A Pilot Study of a Three-Session Heart Rate Variability Biofeedback Intervention for Veterans with Posttraumatic Stress Disorder.

Many veterans do not complete traditional trauma treatments; others may continue to struggle with posttraumatic stress disorder (PTSD) even after completing a full course of therapy (Blasé et al., in Int J Environ Res Public Health 18(7):Article 3329, https://doi.org/10.3390/ijerph18073329 , 2016). Heart rate variability (HRV) biofeedback (HRVB) is a non-invasive, non-pharmacological, breathing-based cardiorespiratory training technique that can reduce trauma symptoms and improve HRV parameters. Prior studies have demonstrated HRVB is well-tolerated by veterans with PTSD symptoms (Tan et al., in Appl Psychophysiol Biofeedback 36(1):27-35, 10.1007/s10484-010-9141-y, 2011; Schuman and Killian, in Appl Psychophysiol Biofeedback 44(1):9-20, https://doi.org/10.1007/s10484-018-9415-3 , 2019). This randomized wait-list controlled pilot study tested a short mobile app-adapted HRVB intervention in combination with treatment as usual for veterans with military-related PTSD to determine if further investigation was warranted. We assessed veterans' military-related PTSD symptoms, depression symptoms, and HRV time and frequency domain measures at baseline, after three clinical sessions, and one month later. This study combined clinical training and home biofeedback with a smartphone app and sensor to reinforce training and validate adherence. In the intervention group, depression and SDNN significantly improved, and we observed marginally significant improvements for PTSD Cluster B (intrusion) symptoms, whereas no significant improvements were observed in the control group. In addition, the brief protocol was acceptable to veterans with PTSD with over 83% of participants completing the study. However, adherence to home practice was low. Findings suggest brief HRVB interventions can decrease comorbid depression and improve overall autonomic function in veterans with PTSD; however, additional research on home biofeedback is necessary to determine the best strategies to increase adherence and which veterans would benefit from brief HRVB interventions.

Pilot Study on Reducing Symptoms of Anxiety with a Heart Rate Variability Biofeedback Wearable and Remote Stress Management Coach.

We assessed the feasibility of using a consumer friendly, heart rate variability biofeedback (HRVB) wearable device in conjunction with a remote stress management coach to reduce symptoms of anxiety. We utilized a discreet, continuously wearable electrocardiogram device, the Lief Smart Patch, which measures and records heart rate and HRV in real time, and guides HRVB exercises using vibrations and visual cues. During the 8-week study, participants (N = 14) wore the Lief Smart Patch, participated in HRVB with the device, utilized the mobile app, and communicated with a remote stress management coach. We collected self-report survey responses to measure symptoms of anxiety (GAD-2) and depression (PHQ-2) every 2 weeks, as well as HRV data throughout the study. Participants' mean GAD-2 score began at 4.6 out of 6. By the trial's completion, the group's mean GAD-2 score dropped to 1.7 (t(13) = 11.0, p < .001) with only 2 of the 14 subjects remaining over the clinical threshold of high anxiety. Similarly, the group's mean PHQ-2 score dropped from 2.93 to 1.29 (t(13) = 3.54, p < .01). In addition, participants increased their HRV (RMSSD) by an average of + 11.4 ms after participating in a low dose biofeedback exercise. These findings suggest that engaging in HRVB through a discreet wearable device in conjunction with a remote stress management program may be effective for reducing symptoms of anxiety and depression.

Symptom Management Among Cancer Survivors: Randomized Pilot Intervention Trial of Heart Rate Variability Biofeedback.

Chronic cancer-related symptoms (stress, fatigue, pain, depression, insomnia) may be linked with sympathetic nervous system over-activation and autonomic imbalance. Decreased heart rate variability (HRV) is an indicator of autonomic dysregulation that is commonly observed among cancer survivors. HRV biofeedback (HRVB) training induces HRV coherence, which maximizes HRV and facilitates autonomic and cardiorespiratory homeostasis. This randomized, wait-list-controlled, pilot intervention trial tested the hypothesis that HRVB can improve HRV coherence and alleviate cancer-related symptoms. The intervention group (n = 17) received 4-6 weekly HRVB training sessions until participants demonstrated skill acquisition. Controls (n = 17) received usual care. Outcomes assessed at baseline and follow-up included 15-min HRV recordings (HRV Coherence Ratio), and symptoms of: stress, distress, post-traumatic stress disorder (PTSD), pain, depression, fatigue, and sleep disturbance. Linear mixed models for repeated measures were used to assess Group-by-Time interactions, pre- versus post-treatment differences in mean symptom scores, and group differences at follow-up. Mean HRV Coherence Ratios (± standard error) improved in the HRVB group at follow-up (baseline: 0.37 ± 0.05, post-intervention: 0.84 ± 0.18, p = 0.01), indicating intervention validity. Statistically significant Group-by-Time interactions indicated treatment-related improvements in HRV Coherence Ratios (p = 0.03, Pre-vs. post-treatment effect size [Cohen's d]: 0.98), sleep symptoms (p = 0.001, d = 1.19), and sleep-related daytime impairment (p = 0.005, d = 0.86). Relative to controls, the intervention group experienced trends toward improvements in stress, distress, fatigue, PTSD, and depression, although no other statistically significant Group-by-Time interactions were observed. This pilot intervention found that HRVB training reduced symptoms of sleep disturbance among cancer survivors. Larger-scale interventions are warranted to further evaluate the role of HRVB for managing symptoms in this population. Registration: NCT03692624 www.clinicaltrials.gov.

Shift Work and Heart Rate Variability Coherence: Pilot Study Among Nurses.

This study used ambient heart rate monitoring among health care workers to determine whether a novel measure of heart rate variability (HRV), as well as sleep disturbances, fatigue, or cognitive performance differed among non-rotating night shift nurses relative to those working permanent day shifts. Continuous ambulatory HRV monitoring was performed among night nurses (n = 11), and a comparison group of permanent day nurses (n = 7), over a 36-h period coinciding with the last two 12-h shifts of each participant's work week. Symptoms and psychomotor vigilance were assessed at the end of the ambient HRV monitoring period, and no differences between shifts were observed. Day nurses exhibited an increase in hourly mean HRV coherence ratios during their sleep period, suggesting a circadian pattern of cardiorespiratory phase coupling, whereas night nurses had no increase in HRV coherence ratios during their sleep period. The HRV coherence patterns were similar to high frequency HRV power among nurses on the same shift. To the authors knowledge, this study was the first to quantify patterns of the HRV coherence ratio among shiftworkers in a non-experimental (work/home) setting. The results suggest a pattern of autonomic dysregulation among night workers during their sleep period relative to those working day shifts. The HRV coherence ratio may serve as a novel indicator of HRV dysregulation among shift workers.

Decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy.

Postesophagectomy anastomotic leak is a common postsurgical complication. The current standard method of detecting leak is esophagram usually late in the postoperative period. Perianastomotic drain amylase level had shown promising results in early detection anastomosis leak. Previous studies have shown that postoperative day 4 amylase level is more specific and sensitive than esophagram. The purpose of this study is to determine if implementing a drain amylase-based screening method for anastomotic leak can reduce length of stay and hospital cost relative to a traditional esophagram-based pathway. The drain amylase protocol we propose uses postoperative day 4 drain amylase level to direct the initiation of PO intake and discharge. We designed a decision analysis tree using TreeAge Pro software to compare the drain amylase-based screening method to the standard of care, the esophagram. We performed a retrospective review of postesophagectomy patients from a tertiary academic medical center (University hospital Cleveland medical center) where amylase level was measured routinely postoperatively. The patients were separated into amylase-based pathway group and the standard of care group based on their postop management. The length of stay, costs, complications, and leak rate of these two groups were used to inform the decision analysis tree. In the base-case analysis, the decision analysis demonstrated that an amylase-based screening method can reduce the hospital stay by one day and reduced costs by ∼$3,000 compared to esophagram group. To take the variability of the data into consideration, we performed a Monte Carlo simulation. The result showed again a median saving of 0.71 days and ∼$2,500 per patient in hospital cost. A ballistic sensitivity analysis was performed to show that the sensitivity of postoperative day 4 amylase level in detecting a leak was the most important factor in the model. We conclude that implementing an amylase-based screening method for anastomotic leak in postesophagectomy patient can significantly reduce hospital cost and length of stay. This study demonstrates a novel protocol to improve postesophagectomy care. Based on this result, we believe a prospective multicenter study is appropriate.

