Vincent Mysliwiec

Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study

BACKGROUND AND PURPOSE Restless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleep and has been associated with iron deficiency. The purpose of this study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement. PATIENTS AND METHODS This was a randomized, placebo-controlled, double-blinded study. Eligible patients were randomized to oral iron therapy vs. appearance-matched placebo and followed over a 12 week period. RESULTS Baseline International Restless Leg Scale (IRLS) scores for the treatment (24.8+/-5.72) and placebo (23.0+/-5.03) groups were similar. Baseline ferritin levels for the treatment (40.6+/-15.3ng/ml) and placebo (36.7+/-20.8ng/ml) groups were also similar. After 12 weeks, IRLS scores decreased more in the treatment arm (10.3+/-7.40) than in the placebo arm (1.14+/-5.64), (p=0.01). Ferritin levels increased more in the treatment arm (25.1+/-20.3ng/ml) than in the placebo arm (7.5+/-13.7ng/ml), (p=0.04). We observed a nonsignificant trend toward improved quality of life in the treated patients, (p=0.07). CONCLUSIONS This is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The findings from this study suggest that additional larger randomized placebo-controlled trials of iron as treatment for patients with low-normal ferritin are warranted.

Prevalence and Impact of Short Sleep Duration in Redeployed OIF Soldiers

STUDY OBJECTIVES Short sleep duration (SSD) is common among deployed soldiers. The prevalence of SSD during redeployment, however, is unknown. DESIGN Cross-sectional study of a brigade combat team (n = 3152 US Army soldiers) surveyed 90-180 days after completing a 6-15 month deployment to Iraq as part of Operation Iraqi Freedom (OIF). Survey items targeted sleep habits and comorbid medical conditions. Multivariate logistic regression analyses were performed to calculate adjusted odds ratios of medical comorbidities associated with SSD. SETTING US Army Infantry Post. SUBJECTS All soldiers from a redeploying brigade combat team participated in a health assessment between 90 and 180 days upon return to Ft. Lewis from Iraq. INTERVENTIONS None. MEASUREMENTS AND RESULTS A total of 2738 (86.9%) soldiers answered questions regarding self-perceived sleep and were included in the analysis. Mean sleep duration was 5.8 ± 1.2 hours. Nineteen hundred fifty-nine (72%) slept ≤ 6 h, but only 16% reported a daytime nap or felt their job performance was affected due to lack of sleep. Short sleep was more common among soldiers who reported combat exposure. After controlling for combat exposure, short sleep duration (SSD) was associated with symptoms of depression, posttraumatic stress disorder, panic syndrome, and with high-risk health behaviors such as abuse of tobacco and alcohol products, and suicide attempts. CONCLUSIONS SSD is common among redeployed soldiers. Soldiers who experienced combat are at increased risk for persistent SSD and comorbidities associated with SSD. Efforts to reestablish good sleep habits and aggressive evaluation of soldiers with persistent SSD following deployment may aid in the prevention and management of associated medical conditions.

Sleep disorders and associated medical comorbidities in active duty military personnel.

STUDY OBJECTIVES Describe the prevalence of sleep disorders in military personnel referred for polysomnography and identify relationships between demographic characteristics, comorbid diagnoses, and specific sleep disorders. DESIGN Retrospective cross-sectional study. SETTING Military medical treatment facility. PARTICIPANTS Active duty military personnel with diagnostic polysomnogram in 2010. MEASUREMENTS Primary sleep disorder rendered by review of polysomnogram and medical record by a board certified sleep medicine physician. Demographic characteristics and conditions of posttraumatic stress disorder (PTSD), mild traumatic brain injury (mTBI), anxiety, depression, and pain syndromes determined by medical record review. RESULTS Primary sleep diagnoses (n = 725) included: mild obstructive sleep apnea (OSA), 207 (27.2%); insomnia, 188 (24.7%); moderate-to-severe OSA, 183 (24.0 %); and paradoxical insomnia,39 (5.1%); behaviorally induced insufficient sleep syndrome, 68 (8.9%) and snoring, 40 (5.3%) comprised our control group. Short sleep duration (< 5 h) was reported by 41.8%. Overall 85.2% had deployed, with 58.1% having one or more comorbid diagnoses. Characteristics associated with moderate-to-severe OSA were age (adjusted odds ratio [OR], 1.03 [95% confidence interval {CI}, 1.0-1.05], sex (male) (adjusted OR, 19.97 [95% CI, 2.66-150.05], anxiety (adjusted OR, 0.58 [95% CI, 0.34-0.99]), and body mass index, BMI (adjusted OR 1.19 [95% CI, 1.13-1.25]; for insomnia, characteristics included PTSD (adjusted OR, 2.12 [95% CI, 1.31-3.44]), pain syndromes (adjusted OR, 1.48 [95%CI, 1.01-2.12]), sex (female) (adjusted OR, 0.22 [95% CI, 0.12-0.41]) and lower BMI (adjusted OR, 0.91 [95% CI, 0.87, 0.95]). CONCLUSIONS Service-related illnesses are prevalent in military personnel who undergo polysomnography with significant associations between PTSD, pain syndromes, and insomnia. Despite having sleep disorders, almost half reported short sleep duration. Multidisciplinary assessment and treatment of military personnel with sleep disorders and service-related illnesses are required. CITATION Mysliwiec V; McGraw L; Pierce R; Smith P; Trapp B; Roth BJ. Sleep disorders and associated medical comorbidities in active duty military personnel. SLEEP 2013;36(2):167-174.

Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment.

IMPORTANCE Approximately one-third of military personnel who deploy for combat operations sustain 1 or more traumatic brain injuries (TBIs), which increases the risk for chronic symptoms of postconcussive disorder, posttraumatic stress disorder, and depression and for the development of chronic traumatic encephalopathy. Elevated concentrations of tau are observed in blood shortly following a TBI, but, to our knowledge, the role of tau elevations in blood in the onset and maintenance of chronic symptoms after TBI has not been investigated. OBJECTIVES To assess peripheral tau levels in military personnel exposed to TBI and to examine the relationship between chronic neurological symptoms and tau elevations. DESIGN, SETTING, AND PARTICIPANTS Observational assessment from September 2012 to August 2014 of US military personnel at the Madigan Army Medical Center who had been deployed within the previous 18 months. Plasma total tau concentrations were measured using a novel ultrasensitive single-molecule enzyme-linked immunosorbent assay. Classification of participants with and without self-reported TBI was made using the Warrior Administered Retrospective Casualty Assessment Tool. Self-reported symptoms of postconcussive disorder, posttraumatic stress disorder, and depression were determined by the Neurobehavioral Symptom Inventory, the Posttraumatic Stress Disorder Checklist Military Version, and the Quick Inventory of Depressive Symptomatology, respectively. Group differences in tau concentrations were determined through analysis of variance models, and area under the receiver operating characteristic curve determined the sensitivity and specificity of tau concentrations in predicting TBI and chronic symptoms. Seventy participants with self-reported TBI on the Warrior Administered Retrospective Casualty Assessment Tool and 28 control participants with no TBI exposure were included. MAIN OUTCOMES AND MEASURES Concentration of total tau in peripheral blood. RESULTS Concentrations of plasma tau were significantly elevated in the 70 participants with self-reported TBI compared with the 28 controls (mean [SD], 1.13 [0.78] vs 0.63 [0.48] pg/mL, respectively; F1,97 = 4.97; P = .03). Within the self-reported TBI cases, plasma total tau concentrations were significantly associated with having a medical record of TBI compared with self-reported TBI only (mean [SD], 1.57 [0.92] vs 0.85 [0.52] pg/mL, respectively; F1,69 = 6.15; P = .02) as well as reporting the occurrence of 3 of more TBIs during deployment compared with fewer than 3 TBIs (mean [SD], 1.52 [0.82] vs 0.82 [0.60] pg/mL, respectively; F1,69 = 8.57; P = .008). The severity of total postconcussive symptoms correlated with total tau concentrations in the self-reported TBI group (r = 0.37; P = .003). CONCLUSIONS AND RELEVANCE Military personnel who report multiple TBIs have long-term elevations in total tau concentration. The total tau concentration relates to symptoms of postconcussive disorder.

