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Introduction: Prediction of pain using machine learning algorithms is an emerging field in both computer science and clinical medicine. Several machine algorithms were developed and validated in recent years. However, the majority of studies in this topic was published on bioinformatics or computer science journals instead of medical journals. This tendency and preference led to a gap of knowledge and acknowledgment between computer scientists who invent the algorithm and medical researchers who may use the algorithms in practice. As a consequence, some of these prediction papers did not discuss the clinical utility aspects and were causally reported without following related professional guidelines (e.g., TRIPOD statement). The aim of this protocol is to systematically summarize the current evidences about performance and utility of different machine learning methods used for automatic pain assessments based on human facial expression. In addition, this study is aimed to demonstrate and fill the knowledge gap to promote interdisciplinary collaboration., Methods and Analysis: We will search all English language literature in the following electronic databases: PubMed, Web of Science and IEEE Xplore. A systematic review and meta-analysis summarizing the accuracy, interpretability, generalizability, and computational efficiency of machine learning methods will be conducted. Subgroup analyses by machine learning method types will be conducted., Timeline: The formal meta-analysis will start on Jan 15, 2019 and expected to finish by April 15, 2019., Ethics and Dissemination: Ethical approval will be exempted or will not be required because the data collected and analyzed in this meta-analysis will not be on an individual level. The results will be disseminated in the form of an official publication in a peer-reviewed journal and/or presentation at relevant conferences., Registration: PROSPERO CRD42018103059.

Objective: The extent to which biomedical authors have received training in publication ethics, and their attitudes and opinions about the ethical aspects of specific behaviours, have been understudied. We sought to characterise the knowledge and attitudes of biomedical authors about common issues in publication ethics., Design: Cross-sectional online survey., Setting and Participants: Corresponding authors of research submissions to 20 journals., Main Outcome Measures: Perceived level of unethical behaviour (rated 0 to 10) presented in five vignettes containing key variables that were experimentally manipulated on entry to the survey and perceived level of knowledge of seven ethical topics related to publishing (prior publication, author omission, self-plagiarism, honorary authorship, conflicts of interest, image manipulation and plagiarism)., Results: 4043/10 582 (38%) researchers responded. Respondents worked in 100 countries and reported varying levels of publishing experience. 67% (n=2700) had received some publication ethics training from a mentor, 41% (n=1677) a partial course, 28% (n=1130) a full course and 55% (n=2206) an online course; only a small proportion rated training received as excellent. There was a full range (0 to 10 points) in ratings of the extent of unethical behaviour within each vignette, illustrating a broad range of opinion about the ethical acceptability of the behaviours evaluated, but these opinions were little altered by the context in which it occurred. Participants reported substantial variability in their perceived knowledge of seven publication ethics topics; one-third perceived their knowledge to be less than 'some knowledge' for the sum of the seven ethical topics and only 9% perceived 'substantial knowledge' of all topics., Conclusions: We found a large degree of variability in espoused training and perceived knowledge, and variability in views about how ethical or unethical scenarios were. Ethical standards need to be better articulated and taught to improve consistency of training across institutions and countries., Competing Interests: Competing interests: SS is a full-time employee of the BMJ Publishing Group and has access to all submission data and regularly undertakes research with its authors and reviewers. SM is a former employee of BMJ Publishing Group. EL receives salary support from The BMJ for her services as head of research. This is paid to her employing institution (the Brigham and Women’s Physician Organization). None of the authors work directly for BMJ Open or are involved in the decision-making process for articles submitted to BMJ Open. This paper was sent out for peer review in the usual way and treated in the same way as all submissions to the journal. TTH, JR and DBP have no relevant conflicts of interest., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Residual neuromuscular block (rNMB) after surgery is not difficult to identify if proper neuromuscular monitoring is used, but many clinicians do not use quantitative neuromuscular monitoring., Objective: The aim of this study was to develop a REsidual neuromuscular block Prediction Score (REPS) to predict postoperative rNMB and compare the predictive accuracy of the prediction score with train-of-four count (TOFC) measurement at the end of a surgical case., Design: Retrospective cohort study of data on file., Data Source: Electronic patient data and peri-operative data on vital signs, administered medications, and train-of-four ratio (TOFR) obtained in the postoperative recovery rooms [postanaesthesia care unit (PACU)] at Massachusetts General Hospital in Boston, Massachusetts, USA., Patients: Quantitative TOFR measurements obtained on admission to the PACU were available from 2144 adult noncardiac surgical patients., Main Outcome Measure: Presence of rNMB at PACU admission, defined as a TOFR of less than 0.9., Results: In the score development cohort (n=2144), rNMB occurred in 432 cases (20.2%). Ten independent predictors for residual paralysis were identified and used for the score development. The final model included: hepatic failure, neurological disease, high-neostigmine dose, metastatic tumour, female sex, short time between neuromuscular blocking agent administration and extubation, aminosteroidal neuromuscular blocking agent, BMI more than 35, absence of nurse anaesthetist and having an experienced surgeon. The model discrimination by C statistics was 0.63, 95% confidence interval (0.60 to 0.66), and risk categories derived from the REPS had a higher accuracy than the last documented intra-operative TOFC for predicting rNMB (net reclassification improvement score 0.26, standard error 0.03, P < 0.001)., Conclusion: The REPS can be used to identify patients at greater risk of rNMB. This tool may inform anaesthetists better than an intra-operative TOFC and thus enable peri-operative anaesthetic practices to be tailored to the patient and minimise the undesirable effects of rNMB., Trial Registry Number: Approved by Partners Human Research Committee (protocol number 2016P000940) at MGH in Boston, Massachusetts, USA on 25 April 2016.

We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.

Inappropriate dosing of neostigmine for antagonism of neuromuscular blockade has been associated with postoperative pulmonary complications. We evaluated the effects of a quality improvement initiative tailored to optimise the use of neostigmine in antagonising neuromuscular blockade on postoperative pulmonary complications, costs and duration of hospital stay. The quality improvement initiative consisted of: a reduction in available neostigmine aliquot sizes; a cognitive aid; an educational component; and a financial incentive for the intra-operative documentation of train-of-four measurement before administration of neostigmine. We conducted a pre-specified analysis of data obtained in our quality improvement study. Additional analyses were conducted in a propensity-matched cohort. An interrupted time series design was used to discriminate between the intervention and a counterfactual scenario. We analysed 12,025 consecutive surgical cases performed in 2015. Postoperative pulmonary complications occurred in 220 (7.5%) of 2937 cases pre-intervention and 568 (6.3%) of 9088 cases post-intervention. Adjusted regression analyses showed significantly a lower risk of postoperative pulmonary complications (OR 0.73 (95%CI 0.61-0.88); p = 0.001), lower costs (incidence rate ratio 0.95 (95%CI 0.93-0.97); p < 0.001) and shorter duration of hospital stay (incidence rate ratio 0.91 (95%CI 0.87-0.94); p < 0.001) after implementation of the quality improvement initiative. Analyses in a propensity-matched sample (n = 2936 per group) and interrupted time series analysis (n = 27,202 cases) confirmed the findings. Our data show that a local, multifaceted quality improvement initiative can enhance the quality of intra-operative neuromuscular blocking agent utilisation, thereby reducing the incidence of postoperative pulmonary complications., (© 2018 Association of Anaesthetists.)