IRB and Research Regulatory Delays Within the Military Health System: Do They Really Matter? And If So, Why and for Whom?

Institutional review board (IRB) delays may hinder the successful completion of federally funded research in the U.S. military. When this happens, time-sensitive, mission-relevant questions go unanswered. Research participants face unnecessary burdens and risks if delays squeeze recruitment timelines, resulting in inadequate sample sizes for definitive analyses. More broadly, military members are exposed to untested or undertested interventions, implemented by well-intentioned leaders who bypass the research process altogether. To illustrate, we offer two case examples. We posit that IRB delays often appear in the service of managing institutional risk, rather than protecting research participants. Regulators may see more risk associated with moving quickly than risk related to delay, choosing to err on the side of bureaucracy. The authors of this article, all of whom are military-funded researchers, government stakeholders, and/or human subject protection experts, offer feasible recommendations to improve the IRB system and, ultimately, research within military, veteran, and civilian populations.

The role of sleep and heart rate variability in metabolic syndrome: evidence from the Midlife in the United States study.

STUDY OBJECTIVES: Poor sleep and autonomic dysregulation can both disrupt metabolic processes. This study examined the individual and combined effects of poor sleep and reduced heart rate variability (HRV) on metabolic syndrome among 966 participants in the Midlife in the United States II (MIDUS II) study. METHODS: Self-reported sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI). HRV was acquired from 11-minute resting heart rate recordings. Spearman correlations, general linear regression, and logistic regression models were used to examine the study hypotheses. RESULTS: Poor sleep quality was associated with metabolic syndrome when global PSQI scores were evaluated as a continuous (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.03 to 1.11) or categorical measure (cutoff > 5, OR: 1.58, 95% CI: 1.19 to 2.10), after adjustment for confounding. There also was an association between reduced HRV and metabolic syndrome (ln [HF-HRV] OR: 0.89, 95% CI: 0.80 to 0.99; ln [LF-HRV] OR: 0.82, 95% CI: 0.72 to 0.92; ln [SDRR] OR: 0.59, 95% CI: 0.43 to 0.79; ln [RMSSD] OR: 0.75, 95% CI: 0.60 to 0.94). When the combined effects of poor sleep and low HRV were examined, the association with metabolic syndrome was further strengthened relative to those with normal sleep and HRV. CONCLUSIONS: To the best of the author's knowledge, this is the first study to suggest a combined effect of poor sleep and low HRV on the odds of metabolic syndrome.

Knee Injury and Osteoarthritis Outcome Score Trajectories After Primary Total Knee Arthroplasty in United States Veterans.

INTRODUCTION: The volume of total knee arthroplasty (TKA) procedures continues to increase, including among United States (US) veterans, but there is little data characterizing recovery using validated knee-related questionnaires. METHODS: In this prospective cohort study, we sought to establish the feasibility of longitudinal characterization of recovery after TKA using the validated Knee Injury and Osteoarthritis Outcome Score (KOOS), specifically focusing on two of the KOOS subscales (pain and quality of life (QOL)). We solicited participants who agreed to fill out these knee-related questionnaires preoperatively and 3, 6, and 12 months after discharge following unilateral TKA within the Durham Veterans Affairs Health Care System. We examined rates of prospective completion of the KOOS and face validity of scores at each study time point. We transformed and reported scores on the 0-100 scale, with zero representing significant knee pain or poor QOL and 100 representing no knee pain or good QOL. RESULTS: Of 200 US veterans presenting between May 2017 and 2018, 21 (10.5%) agreed to participate by filling out the KOOS questionnaire longitudinally from before surgery until one year after discharge. All 21 (100%) participants were male and completed the two KOOS subscale questions (pain and QOL) preoperatively. Of those, 16 (76.2%) also completed KOOS at 3 months, 16 (76.2%) at 6 months, and seven (33.3%) at 12 months. Compared to mean preoperative values (pain: 33.47 + 6.78, QOL: 11.91 + 4.99), the KOOS subscale scores had significantly improved by 6 months after TKA (pain: 74.41 + 10.72, QOL: 49.61 + 13.25) but plateaued at 12 months (pain: 74.60 + 20.80, QOL: 50.89 + 20.61). The magnitude of improvement in absolute scores, pain and QOL, was similar and significant at 12 months compared to preoperative values with an increase of 41.13 (p=0.007) and 38.98 (p=0.009), respectively. CONCLUSION: Primary TKA in US veterans with advanced osteoarthritis may lead to improved patient-reported KOOS pain and QOL subscale measures at 12 months compared to preoperative scores, with the majority of improvement occurring by 6 months. Only one in ten US veterans approached preoperatively agreed to complete the validated knee-related outcomes questionnaire prior to undergoing TKA. About three-quarters of those veterans also completed it both three and six months after discharge. Collected KOOS subscale scores demonstrated face validity and showed substantial improvement in pain and QOL over the six-month postoperative period. Only one in three veterans who completed the KOOS questionnaire preoperatively also completed it at 12 months, but this does not support the feasibility of follow-up assessments beyond 6 months. To better understand longitudinal pain and QOL trajectories in US veterans undergoing primary TKA for advanced osteoarthritis and to improve study participation, additional research using the KOOS questionnaire may add further insights into this underreported population.

Review of Perioperative Music Medicine: Mechanisms of Pain and Stress Reduction Around Surgery.

Clinical-experimental considerations and an approach to understanding the autonomic basis of improved surgical outcomes using Perioperative Music Medicine (PMM) are reviewed. Combined surgical, psycho-physiological, and experimental perspectives on Music Medicine (MM) and its relationship to autonomic nervous system (ANS) function are discussed. Considerations are given to the inter-related perioperative effects of MM on ANS, pain, and underlying vagal and other neural circuits involved in emotional regulation and dysregulation. Many surgical procedures are associated with significant pain, which is routinely treated with post-operative opioid medications, which cause detrimental side effects and delay recovery. Surgical trauma shifts the sympathetic ANS to a sustained activation impairing physiological homeostasis and causing psychological stress, as well as metabolic and immune dysfunction that contribute to postoperative mortality and morbidity. In this article, we propose a plan to operationalize the study of mechanisms mediating the effects of MM in perioperative settings of orthopedic surgery. These studies will be critical for the implementation of PMM as a routine clinical practice and to determine the potential limitations of MM in specific cohorts of patients and how to improve the treatment.

A social-ecological model of readiness for transition to adult-oriented care for adolescents and young adults with chronic health conditions.

BACKGROUND: Policy and research related to transition to adult care for adolescents and young adults (AYAs) has focused primarily on patient age, disease skills and knowledge. OBJECTIVE: In an effort to broaden conceptualization of transition and move beyond isolated patient variables, a new social-ecological model of AYA readiness for transition (SMART) was developed. METHODS: SMART development was informed by related theories, literature, expert opinion and pilot data collection using a questionnaire developed to assess provider report of SMART components with 100 consecutive patients in a childhood cancer survivorship clinic. RESULTS: The literature, expert opinion and pilot data collection support the relevance of SMART components and a social-ecological conceptualization of transition. Provider report revealed that many components, representing more than age, disease knowledge and skills, related to provider plans for transferring patients. CONCLUSIONS: SMART consists of inter-related constructs of patients, parents and providers with emphasis on variables amenable to intervention. Results support SMART's broadened conceptualization of transition readiness and need for assessment of multiple stakeholders' perspectives of patient transition readiness. A companion measure of SMART, which will be able to be completed by patients, parents and providers, will be developed to target areas of intervention to facilitate optimal transition readiness. Similar research programmes to establish evidence-based transition measures and interventions are needed.

Shift Work Adaptation Among Police Officers: The BCOPS Study.

