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Introduction: With 36 million older adult U.S. drivers, safety is a critical concern, particularly among those with dementia. It is unclear at what stage of Alzheimer's disease (AD) older adults stop driving and whether preclinical AD affects driving cessation., Methods: Time to driving cessation was examined based on Clinical Dementia Rating (CDR) and AD cerebrospinal fluid biomarkers. 1795 older adults followed up to 24 years received CDR ratings. A subset (591) had cerebrospinal fluid biomarker measurements and was followed up to 17 years. Differences in CDR and biomarker groups as predictors of time to driving cessation were analyzed using Kaplan-Meier curves and Cox proportional models., Results: Higher CDR scores and more abnormal biomarker measurements predicted a shorter time to driving cessation., Discussion: Higher levels of AD biomarkers, including among individuals with preclinical AD, lead to earlier driving cessation. Negative functional outcomes of preclinical AD show a nonbenign phase of the disease., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The clinical setting of acute pain has provided some of the first approaches for the development of analgesic clinical trial methods., Objectives: This article reviews current methods and challenges and provides recommendations for future design and conduct of clinical trials of interventions to treat acute pain., Conclusion: Growing knowledge about important diverse patient factors as well as varying pain responses to different acute pain conditions and surgical procedures has highlighted several emerging needs for acute pain trials. These include development of early-phase trial designs that minimize variability and thereby enhance assay sensitivity, minimization of bias through blinding and randomization to treatment allocation, and measurement of clinically relevant outcomes such as movement-evoked pain. However, further improvements are needed, in particular for the development of trial methods that focus on treating complex patients at high risk of severe acute pain., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Purpose: Older adults experience impaired driving performance, and modify their driving habits, including limiting amount and spatial extent of travel. Alzheimer disease (AD)-related pathology, as well as spatial navigation difficulties, may influence driving performance and driving behaviors in clinically normal older adults. We examined whether AD biomarkers [cerebrospinal fluid (CSF) concentrations of Aβ42, tau, and ptau181] were associated with lower self-reported spatial navigation abilities, and whether navigation abilities mediated the relationship of AD biomarkers with driving performance and extent., Methods: Clinically normal older adults (n=112; aged 65+) completed an on-road driving test, the Santa Barbara Sense of Direction scale (self-report measure of spatial navigation ability), and the Driving Habits Questionnaire for an estimate of driving extent (composite of driving exposure and driving space). All participants had a lumbar puncture to obtain CSF., Results: CSF Aβ42, but not tau or ptau181, was associated with self-reported navigation ability. Lower self-reported navigation was associated with reduced driving extent, but not driving errors. Self-reported navigation mediated the relationship between CSF Aβ42 and driving extent., Conclusions: Findings suggest that cerebral amyloid deposition is associated with lower perceived ability to navigate the environment, which may lead older adults with AD pathology to limit their driving extent.

Purpose of Review: The purpose of this study was to update a national guideline on assessing drivers with dementia, addressing limitations of previous versions which included a lack of developmental rigor and stakeholder involvement., Methods: An international multidisciplinary team reviewed 104 different recommendations from 12 previous guidelines on assessing drivers with dementia in light of a recent review of the literature. Revised guideline recommendations were drafted by consensus. A preliminary draft was sent to specialist physician and occupational therapy groups for feedback, using an a priori definition of 90% agreement as consensus., Recent Findings: The research team drafted 23 guideline recommendations, and responses were received from 145 stakeholders. No recommendation was endorsed by less than 80% of respondents, and 14 (61%) of the recommendations were endorsed by more than 90%.The recommendations are presented in the manuscript. The revised guideline incorporates the perspectives of consensus of an expert group as well as front-line clinicians who regularly assess drivers with dementia. The majority of the recommendations were based on evidence at the level of expert opinion, revealing gaps in the evidence and future directions for research.

Background: "The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE)., Methods: An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance., Results: Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain., Conclusions: This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

We administered the Assessment of Readiness for Mobility Transition (ARMT) to 301 older drivers and compared total scores with participant characteristics. Overall, 18% of participants were not attitudinally ready for mobility transition, while 19% were very ready. Notably, participants with hospitalizations in the past year were either very ready for mobility transition (20% vs 14% without hospitalizations) or not ready at all (30% vs 17%). Significant health events may polarize reactions towards mobility transition. Individualizing communication about driving cessation readiness could help address such differing views. To further consider its effectiveness, ARMT could be utilized in mobility transition counseling interventions.

Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl-β-cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD-diclofenac; and (2) the PK of HPβCD following administration of HPβCD-diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (V z ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between V z (but not CL or elimination half-life, t ½ ) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t ½ . There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD-diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPβCD-diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090)., (© 2017 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Objectives: To prospectively validate and refine the 5-item "CRASH" screening tool for identifying older drivers needing a behind-the-wheel (BTW) test., Design: Prospective observational study., Setting: Geriatric and internal medicine primary care clinics affiliated with a tertiary care hospital and a local BTW program., Participants: Cognitively intact drivers aged 65 and older (N = 315)., Measurements: Participants completed baseline questionnaire (including CRASH tool) and assessments and BTW test (evaluator blinded to questionnaire results) and participated in 1-month telephone follow-up. Analysis included descriptive statistics and examination of predictive ability of the CRASH tool to discriminate normal (pass) from abnormal (conditional pass or fail) on the BTW test, with logistic regression and CART techniques for tool refinement., Results: Two hundred sixty-six participants (84%) had a BTW test; of these, 17% had a normal rating and 83% an abnormal rating. Forty-five percent of those with an abnormal score were advised to limit driving under particular conditions. Neither the CRASH tool nor its individual component variables were significantly associated with the summary BTW score; in refined models with other variables, the best-performing tool had approximately 67% sensitivity and specificity for an abnormal BTW score. Most participants found the BTW test useful and were willing to pay a median of $50. At 1-month follow-up, no participants had stopped driving., Conclusion: The CRASH screening tool cannot be recommended for use in clinical practice. Findings on older adults' perceived utility of the BTW test and the stability of driving patterns at 1-month follow-up could be useful for future research studies and for design of older driver programs., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Despite the reality of older adults living many years after driving cessation, few prepare for the eventuality; empirically, planning for a nondriving future has not been directly quantified or explored. The following study quantifies 1) the extent of current drivers' planning, 2) specific planning behaviors, 3) beliefs about benefits of planning, 4) drivers' intention to plan more for future transportation needs, and 5) group differences associated with planning. In a predominantly female, black, urban sample of current drivers ages 53-92, fewer than half (42.1%) had planned at all for a nondriving future, with correspondingly low levels of planning behaviors reported. However, over 80% believed planning would help them meet their needs post-cessation and transition emotionally to being a nondriver. Most (85%) intended to plan more in the future as well, indicating further potential openness to the topic. Drivers who planned were older, drove less frequently, limited their driving to nearby places, reported less difficulty believing they would become a nondriver, and expected to continue driving three years less than non-planners. These findings suggest that drivers' perceived nearness to driving cessation impacts planning for future transportation needs, and existing perceived benefits of planning may provide leverage to motivate action., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Proteins often undergo slow structural rearrangements that involve several angstroms and surpass the nanosecond timescale. These spatiotemporal scales challenge physics-based simulations and open the way to sample-based models of structural dynamics. This article improves an understanding of current capabilities and limitations of sample-based models of dynamics. Borrowing from widely used concepts in evolutionary computation, this article introduces two conflicting aspects of sampling capability and quantifies them via statistical (and graphical) analysis tools. This allows not only conducting a principled comparison of different sample-based algorithms but also understanding which algorithmic ingredients to use as knobs via which to control sampling and, in turn, the accuracy and detail of modeled structural rearrangements. We demonstrate the latter by proposing two powerful variants of a recently published sample-based algorithm. We believe that this work will advance the adoption of sample-based models as reliable tools for modeling slow protein structural rearrangements.

Background: Adults aged 85 and older, often referred to as the oldest-old, are the fastest-growing segment of the population. The rapidly increasing number of older adults with chronic and multiple medical conditions poses challenges regarding their driving safety., Objective: To investigate the effect of advanced age on driving safety in drivers with medical conditions., Methods: We categorized 3,425 drivers with preexisting medical conditions into four age groups: middle-aged (55-64 years, n = 1,386), young-old (65-74 years, n = 1,013), old-old (75-84 years, n = 803), or oldest-old (85 years and older, n = 223). All underwent a formal driving evaluation. The outcome measures included fitness to drive recommendation by the referring physician, comprehensive fitness to drive decision from an official driving evaluation center, history of motor vehicle crashes (MVCs), and history of traffic violations., Results: The oldest-old reported more cardiopulmonary and visual conditions, but less neurological conditions than the old-old. Compared to the middle-aged, the oldest-old were more likely to be considered unfit to drive by the referring physicians (odds ratio [OR] = 4.47, 95% confidence interval [CI] 2.20-9.10) and by the official driving evaluation center (OR = 2.74, 95% CI 1.87-4.03). The oldest-old reported more MVCs (OR = 2.79, 95% CI 1.88-4.12) compared to the middle-aged., Conclusion: Advanced age adversely affected driving safety outcomes. The oldest-old are a unique age group with medical conditions known to interfere with safe driving. Driving safety strategies should particularly target the oldest-old since they are the fastest-growing group and their increased frailty is associated with severe or fatal injuries due to MVCs., (© 2018 S. Karger AG, Basel.)

