Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics

The sense of hearing is vulnerable to environmental challenges, such as exposure to noise. More than 1.5 billion people experience some decline in hearing ability during their lifetime, of whom at least 430 million will be affected by disabling hearing loss. If not identified and addressed in a timely way, hearing loss can severely reduce the quality of life at various stages. Some causes of hearing loss can be prevented, for example from occupational or leisure noise. The World Health Organization estimates that more than 1 billion young people put themselves at risk of permanent hearing loss by listening to loud music over long periods of time. Mitigating such risks through public health action is essential to reduce the impact of hearing loss in the community. The etiology of sensorineural hearing loss is complex and multifactorial, arising from congenital and acquired causes. This book highlights the diverse range of approaches to sensorineural hearing loss, from designing new animal models of age-related hearing loss, to the use of microRNAs as biomarkers of cochlear injury and drug repurposing for the therapy of age-related and noise-induced hearing loss. Further investigation into the underlying molecular mechanisms of sensorineural hearing loss and the integration of the novel drug, cell, and gene therapy strategies into controlled clinical studies will permit significant advances in a field where there are currently many unmet needs

Assessment and outcomes in mild traumatic brain injury in the Emergency Department

Traumatic brain injury (TBI) is common, affecting up to 600/100,000 people. Mild TBI accounts for up to 90% of all TBI. The Emergency Department attendance rate for head injuries is as high as 1800/100,000 population, and 15-20% of those attendances result in hospital admission. Mild TBI causes symptoms such as headaches, dizziness, disordered balance, cognitive dysfunction and depression which in turn impact on quality of life. Accurate risk assessment and prognostication of patients with acute neurological conditions in the Emergency Department is essential. This PhD consists of a systematic review that examines the hard outcome of ‘return to work’ following a mild TBI; a prospective observational cohort study that reports the difference in neurocognitive function and symptoms that patients experience at baseline and three days after mild TBI; and a prospective observational cohort study that reports the number of patients that attend the Emergency Department with seizure secondary to TBI, and the value of two biomarkers in predicting the recurrence of seizures in patients that attend the Emergency Department having had a seizure. This thesis comprises three studies in which I investigated the short and long-term effects of mild traumatic brain injury (TBI) and prognostication in seizure. In study one, I undertook a systematic review and meta-analysis to determine return to work times for adults with mild TBI. The primary objective was to determine the time taken to return to work following a mild TBI. Articles were included if they reported on adults with mild TBI and recorded the outcome return to work. Six electronic databases and eight clinical trial registries were searched. A narrative synthesis and a random-effects meta-analysis was performed. Bias was assessed using a modified version of the Newcastle Ottawa quality assessment tool. The second study was a prospective observational cohort study of adults with mild TBI and a comparison group of Emergency Department patients without brain injury. The primary outcomes were neurocognitive function and concussion symptom severity at baseline and 72 hours. Adult patients with mild TBI within the last 24 hours were included in the mild TBI group, and adults that attended the Emergency Department with trauma beneath the clavicle, or with a non-neurological medical condition, were included in the comparison group. Outcomes were measured on the Standardized Assessment of Concussion (SCA) and the Concussion Symptom Inventory (CSI) at baseline in the Emergency Department and at follow up at 72 hours. Comparisons were made between baseline and follow up, and between groups at single time points. The third study was a prospective observational cohort study designed to assess the prognostic value of the biomarkers S100B and copeptin in patients with seizure. Adult patients attending the Emergency Department with seizure of any cause were included. The primary outcome was a composite of seizure recurrence, death, hospitalisation, rehospitalisation or re-attendance at the Emergency Department at seven days. S100B and copeptin were measured in the Emergency Department. Statistical comparison of the two groups was performed, optimum thresholds of the biomarkers for diagnosing the endpoint were derived, diagnostic test characteristics were calculated, and logistic regression modelling was performed to identify variables most closely associated with the outcome. The aetiology of the seizure was identified and the proportion that had a seizure secondary to TBI was recorded. In the systematic review and meta-analysis, 14 studies were included. Three reported the average time taken to return to work, and 12 reported the proportion of patients that have returned to work by a pre-specified time point. The pooled proportion of people returned to work at one, three, six and 12 months was 56%, 75%, 83%, and 89% respectively. In the study of short-term effects of mild TBI, 240 patients were included, of which 189 had mild TBI and 51 comprised the non-brain injured comparison group. Patients with mild TBI had marked neurocognitive impairment (SAC at baseline 25 [23-27], difference in SAC score between brain injured and non-brain injured 1, p=0.02, [95% confidence interval [CI] -1.4 to -2.4]), worse symptom severity (CSI at baseline 9 [4-21], difference in CSI between brain injured and non-brain injured 9, p<0.001 [95% CI 8.4 to 13.7]), and high numbers of symptoms (number of symptoms at baseline 4 [2-8], difference between brain injured and non-brain injured 4, p<0.001 [95% CI 2.6 to 4.4]), all of which persisted at 72 hours. In the study of patients with seizures, 97 patients were recruited, of which 52% met the composite primary endpoint. No patients attended with a seizure as a consequence of TBI. S100B and copeptin were significantly higher in patients with compared to without the composite primary endpoint: 0.22 μg/L (95% CI 0.14 to 0.31) vs 0.11 μg/L (95% CI 0.08 to 0.14) (difference 0.02 μg/L, p = 0.01, 95% CI 0.02 to 0.2) for S100B; and 77.0 pmol/L (95% CI 44.3 to 109.7) vs 27.0 (95% CI 18.2 to 35.9) (difference 50 pmol/L, p = 0.004, 95% CI 16.2 to 83.8) for copeptin. Thresholds of 0.088 μg/L and 6.26 pmol/L were identified for S100B and copeptin respectively. At those thresholds, S100B sensitivity and specificity was 58% (95% CI 43-72) and 60% (95% CI 44-74); and copeptin sensitivity and specificity was 80% (95% CI 66-90) and 21% (95% CI 11-36). Epilepsy, complex partial seizure, provoked/acute symptomatic seizure, and pyrexia were identified as factors independently associated with the primary outcome but there was no additional value when the biomarkers were included in the model. In this body of work, I have shown that patients with mild traumatic brain injury have impaired neurocognitive function and a significant symptom burden that persists for several days, and in some patients is likely to persist for many months. Although most patients return to normal activities, including working, by three months after a mild traumatic brain injury, up to a tenth of patients are still unable to return to work at one year after the injury. Around half of patients that attend an Emergency Department with a seizure go on to be admitted or have another seizure by one week, but the biomarkers S100B and copeptin add no extra value to current prediction tools in identifying who will have a recurrent seizure, and few patients have a seizure secondary to TBI