Structural Variations of Prions and Prion-like Proteins Associated with Neurodegeneration.

Neurodegeneration is becoming one of the leading causes of death worldwide as the population expands and grows older. There is a growing desire to understand the mechanisms behind prion proteins as well as the prion-like proteins that make up neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). Both amyloid-ß (Aß) and hyperphosphorylated tau (p-tau) proteins behave in ways similar to those of the infectious form of the prion protein, PrPSc, such as aggregating, seeding, and replicating under not yet fully understood mechanisms, thus the designation of prion-like. This review aims to highlight the shared mechanisms between prion-like proteins and prion proteins in the structural variations associated with aggregation and disease development. These mechanisms largely focus on the dysregulation of protein homeostasis, self-replication, and protein aggregation, and this knowledge could contribute to diagnoses and treatments for the given NDs.

Associations Between Traumatic Brain Injury and Severity of Tinnitus-Related Functional Impairment Among US Military Veterans: A National, Population-Based Study.

OBJECTIVE: To describe associations between a history of traumatic brain injury (TBI) and the severity of tinnitus-related functional impairment among a national, stratified random sample of veterans diagnosed with tinnitus by the Department of Veterans Affairs (VA) healthcare system. SETTING: A multimodal (mailed and internet) survey administered in 2018. Participants: VA healthcare-using veterans diagnosed with tinnitus; veterans with comorbid TBI diagnosis were oversampled. DESIGN: A population-based survey. MAIN MEASURES: TBI history was assessed using International Classification of Diseases (ICD) diagnosis codes in veterans' VA electronic health records. The severity of participants' overall tinnitus-related functional impairment was measured using the Tinnitus Functional Index. Population prevalence and 95% confidence intervals (CIs) were estimated using inverse probability weights accounting for sample stratification and survey nonresponse. Veterans' relative risk ratios of very severe or moderate/severe tinnitus-related functional impairment, versus none/mild impairment, were estimated by TBI history using bivariable and multivariable multinomial logistic regression. RESULTS: The population prevalence of TBI was 5.6% (95% CI: 4.8-6.4) among veterans diagnosed with tinnitus. Veterans with a TBI diagnosis, compared with those without a TBI diagnosis, had 3.6 times greater likelihood of rating their tinnitus-related impairment as very severe (95% CI: 2.1-6.3), and 1.5 times greater likelihood of rating their impairment as moderate/severe (95% CI: 1.0-2.4), versus none/mild. CONCLUSIONS: These findings suggest an important role of TBI in the severity of tinnitus-related functional impairment among veterans. This knowledge can help inform the integration of tinnitus management services into the care received by veterans with TBI.

The influence of tinnitus and hearing loss on the functional status of military Service members and Veterans.

OBJECTIVE: This study evaluated the influence of tinnitus and hearing loss on the functional status of military Service members and Veterans. DESIGN: Participants completed audiologic testing and self-report instruments to assess tinnitus, hearing, and general functioning. We conducted multiple linear regression analyses using cross-sectional data with functional status as the dependent variable. The primary independent variables were tinnitus and average low-, high-, and extended high-frequency hearing thresholds. Secondary independent variables were subjective tinnitus severity and hearing difficulties. Each of the independent variables was modelled separately for Service members and Veterans; covariates for each multivariable model were identified a priori and, depending on the association being modelled, included age, gender, blast-wave exposure, and history of military traumatic brain injury. STUDY SAMPLE: Data were analysed from 283 Service members and 390 Veterans. RESULTS: After controlling for potential confounders, presence of tinnitus, tinnitus severity, average low-frequency hearing thresholds, and subjective hearing difficulties were significantly associated with functional status in Service members and Veterans. CONCLUSIONS: These results suggest that tinnitus and poorer low-frequency hearing, and the perceived severity of tinnitus and hearing difficulties, may be associated with poorer functional status among Service members and Veterans.

Associations between medical conditions and auditory dysfunction in US Veterans.

