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Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo ( p  = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point ( p  = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group ( p  = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) ( p  = 0.028) and sleep quality NRS ( p  = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of −0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effect in phase B of the study, with an increased time to treatment failure in the THC/CBD spray group compared to placebo. These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients.

Background: Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical. Objective: To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal. Methods: An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects’ previous effective and tolerated dose was continued. Results: A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome of time to treatment failure was significantly in favour of Sativex (p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject’s Global Impression of Change scales in favour of Sativex. Conclusions: Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.

Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0–10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open-label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increase with time (up to 9 months); at least half of all patients reported a 30 % improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality 0–10 NRS scores, neuropathic pain scale scores, subject global impression of change and EQ-5D questionnaire scores. THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use. In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia.

The growth studies were carried out using the methods and equipment devised by Professor J M Tanner after I had undertaken training at the Institute of Child Health in London. 4 No invasive procedures were done, hormone assays being carried out on urine or saliva. 5 The parents of children with XXY and XXX karyotypes were given as much information as was then available about their conditions, with the explanation that the purpose of the study was to provide a clearer picture of the whole condition. [...]all three categories have an increased incidence of delayed speech development suggesting that sex chromatin screening of patients attending speech clinics would be beneficial.

European forests have a prominent role in the global carbon cycle and an increase in carbon storage has been consistently reported during the twentieth century. Any further increase in forest carbon storage, however, could be hampered by increases in aridity and extreme climatic events. Here, we use forest inventory data to identify the relative importance of stand structure (stand basal area and mean d.b.h.), mean climate (water availability), and recent climate change (temperature and precipitation anomalies) on forest basal area change during the late twentieth century in three major European biomes. Using linear mixed-effects models we observed that stand structure, mean climate, and recent climatic change strongly interact to modulate basal area change. Although we observed a net increment in stand basal area during the late twentieth century, we found the highest basal area increments in forests with medium stand basal areas and small to medium-sized trees. Stand basal area increases correlated positively with water availability and were enhanced in warmer areas. Recent climatic warming caused an increase in stand basal area, but this increase was offset by water availability. Based on recent trends in basal area change, we conclude that the potential rate of aboveground carbon accumulation in European forests strongly depends on both stand structure and concomitant climate warming, adding weight to suggestions that European carbon stocks may saturate in the near future.

Color and volatile stimulus preferences of Drosophila repleta (Patterson) Diptera: Drosophilidae), a nuisance pest of swine and poultry facilities, were tested using sticky card and bottle traps. Attractions to red, yellow, blue, orange, green, purple, black, grey and a white-on-black contrast treatment were tested in the laboratory. Drosophila repleta preferred red over yellow and white but not over blue. Other than showing preferences over the white control, D. repleta was not observed to have preferences between other colors and shade combinations. Pinot Noir red wine, apple cider vinegar, and wet swine feed were used in volatile preference field trials. Red wine was more attractive to D. repleta than the other volatiles tested, but there were no differences in response to combinations of a red wine volatile lure and various colors. Odor was found to play the primary role in attracting D. repleta.

Enhanced tendon and ligament repair would have a major impact on orthopedic surgery outcomes, resulting in reduced repair failures and repeat surgeries, more rapid return to function, and reduced health care costs. Scaffolds have been used for mechanical and biologic reinforcement of repair and regeneration with mixed results. This review summarizes efforts made using biologic and synthetic scaffolds using rotator cuff and ACL as examples of clinical applications, discusses recent advances that have shown promising clinical outcomes, and provides insight into future therapy.

Summary The influence of tree species diversity and functional group on soil properties (carbon stock, pH and C/N ratio) has not been explored across major European forest types. We evaluated the relative importance of tree species diversity and functional group for soil carbon (C) stocks, C/N ratio and pH in major European forest types in the six regions Finland, Poland, Germany, Romania, Italy and Spain. We sampled soils in 209 permanent plots along a species diversity gradient from monocultures to five‐species mixtures. Carbon stocks in the topsoil (forest floor (FF), 0–10 cm and FF + 0–10 cm) were positively, but weakly, related to diversity across the regions. While the C/N ratio in the FF + 0–10 cm layer decreased significantly with increasing diversity in the Spanish region, pH was unrelated to species diversity across the regions. Tree species functional group (in terms of conifer proportion, CP) explained a larger proportion of the variability in soil properties than diversity. Conifer admixture increased C stock and C/N ratio, and decreased pH, but the impacts differed between the regions in some layers. Differences in mean annual temperature, actual evapotranspiration and soil texture between the regions were possible driving factors behind the different CP effects in Finland, Spain and Germany. The results imply that targeted selection of tree species with desired characteristics, e.g. complementary traits for resource use, is a preferred management approach for influencing soil C stock, C/N ratio and pH in mixed forests rather than increasing tree species diversity per se. A lay summary is available for this article. Lay Summary

To compare the effects of 800 mg of valerian with a placebo on sleep quality and symptom severity in people with restless legs syndrome (RLS). A prospective, triple-blinded, randomized, placebo-controlled, parallel design was used to compare the efficacy of valerian with placebo on sleep quality and symptom severity in patients with RLS. Thirty-seven participants were randomly assigned to receive 800 mg of valerian or placebo for 8 weeks. The primary outcome of sleep was sleep quality with secondary outcomes including sleepiness and RLS symptom severity. Data were collected at baseline and 8 weeks comparing use of valerian and placebo on sleep disturbances (Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale) and severity of RLS symptoms (International RLS Symptom Severity Scale) from 37 participants aged 36 to 65 years. Both groups reported improvement in RLS symptom severity and sleep. In a nested analysis comparing sleepy vs nonsleepy participants who received 800 mg ofvalerian (n=17), significant differences before and after treatment were found in sleepiness (P=.01) and RLS symptoms (P=.02). A strong positive association between changes in sleepiness and RLS symptom severity was found (P=.006). The results of this study suggest that the use of 800 mg of valerian for 8 weeks improves symptoms of RLS and decreases daytime sleepiness in patients that report an Epworth Sleepiness Scale (ESS) score of 10 or greater. Valerian may be an alternative treatment for the symptom management ofRLS with positive health outcomes and improved quality of life.