Effect of Nasal Valve Shape on Downstream Volume, Airflow, and Pressure Drop: Importance of the Nasal Valve Revisited.

OBJECTIVES: The relative importance of the nasal valve relative to the remainder of the nasal airway remains unknown. The goal of this article was to objectively measure the shape of the nasal inlet and its effect on downstream airflow and nasal cavity volume using a physical model and a physiologic flow model. METHODS: A patient who had isolated nasal valve surgery and had pre- and postoperative computed tomography scans available for analysis was studied. Nasal inlet shape measurements, computational fluid dynamics, and nasal volume analysis were performed using the computed tomography data. In addition, a physical model was used to determine the effect of nasal obstruction on downstream soft tissue. RESULTS: The postoperative shape of the nasal inlet was improved in terms of length and degree of tortuosity. Whereas the operated-on region at the nasal inlet showed an only 25% increase in cross-sectional area postoperatively, downstream nonoperated sites in the nasal cavity revealed increases in area ranging from 33% to 51%. Computational fluid dynamics analysis showed that airway resistance decreased by 42%, and pressure drop was reduced by 43%. Intraluminal mucosal expansion was found with nasal obstruction in the physical model. CONCLUSION: By decreasing the degree of bending and length at the nasal valve, inspiratory downstream nonoperated sites of the nasal cavity showed improvement in volume and airflow, suggesting that the nasal valve could play an oversized role in modulating the aerodynamics of the airway. This was confirmed with the physical model of nasal obstruction on downstream mucosa.

Differential protein stability of EGFR mutants determines responsiveness to tyrosine kinase inhibitors.

Non-small cell lung cancer (NSCLC) patients carrying specific EGFR kinase activating mutations (L858R, delE746-A750) respond well to tyrosine kinase inhibitors (TKIs). However, drug resistance develops within a year. In about 50% of such patients, acquired drug resistance is attributed to the enrichment of a constitutively active point mutation within the EGFR kinase domain (T790M). To date, differential drug-binding and altered ATP affinities by EGFR mutants have been shown to be responsible for differential TKI response. As it has been reported that EGFR stability plays a role in the survival of EGFR driven cancers, we hypothesized that differential TKI-induced receptor degradation between the sensitive L858R and delE746-A750 and the resistant T790M may also play a role in drug responsiveness. To explore this, we have utilized an EGFR-null CHO overexpression system as well as NSCLC cell lines expressing various EGFR mutants and determined the effects of erlotinib treatment. We found that erlotinib inhibits EGFR phosphorylation in both TKI sensitive and resistant cells, but the protein half-lives of L858R and delE746-A750 were significantly shorter than L858R/T790M. Third generation EGFR kinase inhibitor (AZD9291) inhibits the growth of L858R/T790M-EGFR driven cells and also induces EGFR degradation. Erlotinib treatment induced polyubiquitination and proteasomal degradation, primarily in a c-CBL-independent manner, in TKI sensitive L858R and delE746-A750 mutants when compared to the L858R/T790M mutant, which correlated with drug sensitivity. These data suggest an additional mechanism of TKI resistance, and we postulate that agents that degrade L858R/T790M-EGFR protein may overcome TKI resistance.

Poststroke rehabilitation: outcomes and reimbursement of inpatient rehabilitation facilities and subacute rehabilitation programs.

BACKGROUND AND PURPOSE: To assess whether poststroke rehabilitation outcomes and reimbursement for Medicare beneficiaries differ across inpatient rehabilitation facilities (IRFs) and skilled nursing facility (SNF) subacute rehabilitation programs. METHODS: Clinical data were linked with Medicare claims for 58,724 Medicare beneficiaries with a recent stroke who completed treatment in 1996 or 1997 in IRFs and subacute rehabilitation SNFs that subscribed to the Uniform Data System for Medical Rehabilitation. Outcome measures were discharge destination, discharge FIM ratings and Medicare Part A reimbursement during the institutional stay. RESULTS: IRF patients that were more likely to have a community-based discharge, compared with rehabilitation SNF patients, were patients with mild motor disabilities and FIM cognitive ratings of 23 or greater (adjusted odds ratio [AOR]=2.19; 95% CI: 1.52 to 3.14), patients with moderate motor disabilities (AOR=1.98; 95% CI: 1.49 to 2.61), patients with significant motor disabilities (AOR=1.26; 95% CI: 1.01 to 1.57) and patients younger than 82 with severe motor disabilities (AOR=1.43; 95% CI: 1.25 to 1.64). IRF patients with significant and severe motor disabilities achieved greater motor function of 2 or more FIM units compared with rehabilitation SNF patients. Medicare Part A payments for IRFs were higher than rehabilitation SNF payments across all subgroups. CONCLUSIONS: For most patients, poststroke rehabilitation in the more costly and intensive IRFs resulted in higher functional outcomes compared with care in a SNF-based rehabilitation program. IRF and SNF outcomes were similar for patients with minimal motor disabilities and patients with mild motor disabilities and significant cognitive disabilities. Cost-effectiveness analyses require considering the costs of the full episode of care.

Outcomes and reimbursement of inpatient rehabilitation facilities and subacute rehabilitation programs for Medicare beneficiaries with hip fracture.

OBJECTIVE: We sought to assess whether outcomes and reimbursement differ for Medicare beneficiaries with hip fracture when treated in an inpatient rehabilitation facility (IRF) compared with a skilled nursing facility (SNF) subacute rehabilitation program. PARTICIPANTS: Clinical data were linked with Medicare claims for 29,793 Medicare fee-for-service beneficiaries with a recent hip fracture who completed treatment in 1996 or 1997 in rehabilitation facilities that subscribed to the Uniform Data System for Medical Rehabilitation. OUTCOME MEASURES: We measured discharge destination, change in motor FIM rating, and Medicare Part A reimbursement. RESULTS: For patients with moderate-to-severe and severe disabilities, case mix groups (CMGs) 704 and 705, the percentage of patients discharged to the community from IRFs was lower than for patients treated in subacute rehabilitation SNFs, after controlling for covariates. Adjusted odds ratios were 0.71 (95% confidence interval 0.55-0.92) for CMG 704 and 0.72 (95% confidence interval 0.63-0.83) for CMG 705. For patients in the 3 other CMGs, no significant differences were detected. Improvement in motor functional status was roughly equivalent for patients treated in IRFs and those treated in the subacute rehabilitation programs across all 5 CMGs, after controlling for covariates. Medicare Part A payments for IRFs were significantly higher than SNF payments across all CMGs. CONCLUSION: SNF-based subacute rehabilitation was less costly and outcomes were in most, but not all, instances similar or better than IRF-based rehabilitation for Medicare fee-for-service beneficiaries who had a recent hip fracture.