A Survey of Implementation of ABCDE Protocols.

BACKGROUND: Spontaneous awakening trials (SATs), spontaneous breathing trials (SBTs), delirium assessment/management, early mobility have been termed the ABCDE bundle. The ABCDE bundle has been proven to improve patient outcomes. However, there is often a long gap in dissemination and implementation of evidence-based medicine. OBJECTIVES: To determine the prevalent implementation of and determinants for ABCDE protocol adoption in Pennsylvania. METHODS: We developed a survey of ABCDE bundle protocols. We surveyed factors around implementation including written protocol presence, standardized assessments to guide protocols, timing of creation of protocols, and estimated adherence to protocols. We also collected data on factors that might be determinants for protocol adoption including ICU staffing models, hospital and ICU level factors. We validated the survey tool using the Michigan Health and Hospital Association Keystone ICU collaborative. We then administered the validated survey to a leader of the medical ICU or mixed medical-surgical ICU of all Pennsylvania Hospitals. Multivariable logistic and ordinal regression were used to determine associations between ICU staffing models and hospital and ICU level factors with the presence of ABCDE bundle protocols. RESULTS: In the study cohort of Pennsylvania ICUs (n = 144), we had 100 respondents (69% response). The median number of hospital beds among the respondents was 185 (IQR 111-355) with a median of 14 ICU beds (IQR 10-20). 86% reported spontaneous awakening trial protocols, 60% reported spontaneous breathing trial protocols, 43% reported delirium assessment/management protocols, and 27% reported early mobility protocols. Being a medical ICU compared to a mixed medical-surgical ICU (OR 3.48, 95% CI 1.19-10.21, P = .02) and presence of multidisciplinary rounds (OR 4.97, 95% CI 2.07-11.94, P < .001) were associated with increasing number of ABCDE bundle protocol components. CONCLUSIONS: Variable implementation of ABCDE bundle protocols was present across Pennsylvania. Team communication is important to implementation of these protocols.

Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models.

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.

Treatment and Outcomes of Oropharyngeal Cancer in People with Human Immunodeficiency Virus.

HIV-positive people are at increased risk for malignancies associated with human papillomavirus (HPV) infection, including oropharyngeal squamous cell carcinoma (OPSCC). The purpose of this study was to determine whether cancer treatment disparities exist between HIV-positive and HIV-negative people with OPSCC. We conducted a retrospective cohort study comparing OPSCC treatment adequacy and treatment outcomes in HIV-positive and HIV-negative people in the post-antiretroviral therapy era. Treatment adequacy was determined by measuring two primary endpoints associated with OPSCC survival: time to therapy and total radiation dose. Treatment outcomes were assessed by measuring disease-free and overall survival. We identified a total of 37 HIV-positive and 149 HIV-negative people with OPSCC. HIV-positive people experienced a median delay of 10 days from time of OPSCC diagnosis to start of therapy compared with HIV-negative people [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.38-0.98]. Total post-radiation dose in HIV-positive people was lower than that in HIV-negative people [58.5 Gray (Gy) versus 64.4 Gy, p = .04]. HIV-positive people also experienced greater hazards for disease recurrence (HR 3.43, 95% CI 1.39-8.46) and death (HR 4.21, 95% CI 1.29-13.80) compared with HIV-negative people. In conclusion, we detected a clinically important delay in time to therapy as well as worse disease-free and overall survival in HIV-positive people with OPSCC compared with their HIV-negative counterparts. These findings are relevant to understanding how HIV-positive people are diagnosed and undergo therapy for HPV-associated malignancies and highlight the need to address cancer treatment disparities in this group.

Use of the vestibular and oculomotor examination for concussion in a pediatric emergency department.

BACKGROUND: Concussion guidelines recommend a vestibular and oculomotor (VOM) examination be performed for all patients with concern for concussion, however the feasibility of performing testing is unknown. We aimed to measure rates of exam performance after implementation of training and support tools in a pediatric emergency department. METHODS: We conducted a retrospective study of patients age 6 to 18 years old presenting over a 12-month period. Charts were obtained via natural language processing, where concussion was suggested as a diagnosis in the electronic health record, and then manually reviewed to record patient and provider factors. A multivariable logistic regression was performed to determine factors associated with exam performance, and a classification and regression tree (CART) analysis was performed to determine if a specific patient type was at risk for not having testing performed. RESULTS: Four hundred patients were included in the analysis. Sixty-four percent received a VOM examination (including 73% of those diagnosed with concussion). Provider type, concussion history, symptom burden, injury mechanism, and final diagnosis were all significantly associated with exam performance. CART analysis determined patients with a non-concussion diagnosis, a non-sports injury mechanism, no prior history of concussion, and two or fewer symptoms had the lowest likelihood (46%) of receiving the exam. CONCLUSION: Performing a VOM examination for concussion is feasible in the acute setting following provider education and using clinical support tools. The exam is more likely to be performed on those children with history or exam findings associated with perceived risk for ongoing symptoms.

