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Evaluate durability of pregabalin's effect on pain associated with fibromyalgia (FM).
Randomized, double-blind, placebo-controlled trial with 1-week single-blind placebo run-in. Patients meeting ACR diagnostic criteria were randomized to pregabalin 300, 450, or 600 mg/d (BID) or placebo for 14 weeks (2-week dosage escalation; 12-week fixed-dosage). Pain was assessed with a daily pain diary using an 11-point numeric scale. Primary efficacy parameter was the LOCF endpoint mean pain score (MPS). Sensitivity analyses were assessed using the Duration Adjusted Average Change (DAAC) and a Mixed Model Repeated Measurements (MMRM).
745 randomized patients: 95% female, mean age=50 years, median FM duration=10 years, baseline MPS=6.7. Placebo-corrected differences in mean change from baseline to endpoint in MPS: 300mg/d, -0.71 (P=0.0009); 450mg/d, -0.98 (P<0.0001); 600mg/d, -1.00 (P<0.0001). Mean differences from placebo at endpoint (adjusted for treatment duration) over the entire treatment period (DAAC): 300mg/d, -.38, P=0.0200; 450mg/d, -.62; P=0.0001 and 600mg/d,-.57 P<0.0001. In the MMRM analysis, all 3 pregabalin treatment groups demonstrated pain relief by Week 1, and every weekly assessment thereafter, with the exception of 300mg/d treatment group at Week 11. Most common AEs: dizziness (all pregabalin, 35.8% vs placebo, 7.6%); somnolence (18.0% vs 3.8%). Most AEs were mild to moderate and resolved with continued treatment.
Pregabalin demonstrated significant reduction in endpoint MPS in FM patients. The DAAC sensitivity analysis confirmed the robustness of this effect. MMRM analyses demonstrated significant pain relief by Week 1 that was maintained throughout pregabalin treatment.
This study (A0081057) was designed to evaluate the long-term safety and efficacy of pregabalin treatment of fibromyalgia (FM).
In this 1-year, open-label (OL) extension of a 13-week randomized, placebo-controlled trial of pregabalin FM patients had the option of continuing pregabalin at doses of 150 to 600 mg/d. Efficacy was measured by the Short-Form McGill Pain Questionnaire (SF-MPQ), which included sensory and affective pain descriptors, Present Pain Intensity (PPI) index, and a Visual Analog Scale (VAS).
429 of 431 screened patients entered OL treatment, 249 (58%) completed, 70 (16.3%) discontinued due to an adverse event (AE), and 110 (25.7%) discontinued for other reasons. Median duration of treatment with pregabalin was 357 days (range, 1-402 days); 114 received pregabalin for ≥1 year. No clinically meaningful increases in dose were noted over the OL treatment period. Weighted mean dose was 414 mg/d in the first 3 months of treatment and 444 mg/d after 9 months of treatment. SF-MPQ sensory, affective, and total scores were improved relative to baseline, VAS pain score decreased 21 points (0-100 scale), and PPI decreased 0.9 point (0-5 scale). The most frequently reported all-causality AEs were dizziness, somnolence, peripheral edema, and increased weight, most of which were mild to moderate in intensity and of limited duration.
Pregabalin administered for up to 1 year was generally well tolerated by FM patients without evidence of dose increase over time. The sustained improvement in pain measures during OL treatment was consistent with that in shorter term double-blind trials.
Examine the evidence for a relationship between pregabalin effect on pain and baseline anxiety and depressive symptoms in patients with fibromyalgia (FM).
Chronic pain and concomitant anxiety and depressive symptoms are common in patients with FM, as well as in other chronic pain disorders. Pregabalin was effective for treating pain in FM patients in three parallel group RCTs (105, 1056, 1077) where data for anxiety and depressive symptom levels were collected.
Patients meeting ACR criteria for FM with a pain VAS score ≥40 mm were followed for 8-14 weeks in 3 randomized, double-blind, placebo-controlled trials. Patients (N=2022) received 150, 300, 450 or 600mg/d pregabalin or placebo. The primary efficacy parameter was change in endpoint Mean Pain Score (MPS) (range 0 [no pain]-10[worst possible pain]). Regression analyses evaluated whether changes in pain bore any relation to the baseline Hospital Anxiety and Depression Scales (HADS-A) and (HADS-D) levels.
Pregabalin 300, 450, and 600 mg/d, but not 150 mg/d, showed statistically significant improvements in pain compared with placebo (p<0.0001). For each pregabalin treatment group, improvements in pain at endpoint were not found to have a statistically significant association with baseline levels of anxiety or depressive symptoms. Adverse events (AEs) were consistent with known side effects of pregabalin; dizziness and somnolence, mild to moderate in intensity, were the most frequently reported AEs for pregabalin patients.
Pregabalin treatment demonstrated significant improvements in pain regardless of baseline anxiety or depressive symptom levels for patients with FM.
Sleep disturbance is prominent in fibromyalgia (FM). This 14-week, randomized, double-blind, placebo-controlled study, evaluated the effect of pregabalin on pain and sleep-related outcomes in FM.
Patients meeting ACR (FM) diagnostic criteria were randomized to pregabalin 300, 450, or 600mg/d (BID) or placebo for 14 weeks (A0081077). Primary efficacy parameter: LOCF endpoint mean pain score (MPS). At baseline and endpoint, patients completed the Medical Outcomes Sleep (MOS) Sleep Scale. Mean Sleep Quality scores (11-point numeric ratings) were derived from patient daily diaries.
745 randomized patients: 95% female, mean age=50 years, baseline MPS: 6.7. Placebo-corrected differences from baseline to endpoint in MPS were: 300mg/d, -0.71 (p=.0009); 450mg/d, -0.98 (p<.0001); 600mg/d, -1.00 (p<.0001). For MOS Sleep Disturbance, all 3 pregabalin groups demonstrated significant improvements versus placebo (300, 450, and 600 mg/d, -8.91 [p=.0006]; -10.63 [p<.0001]; and -14.93 [p<.0001], respectively). Similar improvements were seen in Sleep Quality (300, 450, and 600mg/d; 0.42, p=0.0030; 0.48, p=.0006; and 0.68, p<.0001 respectively) and MOS Sleep Adequacy (300, 450 and 600mg/d; 5.86, p=.0324; 7.89, p=.0036, and 11.16, p<.0001 respectively). Endpoint Mean Sleep Quality scores across all 3 treatment groups showed significant improvements (300, 450 and 600mg/d; -0.74, p=.0006, -1.12, and -1.35, both p<.0001 respectively). Most common AEs: dizziness (all pregabalin, 35.8% vs placebo, 7.6%); somnolence (18.0% vs 3.8%). Incidence of AEs appeared to be dose-related; most were mild to moderate.
Pregabalin treatment demonstrated significant improvements in pain and patient reported measures of sleep disturbance, adequacy, and quality.
Evidence from previous small trials has suggested the effectiveness of early social communication interventions for autism.
The Preschool Autism Communication Trial (PACT) investigated the efficacy of such an intervention in the largest psychosocial autism trial to date.
To provide a stringent test of a pre-school communication intervention for autism.
152 children with core autism aged 2 years - 4 years 11 months in a 3 site 2 arm single (assessor) blinded randomised controlled trial of the parent-mediated communication-focused intervention added to treatment as usual (TAU) against TAU alone. Primary outcome; severity of autism symptoms (modified social communication algorithm from Autism Diagnostic Observation Schedule-Generic, ADOS-G). Secondary outcomes; blinded measures of parent-child interaction, child language, and adaptation in school.
At 13 month endpoint the treatment resulted in strong improvement in parental synchronous response to child (adjusted between-group effect size 1.22 (95% CI 0.85, 1.59) and child initiations with parent (ES 0.41 (0.08, 0.74) but small effect on autism symptomatology (ADOS-G, ES -0.24 (95% CI -0.59, 0.11) ns). Parents (not blind to allocation) reported strong treatment effects on child language and social adaptation but effects on blinded research assessed language and school adaptation were small.
Addition of the PACT intervention showed clear benefit in improving parent-child dyadic social communication but no substantive benefit over TAU in modifying objectively rated autism symptoms. This attenuation on generalisation from ‘proximal’ intervention effects to wider symptom change in other contexts remains a significant challenge for autism treatment and measurement methodology.
Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees.
One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire.
The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean) = 0.92, SD = 1.44, range = 0–12) and most in Portugal (M = 19.06, SD = 17.44, range = 0–100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M = 3.30, SD = 1.26 vs. M = 2.39, SD = 1.06 on a 5-point Likert scale: 1 “completely disagree” to 5 “completely agree”). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio) = 1.21, 95%CI = 1.12–1.30 and OR = 1.18, 95%CI = 1.02–1.37).
