bluuebunny/crossref_metadata_2025 huggingface dataset:
Health-related quality of life by race, ethnicity, and country of origin among cancer survivors
Authors: Reeve Bryce B , Graves Kristi D , Lin Li , Potosky Arnold L , Ahn Jaeil , Henke Debra M , Pan Wei , Fall-Dickson Jane M
Published: December 2022

Background

Typical cancer research studies of health-related quality of life (HRQOL) in the United States do not include country of origin when examining race and ethnic group differences. This population-based, cross-sectional study used an innovative methodology to examine how self-reported racial and ethnic groups, by country of origin, report differential HRQOL experiences after adjusting for clinical and demographic characteristics, including socioeconomic status.

Methods

Recruited from 4 cancer registries in California, Louisiana, and New Jersey, cancer survivors completed Patient-Reported Outcomes Measurement Information System measures of fatigue, pain interference, anxiety, depression, sleep disturbance, physical function, ability to participate in social roles, and cognitive function. Latent profile analysis clustered survivors in HRQOL clusters based on including all the Patient-Reported Outcomes Measurement Information System domains.

Results

The 5366 participants (60% female; 40% male; average age of 59.8 years) included 17% Asian, 18% Black, 21% Hispanic, and 41% White survivors. Survivors were grouped into 4 clusters: high HRQOL (26%), average HRQOL (34%), low HRQOL (29%), and very low HRQOL (11%). Among many differences by race, ethnicity, and country of origin, Caribbean cancer survivors were more likely to be in the very low HRQOL cluster (odds ratio = 2.67, 95% confidence interval = 1.31 to 5.43) compared with non-Hispanic White survivors. Similarly, American Indian and Alaska Native, Cuban, Dominican, and Puerto Rican cancer survivors had relatively high percentages in the very low HRQOL cluster.

Conclusions

This study found statistically significant differences in HRQOL experience by race, ethnicity, and country of origin, even after adjusting for social determinants of health. These findings inform future HRQOL research to include these self-reported factors.
Traumatic Finger Amputation in the U.S. Military
Authors: Jordan James A , Polmear Michael M , Wells Matthew E , Dunn John C
Published: December 2022

Introduction

Finger amputations can lead to loss of work time and suboptimal function, particularly in the active duty military. There is a paucity of epidemiologic and outcome data for these injuries. The purposes of this study are to define key demographic data pertaining to transphalangeal finger amputations in the U.S. Military and to assess epidemiological data to define risk factors for medical readiness following finger injuries.

Materials and Methods

This was a retrospective review of the military electronic medical record of encounters between 2016 and 2019 with traumatic transphalangeal amputation ICD 10 codes S68.5 (thumb) and S68.6 (finger). Primary outcomes included median military occupational activity limitation length, ability to return to duty, and medical separation from the military.

Results

A total of 235 patients were included in the final dataset. 221 (94.0%) of these service members were able to return to full duty, although 14 (6.0%) underwent medical separation from the military because of their finger injuries. The median limited duty timeline was 6 weeks. Significant risk factors identified that led to increased rates of medical separation were the use of tobacco (odds ratio [OR] of 5.53, 95% CI 1.21–25.29), junior enlisted status (OR of 5.51, 95% CI 1.67–18.17), and thumb or index finger involvement (OR of 3.50, 95% CI 1.13–10.83).

Conclusions

Within a physically high-demand population, traumatic finger amputation can limit duties and may lead to medical separation from service. Traumatic finger amputations are common and often require 6 weeks of restricted short-term disability, particularly in a tobacco-using, young, physically active cohort.
Effects of Dextromethorphan on Nicotine-Induced Reward, Behavioral Sensitization, Withdrawal Signs, and Drug Seeking-Related Behavior in Rats
Authors: Huang Eagle Yi-Kung , Hung Hao-Yuan , Chen Yuan-Hao , Kao Jen-Hsin , Tsai Ai-Lun , Chow Lok-Hi
Published: December 2022

Introduction

Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence.

Aims and Methods

Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking–related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC).

Results

Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking–related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS.

Conclusions

The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.

Implications

Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking–related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.
871. Oral Ibrexafungerp Outcomes by Fungal Disease in Patients from an Interim Analysis of a Phase 3 Open-label Study (FURI)
Authors: Thompson George R , King Thomas , Azie Nkechi , Angulo David A , Prattes Juergen
Published: December 2022

Background

There are limited oral treatment options for patients with fungal infections who fail currently available antifungals or have an infection caused by resistant organisms. Ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of, or with fungal disease refractory to, standard antifungal therapy. We present an interim analysis of patient outcomes from the FURI study by fungal disease type.

Methods

FURI patients are eligible for enrollment if they have proven or probable: severe mucocutaneous candidiasis, invasive candidiasis, chronic or invasive aspergillosis, with documented evidence of failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment; or patients who cannot receive approved oral antifungal options (e.g., due to susceptibility), and continued IV antifungal therapy is clinically undesirable or unfeasible.

Results

An independent Data Review Committee (DRC) provided an assessment of treatment response for 113 enrolled patients in the FURI study from 27 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016–2021. Fifty-six patients (49.5%) had invasive candidiasis/candidemia, 32 (28.3%) had mucocutaneous candidiasis, 14 (12.4%) had vulvovaginal candidiasis (VVC), and 11 (9.7%) patients had aspergillosis.

