Monitoring Cochlear Health With Intracochlear Electrocochleography During Cochlear Implantation: Findings From an International Clinical Investigation.

OBJECTIVES: Electrocochleography (ECochG) is emerging as a tool for monitoring cochlear function during cochlear implant (CI) surgery. ECochG may be recorded directly from electrodes on the implant array intraoperatively. For low-frequency stimulation, its amplitude tends to rise or may plateau as the electrode is inserted. The aim of this study was to explore whether compromise of the ECochG signal, defined as a fall in its amplitude of 30% or more during insertion, whether transient or permanent, is associated with poorer postoperative acoustic hearing, and to examine how preoperative hearing levels may influence the ability to record ECochG. The specific hypotheses tested were threefold: (a) deterioration in the pure-tone average of low-frequency hearing at the first postoperative follow-up interval (follow-up visit 1 [FUV1], 4 to 6 weeks) will be associated with compromise of the cochlear microphonic (CM) amplitude during electrode insertion (primary hypothesis); (b) an association is observed at the second postoperative follow-up interval (FUV2, 3 months) (secondary hypothesis 1); and (c) the CM response will be recorded earlier during electrode array insertion when the preoperative high-frequency hearing is better (secondary hypothesis 2). DESIGN: International, multi-site prospective, observational, between groups design, targeting 41 adult participants in each of two groups, (compromised CM versus preserved CM). Adult CI candidates who were scheduled to receive a Cochlear Nucleus CI with a Slim Straight or a Slim Modiolar electrode array and had a preoperative audiometric low-frequency average thresholds of ≤80 dB HL at 500, 750, and 1000 Hz in the ear to be implanted, were recruited from eight international implant sites. Pure tone audiometry was measured preoperatively and at postoperative visits (FUV1 and follow-up visit 2 [FUV2]). ECochG was measured during and immediately after the implantation of the array. RESULTS: From a total of 78 enrolled individuals (80 ears), 77 participants (79 ears) underwent surgery. Due to protocol deviations, 18 ears (23%) were excluded. Of the 61 ears with ECochG responses, amplitudes were < 1 µV throughout implantation for 18 ears (23%) and deemed "unclear" for classification. EcochG responses >1 µV in 43 ears (55%) were stable throughout implantation for 8 ears and compromised in 35 ears. For the primary endpoint at FUV1, 7/41 ears (17%) with preserved CM had a median hearing loss of 12.6 dB versus 34/41 ears (83%) with compromised CM and a median hearing loss of 26.9 dB ( p < 0.014). In assessing the practicalities of measuring intraoperative ECochG, the presence of a measurable CM (>1 µV) during implantation was dependent on preoperative, low-frequency thresholds, particularly at the stimulus frequency (0.5 kHz). High-frequency, preoperative thresholds were also associated with a measurable CM > 1 µV during surgery. CONCLUSIONS: Our data shows that CM drops occurring during electrode insertion were correlated with significantly poorer hearing preservation postoperatively compared to CMs that remained stable throughout the electrode insertion. The practicality of measuring ECochG in a large cohort is discussed, regarding the suggested optimal preoperative low-frequency hearing levels ( < 80 dB HL) considered necessary to obtain a CM signal >1 µV.

Characteristics of pain and their relationship to disease activity in UK patients with Behçet's syndrome: a prospective cohort study.

Background: Behçet's syndrome (BS) is a rare multi-systemic vasculitis of unknown aetiology. Fibromyalgia syndrome (FMS) is more prevalent in rheumatological conditions such-as BS, than the general population. However, there is limited research into the aetiology and characteristics of pain in BS. Objectives: To describe the pain characteristics and incidence of FMS in people with BS and investigate their relationship with BS disease activity. Methods: A cohort study of BS patients attending the Liverpool Behçet's Centre between February 2017 and March 2019. BS was defined using the International Study Group Criteria. BS severity was assessed using the Behçet's Disease Current Activity Form. FMS was determined from consultant diagnosis. Assessments of pain included: Pain Visual Analogue Scale (PVAS), Pain Mannequin, Brief Pain Inventory, EQ-5D-3L and Short Form McGill. Pain and FMS prevalence were compared between high and low disease activity. Results: 90% reported moderate-severe pain with a median PVAS score of 68/100 [38, 81]. 35.6% of participants had FMS and 46.5% experienced generalized pain. 76% of participants with high disease activity reported severe pain, compared to 39.1% with low disease activity (p = .003). Pain was more generalised in high disease activity (72%) compared to low disease activity (37.7%) (p = .003). FMS was more prevalent in the high disease activity group (52%) than the low disease activity group (29%) (p = .04). Conclusions: This is the first study to explore pain in participants with BS in the United Kingdom. The majority of BS patients experience moderate-severe widespread pain. Severe widespread pain is more prevalent in those with high disease activity. We have demonstrated a relationship between high disease activity, worse pain intensity, and FMS. This paper contributes to the understanding of two conditions which remain to be fully understood, FMS and BS, and generates new hypotheses to describe the interplay between.

Comparative proteomic analysis of virulent and rifampicin-attenuated Flavobacterium psychrophilum.

Flavobacterium psychrophilum is the aetiologic agent of bacterial coldwater disease and rainbow trout fry syndrome. In this study, we compared a wild-type strain (CSF 259-93) with a rifampicin-resistant strain and virulence-attenuated strain of F. psychrophilum (CSF 259-93B.17). The attenuated strain harboured a mutation in the rpoB gene consistent with resistance to rifampicin. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry demonstrated an altered proteome with eight proteins characteristic for the parent strain and six that were unique to the attenuated strain. Immunoblotting with a diagnostic monoclonal antibody (FL-43) identified a putative antigen (FP1493) that was subsequently cloned, expressed as a recombinant protein and confirmed as recognized by FL-43. 2D-PAGE, immunoblotting with rainbow trout, Oncorhynchus mykiss (Walbaum), convalescent antisera and mass spectrometry of bacterial whole-cell lysates revealed several uniquely expressed immunoreactive proteins including FP1493. An FP1493 recombinant subunit vaccine was tested, but did not provide protection against challenge with the CSF259-93 strain. While the exact mechanism responsible for altered protein synthesis and attenuation of CSF 259-93B.17 is still unknown, the differentially expressed immunoreactive proteins are a valuable resource to develop subunit vaccines and to identify proteins that are potentially involved in disease.

An experimental vaccine against Aeromonas hydrophila can induce protection in rainbow trout, Oncorhynchus mykiss (Walbaum).

A candidate vaccine against Aeromonas hydrophila in rainbow trout, Oncorhynchus mykiss, was developed using a bacterial lysate. To test the strength of protection, A. hydrophila challenge models were compared using injection into both the intraperitoneal (IP) cavity and the dorsal sinus (DS) with selected doses of live bacteria washed in saline or left untreated. Unlike the IP route, injection into the DS with either saline washed or unwashed cells resulted in consistent cumulative mortality and a dose response that could be used to establish a standard challenge having an LD(50) of approximately 3 x 10(7) colony forming units per fish. Survivors of the challenge suffered significantly lower mortality upon re-challenge than naïve fish, suggesting a high level of acquired resistance was elicited by infection. Passive immunization using serum from hyper-immunized fish also resulted in significantly reduced mortality indicating protection can be transferred and that some portion of resistance may be antibody mediated. Vaccination of groups of rainbow trout with A. hydrophila lysate resulted in significant protection against a high challenge dose but only when injected along with Freund's complete adjuvant. At a low challenge dose, mortality in all groups was low, but the bacterial lysate alone appeared to offer some protection.

Vaccination of rainbow trout, Oncorhynchus mykiss (Walbaum), with recombinant and DNA vaccines produced to Flavobacterium psychrophilum heat shock proteins 60 and 70.

Flavobacterium psychrophilum heat shock proteins (Hsp) 60 and 70 are highly immunogenic and were therefore investigated as potential vaccine candidates. Recombinant Hsps were purified from Escherichia coli and rainbow trout (Oncorhynchus mykiss) were intraperitoneally injected with phosphate buffered saline/Freunds complete adjuvant (FCA), 8 microg of rHsp60/FCA, rHsp70/FCA or a combination of 4 microg each of rHsp60 and rHsp70/FCA. Antibody responses against recombinant Hsp60 and Hsp70 8 weeks post-immunization were observed, but only fish immunized with rHsp70 exhibited highly elevated antibody levels against F. psychrophilum whole cell lysate. Some cross reactivity occurred, which may have been due to the V5 tag common to both proteins. Protection against F. psychrophilum challenge was not observed in any treatments at 8 weeks post-immunization. To further investigate any protective effect of these proteins, hsps were polymerase chain reaction amplified and cloned into pVAX1. Rainbow trout were intramuscularly injected with 8 microg of pVAX1hsp60, pVAX1hsp70 or a combination of 4 microg each of pVAX1hsp60 and pVAX1hsp70. Antibody responses at 4 weeks post-immunization were low and protection was not observed following challenge at 6 or 10 weeks post-immunization. Although Hsps of F. psychrophilum have been shown to be immunodominant, these antigens do not appear to be good vaccine candidates when delivered alone or in combination.

Who is responsible for global road safety? A cross-cultural comparison of Actor Maps.

The traditional three 'E's approach to road safety (engineering, education, enforcement) has had, and will continue to have, a significant impact on road traffic casualty rates worldwide. Nevertheless, with rising motorisation in many countries, global fatality numbers have changed little over the past decade. Following calls for the application of sociotechnical systems thinking to the problem, we widen the road safety discussion with an additional four 'E's; economics, emergency response, enablement, and, the umbrella term for the approach taken, ergonomics. The research presents an application of Rasmussen's Risk Management Framework to the road safety systems of five distinct nations; Bangladesh, China, Kenya, the UK, and Vietnam. Following site visits, reviews of literature, and interviews with subject matter experts in each of the countries, a series of Actor Map models of the countries' road safety systems were developed. These are compared and discussed in terms of the wide variety of interconnecting organisations involved, their influences on road safety outcomes, the differences between nations, and the need to look beyond road users when designing road safety interventions.

Intergenic transcription in the human beta-globin gene cluster.

Our previous studies on nascent transcription across the human beta-globin gene cluster revealed the presence of intergenic transcripts in addition to the expected genic transcripts. We now show that transcription into the beta-globin locus control region (LCR) begins within an ERV9 endogenous retroviral long terminal repeat upstream of DNase I hypersensitive site 5. However, in a transgenic mouse, which has the human beta-globin LCR but lacks the ERV9 LTR, transcription begins upstream of the transgenic locus. We postulate that in this transgenic mouse nearby endogenous mouse promoters are activated by the LCR. Intergenic transcription is also detected across the whole transgenic globin gene locus independently of the stage of erythroid development. Intergenic transcription in the beta-globin cluster is erythroid specific; however, it can be induced in nonerythroid cells by several means: by transinduction with a plasmid transcribing part of the cluster, by exogenous addition of transcription factors, and by treatment with the histone deacetylase inhibitor trichostatin A.

Synergistic interaction between lipid-loading and doxorubicin exposure in Huh7 hepatoma cells results in enhanced cytotoxicity and cellular oxidative stress: implications for acute and chronic care of obese cancer patients.

There has been a dramatic increase in the number of clinically obese individuals in the last twenty years. This has resulted in an increasingly common scenario where obese individuals are treated for other diseases, including cancer. Here, we examine interactions between lipid-induced steatosis and doxorubicin treatment in the human hepatoma cell line Huh7. The response of cells to either doxorubicin, lipid-loading or a combination were examined at the global level by DNA microarray, and for specific endpoints of cytotoxicity, lipid-loading, reactive oxygen species, anti-oxidant response systems, and apoptosis. Both doxorubicin and lipid-loading caused a significant accumulation of lipid within Huh7 cells, with the combination resulting in an additive accumulation. In contrast, cytotoxicity was synergistic for the combination compared to the individual components, suggesting an enhanced sensitivity of lipid-loaded cells to the acute hepatotoxic effects of doxorubicin. We demonstrate that a synergistic increase in reactive oxygen species and deregulation of protective anti-oxidant systems, most notably metallothionein expression, underlies this effect. Transcriptome analysis confirms synergistic changes at the global level, and is consistent with enhanced pro-inflammatory signalling in steatotic cells challenged with doxorubicin. Such effects are consistent with a potentiation of progression along the fatty liver disease spectrum. This suggests that treatment of obese individuals with doxorubicin may increase the risk of both acute (i.e. hepatotoxicity) and chronic (i.e. progress of fatty liver disease) adverse effects. This work highlights the need for more study in the growing therapeutic area to develop risk mitigation strategies.

Stimulation of RNA 3' processing by flanking DNA in Xenopus oocytes.

We have previously shown that the second poly(A) signal of the Xenopus laevis alpha-tubulin gene X alpha T14, which contains the rare hexanucleotide CAUAAA, requires a surprisingly large amount of 3' flanking DNA to be used efficiently in Xenopus oocytes. To investigate the nature of the interaction between the X alpha T14 3' flank and upstream 3' processing sites, we have developed a modified oocyte assay based on the stimulation of processing at a single poly(A) signal. We mutated both the hexanucleotide and GU/U-rich components of a strong synthetic poly(A) signal (SPA) in order to weaken it severely. We found that efficient use of the mutant signal could be fully restored by the addition of 1.2 kb of X alpha T14 3' flank, but only in its natural orientation. Functional dissection of the X alpha T14 3' flank defined two separate regions that were each capable of partially restoring processing efficiency, presumably because they contain multiple, relatively weak processing enhancers. We discuss how the stimulation of 3' processing by flanking regions in oocytes could be explained by mechanisms that operate on the processing machinery directly or by indirect effects mediated by transcriptional pausing.

A survey of contact with offspring and assistance with child care among parents with psychotic disorders.

To help improve services for parents with psychotic disorders, patients with such disorders in three treatment agencies in Queensland, Australia, were surveyed about whether they were parents, how much contact they had with their offspring, and who provided assistance with child care. Of the 342 individuals with psychotic disorders who participated in the study, 124 were parents. Forty-eight parents in the study had children under age 16, and 20 of these parents (42 percent) had their children living with them. Most parents relied on relatives or friends for assistance with child care. Barriers to child care services identified by parents were inability to pay, lack of local services, and fear of losing custody of children.

Evaluation of the Nucleus Spectra 22 processor and new speech processing strategy (SPEAK) in postlinguistically deafened adults.

A new speech processing strategy (SPEAK) has been compared with the previous Multipeak (MPEAK) strategy in a study with 24 postlinguistically deafened adults. The results show that performance with the SPEAK coding strategy was significantly better for 58.31% of subjects on closed-set consonant identification, for 33.3% of subjects on closed-set vowel identification and open-set monosyllabic word recognition, and for 81.8% of subjects on open-set sentence recognition in quiet and in competing noise (+ 10 dB signal-to-noise ratio). By far the largest improvement observed was for sentence recognition in noise, with the mean score across subjects for the SPEAK strategy twice that obtained with MPEAK.

Programming for generalization to high and low risk parenting situations in families with oppositional developmentally disabled preschoolers.

This study examined the generalization effects of a training program for parents of oppositional, mildly developmentally disabled preschool children. Specifically, the study sought to determine the possible differential generalization effects of treatment to high and low risk parenting settings. Treatment comprised child management and planned activities training procedures specifically designed to enhance generalization effects. A multiple baseline design across subjects that incorporated a non-treatment control subject was employed. Dependent measures included deviant child behavior, accuracy of parent implementation of treatment procedures, and specific measures of aversive and non-aversive parent behaviors. Three of the treated families showed marked reductions in levels of deviant behavior, as well as increases in parental implementation of treatment procedures in both the training setting and the low risk generalization setting. Two of these three families showed comparable improvements in the high risk setting. The control subject showed little improvement in either generalization setting. It was concluded that the treatment program was effective in producing generalization effects in parent training.

Electrode impedance in adults and children using the Nucleus 24 cochlear implant system.

This study measured changes in electrode impedance over time in 19 adults and 29 children implanted with the Nucleus 24 cochlear implant system, using common ground and three monopolar modes of stimulation, over a series of time intervals. Impedances increased from the intraoperative to the initial fitting session, decreased during the initial fitting session and for the following week, and were then stable. Impedances were lowest for the common ground mode, while for the monopolar modes, impedances were related to the surface area of the return electrode. Impedances for children were higher than those for adults at the initial fitting session and for the following three weeks. The clinically measured impedance values increased in a basal-to-apical direction. When these data were corrected for differences in electrode surface area, impedances decreased in a basal-to-apical direction. Impedances were influenced by whether the electrodes were stimulated or unstimulated. Adults with higher electrode impedances tended to have lower hearing thresholds and comfortable listening levels, but this did not appear to clearly be the case for children.

Comparison between NRT-based MAPs and behaviourally measured MAPs at different stimulation rates--a multicentre investigation.

Seventeen adult subjects participated in a multicentre trial to compare the performance between an NRT-based MAP and their behavioural MAP. The NRT-based MAP was made using a correction factor to predict T/C levels, calculated from the difference between the ECAP threshold ('T-NRT') and the measured T/C levels at electrode 10, as described by Brown et al. (2000). A secondary aim was to compare T/C levels in behavioural MAPs at different stimulation rates with the predicted T/C levels in NRT-based MAPs. Performance with both MAPs was evaluated using CNC words and sentences. Variations in the T/C levels between all MAPs were found, although results of the speech discrimination tests demonstrated no statistically significant difference between behavioural and NRT-based MAPs.

1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas.

Astrocytic, oligodendroglial and mixed gliomas are the commonest gliomas in adults. They have distinct phenotypes and clinical courses, but as they exist as a continuous histological spectrum, differentiating them can be difficult. Co-deletions of total 1p and 19q are found in the majority of oligodendrogliomas and considered as a diagnostic marker and a prognostic indicator. The 1p status of astrocytomas has not yet been thoroughly examined. Using a chromosome 1 tile path array, we investigated 108 adult astrocytic tumours for copy number alterations. Total 1p deletions were rare (2%), however partial deletions involving 1p36 were frequently identified in anaplastic astrocytomas (22%) and glioblastomas (34%). Multivariate analysis showed that patients with total 1p deletions had significantly longer survival (P=0.005). In nine glioblastomas homozygous deletions at 1p36 were identified. No somatic mutations were found among the five genes located in the homozygously deleted region. However, the CpG island of TNFRSF9 was hypermethylated in 19% of astrocytic tumours and 87% of glioma cell lines. TNFRSF9 expression was upregulated after demethylation of glioma cell lines. Akt3 amplifications were found in four glioblastomas. Our results indicate that 1p deletions are common anaplastic astrocytomas and glioblastomas but are distinct from the 1p abnormalities in oligodendrogliomas.

Predictors of care-giver stress in families of preschool-aged children with developmental disabilities.

BACKGROUND: This study examined the predictors, mediators and moderators of parent stress in families of preschool-aged children with developmental disability. METHOD: One hundred and five mothers of preschool-aged children with developmental disability completed assessment measures addressing the key variables. RESULTS: Analyses demonstrated that the difficulty parents experienced in completing specific care- giving tasks, behaviour problems during these care-giving tasks, and level of child disability, respectively, were significant predictors of level of parent stress. In addition, parents' cognitive appraisal of care-giving responsibilities had a mediating effect on the relationship between the child's level of disability and parent stress. Mothers' level of social support had a moderating effect on the relationship between key independent variables and level of parent stress. CONCLUSIONS: Difficulty of care-giving tasks, difficult child behaviour during care-giving tasks, and level of child disability are the primary factors which contribute to parent stress. Implications of these findings for future research and clinical practice are outlined.

Morphological proportionality in elite age group North American divers.

The purpose of this investigation was to describe the morphological parameters that characterize elite age group divers. Comparisons are made to normative age group data from the Coquitlam Growth Study and the constancy of important characteristics from age group to age group is examined. Data were collected on 27 male and 28 female elite divers who participated in the 1990 North American Age Group Diving Championships. Body build, body composition and skinfold corrected diameters were determined from 36 anthropometric parameters and analysed by ANOVA, t-test and Phantom z-scores procedures. All age groups except the 14- to 15-year-old males were significantly (P < or = 0.05) shorter than their norms but recorded higher androgyny index values. The estimated relative muscle mass increased significantly (P < or = 0.05) with age for males at all ages (40.8-46.3%). The 16- to 18-year-old females had a significantly (P < or = 0.05) larger relative muscle component compared to the younger age groups (40.1-38.4%). When normalized for height, active tissue development of the extremities was comparable between the sexes except in the forearm. The results indicate that at all age levels short stature is an important characteristic for divers. Analysis of regional active tissue development provides further insight into sport-specific prerequisites for success at elite levels.