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Abstract Background Genome-wide gene expression profiling of whole blood is an attractive method for discovery of biomarkers due to its non-invasiveness, simple clinical site processing and rich biological content. Except for a few successes, this technology has not yet matured enough to reach its full potential of identifying biomarkers useful for clinical prognostic and diagnostic applications or in monitoring patient response to therapeutic intervention. A variety of technical problems have hampered efforts to utilize this technology for identification of biomarkers. One significant hurdle has been the high and variable concentrations of globin transcripts in whole blood total RNA potentially resulting in non-specific probe binding and high background. In this study, we investigated and quantified the power of three whole blood profiling approaches to detect meaningful biological expression patterns. Methods To compare and quantify the impact of different mitigation technologies, we used a globin transcript spike-in strategy to synthetically generate a globin-induced signature and then mitigate it with the three different technologies. Biological differences, in globin transcript spiked samples, were modeled by supplementing with either 1% of liver or 1% brain total RNA. In order to demonstrate the biological utility of a robust globin artifact mitigation strategy in biomarker discovery, we treated whole blood ex vivo with suberoylanilide hydroxamic acid (SAHA) and compared the overlap between the obtained signatures and signatures of a known biomarker derived from SAHA-treated cell lines and PBMCs of SAHA-treated patients. Results We found cDNA hybridization targets detect at least 20 times more specific differentially expressed signatures (2597) between 1% liver and 1% brain in globin-supplemented samples than the PNA (117) or no treatment (97) method at FDR = 10% and p-value < 3x10-3. In addition, we found that the ex vivo derived gene expression profile was highly concordant with that of the previously identified SAHA pharmacodynamic biomarkers. Conclusions We conclude that an amplification method for gene expression profiling employing cDNA targets effectively mitigates the negative impact on data of abundant globin transcripts and greatly improves the ability to identify relevant gene expression based pharmacodynamic biomarkers from whole blood.

Background: Prior research has revealed that cervical collars elevate intracranial pressure (ICP) in patients with traumatic brain injury. Two recent small studies evaluated the change in optic sheath nerve diameter (ONSD) measured by ultrasound as a proxy for ICP following cervical collar placement in healthy volunteers., Objective: We sought to validate the finding that ONSD measured by ultrasound increases after cervical collar placement within an independent data set., Methods: This was a prospective, crossover study involving volunteers. Participants were randomized to either have the ONSD measured first without a cervical collar or initially with a cervical collar. Two sonographers performed independent ONSD diameter measurements. Continuous data were analyzed by matched-paired t -tests. Alpha was set at 0.05. The primary outcome parameter was the overall mean difference between ONSD measurements with the cervical collar on and off. Multiple linear regression was performed to examine the relationship between variables and the primary outcome parameter., Results: There were 30 participants enrolled in the study. Overall mean ONSD for participants without the collar was 0.365 ± 0.071 cm and with the collar was 0.392 ± 0.081 cm. The mean change in ONSD for participants with and without the collar was 0.026 ± 0.064 cm (95% confidence interval of difference: 0.015-0.038; P < 0.001). Multiple regression analysis did not identify any variables associated with the variation in ONSD observed for collar versus noncollar., Conclusions: We confirmed that ONSD does vary by a measurable amount with placement of a rigid cervical collar on healthy volunteers when assessed by ultrasound., Competing Interests: There are no conflicts of interest.

Background: Previous research supports the efficacy of the crisis response plan (CRP) for the reduction of suicidal behaviors as compared to treatment as usual (TAU). Patient perspectives and use of the CRP, and their relationship to later suicidal thoughts, remain unknown., Methods: A secondary analysis of a randomized clinical trial comparing a standard CRP (S-CRP), a CRP enhanced with reasons for living (E-CRP), and TAU in a sample of 97 active-duty U.S. Army personnel was conducted. Participants were asked about their use, perceptions, and recall of each intervention. Generalized estimating equations were used to test the conditional effects of intervention use, perceptions, and recall on severity of suicide ideation during follow-up., Results: Across all treatment groups, over 80% of participants retained their written CRP up to 6 months later, but less than 25% had the written plan in their physical possession at the time of each assessment. Participants in S-CRP and E-CRP were more likely to recall self-management strategies and sources of social support. Participants in TAU were more likely to recall use of professional healthcare services and crisis management services. All three interventions were rated as highly useful. More frequent use of the E-CRP and recall of its components were associated with significantly reduced suicide ideation as compared to TAU., Conclusions: Both CRPs have high acceptability ratings. The effect of both CRPs on reduced suicide ideation is associated with patient recall of components. More frequent use of the E-CRP is associated with larger reductions in suicide ideation., (© 2018 Wiley Periodicals, Inc.)

