Scalp block for glioblastoma surgery is associated with lower inflammatory scores and improved survival.

BACKGROUND: Regional anesthesia has anti-inflammatory effects. Recent studies suggest that regional anesthesia might improve the survival of patients with cancer. We hypothesized that the use of a scalp block (SB) during craniotomy for glioblastoma (GB) decreases the postoperative systemic and local inflammatory response and extend their survival. METHODS: This retrospective study included 119 patients with GB who underwent tumor resection. We divided patients into 2 groups based on the use of SB during surgery. Preoperative and postoperative neutrophil-to-lymphocyte (NLR) ratio and platelet-to-lymphocyte (PLR) ratios were calculated as well as the percentage change in postoperative T2/FLAIR (FLuid-Attenuated Inversion Recovery) volume. Both markers of the inflammatory response were compared between patients with and without an SB. Progression-free survival (PFS) was also compared in both groups of patients. Univariate and multivariate analysis were used to test the association between SB and patients' survival. RESULTS: On day 3 after surgery, patients who had an SB showed statistically significant lower NLRs and PLRs than those without an SB. There was also a significant larger reduction in postoperative T2/FLAIR signal in patients with SB than in those without SB. The median PFS (progression-free survival) was longer in patients with SB (16.7 months) than those without an SB (6.5 months, P<0.001). The multivariate analysis indicated that the use of SB was an independent factor for longer PFS (hazard ratio: 0.31 95% confidence interval: 0.07-0.21, P<0.001). CONCLUSIONS: This retrospective study supports the hypothesis that in patients with GB undergoing craniotomy, the use of SB is associated with lower levels of systemic and local inflammation, and longer survival.

Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.

Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3ß-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the ß-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.

Discharge Delays for Patients Requiring In-Hospital Guardianship: A Cohort Analysis.

OBJECTIVE: To assess nonclinical factors delaying hospital discharge of guardianship patients. DATA: Utilization review data over 3 years. DESIGN: Retrospective cohort study. ANALYSIS: Mann-Whitney test was used to compare patients' medically unnecessary days (MUD) of hospitalization with additional subcategories of delays-defined as beyond clinicians' control. FINDINGS: Overall median number of MUD was 19.5; 14 of 48 patients were additionally delayed while awaiting long-term care Medicaid approval (N = 7, 50%), pending insurance (N = 3, 21%), social or transportation difficulties (N = 3, 21%), or preadmission review (N = 1, 7%). The median number of MUD for the 14 delayed patients was 63, a difference of 53 days compared with the routine guardianship cohort (P < .0001) and $5.5M in net revenue opportunity. CONCLUSIONS: Nonclinical discharge delays for guardianship patients are costly and potentially unavoidable. Further exploration into policy change is therefore recommended.

Diagnosis and treatment of psychiatric comorbidity in a patient with charles bonnet syndrome.

Background. A significant proportion of patients with neurological disorders may have comorbid psychiatric symptomology, which may be managed by primary outpatient neurologists. Referral to their psychiatric colleagues is mediated by available consultation-liaison units and according to clinical opinion. Aims of Case Report. We present the case of a patient whose initial referral to epilepsy clinic led to a workup which ultimately diagnosed her with nonepileptic seizures (NES). In the course of her follow-up, she developed intractable headaches, and worsening mood symptoms and eventually exhibited Psychotic Features for which psychiatry became coinvolved in her care. Major Depression with Psychotic Features and Charles Bonnet syndrome were considered as a likely comorbid diagnoses. Her pharmacologic management on venlafaxine and quetiapine eventually caused substantial amelioration of her psychiatric symptomology as longitudinally followed by PHQ-9 and GAD-7 scores. Conclusion. Optimal evaluation and management of mental illness in patients with complex neurologic symptomology may require independent evaluation and treatment by psychiatrists when clinically appropriate.

Quality improvement opportunities in caring for patients with nonepileptic seizures.

Background. Patients with nonepileptic seizures (NES) are challenging to treat for myriad reasons. Often patients may be misdiagnosed with having epilepsy and then may suffer unintended consequences of treatment side effects with antiepileptic medication. In addition, patients may be maligned by health care providers due to a lack of ownership by both psychiatrists and neurologists and a dearth of dedicated professionals who are able to effectively treat and reduce severity and frequency of symptoms. Aims of Case Report. Many psychiatrists and neurologists are unaware of the extent of the barriers to care faced by patients with NES (PWNES) and the degree of perception of maltreatment or lack of therapeutic alliance at various stages of their care, including medical workup, video-EEG monitoring, and follow-up plans. We present the case of a patient with NES who experienced numerous barriers as well as incoordination to her care despite being offered a breadth of resources and discuss the quality improvement opportunities that may exist to improve care of patients with NES. Conclusion. No known literature has documented the extensive barriers to care of PWNES in parallel to quality improvement opportunities for improving their care. We endeavor to contribute to the overall formulation and development of a clinical care pathway for PWNES.

A clinical pathway for guardianship at Dartmouth-Hitchcock Medical Center.

BACKGROUND: Guardianship may be necessary when inpatients lack medical decision-making capacity and are unwilling to go home to be cared for by interested proxy decision makers. Interventions, centered on a clinical pathway, were conducted at Dartmouth-Hitchcock Medical Center (DHMC; Lebanon, New Hampshire). Because guardianship occurs at the interface of clinical care and governmental bureaucracy, quality improvement efforts focused on "in-hospital" processes, while actions were taken to improve communication between clinical teams and the legal system. METHODS: A multidisciplinary quality improvement team mapped the DHMC guardianship process and analyzed the causes for delays before creating the clinical pathway. Specific interventions were designed and implemented to address the identified improvement areas. RESULTS: For the 26 guardianship patients during a two-year period (May 1, 2011-May 1, 2013), the charges incurred totaled approximately $4,000,000--for an average of more than $150,000 per patient. The medically unnecessary days of their length of hospital stay decreased from an average of 27.8 to 11.3, a statistically significant result as demonstrated by statistical process control analysis. The shorter hospitalizations of the last 13 patients amounted to 214.5 medically unnecessary hospital days saved and more than $1.2 million in charges reduced during the two-year period. CONCLUSIONS: Guardianship is a complex process that generates significant delays in appropriate care and increases in charges. The redesigned, standardized guardianship process, as defined in the clinical pathway, reduced associated medically unnecessary days of hospitalization.

Reducing severity of comorbid psychiatric symptoms in an epilepsy clinic using a colocation model: results of a pilot intervention.

RATIONALE: Patients with epilepsy (PWEs) and patients with nonepileptic seizures (PWNESs) constitute particularly vulnerable patient populations and have high rates of psychiatric comorbidities. This potentially decreases quality of life and increases health-care utilization and expenditures. However, lack of access to care or concern of stigma may preclude referral to outpatient psychiatric clinics. Furthermore, the optimal treatment for NESs includes longitudinal psychiatric management. No published literature has assessed the impact of colocated psychiatric services within outpatient epilepsy clinics. We, therefore, evaluated the colocation of psychiatric services within a level 4 epilepsy center. METHODS: From July 2013 to June 2014, we piloted an intervention to colocate a psychiatrist in the Dartmouth-Hitchcock Epilepsy Center outpatient clinic one afternoon a week (0.1 FTE) to provide medication management and time-limited structural psychotherapeutic interventions to all patients who scored greater than 15 on the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and who agreed to referral. Psychiatric symptom severity was assessed at baseline and follow-up visits using validated scales including NDDI-E, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and cognitive subscale items from Quality of Life in Epilepsy-31 (QOLIE-31) scores. RESULTS: Forty-three patients (18 males; 25 females) were referred to the clinic over a one-year interval; 27 (64.3%) were seen in follow-up with a median of 3 follow-up visits (range: 1 to 7). Thirty-seven percent of the patients had NESs exclusive of epilepsy, and 11% of the patients had dual diagnosis of epilepsy and NESs. Psychiatric symptom severity decreased in 84% of the patients, with PHQ-9 and GAD-7 scores improving significantly from baseline (4.6±0.4 SD improvement in PHQ-9 and 4.0±0.4 SD improvement in GAD-7, p-values<0.001). Cognitive subitem scores for NDDI-E and QOLIE-31 at their most recent visit were significantly improved compared with nadir scores (3.3±0.6 SD improvement in NDDI-E and 1.5±0.2 SD improvement in QOLIE-31, p-values<0.001). These results are, moreover, clinically significant-defined as improvement by 4-5 points on PHQ-9 and GAD-7 instruments-and are correlated with overall improvement as measured by NDDI-E and cognitive subscale QOLIE-31 items. CONCLUSION: A colocated psychiatrist demonstrated reduction in psychiatric symptoms of PWEs and PWNESs, improving psychiatric access and streamlining their care. Epileptologists were able to dedicate more time to managing epilepsy as opposed to psychiatric comorbidities. As integrated models of collaborative and colocated care are becoming more widespread, mental health-care providers located in outpatient neurology clinics may benefit both patients and providers.

Treatment of anxiety and depression in a patient with brugada syndrome.

Background. Brugada syndrome is rare and has been a clinically diagnosable entity since 1992. Its clinical manifestations are highly variable, and while some patients remain asymptomatic, others endure sudden cardiac death. Initial presenting symptoms may include palpitations, seizures, syncope, and nocturnal agonal respiration. The diagnosis of Brugada syndrome relies on both clinical findings and characteristic ECG patterns that occur spontaneously or are induced by usage of sodium-channel blocking agents. Aims of Case Report. Many psychiatrists may be unaware of the possibility of medical cocontributing etiologies to physical symptoms of anxiety and depression. We present a case of a patient who was treated psychiatrically for anxiety and panic attacks and who was subsequently diagnosed with Brugada syndrome and treated medically with an implantable cardioverter defibrillator (ICD), the only treatment option demonstrated to be effective. Her psychiatric symptoms predated her diagnosis of Brugada syndrome by at least fifteen years. Conclusion. The patient's eventual diagnosis of Brugada syndrome altered the course of her psychopharmacologic medication management and illustrates the utility of a psychosomatic approach to psychiatric symptom management.

Predictors for readmissions after video-EEG monitoring.

OBJECTIVE: Identification of variables prognosticating 30-day readmission among adult patients admitted for video-EEG (VEEG) monitoring at a major epilepsy center. METHODS: A retrospective cohort study was conducted, examining 865 consecutive admissions to the epilepsy monitoring unit (EMU) from January 2010 to June 2013. Data extracted from chart review included demographics, length of stay (LOS), seizure type(s), number of 30-day readmissions or emergency department (ED) visits and reasons for these, and patient and system/provider factors potentially contributing to the readmission. RESULTS: Of 865 elective admissions for VEEG monitoring, 49 patients accounted for 33 readmissions and 40 ED visits within 30 days of discharge for an overall 30-day encounter rate of 7.0% after excluding those lost to follow-up; 9 patients had more than one ED visit or readmission. Statistically significant risk factors for urgent 30-day encounters included a history of nonepileptic seizures (NES) (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.4), a dual diagnosis of both epilepsy and NES (OR 5.9, 95% CI 3.0-11.8), an urgent index admission to the EMU (OR 2.5, 95%CI 1.4-4.8), and a shorter LOS of index hospitalization (median 4.0 days vs 5.0 days, p < 0.01). The most common contributing patient factors included active psychiatric symptoms, medically refractory epilepsy, and living alone; the most common hospitalization-related factors included antiepileptic drug (AED) treatment adverse events or AED adjustment. CONCLUSIONS: In addition to the presence of intractable epilepsy and shorter LOS, mental health comorbidities and the presence of NES were important risk factors for 30-day readmissions and ED visits in the epilepsy population. Therefore, proactively addressing mental health comorbidities may decrease urgent health care utilization after VEEG monitoring.

Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury.

PURPOSE: Elevated intracranial pressure (ICP) has been associated with increased mortality in patients with severe traumatic brain injury (TBI). We have examined whether raised ICP is independently associated with mortality, functional status and neuropsychological functioning in adult TBI patients. METHODS: Data from a randomized trial of 499 participants were secondarily analyzed. The primary endpoints were mortality and a composite measure of functional status and neuropsychological function (memory, speed of information processing, executive function) over a 6-month period. The area under the curve of the ICP profile (average ICP) during the first 48 h of monitoring was the main predictor of interest. Multivariable regression was used to adjust for a priori defined confounders: age, Glasgow Coma Score, Abbreviated Injury Scale-head and hypoxia. RESULTS: Of the participants, 365 patients had complete 48-h ICP data. The overall 6-month mortality was 18 %. The adjusted odds ratio of mortality comparing 10-mmHg increases in average ICP was 3.12 (95 % confidence interval 1.79, 5.44; p < 0.01). Overall, higher average ICP was associated with decreased functional status and neuropsychological functioning (p < 0.01). Importantly, among survivors, increasing average ICP was not independently associated with worse performance on neuropsychological testing (p = 0.46). CONCLUSIONS: Average ICP in the first 48 h of monitoring was an independent predictor of mortality and of a composite endpoint of functional and neuropsychological outcome at the 6-month follow-up in moderate or severe TBI patients. However, there was no association between average ICP and neuropsychological functioning among survivors.

Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-ß signaling.

Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O(2) consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O(2) homeostasis. Mouse embryos lacking expression of the O(2)-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a(f/f);Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2(+) lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-ß signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-ß signaling in Hif1a(f/f);Tie2-Cre mice. Inhibition of TGF-ß signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK-ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-ß signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.

Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b⁺ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor.

Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation.

Primary tumors facilitate metastasis by directing bone marrow-derived cells (BMDCs) to colonize the lungs before the arrival of cancer cells. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of breast cancer metastatic niche formation through induction of multiple members of the lysyl oxidase (LOX) family, including LOX, LOX-like 2, and LOX-like 4, which catalyze collagen cross-linking in the lungs before BMDC recruitment. Only a subset of LOX family members was expressed in any individual breast cancer, but HIF-1 was required for expression in each case. Knockdown of HIF-1 or hypoxia-induced LOX family members reduced collagen cross-linking, CD11b(+) BMDC recruitment, and metastasis formation in the lungs of mice after orthotopic transplantation of human breast cancer cells. Metastatic niche formation is an HIF-1-dependent event during breast cancer progression.

A reassessment of normal cervical range of motion.

STUDY DESIGN: Intraexaminer and interexaminer/procedure reliability and error analysis using a repeated-measures design. OBJECTIVE: To quantify sources of discrepancies in cervical range of motion values between two procedures that use the same potentiometric technology. SUMMARY OF BACKGROUND DATA: Studies using an early version of an electrogoniometer system, which was connected between a helmet worn by the study participant and a chair on which they sat, reported unusually high values for active and passive cervical range of motion, although measurements were reliable. To understand the sources of the discrepancies between that study and later studies (using upgraded software), the current study was designed to quantify possible sources of error contributed by various components of the procedures: helmet, thoracic reference, chair, and software. METHODS: A total of 22 asymptomatic study participants were evaluated in two separate sessions, 1-3 days apart. Components of two procedures were changed systematically in a series of repeated measurements to provide concurrent reliability and to assess sources of error between the two procedures. RESULTS: The reliabilities of both procedures were generally high with no systematic trends, except for lower values for flexion-extension studies with Procedure 2. Procedure 2 also provided systematically greater range of motion values (2-8 degrees ) than Procedure 1, except for flexion (half-cycle). The source of the greatest discrepancy between the two procedures was the software, when comparing the original with the updated versions. With regard to the instrumentation, the greatest source of variability was in the thoracic reference post; next was the helmet, and least significant was the type of seat used. A comparison of overall procedure discrepancies and summation of individual elements of the procedures accounted for virtually all of the observed error. CONCLUSION: The potentiometer-based electrogoniometer is a reliable instrument for determining cervical range of motion. Measurements appear to be more valid when the thoracic reference point is physically attached to the study participant's body. The original software provided with the system appears to have contributed to systematic overestimation of ranges of motion, but current units provide measurements that are both reliable and valid.