Upon DRC review, the percent of patients with complete or partial response, or for VVC, clinical improvement (defined as vulvovaginal signs and symptoms score ≤ 1) was 58.4%; stable disease was 23.9%; and 11.5% had disease progression (including 2 VVC patients not meeting the criteria for clinical improvement). There was 1 death due to underlying causes, and 6 outcomes were indeterminate. The table presents outcomes by disease type.

Conclusion

Analysis of 113 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options.

Disclosures

George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Thomas King, MS MPH, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds Nkechi Azie, MD MBA FIDSA, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds David A. Angulo, MD, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds.
1583. A Case Series of Low-Level HBV Viremia After Switching to Long-Acting Injectable Cabotegravir/Rilpivirine in Patients with HIV, Hepatitis B Core Antibody Positivity, and Hepatitis B Surface Antigen Negativity
Authors: Welford Elliott , Yin Jeffrey , Hill Lucas , Wooten Darcy
Published: December 2022

Background

Two-drug antiretroviral therapy (ART), including long-acting injectable cabotegravir and rilpivirine (LAI CAB/RPV), is increasingly used for treatment of people with HIV. Many two-drug regimens do not contain tenofovir (TFV), and guidelines recommend ensuring patients are not chronically infected with hepatitis B virus (HBV) before switching to a TFV-free regimen since this could lead to HBV reactivation. The approach to regimen switching in patients who are HBV surface antigen (sAg) negative but who are HBV core antibody (HBcAb) positive is less clear. We describe three cases of HBV low-level viremia in patients switched to LAI CAB/RPV and who were HBcAb positive and sAg negative.

Methods

We conducted a retrospective case series of patients with HIV switching to LAI CAB/RPV who were HBcAb positive and sAg negative. We reviewed pre-switch HBV studies, history of HBV vaccination, current ART, CD4 cell count, and HIV viral load, and liver function tests (LFTs) where available. After switching to LAI CAB/RPV, we reviewed patients’ HBV DNA PCR, HBVsAg, and ART management.

Results

Of the 149 patients in our clinic who were switched to LAI CAB/RPV, 38 (25.5%) were HBcAb positive and sAg negative. Of these 38 patients, three (7.9%) developed HBV viremia (Figure 1). Two of the patients were switched back to a TFV-containing three-drug regimen with subsequent suppression of HBV DNA levels. Through shared decision-making, the third patient opted to continue LAI CAB/RBV. Repeat HBV DNA levels were detected but remained low and the patient’s sAg remained negative. All patients’ LFTs remained within normal limits. Of interest, one of the three patients had a surface antibody level of 115 mIU/mL at baseline.

Conclusion

Our case series describes three cases of HBV low-level viremia following a switch off of HBV-active ART to LAI CAB/RPV. The clinical significance of this low-level viremia is unclear and warrants further investigation. We recommend a post-hoc analysis of stored samples from patients in ATLAS, FLAIR, and ATLAS-2M who were HBcAb positive to determine if low-level HBV viremia occurred in these patients and if surface antibody levels influenced the likelihood of reactivation.

Disclosures

Lucas Hill, PharmD, AAHIVP, Gilead Sciences: Speakers Bureau.
1228. Comparison of surgical site infection between open and robotic-assisted gastrectomy in patients with gastric cancer
Authors: Kim Jinnam , Lee Se Ju , Lee Ki Hyun , Lee Eun Hwa , Baek Yae Jee , Kim Jung Ho , Ahn Jin Young , Jeong Su Jin , Ku Nam Su , Son Taeil , Choi Jun Yong , Yeom Joon-sup
Published: December 2022

Background

Surgical site infection is a clinically significant postoperative complication and a major cost burden of healthcare-associated infections. Although many studies compare minimally invasive surgery and open surgery, few studies have focused on surgical site infection. This study aimed to investigate the differences in the incidence of surgical site infection after open and robotic-assisted gastrectomy in patients with gastric cancer.

Methods

We retrospectively reviewed adult patients with gastric cancer who underwent open and robotic-assisted gastrectomy at a 2,400-bed tertiary hospital in Seoul from January 2015 to December 2015. Postoperative outcomes, including surgical site infection between open and robotic-assisted gastrectomy, were compared. Risk factors of surgical site infection were analyzed by logistic regression multivariable analysis.

Results

A total of 684 patients, including 448 patients who underwent open gastrectomy and 236 patients who underwent robotic-assisted gastrectomy, were enrolled. The median age was 58 years. The overall incidence of surgical site infection was 7.6%. The incidence of surgical site infection was significantly lower in the robotic-assisted gastrectomy group than in the open gastrectomy group (9.2% vs. 4.7%, p=0.035). The length of hospital stay was significantly shorter in the robotic-assisted gastrectomy group than in the open gastrectomy group (5 vs. 8 days, p< 0.001). Multivariate logistic regression revealed that the operative time, history of smoking, and open gastrectomy were independent risk factors influencing the incidence of surgical site infection.

Conclusion

Robotic-assisted gastrectomy is a good multimodality treatment option for gastric cancer in terms of reduced length of hospital stay and incidence of surgical site infection.