Objective: To determine if synchrony in emotional arousal and affective regulation between patients and clinicians reflect emotional bonding during emergency behavioral health appointments., Method: Audio recordings of suicide risk assessment interviews and crisis intervention planning with 54 suicidal active duty soldiers presenting to an emergency department or behavioral health clinic were analyzed. Emotional arousal was assessed using mean fundamental frequency. Patient-rated emotional bond was assessed with the Working Alliance Inventory, Short Form (Hatcher & Gillaspy, 2014). Actor-partner interdependence modeling was used to identify moment-to-moment patterns of covariance among clinician and patient emotional arousal., Results: Greater synchrony in clinician and patient emotional arousal was positively associated with higher emotional bond ratings during the crisis intervention but not the risk assessment interview. During the risk assessment interview, higher emotional bond was associated with a dysregulating effect of the clinician on the patient's emotional arousal (i.e., larger fluctuations in the patient's emotional arousal). The reverse pattern was seen during the intervention: Higher emotional bond was associated with a regulating effect of the clinician on the patient's emotional arousal (i.e., smaller fluctuations in the patient's emotional arousal). Emotional bond during the intervention was also positively associated with a regulating effect of the patient on the clinician's emotional arousal., Conclusion: Emotional bonding during emergency clinical encounters is associated with patient-clinician synchrony in emotional states. During crisis interventions, emotional bonding is also associated with mutual down-regulation of emotional arousal among patients and clinicians. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Objective: The study examined the immediate effect of crisis interventions on the emotional state of acutely suicidal soldiers and clinician decision making., Methods: Soldiers (N=97) presenting to a military emergency department or behavioral health clinic were randomly assigned to receive a contract for safety (N=32), standard crisis response plan (S-CRP; N=32), or enhanced crisis response plan (E-CRP; N=33). Soldiers completed self-report scales before and after the intervention. Clinicians blinded to treatment group assignment rated participants' suicide risk level and made a decision about inpatient psychiatric admission., Results: Larger reductions in negative emotional states occurred in S-CRP and E-CRP. Larger increases in positive emotional states occurred in E-CRP. Clinician suicide risk ratings did not differ across treatment groups. Participants in E-CRP were less likely to be psychiatrically admitted., Conclusions: The CRP immediately reduces negative emotional states among acutely suicidal soldiers. Discussing a patient's reasons for living during a CRP also reduces the likelihood of inpatient psychiatric admission.

Competing Interests: Conflicts of interest: Brian J. Albanese declares that he has no conflicts of interest. Richard J. Macatee declares that he has no conflicts of interest. Norman B. Schmidt declares that he has no conflicts of interest. Bruce Leeson declares that he has no conflicts of interest. Tracy A. Clemans declares that she has no conflicts of interest. Jim Mintz declares that he has no conflicts of interest. M. David Rudd declares that he has no conflicts of interest. Craig J. Bryan declares that he has no conflicts of interest.

Objective: To evaluate the effectiveness of crisis response planning for the prevention of suicide attempts., Method: Randomized clinical trial of active duty Army Soldiers (N=97) at Fort Carson, Colorado, presenting for an emergency behavioral health appointment. Participants were randomly assigned to receive a contract for safety, a standard crisis response plan, or an enhanced crisis response plan. Incidence of suicide attempts during follow-up was assessed with the Suicide Attempt Self-Injury Interview. Inclusion criteria were the presence of suicidal ideation during the past week and/or a lifetime history of suicide attempt. Exclusion criteria were the presence of a medical condition that precluded informed consent (e.g., active psychosis, mania). Survival curve analyses were used to determine efficacy on time to first suicide attempt. Longitudinal mixed effects models were used to determine efficacy on severity of suicide ideation and follow-up mental health care utilization., Results: From baseline to the 6-month follow-up, 3 participants receiving a crisis response plan (estimated proportion: 5%) and 5 participants receiving a contract for safety (estimated proportion: 19%) attempted suicide (log-rank χ 2 (1)=4.85, p=0.028; hazard ratio=0.24, 95% CI=0.06-0.96), suggesting a 76% reduction in suicide attempts. Crisis response planning was associated with significantly faster decline in suicide ideation (F(3,195)=18.64, p<0.001) and fewer inpatient hospitalization days (F(1,82)=7.41, p<0.001). There were no differences between the enhanced and standard crisis response plan conditions., Conclusion: Crisis response planning was more effective than a contract for safety in preventing suicide attempts, resolving suicide ideation, and reducing inpatient hospitalization among high-risk active duty Soldiers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A growing body of empirical research suggests insomnia severity is directly related to suicide ideation, attempts, and death in nonmilitary samples, even when controlling for depression and other suicide risk factors. Few studies have explored this relationship in U.S. military personnel., Methods: The present study entailed secondary data analyses examining the associations of insomnia severity with suicide ideation and attempts in three clinical samples: Air Force psychiatric outpatients (n = 158), recently discharged Army psychiatric inpatients (n = 168), and Army psychiatric outpatients (n = 54). Participants completed the Beck Scale for Suicide Ideation, the Beck Depression Inventory-II or Patient Health Questionnaire-9, the Insomnia Severity Index, and the Posttraumatic Stress Disorder Checklist at baseline; two samples also completed these measures during follow-up., Results: Sleep disturbance was associated with concurrent (β's > 0.21; P's < 0.059) and prospective (β's > 0.39; P's < 0.001) suicide ideation in all three samples. When adjusting for age, gender, depression, and posttraumatic stress, insomnia severity was no longer directly associated with suicide ideation either concurrently (β's < 0.19; P's > 0.200) or prospectively (β's < 0.26; P's > 0.063), but depression was (β's > 0.22; P's < 0.012). Results of a latent difference score mediation model indicated that depression mediated the relation of insomnia severity with suicide ideation., Conclusions: Across three clinical samples of military personnel, depression explained the relationship between insomnia severity and suicide risk., (© 2015 Wiley Periodicals, Inc.)

