Formal Radiologist Interpretations of Intraoperative Spine Radiographs Have Low Clinical Value.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To evaluate the clinical relevance, usefulness, and financial implications of intraoperative radiograph interpretation by radiologists in spine surgery. SUMMARY OF BACKGROUND DATA: Due to rising healthcare costs, spine surgery is under scrutiny to maximize value-based care. Formal radiographic analysis remains a potential source of unnecessary healthcare costs, especially for intra-operative radiographs. METHODS: A retrospective cohort analysis was performed on all adult elective spine surgeries at a single institution between July 2020 and July 2021. Demographic and radiographic data was collected, including intraoperative localization and post-instrumentation radiographs. Financial data was obtained through the institution's price estimator. Radiographic characteristics included time from radiographic imaging to completion of radiologist interpretation report, completion of radiologist interpretation report prior to the conclusion of surgical procedure, clinical relevance, and clinical usefulness. Reports were considered clinically relevant if spinal level of the procedure was described and clinically useful if completed prior to conclusion of the procedure and deemed clinically relevant. RESULTS: 481 intraoperative localization and post-instrumentation radiographs from 360 patients revealed a median delay of 128 minutes between imaging and completion of interpretive report. Only 38.9% of reports were completed before conclusion of surgery. There were 79.4% deemed clinically relevant and only 33.5% were clinically useful. Localization reports were completed more frequently before conclusion of surgery (67.2% vs. 34.4%), but with lower clinical relevance (90.1% vs. 98.5%) and clinical usefulness (60.3% vs. 33.6%) than post-instrumentation reports. Each patient was charged $32-$34 for interpretation fee, cumulating a minimum total cost of $15,392. CONCLUSION: Formal radiographic interpretation of intraoperative spine radiographs was of low clinical utility for spine surgeons. Institutions should consider optimizing radiology workflows to improve timeliness and clinical relevance or evaluate the necessity of reflexive consultation to radiology for intraoperative imaging interpretation to ensure that value-based care is maximized during spine surgeries. LEVEL OF EVIDENCE: 3.

Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.

BACKGROUND: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined. METHODS: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. RESULTS: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts. CONCLUSIONS: Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.

The need to study rural cancer outcome disparities at the local level: a retrospective cohort study in Kansas and Missouri.

BACKGROUND: Rural residence is commonly thought to be a risk factor for poor cancer outcomes. However, a number of studies have reported seemingly conflicting information regarding cancer outcome disparities with respect to rural residence, with some suggesting that the disparity is not present and others providing inconsistent evidence that either urban or rural residence is associated with poorer outcomes. We suggest a simple explanation for these seeming contradictions: namely that rural cancer outcome disparities are related to factors that occur differentially at a local level, such as environmental exposures, lack of access to care or screening, and socioeconomic factors, which differ by type of cancer. METHODS: We conducted a retrospective cohort study examining ten cancers treated at the University of Kansas Medical Center from 2011 to 2018, with individuals from either rural or urban residences. We defined urban residences as those in a county with a U.S. Department of Agriculture Urban Influence Code (UIC) of 1 or 2, with all other residences defines a rural. Inverse probability of treatment weighting was used to create a pseudo-sample balanced for covariates deemed likely to affect the outcomes modeled with cumulative link and weighted Cox-proportional hazards models. RESULTS: We found that rural residence is not a simple risk factor but rather appears to play a complex role in cancer outcome disparities. Specifically, rural residence is associated with higher stage at diagnosis and increased survival hazards for colon cancer but decreased risk for lung cancer compared to urban residence. CONCLUSION: Many cancers are affected by unique social and environmental factors that may vary between rural and urban residents, such as access to care, diet, and lifestyle. Our results show that rurality can increase or decrease risk, depending on cancer site, which suggests the need to consider the factors connected to rurality that influence this complex pattern. Thus, we argue that such disparities must be studied at the local level to identify and design appropriate interventions to improve cancer outcomes.

Purity Independent Subtyping of Tumors (PurIST), A Clinically Robust, Single-sample Classifier for Tumor Subtyping in Pancreatic Cancer.