Background Previous headache trigger studies have primarily utilized checklists to measure beliefs about triggers. While this work has defined the diversity of beliefs across headache sufferers, the strength of association and the frequency at which these triggers are encountered remain unexplored. Objective To measure the strength of association, frequency of encounter, and influences on trigger beliefs and perceptions using a laboratory assessment task. Methods This cross-sectional observational study, part of the HACOGS project, included adult current migraine, tension-type, or cluster headache sufferers. Participants rated the chances they would experience a headache if they were to encounter a specific trigger and the number of days per month they experience that trigger for 33 common triggers. Results All 300 participants contributed data on all triggers, with little missing data (1.2%). All triggers exhibited a high degree of inter-individual variability on the strength of association and encounter perceptions. Many triggers were perceived to be encountered daily (e.g., caffeine, air conditioning), and a full range of perceptions were observed for each trigger. Stress (75% chance of headache), missing a meal (60%), and dehydration (60%) were the triggers with the greatest potency beliefs. Only 8-15% of these beliefs were related to individual differences and 26-27% to the triggers themselves. Conclusions Participants expressed diverse beliefs and perceptions about the strength of many common headache triggers. Variation in these beliefs was not associated with individual differences or the triggers themselves. This finding supports the importance of measuring more than just the presence-absence of trigger beliefs.

Purpose of Review: This review synthesizes the utility of measuring migraine triggers for the purpose of forecasting future headache attacks. The nature of forecasting models, headache triggers as inputs to such models, and how these trigger exposures can be measured for forecasting are reviewed. A critical evaluation of the existing forecasting models in the context of their potential application for preemptive treatment is considered., Recent Findings: A substantial pool of candidate trigger factors could be considered in the creation of forecasting models. However, because mechanistic information about causal factors that precede a migraine attack is not well understood, and such factors are difficult to measure, empirical models that are based on trigger factors that are merely associated with the onset of headache activity are likely to be the focus of forecasting efforts in the near future. Of such factors, stress has considerable empirical support and has been used to successfully forecast future headache attacks within individuals over time. However, at present, existing models possess only modest levels of discrimination and lack strong resolution in generated predictions. Current headache forecasting models represent an important first step in accurately predicting future headache activity. However, to utilize these models in a preemptive treatment paradigm where the risk of headache is treated prior to the actual experience of pain, these models must achieve greater precision with good calibration and generate predictions that are clinically actionable by individuals in their real-time home environments.

Background: Insomnia is frequently comorbid with chronic migraine, and small trials suggest that cognitive-behavioral treatment of insomnia (CBTi) may reduce migraine frequency. This study endeavored to provide a quantitative synthesis of existing CBTi trials for adults with chronic migraine using Bayesian statistical methods, given their utility in combining prior knowledge with sequentially gathered data., Methods: Completer analyses of 2 randomized trials comparing CBTi to a sham control intervention (Calhoun and Ford, 2007; Smitherman et al, 2016) were used to quantify the effects of a brief course of treatment on headache frequency. Change in headache frequency from baseline to the primary endpoint (6-8 weeks posttreatment) was regressed on group status using a Gaussian linear model with each study specified in the order of completion. To estimate the combined effect, posterior distributions from the Calhoun and Ford study were used as informative priors for conditioning on the Smitherman et al data., Results: In a combined analysis of these prior studies, monthly headache frequency of the treatment group decreased by 6.2 days (95%CrI: -9.7 to -2.7) more than the control group, supporting an interpretation that there is a 97.5% chance that the treatment intervention is at least 2.7 days better than the control intervention. The analysis supports the hypothesis that at least for those who complete treatment, there is high probability that individuals who receive CBTi experience greater headache reduction than those who receive a control intervention equated for therapist time and out-of-session skills practice., Conclusion: Cognitive-behavioral interventions for comorbid insomnia hold promise for reducing headache frequency among those with chronic migraine. These findings add to a small but growing body of literature that migraineurs with comorbid conditions often respond well to behavioral interventions, and that targeting comorbidities may improve migraine itself., (© 2018 American Headache Society.)

Patients with autism spectrum disorder (ASD) often require sedation or general anesthesia. ASD is thought to arise from deficits in GABAergic signaling leading to abnormal neurodevelopment. We sought to investigate differences in how ASD patients respond to the GABAergic drug propofol by comparing the propofol-induced electroencephalogram (EEG) of ASD and neurotypical (NT) patients. This investigation was a prospective observational study. Continuous 4-channel frontal EEG was recorded during routine anesthetic care of patients undergoing endoscopic procedures between July 1, 2014 and May 1, 2016. Study patients were defined as those with previously diagnosed ASD by DSM-V criteria, aged 2-30 years old. NT patients were defined as those lacking neurological or psychiatric abnormalities, aged 2-30 years old. The primary outcome was changes in propofol-induced alpha (8-13 Hz) and slow (0.1-1 Hz) oscillation power by age. A post hoc analysis was performed to characterize incidence of burst suppression during propofol anesthesia. The primary risk factor of interest was a prior diagnosis of ASD. Outcomes were compared between ASD and NT patients using Bayesian methods. Compared to NT patients, slow oscillation power was initially higher in ASD patients (17.05 vs. 14.20 dB at 2.33 years), but progressively declined with age (11.56 vs. 13.95 dB at 22.5 years). Frontal alpha power was initially lower in ASD patients (17.65 vs. 18.86 dB at 5.42 years) and continued to decline with age (6.37 vs. 11.89 dB at 22.5 years). The incidence of burst suppression was significantly higher in ASD vs. NT patients (23.0% vs. 12.2%, p < 0.01) despite reduced total propofol dosing in ASD patients. Ultimately, we found that ASD patients respond differently to propofol compared to NT patients. A similar pattern of decreased alpha power and increased sensitivity to burst suppression develops in older NT adults; one interpretation of our data could be that ASD patients undergo a form of accelerated neuronal aging in adolescence. Our results suggest that investigations of the propofol-induced EEG in ASD patients may enable insights into the underlying differences in neural circuitry of ASD and yield safer practices for managing patients with ASD.

