Pre-registered controlled comparison of auditory function reveals no difference between hospitalised adults with and without COVID-19.

OBJECTIVE: Several viruses are known to have a negative impact on hearing health. The global prevalence of COVID-19 means that it is crucial to understand whether and how SARS-CoV2 affects hearing. Evidence to date is mixed, with studies frequently exhibiting limitations in the methodological approaches used or the populations sampled, leading to a substantial risk of bias. This study addressed many of these limitations. DESIGN: A comprehensive battery of measures was administered, including lab-based behavioural and physiological measures, as well as self-report instruments. Performance was thoroughly assessed across the auditory system, including measures of cochlear function, neural function and auditory perception. Hypotheses and analyses were pre-registered. STUDY SAMPLES: Participants who were hospitalised as a result of COVID-19 (n = 57) were compared with a well-matched control group (n = 40) who had also been hospitalised but had never had COVID-19. RESULTS: We find no evidence to support the hypothesis that COVID-19 is associated with deficits in auditory function on any auditory test measure. Of all the confirmatory analyses, only the self-report measure of hearing decline indicated any difference between groups. CONCLUSION: Results do not support the hypothesis that COVID-19 infection has a significant long-term impact on the auditory system.

Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

Patient Experience of Stiffness With Knee Osteoarthritis: An Interpretative Description Study.

INTRODUCTION: Knee OA (KOA) can lead to pain, loss of muscle strength, and changes in gait. Knee stiffness is a classic feature of KOA that can increase the risk of falls but has been understudied. OBJECTIVE: To evaluate the impact of knee stiffness, the factors influencing the severity of stiffness, and the repercussions on participation for patients with KOA. METHODS: This qualitative study used an interpretive description approach. Purposeful sampling was used for patients with KOA over 45 years of age, fluent in English, diagnosed with KOA and reported KOA stiffness within the last 6 months. Participants were recruited through social media and Ontario clinics. Semi-structured interviews were conducted over the phone or using zoom, recorded, and transcribed verbatim. Open, axial, and selective coding were used to identify clinically relevant themes. RESULTS: Twelve participants (5F, 7M) with a mean age of 60 years were included. The five themes identified include elusive and variable perceptions of joint stiffness, inactivity or too much activity exacerbates stiffness, adapting to the ebb and flow of symptoms, risk experiences and safety fears leads to reduced participation, and KOA stiffness impairs quality of life. CONCLUSION: This study highlights characteristics of knee stiffness, consequences on participation, and quality of life for people with KOA. Monitoring knee stiffness for KOA is recommended for more appropriate treatment intensity, which could improve adherence to a home programme and potentially reduce the risk of falls.

Treatment and secondary prevention effects of the probiotics Lactobacillus paracasei or Bifidobacterium lactis on early infant eczema: randomized controlled trial with follow-up until age 3 years.

BACKGROUND: Allergic disease has been associated with altered intestinal microbiota. Therefore, probiotics have been suggested as a potential treatment for eczema. OBJECTIVE: We investigated whether dietary supplementation of infants with eczema at age 3-6 months with Lactobacillus paracasei CNCM I-2116 or Bifidobacterium lactis CNCM I-3446 had a treatment effect or altered allergic disease progression. METHODS: Primary outcome included eczema severity (SCORing Atopic Dermatitis, SCORAD) 3 months post-randomization. Secondary: SCORAD (other visits); infant dermatitis quality of life (IDQoL); gastrointestinal permeability; urinary eosinophilic protein X; allergen-sensitization; allergic symptoms (age 12, 18, 36 months). A total of 208 infants aged 3-6 months with physician-diagnosed eczema were recruited; 137/208 (SCORAD ≥ 10, consuming ≥ 200 mL standard formula/day) were randomized to daily supplements containing L. paracasei or B. lactis or placebo for a 3-month period, while receiving extensively hydrolysed whey-formula (dairy-free diet). There were two open observational groups, one group exclusively breastfed (n = 22) and the other, standard formula-fed (n = 49). TRIAL NUMBER: ISRCTN41490500. RESULTS: Eczema severity decreased significantly over time in all groups. No significant difference was observed between randomized groups after 12-week treatment-period (SCORAD-score pre-/post-intervention: B. lactis 25.9 [95% CI: 22.8-29.2] to 12.8 [9.4-16.6]; L. paracasei 25.4 [22.1-29] to 12.5 [9.2-16.4]; placebo 26.9 [23.4-30.6] to 11.8 [9.6-14.3]; P = 0.7). Results were similar when analysis was controlled for allergen-sensitization, or when only sensitized infants were analysed. No differences were found for secondary outcomes. No difference was observed in SCORAD-score between randomized and observational groups. CONCLUSION AND CLINICAL RELEVANCE: We found no benefit from supplementation with B. lactis or L. paracasei in the treatment of eczema, when given as an adjunct to basic topical treatment, and no effect on the progression of allergic disease from age 1 to 3 years.

