Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony.

In aging, physiologic networks decline in function at rates that differ between individuals, producing a wide distribution of lifespan. Though 70% of human lifespan variance remains unexplained by heritable factors, little is known about the intrinsic sources of physiologic heterogeneity in aging. To understand how complex physiologic networks generate lifespan variation, new methods are needed. Here, we present Asynch-seq, an approach that uses gene-expression heterogeneity within isogenic populations to study the processes generating lifespan variation. By collecting thousands of single-individual transcriptomes, we capture the Caenorhabditis elegans "pan-transcriptome"-a highly resolved atlas of non-genetic variation. We use our atlas to guide a large-scale perturbation screen that identifies the decoupling of total mRNA content between germline and soma as the largest source of physiologic heterogeneity in aging, driven by pleiotropic genes whose knockdown dramatically reduces lifespan variance. Our work demonstrates how systematic mapping of physiologic heterogeneity can be applied to reduce inter-individual disparities in aging.

Polysomnographic airflow shapes and site of collapse during drug-induced sleep endoscopy.

BACKGROUND: Differences in the pharyngeal site of collapse influence efficacy of non-continuous positive airway pressure therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the level of the palate (CCCp) during drug-induced sleep endoscopy (DISE) is associated with reduced efficacy of hypoglossal nerve stimulation, but CCCp is currently not recognisable using polysomnography. Here we develop a means to estimate DISE-based site of collapse using overnight polysomnography. METHODS: 182 OSA patients provided DISE and polysomnography data. Six polysomnographic flow shape characteristics (mean during hypopnoeas) were identified as candidate predictors of CCCp (primary outcome variable, n=44/182), including inspiratory skewness and inspiratory scoopiness. Multivariable logistic regression combined the six characteristics to predict clear presence (n=22) versus absence (n=128) of CCCp (partial collapse and concurrent tongue base collapse excluded). Odds ratios for actual CCCp between predicted subgroups were quantified after cross-validation. Secondary analyses examined complete lateral wall, tongue base or epiglottis collapse. External validation was performed on a separate dataset (ntotal=466). RESULTS: CCCp was characterised by greater scoopiness (ß=1.5±0.6 per 2sd, multivariable estimate±se) and skewness (ß=11.4±2.4) compared with non-CCCp. The odds ratio for CCCp in predicted positive versus negative subgroups was 5.0 (95% CI 1.9-13.1). The same characteristics provided significant cross-validated prediction of lateral wall (OR 6.3, 95% CI 2.4-16.5), tongue base (OR 3.2, 95% CI 1.4-7.3) and epiglottis (OR 4.4, 95% CI 1.5-12.4) collapse. CCCp and lateral wall collapse shared similar characteristics (skewed, scoopy), diametrically opposed to tongue base and epiglottis collapse characteristics. External validation confirmed model prediction. CONCLUSIONS: The current study provides a means to recognise patients with likely CCCp or other DISE-based site of collapse categories using routine polysomnography. Since site of collapse influences therapeutic responses, polysomnographic airflow shape analysis could facilitate precision site-specific OSA interventions.

Tinnitus suppression by means of cochlear implantation: does it affect cognition?

PURPOSE: Recent literature suggests that tinnitus can impact cognition, but results were varied due to a diversity in investigated aspects of cognition and utilized tests, as well as the possible influence of confounding factors. The purpose of this study was to assess the impact of tinnitus loudness on cognition by use of a within-subjects design in patients with a cochlear implant (CI). In this population, tinnitus loudness can be modulated by switching the CI on or off as CI is known to highly suppress tinnitus. METHODS: A total of 18 CI users completed two versions of the Repeatable Battery for Assessment of Neuropsychological Status for Hearing Impaired individuals (RBANS-H), once in unaided condition and once in best aided condition. Tinnitus suppression was defined as a difference in score on a visual-analogue scale (VAS) of at least one point out of ten between these two conditions. RESULTS: No significant differences in RBANS-H scores were found between the suppression and no suppression group, nor for the suppression group alone. No significant correlations between tinnitus loudness and RBANS-H were found, neither for the suppression group alone, nor for the group as a whole. CONCLUSION: The current study shows no significant effect of tinnitus loudness on cognition, which contradicts previous literature. This discrepancy could be explained by the use of a within-subjects design, which controls for confounding factors. Future research should include a larger and more diverse study sample to draw definitive conclusions on this topic.

Clinical findings, surgical techniques, prognostic factors for short-term survival and long-term outcome in horses with acquired inguinal hernias: Ninety-eight cases (2005-2020).

OBJECTIVE: To report findings, outcome and determine variables associated with survival in horses with acquired inguinal hernia (AIH). STUDY DESIGN: Retrospective study. ANIMALS: A total of 98 cases in 97 horses. METHODS: The medical records (2005-2020) of horses diagnosed with AIH were reviewed. Retrieved data included signalment, history, clinical variables, surgical aspects, postoperative complications, and short- and long-term outcomes. Logistic regression analyses were used to determine factors associated with short-term survival (p < .05). RESULTS: Manual reduction was attempted in a third of the cases (32/98, 33%) and emergency surgery to reduce the hernia was performed in 64 of 98 (65%) cases. Concurrent small intestinal (SI) volvulus was identified in 26 (26/98, 27%) cases. Castration was the most common technique used to prevent recurrence (64/94, 68%). Overall AIH recurrence rate was 11% (11/98). A total of 59 (59/98, 60%) cases survived to hospital discharge and 49 of 52 (94%) cases were still alive after 12 months. Cases admitted within 10 h of colic signs had increased odds of survival (72%) compared to those admitted after 10 h (26%; p < .001). Draft breeds (p = .021), high heart rate on admission (p = .001) and concurrent SI volvulus (p = .048) were associated with reduced survival to hospital discharge. CONCLUSIONS: Horses with AIH had a higher risk of concurrent SI volvulus and lower survival than reported. Draft breeds, high heart rate on admission and concurrent SI volvulus were associated with reduced short-term survival. CLINICAL SIGNIFICANCE: The results of this study should help in prognostication for horses with AIH.

Inhomogeneous Magnetization Transfer (ihMT) imaging in the acute cuprizone mouse model of demyelination/remyelination.

BACKGROUND: To investigate the association of ihMT (inhom signals with the demyelination and remyelination phases of the acute cuprizone mouse model in comparison with histology, and to assess the extent of tissue damage and repair from MRI data. METHODS: Acute demyelination by feeding 0.2% cuprizone for five weeks, followed by a four-week remyelination period was applied on genetically modified plp-GFP mice. Animals were scanned at different time points of the demyelination and remyelination phases of the cuprizone model using a multimodal MRI protocol, including ihMT T1D-filters, MPF (Macromolecular Proton Fraction) and R1 (longitudinal relaxation rate). For histology, plp-GFP (proteolipid protein - Green Fluorescent Protein) microscopy and LFB (Luxol Fast Blue) staining were employed as references for the myelin content. Comparison of MRI with histology was performed in the medial corpus callosum (mCC) and cerebral cortex (CTX) at two brain levels whereas ROI-wise and voxel-based analyses of the MRI metrics allowed investigating in vivo the spatial extent of myelin alterations. RESULTS: IhMT high-pass T1D-filters, targeted toward long T1D components, showed significant temporal variations in the mCC consistent with the effects induced by the cuprizone toxin. In addition, the corresponding signals correlated strongly and significantly with the myelin content assessed by GFP fluorescence and LFB staining over the demyelination and the remyelination phases. The signal of the band-pass T1D-filter, which isolates short T1D components, showed changes over time that were poorly correlated with histology, hence suggesting a sensitivity to pathological processes possibly not related to myelin. Although MPF was also highly correlated to histology, ihMT high-pass T1D-filters showed better capability to characterize the spatial-temporal patterns during the demyelination and remyelination phases of the acute cuprizone model (e.g., rostro-caudal gradient of demyelination in the mCC previously described in the literature). CONCLUSIONS: IhMT sequences selective for long T1D components are specific and sensitive in vivo markers of demyelination and remyelination and have successfully captured the spatially heterogeneous pattern of the demyelination and remyelination mechanisms in the cuprizone model. Interestingly, differences in signal variations between the ihMT high-pass and band-pass T1D-filter, suggest a sensitivity of the ihMT sequences targeted to short T1Ds to alterations other than those of myelin. Future studies will need to further address these differences by examining more closely the origin of the short T1D components and the variation of each T1D component in pathology.

