Evaluation of ITX 5061, a scavenger receptor B1 antagonist: resistance selection and activity in combination with other hepatitis C virus antivirals

ITX 5061 is a scavenger receptor B1 antagonist that has entered phase 1 clinical trials in hepatitis C virus (HCV)-infected humans. We evaluated ITX 5061 in combination with interferon-α, ribavirin, and HCV protease and polymerase inhibitors in a genotype 2a infectious virus system. ITX 5061 is a potent inhibitor of HCV replication and is additive to synergistic with interferon-α, ribavirin, BILN2061, VX950, VX1, and 2'-C-methyladenosine. Resistance selection experiments were performed using a Jc1-FEO virus co-culture system and intermittent ITX 5061 exposure under neomycin selection. We identified a mutant virus with a substitution of aspartic acid for asparagine at the highly conserved position 415 in E2 (N415D). Introduction of this mutation into wild-type virus conferred high-level resistance to ITX 5061. There was no cross-resistance between ITX 5061 and HCV protease inhibitors or interferon-α. These results suggest that ITX 5061 is a promising compound for study in combination with other HCV inhibitors.     

Physiologic reactivity despite emotional resilience several years after direct exposure to terrorism

OBJECTIVE: Six and a half to 7 years after the 1995 terrorist bombing in Oklahoma City, the authors assessed autonomic reactivity to trauma reminders and psychiatric symptoms in adults who had some degree of direct exposure to the blast. METHOD: Sixty survivors who were listed in a state health department registry of persons exposed to the bombing and 60 age- and gender-matched members of the Oklahoma City metropolitan area community were assessed for symptoms of PTSD and depression and for axis I diagnoses. Heart rate and systolic, diastolic, and mean arterial blood pressures were measured before, during, and after bombing-related interviews. The two groups were compared on both psychometric and physiologic assessments. RESULTS: Posttraumatic stress but not depressive symptoms were significantly more prevalent in the survivor group than in the comparison group, although symptoms were below levels considered clinically relevant. Despite apparent emotional resilience or recovery, blast survivors had significantly greater autonomic reactivity to trauma reminders on all measures than comparison subjects. CONCLUSIONS: The results suggest that physiologic assessment may capture long-term effects of terrorism that are not identified by psychometric instruments. The consequences of autonomic reactivity despite emotional resilience years after experiencing trauma are unknown but theoretically could range from facilitating a protective vigilance toward future disasters to more maladaptive avoidance behaviors, somatic symptoms, or medical problems.     

Persistent physiological reactivity in a pilot study of partners of firefighters after a terrorist attack

Twenty-four female partners of firefighters participating in recovery efforts associated with the 1995 terrorist bombing in Oklahoma City were assessed 43 to 44 months later. Disaster experiences, psychiatric diagnoses, posttraumatic stress symptoms, and autonomic reactivity in response to an interview about the bombing were examined. Most of the participants with postbombing disorders suffered from pre-existing conditions. The majority found the bombing a "terrible" or "shocking" experience. One participant met all DSM-III-R symptom group criteria for bombing-related posttraumatic stress disorder, and 40% met both B (intrusive re-experiencing) and D (hyperarousal) criteria. More than one half of the sample exhibited autonomic reactivity on at least one measurement. Those who met symptom group criterion D evidenced greater autonomic reactivity than those who did not, suggesting a link between self-reported posttraumatic stress disorder symptoms of arousal and biological manifestations. Thus, it may be important to assess partners of disaster recovery workers for mental health and physiological consequences related to their indirect exposure as these may persist years after the event, even in the absence of a diagnosable mental disorder.     

Generation and application of new rat monoclonal antibodies against synthetic FLAG and OLLAS tags for improved immunodetection

