Bi-modal stimulation in the treatment of tinnitus: a study protocol for an exploratory trial to optimise stimulation parameters and patient subtyping

Introduction: Tinnitus is the perception of sound in the absence of a corresponding external acoustic stimulus. Bi-modal neuromodulation is emerging as a promising treatment for this condition. The main objectives of this study are to investigate the relevance of inter-stimuli timing and the choice of auditory stimuli for a proprietary bi-modal (auditory and somatosensory) neuromodulation device and to explore whether specific subtypes of patients are differentially responsive to this novel intervention for reducing the symptoms of chronic tinnitus. Methods and analysis: This is a two-site, randomised, triple-blind, exploratory study of a proprietary neuromodulation device with a pre-post and 12-month follow-up design. Three different bi-modal stimulation parameter sets will be examined. The study will enrol 342 patients, split 80:20 between two sites (Dublin, Ireland and Regensburg, Germany), to complete 12 weeks of treatment with the device. Patients will be allocated to one of three arms using a step-wise stratification according to four binary categories: tinnitus tonality, sound level tolerance (using Loudness Discomfort Level of <60 dB SL as an indicator for hyperacusis), hearing thresholds, and presence of a noise-induced audiometric profile. The main indicators of relative clinical efficacy for the three different parameter sets are two patient-reported outcomes measures, the Tinnitus Handicap Inventory and the Tinnitus Functional Index, after 12 weeks of intervention. Clinical efficacy will be further explored in a series of patient subtypes, split by the stratification variables and by presence of a somatic tinnitus. Evidence for sustained effects on the psychological and functional impact of tinnitus will be followed up for 12 months. Safety data will be collected and reported. A number of feasibility measures to inform future trial design include: reasons for exclusion, completeness of data collection, attrition rates, patient’s adherence to the device usage as per manufacturer’s instructions and evaluation of alternative methods for estimating tinnitus impact and tinnitus loudness. Ethics and dissemination: This study protocol is approved by the Tallaght Hospital / St. James’s Hospital Joint Research Ethics Committee in Dublin, Republic of Ireland, and by the Ethics Committee of the University Clinic Regensburg, Germany. Findings will be disseminated to relevant research, clinical, health service and patient communities through publications in peer-reviewed and popular science journals and presentations at scientific and clinical conferences. Trial registration number; the trial is registered on ClinicalTrials.gov (NCT02669069). The sponsor is Neuromod Devices, Dublin, Republic of Ireland. STRENGTHS AND LIMITATIONS OF THIS STUDY • The main strength of this study is that it is a large two-site, triple-blinded, randomised trial that will provide exploratory evidence of the relevance of stimulation parameters on the clinical efficacy of different bi-modal stimulation parameters and will inform future trial design. • The study comprehensively characterises patients for subtyping and this will refine candidature for the intervention. • Among the limitations of this study are the variability in duration between screening and enrolment and the selection of the investigated stimulation parameters. • The online recruitment process may inadvertently introduce participant selection bias

“I\u27m making a positive change in my life”: A mixed method evaluation of a well-being tertiary education unit

Issue Addressed: Mental health disorders (MHDs) are prevalent amongst university students with detrimental impacts on individual students, universities and the wider community. There is an urgent need for proactive and preventative strategies to address the mental health crisis in the university population. This study evaluated the efficacy of a 13-week unit developed to directly educate university students about ways to improve and maintain well-being. Methods: Fifty-eight university students from five disciplines participated in a 13-week elective undergraduate unit “Well-Being Fundamentals for Success” as part of their degree. The Act Belong Commit mental health promotion campaign framework formed the basis of teaching materials. Outcome well-being measures were self-assessed at weeks 1, 6 and 12 using four scales: (1) Warwick-Edinburgh Mental Well-being Scale (WEMWBS); (2) Perceived Stress Scale (PSS); (3) Brief Resilience Scale (BRS) and (4) Mindful Attention Awareness Scale (MAAS). Post-unit group interviews (n = 11) were analysed for key themes. Results: Linear mixed models demonstrated a significant improvement in BRS over the semester; well-being (WEMBS) and mindful attention (MAAS) did increase but not significantly. There was a significant increase in stress (PSS) over the semester. Key themes that emerged from the group interviews were that (1) University life contributes to well-being; (2) University life contributes to stress; (3) The well-being unit helped students see and do things differently; (4) An overall endorsement of the unit. Conclusion: University students’ resilience increased over the semester following participation in a curriculum focused on well-being which featured a combination of theoretical content and experiential workshops. So what? Incorporating mental well-being curriculum into tertiary education is proactive preventive health strategy which may assist with the increasing prevalence of MHD in Australia