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

Guidelines that physicians use to assess fitness to drive for dementia are limited in their currency, applicability, and rigor of development. Therefore, we performed a systematic review to determine the risk of motor vehicle collisions (MVCs) or driving impairment caused by dementia, in order to update international guidelines on driving with dementia. Seven literature databases (MEDLINE, CINAHL, Embase, etc.) were searched for all research studies published after 2004 containing participants with mild, moderate, or severe dementia. From the retrieved 12,860 search results, we included nine studies in this analysis, involving 378 participants with dementia and 416 healthy controls. Two studies reported on self-/informant-reported MVC risk, one revealing a four-fold increase in MVCs per 1,000 miles driven per week in 3 years prior, and the other showing no statistically significant increase over the same time span. We found medium to large effects of dementia on driving abilities in six of the seven recent studies that examined driving impairment. We also found that persons with dementia were much more likely to fail a road test than healthy controls (RR: 10.77, 95% CI: 3.00-38.62, z = 3.65, p < 0.001), with no significant heterogeneity (χ 2  = 1.50, p = 0.68, I 2  = 0%) in a pooled analysis of four studies. Although the limited data regarding MVCs are equivocal, even mild stages of dementia place patients at a substantially higher risk of failing a performance-based road test and of demonstrating impaired driving abilities on the road., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat cancer pain, and are recommended for this purpose in the World Health Organization (WHO) cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on paracetamol, updates the evidence., Objectives: To assess the efficacy of oral NSAIDs for cancer pain in adults, and the adverse events reported during their use in clinical trials., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to April 2017, together with reference lists of retrieved papers and reviews, and two online study registries., Selection Criteria: We included randomised, double-blind, single-blind, or open-label studies of five days' duration or longer, comparing any oral NSAID alone with placebo or another NSAID, or a combination of NSAID plus opioid with the same dose of the opioid alone, for cancer pain of any pain intensity. The minimum study size was 25 participants per treatment arm at the initial randomisation., Data Collection and Analysis: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table., Main Results: Eleven studies satisfied inclusion criteria, lasting one week or longer; 949 participants with mostly moderate or severe pain were randomised initially, but fewer completed treatment or had results of treatment. Eight studies were double-blind, two single-blind, and one open-label. None had a placebo only control; eight compared different NSAIDs, three an NSAID with opioid or opioid combination, and one both. None compared an NSAID plus opioid with the same dose of opioid alone. Most studies were at high risk of bias for blinding, incomplete outcome data, or small size; none was unequivocally at low risk of bias.It was not possible to compare NSAIDs as a group with another treatment, or one NSAID with another NSAID. Results for all NSAIDs are reported as a randomised cohort. We judged results for all outcomes as very low-quality evidence.None of the studies reported our primary outcomes of participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). With NSAID, initially moderate or severe pain was reduced to no worse than mild pain after one or two weeks in four studies (415 participants in total), with a range of estimates between 26% and 51% in individual studies.Adverse event and withdrawal reporting was inconsistent. Two serious adverse events were reported with NSAIDs, and 22 deaths, but these were not clearly related to any pain treatment. Common adverse events were thirst/dry mouth (15%), loss of appetite (14%), somnolence (11%), and dyspepsia (11%). Withdrawals were common, mostly because of lack of efficacy (24%) or adverse events (5%)., Authors' Conclusions: There is no high-quality evidence to support or refute the use of NSAIDs alone or in combination with opioids for the three steps of the three-step WHO cancer pain ladder. There is very low-quality evidence that some people with moderate or severe cancer pain can obtain substantial levels of benefit within one or two weeks.

Background: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence., Objectives: To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries., Selection Criteria: We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation., Data Collection and Analysis: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table., Main Results: Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and two had a cross-over design. All used paracetamol as an add-on to established treatment with strong opioids (median daily morphine equivalent doses of 60 mg, 70 mg, and 225 mg, with some participants taking several hundred mg of oral morphine equivalents daily). Other non-paracetamol medication included non-steroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, or neuroleptics. All studies were at high risk of bias for incomplete outcome data and small size; none was unequivocally at low risk of bias.None of the studies reported any of our primary outcomes: participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with pain no worse than mild at the end of the treatment period; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). What pain reports there were indicated no difference between paracetamol and placebo when added to another treatment. There was no convincing evidence of paracetamol being different from placebo with regards to quality of life, use of rescue medication, or participant satisfaction or preference. Measures of harm (serious adverse events, other adverse events, and withdrawal due to lack of efficacy) were inconsistently reported and provided no clear evidence of difference.Our GRADE assessment of evidence quality was very low for all outcomes, because studies were at high risk of bias from several sources., Authors' Conclusions: There is no high-quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three-step WHO cancer pain ladder. It is not clear whether any additional analgesic benefit of paracetamol could be detected in the available studies, in view of the doses of opioids used.

This IASP Satellite Symposium surveyed opioid adverse effects upon patients and society, current and future drug and nondrug alternatives, and strategies to optimize postoperative outcomes through quality improvement.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials., Perspective: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability., (Copyright © 2017 American Pain Society. All rights reserved.)

Background: Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews., Objectives: To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries., Selection Criteria: We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment., Data Collection and Analysis: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables., Main Results: We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events., Authors' Conclusions: There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.

Objective: With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain., Setting: Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM)., Methods: As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions., Perspective: The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms., Conclusions: Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Inventory one medical school's first- and second-year pain-related curriculum in order to explore opportunities to teach about pain both as a social, population-based process and as a neuron-centered phenomenon., Design: Deconstruction of pain-related curricular content through a detailed content inventory and analysis by students and faculty., Setting and Subjects: University-affiliated US medical school., Methods: Detailed inventory and content analysis of first- and second-year curricular materials., Results: The inventory of pain content showed fragmentation, mostly presenting it as a symptom without an underlying framework., Conclusion: Analysis of one medical school's pain-related curricular materials reveals opportunities for a more unified perspective that includes pain as a widespread disease state (not merely a symptom) and to provide an emphasis in the curriculum consistent with pain's public health burden., (© 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: To reshape medical education about pain to present it as a population-based public health process as well as a neuron-centered phenomenon., Design: Collaborate with students to apply a recent inventory of pain-related preclinical curricular content and clinical training in order to modify the current multiyear presentation and offer a broadened social perspective on pain. Appraise fourth-year medical students' pain-related educational needs by surveying their knowledge, attitudes, experience with the curriculum, and self-reported assessment of pain-related competencies., Setting and Subjects: University-affiliated medical school and its fourth-year medical students., Methods: Analysis of a detailed inventory of first- and second-year curricula. Survey of graduating medical students assessing attitudes, skills, and confidence. Construction of a fourth-year pain education elective and collaboration with enrollees to better integrate pain throughout the four-year curriculum., Results: This student-faculty collaboration produced an evidence-guided proposal to reorganize pain-related content across the longitudinal medical curriculum. An attitudes/skills/confidence survey of graduating medical students (104 respondents of 200 polled) found that 70% believed chances for successful outcomes treating chronic pain were low. Self-evaluated competency was high for evaluating (82%) and managing (69%) acute pain; for chronic pain, both were lower (evaluating = 38%; managing = 6%). Self-evaluated knowledge of pain physiology and neurobiology was poor (14%), fair (54%), or good (30%), but rarely excellent (2%)., Conclusions: To meet graduating students' desire for increased competency in pain, pain-related curricula can and should be reorganized to include pain as a disease state and a widespread public health burden, not merely a symptom., (© 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Topical local anaesthetics provide effective analgesia for patients undergoing numerous superficial procedures, including repair of dermal lacerations. The need for cocaine in topical anaesthetic formulations has been questioned because of concern about adverse effects, thus novel preparations of cocaine-free anaesthetics have been developed. This review was originally published in 2011 and has been updated in 2017., Objectives: To assess whether benefits of non-invasive topical anaesthetic application occur at the expense of decreased analgesic efficacy. To compare the efficacy of various single-component or multi-component topical anaesthetic agents for repair of dermal lacerations. To determine the clinical necessity for topical application of the ester anaesthetic, cocaine., Search Methods: For this updated review, we searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), Cumulative Index to Nursing and Allied Health Literature (CINAHL; 2010 to December 2016), Embase (2010 to December 2016) and MEDLINE (2010 to December 2016). We did not limit this search by language or format of publication. We contacted manufacturers, international scientific societies and researchers in the field. Weemailed selected journalsand reviewed meta-registers of ongoing trials. For the previous version of this review, we searched these databases to November 2010., Selection Criteria: We included randomized controlled trials (RCTs) that evaluated the efficacy and safety of topical anaesthetics for repair of dermal laceration in adult and paediatric participants., Data Collection and Analysis: Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information when needed. We collected adverse event information from trial reports. We assessed methodological risk of bias for each included study and employed the GRADE approach to assess the overall quality of the evidence., Main Results: The present updated review included 25 RCTs involving 3278 participants. The small number of trials in each comparison group and the heterogeneity of outcome measures precluded quantitative analysis of data for all but one outcome: pain intensity. In two pooled studies, the mean self-reported visual analogue scale (VAS; 0 to 100 mm) score for topical prilocaine-phenylephrine (PP) was higher than the mean self-reported VAS (0 to 100 mm) score for topical tetracaine-epinephrine-cocaine (TAC) by 5.59 points (95% confidence interval (CI) 2.16 to 13.35). Most trials that compared infiltrated and topical anaesthetics were at high risk of bias, which is likely to have affected their results. Researchers found that several cocaine-free topical anaesthetics provided effective analgesic efficacy. However, data regarding the efficacy of each topical agent are based mostly on single comparisons in trials with unclear or high risk of bias. Mild, self-limited erythematous skin induration occurred in one of 1042 participants who had undergone application of TAC. Investigators reported no serious complications among any of the participants treated with cocaine-based or cocaine-free topical anaesthetics. The overall quality of the evidence according to the GRADE system is low owing to limitations in design and implementation, imprecision of results and high probability of publication bias (selective reporting of data). Additional well-designed RCTs with low risk of bias are necessary before definitive conclusions can be reached., Authors' Conclusions: We have found two new studies published since the last version of this review was prepared. We have added these studies to those previously included and have conducted an updated analysis, which resulted in the same review conclusions as were presented previously.Mostly descriptive analysis indicates that topical anaesthetics may offer an efficacious, non-invasive means of providing analgesia before suturing of dermal lacerations. Use of cocaine-based topical anaesthetics might be hard to justify, given the availability of other effective topical anaesthetics without cocaine. However, the overall quality of the evidence according to the GRADE system is low owing to limitations in design and implementation, imprecision of results and high probability of publication bias (selective reporting of data). Additional well-designed RCTs with low risk of bias are necessary before definitive conclusions can be reached.

Introduction: Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs., Methods: 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits., Results: Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 ., Discussion: Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials., Competing Interests: Declaration of interest Dr. Roe reports no conflicts of interest. Dr. Babulal reports no conflicts of interest. Dr. Head reports no conflicts of interest. Ms. Stout reports no conflicts of interest. Ms. Vernon reports no conflicts of interest. Dr. Ghoshal reports no conflicts of interest. Mr. Garland reports no conflicts of interest. Dr. Barco reports no conflicts of interest. Dr. Williams reports no conflicts of interest. Ms. Johnson reports no conflicts of interest. Ms. Fierberg reports no conflicts of interest. Mr. Fague reports no conflicts of interest. Dr. Xiong reports no conflicts of interest. Dr. Mormino reports no conflicts of interest. Dr. Grant reports no conflicts of interest. Dr. Holtzman reports no conflicts of interest. Dr. Holtzman reports no conflicts of interest. Dr. Fagan reports no conflicts of interest. Dr. Ott reports no conflicts of interest. Dr. Carr reports no conflicts of interest. Dr. Morris reports no conflicts of interest.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42). Higher ratios of CSF tau/Aβ42, ptau181/Aβ42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving., Competing Interests: Possible Conflicts of Interest: Dr. Roe has no conflicts of interest. Dr. Barco has no conflicts of interest. Dr. Head has no conflicts of interest. Dr. Ghoshal has no conflicts of interest. Ms. Selsor reports no disclosures and has no conflicts of interest. Dr. Babulal has no conflicts of interest. Ms. Fierberg reports no disclosures and has no conflicts of interest. Ms. Vernon reports no disclosures and has no conflicts of interest. Mr. Shulman reports no disclosures and has no conflicts of interest. Ms. Johnson reports no conflicts of interest. Mr. Fague has no conflicts of interest. Dr. Xiong has no conflicts of interest. Dr. Grant has no conflicts of interest. Ms. Campbell reports no disclosures and has no conflicts of interest. Dr. Ott reports no conflicts of interest. Dr. Holtzman has no conflicts of interest. Dr. Benzinger has no conflicts of interest. Dr. Fagan has no conflicts of interest. Dr. Carr has no conflicts of interest. Dr. Morris has no conficts of interest.