OBJECTIVE: To examine associations between non-otologic medical conditions and auditory dysfunction. DESIGN: Cross-sectional analysis of baseline data from the Noise Outcomes in Service members Epidemiology (NOISE) study. Logistic regression was used to estimate the association between medical conditions (0, 1, and 2 or more conditions) and auditory dysfunction (hearing loss pure tone average ≥20 dB HL and tinnitus), adjusting for key confounders including noise exposure. Secondarily, the association between specific medical conditions and auditory dysfunction was examined. All variables were self-reported. STUDY SAMPLE: United States military Veterans (n = 580) with mean age 34.1 years (standard deviation = 9.2), who were within approximately 2.5 years of separation from service. RESULTS: Compared to Veterans reporting no medical conditions, Veterans reporting two or more had increased odds on low-frequency hearing loss and on tinnitus but not on high or extended-high frequency hearing loss. Furthermore, specific conditions sleep disorder and arthritis were associated with auditory dysfunction. CONCLUSIONS: Non-otologic medical conditions were associated with low-frequency hearing loss and tinnitus in this sample of young Veterans. This suggests medical conditions may play a role in Veterans' hearing health. Whether management of medical conditions earlier in life reduces the risk of hearing loss and tinnitus requires further study.

The Risk of Acute Infection Following Intra-Articular Corticosteroid Injection During Total Knee Manipulation Under Anesthesia.

BACKGROUND: Manipulation under anesthesia (MUA) is an established option for improving motion in patients presenting with early stiffness following total knee arthroplasty (TKA). Intra-articular corticosteroid injections (IACI) are sometimes administered adjunctively, yet literature examining their efficacy and safety remains limited. STUDY DESIGN: Retrospective, Level IV. METHODS: A total of 209 patients (TKA = 230) were retrospectively examined to determine the incidence of prosthetic joint infections within 3 months following manipulation with IACI. Approximately 4.9% of initial patients had inadequate follow-up where the presence of infection could not be determined. Range of motion was assessed in patients who had follow-up at or beyond one year (n = 158) and was recorded over multiple time points. RESULTS: No infections (0 of 230) were identified within 90 days of receiving IACI during TKA MUA. Before receiving TKA (preindex), patients averaged 111° of total arc of motion and 113° of flexion. Following index procedures, just prior to manipulation (pre-MUA), patients averaged 83° and 86° of total arc and flexion motion, respectively. At final follow-up, patients averaged 110° of total arc of motion and 111° of flexion. At six weeks following manipulation, patients had gained a mean of 25° and 24° of their total arc and flexion motion found at 1 year. This motion was preserved through a 12-month follow-up period. CONCLUSION: Administering IACI during TKA MUA does not harbor an elevated risk for acute prosthetic joint infections. Additionally, its use is associated with substantial increases in short-term range of motion at six weeks following manipulation, which remain preserved through long-term follow-up.

Enhanced piroctone olamine retention from shampoo for superior anti-dandruff efficacy.

BACKGROUND: Dandruff is a pervasive chronic condition which negatively impacts quality of life. Effective treatment requires efficient delivery of scalp benefit agents that control commensal scalp Malassezia levels. Delivery of benefit agents from shampoos requires balancing many technical parameters to achieve the desired outcome without sacrificing secondary parameters, such as cosmetic attributes. AIM: To develop formulation technologies that increase the shampoo delivery efficiency of the scalp benefit agent piroctone olamine (PO). Increased delivery should result in increased anti-dandruff efficacy. METHODS: Micellar Stability and Association parameters were quantified via dynamic surface tension and nuclear magnetic resonance (NMR) diffusion parameters, respectively. PO delivery has been assessed in vivo both on the scalp surface and follicular infindibula using extraction procedures and analytical analysis. Clinical anti-dandruff efficacy was assessed for an advanced delivery technology prototype in comparison to standard delivery technology. RESULTS: Shampoo prototypes have been developed that increase the delivery efficiency of PO. Both surfactant and polymer coacervate-based approaches have been developed. Decreased micellar stability results in weaker association between PO and micelles, resulting in more efficient PO retention on the scalp surface and delivery to the infundibula. Increased charge density of cationic polymers optimizes coacervation enabling improved PO delivery as well. Increased PO delivery has been shown clinically to result in higher anti-dandruff efficacy as measured by both visible flakes and underlying biomarkers. CONCLUSION: Increased efficiency PO delivery shampoos have been developed by optimization of both surfactant and coacervate parameters. The increased deposition efficiency results in significantly more products with significantly greater anti-dandruff efficacy.