PURPOSE: Molecular subtyping for pancreatic cancer has made substantial progress in recent years, facilitating the optimization of existing therapeutic approaches to improve clinical outcomes in pancreatic cancer. With advances in treatment combinations and choices, it is becoming increasingly important to determine ways to place patients on the best therapies upfront. Although various molecular subtyping systems for pancreatic cancer have been proposed, consensus regarding proposed subtypes, as well as their relative clinical utility, remains largely unknown and presents a natural barrier to wider clinical adoption. EXPERIMENTAL DESIGN: We assess three major subtype classification schemas in the context of results from two clinical trials and by meta-analysis of publicly available expression data to assess statistical criteria of subtype robustness and overall clinical relevance. We then developed a single-sample classifier (SSC) using penalized logistic regression based on the most robust and replicable schema. RESULTS: We demonstrate that a tumor-intrinsic two-subtype schema is most robust, replicable, and clinically relevant. We developed Purity Independent Subtyping of Tumors (PurIST), a SSC with robust and highly replicable performance on a wide range of platforms and sample types. We show that PurIST subtypes have meaningful associations with patient prognosis and have significant implications for treatment response to FOLIFIRNOX. CONCLUSIONS: The flexibility and utility of PurIST on low-input samples such as tumor biopsies allows it to be used at the time of diagnosis to facilitate the choice of effective therapies for patients with pancreatic ductal adenocarcinoma and should be considered in the context of future clinical trials.

An integrated electronic health record-based workflow to improve management of colonoscopy-generated pathology results.

PURPOSE: Managing and communicating colonoscopy-generated pathology results and appropriate follow-up recommendations can be challenging. To improve this process, we developed and implemented a standardized electronic health record-based intervention with built-in decision support. METHODS: Fourteen attending endoscopists performed enough colonoscopies to qualify for the study. For each, we randomly sampled and abstracted data from 35 colonoscopies that met prespecified inclusion criteria during both the pre-intervention and also post-intervention periods. Follow-up recommendations were compared to guidelines. We used the Wilcoxon Signed Rank Test to assess the change in the proportion of cases with guideline-concordant results, the proportion with a documented follow-up result letter, and the median time to letter completion. A brief survey assessed endoscopists' satisfaction with the intervention. RESULTS: In total, 1,947 colonoscopies were extracted, of which 968 met inclusion criteria. The proportion of follow-up recommendations that were guideline concordant increased from a median of 82.9% pre-intervention to 85.7% post-intervention (P=0.72). The proportion of observations with a documented follow-up result letter increased from a median of 88.9% pre-intervention to 97.1% post-intervention (P=0.07). The number of calendar days between the date of the colonoscopy and the date the letter was sent decreased from a median of 7.7 days pre-intervention to 6.8 days post-intervention (P=0.79). Eighty-six percentage of endoscopists were either "very satisfied" or "satisfied" with the overall process. CONCLUSION: The intervention was not associated with a statistically significant increase in guideline-concordant recommendations or efficiency measures, perhaps due to high baseline performance. The intervention was well received by endoscopists and captured data necessary for important downstream processes.

Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models.

Background FSGS is a pattern of podocyte injury that leads to loss of glomerular function. Podocytes support other podocytes and glomerular capillary structure, oppose hemodynamic forces, form the slit diaphragm, and have mechanical properties that permit these functions. However, the biophysical characteristics of glomeruli and podocytes in disease remain unclear.Methods Using microindentation, atomic force microscopy, immunofluorescence microscopy, quantitative RT-PCR, and a three-dimensional collagen gel contraction assay, we studied the biophysical and structural properties of glomeruli and podocytes in chronic (Tg26 mice [HIV protein expression]) and acute (protamine administration [cytoskeletal rearrangement]) models of podocyte injury.Results Compared with wild-type glomeruli, Tg26 glomeruli became progressively more deformable with disease progression, despite increased collagen content. Tg26 podocytes had disordered cytoskeletons, markedly abnormal focal adhesions, and weaker adhesion; they failed to respond to mechanical signals and exerted minimal traction force in three-dimensional collagen gels. Protamine treatment had similar but milder effects on glomeruli and podocytes.Conclusions Reduced structural integrity of Tg26 podocytes causes increased deformability of glomerular capillaries and limits the ability of capillaries to counter hemodynamic force, possibly leading to further podocyte injury. Loss of normal podocyte mechanical integrity could injure neighboring podocytes due to the absence of normal biophysical signals required for podocyte maintenance. The severe defects in podocyte mechanical behavior in the Tg26 model may explain why Tg26 glomeruli soften progressively, despite increased collagen deposition, and may be the basis for the rapid course of glomerular diseases associated with severe podocyte injury. In milder injury (protamine), similar processes occur but over a longer time.