Association Between Depression and Condom Use Differs by Sexual Behavior Group in Patients with HIV.

Identifying a relationship between depression and sexual risk behavior in HIV-infected patients could establish a mechanism to enhance prevention efforts. We conducted a cross-sectional analysis using data from the University of Pennsylvania Center for AIDS Research and used ordinal logistic regression to measure the association between depression and non-condom use. 716 men who have sex with men (MSM), 262 heterosexual men and 277 heterosexual women were included. The association between depression and non-condom use was strongest in heterosexual men with and without HIV-infected regular partners (OR 8.53, 95% CI 1.18-61.89 and OR 2.30, 95% CI 0.99-5.36 respectively), but absent in heterosexual women regardless of partner. Although the OR was low in MSM overall, an association was detected in MSM without HIV-infected regular partners (OR 2.44, 95% CI 1.39-4.31). In conclusion, we demonstrated an association between depression and non-condom use driven by heterosexual men and MSM without HIV-infected regular partners. Sexual risk should be addressed when intervening on depressive symptoms in these subgroups.

The Effect of Skin Pigmentation on the Accuracy of Pulse Oximetry in Infants with Hypoxemia.

To compare pulse oximetry measurement bias between infants with hypoxemia with either dark skin or light skin with Masimo Radical 7 and Nellcor Oximax. There was no significant difference in systematic bias based on skin pigment for either oximeter.

Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial.

RATIONALE: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown. OBJECTIVES: We aimed to determine the safety and efficacy of anastrozole in PAH. METHODS: We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers. MEASUREMENTS AND MAIN RESULTS: A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co-primary outcomes were percent change from baseline in 17ß-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: -40%; interquartile range [IQR], -61 to -26% vs. -4%; IQR, -14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = -12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo -2%; IQR, -7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events. CONCLUSIONS: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH. Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).

Is self-reported adherence associated with clinical outcomes in women treated with anticholinergic medication for overactive bladder?

AIM: To determine the association between self-reported adherence to anticholinergic medication and clinical outcomes in women with overactive bladder (OAB). METHODS: A prospective study of women with OAB treated with fesoterodine for 8 weeks. Adherence to medication was measured using the Medication Adherence Self-report Inventory (MASRI). A self reported adherence rate of ≥80% was considered adherent. The association between self-reported adherence and clinical outcomes (Global Index of Improvement, Global impression of Severity, urinary symptom and quality of life scores) was examined. We hypothesized that adherent women would have greater improvement in urinary symptoms and quality of life than non-adherent women. RESULTS: Based on the MASRI, 115 (62.5%) women were adherent and 69 (37.5%) were non-adherent to anticholinergic medication at 8weeks. Adherent women were more likely to report overall improvement in their symptoms compared to non-adherent women (84% vs. 24%, P < 0.001). Significantly more non-adherent women described their bladder symptoms as "moderate" or "severe" at 8 weeks compared to adherent women (74% vs. 44%, P = 0.03). At 8 weeks, adherent women reported significantly greater improvement (change) in urinary symptoms from baseline to 8 weeks than non-adherent women (-13.3 ± 25.8 vs. 2.5 ± 14.4, P = 0.04). Similarly, adherent women reported greater improvement in quality of life scores than non-adherent women (- 7.9 ± 24.0 vs. -1.8 ± 11.9, P = 0.003). CONCLUSION: Self-reported non-adherence, as measured by the MASRI, is associated with clinically meaningful outcomes in women with OAB. This further validates the MASRI as a clinically useful tool for measuring adherence to anticholinergic medications in women with OAB. Neurourol. Urodynam. 35:738-742, 2016. © 2015 Wiley Periodicals, Inc.

Unconventional Gas and Oil Drilling Is Associated with Increased Hospital Utilization Rates.

Over the past ten years, unconventional gas and oil drilling (UGOD) has markedly expanded in the United States. Despite substantial increases in well drilling, the health consequences of UGOD toxicant exposure remain unclear. This study examines an association between wells and healthcare use by zip code from 2007 to 2011 in Pennsylvania. Inpatient discharge databases from the Pennsylvania Healthcare Cost Containment Council were correlated with active wells by zip code in three counties in Pennsylvania. For overall inpatient prevalence rates and 25 specific medical categories, the association of inpatient prevalence rates with number of wells per zip code and, separately, with wells per km2 (separated into quantiles and defined as well density) were estimated using fixed-effects Poisson models. To account for multiple comparisons, a Bonferroni correction with associations of p<0.00096 was considered statistically significant. Cardiology inpatient prevalence rates were significantly associated with number of wells per zip code (p<0.00096) and wells per km2 (p<0.00096) while neurology inpatient prevalence rates were significantly associated with wells per km2 (p<0.00096). Furthermore, evidence also supported an association between well density and inpatient prevalence rates for the medical categories of dermatology, neurology, oncology, and urology. These data suggest that UGOD wells, which dramatically increased in the past decade, were associated with increased inpatient prevalence rates within specific medical categories in Pennsylvania. Further studies are necessary to address healthcare costs of UGOD and determine whether specific toxicants or combinations are associated with organ-specific responses.