There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training.
The influence of pharmaceutical industry (PI) on clinical practice and research in psychiatry has been considered a serious problem. Strict rules and guidelines were developed to regulate the interactions between doctors and PI. However, there is an ongoing debate whether these were thoroughly implemented in practice and internalized by physicians. The objective of our study was to assess the attitudes and behaviors of trainees in psychiatry and child & adolescent psychiatry toward PI across Europe. Methodologically, a validated questionnaire with additional items was administered to1444 trainees in 20 European countries. The minimum response rate was set at 60%. We found a high variation across countries in number of interactions between trainees and PI representatives; Portugal and Turkey had the highest number of interactions. The majority (59.76%) agreed that interactions with PI representatives have an impact on physicians’ prescribing behavior; whereas only 29.26% and 19.79% agreed interactions with PI representatives and gifts from PI have impact on their own prescribing behavior, respectively. Most of the gifts were considered appropriate by the majority, except tickets to vacation spot and social dinner at a restaurant. Of the sample, 70.76% think they have not been given sufficient training regarding how to interact with PI representatives. Only less than 20% indicated they have guidelines at institutional or national level. In conclusion, there is substantial interaction between trainees and PI across countries. The majority feel inadequately trained regarding professional interaction with PI, and believes they are immune to the influence of PI.
No existing models of alcohol prevention concurrently adopt universal and selective approaches. This study aims to evaluate the first combined universal and selective approach to alcohol prevention.
A total of 26 Australian schools with 2190 students (mean age: 13.3 years) were randomized to receive: universal prevention (Climate Schools); selective prevention (Preventure); combined prevention (Climate Schools and Preventure; CAP); or health education as usual (control). Primary outcomes were alcohol use, binge drinking and alcohol-related harms at 6, 12 and 24 months.
Climate, Preventure and CAP students demonstrated significantly lower growth in their likelihood to drink and binge drink, relative to controls over 24 months. Preventure students displayed significantly lower growth in their likelihood to experience alcohol harms, relative to controls. While adolescents in both the CAP and Climate groups demonstrated slower growth in drinking compared with adolescents in the control group over the 2-year study period, CAP adolescents demonstrated faster growth in drinking compared with Climate adolescents.
Findings support universal, selective and combined approaches to alcohol prevention. Particularly novel are the findings of no advantage of the combined approach over universal or selective prevention alone.
We agree with Lake and colleagues on their list of “key ingredients” for building human-like intelligence, including the idea that model-based reasoning is essential. However, we favor an approach that centers on one additional ingredient: autonomy. In particular, we aim toward agents that can both build and exploit their own internal models, with minimal human hand engineering. We believe an approach centered on autonomous learning has the greatest chance of success as we scale toward real-world complexity, tackling domains for which ready-made formal models are not available. Here, we survey several important examples of the progress that has been made toward building autonomous agents with human-like abilities, and highlight some outstanding challenges.
Most empirical studies into the covariance structure of psychopathology have been confined to adults. This work is not developmentally informed as the meaning, age-of-onset, persistence and expression of disorders differ across the lifespan. This study investigates the underlying structure of adolescent psychopathology and associations between the psychopathological dimensions and sex and personality risk profiles for substance misuse and mental health problems.
This study analyzed data from 2175 adolescents aged 13.3 years. Five dimensional models were tested using confirmatory factor analysis and the external validity was examined using a multiple-indicators multiple-causes model.
A modified bifactor model, with three correlated specific factors (internalizing, externalizing, thought disorder) and one general psychopathology factor, provided the best fit to the data. Females reported higher mean levels of internalizing, and males reported higher mean levels of externalizing. No significant sex differences emerged in liability to thought disorder or general psychopathology. Liability to internalizing, externalizing, thought disorder and general psychopathology was characterized by a number of differences in personality profiles.
This study is the first to identify a bifactor model including a specific thought disorder factor. The findings highlight the utility of transdiagnostic treatment approaches and the importance of restructuring psychopathology in an empirically based manner.
