The association between changes in clinical pain severity and IL-6 reactivity among patients undergoing total knee Arthroplasty: The moderating role of change in insomnia.

Knee osteoarthritis (KOA) is linked to an enhanced release of interleukin-6 (IL-6). Increased levels of IL-6 are associated with greater pain and insomnia. While total knee arthroplasty (TKA) typically results in the reduction of pain, for a subgroup of patients, pain does not improve. Understanding patients' propensity to upregulate IL-6 may provide insight into variation in the clinical success of TKA for improving pain, and insomnia may play an important modulatory role. We investigated the association between pre- and post-surgical changes in clinical pain and IL-6 reactivity, and whether change in insomnia moderated this association. Patients (n = 39) with KOA came in-person before and 3-months after TKA. At both visits, patients completed validated measures of clinical pain and insomnia, as well as underwent quantitative sensory testing (QST). Blood samples were collected to analyze IL-expression both before and after QST procedures to assess changes in IL-6 in response to QST (IL-6 reactivity). Patients were categorized into two groups based on change in clinical pain from pre- to post-surgery: 1) pain decreased > 2 points (pain improved) and 2) pain did not decrease > 2 points (pain did not improve). Based on this definition, 49 % of patients had improved pain at 3-months. Among patients with improved pain, IL-6 reactivity significantly decreased from pre- to post-surgery, whereas there was no significant change in IL-6 reactivity among those whose pain did not improve. There was also a significant interaction between pain status and change in insomnia, such that among patients whose insomnia decreased over time, improved pain was significantly associated with a reduction in IL-6 reactivity. However, among patients whose insomnia increased over time, pain status and change in IL-6 reactivity were not significantly associated. Our findings suggest that the resolution of clinical pain after TKA may be associated with discernible alterations in pro-inflammatory responses that can be measured under controlled laboratory conditions, and this association may be moderated by perioperative changes in insomnia. Randomized controlled trials which carefully characterize the phenotypic features of patients are needed to understand how and for whom behavioral interventions may be beneficial in modulating inflammation, pain, and insomnia.

Bumblebee nest departures under low light conditions at sunrise and sunset.

Only a few diurnal animals, such as bumblebees, extend their activity into the time around sunrise and sunset when illumination levels are low. Low light impairs viewing conditions and increases sensory costs, but whether diurnal insects use low light as a cue to make behavioural decisions is uncertain. To investigate how they decide to initiate foraging at these times of day, we observed bumblebee nest-departure behaviours inside a flight net, under naturally changing light conditions. In brighter light bees did not attempt to return to the nest and departed with minimal delay, as expected. In low light the probability of non-departures increased, as a small number of bees attempted to return after spending time on the departure platform. Additionally, in lower illumination bees spent more time on the platform before flying away, up to 68 s. Our results suggest that bees may assess light conditions once outside the colony to inform the decision to depart. These findings give novel insights into how behavioural decisions are made at the start and the end of a foraging day in diurnal animals when the limits of their vision impose additional costs on foraging efficiency.

Preoperative decreased physical activity is associated with greater postoperative pain: the mediating role of preoperative sleep disturbance.

PURPOSE: Engagement in physical activity (PA) is often associated with better sleep quality and less pain severity among patients diagnosed with breast cancer. However, less research has focused on whether patients' PA prior to breast surgery, including their perceived decrease in PA level, is associated with worse preoperative sleep quality, and subsequently, greater postoperative pain. This longitudinal study investigated whether patients' preoperative PA was associated with their postoperative pain. We also explored whether preoperative sleep disturbance partially mediated the relationship between preoperative PA and postoperative pain. METHODS: Prior to breast surgery, patients self-reported both their overall level of PA and whether they perceived a decrease in their PA since the diagnosis/onset of treatment for cancer. Patients also completed a measure of preoperative sleep disturbance. Two weeks after surgery, patients completed a measure of postoperative surgical-area pain severity. RESULTS: Our results showed that preoperatively perceiving a decrease in PA level was significantly associated with greater preoperative sleep disturbance and postoperative pain. A mediation analysis revealed that the association between preoperative decreased PA and postoperative pain was partially mediated by preoperative sleep disturbance. Notably, patients' overall preoperative level of PA was not related to preoperative sleep disturbance or postoperative pain. CONCLUSION: These findings suggest that maintaining, or even increasing, PA after diagnosis/treatment may be more important than the absolute amount of PA that women engage in during the preoperative period. Potentially, some patients with breast cancer may benefit from a preoperative intervention focused on both maintaining PA and bolstering sleep quality.

Elevated pain sensitivity is associated with reduced rapid eye movement (REM) sleep in females with comorbid temporomandibular disorder and insomnia.

OBJECTIVE: Patients with chronic pain disorders, including Temporomandibular Disorders (TMDs) endorse high levels of sleep disturbances, frequently reporting reduced sleep quality. Despite this, little is known about the effect that daytime pain has on the microstructure and macro-architecture of sleep. Therefore, we aimed to examine the extent to which daytime pain sensitivity, measured using quantitative sensory testing (QST), is associated with objective sleep parameters the following night, including sleep architecture and power spectral density, in women with TMD. METHODS: 144 females with myalgia and arthralgia by examination using the Diagnostic criteria for TMD completed a comprehensive QST battery consisting of General Pain Sensitivity, Central Sensitization Index, and Masseter Pressure Pain Threshold assessments. Polysomnography was collected the same night to measure sleep architecture and calculate relative power in delta, theta, alpha, sigma, and beta power bands. RESULTS: Central Sensitization (B = -3.069, P = .009), General Pain Sensitivity Indices (B = -3.069, P = .007), and Masseter Pain Pressure Threshold (B = 0.030, P = .008) were significantly associated with lower REM% both before and after controlling for covariates. Pain sensitivity measures were not significantly associated with relative power in any of the spectral bands nor with any other sleep architectural stages. CONCLUSIONS: Our findings demonstrate that higher generalized pain sensitivity, masseter pain pressure threshold, as well as central sensitization were associated with a lower percentage of REM in participants with myofascial pain and arthralgia of the masticatory system. These findings provide an important step toward understanding the mechanistic underpinnings of how chronic pain interacts with sleep physiology.

A Preliminary Examination of the Effects and Mechanisms of Cognitive Behavioral Therapy for Insomnia on Systemic Inflammation Among Patients with Knee Osteoarthritis.

BACKGROUND: Systemic inflammation, particularly the elevation of interleukin-6 (IL-6), plays an important role in the maintenance and progression of knee osteoarthritis. Insomnia, being highly prevalent in knee osteoarthritis, is understood to be a risk factor for systemic inflammation. The present study examined if cognitive behavioral therapy for insomnia (CBT-I) would reduce circulating IL-6 levels to a larger extent than the active control condition via greater improvement in sleep maintenance disturbance at mid-treatment, among individuals with knee osteoarthritis and insomnia disorder. METHODS: This is an ancillary study (N = 64) from a larger double-blind, randomized, active controlled clinical trial. Serum IL-6 was measured at baseline, post-treatment, and 3- and 6-month follow-ups. Sleep was measured by daily sleep diaries. RESULTS: Overall, there was no significant IL-6 trajectory differences between CBT-I and the active control (p = .64). Compared to the active control, CBT-I demonstrated greater improvement in sleep maintenance disturbance at mid-treatment (p = .01), which, in turn, was significantly associated with lower levels of IL-6 at 3-month follow-up (p < .05). Sleep maintenance disturbance at mid-treatment did not significantly predict changes in IL-6 levels at post-treatment (p = .43) and 6-month follow-up (p = .90). CONCLUSIONS: Our study demonstrates that CBT-I can be efficacious in improving sleep maintenance disturbance among individuals with knee osteoarthritis and insomnia disorder. However, no convincing evidence was found that CBT-I can substantially reduce IL-6 levels via improvement in sleep. CBT-I alone may not be effective in reducing systematic inflammation in this clinical population. TRIAL REGISTRATION: NCT00592449.

Patients with IBD Want to Talk About Sleep and Treatments for Insomnia with Their Gastroenterologist.

BACKGROUND AND AIMS: Poor sleep may be prospectively associated with worse disease course in inflammatory bowel disease (IBD). Chronic insomnia is the most common cause of poor sleep complaints in IBD and is theorized to be maintained by dysfunctional thoughts and behavioral patterns. However, data characterizing patterns specific to insomnia in IBD are lacking. Understanding the nuances of insomnia and patients' preferences for treatment is critical for addressing this significant comorbidity in IBD. METHODS: We conducted an anonymous, mixed-method online survey of people with IBD and asked questions about sleep patterns, thoughts, and behaviors related to sleep, treatment preferences, and barriers to treatment. RESULTS: 312 participants (60.9% Crohn's, 66.3% women, mean age of 48.62 years) were included in this study. Participants with insomnia were significantly more concerned about the consequences of sleep loss, felt more helpless about their sleep, and were more likely to engage in behaviors known to perpetuate insomnia (e.g., spending time in bed in pain; ps ≤ 0.001) than those without insomnia. 70.3% of participants were interested in discussing sleep as part of IBD care, 63.5% were interested in receiving sleep recommendations from their gastroenterologist, and 84.6% of those with insomnia were interested in participating in sleep treatments. CONCLUSION: Participants with IBD and insomnia are interested in treatment and reported patterns that can be targeted in Cognitive Behavioral Therapy for Insomnia, as opposed to traditional sleep hygiene guidelines. Additionally, people with insomnia engaged in several sleep-interfering behaviors related to pain. Clinical trials that target insomnia in people with IBD should include pain management in the intervention.

Presurgical sleep and pain behaviors predict insomnia symptoms and pain after total knee arthroplasty: a 12-month longitudinal, observational study.

OBJECTIVE: Up to 40% of individuals who undergo total knee arthroplasty (TKA) experience some degree of pain following surgery. Presurgical insomnia has been identified as a predictor of postsurgical pain; however, modifiable presurgical behaviors related to insomnia have received minimal attention. The objective of the present study was to develop a 2-item sleep and pain behavior scale (SP2) to investigate a maladaptive sleep and pain behavior and is a secondary analysis of a larger, parent study. METHODS: Patients (N = 109) completed SP2 at baseline and 12 months and questionnaires assessing sleep and pain at baseline (pre-TKA), 6 weeks, 3, 6, and 12 months post-TKA. SP2 demonstrated adequate preliminary psychometric properties. RESULTS: As hypothesized, even after controlling for baseline insomnia, pain, anxiety and other covariates, baseline SP2 predicted insomnia symptom severity at 6 weeks (ß = 2.828), 3 (ß = 2.140), 6 (ß = 2.962), and 12 months (ß = 1.835) and pain at 6 weeks (ß = 6.722), 3 (ß = 5.536), and 6 months (ß = 7.677) post-TKA (P < .05). Insomnia symptoms at 6-weeks post-TKA mediated the effect of presurgical SP2 on pain at 3 (95% CI: 0.024-7.054), 6 (95%CI: 0.495-5.243), and 12 months (95% CI: 0.077-2.684). CONCLUSIONS: This provides preliminary evidence that patients who cope with pain by retiring to their bed and bedroom have higher rates of post-surgical insomnia and pain and supports efforts to target this maladaptive sleep and pain behavior to reduce postsurgical pain.

Brief Mindfulness-Based Cognitive Behavioral Therapy is Associated with Faster Recovery in Patients Undergoing Total Knee Arthroplasty: A Pilot Clinical Trial.