Is Endoscopic Band Ligation a Superior Treatment Modality for Gastric Antral Vascular Ectasia Compared to Argon Plasma Coagulation?

Background/Aims Gastric antral vascular ectasia (GAVE) is a rare acquired vascular lesion of the gastric antrum. The most frequent presentation of GAVE is iron deficiency anemia. Endoscopic therapy is the mainstay of treatment. However, there is no consensus regarding the optimal treatment modality. Methods A retrospective cohort study was performed on patients with GAVE, including patients receiving endoscopic therapy. Treatment was with either argon plasma coagulation (APC) or endoscopic band ligation (EBL). Basic demographic data, indication for index procedure, number of sessions, and pre- and post-hemoglobin levels were collected. The aim of the study was to compare outcomes across the two treatment modalities. Results One hundred and seventeen diagnoses of GAVE were made. Sixty-two patients (53%) required endoscopic treatment for symptomatic GAVE (female, n=38, 61%; mean age of 74.4 years). Two hundred and eighteen procedures were performed during the study period. APC was performed (n=161, 74%) more frequently than EBL (n=57, 26%). Patients treated with APC at index required a median 5 subsequent therapeutic interventions (APC or EBL), while those treated with EBL at index required a further 2.9 treatments (EBL only) (p<0.05). Conclusions APC was the most common treatment modality employed. We demonstrate an increasing incidence of EBL. Patients treated with EBL at index treatment required fewer subsequent treatment sessions and had a greater mean rise in hemoglobin. This suggests a more effective endoscopic response with EBL

Bimodal neuromodulation combining sound and tongue stimulation reduces tinnitus symptoms in a large randomized clinical study

Tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating for 10-15% of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition. Animal research has revealed that sound paired with electrical somatosensory stimulation can drive extensive plasticity within the brain for tinnitus treatment. To investigate this bimodal neuromodulation approach in humans, we evaluated a noninvasive device that delivers sound to the ears and electrical stimulation to the tongue in a randomized, double-blinded, exploratory study that enrolled 326 adult subjects with chronic subjective tinnitus. Participants were randomized into three parallel arms with different stimulation settings. Clinical outcomes were evaluated over a 12-week treatment period and a 12-month post-treatment phase. For the primary endpoints, participants achieved a statistically significant reduction in tinnitus symptom severity at the end of treatment based on two commonly used outcome measures, Tinnitus Handicap Inventory (Cohen’s d effect size: 0.87 to 0.92 across arms; p<0.001) and Tinnitus Functional Index (0.77 to 0.87; p<0.001). Therapeutic improvements continued for 12 months post-treatment for specific bimodal stimulation settings. Long-term benefits lasting 12 months have not previously been demonstrated in a large cohort for a tinnitus intervention. The treatment also achieved high compliance and satisfaction rates with no treatment-related serious adverse events. These positive therapeutic and long-term results motivate further clinical trials towards establishing bimodal neuromodulation as the first clinically recommended device treatment for tinnitus

Resistant Starches Protect against Colonic DNA Damage and Alter Microbiota and Gene Expression in Rats Fed a Western Diet123

Resistant starch (RS), fed as high amylose maize starch (HAMS) or butyrylated HAMS (HAMSB), opposes dietary protein-induced colonocyte DNA damage in rats. In this study, rats were fed Western-type diets moderate in fat (19%) and protein (20%) containing digestible starches [low amylose maize starch (LAMS) or low amylose whole wheat (LAW)] or RS [HAMS, HAMSB, or a whole high amylose wheat (HAW) generated by RNA interference] for 11 wk (n = 10/group). A control diet included 7% fat, 13% protein, and LAMS. Colonocyte DNA single-strand breaks (SSB) were significantly higher (by 70%) in rats fed the Western diet containing LAMS relative to controls. Dietary HAW, HAMS, and HAMSB opposed this effect while raising digesta levels of SCFA and lowering ammonia and phenol levels. SSB correlated inversely with total large bowel SCFA, including colonic butyrate concentration (R2 = 0.40; P = 0.009), and positively with colonic ammonia concentration (R2 = 0.40; P = 0.014). Analysis of gut microbiota populations using a phylogenetic microarray revealed profiles that fell into 3 distinct groups: control and LAMS; HAMS and HAMSB; and LAW and HAW. The expression of colonic genes associated with the maintenance of genomic integrity (notably Mdm2, Top1, Msh3, Ung, Rere, Cebpa, Gmnn, and Parg) was altered and varied with RS source. HAW is as effective as HAMS and HAMSB in opposing diet-induced colonic DNA damage in rats, but their effects on the large bowel microbiota and colonocyte gene expression differ, possibly due to the presence of other fiber components in HAW

Huntingtin facilitates polycomb repressive complex 2

Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in the huntingtin protein. Full-length huntingtin is thought to be a predominant HEAT repeat α-solenoid, implying a role as a facilitator of macromolecular complexes. Here we have investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex 2 (PRC2), suggested by shared embryonic deficiency phenotypes. Analysis of a set of full-length recombinant huntingtins, with different polyglutamine regions, demonstrated dramatic conformational flexibility, with an accessible hinge separating two large α-helical domains. Moreover, embryos lacking huntingtin exhibited impaired PRC2 regulation of Hox gene expression, trophoblast giant cell differentiation, paternal X chromosome inactivation and histone H3K27 tri-methylation, while full-length endogenous nuclear huntingtin in wild-type embryoid bodies (EBs) was associated with PRC2 subunits and was detected with trimethylated histone H3K27 at Hoxb9. Supporting a direct stimulatory role, full-length recombinant huntingtin significantly increased the histone H3K27 tri-methylase activity of reconstituted PRC2 in vitro, and structure–function analysis demonstrated that the polyglutamine region augmented full-length huntingtin PRC2 stimulation, both in HdhQ111 EBs and in vitro, with reconstituted PRC2. Knowledge of full-length huntingtin's α-helical organization and role as a facilitator of the multi-subunit PRC2 complex provides a novel starting point for studying PRC2 regulation, implicates this chromatin repressive complex in a neurodegenerative disorder and sets the stage for further study of huntingtin's molecular function and the impact of its modulatory polyglutamine region

Safety in Nonhuman Primates of Ocular AAV2-\u3cem\u3eRPE65\u3c/em\u3e, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision has been restored by subretinal delivery of AAV- RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2. RPE65 in RPE65 -mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vector-related toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular injections of AAV-2/2. RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2. RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina

High-Throughput Analysis of Promoter Occupancy Reveals New Targets for Arx, a Gene Mutated in Mental Retardation and Interneuronopathies

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations

The Woody Guthrie Centennial Bibliography

This bibliography updates two extensive works designed to include comprehensively all significant works by and about Woody Guthrie. Richard A. Reuss published A Woody Guthrie Bibliography, 1912–1967 in 1968 and Jeffrey N. Gatten\u27s article “Woody Guthrie: A Bibliographic Update, 1968–1986” appeared in 1988. With this current article, researchers need only utilize these three bibliographies to identify all English-language items of relevance related to, or written by, Guthrie

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely