Research Spotlight

Srivastava, S., van Zyl, J., Cirrincione, K., Martin, K., Thomas, T., Deshpande, D., Alffenaar, J.W., Seddon, J.A. and Gumbo, T. (2020). “Evaluation of Ceftriaxone Plus Avibactam in an Intracellular Hollow Fiber Model of Tuberculosis: Implications for the Treatment of Disseminated and Meningeal Tuberculosis in Children.” Pediatr Infect Dis J 39(12): 1092-1100.

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BACKGROUND: Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing. METHODS: First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%TMIC) ranging from 0 to 100%. In a third HFS-TB experiment, the “double cephalosporin” regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence. CONCLUSION: The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %TMIC <42 had no microbial effect in the HFS-TB, %TMIC >54% demonstrated a 4.1 log10 colony-forming units per milliliter M. tuberculosis kill, while %TMIC mediating Emax was 68%. The “double cephalosporin” combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day. CONCLUSION: The combination of ceftriaxone-avibactam at 100 mg/kg could achieve Emax in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.

Daoud, E.V., Patel, A., Gagan, J., Raisanen, J.M., Snipes, G.J., Mantilla, E., Krothapally, R., Hatanpaa, K.J. and Pan, E. (2020). “Spinal Cord Pilocytic Astrocytoma With FGFR1-TACC1 Fusion and Anaplastic Transformation.” J Neuropathol Exp Neurol Nov 19;nlaa122. [Epub ahead to print.].

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Pilocytic astrocytoma (PA) is a WHO grade 1 primary neoplasm that accounts for ∼5.4% of all gliomas, occurs predominantly in childhood and adolescence, and usually arises in the cerebellum or cerebral midline structures (1, 2). The treatment of choice is surgical resection and the prognosis is excellent, with survival over 95% at 10 years (3). If a gross total resection (GTR) is achieved, postoperative radiation therapy or chemotherapy is not warranted, with low reported recurrence rates (4, 5). Development of anaplastic features is extremely uncommon, and many such tumors are associated with prior radiation therapy (6–8). However, little is known about the mechanisms and driver mutations associated with PA anaplasia (7). [No abstract; excerpt from article.].

Packer, M., Butler, J., Filippatos, G., Zannad, F., Ferreira, J.P., Zeller, C., Brueckmann, M., Jamal, W., Pocock, S. and Anker, S.D. (2020). “Design of a Prospective Patient-Level Pooled Analysis of Two Parallel Trials of Empagliflozin in Patients With Established Heart Failure.” Eur J Heart Fail Nov 30. [Epub ahead of print.].

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The EMPEROR-Reduced trial demonstrated that empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with a reduced ejection fraction, and the EMPEROR-Preserved trial is currently evaluating the effect of the drug on the same endpoint in patients with an ejection fraction > 40%. However, neither the trial was designed to have adequate statistical power to evaluate the effects of empagliflozin and dapagliflozin on major adverse renal outcomes or on mortality. Herein we describe the design of a prospective individual patient-level pooled analysis of two large-scale trials with empagliflozin (EMPEROR-Reduced and EMPEROR-Preserved) in patients with heart failure across the spectrum of ejection fraction. The trials were carried out in parallel using the same administrative structure and committees, randomization procedure, schedule of study visits and adjudication criteria and similar groups of investigators and case report forms. The two component trials specified the same primary and key secondary endpoints and used an identical hierarchical testing procedure, which included a pooled analysis of the two trials as a key component of the hierarchy. Consequently, the pooled analysis has been prospectively assigned a false positive error rate, which is conditional on one or both trials first achieving success on their primary and one or both key secondary endpoints. The pooled analysis has its own statistical plan with its own endpoints, and this plan was finalized before either trial had begun recruitment of patients into either study. The primary endpoint of the pooled analysis is a composite of serious adverse renal outcomes, defined by chronic dialysis, renal transplantation and a profound or sustained decrease in glomerular filtration rate. All-cause and cardiovascular mortality are specified as secondary endpoints. The planned pooled analysis has an unusually high degree of statistical rigor that will allow it to address important questions that cannot be fully addressed by the individual trials.

McGraw, M., White, H.D., Boethel, C., Zolfaghari, K., Hochhalter, A. and Arroliga, A. (2020). “Corticosteroid Dosing and Glucose Levels in COPD Patients Are Not Associated with Increased Readmissions.” Chronic Obstr Pulm Dis Nov 25. [Epub ahead of print.].

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INTRODUCTION: Hospital admissions and readmissions for chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased mortality and higher cost. The management of exacerbations with a shortened course of systemic corticosteroids has similar efficacy as compared to longer steroid courses, but actual overall steroid dose given is still variable. The outcomes associated with steroid side effects, such as hyperglycemia, need further evaluation. We hypothesize that the use of higher doses of corticosteroids, and the subsequent hyperglycemia, contributes to readmission. METHODS: This is an retrospective study at a tertiary care referral center in Central Texas between February 2014 and July 2016. Daily corticosteroid dose, blood glucose levels, and readmission rates at 30 and 31-90 days were recorded. Sample characteristics are described using descriptive statistics. A chi-square test or student’s t-test were used to test for associations in bivariate comparisons. Multivariable logistic regression assessed the association between readmission rate and demographic and clinical characteristics. RESULTS: There were 1,120 patients admitted for COPD exacerbation between February 2014 and July 2016. Fifty seven percent were female, mean age was 69 (SD 12), and average BMI was 29.4 (SD 9.8). Of the total, 349 (31%) had diabetes prior to admission. The 30 days readmission rate was 16%, and the readmission rate from 31-90 days was 14%. The average prednisone equivalent dose per day during hospitalization was 86 mg (SD 52). A multivariable logistic regression model did not show any significant association between readmission and average daily glucose, high maximum glucose (>180 mg/dL on any reading), or prednisone equivalent administered per day. CONCLUSION: Corticosteroid dose and hyperglycemia were not associated with an increased 30 or 31-90 days readmission rate after COPD exacerbation discharge. In addition, using higher doses of corticosteroids instead of standard-of-care (Prednisone 40 mg per day for a 5-day period) did not appear to affect the readmission rate in this cohort.

Ribot Trafí, F., García Bartual, M., García-Nos, E., Altamirano Enciso, A.J., Nevgloski, A.J. and Wang, Q. (2020). “Another interpretation of Homo antecessor.” J Anthropol Sci 98. Oct 31. [Epub ahead of print.].

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We have carefully read the article by Bermúdez de Castro & Martinón-Torres (2019) titled “What does Homo antecessor tell us about the origin of the ‘emergent humanity’ that gave
rise to Homo sapiens? The authors update their thoughts on the human remains of the TD6.2 level of Gran Dolina de Atapuerca (Burgos, Spain), and then support their research with previous work by members of the Atapuerca team.