Decellularized Extracellular Matrix Hydrogels as a Delivery Platform for MicroRNA and Extracellular Vesicle Therapeutics.

In the last decade, the use of microRNA (miRNA) and extracellular vesicle (EV) therapies has emerged as an alternative approach to mitigate the negative effects of several disease pathologies ranging from cancer to tissue and organ regeneration; however, delivery approaches towards target tissues have not been optimized. To alleviate these challenges, including rapid diffusion upon injection and susceptibility to degradation, porcine-derived decellularized extracellular matrix (ECM) hydrogels are examined as a potential delivery platform for miRNA and EV therapeutics. The incorporation of EVs and miRNA antagonists, including anti-miR and antago-miR, in ECM hydrogels results in a prolonged release as compared to the biologic agents alone. In addition, individual in vitro assessments confirm the bioactivity of the therapeutics upon release from the ECM hydrogels. This work demonstrates the feasibility of encapsulating miRNA and EV therapeutics in ECM hydrogels to enhance delivery and potentially efficacy in later in vivo applications.

Accuracy and Safety of the Cytosponge for Assessing Histologic Activity in Eosinophilic Esophagitis: A Two-Center Study.

OBJECTIVES: Management of eosinophilic esophagitis (EoE) requires repeated endoscopic mucosal sampling to assess disease activity. A less invasive and expensive means of monitoring of EoE is required. The objective of this study was to assess the accuracy, safety, and tolerability of the cytosponge compared to endoscopy and biopsy for histologic assessment of EoE. METHODS: In this prospective two-center cross-sectional study, patients with known EoE underwent cytosponge sampling followed by endoscopy and biopsy. Sample adequacy and eosinophil counts (eos/HPF) were determined for both cytosponge and endoscopic samples. The cytosponge was assessed for diagnostic accuracy, safety, and patient preference as compared to endoscopy. RESULTS: Six patients (7%) failed to swallow the sponge. One hundred and five procedures were successfully performed in 80 patients (66% male, 100% white, 19% stricture). The cytosponge sample was adequate in 102 and the biopsy in 104; 101 procedures had adequate samples by both techniques. Fifty-seven biopsies were graded as active EoE with ≥15 eos/HPF as the gold standard. Eosinophil counts highly correlated between the biopsy and cytosponge (r=0.78, P<0.0001). Using a cutoff of ≤15 eos/HPF for inactive disease, the sensitivity and specificity of the cytosponge was 75% and 86%, respectively. Six patients had active EoE on cytosponge not found on biopsy. For biopsies with inactive EoE, the cytosponge identified 38/44. No complications occurred, and cytosponge endoscopic abrasion scores were low (0.34/4). Patients preferred cytosponge to endoscopy with higher rating scores (7.27 vs. 6.11, P=0.002). CONCLUSIONS: Compared to endoscopy with biopsy, cytosponge provided a minimally invasive, safe, well tolerated, and accurate method to assess EoE histologic activity. (ClinicalTrial.gov number NCT01585103).

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts.

The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2 We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomerase-immortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2 Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.

Perceptions of social norms and exposure to pro-marijuana messages are associated with adolescent marijuana use.

Despite consistent declines in rates of cigarette use among adolescents in the last five years, rates of marijuana use have remained constant, with marijuana being the most widely used illegal drug among adolescents. More work is needed to understand how social norms, perceived risks and benefits, and social media messaging impact use of marijuana. This study compared perceptions and social norms related to marijuana, blunts and cigarettes. Additionally, we assessed how perceptions related to social norms, risks and benefits, and exposure to pro- versus anti-marijuana messaging is related to use. Participants were 786 adolescents from Southern and Northern California (36.7% male, 63.21% females; mean age=16.1years; SD=1.6). Participants came from diverse ethnic backgrounds, with 207 (26.61%) White, 171 (21.98%) Asian/Pacific Islander, 232 (29.82%) Hispanic, and 168 (21.59%) other. Results indicated that marijuana and blunts were consistently perceived as more socially acceptable and less risky than cigarettes (p<0.01). Participants who reported that their friends used marijuana had a 27% greater odds of using marijuana themselves. Further, seeing messages about the good things or benefits of marijuana use was associated with a 6% greater odds of use [OR 1.06 (CI 1.00, 1.12)]. This study's findings offer a number of important public health implications, particularly as states move towards legalization of marijuana for recreational use. As this occurs, states need to take adolescents' perceptions of risks, benefits, social norms, and peer influences into account as they implement strategies to reduce youth use of marijuana and blunts.