Objectives: To examine the relationship between key functional impairments, co-morbid conditions and driving performance in a sample of cognitively normal older adults., Design: Prospective observational study., Setting: The Knight Alzheimer's Disease Research Center, Washington University at St. Louis., Participants: Individuals with normal cognition, 64.9 to 88.2 years old (N = 129), with a valid driver's license, who were currently driving at least once per week, and who had participated in longitudinal studies at the Knight Alzheimer's Disease Research Center., Measurements: Static visual acuity, contrast sensitivity, physical frailty measures, motor skills, total medical conditions, and the modified Washington University Road Test., Results: When controlling for age, race, gender, APOE, and education the total number of medical conditions was unassociated with both road test scores (pass vs. marginal + fail) and the total driver error count. There were marginal associations of our measure of physical frailty (p = 0.06) and contrast sensitivity score (p = 0.06) with total driving error count., Conclusion: Future research that focuses on older adults and driving should consider adopting measures of physical frailty and contrast sensitivity, especially in samples that may have a propensity for disease impacting visual and/or physical function (e.g. osteoarthritis, Parkinson's, eye disorders, advanced age >80 years, etc.)., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests. DBC: Grants/Funds: NIA, Missouri Department of Transportation, State Farm Insurance; Speaker Forum: St. Louis Alzheimer’s Association, Association for Driver Rehabilitation Specialists (ADED), Canadian Psychiatric Association; Consultant: Medscape, Traffic Injury Research Foundation, University of Ontario, AAA Foundation for Traffic Safety; Board Member: Committee Member on Advocacy for St. Louis Chapter Alzheimer’s Association. PPB: Employment/Affiliation: PRN Occupational Therapist Driving Specialist at The Rehabilitation Institute of St. Louis; Grants/Funds: NIA, Missouri Department of Transportation; Consultant: Traffic Injury Research Foundation; Copyright: Record of Driving Errors (RODE). SHS: Grants/Funds: NIA. AMJ: Grants/Funds: NIA, Missouri Department of Transportation. JMC: Grants/Funds: NIA; Honoraria: Eli Lilly; Consultant: Takeda Pharmaceuticals; Royalties: Blackwell Medical Publishers and Taylor & Francis; Board Member: AAN Board of Directors. CMR: Grants/Funds: NIA. These relationships and our willingness to provide the data do not alter our adherence to PLOS ONE policies on sharing data and materials.

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPβCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPβCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPβCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPβCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPβCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPβCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPβCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Postmortem studies suggest that fibrillar brain amyloid places people at higher risk for hazardous driving in the preclinical stage of Alzheimer's disease (AD)., Methods: We administered driving questionnaires to 104 older drivers (19 AD, 24 mild cognitive impairment, and 61 cognitive normal) who had a recent 18 F-florbetapir positron emission tomography scan. We examined associations of amyloid standardized uptake value ratios with driving behaviors: traffic violations or accidents in the past 3 years., Results: The frequency of violations or accidents was curvilinear with respect to standardized uptake value ratios, peaking around a value of 1.1 (model r 2  = 0.10, P  = .002); moreover, this relationship was evident for the cognitively normal participants., Discussion: We found that driving risk is strongly related to accumulating amyloid on positron emission tomography, and that this trend is evident in the preclinical stage of AD. Brain amyloid burden may in part explain the increased crash risk reported in older adults.

Objectives: A recent US federal review and clinical guideline on opioids for chronic pain asserted that the literature contributes no evidence on efficacy because all trials had "inadequate duration." To explore the evidence, we examined durations of studies on opioid, nonopioid drug, and behavioral therapies for chronic pain., Methods: We retrieved Cochrane reviews of anticonvulsants, antidepressants, NSAIDs, opioids, or behavioral interventions for chronic pain. We also examined all opioid treatment studies retrieved for the federal evidence report but excluded due to "inadequate duration.", Results: Of 378 Cochrane reviews retrieved, 72 evaluated one of the five therapies. Six of these 72 were excluded because they were proposals without data or investigated acute pain. Fourteen addressed multiple interventions, leaving 52 for analysis. We graphed numbers of trials vs duration for the five treatments reviewed in the Cochrane Library, compared with durations of opioid trials dropped from the federal evidence report. Most graphs were overdispersed Poisson distributions. Nearly all trials had active treatment durations of 12 weeks or less., Conclusions: No common nonopioid treatment for chronic pain has been studied in aggregate over longer intervals of active treatment than opioids. To dismiss trials as "inadequate" if their observation period is a year or less is inconsistent with current regulatory standards. The literature on major drug and nondrug treatments for chronic pain reveals similarly shaped distributions across modalities. Considering only duration of active treatment in efficacy or effectiveness trials, published evidence is no stronger for any major drug category or behavioral therapy than for opioids., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Preterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48 hours of rescue tocolysis improves neonatal outcome is unproven., Objectives: To evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA)., Search Strategy: We searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour., Selection Criteria: We selected trials including pregnant women between 24 and 36(6/7)  weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48 hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment., Data Collection and Analysis: The primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed., Main Results: Six randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n = 390 for nifedipine; n = 397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR 1.36; 95% confidence interval, 95% CI 0.35-5.33), intraventricular haemorrhage (IVH) ≥ grade II (RR 0.65; 95% CI 0.16-2.67), necrotising enterocolitis (NEC) (RR 1.15; 95% CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR 0.98; 95% CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR 0.74; 95% CI 0.55-1.01)., Conclusion: Maintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice., Tweetable Abstract: Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Background/Objectives : Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. Our objective was to describe the process and associated challenges in adapting an existing, commercial, off-the-shelf (COTS), in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers. Design : The Azuga G2 Tracking Device TM was installed in each participant's vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven.  Setting : The Knight Alzheimer's Disease Research Center at Washington University School of Medicine. Participants : Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance.  Participants were aged 65+ years and had normal cognition. Measurements :  Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations.  Temporal components included number of trips taken during different times of the day.  Behavioral components included number of hard braking, speeding and sudden acceleration events. Methods :  Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS.  Results : Primary locations were confirmed to be 100% accurate when compared to known addresses.  Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns.  Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night.  Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period. Conclusions : Compared to cameras and highly instrumented vehicle in other naturalistic studies, the compact COTS device was quickly installed and transmitted high volumes of data. Driving Profiles for older adults can be created and compared month-to-month or year-to-year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions.