CONTEXTE: Les pellicules sont une maladie chronique omniprésente qui a un impact négatif sur la qualité de vie. Un traitement efficace nécessite une administration efficace d'agents bénéfiques pour le cuir chevelu qui contrôlent les niveaux commensaux de Malassezia. L'administration d'agents bénéfiques à partir de shampooings nécessite d'équilibrer de nombreux paramètres techniques pour obtenir le résultat souhaité sans sacrifier des paramètres secondaires tels que les attributs cosmétiques. BUT: Développer des technologies de formulation qui augmentent l'efficacité d'administration du shampooing de l'agent bénéfique pour le cuir chevelu piroctone olamine (PO). Une livraison accrue devrait entraîner une efficacité antipelliculaire accrue. MÉTHODES: La stabilité micellaire et les paramètres d'association ont été quantifiés via les paramètres de tension superficielle dynamique et de diffusion RMN, respectivement. L'administration de PO a été évaluée in vivo à la fois sur la surface du cuir chevelu et sur l'indibula folliculaire à l'aide de procédures d'extraction et d'analyses analytiques. L'efficacité antipelliculaire clinique a été évaluée pour un prototype de technologie d'administration avancée par rapport à la technologie d'administration standard. RÉSULTATS: Des prototypes de shampooing ont été développés pour augmenter l'efficacité de livraison des PO. Des approches à base de tensioactifs et de coacervats polymères ont été développées. Une diminution de la stabilité micellaire entraîne une association plus faible entre le PO et les micelles, ce qui entraîne une rétention plus efficace du PO sur la surface du cuir chevelu et une livraison à l'infundibula. L'augmentation de la densité de charge des polymères cationiques optimise la coacervation, permettant également une meilleure administration de PO. Il a été démontré cliniquement que l'augmentation de l'administration de PO entraîne une efficacité antipelliculaire plus élevée, mesurée à la fois par les squames visibles et les biomarqueurs sous-jacents. CONCLUSION: Des shampooings à libération de PO à efficacité accrue ont été développés en optimisant à la fois les paramètres du tensioactif et du coacervat. L'efficacité de dépôt accrue se traduit par beaucoup plus de produits avec une efficacité antipelliculaire nettement supérieure.

Cardiac arrest in diving: The key to success.

This case report describes the successful management of an out-of-hospital arrest in a diver following a suspected arterial gas embolism (AGE). It illustrates both the inherent risks of diving and the importance of prompt and effective implementation of the "chain of survival" from bystanders. Rapid on-scene responses from paramedics and helicopter emergency medical services facilitated prompt evacuation to a Category 1 (multiplace) recompression chamber (RCC) where specialists in cardiology and hyperbaric medicine were available. Alternative causes of cardiac arrest were considered, with a presumed AGE successfully treated with multiple rounds of hyperbaric oxygen therapy. The key factors which led to this successful outcome are discussed, including early recognition and call for help, competent cardiopulmonary resuscitation, and direct evacuation to a Category 1 RCC, with additional consideration of the diagnosis leading to cardiac arrest. The case clearly illustrates the need for all those involved in diving regularly to be competent and confident in performing basic life support, as well as the awareness of the emergency services of the need for diving casualties to be treated at appropriate hyperbaric facilities. Were it not for the simple, prompt and effective treatment this diver received, both on scene and in hospital, it is highly unlikely that such a positive outcome would have been achieved.

Cognitive Behavioral Therapy for Tinnitus: Addressing the Controversy of Its Clinical Delivery by Audiologists.

Audiologists' role in providing care for tinnitus typically includes conducting an audiologic evaluation, fitting hearing aids when appropriate, assessing the impact of tinnitus, and facilitating use of sound to improve quality of life with tinnitus when appropriate. Cognitive behavioral therapy (CBT) is consistently judged by systematic reviews as having the strongest evidence relative to other therapies for improving quality of life with tinnitus. Because audiologists are already playing an active role in providing care for tinnitus, and the relative paucity of behavioral health providers who are experienced in implementing CBT for tinnitus, a logical question is whether audiologists can provide CBT and whether it is within their scope of practice. In this article, we present both sides of the argument as to whether audiologists can provide CBT and we make recommendations for appropriate administration of CBT for tinnitus management.