Few studies have examined shiftwork adaptation among police officers or potential differences in disease biomarkers among adapted and maladapted shiftworkers. This study characterized shiftwork adaptation among 430 police officers from the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) study. Police officers working fixed night shifts with symptoms characteristic of adaptation and maladaptation were identified using latent class analysis (n = 242). Two approaches were applied, one with police-specific symptoms and another using more general symptoms as shiftwork adaptation indicators. Biomarkers of inflammation, heart rate variability, and cardiometabolic risk were then compared between shiftwork adaptation groups, and with officers working day shifts, after adjusting for confounding. When analyses included police-specific symptoms, maladapted shiftworkers (n = 73) had more self-reported stress, sleep disturbances, fatigue, and less social support than adapted shiftworkers (n = 169). Using more general symptoms, maladapted officers (n = 56) reported more stress and depression, and less social support than adapted officers (n = 186). In police-specific models, adjusted (least-squares) means (± standard error) of circulating interleukin-6 (IL-6) concentrations in maladapted officers (0.8 ± 0.1 ln[pg/ml]) were modestly elevated relative to adapted shiftworkers (0.7 ± 0.1 ln[pg/ml], p = .09) and relative to permanent day workers (0.5 ± 0.1 ln[pg/ml], p ≤ 0.01), and leptin levels in maladapted officers (9.6 ± 0.1 ln[pg/ml]) exceeded those in the adapted (9.4 ± 0.1 ln[pg/ml], p ≤ 0.01) and day shift groups (9.4 ± 0.1 ln[pg/ml], p = .03). In the general model, adjusted mean tumor necrosis factor-alpha (TNF-α) concentrations among maladapted officers (5.6 ± 0.23 pg/ml) exceeded the adapted (4.8 ± 0.2 pg/ml, p ≤ 0.01) and day workers (5.0 ± 0.2 pg/ml, p = .04), and insulin among maladapted officers was higher (2.4 ± 0.1 ln[uu/ml]) than the adapted group (1.8 ± 0.1 ln[uu/ml], p = .03). No differences were observed for the other biomarkers. The results suggest that maladaptation among police officers working fixed night shifts may lead to increases in leptin, insulin, IL-6, and TNF-α; however, the cross-sectional design and possible residual confounding preclude interpretation of cause and effect. Prospective studies are planned to further characterize the relationship between shiftwork maladaptation and biomarkers of chronic disease risk in this police officer cohort.

An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety.

BACKGROUND: Gonadal damage is a consequence of therapy for pediatric malignancies. Prepubertal males have no semen or mature spermatozoa, posing a challenge for fertility preservation. Testicular tissue cryopreservation is a potential option but is still experimental. We report on a pilot protocol that offered testicular biopsy cryopreservation to families of prepubertal boys with newly diagnosed malignancy. The aims were to determine the acceptability and safety of this procedure. METHODS: Parents of prepubertal boys with diagnoses at highest risk for treatment-related gonadal damage were offered the option of testicular cryopreservation. Half of the biopsy was frozen for the subject's potential future use and the remainder used for research. Data on negative intraoperative and/or 7 day post-operative sequelae of testicular biopsies were assessed. Two to four weeks later, parents were asked to complete a questionnaire on factors influencing their decision to have the biopsy or not. RESULTS: Since January 2008, 24 boys have met the eligibility criteria but three required immediate treatment and were excluded. Sixteen of 21 families (76%) consented to testicular biopsy, indicating the prospective acceptability of this option to parents of boys aged 3 months to 14 years; 14 underwent the procedure without any negative intra- or post-operative sequelae. Although the time at diagnosis is stressful, families can give thoughtful consideration to this option. Factors such as religion, finance, ethics and the experimental nature of cryopreservation did not play a major role in decision-making. CONCLUSIONS: Parents of prepubertal boys with cancer are willing to pursue testicular tissue cryopreservation at diagnosis, and testicular biopsy caused no acute adverse effects.

Discriminative delay Pavlovian eyeblink conditioning in veterans with and without posttraumatic stress disorder.

BACKGROUND: Impaired eyeblink (EB) classical conditioning using a delay paradigm has previously been shown in combat veterans, as well as in a group of depressed adults, compared to normal individuals. Significant deficits in immediate memory (IM) in combat PTSD+ veterans, compared to normal controls, have also been previously shown, but these differences became non-significant after controlling for level of self-reported depression. Furthermore, EB conditioning has been shown to be significantly correlated with heart rate variability (HRV) in normal adults. The present study examined how depression (self-reported), IM, and resting HRV are related to discriminative delay classical EB conditioning in veterans with and without PTSD. METHOD: Three groups of subjects (combat PTSD+, combat PTSD-, and non-combat PTSD-) were assessed for self-report of depression and anxiety, as well as IM and HRV. Subjects received a single session of discriminative EB classical conditioning in which the conditioned stimulus (CS) was a light signal (either red or green) compounded with a tone. On CS+ trials, the light-tone compound stimulus co-terminated with a corneal airpuff (unconditioned stimulus, US), thus producing a delay paradigm. On CS- trials the appropriate light-tone stimulus was presented but not followed by the airpuff US. EB amplitude and frequency were recorded. RESULTS: PTSD+ subjects had greater self-reported depression and anxiety scores than the two control groups, as well as lower scores on a measure of IM. However, the IM difference was not significant after the effects of self-reported depression and anxiety were controlled. EB CR amplitude was significantly greater to CS+ than CS- for all three groups. EB amplitude to both the US (airpuff) and the CS+ declined over trials, but was significantly lower in the combat PTSD+ group compared to the combined PTSD- groups. Subjects who reached an EB CR acquisition criterion had significantly greater scores on IM than those who did not reach criterion. Factor analysis of the entire data set revealed four factors corresponding to (1) self-reported depression and anxiety, (2) IM, (3) HRV, and (4) EB amplitude. EB frequency was significantly predicted by IM and HRV. CONCLUSIONS: These data extend our previous results by showing deficits in EB conditioning among combat PTSD+ veterans that were associated with lower IM and resting HRV, but were not associated with self-report of depression.

Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis.

Despite its affinity for fibrin, tissue plasminogen activator (t-PA) administration causes systemic fibrinogenolysis. To investigate the mechanism, t-PA was incubated with plasma in the presence or absence of a fibrin clot, and the extent of fibrinogenolysis was determined by measuring B beta 1-42. In the presence of fibrin, there is a 21-fold increase in B beta 1-42 levels. The potentiation of fibrinogenolysis in the presence of fibrin is mediated by soluble fibrin degradation products because (a) the extent of t-PA induced fibrinogenolysis and clot lysis are directly related, (b) once clot lysis has been initiated, fibrinogenolysis continues even after the clot is removed, and (c) lysates of cross-linked fibrin clots potentiate t-PA-mediated fibrinogenolysis. Fibrin degradation products stimulate fibrinogenolysis by binding t-PA and plasminogen because approximately 70% of the labeled material in the clot lysates binds to both t-PA- and plasminogen-Sepharose, and only the bound fractions have potentiating activity. The binding site for t-PA and plasminogen is on the E domain because characterization of the potentiating fragments using gel filtration followed by PAGE and immunoblotting indicates that the major species is (DD)E complex, whereas minor components include high-molecular weight derivatives containing the (DD)E complex and fragment E. In contrast, D-dimer is the predominant species found in the fractions that do not bind to the adsorbants, and it has no potentiating activity. Thus, soluble products of t-PA-induced lysis of cross-linked fibrin potentiate t-PA-mediated fibrinogenolysis by providing a surface for t-PA and plasminogen binding thereby promoting plasmin generation. The occurrence of this phenomenon after therapeutic thrombolysis may explain the limited clot selectivity of t-PA.

Human tissue-type plasminogen activator releases fibrinopeptides A and B from fibrinogen.

In five patients with venous thromboembolic disease treated with recombinant tissue-type plasminogen activator (rt-PA), there was a marked increase in the mean concentrations of fibrinopeptide A (from 0.6 to 5.9 nM; P less than 0.0001) and desarginine fibrinopeptide B (from 5.6 nM to 24.1 nM; P less than 0.01) 30 min after a bolus of rt-PA (0.6 mg/kg). Thrombin was unlikely to be responsible because the levels of desarginine fibrinopeptide B exceeded those of fibrinopeptide A and the changes occurred despite concomitant heparin therapy. The purpose of this study therefore, was to determine whether rt-PA directly releases the fibrinopeptides from fibrinogen. Incubation of rt-PA with heparinized plasma or purified fibrinogen resulted in time and dose-dependent release of both fibrinopeptide A and B. Contaminating thrombin was not responsible for this activity by the following criteria: the rate of rt-PA mediated fibrinopeptide B release was considerably faster than that of fibrinopeptide A, and fibrinopeptide release was unaffected by heparin, hirudin, or a monospecific antithrombin IgG. Aprotinin also had no effect on fibrinopeptide release, indicating that this activity was not plasmin mediated. Fibrinopeptide release was shown to be due to rt-PA because this activity was completely blocked by a monoclonal antibody against the enzyme. Further, the specificity of rt-PA for the thrombin cleavage sites on fibrinogen was confirmed by the demonstration that rt-PA released fibrinopeptide A or fibrinopeptide B from fibrinopeptide A or B-containing substrates, respectively. These studies thus demonstrate that (a) rt-PA releases fibrinopeptides A and B from fibrinogen thereby indicating that this enzyme is not specific for plasminogen, and (b) plasma fibrinopeptide A and desarginine fibrinopeptide B levels are not specific markers of thrombin action on fibrinogen in patients receiving rt-PA.

A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement.

BACKGROUND: LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development. OBJECTIVES: The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin. METHODS: In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint. RESULTS: Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients. CONCLUSIONS: Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.

An Overview of Heart Rate Variability Metrics and Norms.

Healthy biological systems exhibit complex patterns of variability that can be described by mathematical chaos. Heart rate variability (HRV) consists of changes in the time intervals between consecutive heartbeats called interbeat intervals (IBIs). A healthy heart is not a metronome. The oscillations of a healthy heart are complex and constantly changing, which allow the cardiovascular system to rapidly adjust to sudden physical and psychological challenges to homeostasis. This article briefly reviews current perspectives on the mechanisms that generate 24 h, short-term (~5 min), and ultra-short-term (<5 min) HRV, the importance of HRV, and its implications for health and performance. The authors provide an overview of widely-used HRV time-domain, frequency-domain, and non-linear metrics. Time-domain indices quantify the amount of HRV observed during monitoring periods that may range from ~2 min to 24 h. Frequency-domain values calculate the absolute or relative amount of signal energy within component bands. Non-linear measurements quantify the unpredictability and complexity of a series of IBIs. The authors survey published normative values for clinical, healthy, and optimal performance populations. They stress the importance of measurement context, including recording period length, subject age, and sex, on baseline HRV values. They caution that 24 h, short-term, and ultra-short-term normative values are not interchangeable. They encourage professionals to supplement published norms with findings from their own specialized populations. Finally, the authors provide an overview of HRV assessment strategies for clinical and optimal performance interventions.

Once versus twice daily aspirin after coronary bypass surgery: a randomized trial.