Background: The use of intraoperative opioids may influence the rate of postoperative complications. This study evaluated the association between intraoperative opioid dose and the risk of 30-day hospital readmission., Methods: We conducted a pre-specified analysis of existing registry data for 153 902 surgical cases performed under general anaesthesia at Massachusetts General Hospital and two affiliated medical centres. We examined the association between total intraoperative opioid dose (categorised in quintiles) and 30-day hospital readmission, controlling for several patient-, anaesthetist-, and case-specific factors., Results: Compared with low intraoperative opioid dosing [quintile 1, median (inter-quartile range): 8 (4-9) mg morphine equivalents], exposure to high-dose opioids during surgery [quintile 5: 32 (27-41) equivalents] is an independent predictor of 30-day readmission [odds ratio (OR) 1.15 (95% confidence interval 1.07-1.24); P<0.001]. Ambulatory surgery patients receiving high opioid doses were found to have the greatest adjusted risk of readmission (OR 1.75; P<0.001) with a clear dose-response effect across quintiles (P for trend <0.05), and were more likely to be readmitted early (postoperative days 0-2 vs 3-30; P<0.001). Opioid class modified the association between total opioid dose and readmission, with longer-acting opioids demonstrating a stronger influence (P<0.001). We observed significant practice variability across individual anaesthetists in the utilisation of opioids that could not be explained by patient- and case-specific factors., Conclusions: High intraoperative opioid dose is a modifiable anaesthetic factor that varies in the practice of individual anaesthetists and affects postoperative outcomes. Conservative standards for intraoperative opioid dosing may reduce the risk of postoperative readmission, particularly in ambulatory surgery., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective To quantitatively synthesize extant literature on perceived triggers of primary headache disorders. Methods A meta-analytic review of headache trigger survey studies was conducted. Endorsement rates, assessment method, and headache and sample characteristics were extracted from included articles. Separate random-effects models were used to assess trigger endorsement rates and post-hoc meta-regressions examined potential moderator variables. Results 85 articles from 1958 to 2015 were included, involving 27,122 participants and querying 420 unique triggers (collapsed into 15 categories). Four-fifths (0.81; 95% CI .75 to .86) of individuals with migraine or tension-type headache endorsed at least one trigger. Rates increased with the number of categories queried (OR: 1.18, 1.08-1.30) and year of publication (OR: 1.04, 1.00-1.08). The triggers most commonly endorsed were stress (.58, .53-.63) and sleep (.41, .36-.47). Conclusions Extreme heterogeneity characterizes the headache trigger literature. Most individuals with a primary headache disorder perceive their attacks to be triggered by one or more precipitants, the most common of which are stress and sleep. However, trigger endorsement is influenced by method of assessment. Enhancing methodological consistency and prioritizing experimental studies would improve our understanding of headache triggers.

Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.

Introduction: Delirium, which is prevalent in postcardiac surgical patients, is an acute brain dysfunction characterised by disturbances in attention, awareness and cognition not explained by a pre-existing neurocognitive disorder. The pathophysiology of delirium remains poorly understood. However, basic science and clinical studies suggest that sleep disturbance may be a modifiable risk factor for the development of delirium. Dexmedetomidine is a α-2A adrenergic receptor agonist medication that patterns the activity of various arousal nuclei similar to sleep. A single night-time loading dose of dexmedetomidine promotes non-rapid eye movement sleep stages N2 and N3 sleep. This trial hypothesises dexmedetomidine-induced sleep as pre-emptive therapy for postoperative delirium., Methods and Analysis: The MINDDS (Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep) trial is a 370-patient block-randomised, placebo-controlled, double-blinded, single-site, parallel-arm superiority trial. Patients over 60 years old, undergoing cardiac surgery with planned cardiopulmonary bypass, will be randomised to receive a sleep-inducing dose of dexmedetomidine or placebo. The primary outcome is the incidence of delirium on postoperative day 1, assessed with the Confusion Assessment Method by staff blinded to the treatment assignment. To ensure that the study is appropriately powered for the primary outcome measure, patients will be recruited and randomised into the study until 370 patients receive the study intervention on postoperative day 0. Secondary outcomes will be evaluated by in-person assessments and medical record review for in-hospital end points, and by telephone interview for 30-day, 90-day and 180-day end points. All trial outcomes will be evaluated using an intention-to-treat analysis plan. Hypothesis testing will be performed using a two-sided significance level (type I error) of α=0.05. Sensitivity analyses using the actual treatment received will be performed and compared with the intention-to-treat analysis results. Additional sensitivity analyses will assess the potential impact of missing data due to loss of follow-up., Ethics and Dissemination: The Partners Human Research Committee approved the MINDDS trial. Recruitment began in March 2017. Dissemination plans include presentations at scientific conferences, scientific publications and popular media., Trial Registration Number: NCT02856594., Competing Interests: Competing interests: OA and ENB have a provisional patent application describing the use of alpha-2 agonists for promoting N3 sleep., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Study Objectives: To measure prevalence and severity of third trimester obstructive sleep apnea and evaluate postpartum resolution. To assess a novel biomarker for screening for obstructive sleep apnea in pregnancy., Methods: This prospective observational study was performed at Wake Forest School of Medicine obstetrics clinics between April 2014 and December 2015. Fractional exhaled nitric oxide measurements and sleep studies were obtained and compared at 32 0/7 to 35 6/7 weeks gestation and postpartum. Exhaled nitric oxide and risk factors for the development of gestational sleep apnea were evaluated for predictive ability independently and in screening models., Results: Of 76 women enrolled, 73 performed valid sleep studies in pregnancy and 65 had an additional valid study 6 to 15 weeks postpartum. Twenty-four women (37%) had gestational sleep apnea compared with 23 (35%) with postpartum sleep apnea ( P > .99). Eight of 11 women (73%) retested 6 to 8 months postpartum had persistent sleep apnea. Exhaled nitric oxide had moderate discrimination screening for sleep apnea in pregnancy (area under the receiver operating characteristic curve = 0.64). A model utilizing exhaled nitric oxide, pregnancy-specific screening, and Mallampati score improved ability to identify women at risk for gestational sleep apnea (sensitivity = 46%, specificity = 91% and likelihood ratio = 5.11, area under receiver operating characteristic curve = 0.75)., Conclusions: Obstructive sleep apnea is common in the early postpartum period and often persisted at least 6 months. Exhaled nitric oxide as a sole biomarker to screen for sleep apnea in pregnancy has only modest discrimination. Combined with additional parameters sensitivity and specificity improved., Clinical Trial Registration: Registry: ClinicalTrials.gov, Identifier: NCT02100943, Title: Exhaled Nitric Oxide as a Biomarker of Gestational Obstructive Sleep Apnea and Persistence Postpartum, URL: https://clinicaltrials.gov/ct2/show/NCT02100943., (© 2018 American Academy of Sleep Medicine.)

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Importance: Perioperative stroke is a major complication for patients undergoing surgery. Patent foramen ovale (PFO) represents a possible anatomical link between venous thrombosis and stroke., Objective: To determine whether a preoperatively diagnosed PFO is associated with increased risk of perioperative ischemic stroke., Design, Setting, and Participants: Retrospective cohort study from Massachusetts General Hospital and 2 affiliated community hospitals between January 1, 2007, and December 31, 2015. Participants were 182 393 consecutive adults undergoing noncardiac surgery with general anesthesia., Exposures: Preoperatively diagnosed PFO., Main Outcomes and Measures: Perioperative ischemic stroke occurring within 30 days of surgery; stroke subtype by Oxfordshire Community Stroke Project classification and stroke severity by National Institute of Health Stroke Scale (NIHSS)., Results: Among the 150 198 patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had a diagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokes occurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801 [0.5%] among patients without PFO). In adjusted analyses, patients with PFO had an increased risk of ischemic stroke compared with patients without PFO (odds ratio, 2.66 [95% CI, 1.96-3.63]; P < .001). The estimated risks of stroke were 5.9 for every 1000 patients with PFO and 2.2 for every 1000 patients without PFO (adjusted absolute risk difference, 0.4% [95% CI, 0.2%-0.6%). Patients with PFO also had an increased risk of large vessel territory stroke (relative risk ratio, 3.14 [95% CI, 2.21-4.48]; P < .001) and a more severe stroke-related neurologic deficit measured by NIHSS (median, 4 [interquartile range {IQR}, 2-10] vs median, 3 [IQR, 1-6] for those without PFO; P = .02)., Conclusions and Relevance: Among adult patients undergoing noncardiac surgery at 3 hospitals, having a preoperatively diagnosed PFO was significantly associated with increased risk of perioperative ischemic stroke within 30 days after surgery. Further research is needed to confirm these findings and to determine whether interventions would decrease this risk.