Randomised controlled trial of interventions for bothersome tinnitus: DesyncraTM versus cognitive behavioural therapy.

OBJECTIVE: Compare the relative efficacy of DesyncraTM and Cognitive Behavioural Therapy (CBT). DESIGN AND STUDY SAMPLE: Sixty-one participants were randomly assigned to receive either DesyncraTM (n = 29) or CBT (n = 32). Randomisation included stratification regarding current hearing aid (HA) use. Depending on group assignment, participants attended approximately 7-12 visits. Tinnitus distress was measured using the Tinnitus Questionnaire (TQ). RESULTS: Mean TQ scores decreased post-baseline from 5-15 points across treatment arms and strata. Model-based findings for the no-HA stratum showed a difference of -2.0 TQ points favouring Desyncra at 24-weeks, with a 90% posterior interval varying from -5.4 points favouring Desyncra to 0.8 TQ points favouring CBT. For the HA stratum, results show a difference of -1.0 TQ points favouring Desyncra, with a 90% posterior interval ranging from -4.7 points favouring Desyncra to 2.9 points favouring CBT. CONCLUSIONS: The difference between Desyncra and CBT on average showed greater improvement with Desyncra in the no-HA stratum by about 2 TQ points. To the extent that the study sample represents a clinical population and recognising the assumptions in the design and analysis, these results suggest Desyncra is just as effective or more so than CBT in reducing tinnitus distress.

CRISPR-TAPE: protein-centric CRISPR guide design for targeted proteome engineering.

Rational molecular engineering of proteins with CRISPR-based approaches is challenged by the gene-centric nature of gRNA design tools. To address this, we have developed CRISPR-TAPE, a protein-centric gRNA design algorithm that allows users to target specific residues, or amino acid types within proteins. gRNA outputs can be customized to support maximal efficacy of homology-directed repair for engineering purposes, removing time-consuming post hoc curation, simplifying gRNA outputs and reducing CPU times.

Occupational Noise Exposure and Longitudinal Hearing Changes in Post-9/11 US Military Personnel During an Initial Period of Military Service.

OBJECTIVES: Auditory impairments, particularly those resulting from hazardous occupational noise exposures, are pressing concerns for the US Departments of Defense (DoD) and Veterans Affairs (VA). However, to date, no studies have estimated the rate of hearing threshold change that occurs during service or how changes may vary by military occupation. Hearing threshold changes during military service have historically been reported as the proportion of Service members demonstrating a significant threshold shift. This approach does not capture the rate of the hearing threshold change or the specific audiometric frequencies impacted. Determining the rate of hearing threshold change, and factors that affect the rate of change, is important to elucidate the impact of military service on hearing and to guide prevention strategies and subsequent hearing health care. Our primary objective was to estimate the annual rate of hearing threshold change during military service as a consequence of military occupational noise exposure ranking. DESIGN: We linked audiometric data, collected from military personnel as part of a DoD hearing conservation program, to data describing demographic and military-service characteristics obtained from individuals enrolled in the Noise Outcomes In Service members Epidemiology Study. The analytic cohort included Veterans who enlisted in military service after September 2001 (n = 246). We examined the longitudinal association between military occupations categorized as having a low, moderate, or high noise exposure ranking and pure-tone hearing thresholds (500 to 6000 Hz) using a hierarchical linear model. The average annual rate of hearing threshold change and their 95% confidence intervals were estimated by service branch, military occupational noise exposure ranking, and audiometric test frequency. RESULTS: On average, hearing threshold change ranged between -0.5 and 1.1 dB/year and changes over time varied by service branch, audiometric test frequency, and military occupation noise ranking. Generally, higher test frequencies (3000 to 6000 Hz) and military occupations with moderate or high noise exposure rankings had the greatest average annual rates of hearing threshold change; however, no dose-response relationship was observed. Among Marine Corps personnel, those exposed to occupations with high noise rankings demonstrated the greatest average annual rate of change (1.1 dB/year at 6000 Hz). Army personnel exposed to occupations with moderate noise rankings demonstrated the greatest average annual rate of change (0.6 dB/year at 6000 Hz). CONCLUSIONS: This study (1) demonstrates the unique use of DoD hearing conservation program data, (2) is the first analysis of hearing threshold changes over time using such data, and (3) adds to the limited literature on longitudinal changes in hearing. The difference in hearing threshold changes across military branches is likely indicative of their varying noise exposures, hearing protection device use and enforcement, and surveillance practices. Results suggest Marine Corps and Army personnel are at risk for hearing threshold changes and that, among Army personnel, this is most pronounced among those exposed to moderate levels of occupational noise exposure. Estimates of the rate of hearing threshold change by frequency and factors that impact hearing are useful to inform the DoD's efforts to protect the hearing of their Service members and to the Veterans Affairs's efforts to identify and rehabilitate those most likely to experience hearing threshold change.

Noise Outcomes in Servicemembers Epidemiology (NOISE) Study: Design, Methods, and Baseline Results.

OBJECTIVES: Military Service members and Veterans commonly report hearing loss and tinnitus, both of which can result in significant disability. During military service, Service members are exposed to many different types of loud noise, which is strongly associated with hearing loss and tinnitus. Other military-related exposures, such as chemicals and traumatic brain injury (TBI), are also linked with auditory problems. The purpose of the "Noise Outcomes in Servicemembers Epidemiology" (NOISE) study is to gather information from Active-Duty Service members and recently separated Veterans about their military and nonmilitary noise exposures, other relevant military and nonmilitary exposures, and potential outcomes of these exposures including tinnitus, hearing loss, and other hearing-related health concerns. DESIGN: The NOISE study assesses lifetime noise exposures, chemical and blast exposures, TBI, physical and psychiatric comorbidities, and other military and nonmilitary exposures and outcomes that can affect auditory function. Participants undergo comprehensive in-person audiologic examinations; those who experience tinnitus undergo a complete tinnitus assessment. Exposures and select outcomes are reassessed annually by mail, and the comprehensive in-person assessment is completed every 5 years. This report presents descriptive, baseline data obtained from the first 690 participants enrolled between 2014 and 2018. RESULTS: Some notable findings from this analysis include: (1) the prevalence of hearing loss in the sample was 8% for low frequencies (0.25 to 2 kHz), 20% for high frequencies (3 to 8 kHz), and 39% for extended high frequencies (9 to 16 kHz); (2) the prevalence of tinnitus was 53%; (3) the prevalence of both hearing loss and tinnitus was higher among those with higher age, more years of military service, greater degree of noise exposure, and exposures to blasts and/or TBI in the military; and (4) tinnitus was most prevalent among participants who serve/served in the Army relative to the other military branches. CONCLUSIONS: The NOISE study is acquiring comprehensive data on military-related auditory dysfunction. It is the first of its kind to enroll active Service members and recently separated Veterans into a longitudinal study to examine the etiology and outcomes of tinnitus and hearing loss in this population. Although these data do not necessarily represent the entire military and Veteran populations, ongoing enrollment is focused on increasing generalizability and will also provide the statistical power to conduct multivariable analyses. This will allow us to examine longitudinal associations of interest while controlling for potential confounders and other possible sources of error. These data will provide critical knowledge to refine future military hearing conservation efforts and inform efforts to develop future treatments.

Giant Fine Structure Splitting of the Bright Exciton in a Bulk MAPbBr3 Single Crystal.

Exciton fine structure splitting in semiconductors reflects the underlying symmetry of the crystal and quantum confinement. Because the latter factor strongly enhances the exchange interaction, most work has focused on nanostructures. Here, we report on the first observation of the bright exciton fine structure splitting in a bulk semiconductor crystal, where the impact of quantum confinement can be specifically excluded, giving access to the intrinsic properties of the material. Detailed investigation of the exciton photoluminescence and reflection spectra of a bulk methylammonium lead tribromide single crystal reveals a zero magnetic field splitting as large as ∼200 µeV. This result provides an important starting point for the discussion of the origin of the large bright exciton fine structure splitting observed in perovskite nanocrystals.

Thomas Robert Malthus, naturalist of the mind.

In 1798, Thomas Robert Malthus's infamous An Essay on the Principle of Population was published. The publication of the Essay is best remembered for Malthus's principle - that population multiplies geometrically as opposed to subsistence increasing arithmetically. What is not well known, however, is that Malthus's Essay also offered a sophisticated - and heterodox - theory of mind. Despite a recent revival in Malthusian scholarship, Malthus's theory of mind has been largely forgotten. The present study attempts to address this neglected area within the literature, by evaluating Malthus's contribution to the naturalization of the soul. I first situate Malthus's theory of mind within the Essay's broader naturalization project, examining Malthus's role as naturalist; his views on humans as animals; and the Essay's cosmology. This is followed by an exploration of the making and reception of the Essay, illustrating how readers widely interpreted Malthus's theory of mind as a theory of naturalization. Finally, I reconstruct Malthus's naturalized system of mind, discussing the mechanisms and dynamics involved in the operation of a materialist mind. In sum, I argue for the centrality of Malthus's Essay in the larger naturalization movement, specifically as it pertains to the soul.

Telephone-Based Progressive Tinnitus Management for Persons With and Without Traumatic Brain Injury: A Randomized Controlled Trial.

OBJECTIVES: This randomized controlled trial evaluated the efficacy of delivering coping skills education from Progressive Tinnitus Management (PTM) by telephone (Tele-PTM). The trial followed a previous pilot study that showed positive results for Tele-PTM. DESIGN: Participants included individuals with bothersome tinnitus (N = 205) located anywhere within the United States. A special emphasis was given to including individuals who had experienced one or more traumatic brain injuries (TBIs). Participants were randomized to either Tele-PTM intervention or 6-month wait-list control (WLC). The Tele-PTM intervention involved five telephone appointments-two led by an audiologist (teaching how to use therapeutic sound) and three by a psychologist (teaching coping skills derived from cognitive-behavioral therapy). It was hypothesized that Tele-PTM would be more effective than WLC in reducing functional effects of tinnitus as measured with the Tinnitus Functional Index. Additional outcome measures included the Self-Efficacy for Managing Reactions to Tinnitus questionnaire and the Hospital Anxiety and Depression Scale. The effect of Tele-PTM on outcomes was estimated using linear mixed models. RESULTS: Overall results showed convincingly that the Tele-PTM group had significantly better outcomes than the WLC group. These results were consistent across all outcome measures, indicating not only a reduction of tinnitus functional distress but also increased self-efficacy. Improvements in measures of anxiety and depression were also observed. Tele-PTM participants in all TBI categories showed significant improvement. CONCLUSIONS: Results provide strong support for use of Tele-PTM methodology for persons with bothersome tinnitus, regardless of whether the person also has TBI symptoms. The effect size for Tele-PTM was high for the primary outcome measure, the Tinnitus Functional Index, and all other outcome measures showed significant improvement. Combined with our previous pilot study, the Tele-PTM method is validated for potential nationwide provision of tinnitus services.

Cancer pain and neuropathic pain are associated with A ß sensory neuronal plasticity in dorsal root ganglia and abnormal sprouting in lumbar spinal cord.

Evidence suggests that there are both nociceptive and neuropathic components of cancer-induced pain. We have observed that changes in intrinsic membrane properties and excitability of normally non-nociceptive Aß sensory neurons are consistent in rat models of peripheral neuropathic pain and cancer-induced pain. This has prompted a comparative investigation of the intracellular electrophysiological characteristics of sensory neurons and of the ultrastructural morphology of the dorsal horn in rat models of neuropathic pain and cancer-induced pain. Neuropathic pain model rats were induced with a polyethylene cuff implanted around a sciatic nerve. Cancer-induced pain model rats were induced with mammary rat metastasis tumour-1 rat breast cancer or MATLyLu rat prostate cancer cells implanted into the distal epiphysis of a femur. Behavioural evidence of nociception was detected using von Frey tactile assessment. Aß-fibre low threshold mechanoreceptor neurons in both cancer-induced pain and neuropathic pain models exhibited slower dynamics of action potential genesis, including a wider action potential duration and lower action potential amplitude compared to those in control animals. Enhanced excitability of Aß-fibre low threshold mechanoreceptor neurons was also observed in cancer-induced pain and neuropathic pain models. Furthermore, both cancer-induced pain and neuropathic pain models showed abundant abnormal axonal sprouting in bundles of myelinated axons in the ipsilateral spinal laminae IV and V. The patterns of changes show consistency between rat models of cancer-induced pain and neuropathic pain. These findings add to the body of evidence that animal models of cancer-induced pain and neuropathic pain share features that may contribute to the peripheral and central sensitization and tactile hypersensitivity in both pain states.

Comparison of acoustic therapies for tinnitus suppression: a preliminary trial.

OBJECTIVE: This study obtained preliminary data using two types of sound therapy to suppress tinnitus and/or reduce its functional effects: (1) Notched noise (1000-12,000 Hz notched within a 1-octave range centred around the tinnitus pitch match [PM] frequency); and (2) Matched noise (1-octave wide band of noise centred around the PM frequency). A third (Placebo) group listened to low frequency noise (250-700 Hz). DESIGN: Participants with bothersome tinnitus were randomised into one of the three groups and instructed to listen to the acoustic stimulus for 6 hours a day for 2 weeks. Stimuli were delivered using an iPod Nano, and tinnitus counselling was not performed. Outcome measures were recorded at the 0, 2 and 4 week study visits. STUDY SAMPLE: Thirty participants with constant and bothersome tinnitus were recruited and randomised. RESULTS: All groups showed, on average, overall improvement, both immediately post-treatment and 2 weeks following treatment. Outcomes varied between groups on the different measures and at the two outcome points. CONCLUSION: This study showed improvement for all of the groups, lending support to the premise that any type of sound stimulation is beneficial for relieving effects of tinnitus. These results may serve as a preliminary evidence for a larger study.

Development and field testing of a smartphone "App" for tinnitus management.

OBJECTIVE: This study's objective was to develop and test a smartphone app that supports learning and using coping skills for managing tinnitus. DESIGN: The app's content was based on coping skills that are taught as a part of progressive tinnitus management (PTM). The study involved three phases: (1) develop a prototype app and conduct usability testing; (2) conduct two focus groups to obtain initial feedback from individuals representing potential users; and (3) conduct a field study to evaluate the app, with three successive groups of participants. STUDY SAMPLE: Participants were adults with bothersome tinnitus. For Phase 2, two focus groups were attended by a total of 17 participants. Phase 3 involved three consecutive rounds of participants: five from the focus groups followed by two rounds with 10 participants each who had not seen the app previously. RESULTS: In both the focus groups and field studies, participants responded favourably to the content. Certain features, however, were deemed too complex. CONCLUSION: Completion of this project resulted in the development and testing of the delivery of PTM coping skills via a smartphone app. This new approach has the potential to improve access to coping skills for those with bothersome tinnitus.

Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.

The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.

Differences in electrophysiological properties of functionally identified nociceptive sensory neurons in an animal model of cancer-induced bone pain.

BACKGROUND: Bone cancer pain is often severe, yet little is known about mechanisms generating this type of chronic pain. While previous studies have identified functional alterations in peripheral sensory neurons that correlate with bone tumours, none has provided direct evidence correlating behavioural nociceptive responses with properties of sensory neurons in an intact bone cancer model. RESULTS: In a rat model of prostate cancer-induced bone pain, we confirmed tactile hypersensitivity using the von Frey test. Subsequently, we recorded intracellularly from dorsal root ganglion neurons in vivo in anesthetized animals. Neurons remained connected to their peripheral receptive terminals and were classified on the basis of action potential properties, responses to dorsal root stimulation, and to mechanical stimulation of the respective peripheral receptive fields. Neurons included C-, Aδ-, and Aß-fibre nociceptors, identified by their expression of substance P. We suggest that bone tumour may induce phenotypic changes in peripheral nociceptors and that these could contribute to bone cancer pain. CONCLUSIONS: This work represents a significant technical and conceptual advance in the study of peripheral nociceptor functions in the development of cancer-induced bone pain. This is the first study to report that changes in sensitivity and excitability of dorsal root ganglion primary afferents directly correspond to mechanical allodynia and hyperalgesia behaviours following prostate cancer cell injection into the femur of rats. Furthermore, our unique combination of techniques has allowed us to follow, in a single neuron, mechanical pain-related behaviours, electrophysiological changes in action potential properties, and dorsal root substance P expression. These data provide a more complete understanding of this unique pain state at the cellular level that may allow for future development of mechanism-based treatments for cancer-induced bone pain.