Scientific Review Panel Research Articles

Development of a Comprehensive Regulatory Model for Medical Devices

Abstract Background: The development of a comprehensive regulatory model for medical devices is essential to ensure the safety, efficacy, and quality of medical devices throughout their lifecycle, from design and development to post-market surveillance. This paper outlines a robust framework for such a regulatory model, detailing key components and processes necessary for effective regulation. Methods: The data and literature were collected from various databases including Springer, Science Direct, Taylor and Francis, Wiley, Bentham Science, and websites of different regulatory agencies. The collected data were utilized in the research work to formulate the new regulatory model. Results: Different guidelines represent acceptable regulatory practices for all medical items. There are four risk classification levels of the medical devices (class I–IV, based on the risk level). For every country, the regulatory requirements are different. Global regulations for medical device approval are essential to guaranteeing their quality, safety, efficacy, and performance before they can be put on the market to safeguard, prevent, enhance, and maintain public health. Different classes have different regulatory steps for approval of the devices, which varies from region to region. The World Health Organization’s Department of Essential Health Technologies’ Diagnostic Imaging and Medical Devices team has developed and implemented the Baseline Country Survey on Medical Devices. The proposed model includes the establishment of a clear legislative and regulatory framework, featuring a risk-based classification system aligned with international standards. It emphasizes rigorous pre-market requirements, including design controls, clinical evaluation, quality management systems, and technical documentation. Market authorization processes are described, highlighting pathways such as Premarket Notification (510(k)), Premarket Approval (PMA), and De Novo Classification, supported by thorough scientific review and expert advisory panels. The present study is all about the global requirements of the regulation of the medical devices and it was concluded that overall, a global comprehensive regulatory model for medical devices aims to strike a balance between ensuring patient safety, facilitating innovation, and enabling timely access to life-saving medical technologies around the world. Conclusion: The model advocates for international harmonization and collaboration, promoting regulatory convergence and the adoption of global standards. It also supports innovation through accelerated approval pathways and regulatory sandboxes, alongside continuous improvement driven by regulatory science research and stakeholder engagement. By integrating these elements, the comprehensive regulatory model aims to protect public health while fostering medical device innovation and ensuring global regulatory compatibility.

Award for Distinguished Contributions to Research in Public Policy: Martin Y. Iguchi.

The Award for Distinguished Contributions to Research in Public Policy is given to a psychologist who has made a distinguished empirical and/or theoretical contribution to research in public policy, either through a single extraordinary achievement or a lifetime of work. This contribution may consist of such factors as research leading others to view specific national policies differently; research demonstrating the importance of the application of psychological methods and theory to public policy; or research clarifying the ways in which scientific knowledge of human behavior informs public policy. Martin Y. Iguchi's work continues to impact the underserved in our communities, particularly his work to decrease the consequences of addiction and disease. He has a long history of bridge-building between academic entities, between academia and communities, and between academia and the public at large. Dr. Iguchi was an invaluable mentor to scholars of color and a role model to first-generation researchers. Dr. Iguchi served on numerous APA boards and committees, journal editorial boards, advisory boards, and scientific review panels. His dedication and humanism have been recognized with countless prestigious awards, and his influence in the field of psychology continues to this day. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

TriService Nursing Research Program: A critical component to support military nursing science

TriService Nursing Research Program: A critical component to support military nursing science

African Penguins and Localized Fisheries Management: Response to Butterworth and Ross-Gillespie

Abstract We present a response to Butterworth and Ross-Gillespie's (2022) comment on our perspectives on how forage fish fisheries are impacting the endangered African penguin (Sphenicus demersus), and corresponding management options. Butterworth and Ross-Gillespie overstate model uncertainties and downplay the clear ecological and conservation significance of the fisheries closure experiment. We demonstrate that their criticism of “pseudo-replication” is weak, and not in line with their own analyses nor with the interpretations of many international scientific review panels commissioned by the government of South Africa to evaluate experimental results. Their comment does not alter our fundamental conclusions that forage fisheries operating near penguin breeding colonies compete with the birds for food resources, are detrimental to the penguin's population health, and are impeding recovery. Given that sardines are depleted (DFFE, 2021) and the African penguin is approaching a conservation crisis, we reiterate our position that continuing the precautionary approach of closures at the local scale of central-place foraging penguins is warranted to facilitate their population growth under fisheries management goals to conserve and maintain ecosystem functions.

80. Heme Oxygenase-1 Gene promoter and associations with inflammation and subclinical vascular disease in Ugandan adolescents with and without HIV

Abstract Background Heme oxygenase-1 (HO-1) is a cytoprotective enzyme with potent anti-inflammatory, and anti-oxidant effects. The HO-1 response is modulated by functional polymorphisms (a dinucleotide (GT)n repeat length variation) in the HO-1 gene promoter region which have been associated with cardiovascular disease (CVD) susceptibility in adults. HO-1 polymorphisms and their associations with markers of inflammation and CVD in Ugandan adolescents with (HIV+) and without HIV (HIV-) have not been investigated. Methods We included 177 children (92 HIV+, 85 HIV-) enrolled in an ongoing observational cohort study at the Joint Clinical Research Center, Kampala, Uganda. All HIV+ participants were on ART. HO-1 (GT)n allele genotypes were determined by PCR of the (GT)n repeat region followed by fragment size determination on a capillary sequencer in DNA extracted from blood samples. Allele designations were assigned by number of (GT)n repeats: S < 27, M 27-34, or L > 34 repeats. We measured mean common carotid artery intima-media thickness (IMT) as a marker of CVD, markers of systemic inflammation (hsCRP, IL6, sTNFRI), monocyte activation (sCD14 and sCD163), and T-cell activation (expression of CD38 and HLA-DR on CD4+ and CD8+) , oxidized lipids, markers of gut integrity and fungal translocation (BDG). Results Median age (IQR) was 13 (11, 14), 44% were females, 86% had viral load < 20 copies/mL. 19% had a short allele genotype, 37% had a medium allele genotype and 44% had a long allele genotype (Figure). The shortest and longest allele length correlated with lower IMT in HIV- only (r=-0.36 and -0.30, respectively, p≤ 0.01 for both). Among biomarkers, only the medium allele correlated with oxidized lipids in HIV+ and with hsCRP and BDG in HIV- (p≤ 0.05). After adjusting for age, sex, and BMI, the presence of a long allele was associated with lower IMT. This was no longer significant after adjusting for markers of inflammation or oxidized lipids (Table). Heme Oxygenase-1 genotype allele length frequency in Ugandan cohort of HIV+ and HIV- youth 1: Models are adjusted for age (years), sex (male vs female), BMI (kg/m2) and HIV status (positive vs negative) 2: Models are adjusted for age (years), sex (male vs female), BMI (kg/m2), sCD14 (pg/mL) and HIV status (positive vs negative) 3: Models are adjusted for age (years), sex (male vs female), BMI (kg/m2), high sensitivity C reactive protein (ng/mL) and HIV status (positive vs negative) 4: Models are adjusted for age (years), sex (male vs female), BMI (kg/m2), oxidized lipids and HIV status (positive vs negative) Conclusion These findings underscore the potential of the HO pathways in modulating future risk for CVD in adolescents through inflammation. HIV status in this setting, likely influences the associations with the genotype with the risk of CVD. Further studies to validate our findings in this population are required. Disclosures Grace A. McComsey, MD, Gilead (Consultant, Advisor or Review Panel member)Janssen (Consultant, Advisor or Review Panel member)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Redhill (Research Grant or Support)Roche (Grant/Research Support)Tetraphase, Astellas (Research Grant or Support)Theratechnologies (Consultant)Vanda (Grant/Research Support)ViiV/GSK (Scientific Research Study Investigator, Advisor or Review Panel member)

1266. Melatonin for Renal Protection of Patients Treated with Polymyxin B: A Double Blind Randomized Clinical Trial

BackgroundPolymyxins are one of the last resort treatments for carbapenem resistant gram-negative infections. Nephrotoxicity is its main adverse effect and has been related to oxidative stress mechanisms. Melatonin was associated to reduction in polymyxins nephrotoxicity in animal studies. Our objective is to evaluate the effect of melatonin on renal protection of patients receiving polymyxin B.MethodsWe did a single center, double blind, randomized clinical trial (NCT03725267) of melatonin 30mg versus placebo for patients treated with polymyxin B from October 2018 to April 2021, in Porto Alegre, Brazil. Patients ≥18 years old, receiving polymyxin B for ≤48 hours, who accepted informed consent terms were included and excluded if intensive care unit (ICU) admission at enrollment, estimated glomerular rate estimated glomerular rate < 10ml/min, dialysis or previous melatonin use. Treatment with melatonin or placebo was randomized in blocks of 4 and maintained until the end of polymyxin B treatment of for a maximum of 14 days. Our main outcome was any level of nephrotoxicity by RIFLE score. Secondary outcomes were renal failure and need for dialysis. We estimated a sample size of 100 patients, however the study had to be stopped earlier due to recruitment restrictions imposed by the COVID-19 pandemic.ResultsEighty-eight patients were randomized, 44 received melatonin and 44 received identical placebo pills. Patients had a mean age of 63.6±17.3 years, 60.2% were male, and had a median Charlson index of 5 (3-8.3). Most infections (79.5%) were microbiologically confirmed, having 68.6% Klebsiella sp isolated. Urinary tract accounted for47.7% of infection sites. Median time of polymyxin B therapy was 9.1±6.6 days. Combination therapy was prescribed for 89.8% of patients and 38.6% received at least another nephrotoxic drug. All variables were equally distributed among groups. Nephrotoxicity rates occurred in 23 of 44 (52.3%) in both groups, P=0.99. Patients who developed renal failure were 8(18.2%) vs 9(20.5%) and dialysis occurred in 4(9.1%) vs 5 (11.4%) of melatonin and placebo groups respectively.ConclusionMelatonin did not show a clinically significant renal protective effect in patients treated with polymyxin B.Disclosures Maria Helena Rigatto, MD, PhD, CNPq (Grant/Research Support) Diego Rodrigues Falci, MD, MSc, PhD, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)GSK (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)MSD (Speaker’s Bureau)Pfizer (Speaker’s Bureau)United Medical (Speaker’s Bureau, Other Financial or Material Support) Alexandre Zavascki, MD, PhD, Pfizer (Grant/Research Support)

894. Trend of Transmitted Resistance Associated Mutations in People Living with HIV (PLWH) in a Large Southeastern U.S. Ryan White Clinic

BackgroundDepartment of Health and Human Services (DHHS) guidelines recommend integrase strand transfer inhibitors (INSTIs) as the backbone of preferred initial antiretroviral (ART) regimens (1). Baseline mutation rates for the INSTI class is 0.8% compared with an overall rate of 19% for all ART classes, based on Centers for Disease Control and Prevention (CDC) U.S. data from 2013-16 (2). First-generation INSTIs (raltegravir and elvitegravir) have a lower genetic barrier to resistance compared with newer, second generation INSTIs (bictegravir and dolutegravir) (3, 4). DHHS guidelines do not currently recommend routine HIV genotypic resistance testing to INSTIs prior to ART initiation (1). Our study seeks to determine the current prevalence of transmitted INSTI and overall resistance in a large southeastern U.S. Ryan White clinic.MethodsThis was a single-center, retrospective analysis of treatment naïve PLWH presenting for care from January 1, 2017 to December 31, 2020. Of these, 164 had a baseline genotype performed by one of two commercially available assays – Vela Genomics or ViroSeq. Subsequent interpretations were based on Stanford HIV Drug Resistance Database. Results65 patients (39.6%) had at least one transmitted resistance associated mutation (RAMs). Of these, 24 (36.9%) had an INSTI RAM. Baseline PI, NRTI, and NNRTI RAMs declined during the four-year interval (2017-2020), while the rate of INSTI RAMs increased from 11.1% to 19%; all conferred resistance to the first generation INSTIs with one also conferring resistance to second generation INSTIs.INSTI Resistance Associated Mutation Prevalence 2017-2020 Frequency of Antiretroviral Therapy Class Mutations Per Year Trend of INSTI Mutations and Resistance Associated Mutations 2017-2020 ConclusionUnlike the CDC data which showed the overall prevalence of INSTI RAM transmission rates during 2013-2016 to be 0.8%, our data suggests a higher rate of INSTI RAMs (14.6%) with overall ART RAM transmission of 39.6%. This increase in baseline resistance to the INSTI class, which occurred over time, mimics the historical development of RAMs seen in the earlier ART classes. Though suboptimal adherence in the population promotes development of RAMs, increased frequency of INSTI RAMs may be due to a lower barrier to resistance of first generation INSTIs. Should our observed trend continue, routine baseline INSTI resistance testing may need to be considered prior to ART initiation.Disclosures Cheryl Newman, MD, Gilead (Scientific Research Study Investigator)GSK/ViiV (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Janssen (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)

351. Antibiotic Management Decisions and Use of a Multiplex PCR Panel for Pneumonia Diagnosis Among Critically Ill Patients with COVID-19

BackgroundAntibiotic use among patients with COVID-19 is common, exceeds the prevalence of probable bacterial co-infection, and promotes development of resistant organisms. Lack of diagnostic microbiological data may prolong empiric broad-spectrum therapy. Here we evaluate the use of the BioFire FilmArray pneumonia panel (PP), a novel rapid diagnostic test, and antibiotic decisions among intensive care unit (ICU) patients with COVID-19.MethodsWe conducted a retrospective review of adult ICU patients admitted with COVID-19 between January 2020 and May 2021 at an academic medical center. ICU patients who underwent bronchoscopy/bronchoalveolar lavage (BAL) with PP (PP group) were matched by age (< 65 or ≥65), BMI (< 30 or ≥30), and BAL date (within 60 days) to ICU patients who did not undergo BAL (no-BAL group). PP patients were matched by age and BMI to ICU patients who underwent BAL without PP (no-PP group). Antibiotic use was compared between groups. Chi squared analysis, t-test, and ANOVA were used for comparisons as appropriate. Results65 patients were included; the majority were male (65%), < 65 years (86%), and had BMI ≥30 (54%) (Table 1). Only 17 no-PP matches were identified for PP patients due to infrequent BALs. Similar proportion of patients in PP and no-PP groups had organisms identified from BAL (54% vs. 47%, p=0.65). Among PP patients with a detected organism, all (n=13) had subsequent changes in antibiotic regimen ≤72 hours after BAL; 10/13 (77%) had a change targeted to detected organism and 5/13 (39%) had antibiotic narrowing. Among PP patients with no detected organism, only 4/11 (36%) had antibiotic narrowing or maintenance off antibiotics. In all groups, average antibiotic use exceeded 70% of admission duration.Table 1. Patient characteristics and antibiotic management. Abbreviations: BAL - bronchoalveolar lavage ConclusionRapid, highly sensitive diagnostic tests have potential to guide clinical decisions and promote antibiotic stewardship among patients with severe viral pneumonia and suspected bacterial co-infection. In this descriptive analysis, antibiotic management did not differ significantly with use of PP. While most patients with detected organism on PP had targeted antibiotic changes, a negative PP did not appear to influence antibiotic narrowing. Larger studies and provider education are needed to evaluate potential of the PP for antibiotic stewardship. Disclosures Jason Zucker, MD, MS, Nothing to disclose Daniel A. Green, M.D., BioFire (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Deborah Theodore, MD, BioFire Diagnostics (Other Financial or Material Support, Donation of testing materials to support investigator-initiated research)

