Abstract Background Microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying pathogen DNA from the plasma of infected patients. Here, we describe the potential impact of a positive mcfDNA result on clinical decision making among immunocompromised adults with suspected pneumonia. Methods This prospective observational study evaluated the potential utility of mcfDNA sequencing in adults with active hematological malignancies undergoing a diagnostic bronchoscopy for pneumonia at 10 US Medical Centers as part of the PICKUP Study (Abstract # 544 IDWeek 2022). Plasma mcfDNA was collected on all participants at the time of bronchoscopy. Clinical impact of the mcfDNA sequencing results vs usual care (UC) testing – including bronchoscopy- were adjudicated and then compared for: 1) identification of probable cause of pneumonia or clinically significant non-pulmonary infection and 2) potential changes to antimicrobial therapy if mcfDNA sequencing results were available to treating clinicians. Results Of 223 participants analyzed, median (IQR) age was 62 (50-69) years and 72 (32.3%) were female. Plasma mcfDNA identified a probable cause of pneumonia in 57/223 (25.6%, 95% CI 20.0-31.8) participants and could have changed antimicrobial therapy in 21/57 (36.8%, 95% CI 24.4-50.7). A probable cause of pneumonia was identified by mcfDNA in 23/223 (10.3%, 95% CI 6.7-15.1) participants when no cause was identified by UC, and these detections could have resulted in an antimicrobial change in 17/23 (73.9%, 95% CI 51.6-89.8). A clinically relevant non-pulmonary infection was identified in 88/223 (39.5%, 95% CI 33.0-46.2) participants and antimicrobial therapy could have changed in 22/88 (25.0%, 95% CI 16.4-35.4). Collectively, antimicrobial therapy could have changed for 41/223 (18.4%, 95% CI 13.5-24.1) participants if mcfDNA results were available to treating clinicians. Conclusion Positive plasma mcfDNA sequencing results could have supported changes in clinical management for pneumonia and non-pulmonary infections among immunocompromised patients undergoing bronchoscopy. Further studies are needed to refine the optimal timing of mcfDNA in relation to UC testing and establish the impact of real-time mcfDNA results on patient outcomes. Disclosures Deng B. Madut, MD, Karius: Advisor/Consultant Roy F. Chemaly, MD/MPH, Eurofins-VViracor: Grant/Research Support|Karius: Advisor/Consultant Sanjeet S. Dadwal, MD, FACP, FIDSA, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope, Inc: Stocks/Bonds|Astellas: Honoraria|Karius: Grant/Research Support|Matinas Biopharma: Stocks/Bonds|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer/Amplyx: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria|Viracor: Honoraria Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Century Therapeutics: Advisor/Consultant|Covance/CSL: Advisor/Consultant|Deverra: Grant/Research Support|Eversana Life Science Services, LLC: Advisor/Consultant|GeoVax: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Moderna DSMB: Advisor/Consultant|Octapharma AG: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer (previously Amplyx/Medpace): Advisor/Consultant|Senti BioSciences, Inc: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Up-to-Date: Advisor/Consultant Yeon Joo Lee, MD, MPH, AiCuris: institutional research support for clinical trials|Karius: institutional research support for clinical trials|Merck: Grant/Research Support|Scynexis: institutional research support for clinical trials Ghady Haidar, MD, Allovir: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|NIH: Grant/Research Support Alfred Luk, MD, Bill & Melinda Gates Foundation: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support Fareed Khawaja, MBBS, MEDSCAPE: Honoraria|Viracor: Grant/Research Support Genovefa Papanicolaou, MD, Allovir: Advisor/Consultant|Amplyx: Advisor/Consultant|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|CSL Behring: Advisor/Consultant|DSMC: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: institutional research support for clinical trials|MSD: Advisor/Consultant|Octapharma: Advisor/Consultant|Partners Rx: Advisor/Consultant|Shire/Takeda: institutional research support for clinical trials|Symbio: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant|Vera Pharma: Advisor/Consultant Micah T. McClain, MD, PhD, Biomeme Inc: Methods to diagnose and treat acute respiratory infections Eileen K. Maziarz, MD, Karius, Inc: Advisor/Consultant Robert Bigelow, PhD, Covidien: Stocks/Bonds|Elixir Medical: Advisor/Consultant|Johnson & Johnson: Stocks/Bonds|Mckesson: Stocks/Bonds|Merck: Stocks/Bonds|Organon: Stocks/Bonds|Pfizer: Stocks/Bonds|Sanofi: Stocks/Bonds|Viatris: Stocks/Bonds Daniel Lupu, MD, PHD, Karius Inc: Employee|Karius Inc: Stocks/Bonds Sivan Bercovici, PhD, Karius: Stocks/Bonds Bradley A. Perkins, MD, Karius, Inc: Stocks/Bonds Timothy A. Blauwkamp, PhD, Karius: Board Member|Karius: Ownership Interest Vance G. Fowler, MD, MHS, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, Astra Zeneca: Advisor/Consultant|Genentech, Regeneron, Deep Blue, Basilea, Janssen;: Grant/Research Support|Infectious Diseases Society of America: Honoraria|MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius;: Grant/Research Support|Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny,: Advisor/Consultant|Sepsis diagnostic: Patent pending|UpToDate: Royalties|Valanbio and ArcBio: Stock Options Thomas L. Holland, MD, Aridis: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|Karius: Advisor/Consultant|Lysovant: Advisor/Consultant Stephen P. Bergin, MD, Karius, Inc.: Grant/Research Support
The TELE study examined the feasibility and potential efficacy of phone calls to patients after discharge from short‐ term inpatient and residential substance abuse treatment programs to encourage compliance with continuing care plans. After review of their continuing care plans, 339 patients from four programs were randomized either to receive calls or to have no planned contact. Ninety‐two percent of patients randomized to receive calls received at least one call. No difference was found between groups in self‐reported attendance at one or more outpatient counseling sessions after discharge (p = .89). When program records of all participants were examined, those receiving calls had a greater likelihood of documented attendance (48%) than those not called (37%). Results were not statistically significant (p < .003) because of the Hochberg correction for multiple tests. While the phone calls were feasible, the lack of clear evidence of efficacy of the calls suggests the need for further investigation of the role of telephone intervention to encourage compliance and improve outcomes.
Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinised. The VALsartan In Acute myocardial iNfarcTion, a large multinational, pragmatic, randomised, double-blind, multicentre trial, was retrospectively evaluated for evidence of research conduct consistent with a performance “learning curve”.
Design
Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (eg, first, second), recruitment rate and first enrolment relative to study start date.
Setting
Computerised data from a trial coordinated by an academic research organisation collaborating with 10 academic and 2 commercial research organisations and an industry sponsor.
Interventions
931 sites enrolled 14 703 patients. Departures were restricted to the first year. Exclusions included patient9s death or loss to follow-up within 12 months and subjects enrolled 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment and later start date.
Methods and results
12 367 patients at 931 sites were analysed. Departures were more common for patients enrolled earlier at a site (p<0.0001). For example, compared with the 30th patient, the first had 47% more departures. Departures were also more common with slower enrolment and site start closer to the trial start date (p<0.0001). Similar patterns existed for queries.
Conclusions
Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a “learning curve”. Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct.
Background Smoking is known to be a strong risk factor for premature atherosclerosis, myocardial infarction, and sudden cardiac death. Unexpectedly, in the reperfusion era, investigators have reported that patients who smoke have a more favorable prognosis after thrombolysis compared with nonsmokers. Since smoking is associated with a relatively hypercoagulable state, we hypothesized that the coronary occlusion responsible for infarction may be primarily thrombotic, with improved outcome relating to enhanced patency or the absence of a residual stenosis after thrombolytic therapy. Methods and Results To examine this issue, we evaluated 1619 patients treated with TPA, urokinase, or both in six consecutive myocardial infarction trials, of whom 878 (54%) were currently smoking. Patients underwent 90-minute and predischarge catheterizations, which were quantified blinded to the patients’ smoking status. As expected, baseline fibrinogen (2.8 [2.5, 3.6] versus 2.7 [2.4, 3.5] g/dL, P =.003) and hematocrit (44% [41%, 47%] versus 43% [40%, 45%], P =.0001) levels were greater in smokers. Although there were no differences between smokers and nonsmokers with regard to 90-minute patency (73% versus 74%), smokers were more likely to have TIMI-3 flow (41.1% versus 34.6%, P =.034), with a larger minimum lumen diameter of the infarct stenosis both acutely (0.82 [0.51, 1.11] versus 0.72 [0.43, 1.04] mm, P =.0432) and at follow-up (1.2 [0.8, 1.74] versus 1.0 [0.7, 1.5], P =.002). Although smokers tended to have reduced in-hospital mortality compared with nonsmokers in univariate analysis (4.0% versus 8.9%, P =.0001), after adjustment for baseline differences between smokers and nonsmokers in age (54 [47, 62] versus 60 [54, 68] years, P <.0001), inferior infarct location (60% versus 53%, P <.0001), three-vessel disease (16% versus 22%, P <.001), and baseline ejection fraction (53% [44%, 60%] versus 50% [42%, 58%], P =.0069), smoking history was of no independent prognostic significance. Conclusions Therefore, smokers have a relatively hypercoagulable state, documented by increased hematocrit and fibrinogen levels. Quantitative coronary angiographic analysis suggests that the mechanism of infarction in smokers is more often thrombosis of a less critical atherosclerotic lesion compared with nonsmokers. Enhanced perfusion status, as well as favorable baseline clinical and angiographic characteristics, may be responsible for the more benign prognosis of current smokers.
Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery.In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5.A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups.Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).