This study examined recent-onset (i.e., acute) and persistent (i.e., chronic) life stressors among 54 acutely suicidal US Army Soldiers and examined their relationship to persistence of suicidal crises over time. Soldiers with a history of multiple suicide attempts reported the most severe suicide ideation (F(2,51) = 4.18, p = 0.021) and the greatest number of chronic stressors (F(2,51) = 5.11, p = 0.009). Chronic but not acute stressors were correlated with severity of suicide ideation (r = 0.24, p = 0.026). Participants reporting low-to-average levels of chronic stress resolved suicide ideation during the 6-month follow-up, but participants reporting high levels of chronic stress did not (Wald χ(1) = 4.57, p = 0.032). Soldiers who are multiple attempters report a greater number of chronic stressors. Chronic, but not acute-onset, stressors are associated with more severe and longer-lasting suicidal crises.

On June 7, 2013, a man was diagnosed in a Texas hospital with rabies. He had been detained in a U.S. detention facility during his infectious period. To identify persons exposed to rabies who might require rabies postexposure prophylaxis (PEP), CDC and the Texas Department of State Health Services (DSHS) conducted investigations at four detention facilities, one medical clinic, and two hospitals. In all, 25 of 742 persons assessed for rabies exposure were advised to receive PEP. Early diagnosis of rabies is essential for implementation of appropriate hospital infection control measures and for rapid assessment of potential contacts for PEP recommendations.

We report a case of a 22-year-old man who presented to the emergency department (ED) with altered mental status and was diagnosed with eosinophilic meningitis due to Angiostrongylus cantonensis (AC) acquired in the United States after exposure to snails.

Bedside ultrasound (US) was introduced to the emergency department more than 20 years ago. Since this time, many new applications have evolved to aid the emergency physician in diagnostic, procedural, and therapeutic interventions and the scope of bedside ultrasound continues to grow. Many US scanning techniques easily translate from adult applications to the pediatric population. Consequently, US has been adopted by many pediatric emergency providers. This article reviews the use of bedside ultrasound in pediatric emergency medicine., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Genome-wide gene expression profiling of whole blood is an attractive method for discovery of biomarkers due to its non-invasiveness, simple clinical site processing and rich biological content. Except for a few successes, this technology has not yet matured enough to reach its full potential of identifying biomarkers useful for clinical prognostic and diagnostic applications or in monitoring patient response to therapeutic intervention. A variety of technical problems have hampered efforts to utilize this technology for identification of biomarkers. One significant hurdle has been the high and variable concentrations of globin transcripts in whole blood total RNA potentially resulting in non-specific probe binding and high background. In this study, we investigated and quantified the power of three whole blood profiling approaches to detect meaningful biological expression patterns., Methods: To compare and quantify the impact of different mitigation technologies, we used a globin transcript spike-in strategy to synthetically generate a globin-induced signature and then mitigate it with the three different technologies. Biological differences, in globin transcript spiked samples, were modeled by supplementing with either 1% of liver or 1% brain total RNA. In order to demonstrate the biological utility of a robust globin artifact mitigation strategy in biomarker discovery, we treated whole blood ex vivo with suberoylanilide hydroxamic acid (SAHA) and compared the overlap between the obtained signatures and signatures of a known biomarker derived from SAHA-treated cell lines and PBMCs of SAHA-treated patients., Results: We found cDNA hybridization targets detect at least 20 times more specific differentially expressed signatures (2597) between 1% liver and 1% brain in globin-supplemented samples than the PNA (117) or no treatment (97) method at FDR = 10% and p-value < 3x10-3. In addition, we found that the ex vivo derived gene expression profile was highly concordant with that of the previously identified SAHA pharmacodynamic biomarkers., Conclusions: We conclude that an amplification method for gene expression profiling employing cDNA targets effectively mitigates the negative impact on data of abundant globin transcripts and greatly improves the ability to identify relevant gene expression based pharmacodynamic biomarkers from whole blood.