Fast-spin-echo versus rapid gradient-echo for 3D magnetization-prepared acquisitions: Application to inhomogeneous magnetization transfer.

PURPOSE: To evaluate the benefits of fast spin echo (FSE) imaging over rapid gradient-echo (RAGE) for magnetization-prepared inhomogeneous magnetization transfer (ihMT) imaging. METHODS: A 3D FSE sequence was modified to include an ihMT preparation (ihMT-FSE) with an optional CSF suppression based on an inversion-recovery (ihMT-FLAIR). After numeric simulations assessing SNR benefits of FSE and the potential impact of an additional inversion-recovery, ihMT-RAGE, ihMT-FSE, and ihMT-FLAIR sequences were compared in a group of six healthy volunteers, evaluating image quality, thermal, and physiological noise as well as quantification using an ihMT saturation (ihMTsat) approach. A preliminary exploration in the cervical spinal cord was also conducted in a group of three healthy volunteers. RESULTS: Several fold improvements in thermal SNR were observed with ihMT-FSE in agreement with numerical simulations. However, we observed significantly higher physiological noise in ihMT-FSE compared to ihMT-RAGE that was mitigated in ihMT-FLAIR, which provided the best total SNR (+74% and +49% compared to ihMT-RAGE in the white and gray matter, P ≤ 0.004). IhMTsat quantification was successful in all cases with strong correlation between all sequences (r2 > 0.75). Early experiments showed potential for spinal cord imaging. CONCLUSIONS: FSE generally offers higher SNR compared to gradient-echo based acquisitions for magnetization-prepared contrasts as illustrated here in the case of ihMT. However, physiological noise has a significant effect, but an inversion-recovery-based CSF suppression was shown to be efficient in mitigating effects of CSF motion.

Quantitative magnetization transfer MRI unbiased by on-resonance saturation and dipolar order contributions.

PURPOSE: To demonstrate the bias in quantitative MT (qMT) measures introduced by the presence of dipolar order and on-resonance saturation (ONRS) effects using magnetization transfer (MT) spoiled gradient-recalled (SPGR) acquisitions, and propose changes to the acquisition and analysis strategies to remove these biases. METHODS: The proposed framework consists of SPGR sequences prepared with simultaneous dual-offset frequency-saturation pulses to cancel out dipolar order and associated relaxation (T1D ) effects in Z-spectrum acquisitions, and a matched quantitative MT (qMT) mathematical model that includes ONRS effects of readout pulses. Variable flip angle and MT data were fitted jointly to simultaneously estimate qMT parameters (macromolecular proton fraction [MPF], T2,f , T2,b , R, and free pool T1 ). This framework is compared with standard qMT and investigated in terms of reproducibility, and then further developed to follow a joint single-point qMT methodology for combined estimation of MPF and T1 . RESULTS: Bland-Altman analyses demonstrated a systematic underestimation of MPF (-2.5% and -1.3%, on average, in white and gray matter, respectively) and overestimation of T1 (47.1 ms and 38.6 ms, on average, in white and gray matter, respectively) if both ONRS and dipolar order effects are ignored. Reproducibility of the proposed framework is excellent (ΔMPF = -0.03% and ΔT1 = -19.0 ms). The single-point methodology yielded consistent MPF and T1 values with respective maximum relative average bias of -0.15% and -3.5 ms found in white matter. CONCLUSION: The influence of acquisition strategy and matched mathematical model with regard to ONRS and dipolar order effects in qMT-SPGR frameworks has been investigated. The proposed framework holds promise for improved accuracy with reproducibility.

Inhomogeneous magnetization transfer imaging: Concepts and directions for further development.

Off-resonance radio frequency irradiation can induce the ordering of proton spins in the dipolar fields of their neighbors, in molecules with restricted mobility. This dipolar order decays with a characteristic relaxation time, T1D , that is very different from the T1 and T2 relaxation of the nuclear alignment with the main magnetic field. Inhomogeneous magnetization transfer (ihMT) imaging is a refinement of magnetization transfer (MT) imaging that isolates the MT signal dependence on dipolar order relaxation times within motion-constrained molecules. Because T1D relaxation is a unique contrast mechanism, ihMT may enable improved characterization of tissue. Initial work has stressed the high correlation between ihMT signal and myelin density. Dipolar order relaxation appears to be much longer in membrane lipids than other molecules. Recent work has shown, however, that ihMT acquisitions may also be adjusted to emphasize different ranges of T1D . These newer approaches may be sensitive to other microstructural components of tissue. Here, we review the concepts and history of ihMT and outline the requirements for further development to realize its full potential.

The effect of CPAP on the upper airway and ventilatory flow in patients with obstructive sleep apnea.

BACKGROUND: Continuous positive airway pressure (CPAP) is the mainstay of treatment for obstructive sleep apnea (OSA). However, data about its effect on the upper airway, especially the epiglottis, are scarce. The aim of this study was to investigate the changes in upper airway dimensions and inspiratory flow in response to incremental pressure levels. METHODS: This is a secondary analysis of a prospective clinical trial in which patients with moderate to severe OSA underwent drug-induced sleep endoscopy with simultaneous recordings of flow and mask pressure. CPAP was titrated in small increments. For each pressure level a representative 3-breath segment was selected to determine specific flow features. The corresponding endoscopic footage was reviewed to assess the degree of upper airway collapse in a semi-quantitative manner. RESULTS: A total of 214 breath segments were obtained from 13 participants (median [Q1-Q3]; apnea-hypopnea index, 24.9 [20.1-43.9] events/h; body mass index 28.1 [25.1-31.7] kg/m²). CPAP significantly increased cross-sectional dimensions of the soft palate, lateral walls and tongue base, but not of the epiglottis, and induced epiglottis collapse in one subject. Increased pressure improved peak inspiratory flow and median ventilation in all patients, even in the presence of persistent epiglottis collapse. CONCLUSION: CPAP does not effectively address epiglottis collapse in patients with OSA. However, it normalizes inspiratory flow regardless of its effect on the epiglottis. This clinical trial was registered on January 18th, 2020 on ClinicalTrials.gov with identifier NCT04232410.

A hierarchical process model links behavioral aging and lifespan in C. elegans.

Aging involves a transition from youthful vigor to geriatric infirmity and death. Individuals who remain vigorous longer tend to live longer, and within isogenic populations of C. elegans the timing of age-associated vigorous movement cessation (VMC) is highly correlated with lifespan. Yet, many mutations and interventions in aging alter the proportion of lifespan spent moving vigorously, appearing to "uncouple" youthful vigor from lifespan. To clarify the relationship between vigorous movement cessation, death, and the physical declines that determine their timing, we developed a new version of the imaging platform called "The Lifespan Machine". This technology allows us to compare behavioral aging and lifespan at an unprecedented scale. We find that behavioral aging involves a time-dependent increase in the risk of VMC, reminiscent of the risk of death. Furthermore, we find that VMC times are inversely correlated with remaining lifespan across a wide range of genotypes and environmental conditions. Measuring and modelling a variety of lifespan-altering interventions including a new RNA-polymerase II auxin-inducible degron system, we find that vigorous movement and lifespan are best described as emerging from the interplay between at least two distinct physical declines whose rates co-vary between individuals. In this way, we highlight a crucial limitation of predictors of lifespan like VMC-in organisms experiencing multiple, distinct, age-associated physical declines, correlations between mid-life biomarkers and late-life outcomes can arise from the contextual influence of confounding factors rather than a reporting by the biomarker of a robustly predictive biological age.

Dual-site transcranial direct current stimulation to treat tinnitus: a randomized controlled trial.

Transcranial direct current stimulation (tDCS) has been proposed as a potential intervention for subjective tinnitus, but supporting evidence remains limited. We aimed to investigate the effect of anodal high-definition tDCS of the left temporal area and right dorsolateral prefrontal cortex on tinnitus severity. This double-blind randomized controlled trial included 77 patients (age range 18-79, 43 male) with chronic subjective tinnitus as their primary complaint. Thirty-eight subjects received six consecutive sessions of dual-site sequential high-definition-tDCS with electrodes positioned over the left temporal area and right dorsolateral prefrontal cortex. Both areas were stimulated for 15 min per session, with total stimulation time amounting to 30 min. Thirty-nine subjects received sham stimulation. The primary outcome measure was the change in tinnitus severity, as evaluated by the Tinnitus Functional Index, from baseline to a follow-up visit at 8 ± 2 weeks after treatment completion. Secondary outcomes included changes in perceived tinnitus loudness, as measured with a visual analogue scale and a tinnitus matching procedure, as well as scores on the Hospital Anxiety and Depression Scale, and the Hyperacusis Questionnaire. No differences in Tinnitus Functional Index change scores were identified between the active treatment and sham control groups (linear regression: P = 0.86). The Tinnitus Functional Index scores decreased significantly over time in both groups (P = 0.0012), indicating the presence of a considerable placebo effect. These change scores were significantly influenced by sex (linear regression: P = 0.037) and baseline symptoms of anxiety (linear regression: P = 0.049) in both groups. In general, Tinnitus Functional Index scores decreased more profoundly in males and in subjects with a higher degree of anxiety at baseline. None of the included secondary measures differed significantly between experimental arms. Our results suggest that dual-site sequential high-definition-tDCS of the left temporal area and right dorsolateral prefrontal cortex does not alleviate tinnitus severity. Interestingly, in our study population, fluctuations in tinnitus severity were influenced by gender and concurrent mental condition. It is therefore important to take these factors into account when conducting or planning randomized controlled trials in tinnitus populations.

Clinical and subclinical findings in heterozygous ABCC6 carriers: results from a Belgian cohort and clinical practice guidelines.

BACKGROUND: Biallelic pathogenic variants in the ATP-binding cassette subfamily C member 6 (ABCC6) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous ABCC6 variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic ABCC6 variants in the general population is estimated at ~1%, identifying additional ABCC6-related (sub)clinical manifestations in heterozygous carriers is of the utmost importance to reduce this burden of disease. Here, we present a large Belgian cohort of heterozygous ABCC6 carriers with comprehensive clinical, biochemical and imaging data. Based on these results, we formulate clinical practice guidelines regarding screening, preventive measures and follow-up of ABCC6 carriers. METHODS: The phenotype of 56 individuals carrying heterozygous pathogenic ABCC6 variants was assessed using clinical (eg, detailed ophthalmological examinations), biochemical, imaging (eg, cardiovascular and abdominal ultrasound) and genetic data. Clinical practice guidelines were then drawn up. RESULTS: We found that ABCC6 heterozygosity is associated with distinct retinal alterations ('comet-like') (24%), high prevalence of hypercholesterolaemia (>75%) and diastolic dysfunction (33%), accelerated lower limb atherosclerosis and medial vascular disease, abdominal organ calcification (26%) and testicular microlithiasis (28%), though with highly variable expression. CONCLUSION: In this study, we delineated the multisystemic ABCC6 heterozygosity phenotype characterised by retinal alterations, aberrant lipid metabolism, diastolic dysfunction and increased vascular, abdominal and testicular calcifications. Our clinical practice guidelines aimed to improve early diagnosis, treatment and follow-up of ABCC6-related health problems.

Hypoglossal nerve stimulation versus positive airway pressure therapy for obstructive sleep apnea.

