Citations

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 ( P = 0.014) and IL-16 ( P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group ( P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Abstract Background Treatment for first recurrent Clostridioides difficile infection (frCDI) or multiply recurrent CDI (mrCDI) is complex and may include antibiotics, monoclonal antibodies, or fecal transplantation. Improved understanding of rCDI pathogenesis can help guide treatment. We report microbiome findings of patients (pts) with frCDI and mrCDI from a post hoc analysis of two phase 3 trials with fecal microbiota spores, live-brpk (FMS; formerly SER-109), an FDA-approved, microbiota-based therapeutic comprised of Firmicutes spores. Methods Stool samples were collected from pts with mrCDI in ECOSPOR III (n=158) and with frCDI or mrCDI in ECOSPOR IV (n=218) at baseline (pre-dose) and Week 1 post treatment. Shannon diversity was calculated from species profiles from analysis of whole metagenomic sequencing data using MetaPhlAn2. Primary (1°BA) and secondary bile acid (2°BA) concentrations were measured via targeted liquid chromatography–mass spectrometry panel. Subgroup differences were analyzed with linear mixed models. Results At baseline, Shannon diversity was not significantly different between mrCDI and frCDI groups (P&gt;0.05). At Week 1, Shannon diversity (Fig 1) was greater vs baseline (P&lt; 0.001); gains were not significantly different between subgroups (P&gt;0.05). For pts receiving FMS vs placebo in ECOSPOR III, greater reductions in 1°BA and increases in 2°BA from baseline–Week 1 were observed, similar to FMS-treated pts in ECOSPOR IV. At Week 1, 2°BA concentrations were greater vs baseline (P&lt; 0.001); similar gains were seen between subgroups (P&gt;0.05) (Fig 2). Consistent with these microbiome findings, in an integrated analysis, rCDI rates with FMS at Week 8 were low in both subgroups (frCDI, 6.5% [5/77] vs mrCDI, 10.3% [28/271]). Conclusion After antibiotics, pts with frCDI or mrCDI had low Shannon diversity and 2°BA concentrations that were no different between subgroups, highlighting a need for microbiome restoration. Both subgroups showed rapid, significant improvement in Shannon diversity and 2°BA concentrations and reductions in 1°BA after FMS, with comparable clinical outcomes. These data suggest that regardless of number of prior CDI episodes, FMS therapy following antibiotics may be an optimal treatment. Disclosures Colleen R. Kelly, MD, Openbiome: Advisor/Consultant|Sebela Pharmaceuticald: Advisor/Consultant Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Jennifer R. Wortman, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Darrell Pardi, MD, Abbvie: Advisor/Consultant|AMT: Grant/Research Support|BI: Advisor/Consultant|Immunic: Advisor/Consultant|Rise: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit: Advisor/Consultant|Takeda: Grant/Research Support|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds

Abstract Background Implementing effective antimicrobial stewardship interventions is an important component of antimicrobial stewardship programs. Recently, stewardship research has shown that clinician characteristics may have an impact on antimicrobial stewardship intervention methods and acceptance rates. Methods A multisite health system antimicrobial stewardship prospective audit and feedback program interventions performed by stewardship staff using a standardized electronic medical record (EMR) tool were compared by stewardship clinician profession (pharmacist, physician, or advanced practice provider, APP) from 7/1/2017 to 6/30/2022. Outcomes assessed were intervention rates, communication methods, and intervention acceptance by patient age and intensive care unit (ICU) status of patient. Generalized estimating equations utilizing logistic regression were used to assess for associations between staff. Associations were assessed both univariately and after adjusting for other factors. Results Of 69,503 prospective audit and feedback EMR based rules, there were 14,699 rules associated with an intervention. The majority of rules were reviewed by pharmacists (90.7%) followed by physician (9.2%) and APP (&lt; 1%). Of 9,034 interventions with an outcome documented, 7326 (85.5%) pharmacist interventions were accepted and 360 (77.3%) physician interventions were accepted (adjusted p=0.047). Pharmacists intervened by direct action (ie, adjust a medication order) in 6.6% of interventions; whereas, physicians did so rarely (0.4%). Pharmacists were more likely to use synchronous communication than physicians in the adjusted model (pharmacist vs. physician: 63.8% vs 52.5%; p=0.004). Patients in the ICU had a significantly lower intervention acceptance rate (non-ICU vs. ICU: 86.6% vs. 78.0%; adjusted OR 0.57 [95% CI 0.46-0.70], p&lt; 0.001).Table 1.Intervention Rate by Baseline Demographics of Stewardship Clinicians and Patients. *% are reported as row % **Multivariable model was also adjusted for day of week and time of day APP-Advanced practice provider; ICU-intensive care unitTable 2.Intervention Acceptance. *% are reported as row % **Multivariable model was also adjusted for day of week and time of day APP-Advanced practice provider; ICU-intensive care unit Conclusion Antimicrobial stewardship pharmacists and physicians are both effective at prospective audit and feedback but used different intervention styles. Advanced practice providers were vastly underrepresented. Patients in the ICU may benefit from tailored ASP efforts. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Caitlin Brown, PharmD, Alexion: Grant/Research Support|Trevena: Advisor/Consultant Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria

Abstract Background Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) remain significant causes of morbidity and mortality among patients admitted to a medical facility. Consensus guidelines for the treatment of HAP/VAP recommend patients with certain risk factors be empirically treated with an anti-methicillin resistant Staphylococcus aureus (MRSA) and anti-pseudomonal antibiotic. The most commonly utilized anti-pseudomonal agents at BJC hospitals include cefepime, followed by piperacillin/tazobactam and meropenem. The purpose of this study is to determine if there is a difference in clinical outcomes between cefepime and the other most commonly used anti-pseudomonal antibiotics, piperacillin/tazobactam or meropenem, at these institutions for the treatment of HAP/VAP. Methods This retrospective, multicenter cohort study included adult patients with HAP/VAP who received cefepime, meropenem, or piperacillin/tazobactam. Major exclusion criteria included patients that received antibiotics within 48 hours of hospital admission or less than 48 hours of empiric antibiotics. The primary outcome was in-hospital mortality. Secondary outcomes included change in initial antibiotic, mechanical ventilation-free days, ICU length of stay, hospital length of stay, hospital readmission, and new C. difficile infection. Results Of 1,117 included patients, 1,008 patients received cefepime and 109 received meropenem or piperacillin/tazobactam. Incidence of in-hospital mortality was not observed to be significantly different among empiric Gram-negative regimens (cefepime group 19.4% vs. meropenem or piperacillin/tazobactam 22%, p=0.521. Change in initial antibiotic, ICU length of stay, and hospital length of stay were observed to be significantly higher in the cefepime group. Conclusion We observed no difference in in-hospital mortality between cefepime and piperacillin/tazobactam or meropenem. However, there was a significantly higher incidence of change in initial antibiotic, ICU length of stay, and hospital length of stay observed in the cefepime group, though additional research is needed to corroborate these observations. Disclosures Kevin Betthauser, PharmD, La Jolla Pharmaceutical Company: Advisor/Consultant|La Jolla Pharmaceutical Company: Grant/Research Support Paul Juang, Pharm.D., Merck & Co: Grant/Research Support

Background Esophageal pathology such as perforation or malignancy often necessitates esophageal reconstruction. However, the optimal method of esophageal primary repair and anastomosis are unclear. We aim to determine stress to failure of esophageal anastomosis for full thickness and mucosal‐submucosal anastomotic techniques. Methods Six esophagi from freshly sacrificed 60 kilogram swine were transected at the mid thoracic portion of the esophagus. Esophageal anastomoses were created and subsequently primarily anastomosed using 2‐0 running continuous polyglactin (Vicryl, Ethicon, Somerville, NJ) suture either as full thickness or partial thickness (mucosa‐submucosa alone). The sutured specimens were then mounted on cannulae. Using a syringe pump system, the esophagi were infused with colored saline while monitoring pressure continuously with optical tracking for detection of fluid leak. Data acquisition software was used to collect stress‐to‐failure data. Synchronized video and pressure data were analyzed post hoc for visualization of the leak and concurrent pressure to determine failure pressure. Results The full‐thickness anastomosis failed at a mean ± (SEM) pressure of 15.33 ± (1.45) mmHg while the mucosal‐submucosal anastomosis failed at a mean ± (SEM) pressure of 36.33 ± (3.76) mmHg, ( P = 0.02, unpaired t ‐test with Welch's correction). MATLAB (MathWorks, Natick, MA) was used calculate the statistical results. Conclusion While the optimal in vivo method for esophageal anastomosis is unclear, we present evidence that an anastomosis incorporating only the mucosa and submucosa may be superior to full thickness. Additional research is needed to further clarify optimal technique and post‐operative outcomes. Support or Funding Information Dr. Aho reports funding from a Grant from the National Heart, Lung, and Blood Institute T32 HL105355, a component of the National Institutes of Health (NIH).