Essentials Coronary artery bypass graft (CABG) failure is associated with myocardial infarction and death. We tested whether more frequent dosing improves aspirin (ASA) response following CABG surgery. Twice-daily compared with once-daily dosing reduces ASA hyporesponsiveness after CABG surgery. The efficacy of twice-daily ASA needs to be tested in a trial powered for clinical outcomes. SUMMARY: Background Acetyl-salicylic acid (ASA) hyporesponsiveness occurs transiently after coronary artery bypass graft (CABG) surgery and may compromise the effectiveness of ASA in reducing thrombotic graft failure. A reduced response to ASA 81 mg once-daily after CABG surgery is overcome by four times daily ASA dosing. Objectives To determine whether ASA 325 mg once-daily or 162 mg twice-daily overcomes a reduced response to ASA 81 mg once-daily after CABG surgery. Methods Adults undergoing CABG surgery were randomized to ASA 81 mg once-daily, 325 mg once-daily or 162 mg twice-daily. The primary outcome was median serum thromboxane B2 (TXB2 ) level on postoperative day 4. We pooled the results with those of our earlier study to obtain better estimates of the effect of ASA 325 mg once-daily or in divided doses over 24 h. Results We randomized 68 patients undergoing CABG surgery. On postoperative day 4, patients randomized to receive ASA 81 mg once-daily had a median day 4 TXB2 level of 4.2 ng mL-1 (Q1, Q3: 1.5, 7.5 ng mL-1 ), which was higher than in those randomized to ASA 162 mg twice-daily (1.1 ng mL-1 ; Q1, Q3: 0.7, 2.7 ng mL-1 ) and similar to those randomized to ASA 325 mg once-daily (1.9 ng mL-1 ; Q1, Q3: 0.9, 4.7 ng mL-1 ). Pooled data showed that the median TXB2 level on day 4 in groups receiving ASA 162 mg twice-daily or 81 mg four times daily was 1.1 ng mL-1 compared with 2.2 ng mL-1 in those receiving ASA 325 mg once-daily. Conclusions Multiple daily dosing of ASA is more effective than ASA 81 mg once-daily or 325 mg once-daily at suppressing serum TXB2 formation after CABG surgery. A twice-daily treatment regimen needs to be tested in a clinical outcome study.

Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation.

Chronic inflammation is a characteristic of post-traumatic stress disorder (PTSD). The initiation of inflammation and molecules involved are not yet clearly understood. Here, we provide compelling evidence that the inflammation seen in PTSD may result from the dysregulated miRNA processing pathway. Using microarray analysis with a discovery group of peripheral blood mononuclear cell (PBMC) samples from War Veterans with PTSD, we found 183 significantly downregulated miRNAs, several of which target numerous genes categorized to be pro-inflammatory in nature. This observation was further confirmed in a replicate group by including more samples. Furthermore, employing RNA-sequencing, quantitative real time PCR (qRT-PCR) and in vitro experiments, we found that Argonaute 2 (AGO2) and Dicer1 (DCR1) were downregulated in PTSD and provided convincing evidence that their downregulation affects mature miRNA generation. In addition, we noted that STAT3 transcript was reduced in PTSD and this was possibly responsible for reduced AGO2 and DCR1, which in turn affected miRNA synthesis. Furthermore, we observed that activation of CD4+ T cells or monocytes led to reduced mature miRNA availability. Finally, the inflammation seen in PTSD was associated with downregulated miRNA profile. Altogether, the current study demonstrates that the chronic inflammation seen in PTSD may be a result of dysregulated miRNA biogenesis pathway due to diminished expression of the key molecules like AGO2, DCR1 and STAT3.

A review of upper extremity deep vein thrombosis in pregnancy: unmasking the 'ART' behind the clot.

BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) is uncommon and is associated with well-defined risk factors in the general population. Increasingly, UEDVTs are being reported during pregnancy, particularly those achieved with the use of assisted reproductive techniques (ART), and in conjunction with ovarian hyperstimulation syndrome (OHSS). AIM: We performed this review was to estimate the incidence of UEDVT associated with ART, to examine the risk factors and presentation of UEDVT in pregnancy, and to determine if differences exist between this cohort and the general population. RESULTS: There were 35 published case reports of UEDVT in pregnant women. The incidence of this condition is estimated to be 0.08-0.11% of treatment cycles in women undergoing ART. The development of UEDVT is not always be preceded by OHSS. In addition, commonly associated risk factors for UEDVT were not often reported for UEDVT that developed during pregnancy. Instead the association of UEDVT and ART was common. UEDVT in pregnancy also appears to involve the internal jugular vein more often than the subclavian vein. The reported risk of thrombus extension in this cohort, despite anticoagulation therapy, is also disconcerting. CONCLUSION: Because UEDVT may not be a rare entity during pregnancy in association with the use of ART, clinicians should be better informed of its presentation and clinical course in these women. Once UEDVT develops, appropriate therapeutic anticoagulation should be instituted and patient carefully monitored. The long-term implications and recurrence rate of this condition in pregnancy warrants further prospective studies.