Difference in patterns of prescribing antidepressants known for their weight-modulating and cardiovascular side effects for patients with obesity compared to patients with normal weight.

BACKGROUND: Patients with depression and comorbid obesity may be more prone to weight modulating and cardiovascular side effects of selected antidepressants (AD). It is important to ascertain whether these AD prescriptions differ by patient weight status. METHODS: Canadian Primary Care Sentinel Surveillance Network (CPCSSN) electronic medical records were used. Participants were adults with depression prescribed an AD in 2000-2016, with weight categories established before the first prescription. Logistic regression and mixed effects models were applied to examine associations between obesity and AD prescribing, adjusted for sex, age, and comorbidities. Machine learning algorithm random forest (RF) was used to evaluate the importance of weight in predicting prescribing patterns. RESULTS: Of 26,571 participants, 72.4% were women, mean age was 38.9 years (standard deviation (SD)=14.2) and mean BMI 27.0 kg/m2 (SD = 6.5); 9.5% had ≥ 1 comorbidity. Patients with obesity, compared to normal weight patients, were more likely to receive bupropion (adjusted odds ratio (aOR) 1.24, 95%CI: 1.09,1.42), fluoxetine (aOR 1.14, 95%CI: 0.97,1.34), and amitriptyline (aOR 1.13, 95%CI: 0.93,1.36), and less likely to receive mirtazapine (aOR 0.55, 95%CI: 0.44,0.68) and escitalopram (aOR 0.88, 95%CI: 0.80, 0.97). RF analysis showed that weight was among the most important predictors of prescribing patterns, equivalent to age and more important than sex. CONCLUSIONS: AD prescribing patterns for patients with obesity appear to be different for selected AD types, including AD known for their weight-modulating and cardiovascular side effects. Longitudinal studies are needed to examine whether these prescribing patterns are associated with significant health outcomes.

BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory.

BACE inhibitors, which decrease BACE1 (ß-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer's disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function. Mice were treated with an in-diet BACE inhibitor for 4-8 weeks to achieve a clinically-relevant level of amyloid-ß40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins. Wild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light-dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. Chronic BACE inhibition for 1-2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.

The phase diagram of Ti-6Al-4V at high-pressures and high-temperatures.

We report results from a series of diamond-anvil-cell synchrotron x-ray diffraction and large-volume-press experiments, and calculations, to investigate the phase diagram of commercial polycrystalline high-strength Ti-6Al-4V alloy in pressure-temperature space. Up to ∼30 GPa and 886 K, Ti-6Al-4V is found to be stable in the hexagonal-close-packed, orαphase. The effect of temperature on the volume expansion and compressibility ofα-Ti-6Al-4V is modest. The martensiticα→ω(hexagonal) transition occurs at ∼30 GPa, with both phases coexisting until at ∼38-40 GPa the transition to theωphase is completed. Between 300 K and 844 K theα→ωtransition appears to be independent of temperature.ω-Ti-6Al-4V is stable to ∼91 GPa and 844 K, the highest combined pressure and temperature reached in these experiments. Pressure-volume-temperature equations-of-state for theαandωphases of Ti-6Al-4V are generated and found to be similar to pure Ti. A pronounced hysteresis is observed in theω-Ti-6Al-4V on decompression, with the hexagonal structure reverting back to theαphase at pressures below ∼9 GPa at room temperature, and at a higher pressure at elevated temperatures. Based on our data, we estimate the Ti-6Al-4Vα-ß-ωtriple point to occur at ∼900 K and 30 GPa, in good agreement with our calculations.

The high-pressure, high-temperature phase diagram of cerium.

We present an experimental study of the high-pressure, high-temperature behaviour of cerium up to ∼22 GPa and 820 K using angle-dispersive x-ray diffraction and external resistive heating. Studies above 820 K were prevented by chemical reactions between the samples and the diamond anvils of the pressure cells. We unambiguously measure the stability region of the orthorhombic oC4 phase and find it reaches its apex at 7.1 GPa and 650 K. We locate the α-cF4-oC4-tI2 triple point at 6.1 GPa and 640 K, 1 GPa below the location of the apex of the oC4 phase, and 1-2 GPa lower than previously reported. We find the α-cF4 → tI2 phase boundary to have a positive gradient of 280 K (GPa)-1, less steep than the 670 K (GPa)-1 reported previously, and find the oC4 → tI2 phase boundary to lie at higher temperatures than previously found. We also find variations as large as 2-3 GPa in the transition pressures at which the oC4 → tI2 transition takes place at a given temperature, the reasons for which remain unclear. Finally, we find no evidence that the α-cF4 → tI2 is not second order at all temperatures up to 820 K.

Thallium under extreme compression.

We present a combined theoretical and experimental study of the high-pressure behavior of thallium. X-ray diffraction experiments have been carried out at room temperature (RT) up to 125 GPa using diamond-anvil cells (DACs), nearly doubling the pressure range of previous experiments. We have confirmed the hcp-fcc transition at 3.5 GPa and determined that the fcc structure remains stable up to the highest pressure attained in the experiments. In addition, HP-HT experiments have been performed up to 8 GPa and 700 K by using a combination of XRD and a resistively heated DAC. Information on the phase boundaries is obtained, as well as crystallographic information on the HT bcc phase. The equation of state (EOS) for different phases is reported. Ab initio calculations have also been carried out considering several potential high-pressure structures. They are consistent with the experimental results and predict that, among the structures considered in the calculations, the fcc structure of thallium is stable up to 4.3 TPa. Calculations also predict the post-fcc phase to have a close-packed orthorhombic structure above 4.3 TPa.

Catalysis of reduction of carbohydrate 2-oxoaldehydes (osones) by mammalian aldose reductase and aldehyde reductase.

In mammalian tissues, carbohydrate 2-oxoaldehydes, or 'osones', formed by cleavage of carbohydrate residues from glycated proteins, cause damage to cells and tissues by cross-linking of proteins. In the substrate specificity study reported here, we show that several osones are relatively good substrates for the reduced, unactivated form of aldose reductase (EC 1.1.1.21) from human and pig muscle, and aldehyde reductase (EC 1.1.1.2) from pig kidney, enzymes that have been well characterised both structurally and mechanistically. Since these enzymes are relatively ubiquitous, they may serve to protect a large number of tissues from damage, by catalysing the reduction of locally-produced osones. Reduction of all substrates by aldehyde reductase obeyed Michaelis-Menten kinetics. In contrast, a Hill constant of about 0.5 was obtained for aldose reductase-catalysed reduction of each of the carbohydrate 2-oxoaldehydes, and for several other substrates that were examined. Although this deviation from Michaelis-Menten kinetics has been ascribed to the presence of two forms of the enzyme, activated and unactivated, our results suggest that it is a characteristic of the unactivated form.

Rapid Increase in Neural Conduction Time in the Adult Human Auditory Brainstem Following Sudden Unilateral Deafness.

Individuals with sudden unilateral deafness offer a unique opportunity to study plasticity of the binaural auditory system in adult humans. Stimulation of the intact ear results in increased activity in the auditory cortex. However, there are no reports of changes at sub-cortical levels in humans. Therefore, the aim of the present study was to investigate changes in sub-cortical activity immediately before and after the onset of surgically induced unilateral deafness in adult humans. Click-evoked auditory brainstem responses (ABRs) to stimulation of the healthy ear were recorded from ten adults during the course of translabyrinthine surgery for the removal of a unilateral acoustic neuroma. This surgical technique always results in abrupt deafferentation of the affected ear. The results revealed a rapid (within minutes) reduction in latency of wave V (mean pre = 6.55 ms; mean post = 6.15 ms; p < 0.001). A latency reduction was also observed for wave III (mean pre = 4.40 ms; mean post = 4.13 ms; p < 0.001). These reductions in response latency are consistent with functional changes including disinhibition or/and more rapid intra-cellular signalling affecting binaurally sensitive neurons in the central auditory system. The results are highly relevant for improved understanding of putative physiological mechanisms underlying perceptual disorders such as tinnitus and hyperacusis.

Inhibition of endotoxin-induced temperature change by behavioral conditioning using alpha-melanocyte-stimulating hormone as an unconditioned stimulus.

The experiments reported here investigate the conditionability, using taste aversion conditioning, of the antagonistic effects of alpha-MSH on the thermoregulatory changes associated with injection of bacterial endotoxin lipopolysaccharide (LPS) in rats. Animals were administered LPS and then given alpha-MSH, as an unconditioned stimulus (UCS), in association with the novel taste of saccharin, the conditioned stimulus (CS). The temperature response at this time in alpha-MSH-treated rats was similar to that observed in control animals. However, 7 days later, when these animals were again injected with LPS but re-exposed to saccharin alone, there was a significant reduction in the temperature response profile compared to controls. These results demonstrate that in male rats the conditioned antipyretic effect following conditioning with alpha-MSH as the UCS is sufficiently robust to counteract the acute effects on body temperature of an LPS injection at the time of CS reexposure. This complements previous experiments demonstrating that thermoregulation may be influenced by cognitive association.

Investigation into the thermal distribution of microwave helical antennas designed for the treatment of Barrett's oesophagus.

A set of helical microwave antennas was designed to investigate their potential use in thermal therapy of Barrett's oesophagus. The antennas had a diameter of up to 3.3 mm and various lengths between 20 and 37 mm; these were designed to operate at 915 MHz. Sets of polytetrafluoroethylene (PTFE) formers were constructed to improve the repeatability and reproducibility of the helix manufacture. Small diameter copper wire was wound over the formers and connected to the coaxial cable at the inner and outer conductor junctions. The power deposition profiles of the antennas were measured in a muscle-equivalent phantom using an infrared camera. The effects of antenna length and coil spacing were characterized. It was observed that uniform temperature profiles along the antenna length were achieved with a length of wire of 99 mm +/- 2 mm. The effective heating length (length of the antenna that exhibits > 50% of the maximum temperature rise) was comparable to the antenna length. The radial penetration depth of 50% of the antenna surface temperature for the optimum 20 mm antenna was 2.5 mm from the antenna outer surface.

Characteristics of glycoprotein B of equine herpesvirus 1 expressed by a recombinant baculovirus.

A recombinant baculovirus (Bac-EgB) containing the complete open reading frame of equine herpesvirus 1 glycoprotein B (EHV-1 gB) expressed recombinant products of 107-133 kDa, 58-75 kDa and 53-57 kDa, corresponding to EHV-1 gB precursor, large and small subunits respectively. High molecular mass products (>200 kDa) in the Bac-EgB infected insect cells were consistent with oligomerisation of the recombinant EHV-1 gB products, and analysis with tunicamycin and endoglycosidases indicated that the baculovirus-expressed gB contained N-linked sugars with high mannose and hybrid chains. N-terminal amino acid sequence analysis of the gB forms revealed identical signal and endoproteolytic cleavage sites to those of gB in EHV-1 infected mammalian cells, and authenticity of processing and transport was supported by the presence of EHV-1 gB antigen at the surface of infected insect cells. Immunogold labelling and electron microscopy of recombinant baculovirus particles indicated that the recombinant gB was also present in baculovirus envelopes. Bac-EgB infected insect cells were able to induce low levels of complement dependent virus neutralising antibody, and have been shown to evoke protective immune responses in murine models of respiratory disease and abortion.

An improvement in hearing sensitivity following hearing-aid fitting in a child with an apparent sensorineural hearing impairment.

This case describes an apparent improvement in hearing sensitivity in a young girl over a period of 12 months, after she was fitted with binaural hearing-aids. Discrepancies between objective and subjective test results are highlighted. Even if the underlying reason for the conflicting test results was due to poor listening skills or test error, this child behaved like a hearing-impaired child and her performance improved after hearing-aid use. The case also illustrates the application of earphone testing from six months of age. The importance of closely monitoring all children who are fitted with hearing-aids is highlighted.

Resistance to synthetic pyrethroids in South Australian populations of sheep lice (Bovicola ovis).

Lice were collected from 71 flocks detected as infested at market inspection in 1990 and 1991, from 16 flocks where resistance was suspected and from 31 flocks from Kangaroo Island. Susceptibility to cypermethrin was measured by a treated surface technique and survival of lice at 5 ppm or greater was taken as an indication of resistance. The prevalence of resistance was 34% in louse populations from the market inspection sample, 50% in flocks in which resistance was suspected and 68% in flocks from Kangaroo Island. Most resistance factors were in the range 1 to 20 although one louse population with a resistance factor of 91 was found on Kangaroo Island.

Investigation of hearing impairment in Cavalier King Charles spaniels using auditory brainstem response audiometry.

Auditory brainstem response audiometry was used to investigate nine Cavalier King Charles spaniels with a history of hearing impairment. Successful recordings were made in all cases. In eight of the dogs, the hearing impairment was between 40 and 85 decibels re normal hearing level. In addition to confirming the degree of impairment in each ear, information was obtained concerning the site of the lesion. The auditory brainstem technique may have an important role to play in assessing treatment outcome. Other applications include screening animals used in breeding programmes as well as working dogs requiring good binaural hearing.

Normative auditory brainstem response data for bone conduction in the dog.

Auditory brainstem response (ABR) is a valuable tool for the diagnosis of hearing disorders in dogs, but is hampered by the lack of published normative data. The aim of the present study was to obtain normative data for bone conduction, without masking, under clearly defined conditions. Subjects comprised 20 Dalmatians and 20 Jack Russell terriers. Two methods were investigated: holding the bone vibrator against the head by hand or by applying a 500 g weight. The results revealed no difference in hearing threshold between the two breeds or for the two methods of applying the bone vibrator to the head. The mean hearing threshold was close to 0 decibels re normal hearing level (dB nHL), which is the biological norm for humans. Hence, bone conduction thresholds can be used for confirmation of conductive hearing impairment in the dog, in the same way as in humans.

Normative auditory brainstem response data for hearing threshold and neuro-otological diagnosis in the dog.

There is growing interest in the application of auditory brainstem response (ABR) audiometry for hearing assessment in dogs. The technique is far from standardised, however, resulting in large discrepancies between studies. This study aimed to obtain normative data, under clearly defined conditions, for two breeds of significantly different size; head size being a potential factor determining ABR latency values. The subjects, 20 dalmatians and 20 Jack Russell terriers, were sedated prior to ABR testing, and subcutaneous scalp electrodes used to detect the evoked potential elicited by a click stimulus presented via insert earphones. The mean ABR thresholds for the two breeds, 0 and -5 decibels re normal hearing level (dB nHL), respectively, were very similar to those for humans. The latency values of the main ABR waves and the interval between them were statistically significantly smaller for the smaller breed, but there was no correlation with head size within either breed. The results provide a baseline to assist with confirmation of hearing impairment and neuro-otological diagnosis in the dog.