Background: The purpose of this study was to determine whether significant variation exists in the use of protective ventilation across individual anesthesia providers and whether this difference can be explained by patient, procedure, and provider-related characteristics., Methods: The cohort consisted of 262 anesthesia providers treating 57,372 patients at a tertiary care hospital between 2007 and 2014. Protective ventilation was defined as a median positive end-expiratory pressure of 5 cm H2O or more, tidal volume of <10 mL/kg of predicted body weight and plateau pressure of <30 cm H2O. Analysis was performed using mixed-effects logistic regression models with propensity scores to adjust for covariates. The definition of protective ventilation was modified in sensitivity analyses., Results: In unadjusted analysis, the mean probability of administering protective ventilation was 53.8% (2.5th percentile of provider 19.9%, 97.5th percentile 80.8%). After adjustment for a large number of covariates, there was little change in the results with a mean probability of 51.1% (2.5th percentile 24.7%, 97.5th percentile 77.2%). The variations persisted when the thresholds for protective ventilation were changed., Conclusions: There was significant variability across individual anesthesia providers in the use of intraoperative protective mechanical ventilation. Our data suggest that this variability is highly driven by individual preference, rather than patient, procedure, or provider-related characteristics.

Objectives: Sleep, which comprises of rapid eye movement (REM) and non-REM stages 1-3 (N1-N3), is a natural occurring state of decreased arousal that is crucial for normal cardiovascular, immune and cognitive function. The principal sedative drugs produce electroencephalogram beta oscillations, which have been associated with neurocognitive dysfunction. Pharmacological induction of altered arousal states that neurophysiologically approximate natural sleep, termed biomimetic sleep, may eliminate drug-induced neurocognitive dysfunction., Methods: We performed a prospective, single-site, three-arm, randomized-controlled, crossover polysomnography pilot study (n = 10) comparing natural, intravenous dexmedetomidine- (1-μg/kg over 10 min [n = 7] or 0.5-μg/kg over 10 min [n = 3]), and zolpidem-induced sleep in healthy volunteers. Sleep quality and psychomotor performance were assessed with polysomnography and the psychomotor vigilance test, respectively. Sleep quality questionnaires were also administered., Results: We found that dexmedetomidine promoted N3 sleep in a dose dependent manner, and did not impair performance on the psychomotor vigilance test. In contrast, zolpidem extended release was associated with decreased theta (∼5-8 Hz; N2 and N3) and increased beta oscillations (∼13-25 Hz; N2 and REM). Zolpidem extended release was also associated with increased lapses on the psychomotor vigilance test. No serious adverse events occurred., Conclusions: Pharmacological induction of biomimetic N3 sleep with psychomotor sparing benefits is feasible., Significance: These results suggest that α2a adrenergic agonists may be developed as a new class of sleep enhancing medications with neurocognitive sparing benefits., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We know little about the individual pain experience of patients recovering from surgery in the first weeks after hospital discharge. Here, we examine individual differences in the day-to-day experience after 2 major surgeries: lower limb total major joint arthroplasty (TJA) and cesarean delivery (CD). Fifty-five TJA patients and 157 CD patients were recruited to complete questionnaires and record their daily pain experiences after surgery. After hospital discharge, patients recorded their pain intensity once daily for 60 days (CD) or twice daily for 2 weeks, once daily for 2 weeks, weekly for 8 weeks, and monthly for 3 months (TJA). Pain scores were modeled using growth curve and Bayesian change-point models. Individual differences in the model fits were examined for evidence of day-to-day differences in pain. A log time model was the simplest model that fit the data, but examination of the residuals revealed high autocorrelation representing misspecification. A change-point model fit the data better and revealed that the form of recovery fundamentally changed between days 10 and 21 after surgery. These data add meaningfully to our understanding of recovery from pain after surgery by extending the period of frequent observations a few days after surgery to a 2-month period. These high time resolution data suggest that there is a typical experience of pain resolution after surgery, but that meaningful subpopulations of experience may exist. They also indicate that a transition occurs within 1 month after surgery from 1 pattern of change in pain over time to another.

Objectives: To investigate migraine patterns in the United States using Google search data and utilize this information to better understand societal-level trends. Additionally, we aimed to evaluate time-series relationships between migraines and social factors., Background: Extensive research has been done on clinical factors associated with migraines, yet population-level social factors have not been widely explored. Migraine internet search data may provide insight into migraine trends beyond information that can be gleaned from other sources., Methods: In this longitudinal analysis of open access data, we performed a time-series analysis in which about 12 years of Google Trends data (January 1, 2004 to August 15, 2016) were assessed. Data points were captured at a daily level and Google's 0-100 adjusted scale was used as the primary outcome to enable the comparison of relative popularity in the migraine search term. We hypothesized that the volume of relative migraine Google searches would be affected by societal aspects such as day of the week, holidays, and novel social events., Results: Several recurrent social factors that drive migraine searches were identified. Of these, day of the week had the most significant impact on the volume of Google migraine searches. On average, Mondays accumulated 13.31 higher relative search volume than Fridays (95% CI: 11.12-15.51, P ≤ .001). Surprisingly, holidays were associated with lower relative migraine search volumes. Christmas Day had 13.84 lower relative search volumes (95% CI: 6.26-21.43, P ≤ .001) and Thanks giving had 20.18 lower relative search volumes (95% CI: 12.55-27.82, P ≤ .001) than days that were not holidays. Certain novel social events and extreme weather also appear to be associated with relative migraine Google search volume., Conclusions: Social factors play a crucial role in explaining population level migraine patterns, and thus, warrant further exploration., (© 2017 American Headache Society.)

Background: In adults, frontal electroencephalogram patterns observed during propofol-induced unconsciousness consist of slow oscillations (0.1 to 1 Hz) and coherent alpha oscillations (8 to 13 Hz). Given that the nervous system undergoes significant changes during development, anesthesia-induced electroencephalogram oscillations in children may differ from those observed in adults. Therefore, we investigated age-related changes in frontal electroencephalogram power spectra and coherence during propofol-induced unconsciousness., Methods: We analyzed electroencephalogram data recorded during propofol-induced unconsciousness in patients between 0 and 21 yr of age (n = 97), using multitaper spectral and coherence methods. We characterized power and coherence as a function of age using multiple linear regression analysis and within four age groups: 4 months to 1 yr old (n = 4), greater than 1 to 7 yr old (n = 16), greater than 7 to 14 yr old (n = 30), and greater than 14 to 21 yr old (n = 47)., Results: Total electroencephalogram power (0.1 to 40 Hz) peaked at approximately 8 yr old and subsequently declined with increasing age. For patients greater than 1 yr old, the propofol-induced electroencephalogram structure was qualitatively similar regardless of age, featuring slow and coherent alpha oscillations. For patients under 1 yr of age, frontal alpha oscillations were not coherent., Conclusions: Neurodevelopmental processes that occur throughout childhood, including thalamocortical development, may underlie age-dependent changes in electroencephalogram power and coherence during anesthesia. These age-dependent anesthesia-induced electroencephalogram oscillations suggest a more principled approach to monitoring brain states in pediatric patients.

Objective: To define the amount of opioid analgesics prescribed and consumed after discharge after cesarean delivery., Methods: We conducted a survey at six academic medical centers in the United States from September 2014 to March 2016. Women who had undergone a cesarean delivery were contacted by phone 2 weeks after discharge and participated in a structured interview about the opioid prescription they received on discharge and their oral opioid intake while at home., Results: A total of 720 women were enrolled; of these, 615 (85.4%) filled an opioid prescription. The median number of dispensed opioid tablets was 40 (interquartile range 30-40), the median number consumed was 20 (interquartile range 8-30), and leftover was 15 (interquartile range 3-26). Of those with leftover opioids, 95.3% had not disposed of the excess medication at the time of the interview. There was an association between a larger number of tablets dispensed and the number consumed independent of patient characteristics. The amount of opioids dispensed did not correlate with patient satisfaction, pain control, or the need to refill the opioid prescription., Conclusion: The amount of opioid prescribed after cesarean delivery generally exceeds the amount consumed by a significant margin, leading to substantial amounts of leftover opioid medication. Lower opioid prescription correlates with lower consumption without a concomitant increase in pain scores or satisfaction.

Venous thromboembolism remains a major source of morbidity and mortality in obstetrics with an incidence of 29.8/100,000 vaginal delivery hospitalizations; cesarean delivery confers a 4-fold increased risk of thromboembolism when compared with vaginal delivery. Revised national guidelines now stipulate that the majority of women delivering via cesarean and women at risk for ante- or postpartum venous thromboembolism receive mechanical or pharmacological thromboprophylaxis. This practice change has important implications for obstetric anesthesiologists concerned about the risk of spinal epidural hematoma (SEH) among anticoagulated women receiving neuraxial anesthesia. We conducted a systematic review of published English language studies (1952-2016) and of the US Anesthesia Closed Claims Project Database (1990-2013) to identify cases of SEH associated with neuraxial anesthesia and thromboprophylaxis. We also report on SEH in obstetric patients receiving thromboprophylaxis and neuraxial anesthesia without adherence to the American Society of Regional Anesthesia (ASRA) recommendations. In our review, we initially identified 736 publications of which 10 met inclusion criteria; these were combined with the 5 cases of SEH identified in 546 obstetric Anesthesia Closed Claims reviews. None of these publications revealed SEH associated with neuraxial anesthesia and thromboprophylaxis with unfractionated heparin or low-molecular-weight heparin in obstetric patients. Based on data from 6 reports, 28 parturients had their neuraxial blockade before the minimum ASRA recommended time interval between the last anticoagulant dose and the neuraxial procedure. Based on data from 2 reports, 52 parturients received neuraxial anesthesia without their low-molecular-weight heparin dose being discontinued during the intrapartum period. Although the very low level of evidence and high heterogeneity in these reports make it difficult to draw quantitative conclusions from this systematic review, it is encouraging that this comprehensive search did not identify a single case of SEH in an obstetric patient receiving thromboprophylaxis and neuraxial anesthesia. Analysis of large-scale registries (eg, the Anesthesia Incident Reporting System of the Anesthesia Quality Institute) with more granular clinical and pharmacological data is needed to assess the impact of these practice changes on obstetric SEH incidence. In the interim, optimal care of obstetric patients depends on multidisciplinary planning of anticoagulation dosing to facilitate neuraxial anesthesia and thoughtful weighing of the relative risks and benefits of providing versus withholding neuraxial in favor of general anesthesia.

Objective: To develop and validate a prediction model that forecasts future migraine attacks for an individual headache sufferer., Background: Many headache patients and physicians believe that precipitants of headache can be identified and avoided or managed to reduce the frequency of headache attacks. Of the numerous candidate triggers, perceived stress has received considerable attention for its association with the onset of headache in episodic and chronic headache sufferers. However, no evidence is available to support forecasting headache attacks within individuals using any of the candidate headache triggers., Methods: This longitudinal cohort with forecasting model development study enrolled 100 participants with episodic migraine with or without aura, and N = 95 contributed 4626 days of electronic diary data and were included in the analysis. Individual headache forecasts were derived from current headache state and current levels of stress using several aspects of the Daily Stress Inventory, a measure of daily hassles that is completed at the end of each day. The primary outcome measure was the presence/absence of any headache attack (head pain > 0 on a numerical rating scale of 0-10) over the next 24 h period., Results: After removing missing data (n = 431 days), participants in the study experienced a headache attack on 1613/4195 (38.5%) days. A generalized linear mixed-effects forecast model using either the frequency of stressful events or the perceived intensity of these events fit the data well. This simple forecasting model possessed promising predictive utility with an AUC of 0.73 (95% CI 0.71-0.75) in the training sample and an AUC of 0.65 (95% CI 0.6-0.67) in a leave-one-out validation sample. This forecasting model had a Brier score of 0.202 and possessed good calibration between forecasted probabilities and observed frequencies but had only low levels of resolution (ie, sharpness)., Conclusions: This study demonstrates that future headache attacks can be forecasted for a diverse group of individuals over time. Future work will enhance prediction through improvements in the assessment of stress as well as the development of other candidate domains to use in the models., (© 2017 American Headache Society.)

Background: The locus coeruleus (LC) signals salience to sensory stimuli and these responses can modulate the experience of pain stimuli. The pupil dilation response (PDR) to noxious stimuli is thought to be a surrogate for LC responses, but PDR response to Peltier-controlled noxious heat stimuli, the most commonly used method in experimental pain research, has not been described., New Method: Healthy volunteers were presented with randomly presented heat stimuli of 5 sec duration and provided pain intensity ratings to each stimulus. Pupillometry was performed and a method developed to quantify the PDR relevant to these stimuli. The stimulus response, reliability, and effect of commonly used manipulations on pain experience were explored., Results: A method of artifact removal and adjusting for lag from stimulus initiation to PDR response was developed, resulting in a close correlation between pain intensity rating and PDR across a large range of heat stimuli. A reliable assessment of PDR within an individual was achieved with fewer presentations as heat stimulus intensity increased. The correlation between pain rating and PDR was disrupted when cognitive load is increased by manipulating expectations or presenting a second pain stimulus., Comparison With Existing Methods: The PDR began later after skin heating than electrical stimuli and this is the first examination of the PDR using standard nociceptive testing and manipulations of expectations and competing noxious stimulation., Conclusions: A method is described applying PDR to standard heat nociceptive testing, demonstrating stimulus response, reliability, and disruption by cognitive manipulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Previous studies have shown that etomidate modulates γ-aminobutyric acid type A receptors by binding at the β-α subunit interface within the transmembrane domain of receptors that incorporate β2 or β3 subunits. Introducing an asparagine-to-methionine (N265M) mutation at position 265 of the β3 subunit, which sits within the etomidate-binding site, attenuates the hypnotic effect of etomidate in vivo. It was reported recently that the photoactivatable barbiturate R-mTFD-MPAB also acts on γ-aminobutyric acid type A receptors primarily by binding to a homologous site at the γ-β interface. Given this difference in drug-binding sites established by the in vitro experiments, we hypothesized that the β3-N265M-mutant mice would not be resistant to the anesthetic effects of R-mTFD-MPAB in vivo, whereas the same mutant mice would be resistant to the anesthetic effects of R-etomidate., Methods: We measured the effects of IV injection of etomidate and R-mTFD-MPAB on loss and recovery of righting reflex in wild-type mice and in mice carrying the β3-N265M mutation., Results: Etomidate-induced hypnosis, as measured by the duration of loss of righting reflex, was attenuated in the N265M knock-in mice, confirming prior results. By contrast, recovery of balance and coordinated movement, as measured by the ability to maintain all 4 paws on the ground, was unaffected by the mutation. Neither hypnosis nor impairment of coordinated movement produced by the barbiturate R-mTFD-MPAB was affected by the mutation., Conclusions: The findings confirmed our hypothesis that mutating the etomidate-binding site would not alter the response to the barbiturate R-mTFD-MPAB. Furthermore, we confirmed previous studies indicating that etomidate-induced hypnosis is mediated in part by β3-containing receptors. We also extended previous findings by showing that etomidate-impaired balance and coordinated movement are not mediated by β3-containing receptors, thus implicating β2-containing receptors in this end point., Competing Interests: The authors declare no conflicts of interest.

Many migraine sufferers use daily prophylactic therapy to reduce the frequency of their headache attacks. The Food and Drug Administration has approved several different medications for migraine prophylaxis, but it is not clear whether sufferers perceive these treatments to provide clinically significant benefits given their side effect profiles. Three hundred headache sufferers were recruited from the community and local headache clinics using print and television advertising. Participants reported experiencing problematic headache attacks with a median (IQR) frequency of 7.0 (4-13) headache days per month. These sufferers participated in a cross-sectional, single-site, study that used a specially designed computer assessment task. Participants were instructed on the probability of experiencing the 3 most commonly experienced side effects for several blinded medication profiles: divalproex sodium, venlafaxine, gabapentin, propranolol, and topiramate. After learning the likelihood of experiencing side effect profiles of each medication, participants were asked whether they would be willing to take the medication for a given headache reduction level, which ranged from 0 to 7 days per month. The side effect profile for divalproex sodium was associated with the smallest willingness to take, with gabapentin, propranolol, and topiramate perceived to be much more agreeable. However, <60% of participants reported willingness to take any of these medications even if they provided a 50% reduction in headache frequency. Several general predictors of willingness to take were observed including high headache-related disability, depressive symptoms, and pain medication concerns including fear of tolerance. These findings suggest that if properly informed of the side effect profiles of these medications, many patients might opt for other treatments.

Background: Migraine frequently co-occurs with and is triggered by sleep disturbance, particularly insomnia, and the large majority of patients with chronic migraine (CM) have comorbid insomnia. Limited evidence suggests that behavioral regulation of sleep may reduce migraine frequency, but studies to date have not assessed the viability of stimulus control and sleep restriction interventions or included objective measurement of sleep parameters. The aim of this study, thus, was to pilot-test the efficacy of a brief behavioral insomnia intervention for adults with CM and comorbid insomnia; headache diaries and actigraphy were included to assess outcomes throughout the trial., Methods: This randomized parallel-arm pilot trial recruited adults with both CM and comorbid insomnia. Participants were randomly assigned to three 30-minute biweekly sessions of cognitive-behavioral therapy for insomnia (CBTi) or control treatment. Participants were blinded to treatment and control conditions to control for outcome expectations. Each treatment condition involved training in and daily practice in 5 instructions/skills. The CBTi group learned and practiced skills pertaining to stimulus control and sleep restriction. The control intervention was the same as used by Calhoun and Ford (2007) and involved training in and daily practice of skills pertaining to keeping a consistent food/liquid intake, range of motion exercises, and acupressure. Participants provided outcome data via daily headache diaries, actigraphy, and self-report measures. The primary outcome was reduction in headache frequency at 2 weeks post-treatment and 6-week follow-up; secondary outcomes included other headache parameters, objective actigraphic and subjective changes in sleep, and treatment effect sizes and perceived credibility. Generalized estimating equations with a binomial logit link and inverse probability weights were used to assess the primary outcome among the intent-to-treat sample, and repeated measures generalized linear models were used to assess changes in secondary outcomes after controlling for baseline values., Results: The intent-to-treat analyses included 31 adults (M age = 30.8 [12.9] years; 90.3% female; 80.6% white) with CM and comorbid insomnia. Both interventions yielded reductions in headache frequency at post-treatment (26.9% reduction for CBTi vs. 36.2% for control) and follow-up (48.9% for CBTi vs. 25.0% for control). At follow-up the odds of experiencing headache were 60% lower for CBTi than for control treatment, indicative of a large effect size that did not reach statistical significance after Bonferroni correction for assessing two primary endpoints (odds ratio: 0.40; 95% CI: 0.17, 0.91; P = .028). CBTi produced significantly larger increases than control treatment in total sleep time and sleep efficiency as quantified by actigraphy, as well as in self-reported insomnia severity. Adherence was high and treatments were perceived as credible without differences between groups, but the control group experienced a higher rate of dropouts. No adverse events were reported., Conclusions: Behavioral treatment of comorbid insomnia in individuals with CM produced large reductions in headache frequency, though some improvement in headache occurred with a behavioral intervention not focused on modifying sleep. Among the CBTi group only, both headache frequency and sleep parameters continued to improve after treatment, suggesting the presence of enduring effects over time. Directly treating insomnia using components of stimulus control and sleep restriction holds promise for reducing comorbid migraine. Development of and comparison to a truly inert pseudotherapy control presents unique challenges that future studies should address., (© 2016 American Headache Society.)

Background: Engagement in regular exercise routinely is recommended as an intervention for managing and preventing migraine, and yet empirical support is far from definitive. We possess at best a weak understanding of how aerobic exercise and resulting change in aerobic capacity influence migraine, let alone the optimal parameters for exercise regimens as migraine therapy (eg, who will benefit, when to prescribe, optimal types, and doses/intensities of exercise, level of anticipated benefit). These fundamental knowledge gaps critically limit our capacity to deploy exercise as an intervention for migraine., Overview: Clear articulation of the markers and mechanisms through which aerobic exercise confers benefits for migraine would prove invaluable and could yield insights on migraine pathophysiology. Neurovascular and neuroinflammatory pathways, including an effect on obesity or adiposity, are obvious candidates for study given their role both in migraine as well as the changes known to accrue with regular exercise. In addition to these biological pathways, improvements in aerobic fitness and migraine alike also are mediated by changes in psychological and sociocognitive factors. Indeed a number of specific mechanisms and pathways likely are operational in the relationship between exercise and migraine improvement, and it remains to be established whether these pathways operate in parallel or synergistically. As heuristics that might conceptually benefit our research programs here forward, we: (1) provide an extensive listing of potential mechanisms and markers that could account for the effects of aerobic exercise on migraine and are worthy of empirical exploration and (2) present two exemplar conceptual models depicting pathways through which exercise may serve to reduce the burden of migraine., Conclusion: Should the promise of aerobic exercise as a feasible and effective migraine therapy be realized, this line of endeavor stands to benefit migraineurs (including the many who presently remain suboptimally treated) by providing a new therapeutic avenue as an alternative or augmentative compliment to established interventions for migraine., (© 2015 American Headache Society.)

