The obstructive sleep apnoea endotypes are similar in elderly trauma-exposed veterans with and without diagnosed PTSD.

BACKGROUND: Approximately 60% of veterans living with posttraumatic stress disorder (PTSD) experience obstructive sleep apnoea (OSA). Why OSA is so prevalent in individuals with PTSD remains unknown, though PTSD may influence the underlying endotypes known to cause OSA. We examined whether these endotypes (upper airway collapsibility, muscle compensation, loop gain, and the arousal threshold) differ between those with comorbid OSA and PTSD relative to their counterparts with OSA-only. METHODS: Using the ventilatory flow pattern from diagnostic polysomnography, the OSA endotypes were measured in a retrospective cohort of 21 OSA patients with PTSD and 27 OSA-only patients. All participants were trauma exposed elderly male Australian Vietnam War veterans with mild-to-severe OSA (median Apnoea-Hypopnea index: 20.2 vs. 23.6 events/h). Age and BMI were similar between groups (70.7 vs. 71.7 years, and 28.4 vs. 28.4 kg/m2). RESULTS: There were no significant differences in the OSA endotype traits between PTSD + OSA and OSA-only patients for upper airway collapsibility (76.68 [71.53-83.56] vs. 78.35 [72.81-83.82] %Veupnea, median [IQR]), muscle compensation (4.27 [0.34-9.18] vs. 5.41 [1.83-7.21] %Veupnea), loop gain (0.56(0.17) vs. 0.60(0.14)), and arousal threshold (135.76 [126.59-147.54] vs. 146.95 [128.64-151.28] %Veupnea). CONCLUSION: The OSA endotypes in veterans with PTSD were similar to their trauma exposed OSA-only counterparts. PTSD appears to exert little influence on the OSA endotypes beyond the effect that age and trauma exposure may have. The aetiology of increased prevalence of OSA in PTSD remains unclear. Further work examining OSA endotypes using larger and more diverse samples is needed before robust conclusions can be made.

Posttraumatic sleep disturbances in veterans: A pilot randomized controlled trial of cognitive behavioral therapy for insomnia and imagery rehearsal therapy.

OBJECTIVES: Posttraumatic stress disorder (PTSD) is associated with sleep disturbances including insomnia and nightmares. This study compared cognitive behavioral therapy for insomnia (CBT-I) with CBT-I combined with imagery rehearsal therapy (IRT) for nightmares to evaluate if the combined treatment led to greater reductions in trauma-related sleep disturbances in Australian veterans. METHODS: Veterans with diagnosed PTSD, high insomnia symptom severity, and nightmares (N = 31) were randomized to eight group CBT-I sessions or eight group CBT-I + IRT sessions. Self-reported sleep, nightmare, and psychological measures (primary outcome: Pittsburgh Sleep Quality Index), and objective actigraphy data were collected; the effect of obstructive sleep apnea (OSA) risk on treatment outcomes was also examined. RESULTS: No treatment condition effects were detected for the combined treatment compared to CBT-I alone, and no moderating effect of OSA risk was detected. On average, participants from both groups improved on various self-report measures over time (baseline to 3 months posttreatment). Despite the improvements, mean scores for sleep-specific measures remained indicative of poor sleep quality. There were also no significant differences between the groups on the actigraphy indices. CONCLUSIONS: The findings indicate that there is potential to optimize both treatments for veterans with trauma-related sleep disturbances.

DNA methylation from germline cells in veterans with PTSD.

In this study we investigated genome-wide sperm DNA methylation patterns in trauma-exposed Vietnam veterans. At the genome-wide level, we identified 3 CpG sites associated with PTSD in sperm including two intergenic and one CpG within the CCDC88C gene. Of those associated with PTSD in sperm at a nominal level, 1868 CpGs were also associated with PTSD in peripheral blood (5.6% overlap) including the RORA, CRHR1 and DOCK2 genes that have been previously implicated in PTSD. A total of 10 CpG sites were significantly associated with a reported history of a diagnosed mental health condition in children and reached genome-wide significance. CpGs associated with a history of a reported mental health condition in children were also enriched (90% of tested genes) for genes previously reported to be resistant to demethylation, making them strong candidates for transgenerational inheritance. In conclusion, our findings identify a unique sperm-specific DNA methylation pattern that is associated with PTSD.

Comparison of Sleep Patterns in Vietnam Veterans With and Without Posttraumatic Stress Disorder Using Wrist Actigraphy.

STUDY OBJECTIVES: Disturbed sleep is a hallmark feature of posttraumatic stress disorder (PTSD). However, few studies have examined sleep objectively in individuals with PTSD compared to trauma-exposed controls. This study used wrist actigraphy to measure and compare sleep patterns in trauma-exposed Australian Vietnam veterans (VV) with and without PTSD. METHODS: Trauma-exposed Australian VV with and without PTSD were recruited from the PTSD Initiative. VV wore wrist accelerometers over 14 days and completed daily sleep diaries. Sleep parameters were compared between groups including sleep latency (SL), time in bed (TIB), total sleep time (TST), wake after sleep onset (WASO), and movement index (MI). Night-to-night and overall within-individual variability were assessed by root mean squared successive differences and comparison of individual standard deviations. Correlations between sleep diary (self-reported) and wrist actigraphy (objective) variables were also assessed. RESULTS: A total of 40 male VV (20 with PTSD) participated in the study. We found no difference in sleep patterns determined by wrist actigraphy between groups with the exception of reduced SL in VV with PTSD (3.9 ± 0.9 versus 4.9 ± 1.4 minutes, P < .05). Overall within-individual variability was significantly greater in VV with PTSD for TIB, TST, WASO, and MI. Self-reported and objective TST and WASO were more strongly correlated in VV without PTSD than those with PTSD. CONCLUSIONS: Although there were no significant differences in sleep parameters, VV with PTSD had increased within-individual overall sleep variability and reduced correlation between self-reported and objective sleep parameters compared to trauma-exposed controls. Further evaluation of extended sleep patterns by actigraphy in VV with PTSD is warranted.

Detailed Polysomnography in Australian Vietnam Veterans With and Without Posttraumatic Stress Disorder.

STUDY OBJECTIVES: Recent results from the PTSD Initiative, a cross-sectional cohort study in Australian Vietnam veterans (VV) with and without posttraumatic stress disorder (PTSD), demonstrated an increased prevalence of self-reported sleep disturbances in those with PTSD. This study aimed to objectively assess the prevalence of sleep disorders in the same cohort using detailed polysomnography (PSG). METHODS: Participants from the PTSD Initiative were recruited to undergo PSG. PTSD status was determined with the Clinician Administered PTSD Scale for DSM-5 (CAPS-5). Subjective sleep information was attained via structured questionnaires. Data from single night PSG were compared between trauma-exposed VV with and without PTSD. RESULTS: A total of 74 trauma-exposed male VV (40 with PTSD) underwent PSG (prospective n = 59, retrospective n = 15). All PSG parameters were similar between groups. No difference was seen in PSG-diagnosed obstructive sleep apnea (OSA) or periodic limb movements of sleep (PLMS). VV with PTSD showed a trend toward increased duration of sleep with oxygen saturations < 90% (10% versus 1.8%; P = .07). VV with PTSD reported increased sleep onset latency (42.4 versus 13.3 minutes; P < .01); were less likely to report sleeping well (32.5% versus 67.5%; P < .01); had higher OSA risk using Berlin Questionnaire (BQ) (70% versus 38.2%; P < .01); and had higher rates of partner-reported limb movements (56.4% versus 17.6%; P < .01). No association between PSG-diagnosed OSA and PTSD severity was evident. CONCLUSIONS: In Australian VV with and without PTSD, no difference was seen across all PSG parameters including the diagnosis and severity of OSA and PLMS. However, VV with PTSD demonstrated an increased perception of sleep disturbances.

Sleep Disturbances in Australian Vietnam Veterans With and Without Posttraumatic Stress Disorder.

STUDY OBJECTIVES: Posttraumatic stress disorder (PTSD) is a condition that may develop after a traumatic event, particularly combat-related trauma. Although sleep disturbance is a hallmark of PTSD, the prevalence of sleep disturbances in Australian veterans with PTSD remains uncertain. This study aimed to subjectively compare the prevalence of sleep disturbances in Australian Vietnam veterans with and without PTSD. METHODS: A cross-sectional cohort study compared trauma-exposed Australian Vietnam veterans with and without PTSD. PTSD diagnosis was confirmed using the Clinician Administered PTSD Scale for DSM-5. Sleep information was evaluated using supervised structured questionnaires, including Epworth Sleepiness Scale (ESS) and Berlin and Mayo Questionnaires. RESULTS: Two hundred fourteen male Vietnam veterans (108 with PTSD) were included. Participants with PTSD had higher body mass index (30.3 versus 29 kg/m2; P < .05), higher ESS score (9.2 versus 7.6; P < .05), and increased alcohol or medication use to assist with sleep (19% versus 6%; P < .01; and 44% versus 14%; P < .01). Those with PTSD were less likely to sleep well (32% versus 72%; P < .01) and reported higher rates of restless legs (45% versus 25%; P < .01), nightmares (91% versus 29%; P < .01), nocturnal screaming (73% versus 18%; P < .01), sleep terrors (61% versus 13%; P < .01) and dream enactment (78% versus 11.8%; P < .01). The PTSD group had higher rates of diagnosed OSA (42% versus 21%; P < .01) and an increased risk of OSA on the Berlin Questionnaire (69% versus 43%; P < .01). CONCLUSIONS: Compared to trauma-exposed controls, Australian Vietnam veterans with PTSD demonstrated an increased prevalence of a wide range of sleep disturbances, including OSA. In veterans with PTSD, detailed sleep assessment, including consideration of polysomnography, is paramount.

Increased risk of attempted suicide in Australian veterans is associated with total and permanent incapacitation, unemployment and posttraumatic stress disorder severity.

BACKGROUND: Military veterans have higher rates of suicidality and completed suicides compared to the general population. Previous research has demonstrated suicidal behaviour is higher in US combat veterans who are younger, suffer from posttraumatic stress disorder, depression and anxiety and score lower on measures of health. However, research on predictors of suicide for Australian veterans is limited. The aim of this study was to identify significant demographic and psychological differences between veterans with posttraumatic stress disorder who had attempted suicide and those with posttraumatic stress disorder who had not, as well as determine predictors of suicide attempts within an Australian cohort. METHODS: A retrospective analysis was conducted on 229 ex-service personnel diagnosed with posttraumatic stress disorder who had attended a Military Service Trauma Recovery Day Program as outpatients at Toowong Private Hospital from 2007 to 2014. Patients completed a battery of mental health self-report questionnaires assessing symptoms of posttraumatic stress disorder, alcohol use, anger, depression, anxiety and quality of life. Demographic information and self-reported history of suicide attempts were also recorded. RESULTS: Results indicated the average age was significantly lower, and the rates of posttraumatic stress disorder, anger, anxiety and depression symptoms were significantly higher in those veterans with history of a suicide attempt. Multivariate logistic regression analyses indicated posttraumatic stress disorder symptom severity, unemployment or total and permanent incapacity pension status significantly predicted suicide attempt history. CONCLUSION: Among a cohort of Australian veterans with posttraumatic stress disorder, psychopathology severity, unemployment and total and permanent incapacity status are significantly associated with suicidality. This study highlights the importance of early identification of posttraumatic stress disorder and psychopathology, therapeutic and social engagement, and prioritisation of tangible employment options or meaningful and goal-directed activities for veterans deemed unable to work.

Physical comorbidities of post-traumatic stress disorder in Australian Vietnam War veterans.

OBJECTIVE: To determine whether the prevalence of physical comorbidities in Australian Vietnam War veterans with post-traumatic stress disorder (PTSD) is higher than in trauma-exposed veterans without PTSD. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of the health status (based on self-reported and objective clinical assessments) of 298 Australian Vietnam War veterans enrolled by the Gallipoli Medical Research Institute (Brisbane) during February 2014 - July 2015, of whom 108 were confirmed as having had PTSD and 106 served as trauma-exposed control participants.Main outcomes and measures: Diagnostic psychiatric interview and psychological assessments determined PTSD status, trauma exposure, and comorbid psychological symptoms. Demographic data, and medical and sleep history were collected; comprehensive clinical examination, electrocardiography, spirometry, liver transient elastography, and selected pathology assessments and diagnostic imaging were performed. Outcomes associated with PTSD were identified; regression analysis excluded the effects of potentially confounding demographic and risk factors and comorbid symptoms of depression and anxiety. RESULTS: The mean total number of comorbidities was higher among those with PTSD (17.7; SD, 6.1) than in trauma-exposed controls (14.1; SD, 5.2; P < 0.001). For 24 of 171 assessed clinical outcomes, morbidity was greater in the PTSD group, including for conditions of the gastrointestinal, hepatic, cardiovascular, and respiratory systems, sleep disorders, and laboratory pathology measures. In regression analyses including demographic factors, PTSD remained positively associated with 17 adverse outcomes; after adjusting for the severity of depressive symptoms, it remained significantly associated with ten. CONCLUSION: PTSD in Australian Vietnam veterans is associated with comorbidities in several organ systems, independent of trauma exposure. A comprehensive approach to the health care of veterans with PTSD is needed.

Population pharmacokinetics of rabeprazole and dosing recommendations for the treatment of gastroesophageal reflux disease in children aged 1-11 years.

BACKGROUND AND OBJECTIVE: Rabeprazole sodium is a proton pump inhibitor used for the treatment of gastroesophageal reflux disease (GERD). The objective of this study was to develop a population pharmacokinetic model for rabeprazole that describes concentration-time data arising from phase I and phase III studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1-11 years. METHODS: A total of 4,417 pharmacokinetic observations from 597 subjects aged 6 days to 55.7 years with body weights of 1.15-100 kg were used to develop the population pharmacokinetic model using non-linear mixed-effects modeling techniques. Weight and age were included in the structural model to describe clearance (CL) and central volume of distribution (V c). Other covariates considered during model development included sex, race, creatinine clearance, hepatic function, formulation, feeding status, and route of administration. The final model was used to determine doses for pediatric subjects aged 1-11 years to achieve a steady-state area under the plasma concentration-time curve across the dose interval of 24 h (AUC24) within the target adult AUC24 range obtained following a rabeprazole 10 mg dose. RESULTS: The best model was a two-compartment disposition model with a sequential zero-order duration of input (Dur), first-order absorption (k a) following a lag time (T lag), with weight and age effects on CL and V c. Formulation type and feeding status described some of the variability in bioavailability and the absorption parameters T lag, Dur, and k a. A dosage regimen of 5 mg once daily for children <15 kg, and 10 mg for children ≥15 kg is recommended for 1- to 11-year-old pediatric patients with GERD. CONCLUSIONS: The pharmacokinetics of rabeprazole were described with good precision following administration of rabeprazole across a range of doses and in a range of formulations.

Population pharmacokinetics of bedaquiline (TMC207), a novel antituberculosis drug.

Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

Reporting a population pharmacokinetic-pharmacodynamic study: a journal's perspective.

The key purpose of performing pharmacometric research is to aid optimization of drug dosing strategies. The statistical techniques required for this research are advanced, which can make interpretation of results difficult to convey to the target audience if they are unfamiliar with pharmacometric concepts. This article provides a basic guide for authors who wish to publish pharmacometric analyses in peer-reviewed journals. This guide is intended to enhance the readability, reproducibility and understanding of the work for a general readership, which may include clinicians, pharmacists and pharmacometricians. Presentation techniques and examples are offered, as well as a checklist of suggested contents for the manuscript.

The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007.

BACKGROUND: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. AIM: The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. METHODS: Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a 'nonlinear' relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting 'other' relationships (e.g. linear increase in CL with TBW, ideal body weight or height). RESULTS: A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)(2/3), or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. CONCLUSIONS: To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.

Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice.

Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter-1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1-/- mice by gene disruption. These mice exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder. Sat1-/- mice also displayed hypersulfaturia, hyposulfatemia, and enhanced acetaminophen-induced liver toxicity. These data suggest that Sat1 regulates both oxalate and sulfate homeostasis and may be critical to the development of calcium oxalate urolithiasis and hepatotoxicity.

Encouraging the move towards predictive population models for the obese using propofol as a motivating example.

PURPOSE: To develop a predictive pharmacokinetic model for propofol that could inform development of a dosing strategy for the obese population. METHODS: A prior model that included a nonlinear relationship between clearance (CL) and Total Body Weight (TBW) was re-parameterized with a linear relationship between CL and Lean Body Weight (LBW). The predictive performance of both models was compared and the LBW model used to explore propofol exposure from normal to obese patients. A dosing strategy was evaluated that normalized awakening time across a range of patient weights. RESULTS: The predictive performance of the LBW model was similar to the nonlinear TBW model for normal weighted subjects. Simulations in 70-160 kg subjects indicated that dosing linearly on TBW (label recommendation), in contrast to LBW, resulted in increased plasma concentrations in the larger weight groups. This result might explain why obese subjects take longer to awaken from anesthesia compared to normal weighted subjects. Dosing by LBW normalized patient awakening times across this weight range. CONCLUSIONS: LBW as a covariate provides a plausible mechanistic explanation for an observed nonlinear increase in drug CL with TBW and may be suitable for developing dosing strategies that are appropriate for use in the obese population.