Obesity-related Changes in Diffusing Capacity and Transfer Coefficient of the Lung for Carbon Monoxide and Resulting Patterns of Abnormality across Reference Equations.

Rationale: In 2017, an American Thoracic Society/European Respiratory Society Task Force report recommended further research on the effects that body mass index (BMI) has on diffusing capacity of the lung for carbon monoxide (DlCO), the transfer coefficient (Kco), and the alveolar volume (VA). Objectives: Our goals were to 1) quantify the magnitude and direction of change to measured and predicted DlCO values as BMI increases in patients free of cardiopulmonary disease and 2) identify how BMI and obesity-related changes differ by reference set. Methods: Using data from a prospective cohort study of service members free of cardiopulmonary disease, we modeled the effect that BMI has on measured values of DlCO, Kco, and VA, after adjusting for age, sex, hemoglobin (Hgb), and height. We then referenced DlCO, Kco, and VA to normal values using four different reference equations. Results: There were 380 patients with data available for analysis, and 130 had a BMI ⩾ 30 kg/m2 (87.7% class I obesity). After controlling for age, sex, Hgb, and height, increased BMI was significantly associated with Kco (ß = 0.09, P < 0.01) and VA (ß = -0.15, P < 0.01) but not DlCO. After adjustment for Hgb, for every 5-kg/m2 increase in BMI, the mean increase in percent predicted (PPD) values ranged from 4.2% to 6.5% and from 5.0% to 7.5% for DlCO and Kco, respectively; and the mean decrease in VA PPD was 3.2-4.0%. In the presence of obesity (BMI ⩾ 30 kg/m2), the prevalence of DlCO and Kco abnormalities dropped by 4.1-12.1% and 0.4-16.3%, respectively, across equations, whereas VA abnormalities increased from 7.7% to 9.9%. Eliminating 163 patients with abnormal trans-thoracic echocardiogram (TEE), high-resolution computed tomographic (HRCT) scan, or Hgb altered the magnitude of relationships, but significance was preserved. Conclusions: In an otherwise healthy population with predominantly class I obesity and normal TTE, HRCT scan, and Hgb, we found that Kco and VA were more affected by BMI than DlCO. Increases in PPD values varied across equations and were modest but significant and could change clinical decision making by reducing sensitivity for detecting gas-exchange abnormalities. BMI and obesity had the smallest effect on Global Lung Function Initiative PPD values.

Automation of the I-PASS Tool to Improve Transitions of Care.

INTRODUCTION: Errors in communication during handoffs are a significant source of medical error and put patients at risk. The I-PASS system was designed to systematically communicate information to the oncoming healthcare provider and has been shown to decrease the risk of communication errors. The objective of this observational quality improvement study was to determine whether the addition of a partially automated, electronic handoff tool would further decrease errors in communication during transitions of care for inpatient medical teams. METHODS: We created an electronic tool to incorporate user-generated patient information in the I-PASS format with automatically compiled data derived from the electronic medical record. Numbers of errors in the printed handoff document were recorded before and after intervention. RESULTS: The first implementation cycle demonstrated an absolute risk reduction for written errors of 45.6% (95% confidence interval [CI] 39.2-51.2%) and a number needed to treat (NNT) of three patients. The second cycle showed an absolute risk reduction of 53.3% (95% CI 39.8-63.9%; NNT 2). Aggregate data showed an absolute risk reduction of 46.6% (95% CI 41.0-51.7%, NNT 3). CONCLUSIONS: Improving the routine task of patient handoff through the thoughtful application of technology can yield benefits in terms of decreasing documentation errors and streamlining workflow before patient handoff.

N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation in ovarian cancer cells.

Doxorubicin has been used clinically to treat various types of cancer, and yet the molecular mode of actions of doxorubicin remains to be fully unraveled. In this study, we investigated the effect of doxorubicin on cultured ovarian cancer cells (CaOV3). MTT assay data showed that doxorubicin inhibits cell proliferation in a time- and dose-dependent manner. Phagokinetic cell motility assay data indicated that doxorubicin inhibits both basal level and EGF-induced cell migration in CaOV3 cells. Confocal microscopic data revealed that doxorubicin induces reorganization of cytoskeletal proteins including actin, tubulin and vimentin. Doxorubicin induces phosphorylation of p53 at Ser15 and 20, acetylation of p53 and ATM activation. Doxorubicin also induces phosphorylation of histone H2AX at Ser139. Interestingly, doxorubicin also inhibits mTOR activity, measured by phosphorylation of S6 ribosomal protein. Pretreatment of CaOV3 cells with antioxidant N-acetylcysteine (NAC), but not pyrrolidine dithiocarbamate (PDTC) potentiates doxorubicin-induced phosphorylation of p53 and ATM. Collectively, we conclude that doxorubicin induces ATM/p53 activation leading to reorganization of cytoskeletal networks, inhibition of mTOR activity, and inhibition of cell proliferation and migration. Our data also suggest that removal of oxidants by antioxidants such as NAC may enhance the efficacy of doxorubicin in vivo.

Paclitaxel disrupts polarized entry of membrane-permeable C6 ceramide into ovarian cancer cells resulting in synchronous induction of cell death.

Exogenous cell-permeable C6 ceramide has been demonstrated to act synergistically with chemotherapeutic drugs, including paclitaxel, cisplatin, doxorubicin and the histone deacetylase inhibitor, trichostatin A, to induce cell death in a variety of cancer cells. We previously demonstrated that C6 ceramide and paclitaxel function synergistically to induce ovarian cancer cell death via modulation of the PI3/AKT cell survival pathway. In the present study, the entry pattern of C6 ceramide into ovarian cancer cells was investigated using fluorescent short chain C6-NBD sphingomyelin (C6-NBD). Confocal microscopy revealed that C6-NBD enters the cells in a polarized pattern, characterized by marked signals at one cellular end, representing a likely mitosis initiation site. Pretreatment of the cells with filipin, an inhibitor of the lipid raft/caveolae endocytosis pathway, decreases C6-NBD entry into the cells. A pretreatment with the water channel inhibitor, CuSO4, was also found to reduce the entry of C6-NBD. Notably, the pretreatment with paclitaxel was shown to disrupt the polarized entry of C6-NBD into the cells, resulting in an even distribution of C6-NBD in the cytoplasm. In addition, the pretreatment of the cells with paclitaxel destabilized the cytoskeletal proteins, releasing an increased number of short tubulin fragments. The results of the present study indicate that C6 ceramide preferentially enters the cells via a predetermined initiation site of mitosis. In addition to diffusion, short chain C6 ceramide may also enter cells via water channels and caveolae-mediated endocytosis. Paclitaxel disrupts the cell cytoskeleton and induces an even distribution of C6 ceramide in the cytoplasm resulting in synergistic ovarian cancer cell death.