Epidermal growth factor promotes a mesenchymal over an amoeboid motility of MDA-MB-231 cells embedded within a 3D collagen matrix.

The receptor of epidermal growth factor (EGFR) critically regulates tumor cell invasion and is a potent therapeutic target for treatment of many types of cancers, including carcinomas and glioblastomas. It is known that EGF regulates cell motility when tumor cells are embedded within a 3D biomatrix. However, roles of EGF in modulating tumor cell motility phenotype are largely unknown. In this article, we report that EGF promotes a mesenchymal over an amoeboid motility phenotype using a malignant breast tumor cell line, MDA-MB-231, embedded within a 3D collagen matrix. Amoeboid cells are rounded in shape, while mesenchymal cells are elongated, and their migrations are governed by a distinctly different set of biomolecules. Using single cell tracking analysis, we also show that EGF promotes cell dissemination through a significant increase in cell persistence along with a moderate increase of speed. The increase of persistence is correlated with the increase of the percentage of the mesenchymal cells within the population. Our work reveals a novel role of microenvironmental cue, EGF, in modulating heterogeneity and plasticity of tumor cell motility phenotype. In addition, it suggests a potential visual cue for diagnosing invasive states of breast cancer cells. This work can be easily extended beyond breast cancer cells.

Extracellular vesicle-mediated phenotype switching in malignant and non-malignant colon cells.

BACKGROUND: Extracellular vesicles (EVs) are secreted from many cells, carrying cargoes including proteins and nucleic acids. Research has shown that EVs play a role in a variety of biological processes including immunity, bone formation and recently they have been implicated in promotion of a metastatic phenotype. METHODS: EVs were isolated from HCT116 colon cancer cells, 1459 non-malignant colon fibroblast cells, and tumor and normal colon tissue from a patient sample. Co-cultures were performed with 1459 cells and malignant vesicles, as well as HCT116 cells and non-malignant vesicles. Malignant phenotype was measured using soft agar colony formation assay. Co-cultures were also analyzed for protein levels using mass spectrometry. The importance of 14-3-3 zeta/delta in transfer of malignant phenotype was explored using siRNA. Additionally, luciferase reporter assay was used to measure the transcriptional activity of NF-κB. RESULTS: This study demonstrates the ability of EVs derived from malignant colon cancer cell line and malignant patient tissue to induce the malignant phenotype in non-malignant colon cells. Similarly, EVs derived from non-malignant colon cell lines and normal patient tissue reversed the malignant phenotype of HCT116 cells. Cells expressing an EV-induced malignant phenotype showed increased transcriptional activity of NF-κB which was inhibited by the NF--κB inhibitor, BAY117082. We also demonstrate that knock down of 14-3-3 zeta/delta reduced anchorage-independent growth of HCT116 cells and 1459 cells co-cultured with HCT derived EVs. CONCLUSIONS: Evidence of EV-mediated induction of malignant phenotype, and reversal of malignant phenotype, provides rational basis for further study of the role of EVs in tumorigenesis. Identification of 14-3-3 zeta/delta as up-regulated in malignancy suggests its potential as a putative drug target for the treatment of colorectal cancer.

The α1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium.