Background: Although early proponents for each of the four basic articles of operating room clothing--gowns, caps, masks, and gloves--can be identified, it is unclear from historical commentaries when each article achieved general acceptance and was consistently worn by surgeons and by anesthesia providers., Methods: Historical photographs were identified from the Web sites of the National Library of Medicine, Google, and the archives of the Wood Library-Museum of Anesthesiology for the 11 decades 1860 to 1970. The presence or absence of each article of clothing was then determined for the surgical and anesthesia providers depicted., Results: Over 1,000 photographs were identified and examined. Photographs were then eliminated for repetition, lack of available dating, questionable dating, and poor quality. In 338 remaining photographs that met inclusion criteria, 640 surgical providers and 219 anesthesia providers were depicted and used in the analysis. Statistical definitions for historical terms general acceptance and routine use were proposed. The probability that a surgeon was wearing nonstreet clothes (gown) was 0.66 (95% CI, 0.22 to 0.93) in 1863. The years (95% lower bound to 95% upper bound) associated with a 0.5 probability for wearing cap, gloves, and mask were 1900 (1896 to 1904), 1907 (1903 to 1910), and 1916 (1913 to 1919), respectively. The years associated with a 0.5 probability that an anesthesia provider would be wearing nonstreet clothes (gown), cap, and mask were 1883 (1863 to 1889), 1905 (1900 to 1911), and 1932 (1929 to 1937), respectively., Conclusion: Timelines for the adoption of each basic article of surgical attire by surgeons and anesthesia providers were determined by analysis of historical operating room photographs from 1863 to 1969.

This paper provides an overview of the well-established and empirically supported behavioral interventions for the treatment of migraine. The considerable evidence base addressing behavioral interventions amassed since 1969 has conclusively established the efficacy of therapies featuring combinations of relaxation, biofeedback, and stress management training, and demonstrated they are capable of yielding benefits on par with pharmacological therapies for migraine. Behavioral interventions also are well suited for delivery across a variety of different contexts (e.g., group vs. individual, standard clinic vs. limited therapist contact, face-to-face vs. technology-assisted). Despite the amply established efficacy and effectiveness of these self-management interventions for the treatment of migraine, the availability and implementation of these approaches remain limited for many headache sufferers. We anticipate the technological advances in delivery platforms will provide better access to behavioral self-management strategies for migraine.

Background: Anxiety sensitivity (AS), the fear of arousal-related bodily sensations due to beliefs about presumed harmful consequences, predicts fear and avoidance among musculoskeletal pain patients but remains largely unexplored in headache. The aims of this cross-sectional study were to evaluate AS among young adult migraine and tension-type headache sufferers and to assess relations with headache impact and perceived susceptibility to headache triggers., Methods: A total of 2350 young adults (72.6% with primary headache; 64.9% female; 22.5% minority) completed measures of AS and headache symptomatology. Generalized linear models assessed relations between AS and ICHD-II diagnosis, headache-related disability, and perceived trigger susceptibility. Canonical correlation analyses quantified relations with headache symptomatology., Results: AS reliably differentiated headache sufferers from those without headache, being highest among chronic migraineurs and episodic migraineurs with aura. AS accounted for 8.4% of variance in headache symptomatology and was most strongly associated with prototypical migraine symptoms. AS predicted headache-related disability and trigger variables, even after controlling for headache frequency and severity. AS accounted for more unique variance in disability than depression and anxiety symptoms combined., Conclusions: AS predicts pain itself, adjustment to pain, and evaluation of factors influencing pain among primary headache sufferers, even after controlling for headache burden. Further study of AS among headache patients is warranted., (© International Headache Society 2014.)

The objective of this study was to assess whether migraine and tension-type headache (TTH) are best viewed as discrete entities or points on a severity continuum using taxometric analysis. Historically, classification systems have conceptualized the primary headache disorders of migraine and TTH as fundamentally different disorders that are differentiated by their characteristic symptom profiles and, as such, imply differing pathophysiologies and required treatments. Despite this categorical nosology, findings continue to emerge suggesting that migraine and TTH instead reflect dimensions of severity within the same headache construct. However, few studies have assessed this issue using taxometric statistical analyses or investigated how this taxonomic structure varies as a function of age and headache frequency. We conducted a latent-mode factor analysis of headache symptomatology obtained from 3449 individuals with headache from 2 previous, large-scale cross-sectional studies of primary headache sufferers (Martin et al., 2005, and Smitherman and Kolivas, 2013). Stratified taxometric analyses suggest that the validity of a categorical vs dimensional classification varies as a function of sample characteristics. Specifically, graphical results revealed that high headache frequency (>15 d/mo) and younger age (<24 years old) were associated with unimodal distributions suggestive of a dimensional construct of primary headache, whereas lower headache frequency and older age were associated with bimodal distributions characteristic of discrete diagnostic entities. Conceptualizing primary headache as a severity continuum was supported for young adults and those with frequent headaches. The distinctions of a categorical classification system were supported for adults (>24 years old) and those with infrequent headache.

Background: Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models., Methods: CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine β-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation., Results: The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine β-hydroxylase-saporin. Dopamine β-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine β-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery., Conclusion: Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Objective: To assess the relative effectiveness of an interdisciplinary, family-centered, tertiary-care pediatric weight management program for the treatment of patients with and without cognitive disabilities (CD)., Methods: Retrospective analysis of the clinical database of a tertiary-care pediatric weight management clinic (n = 453), extracting data from electronic health records including longitudinal change in weight status (body mass index [BMI] z-score) and frequency of attrition from treatment. Upon review of medical records, children enrolled in the treatment program were classified as having no CD (n = 342) or CD (n = 111)., Results: At baseline, there were no between-group differences in BMI or BMI z-score. After 4 months of treatment, 66% (299) of patients remained enrolled, and complete case data were available for 219 children in final analyses. There were no statistically significant differences in attrition between the 2 groups (no CD vs CD). Mean change in BMI z-score across all groups was -0.03 ± 0.13 (P < .001). Change in BMI z-score was significantly greater among patients with CD (-0.07 ± 0.15) compared to those without CD (-0.03 ± 0.12) (difference 0.04, 95% confidence interval 0.005-0.08, P = .029). These change estimates were observed after adjusting for processes potentially associated with attrition., Conclusions: Children with CD treated in an interdisciplinary, family-centered obesity clinic had similar or better outcomes compared to peers without CD. This success may be attributable to the patient-centered nature of this behavioral weight management program, which focused on leveraging the unique strengths and capabilities of each individual patient and family., (Copyright © 2015 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Chronic pain after nerve injury is often accompanied by hypersensitivity to mechanical stimuli, yet whether this reflects altered input, altered processing, or both remains unclear. Spinal nerve ligation or transection results in hypersensitivity to mechanical stimuli in skin innervated by adjacent dorsal root ganglia, but no previous study has quantified the changes in receptive field properties of these neurons in vivo. To address this, we recorded intracellularly from L4 dorsal root ganglion neurons of anesthetized young adult rats, 1 wk after L5 partial spinal nerve ligation (pSNL) or sham surgery. One week after pSNL, hindpaw mechanical withdrawal threshold in awake, freely behaving animals was decreased in the L4 distribution on the nerve-injured side compared with sham controls. Electrophysiology revealed that high-threshold mechanoreceptive cells of A-fiber conduction velocity in L4 were sensitized, with a seven-fold reduction in mechanical threshold, a seven-fold increase in receptive field area, and doubling of maximum instantaneous frequency in response to peripheral stimuli, accompanied by reductions in after-hyperpolarization amplitude and duration. Only a reduction in mechanical threshold (minimum von Frey hair producing neuronal activity) was observed in C-fiber conduction velocity high-threshold mechanoreceptive cells. In contrast, low-threshold mechanoreceptive cells were desensitized, with a 13-fold increase in mechanical threshold, a 60% reduction in receptive field area, and a 40% reduction in instantaneous frequency to stimulation. No spontaneous activity was observed in L4 ganglia, and the likelihood of recording from neurons without a mechanical receptive field was increased after pSNL. These data suggest massively altered input from undamaged sensory afferents innervating areas of hypersensitivity after nerve injury, with reduced tactile and increased nociceptive afferent response. These findings differ importantly from previous preclinical studies, but are consistent with clinical findings in most patients with chronic neuropathic pain., (Copyright © 2015 the American Physiological Society.)

Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury-induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an adeno-associated virus-type 8 viral vector with the CAG promoter and was administered by intrathecal injection resulting in expression in myelinated neurons. Optical inhibition of peripheral neurons at the soma and transcutaneously was possible in the neurons expressing ArchT, but not in neurons from control animals. Receptive field characteristics and electrophysiology determined that inhibition was neuronal subtype-specific with only AHTMR neurons being inhibited. One week after nerve injury the AHTMR are hyperexcitable, but can still be inhibited at the soma and transcutaneously. Withdrawal thresholds to mechanical stimuli in normal and in hyperalgesic nerve-injured animals also were increased by transcutaneous light to the affected hindpaw. This suggests that AHTMR neurons play a role not only in threshold-related withdrawal behavior in the normal animal, but also in sensitized states after nerve injury. This is the first time this subpopulation of neurons has been reversibly modulated to test their contribution to withdrawal-related behaviors before and after nerve injury. This technique may prove useful to define the role of selective neuronal populations in different pain states., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: Recovery from pain after surgery exhibits large interindividual variability, with very slow recovery equated to chronic pain. Surgical injury in the postpartum period modestly increases initial recovery after major nerve injury. In this study, the authors use a nerve injury that recovers over 2 to 3 months and apply growth curve modeling to further understand the effect of the postpartum period on speed of recovery., Methods: Withdrawal threshold to mechanical stimulus on the hind paw was determined in 41 Sprague-Dawley rats before and for 10 weeks after partial spinal nerve ligation. Age-matched male and female rats and postpartum females with pups or those separated from pups at delivery were studied. Growth curve analyses were applied to model recovery after surgery despite varying timing of measurements across groups and missing data, and these results were compared with those of two-way repeated-measures ANOVA., Results: The recovery time course was similar between males and females. In contrast, recovery was hastened in the postpartum groups, with nonoverlapping 95% CIs of modeled trajectories between days 6 and 66 after surgery. CIs were more precise at most time periods with growth curve analysis compared with ANOVA., Conclusions: The authors describe a method of analysis to quantify recovery from hypersensitivity after surgery in rats with several distinct advantages over traditionally used methods. Study results do not support a sex difference in trajectory of recovery but confirm and extend previous observations that injury at the time of obstetric delivery is associated with an abnormally rapid recovery.

Objective: To determine whether the utilization of healthcare resources is reduced after chronic migraine patients are treated for 6 months with onabotulinumtoxinA., Background: OnabotulinumtoxinA is indicated for headache prophylaxis in patients with chronic migraine, but its effect on healthcare resource use is unknown., Methods: We analyzed data from an open-label study of 230 chronic migraine patients refractory to ≥2 oral prophylactics who presented to a headache specialty clinic and who were treated with two cycles of onabotulinumtoxinA. Frequency and cost of migraine-related healthcare resource use, including visits to emergency departments, urgent care, or hospitalization, were compared for the 6 months before and after initial treatment. Costs were based on publicly available sources., Results: Compared with the 6 months predating initial treatment, patients had 55% fewer emergency department visits (174 vs 385), 59% fewer urgent care visits (61 vs 150), and 57% fewer hospitalizations (19 vs 45) during the 6-month treatment period (P < .01 for all). Analysis of treatment-related costs yielded an average reduction of $1219.33/patient, off-setting 49.7% of the total estimated cost for 6 months of treatment with onabotulinumtoxinA., Conclusions: Although we are unable to distinguish onabotulinumtoxinA's treatment effect from other potential confounding variables, our analysis showed that severely afflicted, treatment-refractory patients with chronic migraine experienced a significant cost-offset through reduced migraine-related emergency department visits, urgent care visits, and hospitalizations in the 6 months following treatment initiation of onabotulinumtoxinA. Future analyses will assess the longer-term effect of onabotulinumtoxinA treatment and the potential contribution of regression to the mean., (© 2014 The Authors. Headache published by Wiley Periodicals, Inc. on behalf of American Headache Society.)

Objective: Our objective was to assess the safety, feasibility, and effects of the standardized 8-week mindfulness-based stress reduction (MBSR) course in adults with migraines., Background: Stress is a well-known trigger for headaches. Research supports the general benefits of mind/body interventions for migraines, but there are few rigorous studies supporting the use of specific standardized interventions. MBSR is a standardized 8-week mind/body intervention that teaches mindfulness meditation/yoga. Preliminary research has shown MBSR to be effective for chronic pain syndromes, but it has not been evaluated for migraines., Methods: We conducted a randomized controlled trial with 19 episodic migraineurs randomized to either MBSR (n = 10) or usual care (n = 9). Our primary outcome was change in migraine frequency from baseline to initial follow-up. Secondary outcomes included change in headache severity, duration, self-efficacy, perceived stress, migraine-related disability/impact, anxiety, depression, mindfulness, and quality of life from baseline to initial follow-up., Results: MBSR was safe (no adverse events), with 0% dropout and excellent adherence (daily meditation average: 34 ± 11 minutes, range 16-50 minutes/day). Median class attendance from 9 classes (including retreat day) was 8 (range [3, 9]); average class attendance was 6.7 ± 2.5. MBSR participants had 1.4 fewer migraines/month (MBSR: 3.5 to 1.0 vs control: 1.2 to 0 migraines/month, 95% confidence interval CI [-4.6, 1.8], P = .38), an effect that did not reach statistical significance in this pilot sample. Headaches were less severe, although not significantly so (-1.3 points/headache on 0-10 scale, [-2.3, 0.09], P = .053) and shorter (-2.9 hours/headache, [-4.6, -0.02], P = .043) vs control. Migraine Disability Assessment and Headache Impact Test-6 dropped in MBSR vs control (-12.6, [-22.0, -1.0], P = .017 and -4.8, [-11.0, -1.0], P = .043, respectively). Self-efficacy and mindfulness improved in MBSR vs control (13.2 [1.0, 30.0], P = .035 and 13.1 [3.0, 26.0], P = .035 respectively)., Conclusions: MBSR is safe and feasible for adults with migraines. Although the small sample size of this pilot trial did not provide power to detect statistically significant changes in migraine frequency or severity, secondary outcomes demonstrated this intervention had a beneficial effect on headache duration, disability, self-efficacy, and mindfulness. Future studies with larger sample sizes are warranted to further evaluate this intervention for adults with migraines. This study was prospectively registered (ClinicalTrials.gov identifier NCT01545466)., (© 2014 American Headache Society.)