Disclosures

All Authors: No reported disclosures.
1323. Laboratory Abnormalities in Children Undergoing Outpatient Therapy for Staphylococcus aureus Acute Hematogenous Osteomyelitis: Should We Worry?
Authors: McNeil Jonathon C , Sommer Lauren M , Joseph Marritta , Kaplan Sheldon L , Vallejo Jesus G
Published: December 2022

Background

Recent PIDS practice guidelines for acute hematogenous osteomyelitis (AHO) advocate for regular laboratory monitoring for adverse drug events. Data are limited however with respect to the frequency or clinical impact of antibiotic-related laboratory abnormalities (ARLA) in pediatric AHO. We reviewed the experience with ARLA in children undergoing treatment for S. aureus AHO.

Methods

Cases of S. aureus AHO in children were reviewed from 2011-2020. Eligible cases were those 1) discharged to complete therapy at home (IV or oral), 2) with baseline complete blood count (CBC), creatinine and AST/ALT obtained during the hospitalization and 3) at least one CBC, creatinine, and/or AST/ALT measurement in the outpatient setting while receiving AHO therapy. Neutropenia, thrombocytopenia and AST/ALT elevation were defined using the NIH DAIDS pediatric toxicity grading system; acute kidney injury (AKI) was defined using pRIFLE.

Results

207 subjects met inclusion criteria. Outpatient CBC was obtained in 187 subjects, creatinine in 121 and AST/ALT in 63. Patients with and without ARLA were similar with respect to age and demographics. Neutropenia developed in 12 (6.4%) and thrombocytopenia in 5 (2.7%) at a median of 23 and 18 days of therapy, respectively (Figures 1). Outpatient hematologic abnormalities were more common among subjects with MRSA, history of inpatient ARLA and those receiving certain antibiotics, specifically vancomycin (Figures 2, 3). There was no clear relationship with hematologic abnormalities and vancomycin daily dose. Neutropenia prompted modification of therapy in 1 case. No infections or bleeding events were attributable to ARLA. Three cases of outpatient AKI occurred (2.1% [vancomycin, n=1; cefazolin, n=2]); one subject had therapy discontinued. Outpatient AST/ALT elevation occurred in six (9.5%), none of which were symptomatic. Patients with AST/ALT elevation were disproportionately treated with cefazolin (p=0.006).

Panel A. The number of patients experiencing antibiotic-related laboratory abnormalities (ARLA). Panel B. Box plots depicting the timing of ARLA relative to initiation of antimicrobial therapy.

Conclusion

ARLAs, particularly neutropenia, are common in patients receiving outpatient therapy for AHO after 2-3 weeks of therapy. However, the majority of ARLA are mild and do not result in symptoms or modification of therapy. Further study is necessary to appreciate how these findings might be applicable to all cause osteomyelitis.

Disclosures

Jonathon C. McNeil, MD, Agency for Healthcare Research and Quality: Grant/Research Support|Allergan: Provided reagents for unrelated research|Nabriva: Site investigator for multicenter clinical trial Sheldon L. Kaplan, MD, MeMed: Grant/Research Support|Pfizer: Grant/Research Support.
1345. The Cascade of Care for Early Infant Diagnosis in Zimbabwe: Point of Care HIV Testing at Birth and 6-8 weeks
Authors: Aitcheson Nancy , Sacks Emma , Cohn Jennifer
Published: December 2022

Background

Routine birth testing of HIV exposed infants (HEI) using point of care (POC) nucleic acid testing may allow for earlier diagnosis and treatment of HIV-infected infants than current methods, but more data are needed on retention in care for those diagnosed as HIV-positive at birth and on re-testing for those with a negative HIV test at birth.

Methods

POC birth testing (within 48 hours of birth) was offered to all HEI born at ten public maternities in Zimbabwe from November 2018 to July 2019. Data from routine registers, including information on re-testing at 6–8 weeks for infants testing HIV-negative at birth and six-month retention in care among infants testing HIV-positive at birth.

Results

Of 2,854 eligible HEI, 2,806 (98.3%) received a POC HIV birth test. We identified 39 HIV-infected infants (1.4%), and 23 (59%) were started on ART. Of those, 20 infants (87%) remained on ART at six months. Of the 2,694 infants who tested negative at birth, 1,229 (46.5%) had a documented re-test at 6-8 weeks, and 7 (0.6%) of those infants tested positive.

Conclusion

Uptake of POC birth testing was high in the 10 study facilities. However, ART initiation for HIV-positive infants was low. Among infants initiated on ART, most but not all continued ART at 6 months. Among infants who tested negative at birth, rates of testing at 6-8 weeks of life were similar to national rates of testing at the same age without a birth test (56%). Improving infant HIV testing rates at 6-8 weeks, regardless of birth testing, should be a priority. Additionally, insuring that HIV-positive newborns are started and retained on ART is critical for preventing morbidity and mortality among HIV-infected infants.

Disclosures

All Authors: No reported disclosures.
1431. Evaluation of Drug-induced Liver Injury in Patients Receiving Anti-tuberculosis Medications and Subsequent Management
Authors: Acosta Carina , Barsoum Barbara , Doan Thien-Ly
Published: December 2022

Background

For anti-tubercular medications, the risk of drug-induced liver injury (DILI) ranges from 5-33%. DILI may be asymptomatic or may present with fever, nausea, vomiting, anorexia, and lethargy. The objective of this review is to describe the incidence of hepatotoxicity occurring with anti-tuberculosis medications, management of DILI, and re-initiation of therapy.