OBJECTIVE: To assess whether brief mindfulness-based cognitive behavioral therapy (MBCBT) could enhance the benefits of total knee arthroplasty (TKA) in improving pain and pain-related disability. Specifically, to determine 1) whether patients who received MBCBT differed from matched controls who received treatment-as-usual with regard to postsurgical pain outcomes and 2) whether changes in pain catastrophizing, depression, or anxiety explained the potential effects of MBCBT on pain outcomes. DESIGN: Pilot clinical trial. SETTING: An academic teaching hospital serving a large urban and suburban catchment area surrounding the Boston, Massachusetts metropolitan region. SUBJECTS: Sample of 44 patients undergoing TKA. Patients who completed a brief MBCBT intervention (n = 22) were compared with age-, race-, and sex-matched controls who received treatment-as-usual (n = 22). METHODS: The MBCBT intervention included four 60-minute sessions delivered by a pain psychologist in person and via telephone during the perioperative period. Participants were assessed at baseline and at 6 weeks, 3 months, and 6 months after surgery. RESULTS: Compared with matched controls, patients who received MBCBT had lower pain severity and pain interference at 6 weeks after surgery. Group differences in outcomes were mediated by changes in pain catastrophizing but not by changes in depression or anxiety. The MBCBT group had similar reductions in pain severity and interference as the control group did at 3 and 6 months after surgery. CONCLUSIONS: This work offers evidence for a safe and flexibly delivered nonpharmacological treatment (MBCBT) to promote faster recovery from TKA and identifies change in pain catastrophizing as a mechanism by which this intervention could lead to enhanced pain-related outcomes.

Sleep, Positive Affect, and Circulating Interleukin-6 in Women With Temporomandibular Joint Disorder.

OBJECTIVE: Systemic inflammation is commonly observed in idiopathic chronic pain conditions, including temporomandibular joint disorder (TMD). Trait positive affect (PA) is associated with lower inflammation in healthy controls, but those effects may be threatened by poor sleep. The associations between PA with proinflammatory cytokine activity and potential moderation by sleep in chronic pain are not known. We thus investigated the association between PA and circulating interleukin-6 (IL-6) and moderation of that association by sleep in a sample of women with TMD and sleep difficulties. METHODS: Participants (n = 110) completed the insomnia severity index and provided blood samples at five intervals throughout an evoked pain testing session. They then completed a 14-day diary assessing sleep and affect, along with wrist actigraphy. RESULTS: There was not a significant main effect of PA on resting or pain-evoked IL-6 (b = 0.04, p = .33). Diary total sleep time (b = -0.002, p = .008), sleep efficiency (b = -0.01, p = .005), sleep onset latency (b = 0.006, p = .010), and wake after sleep onset (b = 0.003, p = .033) interacted with PA to predict IL-6, such that PA inversely predicted IL-6 at higher levels of total sleep time and sleep efficiency and at lower levels of sleep onset latency and wake after sleep onset. Surprisingly, when sleep was poor, PA predicted greater IL-6. CONCLUSIONS: The potential salutary effects of PA on resting IL-6 erode when sleep is poor, underscoring the importance of considering sleep in conceptual and intervention models of TMD.

Poor Sleep in Inflammatory Bowel Disease Is Reflective of Distinct Sleep Disorders.

BACKGROUND: Poor sleep is common in inflammatory bowel disease (IBD), predicting increased risk of flares, surgery, and/or hospitalization and reducing quality of life. AIMS: To profile specific sleep disorder symptoms in IBD, informing intervention efforts. METHODS: 312 adults with Crohn's disease or ulcerative colitis were recruited from an academic medical center in New Hampshire, USA. Participants completed online surveys about sleep including well-validated measures of sleep quality, insomnia, restless leg syndrome, sleep apnea, and circadian rhythms. Participants also answered questions about IBD-related problems that could interfere with sleep. RESULTS: 69.4% of participants reported experiencing poor sleep and 50% reported clinically significant insomnia. Participants with active IBD symptoms were more likely to have poor sleep and insomnia. Of those with poor sleep, 67.8% met the clinical threshold for insomnia disorder and 31.3% met criteria for two or more sleep disorders. IBD-related sleep disruptions (e.g., nighttime awakenings due to bowel movements) were not significantly related to poor sleep quality, but significantly related to insomnia severity for participants with active Crohn's disease. CONCLUSIONS: While poor sleep in IBD is reflective of a number of different sleep problems, it is most frequently related to insomnia. IBD symptom severity contributes to insomnia, but insomnia is also distinct from IBD-related sleep disruptions. Future research on the treatment of insomnia disorder in particular in individuals with IBD is warranted.

The Influence of Expectancies on Pain and Function Over Time After Total Knee Arthroplasty.

OBJECTIVE: Expectancies have a well-documented influence on the experience of pain, responses to treatment, and postsurgical outcomes. In individuals with osteoarthritis, several studies have shown that expectations predict increased pain and disability after total knee replacement surgery. Despite the growing recognition of the importance of expectancies in clinical settings, few studies have examined the influence of expectancies throughout postsurgical recovery trajectories. The objective of the present study was to examine the role of presurgical expectancies on pain and function at 6-week, 6-month, and 1-year follow-ups after total knee arthroplasty. DESIGN AND PARTICIPANTS: Data were collected from patients scheduled for total knee arthroplasty 1 week before surgery and then at 6 weeks, 6 months, and 1 year after surgery. Correlational and multivariable regression analyses examined the influence of expectancies on patients' perceptions of pain reduction and functional improvement at each time point. Analyses controlled for age, sex, body mass index, presurgical pain intensity and function, pain catastrophizing, anxiety, and depression. RESULTS: Results revealed that expectancies significantly predicted pain reduction and functional improvement at 1-year follow-up. However, expectancies did not predict outcomes at the 6-week and 6-month follow-ups. Catastrophizing and depressive symptoms emerged as short-term predictors of postsurgical functional limitations at 6-week and 6-month follow-ups, respectively. CONCLUSIONS: The results suggest that targeting high levels of catastrophizing and depressive symptoms could optimize short-term recovery after total knee arthroplasty. However, the results demonstrate that targeting presurgical negative expectancies could prevent prolonged recovery trajectories, characterized by pain and loss of function up to 1 year after total knee arthroplasty.

Multimodal prediction of pain and functional outcomes 6 months following total knee replacement: a prospective cohort study.

BACKGROUND: Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence and impact around the globe. In the U.S., the rising prevalence of knee OA has been paralleled by an increase in annual rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, post-operative trajectories of pain and functional status vary substantially; a significant minority of patients report ongoing pain and impaired function following TKA. A number of studies have identified sets of biopsychosocial risk factors for poor post-TKA outcomes (e.g., comorbidities, negative affect, sensory sensitivity), but few prospective studies have systematically evaluated the unique and combined influence of a broad array of factors. METHODS: This multi-site longitudinal cohort study investigated predictors of 6-month pain and functional outcomes following TKA. A wide spectrum of relevant biopsychosocial predictors was assessed preoperatively by medical history, patient-reported questionnaire, functional testing, and quantitative sensory testing in 248 patients undergoing TKA, and subsequently examined for their predictive capacity. RESULTS: The majority of patients had mild or no pain at 6 months, and minimal pain-related impairment, but approximately 30% reported pain intensity ratings of 3/10 or higher. Reporting greater pain severity and dysfunction at 6 months post-TKA was predicted by higher preoperative levels of negative affect, prior pain history, opioid use, and disrupted sleep. Interestingly, lower levels of resilience-related "positive" psychosocial characteristics (i.e., lower agreeableness, lower social support) were among the strongest, most consistent predictors of poor outcomes in multivariable linear regression models. Maladaptive profiles of pain modulation (e.g., elevated temporal summation of pain), while not robust unique predictors, interacted with psychosocial risk factors such that the TKA patients with the most pain and dysfunction exhibited lower resilience and enhanced temporal summation of pain. CONCLUSIONS: This study underscores the importance of considering psychosocial (particularly positively-oriented resilience variables) and sensory profiles, as well as their interaction, in understanding post-surgical pain trajectories.

A Preliminary Investigation of the Underlying Mechanism Associating Daily Sleep Continuity Disturbance and Prescription Opioid Use Among Individuals With Sickle Cell Disease.

