Research Spotlight

Posted August 15th 2016

Thioridazine as chemotherapy for mycobacterium avium complex diseases.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, S. Musuka and T. Gumbo (2016). “Thioridazine as chemotherapy for mycobacterium avium complex diseases.” Antimicrob Agents Chemother 60(8): 4652-4658.

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Mycobacterium avium-intracellulare complex (MAC) causes an intractable intracellular infection that presents as chronic pulmonary disease. Currently, therapy consists of ethambutol and macrolides and takes several years to complete. The neuroleptic phenothiazine thioridazine kills mycobacteria by inhibiting the electron transport chain. In several experiments with bacterial populations of up to 10(12) CFU/ml, we failed to isolate any bacteria resistant to 3 times the MIC of thioridazine, suggesting the absence of resistant mutants at bacterial burdens severalfold higher than those encountered in patients. In the hollow-fiber model of intracellular MAC (HFS-MAC), thioridazine achieved an extracellular half-life of 16.8 h and an intracellular half-life of 19.7 h. Thioridazine concentrations were >28,000-fold higher inside infected macrophages than in the HFS-MAC central compartment (equivalent to plasma). Thioridazine maximal kill was 5.20 +/- 0.75 log10 CFU/ml on day 7 (r(2) = 0.96) and 7.19 +/- 0.31 log10 CFU/ml on day 14 (r(2) = 0.99), the highest seen with any drug in the system. Dose fractionation studies revealed that thioridazine efficacy and acquired drug resistance were driven by the peak concentation-to-MIC ratio, with a 50% effective concentration (EC50) of 2.78 +/- 0.44 for microbial killing. Acquired drug resistance was encountered by day 21 with suboptimal doses, demonstrating that fluctuating drug concentrations drive evolution faster than static concentrations in mutation frequency studies. However, the thioridazine EC50 changed 16.14-fold when the concentration of fetal bovine serum was changed from 0% to 50%, suggesting that intracellular potency could be heavily curtailed by protein binding. Efficacy in patients will depend on the balance between trapping of the drug in the pulmonary system and the massive intracellular concentrations versus very high protein binding of thioridazine.


Posted August 15th 2016

Ratio of lumbar 3-column osteotomy closure: Patient-specific deformity characteristics and level of resection impact correction of truncal versus pelvic compensation.

Richard Hostin M.D.

Richard Hostin M.D.

Diebo, B. G., R. Lafage, C. P. Ames, S. Bess, I. Obeid, E. Klineberg, M. E. Cunningham, J. S. Smith, R. Hostin, S. Liu, P. G. Passias, F. J. Schwab and V. Lafage (2016). “Ratio of lumbar 3-column osteotomy closure: Patient-specific deformity characteristics and level of resection impact correction of truncal versus pelvic compensation.” Eur Spine J 25(8): 2480-2487.

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PURPOSE: The resection point of a lumbar three-column osteotomy (3CO) creates separation of the spino-pelvic complex. This study investigates the impact of patients’ baseline deformity and level of 3CO resection on the distribution of correction between the trunk and the pelvis following osteotomy closure. METHODS: Patients who underwent single lumbar 3CO, upper instrumented vertebra (UIV) T1-T10, and 6 month follow-up were included. The truncal and pelvic closures were calculated based on the vertebrae adjacent to the osteotomy level and the impact of radiographic parameters and level of 3CO on the closures were analyzed. RESULTS: 113 patients were included. Patients who experienced more pelvic correction had significantly higher Pelvic Tilt and lower Sagittal Vertical Axis at baseline. Patients who underwent more caudal osteotomies with higher pelvic compensation with modest SVA sustained more pelvic correction. CONCLUSIONS: The osteotomy closure is driven by patient’s specific deformity. More caudal osteotomy level leads to greater pelvic tilt improvement.


Posted August 15th 2016

Public Health Nursing Practice in the Affordable Care Act Era: A National Survey.

Richard E. Gilder R.N.

Richard E. Gilder R.N.

Edmonds, J. K., L. A. Campbell and R. E. Gilder (2016). “Public health nursing practice in the affordable care act era: A national survey.” Public Health Nurs: 2016 Jul [Epub ahead of print].