Slow, deep breathing (SDB) is thought to lead to reductions in blood pressure by decreasing vascular‐sympathetic coupling. Venous Occlusion Plethysmography (VOP) is used to assess forearm blood flow (FBF) (ml/min/100 dl tissue). We used this technique to determine the vasodilatory effect of device‐guided (DG) vs self‐paced (SP) slow, deep breathing. We hypothesized that SP would lead to a larger vasodilation response than DG due to a more profound reduction in vascular‐sympathetic coupling, and that this would be correlated with psychological evaluations. Young, healthy male subjects (Mean age: 20 yr; DG: n=10; SP: n=11) rested supine for 20 minutes (baseline), followed by 20 minutes of SP or DG slow, deep breathing, then completed 20 minutes of endogenous breathing (recovery). At baseline, there was no difference in breathing rate between SP and DG (14.36±1.03 vs 15.39±1.29 breaths per minute, p=0.27) and respiratory rate was reduced to 8.36±0.74 breaths per minute (BPM) in the SP group (p<0.01 compared to baseline) and to 6.37±0.10 BPM in the DG group (p<0.01 compared to baseline). Respiratory rates between the two groups differed significantly during SDB (p<0.01 between groups). There was a significant increase in SP FBF compared to baseline at the end of the 20 minute intervention (p<0.05),while the DG group saw no significant increases. In DG, there was a strong negative correlation with the cognitive interference scores to VOP responsiveness (−0.77; R2=0.591), as well as between the cognitive failure score and VOP responsiveness (−0.61; R2=0.3693). In contrast, the SP groups had positive correlations when comparing VOP responsiveness to cognitive interference (0.1; R2=0.093) or cognitive failure (0.30; R2=0.011). For subjects in either breathing group, those who had an increase in FBF in response to SDB also had reductions in STAI anxiety score after the intervention whereas those with a decrease in FBF to SDB had an increase in anxiety score during the slow breathing (p=0.04). Overall, male subjects have a variable vasodilator responses to two types of SDB practices related to underlying psychological metrics. Our data underscores the importance of psychological metrics in physiological outcomes related to SDB practices.

Abstract Background In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug–drug interactions, but also a potential cardioprotective effect of these drugs. Aim In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. Method A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. Outcomes Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. Results An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug–drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non–PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non–PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. Clinical Implications Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. Strengths and Limitations Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. Conclusion The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

AbstractBackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Abstract Background Patients with ulcerative colitis and total abdominal proctocolectomy with ileal pouch-anal anastomosis have a 50% risk of pouchitis and a 5% to 10% risk of chronic pouchitis. Aims The goal of the study was to compare pouch microbiota and stool bile acid composition in patients with chronic pouchitis, chronic pouchitis and primary sclerosing cholangitis, and normal pouch. Methods Patients with ulcerative colitis and ileal pouch-anal anastomosis were recruited from March 20, 2014, to August 6, 2019, and categorized into normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis groups. Stool samples were subjected to bile acid quantification and 16S rRNA gene sequencing. Statistical comparisons of absolute bile acid abundance and pouch microbiota α-diversity, β-diversity, and taxa abundance were performed among the patient groups. Results A total of 51 samples were analyzed. Both α-diversity (P = .01, species richness) and β-diversity (P = .001) significantly differed among groups. Lithocholic acid was significantly lower in patients with chronic pouchitis/primary sclerosing cholangitis than in those with chronic pouchitis (P = .01) or normal pouch (P = .03). Decreased α-diversity was associated with an increased primary to secondary bile acid ratio (P = .002), which was also associated with changes in β-diversity (P = .006). Conclusions Pouch microbiota α- and β-diversity differed among patients with normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis. Lithocholic acid level and primary to secondary bile acid ratio were highly associated with pouch microbiota richness, structure, and composition. These findings emphasize the associations between pouch microbiota and bile acid composition in dysbiosis and altered metabolism, suggesting that secondary bile acids are decreased in chronic pouchitis.