Sleep Disorders in US Military Personnel: A High Rate of Comorbid Insomnia and Obstructive Sleep Apnea

BACKGROUND Sleep disturbances are among the most common symptoms of military personnel who return from deployment. The objective of our study was to determine the presence of sleep disorders in US military personnel referred for evaluation of sleep disturbances after deployment and examine associations between sleep disorders and service-related diagnoses of depression, mild traumatic brain injury, pain, and posttraumatic stress disorder (PTSD). METHODS This was a cross-sectional study of military personnel with sleep disturbances who returned from combat within 18 months of deployment. Sleep disorders were assessed by clinical evaluation and polysomnogram with validated instruments to diagnose service-related illnesses. RESULTS Of 110 military personnel included in our analysis, 97.3% were men (mean age, 33.6 ± 8.0 years; mean BMI, 30.0 ± 4.3 kg/m2), and 70.9% returned from combat within 12 months. Nearly one-half (47.3%) met diagnostic criteria for two or more service-related diagnoses. Sleep disorders were diagnosed in 88.2% of subjects; 11.8% had a normal sleep evaluation and served as control subjects. Overall, 62.7% met diagnostic criteria for obstructive sleep apnea (OSA) and 63.6% for insomnia. The exclusive diagnoses of insomnia and OSA were present in 25.5% and 24.5% of subjects, respectively; 38.2% had comorbid insomnia and OSA. Military personnel with comorbid insomnia and OSA were significantly more likely to meet criteria for depression (P < .01) and PTSD (P < .01) compared with control subjects and those with OSA only. CONCLUSIONS Comorbid insomnia and OSA is a frequent diagnosis in military personnel referred for evaluation of sleep disturbances after deployment. This diagnosis, which is difficult to treat, may explain the refractory nature of many service-related diagnoses.

Usability and Feasibility of Smartphone Video Capabilities for Telehealth Care in the U.S. Military

The two-way audio/visual capabilities on the latest smartphone platforms bring new possibilities for the delivery of healthcare services to users. Because this technology is so new, the feasibility and the basic usability of the technology need to be evaluated before more research is conducted on its application in the telehealth field. The purpose of this study was to conduct preliminary usability testing of smartphone two-way video capabilities for potential telehealth use for U.S. military service members. Seven service member volunteers communicated with research staff at a large military installation via Apples (Cupertino, CA) FaceTime® app on the iPhone® 4 smartphone platform and conducted basic usability testing of the technology. Preferences for potential use of the technology were also assessed. The results showed that the technology has both limitations as well as potential for telehealth applications that warrant additional research.

Lower health related quality of life in U.S. military personnel is associated with service-related disorders and inflammation

Military personnel who have combat exposures are at increased risk for the service-related disorders of post-traumatic stress disorder (PTSD), depression, sleep disturbances and decreased health related quality of life (HRQOL). Those with a traumatic brain injury (TBI) are at even greater risk. Inflammation is associated with these disorders and may underlie the risk for health declines. We evaluated 110 recently deployed, military personnel presenting with sleep disturbances for service-related disorders (TBI, PTSD, and depression) as well as HRQOL. ANOVA models were used to examine differences among military personnel with two or more service-related disorders (high comorbid group), or one or no disorders (low comorbid group). Logistic regression models were used to determine associations among interleukin-6 (IL-6) to HRQOL and service-related disorders. Approximately one-third of the sample had two or more service-related disorders. HRQOL was lower and IL-6 concentrations were higher in military personnel with PTSD or depression, with the most profound differences in those with more service-related disorders, regardless of sleep disorder. Having symptoms of depression and PTSD resulted in a 3.5-fold risk to be in the lower quartile of HRQOL and the highest quartile of IL-6. In a linear regression model, 41% of the relationship between HRQOL and IL-6 concentrations was mediated by PTSD and depression. Military personnel with PTSD and depression are at high risk for lower HRQOL, and higher IL-6 concentrations. Comprehensive treatment is required to address co-occurring service-related disorders in military personnel to promote health and well-being.

Improved Sleep Quality is Associated with Reductions in Depression and PTSD Arousal Symptoms and Increases in IGF-1 Concentrations.

STUDY OBJECTIVES One-third of deployed military personnel will be diagnosed with insomnia, placing them at high risk for comorbid depression, posttraumatic stress disorder (PTSD), and medical conditions. The disruption of trophic factors has been implicated in these comorbid conditions, which can impede postdeployment recovery. This study determined if improved sleep quality is associated with (1) reductions in depression and posttraumatic symptoms, as well as enrichments in health-related quality of life (HRQOL), and (2) changes in plasma concentrations of brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). METHODS Forty-four military personnel diagnosed with insomnia underwent clinical evaluations and blood draws at pretreatment and at posttreatment following cognitive behavioral therapy for insomnia and automatic positive airway pressure treatment. Participants were classified as sleep improved (n = 28) or sleep declined (n = 16) based on their change in pretreatment to posttreatment Pittsburgh Sleep Quality Index (PSQI) score. Both groups were compared on outcomes of depression, PTSD, HRQOL, BDNF, and IGF-1. RESULTS Paired t-tests of the sleep improved group revealed significant declines in depression (p = 0.005) and posttraumatic arousal (p = 0.006) symptoms, and a significant increase in concentrations of IGF-1 (p = 0.009). The sleep declined group had no relevant change in psychiatric symptoms or trophic factors, and had further declines on five of eight dimensions of HRQOL. Between-group change score differences were significant at p < 0.05. CONCLUSIONS These findings suggest that interventions, which successfully improve sleep quality, are an effective means to reduce the depression and posttraumatic arousal symptoms common to military personnel, as well as increase protective trophic factors implicated in these conditions.

Use of a protocolized approach to the management of sepsis can improve time to first dose of antibiotics

PURPOSE The Surviving Sepsis Guidelines established recommendations for early recognition and rapid treatment of patients with sepsis. Recognizing systemic difficulties that delayed the application of early goal-directed therapy, the Emergency Department and Critical Care leadership instituted a sepsis protocol to identify patients with sepsis and expedite antibiotic delivery. We aimed to determine if the sepsis protocol improved the time to first dose of antibiotics in patients diagnosed with sepsis. MATERIALS AND METHODS We performed a retrospective chart review of patients with sepsis comparing the time from antibiotic order placement to the first dose of antibiotic therapy over a 3-year period. Patients who received vancomycin and ciprofloxacin underwent additional subgroup analysis, as these antibiotics were made available by protocol for use without infectious disease consultation. RESULTS The average time to first dose of antibiotics for the presepsis protocol group was 160 minutes, and the average time for the sepsis protocol group was 99 minutes. Fifty-eight patients received vancomycin, and 30 received ciprofloxacin, with a decrease in time of 65 minutes and 41 minutes, respectively. CONCLUSIONS Initiation of a sepsis protocol, which emphasizes early goal-directed therapy, can improve time to administration of first dose of antibiotics.

Improved Sleep in Military Personnel is Associated with Changes in the Expression of Inflammatory Genes and Improvement in Depression Symptoms

Study objectives Sleep disturbances are common in military personnel and are associated with increased risk for psychiatric morbidity, including posttraumatic stress disorder (PTSD) and depression, as well as inflammation. Improved sleep quality is linked to reductions in inflammatory bio-markers; however, the underlying mechanisms remain elusive. Methods In this study, we examine whole genome expression changes related to improved sleep in 68 military personnel diagnosed with insomnia. Subjects were classified into the following groups and then compared: improved sleep (n = 46), or non-improved sleep (n = 22) following three months of standard of care treatment for insomnia. Within subject differential expression was determined from microarray data using the Partek Genomics Suite analysis program and the ingenuity pathway analysis (IPA) was used to determine key regulators of observed expression changes. Changes in symptoms of depression and PTSD were also compared. Results At baseline, both groups were similar in demographics, clinical characteristics, and gene-expression profiles. The microarray data revealed that 217 coding genes were differentially expressed at the follow-up-period compared to baseline in the participants with improved sleep. Expression of inflammatory cytokines were reduced including IL-1β, IL-6, IL-8, and IL-13, with fold changes ranging from −3.19 to −2.1, and there were increases in the expression of inflammatory regulatory genes including toll-like receptors 1, 4, 7, and 8 in the improved sleep group. IPA revealed six gene networks, including ubiquitin, which was a major regulator in these gene-expression changes. The improved sleep group also had a significant reduction in the severity of depressive symptoms. Conclusion Interventions that restore sleep likely reduce the expression of inflammatory genes, which relate to ubiquitin genes and relate to reductions in depressive symptoms.