Daniel Wu

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration.

Significance Both lamin B1 and lamin B2 have farnesyl lipid anchors, but the importance of this lipid modification has been unclear. We addressed that issue with knock-in mouse models. Mice expressing nonfarnesylated lamin B2 developed normally and were healthy. In contrast, mice expressing nonfarnesylated lamin B1 exhibited a severe neurodevelopmental abnormality accompanied by a striking defect in the cell nucleus. During the migration of neurons, the nuclear lamina was pulled free of the chromatin. Thus, farnesylation of lamin B1—but not lamin B2—is crucial for neuronal migration in the brain and for the retention of chromatin within the nuclear lamina. The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left “naked” (free from the nuclear lamina). Thus, farnesylation of lamin B1—but not lamin B2—is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.

Factors associated with patient satisfaction scores for physician care in trauma patients.

BACKGROUND The Affordable Care Act of 2010 identifies “patient experience of care” as one of five domains of excellent care. We hypothesized that there are specific demographic factors associated with higher or lower physician satisfaction (PS) scores in trauma patients. METHODS Press-Ganey PS scores for September 2004 to December 2010 were compared with trauma variables and the association of a mean PS greater than or equal to 75 (high score) or less than or equal to 50 (low score). Those variables that proved significant on univariate analysis were subjected to multivariate logistic regression analysis. Significance was at p < 0.05. RESULTS There were 12,196 admissions, of whom 1,631 (13.4%) returned patient satisfaction survey. A total of 1,174 patients (75.5%) returned a high PS (≥75), and 126 patients (8.1%) returned a low PS (⩽50). In the multiple logistic regression analysis, 65 years or older (odds ratio [OR], 1.7), having had a surgical procedure (OR, 1.6), and having a positive impression of the hospital care (OR, 7.0) proved significant for a high PS. Those patients who scored a low PS were significantly more likely to be younger (18–29 years: OR, 2.4; 30–64 years: OR, 1.8), to have not had surgery (OR, 2.2), had an Injury Severity Score (ISS) of 16 or lower (OR, 2.6), had a complication of care (OR, 4.4), and rated the hospital care as poor (OR, 9.2). CONCLUSION A trauma patient who is satisfied with his or her physician care is one who is 65 years or older, requires surgery, and is predominantly satisfied with other aspects of their hospital care. Unsatisfied patients are younger, are nonoperative, had lower ISS, had a complication of care, and rated their hospital care as poor. Understanding the specific characteristics of Press-Ganey results for trauma patients will allow trauma surgeons and their hospital partners to develop strategies to improve patients’ satisfaction with their trauma surgeon’s care. LEVEL OF EVIDENCE Epidemiologic study, level III; therapeutic study, level IV.

Has TRISS become an anachronism? A comparison of mortality between the National Trauma Data Bank and Major Trauma Outcome Study databases.

BACKGROUND The Trauma and Injury Severity Score (TRISS) has been the approach to trauma outcome prediction during the past 20 years and has been adopted by many commercial registries. Unfortunately, its survival predictions are based upon coefficients that were derived from a data set collected in the 1980s and updated only once using a data set collected in the early 1990s. We hypothesized that the improvements in trauma care during the past 20 years would lead to improved survival in a large database, thus making the TRISS biased. METHODS The TRISSs from the Pennsylvania statewide trauma registry (Collector, Digital Innovations) for the years 1990 to 2010. Observed-to-expected mortality ratios for each year of the study were calculated by taking the ratio of actual deaths (observed deaths, O) to the summation of the probability of mortality predicted by the TRISS taken over all patients (expected deaths, E). For reference, O/E ratio should approach 1 if the TRISS is well calibrated (i.e., has predictive accuracy). RESULTS There were 408,489 patients with complete data sufficient to calculate the TRISSs. There was a significant trend toward improved outcome (i.e., decreasing O/E ratio; nonparametric test of trend, p < 0.001) over time in both the total population and the blunt trauma subpopulation. In the penetrating trauma population, there was a trend toward improved outcome (decreasing O/E ratio), but it did not quite reach significance (nonparametric test of trend p = 0.073). CONCLUSION There is a steady trend toward improved O/E survival in the Pennsylvania database with each passing year, suggesting that the TRISS is drifting out of calibration. It is likely that improvements in care account for these changes. For the TRISS to remain an accurate outcome prediction model, new coefficients would need to be calculated periodically to keep up with trends in trauma care. This requirement for occasional updating is likely to be a requirement of any trauma prediction model, but because many other deficiencies in the TRISS have been reported, we think that rather than updating the TRISS, it would be more productive to replace the TRISS with a modern statistical model. LEVEL OF EVIDENCE Prognostic study, level II.

Determining venous thromboembolic risk assessment for patients with trauma: the Trauma Embolic Scoring System.

BACKGROUND This study aimed to determine the relative “weight” of risk factors known to be associated with venous thromboembolism (VTE) for patients with trauma based on injuries and comorbidities. METHODS A retrospective review of 16,608 consecutive admissions to a trauma center was performed. Patients were separated into those who developed VTE (n = 141) versus those who did not (16,467). Univariate analysis was performed for each risk factor reported in the trauma literature. Risk factors that were shown to be significant (p < 0.05) by univariate analysis underwent multivariate analysis to develop odds ratios for VTE. The Trauma Embolic Scoring System (TESS) was derived from the multivariate coefficients. The resulting TESS was compared with a data set from the National Trauma Data Bank (2002–2006) to determine its ability to predict VTE. RESULTS The multivariate analysis demonstrated that age, Injury Severity Score, obesity, ventilator use for more than 3 days, and lower-extremity trauma were significant predictors of VTE in our patient population. The TESS was from 0 to 14, with the best prediction for those patients with a score of more than 6 (sensitivity, 81.6%; specificity, 84%). Overall, the model had excellent discrimination in predicting VTE with a receiver operating characteristic curve of 0.89. The VTE rates for TESS in the National Trauma Data Bank data set were similar for all integers except for 3 and 4, in which the VTE rates were significantly higher (3, 0.2% vs. 0.6%; 4, 0.4% vs. 1.0%). CONCLUSION The TESS provides an objective measure of classifying VTE risk for patients with trauma. The TESS could allow informed decision making regarding prophylaxis strategies in patients with trauma. LEVEL OF EVIDENCE Prognostic study, level II.

High-resolution imaging of dietary lipids in cells and tissues by NanoSIMS analysis

Nanoscale secondary ion MS (NanoSIMS) imaging makes it possible to visualize stable isotope-labeled lipids in cells and tissues at 50 nm lateral resolution. Here we report the use of NanoSIMS imaging to visualize lipids in mouse cells and tissues. After administering stable isotope-labeled fatty acids to mice by gavage, NanoSIMS imaging allowed us to visualize neutral lipids in cytosolic lipid droplets in intestinal enterocytes, chylomicrons at the basolateral surface of enterocytes, and lipid droplets in cardiomyocytes and adipocytes. After an injection of stable isotope-enriched triglyceride-rich lipoproteins (TRLs), NanoSIMS imaging documented delivery of lipids to cytosolic lipid droplets in parenchymal cells. Using a combination of backscattered electron (BSE) and NanoSIMS imaging, it was possible to correlate the chemical data provided by NanoSIMS with high-resolution BSE images of cell morphology. This combined imaging approach allowed us to visualize stable isotope-enriched TRLs along the luminal face of heart capillaries and the lipids within heart capillary endothelial cells. We also observed examples of TRLs within the subendothelial spaces of heart capillaries. NanoSIMS imaging provided evidence of defective transport of lipids from the plasma LPs to adipocytes and cardiomyocytes in mice deficient in glycosylphosphatidylinositol-anchored HDL binding protein 1.

Improved recovery of prophylactic inferior vena cava filters in trauma patients: the results of a dedicated filter registry and critical pathway for filter removal.

Background: Temporary inferior vena cava filters (IVCF) are uniquely suited for trauma patients in whom the high risk of venous thromboembolism is transient. Currently, few “retrievable filters” are actually retrieved, with most published series documenting a retrieval rate between 20% and 50%. We sought to determine whether we could achieve a higher rate of retrieval with an improved process of care. Methods: All permanent and temporary filters were entered prospectively into a dedicated filter registry. Within 60 days of filter placement, all temporary filter patients were contacted by a trauma case manager to evaluate ongoing venous thromboembolism risk. Low-risk patients were then evaluated by radiology for removal of the IVCF. If appropriate, removal of the IVCF was scheduled. Initial contacts with patients were made by telephone. If unsuccessful with phone contact, family members, rehabilitation facility, and social work were all contacted to obtain the most recent phone number and address. A follow-up letter was sent to the patient with follow-up visit instructions. Finally, if prior contact measures did not work, a certified letter was sent to the last known address. Results: Between 2006 and 2009, of 7,949 trauma admissions, 420 (5.2%) met indications for filter placement. Of those, 160 were available for removal and 94 were successfully removed (59%). Conclusions: A retrieval rate of 59% can be achieved with an explicit process of care emphasizing disciplined follow-up. Level of Evidence: III.