PURPOSE: Hypoglossal nerve stimulation (HNS) has been shown to treat obstructive sleep apnea (OSA) effectively. The aim of this study was to compare HNS with positive airway pressure (PAP) treatment regarding outcome parameters: (1) sleepiness, (2) apnea-hypopnea index (AHI), and (3) effectiveness. METHODS: Propensity score matching with nearest neighbor algorithm was used to compare outcomes of HNS and PAP therapy in a real-world setting. Data were collected at baseline and 12 months after initiating OSA treatment including demographics, Epworth Sleepiness Scale (ESS), AHI, and objective adherence data. To account for overall treatment efficacy, the mean disease alleviation (MDA) was calculated. RESULTS: Of 227 patients who received treatment consecutively, 126 could be matched 1:1 with regard to age, body mass index, and AHI. After matching, no statistically significant differences between the groups were found. A clinically important symptom improvement was seen at 12 months in both cohorts, though there was a greater difference in ESS improvement in patients treated with HNS (8.0 ± 5.1 points vs. 3.9 ± 6.8 points; p = 0.042). In both groups, mean posttreatment AHI was significantly reduced (HNS: 8.1 ± 6.3/h; PAP: 6.6 ± 8.0/h; p < 0.001). Adherence after 12 months among patients treated with HNS was higher than in those receiving PAP therapy (5.0 ± 2.6 h/night; 4.0 ± 2.1 h/night) but not with statistical significance. Overall effectiveness calculated with the MDA was 59% in patients treated with HNS compared to 51% receiving PAP. CONCLUSION: Patients treated with HNS therapy had significantly greater improvements in daytime sleepiness compared to PAP therapy, while the mean reduction of AHI and overall effectiveness were comparable for both treatments. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT03756805.

Effectiveness of Telerehabilitation Interventions for Self-management of Tinnitus: Systematic Review.

BACKGROUND: Tinnitus is a highly prevalent symptom affecting 10%-20% of the adult population. Most patients with tinnitus have chronic tinnitus, which can directly or indirectly disrupt their daily life and negatively affect the health-related quality of life. Therefore, patients with tinnitus are frequently in need of costly and time-consuming treatments. As an answer, telerehabilitation interventions are on a rise to promote self-management in patients with tinnitus and reduce their dependency on in-person care. OBJECTIVE: This systematic review aimed to provide an overview of the research concerning the effectiveness of telerehabilitation interventions for self-management of tinnitus. METHODS: This systematic review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were eligible for inclusion if study participants were adult patients with complaints of primary subjective tinnitus and the study intervention comprised any possible telerehabilitation form for the self-management of tinnitus complaints. A search for eligible studies was conducted on PubMed, ScienceDirect, Scopus, Web of Science, and Cochrane Library. The Cochrane Risk of Bias 2 tool was used to the assess risk of bias. RESULTS: In total, 29 articles were found eligible, and of these, 5 (17%) studied multiple telerehabilitation forms. Internet-based cognitive behavioral treatment with guidance by a psychologist or audiologist was examined in 17 studies (n=1767), internet-based cognitive behavioral treatment without guidance was examined in 4 studies (n=940), self-help manuals were examined in 1 study (n=72), technological self-help devices were examined in 2 studies (n=82), smartphone apps were examined in 8 studies (n=284), and other internet-based interventions were examined in 2 studies (n=130). These rehabilitation categories were proven to be effective in decreasing tinnitus severity and relieving tinnitus distress as measured by tinnitus questionnaires such as Tinnitus Functional Index, Tinnitus Handicap Inventory, or Tinnitus Reactions Questionnaire. However, dropout rates were often high (range 4%-71.4%). All studies reported between some concerns and high concerns of risk of bias, resulting in low to moderate certainty levels. CONCLUSIONS: Overall, there is low to moderate quality evidence that telerehabilitation interventions effectively reduce tinnitus severity and distress. These interventions form a possible tool to improve the self-management capacities of the patient and the accessibility of tinnitus care as a replacement or an addition to in-person care. Nevertheless, barriers such as lack of time, engagement, motivation, and openness of the patient causing high dropout should be considered. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021285450; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=285450.

Prevalence of tinnitus and hyperacusis in 9-12-year-old children.

OBJECTIVES: To estimate the prevalence of tinnitus and hyperacusis in children aged 9-12 years in Flanders, as well as to explore the associations with hearing abilities and listening behaviours. DESIGN: A cross-sectional survey was undertaken in four different Flemish schools. The questionnaire was distributed among 415 children, with a response rate of 97.3%. RESULTS: The prevalence of permanent tinnitus was 10.5% and of hyperacusis was 3.3%. The hyperacusis prevalence was higher in girls (p < .05). Some children reported effects of tinnitus in terms of anxiety (20.1%), sleep (36.5%), and concentration (24.8%). When listening to personal listening devices, 33.5% of the children reported to listen for at least 1 h at 60% or higher of the volume range. Moreover, 54.9% of children stated to never wear hearing protection. CONCLUSIONS: Tinnitus and hyperacusis are prevalent in children aged 9-12 years. Some of these children might be overlooked and, as such, not receiving the required follow-up or counselling. Development of guidelines for the assessment of these auditory symptoms in children would help to determine the prevalence numbers with greater accuracy. Sensibility campaigns for safe listening are warranted, as more than half of the children never use hearing protection.

Pilot study on the role of somatic modulation in hyperacusis.

BACKGROUND: Hyperacusis is a reduced tolerance to sounds that often co-occurs with tinnitus. Both symptoms have convergent as well as divergent characteristics. Somatic modulation, changes in pitch or loudness during certain movements, is common in patients with a primary complaint of tinnitus. However, thus far, this is not documented in patients with hyperacusis. OBJECTIVES: This study aimed to examine the influence of somatic manoeuvres on the perception of external sounds in patients with a primary complaint of hyperacusis. METHODOLOGY: In this prospective cross-sectional pilot study, 18 patients with a primary complaint of hyperacusis were recruited at the Tinnitus Treatment and Research Center Antwerp (TINTRA). While patients listened to a 1 kHz broadband noise of 30 dB sensation level, six neck manoeuvres (flexion, extension, lateroflexion left/right, traction and compression), three jaw manoeuvres (protrusion, laterotrusion left/right) and one placebo manoeuvre (hand on head) were performed. The primary outcome measure was the change in the perception of the presented sound in terms of loudness and intrusiveness between baseline and each modulation measured by a visual analogue scale (VAS). RESULTS: No overall significant changes were found; however, individual results indicated that five patients presented a clinically relevant change of more than three points out of ten on VAS in terms of hyperacusis after at least one of the executed somatic manoeuvres. CONCLUSIONS: This pilot study did not demonstrate an overall significant change in hyperacusis after somatic manoeuvres but does not rule out the possibility of somatic modulation in some hyperacusis patients. TRIAL REGISTRATION: The protocol of this prospective cross-sectional pilot study was registered on clinicaltrials.gov with registration number NCT04693819.

How can peer teaching influence the development of medical students? a descriptive, longitudinal interview study.

BACKGROUND: Peer-assisted learning (PAL) - where students take up a teaching role at an early stage of their training-is widely used in medical curricula. Many qualitative studies have investigated the perceptions and benefits of PAL, but no studies have longitudinally explored how peer teachers experienced their development. This could allow for a better understanding of PAL. In this study, we explored the perceived impact of being a peer teacher on the development of personal and professional competencies as a medical student. METHODS: We longitudinally conducted semi-structured interviews with peer teachers, during their 2-year teaching period in the skills lab at the University of Antwerp and applied descriptive thematic analysis. RESULTS: In total we gathered 47 interviews in 13 peer teachers (9 female, 4 male,. 1-7 interviews each). Peer teachers reported an increase in self-confidence, which gradually transformed into self-efficacy in clinical and teaching skills., Participants told us to be inspired by the previous generation of peer teachers. Their motivation shifted from personal benefits to benefiting others while becoming a role model themselves. The peer teachers illustrated how they developed maturity by integrating different CanMEDS roles. They grew in reflection, changed/transformed an initial mark-driven study drive into more patient-centered ambitions, and started developing a personal style. CONCLUSIONS: Our study suggests that being a peer teacher leads to more self-efficacy, in clinical and teaching skills, to become a role model with as motivation to benefit others and to grow towards a good doctor maturity. Although the task is to teach peers, this opportunity nurtures the practice and integration of various CanMEDS roles, not only that of scholar but also communicator, collaborator and leader, thereby positively influencing their personal and professional development and their identity as a doctor (professional role).

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.

ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.

Automatic segmentation of deep grey nuclei using a high-resolution 7T magnetic resonance imaging atlas-Quantification of T1 values in healthy volunteers.

We present a new consensus atlas of deep grey nuclei obtained by shape-based averaging of manual segmentation of two experienced neuroradiologists and optimized from 7T MP2RAGE images acquired at (.6 mm)3 in 60 healthy subjects. A group-wise normalization method was used to build a high-contrast and high-resolution T1 -weighted brain template (.5 mm)3 using data from 30 out of the 60 controls. Delineation of 24 deep grey nuclei per hemisphere, including the claustrum and 12 thalamic nuclei, was then performed by two expert neuroradiologists and reviewed by a third neuroradiologist according to tissue contrast and external references based on the Morel atlas. Corresponding deep grey matter structures were also extracted from the Morel and CIT168 atlases. The data-derived, Morel and CIT168 atlases were all applied at the individual level using non-linear registration to fit the subject reference and to extract absolute mean quantitative T1 values derived from the 3D-MP2RAGE volumes, after correction for residual B1+ biases. Three metrics (the Dice and the volumetric similarity coefficients and a novel Hausdorff distance) were used to estimate the inter-rater agreement of manual MRI segmentation and inter-atlas variability, and these metrics were measured to quantify biases due to image registration, and their impact on the measurements of the quantitative T1 values was highlighted. This represents a fully automated segmentation process permitting the extraction of unbiased normative T1 values in a population of young healthy controls as a reference for characterizing subtle structural alterations of deep grey nuclei relevant to a range of neurological diseases.

A strategy to reduce the sensitivity of inhomogeneous magnetization transfer (ihMT) imaging to radiofrequency transmit field variations at 3 T.

PURPOSE: To minimize the sensitivity of inhomogeneous magnetization transfer gradient-echo (ihMT-GRE) imaging to radiofrequency (RF) transmit field ( B1+ ) inhomogeneities at 3 T. METHODS: The ihMT-GRE sequence was optimized by varying the concentration of the RF saturation energy over time, obtained by increasing the saturation pulse power while extending the sequence repetition time (TR). Different protocols were tested using numerical simulations and human in vivo experiments in the brain white matter (WM) of healthy subjects at 3 T. The sensitivity of the ihMT ratio (ihMTR) to B1+ variations was investigated by comparing measurements obtained at nominal transmitter adjustments and following a 20% global B1+ drop. The resulting relative variations (δihMTR ) were evaluated voxelwise as a function of the local B1+ distribution. The reproducibility of the protocol providing minimal B1+ bias was assessed in a test-retest experiment. RESULTS: In line with simulations, ihMT-GRE experiments conducted at high concentration of the RF energy over time demonstrated strong reduction of the B1+ inhomogeneity effects in the human WM. Under the optimal conditions of 350-ms TR and 3-µT root mean square (RMS) saturation power, 73% of all WM voxels presented δihMTR below 10%. Reproducibility analysis yielded a close-to-zero systematic bias (ΔihMTR = -0.081%) and a high correlation (ρ² = 0.977) between test and retest experiments. CONCLUSION: Concentrating RF saturation energy in ihMT-GRE sequences mitigates the sensitivity of the ihMTR to B1+ variations and allows for clinical-ready ihMT imaging at 3 T. This feature is of particular interest for high and ultra-high field applications.