Dysfunction of the right ventricle (RV) is closely related to prognosis for patients with RV failure. Therefore, strategies to improve failing RV function are significant. In a mouse RV failure model, we previously reported that α1-adrenergic receptor (α1-AR) inotropic responses are increased. The present study determined the roles of both predominant cardiac α1-AR subtypes (α1A and α1B) in upregulated inotropy in failing RV. We used the mouse model of bleomycin-induced pulmonary fibrosis, pulmonary hypertension, and RV failure. We assessed the myocardial contractile response in vitro to stimulation of the α1A-subtype (using α1A-subtype-selective agonist A61603) and α1B-subtype [using α1A-subtype knockout mice and nonsubtype selective α1-AR agonist phenylephrine (PE)]. In wild-type nonfailing RV, a negative inotropic effect of α1-AR stimulation with PE (force decreased ≈50%) was switched to a positive inotropic effect (PIE) with bleomycin-induced RV injury. Upregulated inotropy in failing RV occurred with α1A-subtype stimulation (force increased ≈200%), but not with α1B-subtype stimulation (force decreased ≈50%). Upregulated inotropy mediated by the α1A-subtype involved increased activator Ca(2+) transients and increased phosphorylation of myosin regulatory light chain (a mediator of increased myofilament Ca(2+) sensitivity). In failing RV, the PIE elicited by the α1A-subtype was appreciably less when the α1A-subtype was stimulated in combination with the α1B-subtype, suggesting functional antagonism between α1A- and α1B-subtypes. In conclusion, upregulation of α1-AR inotropy in failing RV myocardium requires the α1A-subtype and is opposed by the α1B-subtype. The α1A subtype might be a therapeutic target to improve the function of the failing RV.

Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy.

The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca(2+) decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca(2+)-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca(2+) transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca(2+) content. This abnormal Ca(2+) handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na(+)-Ca(2+) exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy.

Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial.

BACKGROUND: Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy. OBJECTIVE: To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy. DESIGN: A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096) SETTING: Military and civilian treatment centers. PATIENTS: 84 adults with lumbosacral radiculopathy of less than 6 months' duration. INTERVENTION: 2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks. MEASUREMENTS: The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period. RESULTS: The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, -2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, -16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, -5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09). LIMITATION: Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept. CONCLUSION: Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits. PRIMARY FUNDING SOURCE: The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.

Survey of alcohol use in the U.S. Army.

The objective of this study was to collect data that would provide information about the frequency, attitudes, and consequences of alcohol use in the U.S. Army. A questionnaire was used to assess the frequency of alcohol consumption, attitudes related to the use of alcohol, and adverse consequences experienced with alcohol use. The survey was conducted at Walter Reed Army Medical Center in Washington, D.C. Survey participants included both military employees working at Walter Reed Army Medical Center and military patients. No attempt was made to identify the medical status of the participants. The investigators distributed 1,200 questionnaires. Following distribution, the investigators received 1,010 completed questionnaires, resulting in an 84% return rate. Thirty-four percent of the survey participants (n = 335) were deployed to an area of combat operations. There was a significant difference in binge drinking between military personnel assigned to an area of combat operations and those not assigned to an area of combat operations (p = 0.023). Multiple regression results showed that age, marital status, and deployment status were correlated with four or more drinks at one time (p < 0.001). In other words, binge drinking is more likely to occur among military personnel who are younger, experiencing marital problems, and recently returned from an area of combat operations. Significant differences between the two groups also emerged in terms of other specific consequences associated with consumption. Deployment to an area of combat operations seems to influence consumption patterns, alcohol related attitudes, and behaviors. This could be a consequence of wartime experiences. This study should help guide the clinical screening of alcohol use disorders, which may complicate emotional recovery from traumatic experiences if undetected.

The effect of vein repair on the risk of venous thromboembolic events: a review of more than 100 traumatic military venous injuries.