Hyponatremia as a fall predictor in a geriatric trauma population

INTRODUCTION Approximately one in three older adults fall each year, resulting in a significant proportion of geriatric traumatic injuries. In a hospital with a focus on geriatric fall prevention, we sought to characterize this population to develop targeted interventions. As mild hyponatremia, defined as a serum sodium <135meq/L, has been reported to be associated with falls, unsteadiness and attention deficits, we hypothesized that hyponatremia is associated with falls in our geriatric trauma population. METHODS Gender, age, pre-existing conditions (cardiac disease, diabetes, hematologic disorder, liver disease, malignancy, musculoskeletal disorder, neurological disorder, obesity, psychiatric disorder, pulmonary disease, renal disease, thyroid disease), mechanism of injury and admitting serum sodium level were queried for all geriatric trauma admissions from 2008 to 2011. Mechanism of injury was coded as falls admissions and non-falls admissions. Admitting serum sodium levels were coded as hyponatremic (<135mmol/L) and not hyponatremic (≥135mmol/L). RESULTS Of the 2370 geriatric trauma admissions during the study period, there were 1841 (77.7%) falls admissions and 293 (12.4%) patients who were hyponatremic. Gender, age, neurological disorder, hematologic disorder, and hyponatremia were found to be significant predictors of falls in both univariate and multivariable analyses. CONCLUSION Hyponatremic patients are significantly more likely to be admitted for a fall than non-hyponatremic patients, when adjusting for age, neurological disorder, and hematologic disorder. Consequently, hyponatremia identification and management should be an integral part of any geriatric trauma fall prevention programme. Additionally, if hyponatremia is found during a geriatric fall workup, it should be corrected prior to discharge and closely monitored by a primary care physician to prevent recurrent episodes of falls.

Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2.

To assess the redundancy of lamins B1 and B2, knock-in lines were created that produce lamin B2 from the Lmnb1 locus and lamin B1 from the Lmnb2 locus. Both lines developed severe neurodevelopmental abnormalities, indicating that the abnormalities elicited by the loss of one B-type lamin cannot be prevented by increased synthesis of the other.

Big Children or Little Adults? A Statewide Analysis of Adolescent Isolated Severe Traumatic Brain Injury Outcomes at Pediatric versus Adult Trauma Centers.

BACKGROUND The appropriate managing center for adolescent trauma patients is debated. We sought to determine whether outcome differences existed for adolescent severe traumatic brain injury (sTBI) patients treated at pediatric versus adult trauma centers. We hypothesized that no difference in mortality, functional status at discharge (FSD), or overall complication rate would be observed between center types. METHODS All adolescent trauma patients (aged 15–17 years) presenting with isolated sTBI (head Abbreviated Injury Scale [AIS] score ≥3; all other AIS body region scores ⩽2) to accredited Levels I to II trauma centers in Pennsylvania from 2003 to 2015 were extracted from the Pennsylvania Trauma Outcome Study database. Dead on arrival, transfer, and penetrating trauma patients were excluded from analysis. Adult trauma centers were defined as non-pediatirc (PED) (n = 24), whereas standalone pediatric hospitals and adult centers with pediatric affiliation were considered Pediatric (n = 9). Multilevel mixed effects logistic regression models and a generalized linear mixed models assessed the adjusted impact of center type on mortality, overall complications, and FSD. Significance was defined as a p value less than 0.05. RESULTS A total of 1,109 isolated sTBI patients aged 15 to 17 years presented over the 13-year study period (non-PED, 685; PED, 424). In adjusted analysis controlling for age, shock index, head AIS, Glasgow Coma Scale motor, trauma center level of managing facility, case volume of managing facility, and injury year, no significant difference in mortality (adjusted odds ratio, 0.82; 95% confidence interval [CI], 0.23–2.86; p = 0.754), FSD (coefficient, −0.85; 95% CI, −2.03 to 0.28; p = 0.136), or total complication rate (adjusted odds ratio, 1.21; 95% CI, 0.43–3.39; p = 0.714) was observed between center types. CONCLUSION Although the optimal treatment facility for adolescent patients is frequently debated, patients aged 15 to 17 years presenting with isolated sTBI may experience similar outcomes when managed at pediatric and adult trauma centers. LEVEL OF EVIDENCE Epidemiologic study, level III; therapeutic study, level IV.

A new monoclonal antibody, 4-1a, that binds to the amino terminus of human lipoprotein lipase

Lipoprotein lipase (LPL) has been highly conserved through vertebrate evolution, making it challenging to generate useful antibodies. Some polyclonal antibodies against LPL have turned out to be nonspecific, and the available monoclonal antibodies (Mabs) against LPL, all of which bind to LPLs carboxyl terminus, have drawbacks for some purposes. We report a new LPL-specific monoclonal antibody, Mab 4-1a, which binds to the amino terminus of LPL (residues 5-25). Mab 4-1a binds human and bovine LPL avidly; it does not inhibit LPL catalytic activity nor does it interfere with the binding of LPL to heparin. Mab 4-1a does not bind to human hepatic lipase. Mab 4-1a binds to GPIHBP1-bound LPL and does not interfere with the ability of the LPL-GPIHBP1 complex to bind triglyceride-rich lipoproteins. Mab 4-1a will be a useful reagent for both biochemists and clinical laboratories.