’ tends to produce an excess amount of lactic acid in patients with anxiety neurosis (Cohen and White, 1950; Jones and Mellersh, 1946; Linko, 1950; Holmgren and Strom, 1959). Pitts and McClure found that an intravenous infusion of 10 ml. of half-Molar sodium (DL) lactate per kilogram of body weight, given over a twenty minute period, produced an anxiety attack in patients suffering from anxiety neurosis. The symptoms began a minute or two after the infusion was started and developed rapidly, and some patients reported ‘exacerbations of their characteristic symptom profiles for two to five days after the sodium lactate infusion’. In their double-blind study, many fewer symptoms were produced when calcium ion was added to the lactate infusion, and almost no symptoms were produced by an infusion of glucose in saline of similar osmolarity. Many fewer and less severe symptoms were produced in normal controls than in the patient group, both in response to sodium lactate and to lactate with added calcium, and almost no symptoms during the glucose and saline infusion. Pitts and McClure postulated that anxiety symptoms may have a common determining biochemical end-mechanism, involving the complexing of ionized calcium at the surface of excitable membranes by lactate ion with resulting interference ‘with the normal functioning of calcium in transmitting nerve impulses' (Pitts, 1969). They concluded that ‘there may be something highly specific about lactate ion in producing the naturally occurring hypocalcaemic anxiety symptoms in human beings'.

The treatment of phobic states is one of the most challenging psychiatric problems that face doctors today. Many treatments have been advocated, including intensive psychotherapy (Friedman, 1959), behaviour therapy (Wolpe, 1958; Cooper, Gelder and Marks, 1965) and desensitization under drugs (Yorkston et al., 1968). None of these treatments has proved to be completely effective, and many patients still remain ill and incapacitated for many years. In the series to be reported here, some patients had been ill for as long as 40 years, despite many types of treatment.