Methods

Adult patients prescribed pyrazinamide during their hospital stay at Long Island Jewish Medical Center were screened for inclusion criteria of DILI (liver enzymes ≥ 3x upper limit of normal [ULN] from 7/2017 to 2/2022. IRB classified this analysis as a quality improvement project. Using the electronic medical record, retrospective data was collected for those meeting criteria for DILI which included baseline demographics, concomitant hepatotoxic medications, laboratory values (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST], timing of drug interruption, and sequence of re-initiation.

Results

A total of 108 patients were screened and then 17 were included in the analysis. DILI was found in 16% of patients. The mean age was 57 years and 53% were female. None of the patients with liver injury had a history of hepatic disease, prior DILI, or alcohol consumption. Mean baseline laboratory values were total bilirubin 0.52 mg/dL, alkaline phosphatase 166 U/L, AST 54 U/L, and ALT 40 U/L. All patients were initiated on first-line treatment for drug-susceptible tuberculosis. Thirteen patients had concomitant hepatotoxic drugs (11 acetaminophen, 4 statins, 2 azole antifungals, 1 trimethoprim/sulfamethoxazole). Fourteen patients (82%) developed DILI where AST was ≥ 10 times the ULN. Drug interruption was necessary in 16 of the 17 patients (94%). Seven patients (58%) were re-initiated on treatment according to the American Thoracic Society recommendations with a mean of 8 days after drug interruption.

Conclusion

In conclusion, the management of DILI related to anti-tubercular medications in our institution can further be standardized to reintroduce a rifamycin analog with or without ethambutol. Education on the avoidance of concomitant hepatotoxic medications such as acetaminophen and selecting the most appropriate agents to sequentially re-initiate treatment is warranted.

Disclosures

All Authors: No reported disclosures.
1866. Burden of Death Associated with SARS-CoV-2 Infection during the Pandemic in Flint, Michigan (MI): Mortality Trends over the 2-year time period
Authors: Younas Mariam , Rios-Bedoya Carlos , Osterholzer Danielle , Bachuwa Ghassan , Bachuwa Ghassan , McDonald Philip , Seedahmed Elfateh
Published: December 2022

Background

Approximately 2.4 million cases of SARS-CoV-2 infection have been reported in MI, leading to 35,935 deaths. We aimed to study the mortality trends in patients with SARS-CoV-2 infection during the pandemic in Flint, MI.

Methods

Hurley Medical Center, is a 443-bed inner city teaching hospital in Flint, MI. We retrospectively collected basic demographics, treatment data, and outcomes on adults (≥ 18 years (yrs) of age) with confirmed SARS-CoV-2 infection, admitted and discharged from our facility from 03/2020 through 02/2022. The 2-year span was further divided into 6-time periods (Table 1).

Results

During the 2-year study period, the overall crude 90-day mortality rate was 16% (269/1668) and the In-hospital case fatality rate was 15% (244/1668). 90-day mortality was lowest in the time period 5 (Table 1). Men comprised 50% of the cohort and were 1.5 times more likely to die than women (p-value 0.001). African Americans comprised 51% and whites 44% of the cohort. A specific race was not associated with mortality (Table 2). Non-survivors tended to be older, mean age of 68 vs 57 yrs (p-value < .0001). See Table 3 for mean Body Mass Index (BMI). Hypertension (HTN) was the most common co-morbidity (61%), and was strongly associated with mortality (p-value < 0.005) (Table 4). During the study period, 12% of the cohort (207/1668) had received at least one dose of available COVID-19 vaccines (including single dose of Johnson and Johnson’s Jansen vaccine). 89% of non-survivors were unvaccinated (adjusted Odds ratio for mortality 1.61, 95% CI 1.03 - 2.53, p-value 0.038).

Conclusion

Despite substantial changes in supportive care and management, SARS-CoV-2 infection regardless of the circulating variants carried a significant mortality risk. Trend towards improving mortality can partly be attributed to better supportive care-treatments, and some background immunity from prior infection or vaccination. Immunization against COVID-19 is highly protective against severe disease. Vaccination coverage in this high-risk cohort was low, at only 12%. Vaccination coverage in Flint and surrounding areas remains low at less than 50% as reported by Genesee County health department. Public health efforts should be focused at overcoming the barriers to vaccine acceptance in this high-risk unique population.

Disclosures

All Authors: No reported disclosures.
2350. LiaF is required for LiaX mediated protection against Daptomycin and LL-37 in Enterococcus faecalis OG1RF
Authors: Botero Diana Panesso , Singh Kavindra , Gomez-Villegas Sara-Isabel , Khan Ayesha , Supande Adeline , Nguyen April , Rincon Sandra , Hood Kara S , Dinh An , Deyanov Alexander , Miller William R , Shamoo Yousif , Tran Cecilia , Arias Cesar A
Published: December 2022

Background

Daptomycin (DAP) resistance in enterococci is regulated by the LiaFSR three-component regulatory system. Mutations in liaF have been linked to activation of this system, with increased expression of the protein LiaX, and resistance to DAP in clinical isolates. LiaX functions by recognizing DAP in the extracellular medium, and serves as a signal transduction molecule. However, the role of LiaF in signaling and its relationship with LiaX are unknown.