BACKGROUND: The management of venous trauma remains controversial. Critics of venous repair have cited an increased incidence of associated venous thromboembolic events with this management. We analyzed the current treatment of wartime venous injuries in United States military personnel in an effort to answer this question. METHODS: From December 1, 2001, to October 31, 2005, all United States casualties with named venous injuries were evaluated. A retrospective review of a clinical database was performed on demographics, mechanism of injury, associated injuries, treatment, outcomes, and venous thromboembolic events. Data were analyzed using the Fisher exact test, analysis of variance, and logarithmic transformation. RESULTS: During this 5-year period, 82 patients sustained 103 named venous injuries due to combat operations. All patients were male, with an average age of 27.9 years (range, 20.3-58.3 years). Blast injuries accounted for 54 venous injuries (65.9%), gunshot wounds for 25 (30.5%), and motor vehicle accidents for 3 (3.6%). The venous injury was isolated in 28 patients (34.1%), and 16 (19.5%) had multiple venous injuries. The venous injury in two patients was associated with acute phlegmasia, with fractures in 33 (40.2%), and 22 (28.1%) sustained neurologic deficits. Venous injuries were treated by ligation in 65 patients (63.1%) and by open surgical repair in 38 (36.9%). Postoperative extremity edema occurred in all patients irrespective of method of management. Thrombosis after venous repair occurred in six of the 38 cases (15.8%). Pulmonary emboli developed in three patients, one after open repair and two after ligation (P > .99). CONCLUSION: In the largest review of military venous trauma in more than three decades, we found no difference in the incidence of venous thromboembolic complications between venous injuries managed by open repair vs ligation. Blast injuries of the extremities have caused most of the venous injuries. Ligation is the most common modality of treatment in combat zones. Long-term morbidity associated with venous injuries and their management will be assessed in future follow-up studies.

The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients.

UNLABELLED: Fibromyalgia (FM) is a challenging pain syndrome for which no reliable pharmacologic treatment exists. Recent clinical studies suggest that N-methyl-D-aspartate receptors might play a role in the pathogenesis of this disorder. To determine whether an intravenous (IV) ketamine test predicts the response to a therapeutic trial with an oral N-methyl-D-aspartate receptor antagonist, we performed a low-dose (0.1 mg/kg) IV ketamine infusion on 34 consecutive patients with FM, which was subsequently followed by an oral dextromethorphan (DX) treatment regimen. As per previous guidelines, the cutoff value for a positive response to the IV ketamine test was designated to be 67% pain relief, and a positive response to DX treatment was 50% pain reduction at 4- to 6-week follow-up visits. The degree of correlation between pain relief with ketamine and DX was highly significant (Pearson correlation coefficient, 0.66; P < .001). Ten patients responded positively to both ketamine and DX, 19 responded to neither drug, 3 had a positive response to ketamine but not DX, and 2 obtained good pain relief with DX but not ketamine. The sensitivity of the IV ketamine test was 83%, the specificity was 86%, the positive predictive value was 77%, and the negative predictive value was 91%. An association was also found between the development of side effects to the two treatments. PERSPECTIVE: The response to an IV ketamine infusion was found to predict the subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients, with an observed agreement of 83%. Considering the refractory nature of fibromyalgia to conventional pain treatments, the IV ketamine test might enhance patient care by saving time and reducing unnecessary treatment trials.

Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin.

To study the functional consequences of various cardiomyopathic mutations in human cardiac alpha-tropomyosin (Tm), a method of depletion/reconstitution of native Tm and troponin (Tn) complex (Tm-Tn) in cardiac myofibril preparations has been developed. The endogenous Tm-Tn complex was selectively removed from myofibrils and replaced with recombinant wild-type or mutant proteins. Successful depletion and reconstitution steps were verified by SDS-gel electrophoresis and by the loss and regain of Ca2+-dependent regulation of ATPase activity. Five Tm mutations were chosen for this study: the hypertrophic cardiomyopathy (HCM) mutations E62Q, E180G, and L185R and the dilated cardiomyopathy (DCM) mutations E40K and E54K. Through the use of this new depletion/reconstitution method, the functional consequences of these mutations were determined utilizing myofibrillar ATPase measurements. The results of our studies showed that 1) depletion of >80% of Tm-Tn from myofibrils resulted in a complete loss of the Ca2+-regulated ATPase activity and a significant loss in the maximal ATPase activity, 2) reconstitution of exogenous wild-type Tm-Tn resulted in complete regain in the calcium regulation and in the maximal ATPase activity, and 3) all HCM-associated Tm mutations increased the Ca2+ sensitivity of ATPase activity and all had decreased abilities to inhibit ATPase activity. In contrast, the DCM-associated mutations both decreased the Ca2+ sensitivity of ATPase activity and had no effect on the inhibition of ATPase activity. These findings have demonstrated that the mutations which cause HCM and DCM disrupt discrete mechanisms, which may culminate in the distinct cardiomyopathic phenotypes.