Conservation of pro-longevity genes among mammals.

Genes which confer a relative longevity advantage may be regulated at the level of transcription or translation. Alternatively, pro-longevity genes may mediate their effects at the level of protein structure-functional relationships that are beneficially optimized in long-lived species. Longevity associated genes (LAGs) may be operationally defined as genes that confer beneficial effects and are relatively more conserved among long-lived species. Global and local protein sequence alignments of over 10,000 genes across at least 30 mammalian species were examined to identify LAGs. Known LAGs, including growth hormone receptor (GHR), and breast cancer 1, early onset (BRCA1), have strong associations with maximum lifespan by our analysis. Several common categories of protein function were observed among genes ranked with the strongest associations with MLS identified by all regression models. These genes included those that function in the immune system, cell cycle regulation, and DNA damage response. We provide a ranking of genes with the strongest associations with species maximum lifespan (MLS) by several phylogenetic generalized least squares regression models, including adjustment for confounding variables such as body weight and gestation length.

Validation of a self-administered instrument to measure adherence to anticholinergic drugs in women with overactive bladder.

AIM: To validate a self-administered instrument, the Medication Adherence Self-Report Inventory (MASRI) for measuring adherence to anti-cholinergic medication for overactive bladder (OAB). METHODS: Prospective study in 131 women with OAB treated with fesoterodine. Adherence was measured at 8 and 12 weeks using an interviewer administered brief medication questionnaire (BMQ) that assesses barriers to adherence (criterion standard), the MASRI, and pill count. Construct, concurrent and discriminant validity of the MASRI was assessed. We hypothesized that women who were non-adherent as measured by the MASRI would be more likely to have a belief barrier than women who were adherent to medication. RESULTS: Women diagnosed as non-adherent by the MASRI were more likely to report a belief barrier to taking medication as compared to adherent women at 8 weeks (80% vs. 38%, P < 0.001) and at 12 weeks (70% vs. 40%, P = 0.003). Significant correlations were noted between adherence rates measured by the MASRI and the BMQ at 8 weeks (r = 0.87, P < 0.001) and 12 weeks (r = 0.90, P < 0.001). Moderate correlation was noted between the adherence rate as measured by the MASRI and pill count at 8 weeks (r = 0.49, P = 0.02) but not at 12 weeks (r = 0.05, P = 0.87). The MASRI correctly identified 93% and 96% of non-adherent women at 8 and 12 weeks, respectively. Sensitivity, specificity, and positive likelihood ratio of the MASRI for predicting non-adherence was 91%, 82%, and 5.1 at 8 weeks and 90%, 85% and 6.1 at 12 weeks. CONCLUSIONS: The MASRI is a valid self-administered tool for measuring adherence to anti-cholinergic medication in women with OAB.

Urinary incontinence and disability in community-dwelling women: a cross-sectional study.

AIMS: Disability, an individual's reduced capacity to perform physical tasks encountered in daily routine, is associated with urinary incontinence in the elderly. Our objective was to determine if urinary incontinence is associated with disability in community-dwelling women 40 years and older. METHODS: Cross-sectional study among US women ≥40 years (n = 4,458) from National Health and Nutrition Examination Surveys 2005-2010. We estimated the age-stratified weighted prevalence and factors independently associated with disability (Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), mobility, and functional limitations) in women with and without urinary incontinence while controlling for confounders of the association between disability and urinary incontinence. RESULTS: The weighted prevalence of all disabilities was higher in women with urinary incontinence than women without urinary incontinence across most decades of life with the greatest difference in the prevalence of mobility disabilities: 40-49 years (12.1% vs. 7.0%), 50-59 years (17.0% vs. 9.2%), 60-69 years (28.3% vs. 19.8%), and 70+ years (43.8% vs. 33.0%, all P < 0.05). On multivariable analysis, after controlling for the confounding effect of age, co-morbidities, and income-poverty ratio, urinary incontinence was weakly associated with disabilities. The adjusted odds ratio (95% confidence interval) of disabilities for urinary incontinence was ADL 1.96 (1.07, 3.58), IADL 1.18 (0.78, 1.78), mobility 1.26 (1.01, 1.56), and functional limitations 1.36 (1.07, 1.73). CONCLUSIONS: Urinary incontinence is weakly associated with disabilities and cannot be implicated as a cause of disability in community dwelling women.

Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs.

The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs­ibuprofen, naproxen, and celecoxib­to cause a drug-drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug-drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk.

A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma.

Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.

Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus.

IMPORTANCE: Patients with cutaneous lupus erythematosus (CLE) who develop systemic lupus erythematosus (SLE) may have few and mild systemic symptoms. OBJECTIVE: To characterize the types and severity of systemic symptoms in a longitudinal cohort of patients with CLE. DESIGN, SETTING, AND PARTICIPANTS: Prospective, longitudinal cohort study of 77 patients with CLE who presented between January 2007 and April 2011 at a university autoimmune skin disease clinic. MAIN OUTCOMES AND MEASURES: Systemic symptoms and severity were determined from data recorded at each study visit and from medical records. RESULTS: Of 77 patients with CLE, 13 (17%) went on to meet criteria for SLE, with a mean (SD) time from CLE diagnosis to SLE of 8.03 (6.20) years. Of the 13 patients, 1 (8%) solely met the mucocutaneous American College of Rheumatology (ACR) criteria of malar rash, discoid rash, photosensitivity, and oral ulcers, and 3 (23%) met the mucocutaneous ACR criteria plus positive antinuclear and other antibody titers. After a mean (SD) follow-up time of 2.81 (1.34) years, only 5 of the 13 patients with CLE (38%) who progressed to meet SLE criteria developed moderate to severe additional systemic disease. CONCLUSIONS AND RELEVANCE: Patients with CLE who developed SLE during our study did so mostly by meeting the mucocutaneous ACR criteria, and the majority developed none to mild additional systemic disease during the study period. Thus, our study suggests that a small percentage of patients with CLE eventually develop SLE and that even if they do, most patients will have mild systemic disease.

Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers.

SCOPE: Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. METHODS AND RESULTS: The Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-wk randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465 mg eicosapentaenoic acid (EPA) + 375 mg docosahexaenoic acid (DHA)) at "low" (1/day, 900 mg) or "high" (4/day, 3600 mg) dose in healthy individuals (N = 60; age 18-45; BMI 18-30; 43% female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6 ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (p = 0.03) but not low-dose EPA + DHA compared to placebo. Although there was no statistically significant impact of EPA + DHA on individual inflammatory responses (tumor necrosis factor-α (TNF-α), IL-6, monocyte chemotactic protein (MCP-1), IL-1 receptor agonist (IL-1RA), IL-10, C-reactive protein (CRP), serum amyloid A (SAA)), there was a pattern of lower responses across all biomarkers with high-dose (nine of nine observed), but not low-dose EPA + DHA. CONCLUSION: EPA + DHA at 3600 mg/day, but not 900 mg/day, reduced fever and had a pattern of attenuated LPS induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions.

Estimating the efficacy of an interstitial cystitis/painful bladder syndrome medication in a randomized trial with both non-adherence and loss to follow-up.

We are motivated by a randomized clinical trial evaluating the efficacy of amitriptyline for the treatment of interstitial cystitis and painful bladder syndrome in treatment-naïve patients. In the trial, both the non-adherence rate and the rate of loss to follow-up are fairly high. To estimate the effect of the treatment received on the outcome, we use the generalized structural mean model (GSMM), originally proposed to deal with non-adherence, to adjust for both non-adherence and loss to follow-up. In the model, loss to follow-up is handled by weighting the estimation equations for GSMM with one over the probability of not being lost to follow-up, estimated using a logistic regression model. We re-analyzed the data from the trial and found a possible benefit of amitriptyline when administered at a high-dose level.

Improved behavior, motor, and cognition assessments in neonatal piglets.

The alterations of animal behavior after traumatic brain injury (TBI) can be subtle, and their quantitative characterization can present significant methodological challenges. Meeting these challenges is a critical need, because quantitative measures are required in studies that compare the efficacy of different clinical interventions. We developed a battery of assessments to quantify behavioral, motor, and cognitive changes in neonatal piglets with good sensitivity and specificity to the detection of persistent deficits that correlate with axonal injury severity after a rapid non-impact head rotation with a diffuse pattern of axonal injury. The battery of measures developed included open field behaviors of sniffing and moving a toy, locomotion measures of Lempel-Ziv complexity and the probability of remaining in the current location, and a novel metric for evaluating motor performance. Our composite porcine disability score was able to detect brain injury with a sensitivity of 100% and specificity of 85.7% at day +4 post-injury for n=8 injured and n=7 sham piglets and significantly correlated with the percent axonal injury in these animals (day +4: ρ=0.76, p=0.0011). A significant improvement over our previous assessments, this new porcine disability score has potential use in a wide variety of porcine disease and injury models.

Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia.

Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30 000 ng/mL and were elevated in IDH-mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG ≤200 ng/mL (hazard ratio, 3.9; P = .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies.