What Matters Most: The Documented Goals, Values and Motivators of Advanced Cancer Patients.

BACKGROUND: Goals of care conversations are essential to delivery of goal concordant care. Infrequent and inconsistent goals of care documentation potentially limit delivery of goal concordant care. METHODS: At Kaiser Permanente San Francisco Cancer Center, a standardized documentation template was designed and implemented to increase goals of care documentation by oncologists. The centralized, prompt-based template included value clarification of the goals and values of advanced cancer patients beyond treatment preferences. Documented conversations using the template during the initial pilot period were reviewed to characterization the clinical context in which conversations were recorded. Common goals and motivators were also identified. RESULTS: A total of 178 advanced cancer patients had at least 1 documented conversation by a medical oncologist using the goals of care template. Oncologists consistently documented within the template goals of therapy and motivating factors in decision making. The most frequently documented goals of care were "Avoiding Pain and Suffering," "Physical Independence," and "Living as Long as Possible." The least recorded goal was "Comfort Focused Treatment Only." CONCLUSIONS: Review of oncologist documented goals of care conversations using a prompt-based template allowed for characterization of the clinical context, therapy goals and motivators of advanced cancer patients. Communication of goals of care conversations by oncologists using a standardized prompt-based template within a centralized location has the potential to improve delivery of goal concordant care.

Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.

In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating.

Combining electron crystallography and X-ray crystallography to study the MlotiK1 cyclic nucleotide-regulated potassium channel.

We have recently reported the X-ray structure of the cyclic nucleotide-regulated potassium channel, MlotiK1. Here we describe the application of both electron and X-ray crystallography to obtain high quality crystals. We suggest that the combined application of these techniques provides a useful strategy for membrane protein structure determination. We also present negative stain projection and cryo-data projection maps. These maps provide new insights about the properties of the MlotiK1 channel. In particular, a comparison of a 9A cryo-data projection with calculated model maps strongly suggests that there is a very weak interaction between the pore and the S1-S4 domains of this 6 TM tetrameric cation channel and that the S1-S4 domains can adopt multiple orientations relative to the pore.