Background: This is an updated version of the original Cochrane review first published in 2008. Scoliosis surgery is often associated with substantial blood loss and potentially detrimental effects in children. Antifibrinolytic agents are often used to reduce perioperative blood loss. Clinical trials have evaluated their efficacy in children undergoing surgical correction of scoliosis, but no systematic review has been published. This review was first published in 2008 and was updated in 2016., Objectives: To assess the efficacy and safety of aprotinin, tranexamic acid and aminocaproic acid in reducing blood loss and transfusion requirements in children undergoing surgery for correction of idiopathic or secondary scoliosis., Search Methods: We ran the search for the previous review in June 2007. For this updated version, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7), MEDLINE (1946 to August week 1 2015), Embase (1947 to 2015 week 38), Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 14 August 2015), Database of Abstracts of Reviews of Effects (DARE; 2015, Issue 2) and reference lists of reviews and retrieved articles for randomized controlled trials in any language. We also checked the clinical trial registry at http://www.clinicaltrials.gov on 8 October 2015., Selection Criteria: We included blinded and unblinded randomized controlled trials (RCTs) that evaluated the effects of antifibrinolytics on perioperative blood loss in children 18 years of age or younger and undergoing scoliosis surgery., Data Collection and Analysis: Two review authors independently extracted data. The primary outcome was total blood loss (intraoperative and postoperative combined). Secondary efficacy outcomes were the number of participants receiving blood transfusion (both autologous and allogeneic) or receiving allogeneic blood transfusion alone, and the total amount of blood transfused. Safety outcomes included the number of deaths, the number of participants reporting any adverse event or a serious adverse event, withdrawals due to adverse events and the number of participants experiencing a specific adverse event (i.e. renal insufficiency, hypersensitivity or thrombosis). We assessed methodological risk of bias for each included study and employed the GRADE approach to assess the overall quality of the evidence., Main Results: We included three new studies (201 participants) in this updated review, for a total of nine studies (455 participants). All but one study employed placebo as the control group intervention. For the primary outcome, antifibrinolytic drugs decreased the amount of perioperative blood loss by 427 mL (95% confidence interval (CI) 251 to 603 mL), for a reduction of over 20% versus placebo. We rated the quality of evidence for our primary outcome as low on the basis of unclear risk of bias for several domains in most studies and the small total number of participants.For secondary outcomes, fewer participants receiving antifibrinolytic drugs received transfusion (allogeneic or autologous) versus those receiving placebo (risk ratio (RR) 0.65, 95% CI 0.50 to 0.85, number needed to treat to prevent one additional harmful outcome (NNTp) 5; very low-quality evidence). Only two studies specifically evaluated the number of participants transfused with only allogeneic blood (risk difference (RD) -0.15, 95% CI -0.26 to -0.03, NNTp 7; very low-quality evidence). Antifibrinolytic drugs decreased the volume of blood transfused by 327 mL (95% CI -186 to -469 mL; low-quality evidence).No study reported deaths in active or control groups. Data were insufficient to allow performance of meta-analysis for any safety outcome. No studies adequately described their methods in assessing safety. The only adverse event of note occurred in one study, when three participants in the placebo group developed postoperative deep vein thrombosis., Authors' Conclusions: Since the last published version of this review (2008), we have found three new studies. Additional evidence shows that antifibrinolytics reduce the requirement for both autologous and allogeneic blood transfusion. Limited evidence of low to very low quality supports the use of antifibrinolytic drugs for reducing blood loss and decreasing the risk, and volume, of transfusion in children undergoing scoliosis surgery. Evidence is insufficient to support the use of a particular agent, although tranexamic acid may be preferred, given its widespread availability. The optimal dose regimen for any of these three agents has not been established. Although adverse events appear to occur infrequently, evidence is insufficient to confirm the safety of these agents, particularly for rare but potentially catastrophic events. No long-term safety data are available.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Background: Structural excursions of a protein at equilibrium are key to biomolecular recognition and function modulation. Protein modeling research is driven by the need to aid wet laboratories in characterizing equilibrium protein dynamics. In principle, structural excursions of a protein can be directly observed via simulation of its dynamics, but the disparate temporal scales involved in such excursions make this approach computationally impractical. On the other hand, an informative representation of the structure space available to a protein at equilibrium can be obtained efficiently via stochastic optimization, but this approach does not directly yield information on equilibrium dynamics., Methods: We present here a novel methodology that first builds a multi-dimensional map of the energy landscape that underlies the structure space of a given protein and then queries the computed map for energetically-feasible excursions between structures of interest. An evolutionary algorithm builds such maps with a practical computational budget. Graphical techniques analyze a computed multi-dimensional map and expose interesting features of an energy landscape, such as basins and barriers. A path searching algorithm then queries a nearest-neighbor graph representation of a computed map for energetically-feasible basin-to-basin excursions., Results: Evaluation is conducted on intrinsically-dynamic proteins of importance in human biology and disease. Visual statistical analysis of the maps of energy landscapes computed by the proposed methodology reveals features already captured in the wet laboratory, as well as new features indicative of interesting, unknown thermodynamically-stable and semi-stable regions of the equilibrium structure space. Comparison of maps and structural excursions computed by the proposed methodology on sequence variants of a protein sheds light on the role of equilibrium structure and dynamics in the sequence-function relationship., Conclusions: Applications show that the proposed methodology is effective at locating basins in complex energy landscapes and computing basin-basin excursions of a protein with a practical computational budget. While the actual temporal scales spanned by a structural excursion cannot be directly obtained due to the foregoing of simulation of dynamics, hypotheses can be formulated regarding the impact of sequence mutations on protein function. These hypotheses are valuable in instigating further research in wet laboratories.

Background: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews, 2005, Issue 4 (and last updated in the Cochrane Database of Systematic Reviews, 2013 issue 8), on local anaesthetic blockade (LASB) of the sympathetic chain to treat people with complex regional pain syndrome (CRPS)., Objectives: To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure., Search Methods: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (Ovid), EMBASE (Ovid), LILACS (Birme), conference abstracts of the World Congresses of the International Association for the Study of Pain, and various clinical trial registers up to September 2015. We also searched bibliographies from retrieved articles for additional studies., Selection Criteria: We considered randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS compared to placebo, no treatment, or alternative treatments., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. The outcomes of interest were reduction in pain intensity, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table., Main Results: We included an additional four studies (N = 154) in this update. For this update, we excluded studies that did not follow up patients for more than 48 hours. As a result, we excluded four studies from the previous review in this update. Overall we included 12 studies (N = 461), all of which we judged to be at high or unclear risk of bias. Overall, the quality of evidence was low to very low, downgraded due to limitations, inconsistency, imprecision, indirectness, or a combination of these.Two small studies compared LASB to placebo/sham (N = 32). They did not demonstrate significant short-term benefit for LASB for pain intensity (moderate quality evidence).One small study (N = 36) at high risk of bias compared thoracic sympathetic block with corticosteroid and local anaesthetic versus injection of the same agents into the subcutaneous space, reporting statistically significant and clinically important differences in pain intensity at one-year follow-up but not at short term follow-up (very low quality evidence).Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB (very low quality evidence).Eight small randomised studies compared sympathetic blockade to various other active interventions. Most studies found no difference in pain outcomes between sympathetic block versus other active treatments (low to very low quality evidence).One small study compared ultrasound-guided LASB with non-guided LASB and found no clinically important difference in pain outcomes (very low quality evidence).Six studies reported adverse events, all with minor effects reported., Authors' Conclusions: This update's results are similar to the previous versions of this systematic review, and the main conclusions are unchanged. There remains a scarcity of published evidence and a lack of high quality evidence to support or refute the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence, it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention, but the limited data available do not suggest that LASB is effective for reducing pain in CRPS.

Study Objective: Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively., Design: A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPβCD-diclofenac vs placebo and the active comparator ketorolac was conducted., Setting: Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery., Patients: Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose., Interventions: Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery., Measurements: CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated., Main Results: IV HPβCD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HPβCD-diclofenac, ketorolac, and placebo groups, respectively., Conclusions: Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HPβCD-diclofenac does not present an added CV safety risk over placebo., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This is an updated version of the original Cochrane review published in Issue 10, 2011. Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally, rectally, or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol, and IV propacetamol (a prodrug that is metabolized to paracetamol), compared with placebo and other analgesics, is unclear., Objectives: To assess the efficacy and safety of IV formulations of paracetamol for the treatment of postoperative pain in both adults and children., Search Methods: We ran the search for the previous review in May 2010. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (May 2010 to 16 February 2016), EMBASE (May 2010 to 16 February 2016), LILACS (2010 to 2016), a clinical trials registry, and reference lists of reviews for randomized controlled trials (RCTs) in any language and we retrieved articles., Selection Criteria: Randomized, double-blind, placebo- or active-controlled single dose clinical trials of IV paracetamol or IV propacetamol for acute postoperative pain in adults or children., Data Collection and Analysis: Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We contacted study authors for additional information. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence., Main Results: We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants.Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI -9 to -6, low quality evidence) in those receiving paracetamol at six hours.For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid-induced adverse events.Meta-analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti-inflammatory drugs) were either not statistically significant, not clinically significant, or both.Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta-analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event., Authors' Conclusions: Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.