Background: Unexplained significant variation may suggest a quality care problem in a health care system. The objective of this study was to determine the extent of variance in spine surgery Saskatchewan and determine possible causes. Methods: Provincial billing records for new spine surgery consultations from May 2011 through October 2012 were correlated with subsequent lumbar surgery. Two tertiary centers (TC1 and TC2) were compared with reference to the Health Region of origin of the patient. Wait times for surgery and utilization of spine pathway clinics was analyzed. Results: TC1 had significantly higher rates of spine fusion and lumbar spine surgery. The percentage of new referrals that went to surgery was 14.0% in TC1 and 11.8% in TC2 (p<0.0001, Z-Test). Population-based calculation of the rate of new referrals was 1581/482387 = 0.33% for TC1 vs. 970/601739 = 0.16% for TC2 (p<0.0001, Z-Test). Utilization of the spine pathway clinic was lower and wait times for surgery were longer in TC1. Conclusions: Causes of regional variation are unknown and likely multifactorial. In Saskatchewan, the most striking variance was that the rate of primary care referrals for lower back conditions in regions served by TC1 was double that for TC2. This could potentially be reduced through more regionally consistent utilization of the spine pathway.
A previous work suggests that dietary fat may influence canine olfaction. The present study evaluated whether olfactory performance could be influenced by forms of dietary fat and exercise. Seventeen certified detection dogs were fed three different diets (high fat, low fat or high polyunsaturated fat) for 12 weeks. After 12 weeks, olfactory testing was performed using a scent wheel in an olfaction laboratory using three explosive materials. The dogs completed eight to twelve scent trials before and after a 30 min treadmill exercise on five consecutive days. A mixed-effect logistic regression model was used to examine how diet, pre- or post-exercise, trial number, odourant, mass of target and target position influenced the probability of dogs alerting on the target odour. There were no significant changes in the dog's ability to find a target odour at threshold amounts. Dogs were 1·42 (1·08, 1·87; 95 % CI) times as likely to find a target on the high polyunsaturated fat diet relative to the high-fat diet (P = 0·009). The low-fat diet was not significantly different from either the high-fat diet or the high polyunsaturated fat diet (P = 0·12). Dogs were 1·49 (1·26, 1·76; 95 % CI) times as likely to find a target prior to exercise relative to after exercise (P < 0·001). Dogs on the high PUFA diet utilising maize oil showed mild improvement in olfaction. The exact reasons are unknown; however, the higher relative amount of linoleic acid in the diet may play a role in olfactory sensation which warrants further examination of optimal diets for detection dogs.
Antarctic and Southern Ocean science is vital to understanding natural variability, the processes that govern global change and the role of humans in the Earth and climate system. The potential for new knowledge to be gained from future Antarctic science is substantial. Therefore, the international Antarctic community came together to ‘scan the horizon’ to identify the highest priority scientific questions that researchers should aspire to answer in the next two decades and beyond. Wide consultation was a fundamental principle for the development of a collective, international view of the most important future directions in Antarctic science. From the many possibilities, the horizon scan identified 80 key scientific questions through structured debate, discussion, revision and voting. Questions were clustered into seven topics: i) Antarctic atmosphere and global connections, ii) Southern Ocean and sea ice in a warming world, iii) ice sheet and sea level, iv) the dynamic Earth, v) life on the precipice, vi) near-Earth space and beyond, and vii) human presence in Antarctica. Answering the questions identified by the horizon scan will require innovative experimental designs, novel applications of technology, invention of next-generation field and laboratory approaches, and expanded observing systems and networks. Unbiased, non-contaminating procedures will be required to retrieve the requisite air, biota, sediment, rock, ice and water samples. Sustained year-round access to Antarctica and the Southern Ocean will be essential to increase winter-time measurements. Improved models are needed that represent Antarctica and the Southern Ocean in the Earth System, and provide predictions at spatial and temporal resolutions useful for decision making. A co-ordinated portfolio of cross-disciplinary science, based on new models of international collaboration, will be essential as no scientist, programme or nation can realize these aspirations alone.
Specific roles of individual CDPKs vary, but in general they mediate essential biological functions necessary for parasite survival. A comparative analysis of the structure-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis calcium-dependent protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum and Toxoplasma gondii was performed by screening against 333 bumped kinase inhibitors (BKIs). Structural modelling and experimental data revealed that residues other than the gatekeeper influence compound–protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP-binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase, some library compounds exhibit activity against serine- or threonine-containing CDPKs. Divergent BKI sensitivity of CDPK homologues could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP-binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of a threonine gatekeeper in all three CDPKs.