What are the adverse effects of prolonged opioid use in patients with chronic pain?

Constipation, nausea, and dyspepsia are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.) Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports). Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report)

What are the indications for meningococcal vaccination?

Routine vaccination with the meningococcal conjugate vaccine MCV4 (Menactra) is indicated for all US adolescents entering high school and for college freshmen living in dormitories (strength of recommendation [SOR]: B, based on observational studies). Routine vaccination of infants and toddlers with conjugate vaccine may be more cost- effective than targeting adolescents, but conjugate meningococcal vaccine for this age group is not yet available in the US (SOR: B, based on cohort studies)

Is there much risk in using fluoroquinolones in children?

Arthralgias and myalgias have been observed clinically in children and adolescents exposed to fluoroquinolones, but they're transient, disappear when the drug is discontinued, and appear to be no more prevalent than with other antibiotics (strength of recommendation [SOR]: B, 1 structured review and 2 prospective cohort studies). No apparent long-term risk of developmental skeletal growth delay is associated with fluoroquinolone exposure (SOR: B, 1 prospective controlled study)

What precautions should we use with statins for women of childbearing age?

Statins are contraindicated for women who are pregnant or breastfeeding. Data evaluating statin use for women of childbearing age is limited; however, they may be used cautiously with adequate contraception. Pravastatin may be preferred based on its low tissue-penetration properties. Cholesterol-lowering with simvastatin 40 mg/d did not disrupt menstrual cycles or effect luteal phase duration (strength of recommendation: C)

Which asthma patients should get the pneumococcal vaccine?

Adults between the ages of 19 and 64 years who have chronic lung disease, including asthma, should get the vaccine, as should all patients 65 years and older (strength of recommendation [SOR]: C, consensus guide-lines). Evidence doesn't support routine vaccination of children with asthma or adults younger than 65 years who don't have chronic lung disease to decrease asthma-related or pneumonia-related hospitalizations (SOR: B, 1 retrospective cohort study and 1 retrospective, case- controlled cohort study)

What is the preferred treatment for a child with mild persistent asthma?

Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials)

Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury

Locomotor training on treadmills can improve recovery of stepping in spinal cord injured animals and patients. Likewise, lesioned rats treated with antibodies against the myelin associated neurite growth inhibitory protein, Nogo-A, showed increased regeneration, neuronal reorganization and behavioural improvements. A detailed kinematic analysis showed that the hindlimb kinematic patterns that developed in anti-Nogo-A antibody treated versus treadmill trained spinal cord injured rats were significantly different. The synchronous combined treatment group did not show synergistic effects. This lack of synergistic effects could not be explained by an increase in pain perception, sprouting of calcitonin gene-related peptide (CGRP) positive fibres or by interference of locomotor training with anti-Nogo-A antibody induced regeneration and sprouting of descending fibre tracts. The differential mechanisms leading to behavioural recovery during task-specific training and in regeneration or plasticity enhancing therapies have to be taken into account in designing combinatorial therapies so that their potential positive interactive effects can be fully expresse

Electrophysiological Guidance of Epidural Electrode Array Implantation over the Human Lumbosacral Spinal Cord to Enable Motor Function after Chronic Paralysis.

Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI

Introduction to special issue:New Times Revisited: Britain in the 1980s

The authors in this volume are collectively engaged with a historical puzzle: What happens if we examine the decade once we step out of the shadows cast by Thatcher? That is, does the decade of the 1980s as a significant and meaningful periodisation (equivalent to that of the 1960s) still work if Thatcher becomes but one part of the story rather than the story itself? The essays in this collection suggest that the 1980s only makes sense as a political period. They situate the 1980s within various longer term trajectories that show the events of the decade to be as much the consequence as the cause of bigger, long-term historical processes. This introduction contextualises the collection within the wider literature, before explaining the collective and individual contributions made

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies