The Effects of 24-Hour Neurosurgical Call on Fine Motor Dexterity, Cognition, and Mood.

BACKGROUND: Concerns regarding the effects of fatigue on physician performance and quality of life lead to the implementation of duty hour restrictions for residents by the Accreditation Council for Graduate Medical Education (ACGME). These restrictions have been met by strong criticism from the neurosurgical community. This is partly due to a lack of objective evidence that fatigue results in decrements in professional function in neurological surgeons. There is also concern that the restrictions have diminished clinical and operative experience as well as the development of professional responsibility in residency. OBJECTIVE:  To evaluate whether 24-hour neurosurgical call has an objective impact on fine motor dexterity, cognitive thinking skills, and mental well-being. METHODS: Subjects were tested before and after taking 24 hours of neurosurgical call. We evaluated fine motor dexterity using the Vienna Test System Motor Performance Series, cognitive thinking abilities using a battery of paper-pencil neuropsychological tests, and mental well-being using the Profile of Mood States.  Results: A total of 27 subjects were included in this study, 12 seasoned to neurosurgical call and 15 naive to neurosurgical call. The seasoned subjects demonstrated no statistically significant change in performance after call on any of the tests for fine motor dexterity or cognitive thinking abilities. The nonseasoned subjects demonstrated multiple decrements in fine motor dexterity and cognitive thinking abilities after taking call. In the Motor Performance Series, they had a statistically significant decrease in the speed of untargeted movements in the nondominant hand during the tapping test (p = 0.002), and a decline in the precision of fine motor movements and information processing as evidenced by an increase in the number of errors of the dominant hand in the line tracking test (p = 0.014). There was a statistically significant decline in their immediate memory during Hopkins Verbal Learning Test (p = 0.025), and complex attention, mental flexibility, and visual-motor speed in the Trail Making Test (p = 0.03). The Profile of Mood States found no difference in feelings of anger (p = 0.54), tension (p = 0.358), or depression (p = 0.65). There were increased feelings of confusion (p < 0.001) and decreased feelings of vigor (p < 0.001) and friendliness (p = 0.001). Nonseasoned subjects had an increase in total mood disturbance (p = 0.012) but seasoned subjects did not (p = 0.083).  Conclusion: Our results suggest that fatigue-induced decrements in professional function can be ameliorated by experience with prolonged duty hours. In contrast to nonseasoned subjects, those who were conditioned to 24-hour neurosurgical call demonstrated resilience in fine motor dexterity and cognitive thinking skills, and exhibited no change in total mood disturbance. An argument can be made that we are turning the neurosurgical training paradigm upside down with the current ACGME duty hour restrictions.

Moving From Physician Burnout to Resilience.

We contend that work ambivalence is a key building block in fostering physician burnout and its sequalae, while engagement in meaningful work and receiving family support for that work enhances resilience. No singular approach to curbing burnout in OBGYN physicians has received empirical support. Clinical experience suggests that curbing physician burnout requires a combination of workplace redesigns, positive leadership behaviors, and resilience training that teaches practical applications from the fields of resilience, emotional intelligence, positive psychology, and relationship systems. This paper highlights organizational and leadership interventions that foster physician engagement, and describes how physicians can foster personal and family resilience.

Economic Impact of Hospitalization Past Maximal Neurosurgical Inpatient Benefit.

Background The unsustainable cost of healthcare in the United States has made it important for all healthcare professionals to examine their practices for wasteful spending and work to mitigate these costs. When neurosurgical patients remain hospitalized beyond the point of maximum inpatient benefit, this represents a potential source of healthcare economic waste. Objective The objective of this study was to determine the direct and indirect costs to a hospital system when neurosurgical patients remain hospitalized past the maximum inpatient benefit and identify targets to improve this potential wasteful spending.  Methods We performed an extensive chart review of all patients admitted to our neurosurgical service from the months of July to October 2016, who had been deemed medically stable for discharge but remained in the hospital past their ideal date of discharge. We analyzed for significant trends in patient factors, procedural acuity, disposition, funding, and other factors that contributed to the delays in discharge. Results A total of 334 patients were admitted to the Carilion Clinic-Virginia Tech Carilion (CC-VTC) inpatient neurosurgery service, and 50 of these admissions (15%) resulted in medically unnecessary prolonged hospitalizations. These patients were hospitalized for a total of 324 days past the dates of ideal discharge. Elective cases had the maximum number of prolonged hospitalizations, while the emergent cases had the maximum number of prolonged hospitalization days. Patients with private insurance had the shortest number of prolonged hospitalization days, and uninsured patients had the longest. Patients requiring disposition to a rehabilitation or a nursing facility remained in the inpatient setting for longer periods than those destined for home. The most common factors limiting appropriate discharge were related to bed availability at outside facilities, funding issues, and differing opinions on appropriate disposition. The medically unnecessary days accounted for 41% of the total hospitalization but accounted for only 12.9% of the billable charges. The billable cost per medically necessary day was $17,326 in comparison to a medically unnecessary day of $2,070. Indirect costs were inferred from these patients utilizing beds and resources that could have been allocated to others with acute needs, given that our hospital is at capacity and on diversion, a significant percentage of the time. Conclusion Neurosurgical patients remaining hospitalized past their maximal inpatient benefit have a significant economic impact on a hospital system. Identifying patients who are at risk for prolonged hospitalizations may provide us with the targets for improvement to mitigate this healthcare economic waste.

PIK3CB/p110ß is a selective survival factor for glioblastoma.

Background: Glioblastoma (GBM) is difficult to treat. Phosphoinositide 3-kinase (PI3K) is an attractive therapeutic target for GBM; however, targeting this pathway to effectively treat GBM is not successful because the roles of PI3K isoforms remain to be defined. The aim of this study is to determine whether PIK3CB/p110ß, but not other PI3K isoforms, is a biomarker for GBM recurrence and important for cell survival. Methods: Gene expression and clinical relevance of PI3K genes in GBM patients were analyzed using online databases. Expression/activity of PI3K isoforms was determined using immunoblotting. PI3K genes were inhibited using short hairpin RNAs or isoform-selective inhibitors. Cell viability/growth was assessed by the MTS assay and trypan blue exclusion assay. Apoptosis was monitored using the caspase activity assay. Mouse GBM xenograft models were used to gauge drug efficacy. Results: PIK3CB/p110ß was the only PI3K catalytic isoform that significantly correlated with high incidence rate, risk, and poor survival of recurrent GBM. PIK3CA/p110α, PIK3CB/p110ß, and PIK3CD/p110δ were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110γ was barely detected. PIK3CB/p110ß protein levels presented a stronger association with the activities of PI3K signaling than other PI3K isoforms. Blocking p110ß deactivated PI3K signaling, whereas inhibition of other PI3K isoforms had no effect. Specific inhibitors of PIK3CB/p110ß, but not other PI3K isoforms, remarkably suppressed viability and growth of GBM cells and xenograft tumors in mice, with minimal cytotoxic effects on astrocytes. Conclusions: PIK3CB/p110ß is a biomarker for GBM recurrence and selectively important for GBM cell survival.

Patient-derived glioblastoma stem cells respond differentially to targeted therapies.

The dismal prognosis of glioblastoma is, at least in part, attributable to the difficulty in eradicating glioblastoma stem cells (GSCs). However, whether this difficulty is caused by the differential responses of GSCs to drugs remains to be determined. To address this, we isolated and characterized ten GSC lines from established cell lines, xenografts, or patient specimens. Six lines formed spheres in a regular culture condition, whereas the remaining four lines grew as monolayer. These adherent lines formed spheres only in plates coated with poly-2-hydroxyethyl methacrylate. The self-renewal capabilities of GSCs varied, with the cell density needed for sphere formation ranging from 4 to 23.8 cells/well. Moreover, a single non-adherent GSC either remained quiescent or divided into two cells in four-seven days. The stem cell identity of GSCs was further verified by the expression of nestin or glial fibrillary acidic protein. Of the two GSC lines that were injected in immunodeficient mice, only one line formed a tumor in two months. The protein levels of NOTCH1 and platelet derived growth factor receptor alpha positively correlated with the responsiveness of GSCs to γ-secretase inhibitor IX or imatinib, two compounds that inhibit these two proteins, respectively. Furthermore, a combination of temozolomide and a connexin 43 inhibitor robustly inhibited the growth of GSCs. Collectively, our results demonstrate that patient-derived GSCs exhibit different growth rates in culture, possess differential capabilities to form a tumor, and have varied responses to targeted therapies. Our findings underscore the importance of patient-derived GSCs in glioblastoma research and therapeutic development.

Connexin 43 Inhibition Sensitizes Chemoresistant Glioblastoma Cells to Temozolomide.

Resistance of glioblastoma (GBM) to the front-line chemotherapeutic agent temozolomide (TMZ) continues to challenge GBM treatment efforts. The repair of TMZ-induced DNA damage by O-6-methylguanine-DNA methyltransferase (MGMT) confers one mechanism of TMZ resistance. Paradoxically, MGMT-deficient GBM patients survive longer despite still developing resistance to TMZ. Recent studies indicate that the gap junction protein connexin 43 (Cx43) renders GBM cells resistant to TMZ through its carboxyl terminus (CT). In this study, we report insights into how Cx43 promotes TMZ resistance. Cx43 levels were inversely correlated with TMZ sensitivity of GBM cells, including GBM stem cells. Moreover, Cx43 levels inversely correlated with patient survival, including as observed in MGMT-deficient GBM patients. Addition of the C-terminal peptide mimetic αCT1, a selective inhibitor of Cx43 channels, sensitized human MGMT-deficient and TMZ-resistant GBM cells to TMZ treatment. Moreover, combining αCT1 with TMZ-blocked AKT/mTOR signaling, induced autophagy and apoptosis in TMZ-resistant GBM cells. Our findings suggest that Cx43 may offer a biomarker to predict the survival of patients with MGMT-independent TMZ resistance and that combining a Cx43 inhibitor with TMZ could enhance therapeutic responses in GBM, and perhaps other TMZ-resistant cancers.