Has It Worked?—The Goldwater-Nichols Reorganization Act

The overall report card is mixed. In the operational dimension of the Defense Department, which its original sponsors considered most pressing, the Goldwater-Nichols Act has been very successful. The act’s “business” reforms, however, have not worked. These concerns, which may have been secondary fifteen years ago, are urgent now

Concerted loop motion triggers induced fit of FepA to ferric enterobactin

Spectroscopic analyses of fluorophore-labeled Escherichia coli FepA described dynamic actions of its surface loops during binding and transport of ferric enterobactin (FeEnt). When FeEnt bound to fluoresceinated FepA, in living cells or outer membrane fragments, quenching of fluorophore emissions reflected conformational motion of the external vestibular loops. We reacted Cys sulfhydryls in seven surface loops (L2, L3, L4, L5, L7 L8, and L11) with fluorophore maleimides. The target residues had different accessibilities, and the labeled loops themselves showed variable extents of quenching and rates of motion during ligand binding. The vestibular loops closed around FeEnt in about a second, in the order L3 > L11 > L7 > L2 > L5 > L8 > L4. This sequence suggested that the loops bind the metal complex like the fingers of two hands closing on an object, by individually adsorbing to the iron chelate. Fluorescence from L3 followed a biphasic exponential decay as FeEnt bound, but fluorescence from all the other loops followed single exponential decay processes. After binding, the restoration of fluorescence intensity (from any of the labeled loops) mirrored cellular uptake that depleted FeEnt from solution. Fluorescence microscopic images also showed FeEnt transport, and demonstrated that ferric siderophore uptake uniformly occurs throughout outer membrane, including at the poles of the cells, despite the fact that TonB, its inner membrane transport partner, was not detectable at the poles

A Screen against Leishmania Intracellular Amastigotes: Comparison to a Promastigote Screen and Identification of a Host Cell-Specific Hit

The ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmaniasis is a major neglected disease with limited therapeutic options. In order to streamline efforts for the design of productive drug screens against Leishmania, we compared the efficiency of two screening methods, one targeting the free living and easily cultured promastigote (insect–infective) stage, the other targeting the clinically relevant but more difficult to culture intra-macrophage amastigote (mammal-infective) stage. Screening of a 909-member library of bioactive compounds against Leishmania donovani revealed 59 hits in the promastigote primary screen and 27 in the intracellular amastigote screen, with 26 hits shared by both screens. This suggested that screening against the promastigote stage, although more suitable for automation, fails to identify all active compounds and leads to numerous false positive hits. Of particular interest was the identification of one compound specific to the infective amastigote stage of the parasite. This compound affects intracellular but not axenic parasites, suggesting a host cell-dependent mechanism of action, opening new avenues for anti-leishmanial chemotherapy

Patterns of prophylactic gastrostomy tube placement in head and neck cancer patients: A consideration of the significance of social support and practice variation

OBJECTIVES/HYPOTHESIS: The purpose of this study was to examine factors associated with prophylactic placement of feeding tubes in head and neck cancer patients receiving radiation therapy as a part of treatment using multilevel models that account for patient-, physician-, and institution-level sources of variation. STUDY DESIGN: A retrospective analysis using binary logistic regression and hierarchical linear models was run to evaluate independent predictors of prophylactic feeding tube placement. METHODS: Surveillance, Epidemiology, and End Results-Medicare data were used. Head and neck cancer patients diagnosed with locoregionally advanced stage disease from 2000 to 2005 were included in this study (N = 8,306). RESULTS: Across all models, prophylactic gastrostomy tube placement was found to be more likely in patients who had cancer of the larynx or oropharynx compared with those with cancer of the nasopharynx or oral cavity; who had regional instead of local cancer; who did not receive surgery as a part of treatment, but did receive chemotherapy; and who were divorced, separated, or widowed. Additionally, although practice variation was observed to occur, its overall contribution in predicting prophylactic gastrostomy tube placement was minimal. CONCLUSIONS: As health care enters an era of patient-centered care, further investigation of the potential role of social support (or lack of social support) in influencing treatment decisions of head and neck cancer patients and providers is warranted. LEVEL OF EVIDENCE: 2b Laryngoscope, 2013. Society, Inc

Gastrostomy tube placement and use in patients with head and neck cancer

BACKGROUND: Enteral nutritional support is used in care for patients with head and neck cancer. This study describes the frequency and timing of gastrostomy tube placement and corresponding Medicare nutritional support claims in patients with head and neck cancer. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data for patients with head and neck cancer diagnosed from 2000 to 2005 were used in this descriptive study (N = 16,458). RESULTS: In all, 35.1% of patients undergoing treatment had gastrostomy tubes placed; 16.9% had tubes placed before treatment, whereas 83.1% had them placed after treatment. Of those having tubes placed prior to treatment 23.7% had Medicare claims for nutritional support before treatment and 40.9% had claims after treatment began. A total of 35.4% of patients who had tubes placed before treatment and 35.5% who had tubes placed after treatment had no claims for nutritional support. CONCLUSIONS: Future work is warranted to identify predictors and outcomes associated with provision and timing of enteral nutrition support for patients with head and neck cancer

Patterns of prophylactic gastrostomy tube placement in head and neck cancer patients: a consideration of the significance of social support and practice variation.

Objectives/hypothesisThe purpose of this study was to examine factors associated with prophylactic placement of feeding tubes in head and neck cancer patients receiving radiation therapy as a part of treatment using multilevel models that account for patient-, physician-, and institution-level sources of variation.Study designA retrospective analysis using binary logistic regression and hierarchical linear models was run to evaluate independent predictors of prophylactic feeding tube placement.MethodsSurveillance, Epidemiology, and End Results-Medicare data were used. Head and neck cancer patients diagnosed with locoregionally advanced stage disease from 2000 to 2005 were included in this study (N = 8,306).ResultsAcross all models, prophylactic gastrostomy tube placement was found to be more likely in patients who had cancer of the larynx or oropharynx compared with those with cancer of the nasopharynx or oral cavity; who had regional instead of local cancer; who did not receive surgery as a part of treatment, but did receive chemotherapy; and who were divorced, separated, or widowed. Additionally, although practice variation was observed to occur, its overall contribution in predicting prophylactic gastrostomy tube placement was minimal.ConclusionsAs health care enters an era of patient-centered care, further investigation of the potential role of social support (or lack of social support) in influencing treatment decisions of head and neck cancer patients and providers is warranted

Prophylactic percutaneous endoscopic gastrostomy tube placement in treatment of head and neck cancer: a comprehensive review and call for evidence-based medicine

Background: Patients with head and neck cancers (HNCs) are at increased risk of experiencing malnutrition, which is associated with poor outcomes. Advances in the treatment of HNCs have resulted in improved outcomes that are associated with severe toxic oral side effects, placing patients at an even greater risk of malnutrition. Prophylactic placement of percutaneous endoscopic gastrostomy (PEG) tubes before treatment may be beneficial in patients with HNC, especially those undergoing more intense treatment regimens. PEG tube placement, however, is not without risks. Methods: A comprehensive review of the literature was conducted. Results: Systematic evidence assessing both the benefits and harm associated with prophylactic PEG tube placement in patients undergoing treatment for HNC is weak, and benefits and harm have not been established. Conclusions: More research is necessary to inform physician behavior on whether prophylactic PEG tube placement is warranted in the treatment of HNC