Previously, we prepared monoclonal antibodies (mAbs) by immunizing rats with the recombinant fusion proteins of mouse Langerin/CD207, which contained a flexible linker sequence from E. coli OmpF and a FLAG epitope. We found many of new rat mAbs were not reactive to mouse Langerin, and here we identify the epitopes of two of these IgG mAbs, L2 and L5, and assess their efficacy in various immunodetection methods. MAb L5 is a rat IgG mAb against the FLAG epitope, which detected both N-terminal and C-terminal FLAG tagged protein 2 to 8 times better than the conventional anti-FLAG mAb M2 by Western blot. For mAb L2, we found its epitope to be a 14 amino acid sequence SGFANELGPRLMGK which consisted of both sequences from the OmpF derived linker and mouse Langerin. This epitope sequence was named OLLAS (E. coliOmpF Linker and mouse Langerin fusion Sequence), and mAb L2 as mAb OLLA-2. When the OLLAS sequence was inserted into recombinant proteins at N-terminal, C-terminal, or internal sites, the OLLAS tag was detected by mAb OLLA-2 with very high sensitivity compared to other conventional epitope tags and anti-tag mAbs. MAb OLLA-2 recognized OLLAS tagged proteins with at least 100-fold more sensitivity than anti-FLAG M2 and anti-V5 mAbs in Western blot analyses. We also find the OLLAS epitope to be superior in immunoprecipitation and other immunodetection methods, such as fluorescent immunohistochemistry and flow cytometry. In the process, we successfully utilized the OLLAS epitope sequence as an internal linker for fusion between the engineered mAb and the antigen, and thus achieved improved immunodetection.     

Heart rate reactivity and current post-traumatic stress disorder when data are missing

Aims: This study demonstrates that auxiliary and exclusion criteria variables increase the effectiveness of missing imputation in correcting underestimation of physiologic reactivity in relation to post‐traumatic stress disorder (PTSD) caused by deleting cases with missing physiologic data. Methods: This study used data from survivors of the 1995 Oklahoma City bombing and imputed missing heart rate data using auxiliary and exclusion criteria variables. Logistic regression was used to examine heart rate reactivity in relation to current PTSD. Results: Of 113 survivors who participated in the bombing study's 7‐year follow‐up interview, 42 (37%) had missing data on heart rate reactivity due to exclusion criteria (medical illness or use of cardiovascular or psychotropic medications) or non‐participation. Logistic regression results based on imputed heart rate data using exclusion criteria and auxiliary (the presence of any current PTSD arousal symptoms) variables showed that survivors with current bombing‐related PTSD had significantly higher heart rates at baseline and recovered more slowly back to baseline heart rate during resting periods than survivors without current PTSD, while results based on complete cases failed to show significant correlations between current PTSD and heart rates at any assessment points. Conclusions: Suggested methods yielded an otherwise undetectable link between physiology and current PTSD.     

Economic factors in of patients’ nonadherence to antidepressant treatment

Purpose

Patients’ nonadherence to antidepressant treatment hampers cost and efficacy of depression-specific treatment. However, previous studies have failed to find consistent findings in economic effect on nonadherence and also failed to reach consensus in how to measure nonadherence to treatment. The study attempts to investigate income effect on nonadherence to selective serotonin reuptake inhibitors (SSRIs) treatment with clear definitions of nonadherence: self discontinuation of SSRIs (nonpersistence) and under-dose of SSRIs (noncompliance).

Methods

The study extracted data from the National Comorbidity Survey-Replication (NCS-R). The study sample (n?=?280) includes adults between the ages of 18 and 64 who were diagnosed with Diagnostic Statistics Manual IV Major Depressive Episode (MDE) at some point during their lifetime and medicated with SSRIs in the past 12?months.

Results

Just above poverty level of family income and no health insurance increased the risk of medication nonpersistence in SSRIs treatment. The study findings confirmed that African Americans were at higher risk of medication noncompliance than Whites (odds ratio, 4.53) and MDE comorbidity was positively associated with medication noncompliance (odds ratio, 4.25).

Conclusions

Low income level, combined with health insurance status, and race/ethnicity, predict nonadherence to antidepressant treatment. The study findings would help physicians and hospitals developing interventional strategies and programs to increase patients’ adherence rates in antidepressant treatment.     

Bridging Policy and Service Performance of Hospital-Based Nutrition Support by Healthcare Information Technology

Although the healthcare policy was implemented to incentivize the multidisciplinary services of hospital-based nutrition support team (NST) in South Korea, timely completion of the services has been challenging in the hospitals. We enhanced NST healthcare information technology (NST−HIT) to bridge the gap between policy implementation and seamless execution of the policy in the hospital system. A 48 month pre-test−post-test study was performed, including a 12 month pre-intervention period, a six month intervention period, and a 30 month post-intervention period. The enhanced NST−HIT provided sufficient patient data and streamlined communication processes among end-users. A Student’s t-test showed that the timely completion rate of NST consultations, the reimbursement rate of NST consultations, average response times of NST physicians and nurses, and length of hospital stay significantly improved during the post-intervention period. A segmented regression analysis of interrupted time series showed that the average response times of NST physicians had sustained after the interventions. We believe that well-structured, multi-pronged initiatives with leadership support from the hospital improved service performance of hospital NST in response to national-level healthcare policy changes.