Methods

We generated a liaF null mutant in E. faecalis OG117 by adding four stop codons at amino acid positions 11–14 (OG117liaF*11-14) using a CRISPR-Cas9 system. The mutant was complemented by restoring wild-type liaF in its chromosomal location (OG117liaF*11-14::liaF). Mutants were confirmed with whole genome sequencing (WGS). Anionic phospholipid (AP) microdomain distribution was assessed on microscopy using 10-N-nonyl-acridine-orange (NAO). LiaFSR activation was assessed by surface expression of LiaX via ELISA. DAP MICs were performed by broth microdilution in the presence/absence of exogenous LiaX (eLiaX). LL37 (50µg/ml) and DAP (1.5µg/ml) killing assays with eLiaX were also performed in triplicate.

Results

Truncation of liaF did not have any effect on DAP MICs, AP microdomain distribution or LiaX surface expression compared to OG117. No additional mutations were observed by WGS in the mutants. In the presence eLiaX, DAP MIC increased 8-fold in wild-type OG117 but remained the same (1 µg/mL) in OG117liaF*11-14. Complementation of liaF restored the increase in DAP MIC in the presence of eLiaX. In the LL37 killing assay, survival of OG117 was significantly increased on the addition of eLiaX (2.9% vs 11.8%, respectively, P < .002). Addition of eLiaX was unable to rescue OG117liaF*11-14 in the presence of LL-37 (2.4% vs 2.5% respectively, P=0.51), but was able to increase survival in the complemented strain (2.8% vs 7.6%, respectively, P < .002). A similar trend was seen in the DAP killing assay, with increased survival for OG117 (8.7% vs 20%) and OG117liaF*11-14::liaF (11.6% vs 17%), but not OG117liaF*11-14 (0.38% vs 1%).

Conclusion

LiaF is required for full tolerance to the cathelicidin LL37 and DAP in E. faecalis OG1RF. These results suggest that LiaF may interact with LiaX as a part of the LiaFSR stress response.

Disclosures

William R. Miller, MD, Entasis: Grant/Research Support|UpToDate: Honoraria Cesar A. Arias, MD, PhD, Entasis: Grant/Research Support|MeMed Diagnostics Ltd: Grant/Research Support|Merck: Grant/Research Support.
1944. Effectiveness of COVID-19 Vaccines Against Severe Disease and Death and its Durability Over Time Against the Omicron Variant
Authors: Lytras Theodore , Mellou Kassiani , Gkolfinopoulou Kassiani , Gerolymatos Gerasimos , Paraskevis Dimitrios , Zaoutis Theoklis , Tsiodras Sotirios
Published: December 2022

Background

We aimed to estimate COVID-19 Vaccine Effectiveness (VE) and its durability against severe disease (intubation) and death in the Greek population, for all vaccines currently in use.

Methods

Nationwide active surveillance and vaccination registry data between January 2021 – April 2022 were used to estimate VE via quasi-Poisson regression as one minus Incidence Rate Ratio, adjusted for age and calendar time. Interaction terms were included to assess VE by age group, by variant (delta vs omicron) and by time since vaccination (compared to the first month after vaccination).

Results

VE results are summarized in Figures 1-3. After 2-doses (of any vaccine) VE was >95% against delta and >85% against omicron in the 15-59 and 60-79 age groups, but waned significantly at 6 months by 5-10% in the 15-59 group and 15-20% in the 60-79 group. In the 80+ age group, 2-dose VE was much lower against omicron at around 60%, waning to 50% at 6 months. With 3 vaccine doses VE surged to >95% against both delta and omicron in all age groups except 80+, who had VE against omicron of ≈90%; however there was again substantial waning at 6 months by about 10-15% in all groups. In the 80+ age group, VE against omicron dropped to 81.4% (95% CI 76.7–85.2%) for death and 57.7% (95% CI 38.5–70.9%) for intubation. There was little to no evidence of variation in VE between combinations of different vaccines (BNT162b2, mRNA-1273, ChAdOx1 nCov-19 and Ad26.COV2.S), although the majority of the population received 2- or 3-dose BNT162b2. Vaccination prevented an estimated 39,018 COVID-19 deaths (95% CI: 37,791–40,608) over the study period. Figure 1.Vaccine Effectiveness for 1, 2 and 3 doses (any vaccine), ages 15-59Figure 2.Vaccine Effectiveness for 1, 2 and 3 doses (any vaccine), ages 60-79Figure 3.Vaccine Effectiveness for 1, 2 and 3 doses (any vaccine), ages

Conclusion

COVID-19 vaccination remains extremely effective in preventing severe disease and death, even in the context of the omicron variant, as long as 3 doses have been administered. Even after 3 doses, however, effectiveness wanes substantially in the course of 6 months. Additional strategies will be therefore needed in order to minimize COVID-19 mortality and morbidity, including boosting doses especially in the elderly, improved vaccines, early diagnosis and treatment of high-risk groups and measures to reduce community transmission of current or novel SARS-CoV-2 immune escape variants.

