Efficacy of transcranial direct-current stimulation (tDCS) in women with provoked vestibulodynia: study protocol for a randomized controlled trial

Abstract: Background: Provoked vestibulodynia is the most common form of vulvodynia. Despite its high prevalence and deleterious sexual, conjugal, and psychological repercussions, effective evidence-based interventions for provoked vestibulodynia remain limited. For a high proportion of women, significant pain persists despite the currently available treatments. Growing evidence suggests that the central nervous system (CNS) could play a key role in provoked vestibulodynia; thus, treatment targeting the CNS, rather than localized dysfunctions, may be beneficial for women suffering from provoked vestibulodynia. In this study, we aim to build on the promising results of a previous case report and evaluate whether transcranial direct-current stimulation, a non-invasive brain stimulation technique targeting the CNS, could be an effective treatment option for women with provoked vestibulodynia. Methods/design: This single-center, triple-blind, parallel group, randomized, controlled trial aims to compare the efficacy of transcranial direct-current stimulation with sham transcranial direct-current stimulation in women with provoked vestibulodynia. Forty women diagnosed with provoked vestibulodynia by a gynecologist, following a standardized treatment protocol, are randomized to either active transcranial direct-current stimulation treatment for ten sessions of 20 minutes at an intensity of 2 mA or sham transcranial direct-current stimulation over a 2-week period. Outcome measures are collected at baseline, 2 weeks after treatment and at 3-month follow-up. The primary outcome is pain during intercourse, assessed with a numerical rating scale. Secondary measurements focus on the sexual function, vestibular pain sensitivity, psychological distress, treatment satisfaction, and the patient’s global impression of change. Discussion: To our knowledge, this study is the first randomized controlled trial to examine the efficacy of transcranial direct-current stimulation in women with provoked vestibulodynia. Findings from this trial are expected to provide significant information about a promising intervention targeting the centralization of pain in women with provoked vestibulodynia

Randomized clinical trial of multimodal physiotherapy treatment compared to overnight lidocaine ointment in women with provoked vestibulodynia: Design and methods

Provoked vestibulodynia (PVD) is a highly prevalent and debilitating condition yet its management relies mainly on non-empirically validated interventions. Among the many causes of PVD, there is growing evidence that pelvic floor muscle (PFM) dysfunctions play an important role in its pathophysiology. Multimodal physiotherapy, which addresses these dysfunctions, is judged by experts to be highly effective and is recommended as a firstline treatment. However, the effectiveness of this promising intervention has been evaluated through only two small uncontrolled trials. The proposed bi-center, single-blind, parallel group, randomized controlled trial (RCT) aims to evaluate the efficacy of multimodal physiotherapy and compare it to a frequently used first-line treatment, topical overnight application of lidocaine, in women with PVD. A total of 212 women diagnosed with PVD according to a standardized protocol were eligible for the study and were randomly assigned to either multimodal physiotherapy or lidocaine treatment for 10weeks. The primary outcome measure is pain during intercourse (assessed with a numerical rating scale). Secondary measures include sexual function, pain quality, psychological factors (including pain catastrophizing, anxiety, depression and fear of pain), PFM morphology and function, and patients' global impression of change. Assessments are made at baseline, post-treatment and at the 6-month follow-up. This manuscript presents and discusses the rationale, design and methodology of the first RCT investigating physiotherapy in comparison to a commonly prescribed first-line treatment, overnight topical lidocaine, for women with PVD

Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechanoelectrical transducer channel

Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell’s mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol itself in cochlear cultures and also to bind more tightly to the MET channel. At higher concentrations, both carvedilol and this derivative were toxic in cochlear cultures but not in zebrafish, suggesting a good therapeutic window under in vivo conditions

Efficacy of transcranial direct-current stimulation in women with provoked vestibulodynia

Abstract: Background: Provoked vestibulodynia (PVD) is a highly prevalent condition characterized by acute recurrent pain located at the vaginal entrance in response to pressure application or attempt of vaginal penetration. Despite a wide variety of treatments offered to women with PVD, a high proportion of women are refractory to conventional treatment. Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique that has been shown effective for improving various chronic pain conditions. Growing evidence suggests that the central nervous system (CNS) could play a key role in PVD. Targeting the CNS could be a promising treatment avenue for women suffering from PVD. Objective: The purpose of this study was to evaluate and compare the efficacy of active and sham tDCS in reducing pain intensity during intercourse in women with PVD. Study design: We conducted a triple-blind, parallel group, randomized controlled trial (RCT). Women, aged between 17-45 years and diagnosed with PVD by a gynecologist using a validated protocol were randomized to 10 sessions of either active tDCS (intensity = 2mA) or 10 sessions of sham tDCS, over a 2-week period. Both active and sham tDCS were applied for 20 minutes, with the anode positioned over the primary motor cortex (M1), and the cathode, over the contralateral supraorbital area. Outcome measures were collected at baseline, 2 weeks after treatment and at 3-month follow-up by an evaluator blinded to group assignation. The primary objective was pain intensity during intercourse, as assessed with a numerical rating scale. Secondary outcomes focused on sexual function and distress, vestibular sensitivity, psychological distress, treatment ,satisfaction and patient impression of change. Statistical analyses were conducted on the intention-to-treat basis, and treatment effects were evaluated using a mixed linear model for repeated measures. Results: A total of 40 women were randomly assigned to received either active (n=20) or sham (n=20) tDCS treatments between November 2014 and February 2016. Baseline characteristics were similar between active and sham tDCS groups. Active tDCS did not significantly reduced pain during sexual intercourse compared to sham tDCS 2 weeks after treatment (p=0.84) and at follow-up (p=0.09). Mean [95% CI] baseline and 2-week assessment pain intensity were respectively 6.8 [5.9 - 7.7] and 5.6 [4.7 - 6.5] for active tDCS (p=0.03) versus 7.5 [6.6 - 8.4] and 5.7 [4.8 - 6.6] for sham tDCS (p=0.001). Non-significant differences between the two groups were also found in regards to sexual function and distress after treatment (p>0.20) and at follow-up (p>0.10). Overall, at 2-week assessment 68% women assigned to active tDCS reported being very much, much or slightly improved compared to 65% of women assigned to sham tDCS (p=0.82), and still comparable at follow-up 42% versus 65%, respectively (p=0.15). Conclusion: Findings suggest that active tDCS is not more effective than sham tDCS for reducing pain in women with PVD. Likewise, no significant effects were found on sexual function, vestibular sensitivity or psychological distress

Larger and structurally complex woodland creation sites provide greater benefits for woodland plants

Reforestation initiatives are underway across the world. However, we know relatively little about the ecological consequences of creating and restoring forest ecosystems, and there is a lack of studies examining the drivers of species colonisation and establishment across appropriate temporal and spatial scales to inform conservation practice. Using data from a long-term natural experiment (the WrEN project), we explore ground plant species occurrence and community composition in 102 woodland creation sites (10–160 years since planting), and 27 old growth woodlands (>250 years). We conducted field surveys to collect data on occurrence of plant species (classified into woodland specialist, woodland generalist, or non-woodland) and used Structural Equation Modelling to investigate the influence of local (age, size, woodland structure) and landscape-level (amount of surrounding woodland) attributes on species richness. Woodland generalists are readily colonising woodland creation sites to similar levels found in old growth woodlands. However, there were fewer woodland specialist and more non-woodland plants in creation sites than in old growth. Specialists and generalists were more likely to be present in larger woodlands and those with higher variation in tree size (which was higher in older woodlands) and did not appear to be influenced by features of the surrounding landscape. Some plant communities in older creation sites (80–160 years) were similar to old growth, suggesting colonisation of a typical old growth flora over time; however, some sites were shifting away from this trajectory. Specialists are slow to colonise woodland creation sites and their occurrence was low relative to old growth woodlands even after >80 years. However, woodland management to increase structural complexity may enhance the establishment of woodland plants. The lack of influence of the surrounding landscape on species occurrence is likely due to most of the study sites being relatively isolated resulting in limited colonisation. This suggests that new woodlands need to be adjacent or very near to existing woodland to receive the benefits of increased colonisation. Our results highlight the importance of creating large and structurally complex woodlands, close to existing woodlands to facilitate the colonisation and establishment of woodland plants

Complex structural rearrangements are present in high-grade dysplastic Barrett\u27s oesophagus samples

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett’s oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals. Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples. Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples. Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC

The Difference in Pharmacists’ Interventions across the Diverse Settings in a Children’s Hospital

Aims: This study aimed to document and compare the nature of clinical pharmacists’ interventions made in different practice settings within a children’s hospital. Methods: The primary investigator observed and documented all clinical interventions performed by clinical pharmacists for between 35–37 days on each of the five study wards from the three practice settings, namely general medical, general surgical and hematology-oncology. The rates, types and significance of the pharmacists’ interventions in the different settings were compared.Results: A total of 982 interventions were documented, related to the 16,700 medication orders reviewed on the five wards in the three practice settings over the duration of the study. Taking medication histories and/or patient counselling were the most common pharmacists’ interventions in the general settings; constituting more than half of all interventions. On the Hematology-Oncology Ward the pattern was different with drug therapy changes being the most common interventions (n = 73/195, 37.4% of all interventions). Active interventions (pharmacists’ activities leading to a change in drug therapy) constituted less than a quarter of all interventions on the general medical and surgical wards compared to nearly half on thespecialty Hematology-Oncology Ward. The majority (n = 37/42, 88.1%) of a random sample of the active interventions reviewed were rated as clinically significant. Dose adjustment was the most frequent active interventions in the general settings, whilst drug addition constituted the most common active interventions on the Hematology-Oncology Ward. The degree of acceptance of pharmacists’ active interventions by prescribers was high (n = 223/244, 91.4%).Conclusions: The rate of pharmacists’ active interventions differed across different practice settings, being most frequent in the specialty hematology-oncology setting. The nature and type of the interventions documented in the hematologyoncology were also different compared to those in the general medical and surgical settings

Motion style acupuncture treatment (MSAT) for acute low back pain with severe disability: a multicenter, randomized, controlled trial protocol

<p>Abstract</p> <p>Background</p> <p>Acupuncture is widely-used to treat patients with low back pain, despite insufficient evidence of the technique's efficacy for acute back pain. Motion style acupuncture treatment (MSAT) is a non-traditional acupuncture treatment requiring a patient to exercise while receiving acupuncture. In Korea, MSAT is used to reduce musculoskeletal pain and improve functional status. The study aims to evaluate the effect of MSAT on acute low back pain with severe disability.</p> <p>Methods/Design</p> <p>This study is a multicenter, randomized, active-controlled trial with two parallel arms. Participants with acute low back pain and severe functional disability, defined as an Oswestry Disability Index (ODI) value > 60%, will be randomly allocated to the acupuncture group and the nonsteroidal anti-inflammatory drug (NSAID) injection group. The acupuncture group will receive MSAT and the NSAID injection group will receive an intramuscular injection of diclofenac. All procedures will be limited to one session and the symptoms before and after treatment will be measured by assessors blinded to treatment allocation. The primary outcome will be measured at 30 minutes after treatment using the numerical rating scale (NRS) of low back pain while the patient is moving. Secondary outcomes will be measured at 30 minutes after treatment using the NRS of leg pain, ODI, patient global impression of change, range of motion (ROM) of the lumbar spine, and degrees of straight leg raising (SLR). Post-treatment follow-up will be performed to measure primary and secondary outcomes with the exception of ROM and SLR at 2, 4, and 24 weeks after treatment.</p> <p>Discussion</p> <p>The results of this trial will be discussed.</p> <p>Trial Registration</p> <p>ClinicalTrial.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01315561">NCT01315561</a></p

On the Mechanism of Action of SJ-172550 in Inhibiting the Interaction of MDM4 and p53

SJ-172550 (1) was previously discovered in a biochemical high throughput screen for inhibitors of the interaction of MDMX and p53 and characterized as a reversible inhibitor (J. Biol. Chem. 2010; 285∶10786). Further study of the biochemical mode of action of 1 has shown that it acts through a complicated mechanism in which the compound forms a covalent but reversible complex with MDMX and locks MDMX into a conformation that is unable to bind p53. The relative stability of this complex is influenced by many factors including the reducing potential of the media, the presence of aggregates, and other factors that influence the conformational stability of the protein. This complex mechanism of action hinders the further development of compound 1 as a selective MDMX inhibitor

Use of web 2.0 to recruit Australian gay men to an online HIV/AIDS survey

Thériault N, Bi P, Hiller JE, Nor M. Use of Web 2.0 to Recruit Australian Gay Men to an Online HIV/AIDS Survey. J Med Internet Res 2012;14(6):e149. URL: http://www.jmir.org/2012/6/e149/. doi:10.2196/jmir.1819. PMID:23128646BACKGROUND: Continuous prevention efforts for human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) are recommended among those men who have sex with men (MSM). Creative use of e-technologies coupled with a better understanding of social networks could lead to improved health interventions among this risk population. OBJECTIVE: The aims of the study were to (1) compare the impact of various advertising strategies on recruiting MSM participants to an online HIV/AIDS survey, and (2) explore the feasibility of using a social network service (SNS) for study advertising. METHODS: A cross-sectional online survey was conducted in 2009. South Australian men over 18 years were invited to participate if they had had sexual intercourse with men in the previous year. A short questionnaire was used to collect demographics and information on sexual behavior, HIV history, use of the Internet for dating purposes, and sources of health information. The survey was promoted in community settings and online, including advertisements through social networks. RESULTS: A total of 243 men completed the online survey during the 8-week data collection period. Online advertisements recruited 91.7% (220/240) of the sample. Conversely, traditional advertisements in the community recruited only 5.8% (14/240) of the sample. Ten volunteers were asked to advertise on their personal SNS application, but only 2 effectively did so. Only 18/240 (7.5%) of the respondents reported having learned of our study through the SNS application. In this sample, 19.3% (47/243) of participants had never been tested for HIV. Among the participants who had been tested, 12.8% (25/196) reported being HIV-positive. Regarding Internet use, 82.3% (200/243) of participants had dated online in the previous 6 months. Among the participants who had dated online, most (175/200, 87.5%) had found an Internet sexual partner and two-thirds (132/200, 66.0%) had had anal sex with these partner(s). Among men who had anal sex with an Internet partner, 68.2% (90/132) used a condom during sex. CONCLUSIONS: The MSM participants in this study had high-risk profiles for HIV and other sexually transmitted diseases (STDs), which highlights the need for ongoing health interventions among this group. In this study, the SNS marketing strategy did not appear to create a viral effect and it had a relatively poor yield.Nathanaelle Thériault, Peng Bi, Janet E Hiller, Mahdi No