Childhood adversities and risk of posttraumatic stress disorder and major depression following a motor vehicle collision in adulthood.

AIMS: Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions. METHODS: Data came from n = 999 patients ages 18-75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect and bullying. Both dichotomous measures of ever experiencing each CA type and numeric measures of exposure frequency were included in the analysis. Risk ratios (RRs) of these CA measures as well as complex interactions among these measures were examined as predictors of APNS 3 months post-MVC. APNS was defined as meeting self-reported criteria for either PTSD based on the PTSD Checklist for DSM-5 and/or MDE based on the PROMIS Depression Short-Form 8b. We controlled for pre-MVC lifetime histories of PTSD and MDE. We also examined mediating effects through peritraumatic symptoms assessed in the emergency department and PTSD and MDE assessed in 2-week and 8-week follow-up surveys. Analyses were carried out with robust Poisson regression models. RESULTS: Most participants (90.9%) reported at least rarely having experienced some CA. Ever experiencing each CA other than emotional neglect was univariably associated with 3-month APNS (RRs = 1.31-1.60). Each CA frequency was also univariably associated with 3-month APNS (RRs = 1.65-2.45). In multivariable models, joint associations of CAs with 3-month APNS were additive, with frequency of emotional abuse (RR = 2.03; 95% CI = 1.43-2.87) and bullying (RR = 1.44; 95% CI = 0.99-2.10) being the strongest predictors. Control variable analyses found that these associations were largely explained by pre-MVC histories of PTSD and MDE. CONCLUSIONS: Although individuals who experience frequent emotional abuse and bullying in childhood have a heightened risk of experiencing APNS after an adult MVC, these associations are largely mediated by prior histories of PTSD and MDE.

Cannabidiol and refractory epilepsy: parental and caregiver perspectives of participation in a compassionate access scheme.

BACKGROUND: The Compassionate Access Scheme (CAS) being delivered through the Queensland Children's Hospital is designed to allow access to an investigational purified Cannabidiol oral solution to paediatric patients with severe refractory epilepsy. The objectives of this study were to conduct semi-structured interviews to: 1. Understand families' expectations and attitudes about the use of an investigational cannabinoid product for their child's seizures; 2. Understand families' perceptions of Cannabidiol's efficacy for their child's seizures; and other aspects of their child's behaviour, quality of life and/or cognition. METHODS: Children aged 2-18 years had been enrolled in, or were enrolled in a compassionate access scheme for Cannabidiol at the time of the study. Semi-structured interviews (n = 19) with parents or caregivers (n = 23) of children diagnosed with refractory epilepsy were voice-recorded, transcribed and analysed to generate common themes. RESULTS: Key themes emerged relating to seizure activity, family and school engagement, drug safety and legal access, efficacy, clinical support, social acceptance of the medication and program delivery. The use of Cannabidiol was perceived to have benefits in relation to reducing the severity and frequency of seizure activity for almost a third of patients experiencing refractory epilepsy. Participants described other benefits including improved social engagement, wakefulness and a reduction of side effects related to a reduction of conventional medication dosage. CONCLUSION: This study provided unique perspectives of families' experiences managing untreatable epilepsy, their experiences with conventional and experimental pharmacological treatments and health services. Whilst families' perceptions showed the use of Cannabidiol did not provide a therapeutic reduction in the seizure activity for all patients diagnosed with refractory epilepsy, it's use as an additional pharmacological agent was perceived to provide other benefits by some patient families.

Correlates of 1-Year Change in Quality of Life in Patients with Urologic Chronic Pelvic Pain Syndrome: Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

PURPOSE: We evaluated and identified baseline factors associated with change in health related quality of life among patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 191 men and 233 women with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome (collectively referred to as urologic chronic pelvic pain syndrome) were followed for 12 months with bimonthly completion of the Short Form 12 to assess general mental and physical health related quality of life, and with biweekly assessment of condition specific health related quality of life using the Genitourinary Pain Index. A functional clustering algorithm was used to classify participants as improved, stable or worsened for each health related quality of life measure. Ordinal logistic regression was used to determine baseline factors associated with change. RESULTS: Physical health related quality of life improved in 22% of the participants, mental health related quality of life improved in 25% and condition specific health related quality of life improved in 47%. Better baseline physical health related quality of life, older age and the presence of nonurological symptoms were associated with lower likelihood of improvement in physical health related quality of life. Better baseline mental health related quality of life, female sex, and greater baseline depression and stress were associated with a lower likelihood of improvement in mental health related quality of life. Better baseline condition specific health related quality of life and more severe baseline urologic chronic pelvic pain syndrome pain symptoms were associated with a lower likelihood of improvement in condition specific health related quality of life. CONCLUSIONS: While several nonurologic chronic pelvic pain syndrome factors influenced the trajectory of general health related quality of life over time, only condition specific baseline health related quality of life and urologic chronic pelvic pain syndrome symptoms were associated with urologic chronic pelvic pain syndrome specific health related quality of life change. Significant differences in how urologic chronic pelvic pain syndrome impacts various aspects of health related quality of life suggest a multidisciplinary approach to assessment and treatment of these patients.

Altered fMRI resting-state connectivity in individuals with fibromyalgia on acute pain stimulation.

BACKGROUND: Fibromyalgia is a chronic widespread pain condition, with patients commonly reporting other symptoms such as sleep difficulties, memory complaints and fatigue. The use of magnetic resonance imaging (MRI) in fibromyalgia has allowed for the detection of neural abnormalities, with alterations in brain activation elicited by experimental pain and alterations in resting state connectivity related to clinical pain. METHODS: In this study, we sought to monitor state changes in resting brain connectivity following experimental pressure pain in fibromyalgia patients and healthy controls. Twelve fibromyalgia patients and 15 healthy controls were studied by applying discrete pressure stimuli to the thumbnail bed during MRI. Resting-state functional MRI scanning was performed before and immediately following experimental pressure pain. We investigated changes in functional connectivity to the thalamus and the insular cortex. RESULTS: Acute pressure pain increased insula connectivity to the anterior cingulate and the hippocampus. Additionally, we observed increased thalamic connectivity to the precuneus/posterior cingulate cortex, a known part of the default mode network, in patients but not in controls. This connectivity was correlated with changes in clinical pain. CONCLUSIONS: These data reporting changes in resting-state brain activity following a noxious stimulus suggest that the acute painful stimuli may contribute to the alteration of the neural signature of chronic pain. WHAT DOES THIS STUDY/ADD?: In this study acute pain application shows an echo in functional connectivity and clinical pain changes in chronic pain.

Resting state connectivity correlates with drug and placebo response in fibromyalgia patients.

Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response. We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition. 15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex. This study indicates that ACC-IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response.

Functional interaction between medial thalamus and rostral anterior cingulate cortex in the suppression of pain affect.

The medial thalamic parafascicular nucleus (PF) and the rostral anterior cingulate cortex (rACC) are implicated in the processing and suppression of the affective dimension of pain. The present study evaluated the functional interaction between PF and rACC in mediating the suppression of pain affect in rats following administration of morphine or carbachol (acetylcholine agonist) into PF. Vocalizations that occur following a brief noxious tailshock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by injection of morphine or carbachol into PF. Vocalizations that occur during tailshock were suppressed to a lesser degree, whereas, spinal motor reflexes (tail flick and hindlimb movements) were only slightly suppressed by injection of carbachol into PF and unaffected by injection of morphine into PF. Blocking glutamate receptors in rACC (NMDA and non-NMDA) by injecting D-2-amino-5-phosphonovalerate (AP-5) or 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) produced dose-dependent antagonism of morphine-induced increases in vocalization thresholds. Carbachol-induced increases in vocalization thresholds were not affected by injection of either glutamate receptor antagonist into rACC. The results demonstrate that glutamate receptors in the rACC contribute to the suppression of pain affect produced by injection of morphine into PF, but not to the suppression of pain affect generated by intra-PF injection of carbachol.

Honeycomb cysts in idiopathic pulmonary haemosiderosis: high-resolution CT appearances in two adults.

Idiopathic pulmonary haemosiderosis (IPH) is characterized by recurrent episodes of pulmonary haemorrhage. The disease predominates in childhood, with approximately 20% of patients presenting in adulthood. Most patients present with dyspnoea, fatigue and recurrent haemoptysis, resulting in iron deficiency anaemia. High-resolution CT manifestations of IPH include patchy or diffuse ground glass opacity and consolidation resulting from alveolar haemorrhage. We describe a new high-resolution CT finding in two adults with IPH - multiple honeycomb cysts, which were characteristically focal and localized predominantly to the posterior and lateral basal segments. We suggest that the development of honeycombing in patients with IPH is a traction phenomenon resulting from recurrent haemosiderin deposition in the interstitium, which is known to lead to progressive fibrosis. These honeycomb cysts may indicate the sites of the most severe and recurrent alveolar haemorrhage in adults with IPH.

Achievable outcomes in the management of proximal cholangiocarcinoma: an update prepared using "evidence-based practice" techniques.

BACKGROUND: The purpose of this study is to evaluate recently reported outcomes for treatment options for proximal cholangiocarcinoma (CCA). MATERIALS AND METHODS: Standard evidence based practice techniques were used to formulate a question, search, appraise and evaluate the retrieved literature. Our question was "In patients with CCA, how do stenting alone, stenting in addition to brachytherapy (BT) or photodynamic therapy (PDT), resection and orthotopic liver transplantation with neoadjuvant chemoradiation (OLT) compare for long-term survival? RESULTS: Level 1b survival data was available for stenting alone (179 days), BT and metal stenting (388 days) and PDT with plastic stenting (493 days) and no survival difference was evident with metal vs. plastic stenting or unilateral vs. bilateral stenting. Five year survival data (level 3) was available for OLT (80%), formally curative trisegmentectomy with or without portal vein resection (72% and 52%) and hepatectomy (18%-23%). CONCLUSION: All patients with proximal CCA should be reviewed by a multidisciplinary team to determine appropriate treatment. For unresectable CCA, patients should be assessed for OLT with neoadjuvant chemoradiation, while those who are unsuitable would appear to have the longest survival with PDT. Extended resection in operable candidates may improve survival over right or left hepatectomy but increased perioperative mortality is a consideration.

Influence of posture on the incidence of vein cannulation during epidural catheter placement.

BACKGROUND AND OBJECTIVE: Epidural vein cannulation has long been recognized as a problem in parturients due to distension of epidural veins. Epidural vein engorgement is maximal when the pregnant woman is in the supine position and minimal in the lateral position. Following an initial observation of an apparently high incidence of epidural vein cannulation in the sitting position, a randomized trial was conducted to document whether such an association existed. METHODS: A total of 209 term parturients were randomized to either the sitting or lateral position (107 left lateral, 102 sitting). Epidural catheter placement was achieved using a loss of resistance to air technique with an 18-G Tuohy needle. A data sheet was completed for each patient recording patient position, patient characteristics data, stage in labour and the incidence of epidural vein cannulation. Poor labour analgesia was defined as a visual analogue scale (VAS) > 40 mm on a 0-100 mm pain intensity VAS. RESULTS: The risk of epidural vein cannulation was significantly higher in the sitting group (16 of 102 = 15.7%) compared with the lateral position group (4 of 107 = 3.7%), P = 0.011. There was a significant association between epidural vein cannulation and poor analgesia (P = 0.006). These two variables remained independently significant on multiple regression analysis (position, P = 0.009; analgesia, P = 0.006). CONCLUSIONS: We conclude that there is a direct correlation between the incidence of epidural vein cannulation and patient posture during epidural catheter insertion in parturients.

The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam.

Midazolam is a commonly used anaesthetic agent and is metabolised by the 3A4 isoform of the cytochrome P450 enzyme system. Atorvastatin is also metabolised by cytochrome P450 3A4 and, in vitro, atorvastatin inhibits the cytochrome P450 3A4-mediated metabolism of mexazolam. We hypothesised that concurrent administration of atorvastatin and midazolam would result in altered midazolam pharmacokinetics. Fourteen patients scheduled to undergo general anaesthesia for elective surgery were recruited in a matched pair design to receive intravenous midazolam (0.15 mg.kg-1). Of these patients, seven were taking long-term atorvastatin. Atorvastatin patients demonstrated a greater area under the curve (889.4 (standard deviation 388.6) ng-h.ml-1) vs. control patients (629.1 (standard deviation 197.2) ng-h.ml-1) (p < 0.05). Patients taking atorvastatin also demonstrated a decreased clearance (0.18 (standard deviation 0.08) l-kg. h-1) vs. control patients (0.27 (standard deviation 0.08) l-kg.h-1) (p < 0.05). This study suggests that chronically administered atorvastatin decreases the clearance of intravenously administered midazolam.

Antinociceptive effects of morphine injected into the nucleus parafascicularis thalami of the rat.

The antinociceptive action of morphine microinjected into the nucleus parafascicularis thalami (nPf) on pain behaviors organized at different levels of the neuraxis was examined in the rat. Behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization afterdischarges, VADs) levels were elicited by noxious tailshock. Morphine administered into nPf generated dose-dependent increases in thresholds of VDS and VAD, but failed to elevate SMR thresholds. Increases in vocalization thresholds were reversed in a dose-dependent manner by the microinjection of the mu-opiate receptor antagonist, methylnaloxonium, into nPf. Results are discussed in terms of the relative influence of nPf-administered morphine on nociceptive processing at spinal versus supraspinal levels of the neuraxis.