Disclosures

All Authors: No reported disclosures.
2354. Implementation of BPaL in the United States: Experience using a novel all-oral treatment regimen for rifampin-resistant or treatment-intolerant TB disease
Authors: Haley Connie A , Ashkin David , Peloquin Charles A
Published: December 2022

Background

Tuberculosis (TB) remains a leading infectious cause of death and morbidity globally. Rifampin-resistance or intolerance requires prolonged treatment using less effective, more toxic regimens. Recent trials demonstrated that the all-oral six-month “BPaL” regimen, Bedaquiline, Pretomanid and Linezolid, is 90% effective. In these trials, linezolid-induced hematologic and neurologic toxicity was high using 1200mg daily, whereas lower exposure (dose or duration) reduced toxicity. Therapeutic drug monitoring (TDM) is used by U.S. TB experts to maintain a serum linezolid trough < 2ug/ml, which correlates with reduced toxicity. Since U.S. FDA approval in 2019, BPaL has been widely implemented for the treatment of rifampin-intolerant or resistant TB disease.

Methods

We evaluated a cohort of patients with TB treated from October, 2019 through April, 2022, describing patient demographics, BPaL treatment dosing, and adverse events. TDM was performed for clinical purposes using liquid chromatography–mass spectrometry to measure serum levels at trough and 2 and 6h post-linezolid dose. Clinical providers adjusted linezolid dose and dosing interval targeting a trough < 2ug/ml and peak of 12–26ug/ml.

Results

Among 64 BPaL patients, ages were 15–83 years, 22 (34.3%) were female, 6 (9.3%) U.S.-born, 4 (6.3%) HIV-infected. 50 (78.1%) had only pulmonary disease, 6 extrapulmonary, and 8 had both; 61 (91.0%) were culture-confirmed. Most (n=62) started linezolid 600mg daily. Linezolid was adjusted for 39 (66.1%) of the 59 patients with TDM; 18 had a trough >2ug/ml, 30 had dosing interval increased to thrice-weekly, and 17 had a dose increase. 52 (81.3%) patients completed BPaL and 12 remain on therapy. One 81-year-old female with diabetes, hypothyroidism, and B12 deficiency discontinued linezolid at 12 weeks for worsened neuropathy (linezolid trough=1.13ug/ml). She completed 26 weeks of bedaquiline/pretomanid and her symptoms returned to baseline.

Conclusion

Use of BPaL with clinical and TDM monitoring has transformed treatment of rifampin-resistant or intolerant TB in the U.S. Patients previously sentenced to 18–24 months of treatment with 5–7 hard-to-tolerate medications and modest efficacy can now complete treatment in 6–9 months with little toxicity and exceptional cure rates.

Disclosures

All Authors: No reported disclosures.
2358. Dementia and Cognitive Concerns are Risk Factors for Mortality in People with Human Immunodeficiency Virus and COVID-19
Authors: Mukerji Shibani S , Wilcox Douglas R , Rudmann Emily A , Ye Elissa , Noori Ayush , Magdamo Colin , Alabsi Haitham , Triant Virginia A , Robbins Gregory , Brandon Westover M , Das Sudeshna
Published: December 2022

Background

Despite higher prevalence of cognitive disorders in people with human immunodeficiency virus (PWH) and dementia being a risk factor for COVID-19 mortality, the association between dementia and adverse outcomes in PWH with COVID-19 has not been well established.

Methods

This was a matched case-control study (1:10) of patients with and without HIV at an academic institution with documented SARS-CoV-2 polymerase chain reaction (PCR) positivity from March 2020-March 2021. Data were extracted from the electronic health record data registry. PWH were matched to people without HIV (PWoH) by age, sex, race, and zip code. The primary exposures were dementia (identified using International Classification of Diseases, Tenth Revision codes) and cognitive concerns, defined as documentation of possible cognitive impairment up to 12 months prior to COVID-19 diagnosis and ascertained using a semi-automated natural language processing annotation tool. VACS 2.0 Index (including age, sex, body mass index, CD4+ T-cell count and HIV-1 RNA) was calculated. Logistic regression models assessed the effect of dementia and cognitive concerns on the odds of death (OR [95% confidence interval]), adjusted for VACS 2.0 Index.

Results

Sixty-four (0.45%) PWH were identified among 14129 patients with COVID-19 and were matched to 463 PWoH. Among PWH, 59% were virally suppressed, and 14% had CD4< 200 cells/μL. Compared to 463 matched PWoH, PWH had higher prevalence of dementia (16% vs. 6%, p=0.01) and cognitive concerns (22% vs. 16%, p=0.04). Death was more frequent in PWH (17% vs. 6%, p< 0.01) and at younger ages (58 vs. 66 years, p=0.03). Cognitive concerns (2.5 [1.1–5.9], p=0.03) and dementia (3.4 [1.3–8.1], p=0.01) were significantly associated with increased adjusted odds of death in the overall group. Among PWH, cognitive concerns (7.2 [1.1–48], p=0.04) and dementia (6.0 [0.8–43.8], p=0.08) remained associated with mortality.

Conclusion

Dementia and cognitive concerns were associated with mortality among PWH with COVID-19. The magnitude of the effect of cognitive impairment on COVID-19 outcomes may be greater in HIV, and additional studies with larger cohorts will help to assess this association further. Assessment of cognitive status is an important component to care for aging PWH in the COVID-19 era.