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OBJECTIVES: To explore public health nurses’ knowledge, perceptions, and practices under the Affordable Care Act (ACA). DESIGN AND SAMPLE: A cross-sectional, web-based survey was completed by a sample of 1,143 public health nurses (PHNs) in the United States. MEASURES: Descriptive statistics were analyzed for variables related to general knowledge and perception of the ACA and for the extent of involvement in activities related to the implementation of the ACA. Qualitative analysis was conducted on free text comments to two open-ended questions about current and future PHNs involvement in the ACA. RESULTS: Approximately 45% of PHNs reported changes in their daily work due to the ACA. PHNs reported being very or somewhat involved in these activities of the ACA: integration of primary care and public health (62%), provision of clinical preventive services (60.3%), care coordination (55.4%), patient navigation (55.3%), establishment of private-public partnerships (55.3%), population health strategies (53.6%), population health data assessment and analysis (53.8%), community health assessments (49%), involvement in medical homes (37.8%), provision of maternal and child health home visiting services (32.1%), and involvement in Accountable Care Organizations (29.2%). CONCLUSION: PHNs are making substantial contributions to implementation of the ACA.


Posted August 15th 2016

Failure of the amikacin, cefoxitin, and clarithromycin combination regimen for pulmonary mycobacterium abscessus.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Ferro, B. E., S. Srivastava, D. Deshpande, J. G. Pasipanodya, D. van Soolingen, J. W. Mouton, J. van Ingen and T. Gumbo (2016). “Failure of the amikacin, cefoxitin, and clarithromycin combination regimen for pulmonary mycobacterium abscessus.” Antimicrob Agents Chemother: 2016 Jul [Epub ahead of print].

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In the hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin and cefoxitin combination therapy for Mycobacterium abscessus At optimal dosing, a kill rate of -0.09 (95% CI -0.04- 0.03) log10 colony forming units (CFU) per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.


Posted August 15th 2016

Nonoperative management of grade iii blunt thoracic aortic injuries.

John F. Eidt M.D.

John F. Eidt M.D.

Gandhi, S. S., J. V. Blas, S. Lee, J. F. Eidt and C. G. Carsten, 3rd (2016). “Nonoperative management of grade iii blunt thoracic aortic injuries.” J Vasc Surg: 2016 Jul 2022 [Epub ahead of print].

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OBJECTIVE: Blunt thoracic aortic injuries (BTAIs) have historically been treated with open surgery; thoracic endovascular aortic repair (TEVAR), however, is rapidly becoming the standard of care for all grades of injury. Previous studies have shown successful, conservative management of low-grade (I and II) BTAI, but limited literature exists regarding nonoperative management (NOM) for high-grade BTAI. The purpose of this study was to evaluate NOM for grade III BTAI compared with TEVAR. METHODS: There were 75 patients diagnosed with BTAI between January 2004 and June 2015. Of these, 40 were excluded for different grades of BTAI (17), death before any treatment (6), and need for urgent open repair (17). The remaining 35 patients were divided into two groups by treatment approach: NOM (n = 18) and TEVAR (n = 17). Primary end points were complications and mortality. The secondary end point was difference in pseudoaneurysm and aortic diameter measurements between groups. RESULTS: The groups of patients were similar in age, gender, Injury Severity Score, length of stay, in-hospital mortality, and hospital-associated complications. There were four TEVAR-related complications: graft involutions (2), type I endoleak (1), and distal embolization (1). All TEVAR-related complications required either an adjunctive procedure at the time of the primary procedure or an additional procedure. No patients from the NOM group required operative intervention. There were seven in-hospital mortalities: two in the TEVAR group (11.8%) and five in the NOM group (27.8%; P = .402). One death in the NOM group was related to aortic disease. Follow-up computed tomography imaging revealed similar aortic-related outcomes between groups, with a high proportion showing resolved or improved aortic injury (NOM, 87.5%; TEVAR, 92.9%; P = .674). Initial computed tomography imaging showed similar aortic diameters between groups. The average diameter of the aorta distal to the subclavian artery was 22.6 mm in the NOM group vs 22.8 mm in the TEVAR group (P = .85). The average maximum diameter of the pseudoaneurysm was 30.1 mm in the TEVAR group and 29.9 mm in the NOM group (P = .90). The average ratio of diameter of the pseudoaneurysm to diameter of the aorta distal to the subclavian artery was 1.32 for the TEVAR group and 1.33 for the NOM group (P = .85). CONCLUSIONS: The natural history of grade III BTAIs is not well described. This study suggests that observation and NOM of grade III BTAI may be a reasonable therapeutic option in selected patients. It also speaks to the need for further delineation of the natural history of this injury. Serial imaging and long-term follow-up are necessary to monitor the progression of the pseudoaneurysm.