BACKGROUND: There are emerging data indicating that sleep disturbance may be linked with an increase in opioid use. The majority of sickle cell disease (SCD) patients experience sleep disturbances, which can elevate pain severity and pain catastrophizing, both of which are important predictors of opioid consumption. PURPOSE: We conducted a preliminary investigation on the association between previous night sleep disturbance and short-acting opioid use, as well as the potential mediating roles of pain severity and pain catastrophizing. Because sex is associated with sleep disturbance, pain-related experiences, and opioid use, we also explored the potential moderating role of sex. METHODS: Participants were 45 SCD patients who were prescribed opioids. For 3 months, sleep diaries were collected immediately upon participants' awakening. Daily pain severity, pain catastrophizing, and prescription opioid use measures were collected before bedtime. RESULTS: Multilevel structural equation modeling revealed that wake time after sleep onset (WASO) during the previous night (Time 1) predicted greater short-acting opioid use during the next day (Time 2). Pain severity and pain catastrophizing measured during the next day (Time 2) also mediated the association between the two. Sex moderation analysis showed that the positive association between WASO and pain severity was largely driven by women. CONCLUSION: These findings provide some preliminary evidence as to the mechanism linking sleep continuity disturbance and opioid requirement in SCD patients. Future studies should replicate and extend these findings with clearer temporal information and employing more refined measures of sleep continuity and prescription opioid use in a larger sample.

Temporal Association of Pain Catastrophizing and Pain Severity Across the Perioperative Period: A Cross-Lagged Panel Analysis After Total Knee Arthroplasty.

OBJECTIVE: Although numerous studies show that preoperative pain catastrophizing is a risk factor for pain after total knee arthroplasty (TKA), little is known about the temporal course of the association between perioperative pain catastrophizing and pain severity. The present study investigated temporal changes and their dynamic associations between pain catastrophizing and pain severity before and after TKA. DESIGN: A secondary data analysis of a larger observational parent study featuring prospective repeated measurement over 12 months. SETTING: Dual-site academic hospital. SUBJECTS: A total of 245 individuals who underwent TKA. METHODS: Participants completed pain catastrophizing and pain severity questionnaires at baseline, 6 weeks, and 3, 6, and 12 months after TKA. Cross-lagged panel analysis was conducted with structural equation modeling including age, sex, race, baseline anxiety, and depressive symptoms as covariates. RESULTS: Reduction in pain catastrophizing from baseline to 6 weeks after TKA was associated with lower pain severity at 3 months after TKA (standardized ß = 0.14; SE = 0.07, P = 0.046), while reduction in pain severity at 6 weeks after TKA was not associated with pain catastrophizing at 3 months after TKA (P = 0.905). In the chronic postsurgical period (>3 months), pain catastrophizing at 6 months after TKA predicted pain severity at 12 months after TKA (ß = 0.23, P = 0.009) with controlling for auto-correlation and covariates, but not vice versa. CONCLUSIONS: We provide evidence that changes in pain catastrophizing from baseline to 6 weeks after TKA are associated with subsequent pain severity. Future studies are warranted to determine whether targeting pain catastrophizing during the perioperative period may improve clinical outcomes for individuals undergoing TKA.

Individual differences in pain sensitivity are associated with cognitive network functional connectivity following one night of experimental sleep disruption.

Previous work suggests that sleep disruption can contribute to poor pain modulation. Here, we used experimental sleep disruption to examine the relationship between sleep disruption-induced pain sensitivity and functional connectivity (FC) of cognitive networks contributing to pain modulation. Nineteen healthy individuals underwent two counterbalanced experimental sleep conditions for one night each: uninterrupted sleep versus sleep disruption. Following each condition, participants completed functional MRI including a simple motor task and a noxious thermal stimulation task. Pain ratings and stimulus temperatures from the latter task were combined to calculate a pain sensitivity change score following sleep disruption. This change score was used as a predictor of simple motor task FC changes using bilateral executive control networks (RECN, LECN) and the default mode network (DMN) masks as seed regions of interest (ROIs). Increased pain sensitivity after sleep disruption was positively associated with increased RECN FC to ROIs within the DMN and LECN (F(4,14) = 25.28, pFDR = 0.05). However, this pain sensitivity change score did not predict FC changes using LECN and DMN masks as seeds (pFDR > 0.05). Given that only RECN FC was associated with sleep loss-induced hyperalgesia, findings suggest that cognitive networks only partially contribute to the sleep-pain dyad.