132. Standardized Antimicrobial Administration Ratios to Guide Antimicrobial Stewardship in the Neonatal Intensive Care Unit: a Single Center Experience

BackgroundAntimicrobial stewardship (AMS) is particularly challenging in the neonatal population. Both under- and overuse can negatively impact outcomes. There are limited reports of strategies to improve AMS in the neonatal population. Standardized Antimicrobial Administration Ratios (SAARs) are novel metrics of antimicrobial use, recently introduced for neonatal populations by the National Healthcare Safety Network (NHSN). We describe our experience using SAARs to guide AMS in the neonatal intensive care unit (NICU).MethodsThis was a retrospective study conducted from January 2020 to April 2021. A team consisting of AMS and NICU department staff identified and implemented AMS strategies. Based on a review of NICU SAAR data, a goal was set to reduce third generation cephalosporin use by encouraging aminoglycoside use when appropriate. The pre-implementation period was January 2020 to May 2020 and the post-implementation period was July 2020 to April 2021. Antibiotic use was measured as SAARs and compared between study periods. The primary outcome was the neonatal SAAR for third generation cephalosporins. Secondary outcomes included SAARs for aminoglycosides and all neonatal antibacterial agents. SAARs were compared using the NHSN Statistics Calculator.ResultsFor third generation cephalosporins, there were 385 observed antimicrobial days (OAD) and 115 expected antimicrobial days (EAD) in the pre-implementation period compared to 597 OAD and 228 EAD in the post implementation period. This resulted in a SAAR of 3.34 and 2.62, respectively; a reduction of 22% (p < 0.001). For aminoglycosides, there were 713 OAD and 584 EAD compared to 1617 OAD and 1155 EAD. This resulted in a SAAR of 1.22 and 1.4; an increase of 15% (p = 0.002). For all neonatal antibacterial agents, there were 2716 OAD and 1739 EAD compared to 5321 OAD and 3438 EAD. This resulted in a SAAR of 1.56 and 1.55; indicating no change in use (p = 0.70). See Table 1 for results.Table 1. Antibiotic Use ConclusionWhile this initiative resulted in decreased use of third generation cephalosporins, this was not associated with a decrease in antibiotic use overall. Use of SAARs in the NICU may be helpful in both identifying opportunities to improve antibiotic use and monitoring antibiotic use over time.Disclosures Steven Smoke, PharmD, Karius (Advisor or Review Panel member) Shionogi (Scientific Research Study Investigator, Advisor or Review Panel member)

1061. Clinical Phage Microbiology: Evaluating Phages for Biofilm-associated Prosthetic Valve Endocarditis

Background Prosthetic valve endocarditis (PVE) is a major treatment challenge associated with biofilm formation. It requires intensive infectious diseases consultations and prolonged therapy. Nevertheless, high mortality rates are reported even with timely diagnosis and optimal management. Bacteriophage (phage) therapy, the use of bacterial viruses as antimicrobial agents, has been suggested as a potential adjunctive treatment for PVE. This is due to the ability of lytic phages to synergize with antibiotics and to destroy biofilms. However, due to their high specificity, it is crucial to match the phages by in-vitro evaluations that simulate the clinical settings. MethodsIn this study we demonstrate this matching using an in-vitro PVE model of vancomycin-resistant Enterococcus faecalis (VRE). We have looked at the ability of the phage EFLK1, alone or in combination with antibiotics, to destroy mature biofilms from a commonly used bioprosthetic valve. In addition, we tried to predict these effects using several in-vitro phage susceptibility assays.ResultsWe found that the phage EFLK1 presents a significant inhibitory effect against planktonic cultures of VRE, both alone or in combination with ampicillin or ceftriaxone. We then tested the effect of these combinations on mature biofilm grown on a standard 96-well plates. We found that the phage, or its combination with ceftriaxone, led to a two-log reduction in the bacterial viability. In contrast, the addition of ampicillin to the phage caused interference with this antibacterial effect. When tested against biofilm grown on a pericardial patch, the combination of EFLK1 and ceftriaxone was found most efficient. Finally, when tested on the whole bioprosthetic aortic valve, we found that the phage EFLK1 alone was even more efficient than its combination with ceftriaxone.Biofilm Eradication from Bioprosthetic Aortic Valve (A) Representation of E. faecalis biofilm formation on bioprosthetic valves. (B) Following 48-hours of growth, the valves were treated for five days by the phage EFLK1, ceftriaxone or their combination. The valves were then washed from any planktonic cells and the biofilm biomass was established by CFU enumeration.ConclusionThis study demonstrates that a proper in-vitro matching is essential in the treatment of PVE with phages. As seen here, the phage-antibiotic combination intended for treatment should be drawn according to their efficacy on suitable models, simulating the clinical settings, with the specific pathogen, the valve material, and the used phages taken into consideration.Disclosures Ran Nir-Paz, MD, BiomX (Consultant)Technophage (Scientific Research Study Investigator, Advisor or Review Panel member)

1276. Assessment of Anti-biofilm Activity of Staphylococcus aureus Bacteriophages Against Clinical Isolates from Patients with Left Ventricular Assist Device Infections

Abstract Background Staphylococcus aureus is a common cause of biofilm-mediated left ventricular device (LVAD) infections which are difficult to resolve with antibiotics alone and are associated with substantial morbidity and mortality. Recently, bacteriophages (phage) therapy has been used to resolve LVAD infections in a few cases. Our goal was to assess in vitro susceptibility and anti-biofilm activity of two S. aureus bacteriophages against clinical isolates from patients with S. aureus LVAD infections in order to develop a S. aureus phage cocktail for clinical use. Methods Two bacteriophages, OMS1 and OMS2, from the Israeli Phage Bank, were assessed for lytic activity against 15 S.aureus isolates (9 methicillin resistant, MRSA and 6 methicillin susceptible, MSSA) via agar overlay method and plaque forming units (PFU)/mL were enumerated. We then formed bacterial biofilms after overnight incubation at 120 rpm in a 96-well plates in duplicate; experiments were repeated thrice. Wells were then treated with tryptic soy broth (TSB, control) or TSB containing phage at 109 PFU/mL for 24 hours. After washing, biofilms were stained with crystal violet and biomass quantified via optical density at 570mm. Results All bacterial isolates were susceptible to both phages via agar overlay to varying degrees as determined by phage titers obtained via serial dilutions (Figure 1a, 1b). OMS1 led to significant reduction in biofilm of 7/9 MRSA and 3/6 MSSA isolates and OMS2 reduced biofilms in 9/9 MRSA and 4/6 MSSA isolates (Figure 1c). Phage titers and Biofilm Biomass Figure 1a) Phage titers in PFU/ml obtained from each bacterial isolate via agar overlay method. 1b) Representative agar plate demonstrating lytic plaques from OMS1 and OMS2 on a Staphylococcus aureus LVAD isolate. 1c) Biofilm biomass of Staphylococcus aureus isolates alone (SA) or with individual phage (SA+OMSA1 and SA=OMS2) assessed by optical density readings at 570 nm; error bars represent standard error of the mean. Conclusion We demonstrated in vitro lytic and anti-biofilm activity of 2 S. aureus phages against clinical S. aureus isolates from patients with LVAD infection. Our data suggests that phage susceptibility measured with agar overlay does not always correlate with phage susceptibility of S. aureus biofilms, suggesting that more than one method should be used to assess in vitro activity. We plan to assess for synergistic activity with the phage combination. Disclosures Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support) Ran Nir-Paz, MD, BiomX (Consultant)Technophage (Scientific Research Study Investigator, Advisor or Review Panel member) Saima Aslam, MD, MS, BioMx (Consultant)Cystic Fibrosis Foundation (Grant/Research Support)Gilead (Consultant)Johnson and Johnson (Consultant)Merck (Consultant)

547. A Retrospective Cohort Study of Treatment Patterns and Clinical Outcomes in Patients with COVID-19

BackgroundThe SARS-CoV-2 pandemic has caused over 400,000 deaths worldwide thus far, and poses therapeutic challenges for millions of patients. There is currently no treatment for SARS-CoV-2 infection approved by the United States Food and Drug Administration. Multiple agents have been used off-label to treat SARS-CoV-2 infection based on small observational cohorts and in vitro data. Here we present the experience of a large academic medical center in treating SARS-CoV-2 infection.MethodsWe performed a retrospective cohort study of patients admitted for greater than 24 hours with a nasopharyngeal, oropharyngeal, and/or bronchoalveolar lavage sample positive for SARS-CoV-2 by polymerase chain reaction (PCR). Demographic data, comorbidities, clinical data, and treatment data were collected from the electronic medical record. Off-label therapies were used at the discretion of the treating providers guided by regularly updated treatment guidelines assembled by infectious diseases physicians and antimicrobial stewardship pharmacists. The primary outcome assessed was in-hospital mortality. Secondary outcomes included admission to the intensive care unit (ICU), endotracheal intubation, initiation of vasopressors, and drug-related adverse events.ResultsData collection was completed for 448 patients admitted between March 18, 2020 and May 8, 2020. All-cause in-hospital mortality was 13.4% (60/448) during this time. Mortality rates increased with age, up to 45% for patients over 80 years old. Male sex, hypertension, chronic pulmonary disease, end-stage renal disease, chronic liver disease were also risk factors for increased mortality. QTc interval prolongation occurred significantly more frequently in patients who received hydroxychloroquine (HCQ) with or without azithromycin(AZM) than those who did not (HCQ 6%, HCQ+AZM 7.8% vs all other patients, 0%, p< .0001). Review of treatment trends showed close adherence to the treatment recommendations at that time (Figure 1).Patient Characteristics Admission Laboratory Data by Disease Severity QTc Prolongation ConclusionSARS-CoV-2 infection is associated with significant inpatient mortality, and use of off-label treatments was associated with significant drug-related adverse events. Treatment regimens changed rapidly, and providers adhered closely to institutional guidelines as they evolved.Treatment Trends by Week QTC pre/post Treatment by Hydroxychloroquine Use vs. No Hydroxychloroquine Use Disclosures Samir Gupta, MD, Gilead Sciences (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member)ViiV (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)

1012. Efficacy, safety and tolerability of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in HIV-1 infected virologically-suppressed older adults in a real-world setting

BackgroundApproximately 50% of people living with HIV (PLWH) in the United States are ≥50 years old. Efforts are ongoing to identify antiretrovirals associated with fewer drug-drug interactions (DDIs) and long-term side effects in this group. Clinical trials of B/F/TAF demonstrated favorable efficacy and safety in older adults, however, data from real-word settings are needed to validate these results.MethodsThis retrospective analysis evaluated records from PLWH aged ≥ 50 years at the Orlando Immunology Center who were switched to B/F/TAF between 2/7/2018 and 5/31/2019. Eligible patients had baseline HIV-1 RNA< 50 copies/mL and were followed for 48 weeks post-switch. The primary endpoint was maintenance of HIV-1 RNA< 50 copies/mL at week 48. The impact of switching to B/F/TAF on DDIs, adverse events (AEs) and safety parameters were analyzed throughout the study.Results306 patients met inclusion criteria. 62 (20%) were female, 126 (41%) were non-white, median age was 58 years (range [r] 50-81), median duration of HIV infection was 19.5 years (r 2-40), median number of chronic co-morbid conditions was 5 (r 0-20), and median number of baseline concomitant medications was 4 (r 0-23). 159 (52%) patients were switched from regimens containing ritonavir or cobicistat. The most commonly documented reason for switch was simplification (Table 1). At Week 48, 287 (94%) patients maintained an HIV-1 RNA< 50 copies/ml and 19 (6%) had an HIV-1 RNA between 50-200 copies/mL (Figure 1). 1 patient discontinued due to lack of efficacy. A total of 123 potential DDIs were identified in 104 (34%) patients taking a boosting agent or rilpivirine at baseline (Table 2). At Week 48, there was a significant median decline in total cholesterol (15.5 mg/dL, 95% confidence interval [CI]: 9.5; 21.5), LDL cholesterol (9.5 mg/dL, 95% CI: 4; 15.5) and triglycerides (20 mg/dL, 95% CI: 9.5; 32.5), and median weight increased by 2.5 pounds (95% CI: 1.5; 3.5). Treatment-related AEs occurred in 33 (11%) patients (all Grade 1-2) and led to 7 (2%) discontinuations.Table 1-Baseline demographic and clinical characteristics Table 2-Avoidance of Drug-Drug Interactions (DDIs) following switch to B/F/TAF Figure 1-Subgroup analysis of virologic outcomes at Week 48 ConclusionIn this real-world cohort, switching to B/F/TAF was associated with maintenance of virologic control, improvement in lipid parameters, and avoidance of DDIs in a large proportion of patients. These data support use of B/F/TAF as a treatment option in older PLWH.Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Kiran Patel, PharmD, Gilead Sciences (Employee) Federico Hinestrosa, MD, AbbVie (Speaker’s Bureau)Gilead Sciences (Speaker’s Bureau)Merck (Speaker’s Bureau)Theratechnologies (Speaker’s Bureau) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member)

1093. Infectious Complications after Pancreatic Islet Transplantation

BackgroundDespite the significant advancement in islet transplantation over the past three decades, our understanding of infectious complications post islet transplant remains limited.MethodsThis is a single center retrospective review of Islet transplant recipients at the University of Alberta between February 2006 and December 2015. All infectious episodes events occurring after transplant were categorized as opportunistic and non-opportunistic.ResultsWe analyzed 142 patients receiving a median of 2 islet transplants per patient, with 18 patients receiving 1 transplant (13%), 77 (54%) 2, 33 (23%) 3, 13 (9%) 4 and 1(1%) 5 transplants. Median age at first transplant was 50 years and 85 (47%) were male. Lymphocyte depleting agent with thymoglobulin or alemtuzumab was used for induction in 94% in first and 53% in second transplant. CMV serostatus was CMV D+/R- 61 (43%), CMVD+/R+ 52 (37%), CMVD-/R+ 16 (11%) and CMVD-/R- 13 (9%). CMV infection occurred in 21 patients (15%) [CMVD+/R- 6 (9.8%) and CMVR+ 15 (22.1%), p=0.06]. Other opportunistic infections included VZV 7 (4.9%), Nocardia 3(2.1%), and Pneumocystis jirovecii pneumonia 1. Non-opportunistic infections included skin and soft tissue infection 14 (9.9%), urinary tract infection 11 (7.7%), pneumonia 7 (4.9%) clostridium difficile infection (CDI) 4 (2.8%), and non-CDI gastroenteritis 5 (3.5%) (Table 1).Table 1: Infectious Complication post islet transplant ConclusionAlthough the rate of infections after islet cell transplant is less frequent than other types of transplants, opportunistic infections, especially CMV, are not uncommon and should be considered in this setting.Disclosures Carols Cervera, MD, PHD, Merk (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Lecture fees) James Shapiro, MD, PHD FRCS(Eng) FRCSC MSM FRSC, ViaCyte (Consultant) Dima Kabbani, MD, Merck (Research Grant or Support)

1488. Relationship Between Culture Conversion and Clinical Outcomes in Patients With Mycobacterium abscessus (MAB) Lung Disease: A Systematic Literature Review

BackgroundTreatment of MAB lung disease is difficult, and currently there is no consensus on the best course of treatment. We examined the relationship between culture conversion and clinical outcomes among patients with MAB lung disease.MethodsEnglish-language MAB lung disease studies with ≥10 patients and reporting culture conversion and/or an outcome of interest (eg, changes in symptoms, lung function, quality of life, and/or radiography) were identified from Embase, PubMed, relevant congress abstracts, and the Cochrane Library (data cutoff, September 24, 2019) using the National Institute for Health and Clinical Excellence guidance for systematic literature reviews. Two independent reviewers screened 1,551 indexed records; relevant data were extracted and are reported as population-weighted means.ResultsNo study directly correlated culture conversion with a change in symptoms. In 10 studies (N=869) reporting overall symptoms and culture conversion separately, 72.5% of patients (range 36%–96%) reported symptom improvement and 56.5% (range, 13%-99%) achieved culture conversion; a weak trend between symptomatic improvement and higher culture conversion rates (R2=0.36) was observed. Three additional studies (N=106) reported symptomatic improvement and culture conversion as a single measurement (49.6%, range, 25%-81%). Limited data indirectly correlated improvement in cough, dyspnea, hemoptysis, sputum production, and fatigue with culture conversion (1-2 studies each). Two studies directly correlated improved lung function (N=62) with culture conversion, and one study indirectly reported improved health-related quality of life (N=47) with culture conversion; no study reported radiology outcomes in relation to culture conversion.ConclusionThis systematic literature review underscores the lack of data correlating clinical outcomes and culture conversion in patients with MAB lung disease. Limitations include a small number of studies, inconsistencies/non-reporting of methods, and poorly defined outcomes. Although indirect data indicate a weak correlation between symptom improvement and culture conversion, more evidence is needed to demonstrate a clinical outcome benefit associated with culture conversion.Disclosures Patrick A Flume, MD, Insmed Incorporated (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Kevin C Mange, MD, MSCE, Insmed Incorporated (Employee) Zhanna Jumadilova, MD, Insmed Incorporated (Employee) Kristan B Cline, PhD, Insmed Incorporated (Employee) Kevin L Winthrop, MD, MPH, Insmed Incorporated (Consultant, Grant/Research Support)

1149. Baseline Chest CT Findings in Patients with Pulmonary Mold Infections: A Post-Hoc Analysis from the Phase 3 SECURE Study that Compared Isavuconazole to Voriconazole for the Primary Treatment of Invasive Mold Disease

BackgroundSECURE was a global, double-blind, Phase 3 study that randomized 527 patients 1:1 to isavuconazole (ISAV) or voriconazole (VORI) for the primary treatment of invasive mold disease (IMD) caused by Aspergillus or other filamentous fungi. Patients were classified as having proven/probable IMD (PP-IMD) or possible IMD (PS-IMD) according to EORTC/MSG 2008 criteria, and the majority (n=412) had pulmonary disease only. This post-hoc analysis describes baseline CT findings in these patients and explores the association between these findings and treatment outcomes.MethodsA blinded, independent review committee assessed the certainty of diagnosis (PP-IMD vs PS-IMD), location of disease (pulmonary only, pulmonary plus other organ, non-pulmonary only), and both overall and clinical responses at end-of-treatment. Radiology assessments were done by central blinded radiologists who characterized pulmonary lesions as follows: well-defined nodule(s) with or without halo sign, wedge-shaped infiltrate, cavity, air crescent sign, or non-specific focal infiltrate.ResultsOf the 412 patients with pulmonary disease only, 223 (54%) had PP-IMD and 189 (46%) had PS-IMD. Well-defined nodule(s) was the predominant radiological finding at baseline in patients with PP-IMD or PS-IMD (PP-IMD 55%, PS-IMD 63%), followed by non-specific focal infiltrate (PP-IMD 43%, PS-IMD 41%), wedge-shaped infiltrate (PP-IMD 24%, PS-IMD 30%), and halo (PP-IMD 25%, PS-IMD 28%). A small proportion of patients had a cavity (PP-IMD 12%, PS-IMD 9%) or air crescent sign (PP-IMD 2%, PS-IMD 4%).Patients with air crescent sign had low all-cause mortality through Days 42 and 84, and high overall and clinical response rates at end-of treatment (PP-IMD: 0, 0, 75%, 100% and PS-IMD: 0, 13%, 75%, 88%, respectively). There was no other clear association between baseline CT findings and either outcomes of all-cause mortality or overall and clinical responses.Figure. Chest CT findings at baseline in patients with PP-IMD or PS-IMD (pulmonary only) ConclusionIn patients with pulmonary IMD, the predominant radiological finding at baseline was well-defined nodule(s) in both PP-IMD and PS-IMD. Air crescent sign was infrequent, but was associated with lower all-cause mortality and higher overall and clinical responses. Otherwise, baseline CT findings did not appear to predict treatment outcomes in this Phase 3 study.Disclosures Kamal Hamed, n/a, Basilea Pharmaceutica International Ltd. (Employee) Marc Engelhardt, n/a, Basilea Pharmaceutica International Ltd. (Board Member, Consultant, Employee, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Shareholder, Speaker’s Bureau, Independent Contractor, Other Financial or Material Support)Basilea Pharmaceutica International Ltd. (Employee) Mikael Saulay, n/a, Basilea Pharmaceutica International Ltd. (Employee) Laura Kovanda, n/a, Astellas Pharma Inc (Employee)

1468. Culture Conversion and Mortality in Patients With Mycobacterium abscessus (MAB) Lung Disease: A Systematic Literature Review

BackgroundPrognosis for patients with MAB lung disease is poor. We sought to examine the potential association between culture conversion and outcomes (progression, mortality) in patients with MAB lung disease.MethodsEnglish-language MAB lung disease studies with ≥ 10 patients and reporting mortality and/or microbiological outcomes were identified from Embase, PubMed, relevant congress abstracts, and the Cochrane Library (data cutoff, September 24, 2019) using the National Institute for Health and Clinical Excellence guidance for systematic literature reviews. Two independent reviewers screened 1,551 indexed records; relevant extracted data are expressed as population-weighted means.ResultsMean all-cause mortality across 17 studies (N=1,291) was 12.1% (range, 3%–33%); mortality attributable to MAB lung disease was 7.6% (range, 0%–27%; N=526, 9 studies). Culture conversion across 44 studies (N=2,237) was 46.7% (range, 0%–98.6%), with higher rates reported for M. massiliense subspecies (76.9%; N=507,15 studies) than M. abscessus subspecies (35.8%; N=834,18 studies). No direct comparisons were made between mortality and culture conversion; in the 13 studies (N=1,202) that reported both outcomes there was a moderate correlation between increased rate of culture conversion and decreased MAB-attributable mortality (R2=0.60). The most common definition of progression (21 studies) was radiographic worsening supported by persistent symptoms and/or positive cultures. Across 8 studies (N=415) 57.8% patients had improvement while 35.2% progressed with treatment. A broad variance in treatment regimen and duration (range, 32 days to > 3 years) was observed. Limitations include a small number of studies, and inconsistency in methods and outcomes definitions.ConclusionIn this systematic literature review, available data suggest that culture conversion was achieved in less than half of patients and was lower in patients with M. abscessus compared with M. massiliense. One third of patients had disease progression despite treatment. Some data suggest lower MAB-attributed mortality outcomes in studies with higher culture conversion rates, more evidence is needed to demonstrate a survival benefit associated with culture conversion.DisclosuresKevin L Winthrop, MD, MPH, Insmed Incorporated (Consultant, Grant/Research Support) Kevin C Mange, MD, MSCE, Insmed Incorporated (Employee) Zhanna Jumadilova, MD, Insmed Incorporated (Employee) Kristan B Cline, PhD, Insmed Incorporated (Employee) Patrick A Flume, MD, Insmed Incorporated (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)

British Ornithologists’ Union

British Ornithologists’ Union

Yellowstone Lake Ecosystem Restoration: A Case Study for Invasive Fish Management

Invasive predatory lake trout Salvelinus namaycush were discovered in Yellowstone Lake in 1994 and caused a precipitous decrease in abundance of native Yellowstone cutthroat trout Oncorhynchus clarkii bouvieri. Suppression efforts (primarily gillnetting) initiated in 1995 did not curtail lake trout population growth or lakewide expansion. An adaptive management strategy was developed in 2010 that specified desired conditions indicative of ecosystem recovery. Population modeling was used to estimate effects of suppression efforts on the lake trout and establish effort benchmarks to achieve negative population growth (λ &lt; 1). Partnerships enhanced funding support, and a scientific review panel provided guidance to increase suppression gillnetting effort to &gt;46,800 100-m net nights; this effort level was achieved in 2012 and led to a reduction in lake trout biomass. Total lake trout biomass declined from 432,017 kg in 2012 to 196,675 kg in 2019, primarily because of a 79% reduction in adults. Total abundance declined from 925,208 in 2012 to 673,983 in 2019 but was highly variable because of recruitment of age-2 fish. Overall, 3.35 million lake trout were killed by suppression efforts from 1995 to 2019. Cutthroat trout abundance remained below target levels, but relative condition increased, large individuals (&gt; 400 mm) became more abundant, and individual weights doubled, probably because of reduced density. Continued actions to suppress lake trout will facilitate further recovery of the cutthroat trout population and integrity of the Yellowstone Lake ecosystem.

Per‐ and Polyfluoroalkyl Substances, Microplastics, and COVID‐19: Will We Ever Learn?

Per‐ and Polyfluoroalkyl Substances, Microplastics, and COVID‐19: Will We Ever Learn?