Recipient of the 1925 Nobel Prize in Literature, George Bernard Shaw (1856-1950) was an influential critic of the health care establishment in the United Kingdom. Although skeptical of many medical and surgical procedures of the early 20th century, he respected the value of anesthesia, and he advocated its administration by Frederick W. Axham, a medical doctor whose registration was suspended as punishment for providing anesthesia for a bonesetting procedure. In 1924, when a friend needed surgery, Shaw offered to pay the extra fee for the optional anesthesia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: To model the relative contributions of driver data and clinical judgments to clinical ratings of driver capability for a state licensing authority and to compare ratings with on-road test results., Design: Retrospective, logistic regression., Setting: Missouri Driver License Bureau., Participants: Adults aged 60 and older (N = 652; 52% male) evaluated by a physician of their choosing and a portion subsequently road tested (n = 286)., Measurements: Clinical data from an evidence-based physician statement (Form 1528). A three-level rating (likely capable, unclear, not capable) was collapsed into two outcomes (0 likely capable; 1 unclear, not capable) as the dependent variable. Independent variables (predictors) were age, sex, driving exposure, recent crash or police action, number of medical conditions, medication side effects, driver insight, and disease functional severity rating for driving., Results: Three variables in the model (Nagelkerke coefficient of determination = 0.64; P < .001) were significant in the expected direction: disease functional severity for driving (odds ratio (OR = 6.65), insight (OR = 2.35), and age (OR = 1.06). Proportionately more drivers rated likely capable (73%) passed the road test than those rated unclear or not capable (62%)., Conclusion: Judgments of disease severity, decrements in driver insight, and older age influenced clinician ratings of driving capability. Correspondence of physician ratings to on-road test outcomes was imperfect, highlighting the complexities in translation of clinical judgments to on-road performance. Both means of assessment have important and additive roles in driver licensing., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Purpose of the Study: Widespread screening of older drivers, with in-depth evaluation only of those who screen positive ("tiered assessment"), might efficiently balance driver safety and mobility. To inform program development, we sought to examine the perspectives of older drivers and clinicians on the concept of tiered assessment in primary care settings., Design and Methods: Iterative focus groups and interviews with 33 community-dwelling current drivers aged ≥65 years and 8 primary care providers. We used inductive and deductive theme analysis to explore driver and clinician perspectives and to identify barriers and facilitators to establishing a tiered older driver assessment program in primary care settings., Results: Four dominant themes emerged. Two themes addressed the overall concept: (a) support for the concept of tiered older driver assessment and (b) concerns about the consequences of older driver assessment and how these could affect program viability. Two themes addressed screening: (c) tension inherent in using a generalized approach to the highly individualized issue of driving and (d) logistical considerations for screening in primary care settings., Implications: Standardized older driver screening and referral might improve clinician-driver communication, but screening should occur in a context that includes personalized mobility counseling., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We report a case of opioid-induced neurotoxicity (OIN) in an actively dying hospice patient, its reversal and improved analgesia that followed opioid dosage reduction made possible after addition of IV ketamine. We briefly review the diagnosis and treatment of OIN., Setting: OIN, particularly when associated with high dose opioid therapy in palliative care, may pose difficult diagnostic and treatment challenges. Few publications from end-of-life settings provide systematic approaches to management of OIN., Patients: We describe a case of OIN in a hospice patient receiving medical care at home while actively dying., Intervention: Addition of IV ketamine and reduction of the patient's high-dose opioid regimen., Results: The patient's pain was controlled within 24 hours of initiation of IV ketamine while the total opioid dose was reduced. His symptoms of OIN (delirium, tremor, myoclonus, and hallucinations) also rapidly subsided., Conclusion: OIN should be considered as an etiology of CNS dysfunction occurring with prolonged, high-dose opioid therapy. This case highlights the opioid-sparing and analgesic properties of low-dose ketamine, allowing reversal of OIN in the home hospice setting., (© 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To assess the clinical utility of the Trail-Making Tests (TMTs) as screens for impaired road-test performance., Design: Secondary analyses of three data sets from previously published studies of impaired driving in older adults using comparable road test designs and outcome measures., Setting: Two academic driving specialty clinics., Participants: Older drivers (N = 392; 303 with cognitive impairment, 89 controls) from Rhode Island and Missouri., Measurements: Standard operating characteristics were evaluated for the TMT Part A (TMT-A) and Part B (TMT-B), as well as optimal upper and lower test cut-points that could be useful in defining groups of drivers with indeterminate likelihood of impaired driving who would most benefit from further screening or on-road testing., Results: Discrimination remained high (>70%) when cut-points for the TMTs derived from Rhode Island data were applied to Missouri data, but calibration was poor (all P < .01). TMT-A provided the best utility for determining a range of scores (68-90 seconds) for which additional road testing would be indicated in general practice settings. A high frequency of cognitively impaired participants unable to perform the TMT-B test within the allotted time limited the utility of the test (>25%). Mere inability to complete the test in a reasonable time frame (e.g., TMT-A > 48 seconds or TMT-B > 108 seconds) may still be a useful tool in separating unsafe from safe or marginal drivers in such samples., Conclusion: The TMTs (particularly TMT-A) may be useful as screens for driving impairment in older drivers in general practice settings, where most people are still safe drivers, but more-precise screening measures need to be analyzed critically in a variety of clinical settings for testing cognitively impaired older drivers., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Although automobiles remain the mobility method of choice for older adults, late-life cognitive impairment and progressive dementia will eventually impair the ability to meet transport needs of many. There is, however, no commonly utilized method of assessing dementia severity in relation to driving, no consensus on the specific types of assessments that should be applied to older drivers with cognitive impairment, and no gold standard for determining driving fitness or approaching loss of mobility and subsequent counseling. Yet, clinicians are often called upon by patients, their families, health professionals, and driver licensing authorities to assess their patients' fitness-to-drive and to make recommendations about driving privileges. We summarize the literature on dementia and driving, discuss evidenced-based assessments of fitness-to-drive, and outline the important ethical and legal concerns. We address the role of physician assessment, referral to neuropsychology, functional screens, dementia severity tools, driving evaluation clinics, and driver licensing authority referrals that may assist clinicians with an evaluation. Finally, we discuss mobility counseling (e.g. exploration of transportation alternatives) since health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance our patients' social connectedness and quality of life, while meeting their psychological and medical needs and maintaining personal and public safety.