Hospitalization and mortality following non-attendance for hemodialysis according to dialysis day of the week: a European cohort study.

BACKGROUND: The extension of the interdialytic interval due to due to dialysis session non-attendance varies according to which session of the week the patient misses. The impact of this on subsequent hospitalization and mortality is unknown. METHODS: The ARO cohort study prospectively collected data from hemodialysis patients across 15 European countries on demography, comorbidity, laboratory, hospitalisation, mortality and individual hemodialysis sessions from 2007 to 2014. Event rates for death and hospitalisation according to dialysis day of the week were calculated for patients who attended the three previous scheduled hemodialysis sessions, who then on the next scheduled dialysis day either attended or did not attend. The hazard ratio for these events following non-attendance for the first compared to the second dialysis session of the week was estimated using Cox proportional hazards model adjusted for patient demographics. RESULTS: 3.8 million hemodialysis sessions in 9397 patients were analysed. The non-attendance rates for Monday/Wednesday/Friday sessions were 0.8, 0.9% & 1.4% respectively, and for Tuesday/Thursday/Saturday sessions were 0.6, 1.0% & 1.2% respectively. Compared to those who attended, for the 48-72 h between non-attendance and the next scheduled haemodialysis session, mortality significantly increased from 4.86 to 51.9/100 pt-yrs and hospitalisation increased from 0.58 to 2.1/yr. As time from the two-day break increased, the risk associated with non-attendance lessened: compared to missing the second hemodialysis session, missing the first session had a hazard ratio for mortality of 2.04 (95% CI 1.27-3.29), and for hospitalisation 1.78 (95% CI 1.29-2.47). In patients who attended their scheduled dialysis session and the three preceding, after the two-day break there were absolute increases in mortality (8.3 vs. 4.9/100 pt-yrs) and hospitalisation (1.0 vs. 0.6/yr for the rest of the week) comparable to previous studies. CONCLUSIONS: In addition to hospitalisation and mortality increases seen after the two-day break, additional harm may be manifested in the greater increases in mortality and hospitalisation observed after non-attendance for the first hemodialysis session after the two-day break compared to missing other sessions.

Analgesic Effects of Hydromorphone versus Buprenorphine in Buprenorphine-maintained Individuals.

BACKGROUND: Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16 mg sublingual buprenorphine/naloxone. METHODS: Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16 mg of hydromorphone or 4, 4, 8, and 16 mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events. RESULTS: A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32 mg of IV hydromorphone (means ± SD) (10 ± 14 s, P = 0.035) and 32 mg of buprenorphine (3 ± 5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16 mg (18 ± 24 s, P = 0.018) and 32 mg (48 ± 73 s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16 mg (1 ± 15 s, P = 0.619) or 32 mg (7 ± 16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting. CONCLUSIONS: In this acute clinical pain model, high doses of IV hydromorphone (16 to 32 mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid-related analgesia.

Subjective and Objective Measures of Daytime Activity and Sleep Disturbance in Retinitis Pigmentosa.

SIGNIFICANCE: Objectively measured limitations in daytime activity levels appear to be inextricably linked with sleep disturbances in retinitis pigmentosa (RP) patients, as well as associated with unemployment status and central vision loss. Innovative interventional strategies should be developed to help improve these issues and overall quality of life for RP patients. PURPOSE: Novel sensor devices are emerging as valuable tools to objectively assess behavior. We used validated measures of wrist accelerometry to determine relationships between sleep, vision, and physical activity in RP subjects. METHODS: For one week, 33 RP adults wore a wrist Actiwatch to detect movement during the day (average total activity counts) and disturbed sleep at night. They completed Early Treatment Diabetic Retinopathy Study visual acuity testing, Pelli-Robson contrast sensitivity, Goldmann V4e visual fields, and sleep diaries and validated questionnaires to assess their sleep and general health. RESULTS: Greater wake after sleep onset time measured with actigraphy (i.e., sleep disruption) (P = .01), loss of visual acuity (P = .009), and nonemployment/student status (P = .002) were all significant predictors of reduced daytime average total activity counts in a multiple linear regression model, after adjusting for contrast sensitivity as a cooperative suppressor variable (P = .01) (R = 0.54). Fragmentation measured with actigraphy (i.e., restlessness during sleep) (P = .07) and decreased sleep quality ratings reported upon awakening by the participants in a sleep diary (P = .06) were each marginally associated with reduced daytime average total activity counts, whereas nonemployment/student status, reduced visual acuity, and contrast sensitivity were still significant predictors. Objective and subjective measures of sleep or daytime activity were not statistically significantly correlated (P > .05). CONCLUSIONS: We find nonemployment/student status and sleep disturbances appear to be related to reduced daytime activity levels in adults with central vision loss due to RP. These findings underscore the importance of developing and evaluating interventions to help RP patients maintain engagement in productive activities and improve their disturbed sleep.

Establishment and validation of a microfluidic capillary gel electrophoresis platform method for purity analysis of therapeutic monoclonal antibodies.

Capillary and microfluidic chip electrophoresis technologies are heavily utilized for development, characterization, release, and stability testing of biopharmaceuticals. Within the biopharmaceutical industry, CE-SDS and M-CGE are commonly used for purity determination by separation and quantitation of size-based variants. M-CGE is used primarily as an R&D tool for product and process development, while cGMP release and stability testing applications are commonly reserved for CE-SDS. This paper describes the establishment of an M-CGE platform method to be used for R&D and cGMP applications, including release and stability testing, for monoclonal antibodies. The M-CGE platform method enables testing for product development support and cGMP release and stability using the same method, and utilization of one CE technology for the entire lifecycle of a biopharmaceutical product. Critical method parameters were identified, and the analytical design space of those critical parameters was defined using design of experiments (DOE) studies. Once defined through DOE studies, the method design space was validated according to ICH Q2 (R1) guidelines. Additional molecules of the same validated class were verified for use in the method by experimental confirmation of accuracy, specificity, and stability indicating capabilities. The platform method model facilitates rapid utilization of the method in development and GMP testing environments, and eliminates the need for individual validations for assets of the same class entering early stage development.

A therapeutic cancer vaccine against GL261 murine glioma.

BACKGROUND: Glioblastoma (GBM) is the deadliest of brain tumors. Standard treatment for GBM is surgery, followed by combined radiation therapy and chemotherapy. Current therapy prolongs survival but does not offer a cure. We report on a novel immunotherapy against GBM, tested in an animal model of C57BL/6 mice injected intra-cranially with a lethal dose of murine GL261 glioma cells. METHODS: Ten week-old C57BL/6 mice were anesthetized before injection of 2 × 10(4) GL261 cells in the right cerebral hemisphere and after 3 days half of the mice were administered a single subcutaneous (s.c.) injection of irradiated semi-allogeneic vaccine, while mock-vaccinated mice received a s.c. injection of phosphate-buffered saline (PBS). Tumor engraftment was monitored through bioluminescence imaging (BLI). Length of animal survival was measured by Kaplan-Meier graphs and statistics. At time of sacrifice brain tissue was processed for estimation of tumor size and immunohistochemical studies. RESULTS: Overall survival of vaccinated mice was significantly longer compared to mock-vaccinated mice. Five to ten percent of vaccinated mice survived more than 90 days following the engraftment of GL261 cells in the brain and appeared to be free of disease by BLI. Tumor volume in the brain of vaccinated mice was on average five to ten-fold smaller compared to mock-vaccinated mice. In vaccinated mice, conspicuous microglia infiltrates were observed in tumor tissue sections and activated microglia appeared to form a fence along the perimeter of the tumor cells. The results of these animal studies persuaded the Office of Orphan Products Development of the Food and Drug Administration (FDA) to grant Orphan Drug Designation for treatment of GBM with irradiated, semi-allogeneic vaccines. CONCLUSIONS: Our preclinical observations suggest that semi-allogeneic vaccines could be tested clinically on subjects with GBM, as an adjuvant to standard treatment.