Tumorigenesis involves multistep genetic alterations. To elucidate the microRNA (miRNA)-gene interaction network in carcinogenesis, we examined their genome-wide expression profiles in 96 pairs of tumor/non-tumor tissues from hepatocellular carcinoma (HCC). Comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that increased expression of miR-122 seed-matched genes leads to a loss of mitochondrial metabolic function. Furthermore, the miR-122 secondary targets, which decrease in expression, are good prognostic markers for HCC. Transcriptome profiling data from additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. The HCC findings can be recapitulated in mouse liver by silencing miR-122 with antagomir treatment followed by gene-expression microarray analysis. In vitro miR-122 data further provided a direct link between induction of miR-122-controlled genes and impairment of mitochondrial metabolism. In conclusion, miR-122 regulates mitochondrial metabolism and its loss may be detrimental to sustaining critical liver function and contribute to morbidity and mortality of liver cancer patients.

One of the 'second generation' photosensitizing agents is N-acetyl chlorin e6 (NPe6). This product has a strong absorbance band at 665 nm, permitting treatment at a greater depth of tumor than earlier agents based on porphyrin structures. We examined the effects of fractionated drug administration on photodynamic efficacy. Prior studies had shown that it is the level of NPe6 in the circulation that predicts for photodynamic efficacy, indicating vascular shut-down to be the predominant mode of tumor control. Although pharmacokinetic studies revealed that >99% of NPe6 was lost from the circulation, it appears that a fractionated dosage protocol can promote photodamage to neoplastic tissue in vivo. This study also indicated the potential utility of an implantable micro array for tumor irradiation.

Irradiation of murine hepatoma 1c1c7 cultures presensitized with N-aspartyl chlorin e6 (NPe6) caused lysosomal disruption and apoptosis. Tao cells, a variant of the 1c1c7 line having lower aryl hydrocarbon receptor (AhR) contents, were resistant to the pro-apoptotic effects of NPe6 in the same photodynamic therapy protocol. Colony-forming assays were used to establish light dose-dependent and NPe6 concentration-dependent cytotoxicity curves. Lysosomal breakage and cell survival paralleled one another in both cell types. When analyzed at comparable lethal dose conditions, the onset of apoptosis was delayed, and the magnitude of the apoptotic response was muted in Tao cells, as assessed by morphology, annexin V binding, caspase-3 activities, and analyses of Bid, procaspase-9, and pro-caspase-3 cleavage. In contrast, the kinetics/magnitude of pro-caspase-3 activation in the two cell lines were identical after exposure to HA14 -1 or Jo2 antibody, inducers of the intrinsic and extrinsic apoptotic pathways, respectively. Tao endosomal/lysosomal extracts contained approximately 50%, 35%, and 55% of the Bid cleavage and cathepsin B and D activities of 1c1c7 endosomes/lysosomes, respectively. Western blot analyses confirmed reduced cathepsin B/D contents in Tao cells. Analyses of 1c1c7/Tao variants engineered to express antisense/sense AhR constructs suggested that endosomal/lysosomal cathepsin B and D content, but not whole cell content, correlated with AhR expression. These studies provide a mechanism for the resistance of Tao cultures to the proapoptotic effects of a protocol causing targeted disruption of lysosomes. They also suggest that the AhR, in the absence of exogenous ligand, may affect the trafficking/processing of proteases normally found in endosomes/lysosomes.

The purpose of this study was to measure the tensile properties of fresh human calcaneal (Achilles) tendons. Twenty fresh cadaveric (age range = 57-93 years) bone-Achilles tendon complexes were harvested within 24 hr postmortem. The calcaneus together with 15 cm of the Achilles tendon extending proximally from the insertion on the calcaneus was clamped and biomechanically tested. Each tendon was firmly fixed in clamps in an MTS Systems Corporation MTS testing machine and tension was applied at a displacement rate of 8 cm per minute until the tendon failed. The tensile force and tensile strain (as measured using an extensometer) were recorded and plotted using onboard software. The narrow age range of our donors prevented any meaningful correlation between age and tensile properties; however, the results showed that: 1) the average ultimate tensile strength (UTS) of the human Achilles tendon was 1189 N (range = 360-1,965), 2) there was a correlation between left and right legs for UTS, 3) there was a correlation between left and right legs in regard to cross sectional area, and 4) there was no correlation between UTS and cross-sectional area., (Copyright 2003 Wiley-Liss, Inc.)