Disclosures

All Authors: No reported disclosures.
2090. The Impact of Structural Racism and Discrimination on the HIV Pre-exposure Prophylaxis Continuum: Evidence from a Systematic Review of the Published Literature
Authors: Ghadimi Fatemeh , Seyedroudbari Sara , Nkwihoreze Hervette , Momplaisir Florence
Published: December 2022

Background

Pre-exposure prophylaxis (PrEP) is an evidence-based intervention shown to effectively reduce HIV infection. However, PrEP is under-utilized, especially among racial and ethnic minority groups where HIV incidence is the highest. Here, we aim to describe the impact of structural racism and discrimination (SRD) on the PrEP continuum.

Methods

We performed a systematic review of the published literature using MEDLINE database for keywords such as HIV, PrEP, racism, and healthcare disparities. Inclusion criteria were original, U.S.-based studies in English published since 2012. Our main exposure was SRD defined as a socially structured action that is unfair and harms individuals and groups on the basis of race, ethnicity and/or other statuses. Outcome measures included ≥ 1 step of the PrEP continuum. Qualitative analyses were excluded.

Results

The search returned 297 papers, from which 37 studies met inclusion criteria. SRD was described at the individual level in 1 studies, at the interpersonal in 17 studies, and the societal level in 15 studies with some studies including multiple levels of SRD. In 4 studies, there were no reported differences by race and 1 study reported no differences by neighborhood socioeconomic status. Disparities were observed across each step of the PrEP continuum with Black and Hispanic patients being less likely to have a discussion about PrEP, less likely to receive a PrEP prescription and less likely to adhere or be retained in PrEP care compared to White patients. In two large studies, race-based differences in PrEP prescription were particularly stark: one study with 25,886 patients reported that Black race was found to be an independent factor for non-PrEP prescription and the other with 32,853 patients found that PrEP prescription was 6 times higher among Whites compared to Black patients. Potential mediators to poor PrEP continuum outcomes included perceived healthcare-related discrimination, provider related implicit bias and racial stereotypes, housing instability, food insecurity, insurance status, and history of incarceration.

Conclusion

SRD at multiple levels contribute to racial disparities across the PrEP continuum. Strategies that reduce SRD may help to mitigate racial/ethnic disparities in PrEP continuum outcomes.

Disclosures

All Authors: No reported disclosures.
2101. CMV Infections in Multiple Myeloma Patients
Authors: Ilyas Sahrish , Jacobs Samantha E , Rana Meenakshi , Baneman Emily
Published: December 2022

Background

Substantial progress in the treatment of multiple myeloma (MM) has led to improved patient outcomes and prolonged survival of patients. These therapeutic advances have resulted in increased cumulative immunosuppression leading to increased susceptibility to opportunistic infections including CMV infection. The significance of CMV infection in MM patients is not well understood. We sought to describe the clinical characteristics and outcomes of patients with MM who develop CMV infection.

Methods

Retrospective chart review of MM patients at Mount Sinai Hospital in NY who had CMV DNA PCR sent. The Mount Sinai Multiple Myeloma Database was utilized to identify patients who developed CMV viremia. Demographic, clinical and laboratory data were abstracted from electronic medical records. IRB approval was obtained.

Statistical Analysis

Factors associated with 30-day mortality by univariate analysis were evaluated using Fischer’s exact and Wilcoxon rank-sum test.

Results

Demographics

414 MM patients had CMV PCR sent at least once. Forty-six cases of CMV infection were identified.

CMV Infection Characteristics

Forty-six patients were found to have CMV viremia, defined as PCR >500 IU/mL. Twenty-two (47%) had symptomatic infection. One patient had CMV pneumonitis and in 7/46 (15%) patients, CMV end-organ disease was suspected. Twenty (43%) patients had progressive disease status, 73% had prior history of autologous stem cell transplant and 85% had received steroids within 30 days of CMV infection. Twenty-nine (63%) patients had concurrent infections within 30 days of CMV infection, including bloodstream infection (n=16), bacterial pneumonia (n=9), respiratory viral infection (n=6), infectious colitis (n=5), and fungal infection (n=3).

Outcomes

9/46 (19%) patients died within 30 days of CMV infection and 12/46 (26%) required ICU admission during that hospitalization. In univariate analysis of risk factors associated with mortality, higher weekly steroid dose approached statistical significance (p=0.06) and peak CMV PCR >1000 IU/mL (p.008) was associated with lower mortality.

Conclusion

CMV infection is associated with morbidity and mortality in MM patients. Prospective studies are needed to better assess the clinical significance of CMV reactivation in this population.

Disclosures

Emily Baneman, MD, Merck: Grant/Research Support.
128. Association of PBP4 Variants and β-lactam Susceptibility in Enterococcus faecalis
Authors: Tran Truc Cecilia , Simar Shelby R , Egge Stephanie L , Atterstrom Rachel , Dinh An , Hanson Blake M , Contreras German , Zervos Marcus , Abbo Lilian M , Shimose Luis , Shelburne Samuel A , Arias Cesar A , Miller William R
Published: December 2022

Background

Penicillin-binding protein 4 (PBP4) is a low affinity PBP that has been associated with decreased susceptibility to penicillins in Enterococcus faecalis (Efs). In vitro data have shown that changes in the promoter region leading to increased pbp4 gene expression and amino acid changes resulting in active site remodeling contribute to this phenotype. There is limited data on the prevalence of these strains in the United States. We investigated β-lactam susceptibility trends in association with variations in PBP4 (allotypes) and the upstream promoter region.

Methods

Efs bloodstream isolates (n=184) were selected from the multicenter VENOUS cohort from 2016 to 2021. Whole genome sequencing (WGS) was performed on all isolates, and changes in the pbp4 gene and promoter region 200 bp upstream of the start codon were identified using Efs JH2-2 as reference. Broth microdilution (BMD) testing for ampicillin (AMP), penicillin (PCN), piperacillin (PIP), and imipenem (IMI) was performed for 81 isolates. Analysis of MICs vs. WGS results was performed.

Results

A total of 31 PBP4 allotypes and 10 promoter variations were identified. ST6 isolates most frequently carried the promoter mutation ΔA117 (P6), previously shown to increase expression of the pbp4 gene, with allotype 1 PBP4 (Fig 1). ST179 isolates most frequently carried the JH2-2 wild type promoter (P1) with the allotype 30 PBP4. All isolates were susceptible to AMP (MIC50 ≤1 µg/mL, MIC90 2 µg/mL) and PCN (MIC50 ≤2 µg/mL, MIC90 4 µg/mL; Table 1). PIP was the least potent β-lactam, with an MIC50 4 µg/mL and an MIC90 of 8 µg/mL. Isolates with the P6 promoter had significantly higher piperacillin MICs (p< 0.0001) as compared to P1. Figure 1.Phylogenetic Tree of E. faecalis Strains

Conclusion

Changes in the pbp4 gene promoter correlated with an increase in PIP MICs. Caution should be used when choosing β-lactams other than AMP for definitive treatment deep-seated Efs infections.

Disclosures

Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support William R. Miller, MD, Entasis Therapeutics: Grant/Research Support|UpToDate: Royalties - Topic Contributor.
153. Molnupiravir Exhibits a High Barrier to the Development of SARS-CoV-2 Resistance in vitro
Authors: Strizki Julie , Murgolo Nicholas , Gaspar John , Howe John , Hutchins Beth , Mohri Hiroshi , Ho David D , Hazuda Daria , Grobler Jay
Published: December 2022

Background

Molnupiravir is an orally available prodrug of the antiviral nucleoside analog N-Hydroxycytidine (NHC). In preclinical studies NHC has shown broad-spectrum antiviral activity against multiple RNA viruses including SARS-CoV-2. Incorporation of NHC by viral polymerases impairs replication by introducing errors into the viral genome. NHC has been shown to have a high barrier to the development of resistance in vitro with RSV, Influenza and Venezualen Equine Encephalitis viruses. In these studies, we have explored the potential for SARS-CoV-2 to develop resistance to NHC in cell culture.

Methods

Vero E6 cells were infected with SARS-CoV-2 (WA-1) in triplicate in the presence of NHC or a C3L-protease inhibitor (MRK-A). Culture supernatants from wells with the highest drug concentration exhibiting a cytopathic effect (CPE) score of ≥ 2+ were repassaged and at each passage, IC50 values were estimated based on CPE scoring. At each passage, full genome next generation sequencing (NGS) was performed on the viral RNA

Results

No change in susceptibility to NHC (EC50 fold change ≤ 1.1) was noted in 2 of 3 cultures and a 2-fold change was observed in one culture after 30 passages. In contrast, a 3- to 4-fold decreases in susceptibility to the 3CL protease inhibitor were seen by passage by 12, with increasing resistance of 4.6- to 15.7-fold observed by passage 30. NHC passaged viruses exhibited 53 to 99 amino acid changes, including substitutions and deletions (both in-frame and frameshift), across 25 different viral proteins as compared with 10 to 13 changes in 13 proteins in the MRK-A cultures. With NHC, 3 to 4 changes were observed in the viral polymerase; however, these were randomly distributed, and none were observed more than once. In contrast, the 3CL protease passaged virus had a nsp5 T21I substitution detected in all 3 cultures.

Conclusion

No evidence of SARS-CoV-2 phenotypic or genotypic resistance was observed following 30 passages with NHC. A random pattern of amino acid changes were observed across multiple proteins consistent with the mechanism of action of NHC. In the same study, resistance was readily selected to a control 3CL protease inhibitor. Together these data support previous reports demonstrating the high barrier to resistance of NHC.

Disclosures

Julie Strizki, PhD, Merck and Co.: Stocks/Bonds Nicholas Murgolo, PhD, MERCK: Employee|MERCK: Stocks/Bonds John Howe, PhD, Merck & Co Inc: Employee|Merck & Co Inc: Stocks/Bonds Beth Hutchins, PhD, Merck & Co.: Employee|Merck & Co.: Stocks/Bonds Hiroshi Mohri, PhD/MD, Merck: Grant/Research Support Daria Hazuda, PhD, Merck: Employee|Merck: Stocks/Bonds Jay Grobler, PhD, Merck & Co., Inc.: Employee|Merck & Co., Inc.: Stocks/Bonds.