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

A cross-sectional survey of the acceptability of data collection processes for validation of a European point prevalence survey of healthcare-associated infections and antimicrobial use

BACKGROUND: Statistical measurements alone are insufficient to ensure robust data for point prevalence surveys (PPS) of healthcare-associated infections (HAI). Data quality is determined by the type of data, data collection methods and available resources. Data collectors’ views regarding the acceptability of data collection process for validation studies are also important to consider. AIM: To explore data collectors’ views on the acceptability of data collection processes used for a European validation PPS of HAI and antimicrobial use (AMU). METHODS: An anonymous online survey was conducted with 67 data collectors from 10 European countries involved in the study. FINDINGS: Twenty-five (64.1%) participants viewed AMU data collection as easy/quite easy whereas only five (12.8%) thought HAI data collection was easy/quite easy. Six (17%) participants indicated that incentives and 21 (56.8%) that disincentives were possibly/definitely present for reporting cases of HAI. Engagement of staff was not thought to have adversely affected data collection as only one (2.6%) and five (15.4%) participants thought involvement of hospital PPS teams and administration was low/very low, respectively. DISCUSSION: Participants believed the approaches used were appropriate but that more training was required prior to data collection, some case definitions should be reviewed and the number of variables reduced

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

The effect of providing feedback on inhaler technique and adherence from an electronic audio recording device, INCA®, in a community pharmacy setting: study protocol for a randomised controlled trial.

BACKGROUND: Poor adherence to inhaled medication may lead to inadequate symptom control in patients with respiratory disease. In practice it can be difficult to identify poor adherence. We designed an acoustic recording device, the INCA® (INhaler Compliance Assessment) device, which, when attached to an inhaler, identifies and records the time and technique of inhaler use, thereby providing objective longitudinal data on an individual\u27s adherence to inhaled medication. This study will test the hypothesis that providing objective, personalised, visual feedback on adherence to patients in combination with a tailored educational intervention in a community pharmacy setting, improves adherence more effectively than education alone. METHODS/DESIGN: The study is a prospective, cluster randomised, parallel-group, multi-site study conducted over 6 months. The study is designed to compare current best practice in care (i.e. routine inhaler technique training) with the use of the INCA® device for respiratory patients in a community pharmacy setting. Pharmacies are the unit of randomisation and on enrolment to the study they will be allocated by the lead researcher to one of the three study groups (intervention, comparator or control groups) using a computer-generated list of random numbers. Given the nature of the intervention neither pharmacists nor participants can be blinded. The intervention group will receive feedback from the acoustic recording device on inhaler technique and adherence three times over a 6-month period along with inhaler technique training at each of these times. The comparator group will also receive training in inhaler use three times over the 6-month study period but no feedback on their habitual performance. The control group will receive usual care (i.e. the safe supply of medicines and advice on their use). The primary outcome is the rate of participant adherence to their inhaled medication, defined as the proportion of correctly taken doses of medication at the correct time relative to the prescribed interval. Secondary outcomes include exacerbation rates and quality of life measures. Differences in the timing and technique of inhaler use as altered by the interventions will also be assessed. Data will be analysed on an intention-to-treat and a per-protocol basis. Sample size has been calculated with reference to comparisons to be made between the intervention and comparator clusters and indicates 75 participants per cluster. With an estimated 10 % loss to follow-up we will be able to show a 20 % difference between the population means of the intervention and comparator groups with a power of 0.8. The Type I error probability associated with the test of the null hypothesis is 0.05. DISCUSSION: This clinical trial will establish whether providing personalised feedback to individuals on their inhaler use improves adherence. It may also be possible to enhance the role of pharmacists in clinical care by identifying patients in whom alteration of either therapy or inhaler device is appropriate. REGISTRATION: ClinicalTrials.gov NCT02203266

A protocol for a randomised clinical trial of the effect of providing feedback on inhaler technique and adherence from an electronic device in patients with poorly controlled severe asthma.

INTRODUCTION: In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma. METHODS: This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05. TRIAL REGISTRATION NUMBER: NCT01529697; Pre-results

Neonatal brain dynamic functional connectivity in term and preterm infants and its association with early childhood neurodevelopment

Brain dynamic functional connectivity characterises transient connections between brain regions. Features of brain dynamics have been linked to emotion and cognition in adult individuals, and atypical patterns have been associated with neurodevelopmental conditions such as autism. Although reliable functional brain networks have been consistently identified in neonates, little is known about the early development of dynamic functional connectivity. In this study we characterise dynamic functional connectivity with functional magnetic resonance imaging (fMRI) in the first few weeks of postnatal life in term-born (n = 324) and preterm-born (n = 66) individuals. We show that a dynamic landscape of brain connectivity is already established by the time of birth in the human brain, characterised by six transient states of neonatal functional connectivity with changing dynamics through the neonatal period. The pattern of dynamic connectivity is atypical in preterm-born infants, and associated with atypical social, sensory, and repetitive behaviours measured by the Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores at 18 months of age.</p

The Developing Human Connectome Project neonatal data release

The Developing Human Connectome Project has created a large open science resource which provides researchers with data for investigating typical and atypical brain development across the perinatal period. It has collected 1228 multimodal magnetic resonance imaging (MRI) brain datasets from 1173 fetal and/or neonatal participants, together with collateral demographic, clinical, family, neurocognitive and genomic data from 1173 participants, together with collateral demographic, clinical, family, neurocognitive and genomic data. All subjects were studied in utero and/or soon after birth on a single MRI scanner using specially developed scanning sequences which included novel motion-tolerant imaging methods. Imaging data are complemented by rich demographic, clinical, neurodevelopmental, and genomic information. The project is now releasing a large set of neonatal data; fetal data will be described and released separately. This release includes scans from 783 infants of whom: 583 were healthy infants born at term; as well as preterm infants; and infants at high risk of atypical neurocognitive development. Many infants were imaged more than once to provide longitudinal data, and the total number of datasets being released is 887. We now describe the dHCP image acquisition and processing protocols, summarize the available imaging and collateral data, and provide information on how the data can be accessed

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

Conducting a critical interpretive synthesis of the literature on access to healthcare by vulnerable groups

BACKGROUND: Conventional systematic review techniques have limitations when the aim of a review is to construct a critical analysis of a complex body of literature. This article offers a reflexive account of an attempt to conduct an interpretive review of the literature on access to healthcare by vulnerable groups in the UK METHODS: This project involved the development and use of the method of Critical Interpretive Synthesis (CIS). This approach is sensitised to the processes of conventional systematic review methodology and draws on recent advances in methods for interpretive synthesis. RESULTS: Many analyses of equity of access have rested on measures of utilisation of health services, but these are problematic both methodologically and conceptually. A more useful means of understanding access is offered by the synthetic construct of candidacy. Candidacy describes how people's eligibility for healthcare is determined between themselves and health services. It is a continually negotiated property of individuals, subject to multiple influences arising both from people and their social contexts and from macro-level influences on allocation of resources and configuration of services. Health services are continually constituting and seeking to define the appropriate objects of medical attention and intervention, while at the same time people are engaged in constituting and defining what they understand to be the appropriate objects of medical attention and intervention. Access represents a dynamic interplay between these simultaneous, iterative and mutually reinforcing processes. By attending to how vulnerabilities arise in relation to candidacy, the phenomenon of access can be better understood, and more appropriate recommendations made for policy, practice and future research. DISCUSSION: By innovating with existing methods for interpretive synthesis, it was possible to produce not only new methods for conducting what we have termed critical interpretive synthesis, but also a new theoretical conceptualisation of access to healthcare. This theoretical account of access is distinct from models already extant in the literature, and is the result of combining diverse constructs and evidence into a coherent whole. Both the method and the model should be evaluated in other contexts

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy