Decoding brain memory formation by single-cell RNA sequencing.

To understand how distinct memories are formed and stored in the brain is an important and fundamental question in neuroscience and computational biology. A population of neurons, termed engram cells, represents the physiological manifestation of a specific memory trace and is characterized by dynamic changes in gene expression, which in turn alters the synaptic connectivity and excitability of these cells. Recent applications of single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) are promising approaches for delineating the dynamic expression profiles in these subsets of neurons, and thus understanding memory-specific genes, their combinatorial patterns and regulatory networks. The aim of this article is to review and discuss the experimental and computational procedures of sc/snRNA-seq, new studies of molecular mechanisms of memory aided by sc/snRNA-seq in human brain diseases and related mouse models, and computational challenges in understanding the regulatory mechanisms underlying long-term memory formation.

[Bilateral intracochlear schwannomas in a patient with no genetic or clinical features of neurofibromatosis type 2. German version]. / Bilaterale intracochleäre Schwannome bei einer Patientin ohne genetische oder klinische Hinweise auf Neurofibromatose Typ 2.

Schwannomas of the eighth cranial nerve are benign tumours commonly found in the internal auditory meatus or in the cerebellopontine angle. In most cases, they arise from the inferior or vestibular portion of the vestibular nerve. Rarely, these tumours present in the inner ear and are then called intralabyrinthine schwannomas. Bilateral schwannomas are known in neurofibromatosis type 2 (NF2). Bilateral and ipsilateral, multilocular sporadic schwannomas of the eighth cranial nerve have been described as extremely rare findings. This report describes the first case of bilateral sporadic intracochlear schwannomas in a patient with no genetic or clinical features of NF2.

Bilateral intracochlear schwannomas in a patient with no genetic or clinical features of neurofibromatosis type 2.

Schwannomas of the eighth cranial nerve are benign tumours commonly found in the internal auditory meatus or in the cerebellopontine angle. In most cases, they arise from the inferior or vestibular portion of the vestibular nerve. Rarely, these tumours present in the inner ear and are then called intralabyrinthine schwannomas. Bilateral schwannomas are known in neurofibromatosis type 2 (NF2). Bilateral and ipsilateral, multilocular sporadic schwannomas of the eighth cranial nerve have been described as extremely rare findings. This report describes the first case of bilateral sporadic intracochlear schwannomas in a patient with no genetic or clinical features of NF2.

Long-term quality of life in patients with vestibular schwannoma managed with microsurgery.

OBJECTIVE: Little is known about the long term (greater than 10 years) quality of life in patients with vestibular schwannoma. This study aimed to evaluate long-term outcomes in patients with vestibular schwannoma. METHOD: A retrospective cohort study was performed across 2 academic institutions, with patients followed at least 10 years after vestibular schwannoma surgery (2000 to 2007). Telephone interviews were used to assess quality of life using the Glasgow Benefit Inventory and short form 12 item (version 2) health survey. RESULTS: A total of 99 out of 110 patients were included. Increasing age and symptom burden were associated with poorer quality of life (p = 0.01 and 0.02, respectively). The presence of imbalance, headache and facial nerve dysfunction were all associated with poorer quality of life scores (p = 0.01, 0.04 and 0.02, respectively). CONCLUSION: Identifying and managing post-operative symptoms may improve quality of life in vestibular schwannoma patients and can guide clinical decision making.

RNA processing errors triggered by cadmium and integrator complex disruption are signals for environmental stress.

BACKGROUND: Adaptive responses to stress are essential for cell and organismal survival. In metazoans, little is known about the impact of environmental stress on RNA homeostasis. RESULTS: By studying the regulation of a cadmium-induced gene named numr-1 in Caenorhabditis elegans, we discovered that disruption of RNA processing acts as a signal for environmental stress. We find that NUMR-1 contains motifs common to RNA splicing factors and influences RNA splicing in vivo. A genome-wide screen reveals that numr-1 is strongly and specifically induced by silencing of genes that function in basal RNA metabolism including subunits of the metazoan integrator complex. Human integrator processes snRNAs for functioning with splicing factors, and we find that silencing of C. elegans integrator subunits disrupts snRNA processing, causes aberrant pre-mRNA splicing, and induces the heat shock response. Cadmium, which also strongly induces numr-1, has similar effects on RNA and the heat shock response. Lastly, we find that heat shock factor-1 is required for full numr-1 induction by cadmium. CONCLUSION: Our results are consistent with a model in which disruption of integrator processing of RNA acts as a molecular damage signal initiating an adaptive stress response mediated by heat shock factor-1. When numr-1 is induced via this pathway in C. elegans, its function in RNA metabolism may allow it to mitigate further damage and thereby promote tolerance to cadmium.

A population-based study of the association between dysglycaemia and hearing loss in middle age.

AIMS: To investigate the independent associations between hearing loss and dysglycaemia in a sample of middle-aged adults, including separate analysis of those aged < 60 years. METHODS: The first 2023 participants in the cross-sectional Busselton Health Ageing Survey were assessed for hearing loss ≥ 26 dB (better ear) for four-frequency average (4FA) of pure-tone thresholds at 500, 1000, 2000 and 4000 Hz, and high-frequency average (HFA) of pure-tone thresholds at 4000 and 8000 Hz. RESULTS: Valid data from 1864 participants in the Busselton Health Ageing Survey [92.1%; mean ± sd age 56.2 ± 5.5 years, 46.0% men, 120 (7.0%) with diabetes, 274 (14.7%) with prediabetes] were analysed, of whom 103 (5.5%) had four-frequency average hearing loss and 561 (30.1%) had high-frequency average hearing loss. In multivariable analyses, glycaemic status was not independently associated with four-frequency or high-frequency average hearing loss. In the 1286 participants aged < 60 years, there was no relationship between dysglycaemia and high-frequency average hearing loss, but the prevalence of four-frequency average hearing loss increased from 2.3% (95% CI 1.5-3.4) in participants with normoglycaemia to 5.7% (95% CI 3.0-10.6) in those with prediabetes and 10.2% (4.2-21.5) in those with diabetes (trend P = 0.003). In multivariable analysis with normoglycaemia as reference, the odds ratios for four-frequency average hearing loss were 2.84 (95% CI 1.29-6.27) for prediabetes and 5.93 (95% CI 1.67-21.05) for diabetes (P ≤ 0.01) in the < 60 year age group. CONCLUSIONS: There was progressively increasing mid-range hearing loss with worsening glucose tolerance in younger individuals, suggesting dysglycaemia-associated early-onset presbycusis.

Protective benefit of predominant breastfeeding against otitis media may be limited to early childhood: results from a prospective birth cohort study.

OBJECTIVES: To examine the long-term effects of predominant breastfeeding on incidence of otitis media. DESIGN: Prospective birth cohort study. SETTING: The West Australian Pregnancy Cohort (Raine) Study recruited 2900 mothers through antenatal clinics at the major tertiary obstetric hospital in Perth, Western Australia, between 1989 and 1992. PARTICIPANTS: In total, 2237 children participated in a 6-year cohort follow-up, and a subset of 1344 were given ear and hearing assessments. MAIN OUTCOME MEASURES: OM diagnosis at 6 years of age (diagnosed by low-compliance tympanograms, 0-0.1 mmho). This was compared to OM diagnosed at the 3-year cohort follow-up using parent-report measures. Main exposure measures were duration of predominant breastfeeding (defined as the age other milk was introduced) and duration of partial (any) breastfeeding (defined as the age breastfeeding was stopped). RESULTS: There was a significant, independent association between predominant breastfeeding (OR = 1.33 [1.04, 1.69]; P = 0.02) and OM, and breastfeeding duration (OR = 1.35 [1.08, 1.68]; P = 0.01) with OM at 3 years of age. However, at 6 years of age, this relationship was no longer statistically significant (predominant breastfeeding OR = 0.78 [0.48, 1.06]; P = 0.09; duration of breastfeeding, OR = 1.34 [0.81, 2.23]; P = 0.25). CONCLUSIONS: Our findings are in line with a number of epidemiological studies which show a positive association between breastfeeding and OM in early childhood. However, the long-term follow-up of these children revealed that by 6 years of age, there was no significant influence of breastfeeding on presence of OM. These results suggest that the protective effect of predominant breastfeeding for at least 6 months does not extend to school-age children, where other social and environmental factors may be stronger predictors of OM.

Self-reported cochlear implant management skills: development and validation of the self-administered Cochlear Implant Management Skills (CIMS-self) survey.

OBJECTIVE: A self-administered device management survey was developed and validated to investigate the ability of cochlear implant recipients to self-report physical handling and care for their hearing implant device(s) and to identify factors that may influence self-reported management skills. DESIGN: Survey development and validation. A prospective convenience cohort design study. SETTING: Specialist hearing implant clinic. PARTICIPANTS: Forty-nine post-lingually hearing impaired, adult cochlear implant recipients, at least 12 months postoperative. MAIN OUTCOME MEASURES: Survey test-retest reliability, responsiveness, criterion validity and sensitivity and specificity compared to clinician evaluation of device management skills. Correlations between self-reported management skills and participant demographic, audiometric, cognitive function, clinical outcomes and device factors. RESULTS: The self-administered Cochlear Implant Management Skills survey was developed, demonstrating high test-retest reliability (ICC = 0.884, P < 0.001; CI 95%: 0.721-0.952), responsiveness to intervention (management skills training) [t(20) = -3.245, P = 0.004], criterion validity (ICC = 0.765, P < 0.001; CI 95%: 0.584-0.868) and sensitivity (0.89). No associations were found between self-reported management skills and participant factors. CONCLUSIONS: This study demonstrated that a self-report survey is an effective method for the evaluation of skills required for cochlear implant device management.

The role of subtotal petrosectomy in cochlear implantation.

BACKGROUND: Subtotal petrosectomy combined with cochlear implantation is a procedure required in specific situations. METHODS: A retrospective review of all cases of subtotal petrosectomy in cochlear implant surgery over a five-year period was performed. The indications, complications and outcomes for this procedure are outlined. RESULTS: Sixteen patients underwent cochlear implantation in combination with subtotal petrosectomy and blind sac closure of the external auditory meatus from 2008 to 2013. Seventy-five per cent of these were completed as a two-stage procedure and 25 per cent as a single-stage procedure. The most common indications for the procedure were chronic otitis media, previous radical cavity, and for surgical access in challenging anatomy or in drill-out procedures. Mastoids were obliterated with fat or musculoperiosteal flaps. The complication rate relating to blind sac closure was 6 per cent. Cochlear implants were successfully placed in all cases and there was no incidence of device failure. CONCLUSION: For patients with chronic suppurative otitis media or existing mastoid cavities, subtotal petrosectomy with blind sac closure of the external auditory canal, closure of the eustachian tube, and cavity obliteration is an effective technique to facilitate safe cochlear implantation.

Simultaneous cochlear implantation and labyrinthectomy for advanced Ménière's disease.

BACKGROUND: Patients with Ménière's disease can develop unaidable sensorineural hearing loss. Cochlear implantation has recently been utilised in this group with favourable results. A more challenging group are those with intractable vertigo, and they have traditionally posed a significant management dilemma. CASE REPORT: Two female patients with unaidable hearing and recurrent incapacitating vertigo attacks despite conservative management underwent simultaneous labyrinthectomy and cochlear implantation. There was complete resolution of vertigo in both patients. Speech perception in quiet conditions and the ability to hear in background noise improved considerably. CONCLUSION: Surgical labyrinthectomy is effective for the elimination of vertigo in Ménière's disease patients. The major disadvantage in the past was loss of residual hearing. Cochlear implantation is now an option in these patients. The benefits of simultaneous labyrinthectomy with cochlear implantation include the prevention of implantation of a fibrosed or ossified cochlea, a decrease in the duration of deafness, and a single operative procedure.

A prospective study evaluating cochlear implant management skills: development and validation of the Cochlear Implant Management Skills survey.

OBJECTIVE: To investigate the ability of cochlear implant (CI) recipients to physically handle and care for their hearing implant device(s) and to identify factors that may influence skills. To assess device management skills, a clinical survey was developed and validated on a clinical cohort of CI recipients. DESIGN: Survey development and validation. A prospective convenience cohort design study. SETTING: Specialist hearing implant clinic. PARTICIPANTS: Forty-nine post-lingually deafened, adult CI recipients, at least 12 months postoperative. MAIN OUTCOME MEASURES: Survey test-retest reliability, interobserver reliability and responsiveness. Correlations between management skills and participant demographic, audiometric, clinical outcomes and device factors. RESULTS: The Cochlear Implant Management Skills survey was developed, demonstrating high test-retest reliability (0.878), interobserver reliability (0.972) and responsiveness to intervention (skills training) [t(20) = -3.913, P = 0.001]. Cochlear Implant Management Skills survey scores range from 54.69% to 100% (mean: 83.45%, sd: 12.47). No associations were found between handling skills and participant factors. CONCLUSIONS: This is the first study to demonstrate a range in cochlear implant device handling skills in CI recipients and offers clinicians and researchers a tool to systematically and objectively identify shortcomings in CI recipients' device handling skills.

Measurement of the cosmic microwave background polarization lensing power spectrum with the POLARBEAR experiment.

Gravitational lensing due to the large-scale distribution of matter in the cosmos distorts the primordial cosmic microwave background (CMB) and thereby induces new, small-scale B-mode polarization. This signal carries detailed information about the distribution of all the gravitating matter between the observer and CMB last scattering surface. We report the first direct evidence for polarization lensing based on purely CMB information, from using the four-point correlations of even- and odd-parity E- and B-mode polarization mapped over ∼30 square degrees of the sky measured by the POLARBEAR experiment. These data were analyzed using a blind analysis framework and checked for spurious systematic contamination using null tests and simulations. Evidence for the signal of polarization lensing and lensing B modes is found at 4.2σ (stat+sys) significance. The amplitude of matter fluctuations is measured with a precision of 27%, and is found to be consistent with the Lambda cold dark matter cosmological model. This measurement demonstrates a new technique, capable of mapping all gravitating matter in the Universe, sensitive to the sum of neutrino masses, and essential for cleaning the lensing B-mode signal in searches for primordial gravitational waves.

Evidence for gravitational lensing of the cosmic microwave background polarization from cross-correlation with the cosmic infrared background.

We reconstruct the gravitational lensing convergence signal from cosmic microwave background (CMB) polarization data taken by the Polarbear experiment and cross-correlate it with cosmic infrared background maps from the Herschel satellite. From the cross spectra, we obtain evidence for gravitational lensing of the CMB polarization at a statistical significance of 4.0σ and indication of the presence of a lensing B-mode signal at a significance of 2.3σ. We demonstrate that our results are not biased by instrumental and astrophysical systematic errors by performing null tests, checks with simulated and real data, and analytical calculations. This measurement of polarization lensing, made via the robust cross-correlation channel, not only reinforces POLARBEAR auto-correlation measurements, but also represents one of the early steps towards establishing CMB polarization lensing as a powerful new probe of cosmology and astrophysics.

Correlation analysis of ductus venosus velocity indices and fetal cardiac function.

OBJECTIVE: To examine the relationships between the ductus venosus (DV) pulsatility index for veins (PIV), individual DV velocity ratios and diastolic and global myocardial cardiac function. METHODS: Doppler measurements of the DV, atrioventricular (AV) valves and ventricular in- and outflow were analyzed. The DV-PIV and velocity ratios for individual phases (systole (S), end-systolic relaxation (v), early diastole (D), atrial systole (a), and S/v, S/D, S/a, v/D, v/a and D/a ratios) were calculated. The ratio of early and late diastolic peak velocities across AV valves was calculated (E/A ratio). Left modified myocardial performance index (MPI) was calculated from time intervals between valve clicks defining isovolumetric contraction/relaxation and ejection times. All values were transformed to Z-scores. The distributions of DV velocity ratios and DV-PIV were correlated with cardiac Doppler parameters. RESULTS: A total of 1163 examinations from 213 fetuses, most of which were at risk for cardiac dysfunction, were included in the study. In 742 the PIV was normal and in 421 PIV was elevated > 2 SD above the normal mean. The DV-PIV correlated with velocity ratios (P < 0.0001) but not with E/A ratios and the MPI. S/v and v/D ratios were related to tricuspid and mitral E/A ratios and left ventricular MPI. The S/D ratio was only related to both E/A ratios. There was no relationship between a-wave-related velocity ratios and cardiac function. CONCLUSIONS: Velocity ratios of the DV show relationships with cardiac function that are not reflected by the PIV alone. In cases of suspected fetal cardiac dysfunction based on elevated DV-PIV, analysis of velocity ratios or direct cardiac evaluation is suggested to determine the underlying pathophysiology.

Towards a consensus on a hearing preservation classification system.

CONCLUSION: The comprehensive Hearing Preservation classification system presented in this paper is suitable for use for all cochlear implant users with measurable pre-operative residual hearing. If adopted as a universal reporting standard, as it was designed to be, it should prove highly beneficial by enabling future studies to quickly and easily compare the results of previous studies and meta-analyze their data. OBJECTIVES: To develop a comprehensive Hearing Preservation classification system suitable for use for all cochlear implant users with measurable pre-operative residual hearing. METHODS: The HEARRING group discussed and reviewed a number of different propositions of a HP classification systems and reviewed critical appraisals to develop a qualitative system in accordance with the prerequisites. RESULTS: The Hearing Preservation Classification System proposed herein fulfills the following necessary criteria: 1) classification is independent from users' initial hearing, 2) it is appropriate for all cochlear implant users with measurable pre-operative residual hearing, 3) it covers the whole range of pure tone average from 0 to 120 dB; 4) it is easy to use and easy to understand.

Unique microbiology of chronically unstable canal wall down tympanomastoid cavities: considerations for surgical revision.

OBJECTIVE: To review the microbiology of open tympanomastoid cavities in patients who underwent revision surgery due to chronic instability. METHODS: This paper describes a retrospective chart review of surgical revision cases of chronically unstable open mastoid cavities. Patient records from 2000 to 2010 were reviewed for the type of organism cultured, antimicrobial resistance and the presence of cholesteatoma. RESULTS: In total, 121 revision surgical procedures were performed on 101 patients. Seventy-nine procedures involved culture specimen processing, 37 of which were positive. The most commonly cultured organism was Staphylococcus aureus, which was more than twice as common as any other pathogen. The presence of cholesteatoma had no impact on the likelihood of a positive culture or polymicrobial culture. Antimicrobial-resistant pathogens were uncommon. CONCLUSION: A positive culture was not an overwhelmingly common characteristic of unstable tympanomastoid cavities. Furthermore, antimicrobial resistance did not appear to play an essential role in leading patients towards revision open mastoid surgery.

Utilising silk fibroin membranes as scaffolds for the growth of tympanic membrane keratinocytes, and application to myringoplasty surgery.

BACKGROUND: Chronic tympanic membrane perforations can cause significant morbidity. The term myringoplasty describes the operation used to close such perforations. A variety of graft materials are available for use in myringoplasty, but all have limitations and few studies report post-operative hearing outcomes. Recently, the biomedical applications of silk fibroin protein have been studied. This material's biocompatibility, biodegradability and ability to act as a scaffold to support cell growth prompted an investigation of its interaction with human tympanic membrane keratinocytes. METHODS AND MATERIALS: Silk fibroin membranes were prepared and human tympanic membrane keratinocytes cultured. Keratinocytes were seeded onto the membranes and immunostained for a number of relevant protein markers relating to cell proliferation, adhesion and specific epithelial differentiation. RESULTS: The silk fibroin scaffolds successfully supported the growth and adhesion of keratinocytes, whilst also maintaining their cell lineage. CONCLUSION: The properties of silk fibroin make it an attractive option for further research, as a potential alternative graft in myringoplasty.

Surgical anatomy of the anterior supralabyrinthine air cell tract.

INTRODUCTION: In order to safely explore the medial wall of the attic, a working knowledge of the anatomy of the anterior supralabyrinthine air cell tract is required. AIM: To clarify the surgically relevant anatomical relationships that comprise the anterior supralabyrinthine air cell tract. MATERIALS AND METHODS: Surgical dissection of 10 fresh cadaveric temporal bones was undertaken, including measurement of distances between the key anterior supralabyrinthine anatomical landmarks. RESULTS: The following mean distances were calculated: the labyrinthine segment between the geniculate ganglion and the ampullated end of the superior semicircular canal, 2.33 mm (range 1.75-2.75); the tympanic segment between the anterior margin of the oval window niche and the geniculate ganglion, 3.58 mm (range 3.25-4); and from the tympanic segment adjacent to the anterior margin of the oval window niche to the labyrinthine segment adjacent to the superior semicircular canal, 3.48 mm (range 3-4.25). CONCLUSION: The key anatomical landmarks of the anterior supralabyrinthine air cell tract define a distinct triangular segment of bone, knowledge of which is helpful in surgical dissection.

Patient's quality of life and hearing outcomes after stapes surgery.

OBJECTIVES: To determine the quality of life (QOL) after stapes surgery and whether audiological parameters for hearing correlate with specific QOL factors. DESIGN: A retrospective cross-sectional study. SETTING: A tertiary referral centre. PARTICIPANTS: A series of 35 patients who underwent stapes surgery of which three were excluded because they were <18 years of age, chronically or mentally ill, or in a dependant relationship. Response rate was 93% (30/32). Nine were further excluded because they had revision or bilateral surgery, or missing data. Twenty-one patients were included in this study. MAIN OUTCOME MEASURES: The Glasgow Benefit Inventory (GBI) was used to evaluate general QOL and the Hearing Disability and Handicap Scale (HDHS) was used as a disease-specific measure. The Belfast Rule of Thumb and Glasgow Benefit Plot assessed hearing outcomes. RESULTS: Operative success was 86% using the Belfast Rule of Thumb and 95% had closure of the air-bone gap to within 20 dB. 81.8% of patients reported a better overall QOL as surgery. Glasgow Benefit Inventory Social and GBI Physical scores correlated positively with the HDHS speech component (P < 0.05). The duration of hearing loss correlated inversely with the average HDHS score (P < 0.05). CONCLUSION: The majority of patients report a better QOL as undergoing stapes surgery. Speech impacts on people's physical and social QOL of patients. Quality of life tools, in addition to objective audiologic measurements can provide clinicians with patients' subjective perspective that helps guide clinical decision-making and counselling.