The Fifth Croatia Stuttering Symposium: Part I. Treatments for early stuttering.

PURPOSE: The Fifth Croatia Stuttering Symposium in 2022 continued the Fourth Croatia Stuttering Symposium 2019 theme of the connection between research and clinical practice. At the 2022 Symposium, there were 145 delegates from 21 countries. This paper documents the contents of the first of three Symposium modules. METHODS: The module topic was that three treatments for early childhood stuttering are supported by randomized controlled trial evidence. A clinical situation was considered where a parent of a 3-year-old child asked what results to expect of stuttering treatment. RESULTS: A distinguished scholar presented a 5-minute video interpretation of the research concerning the randomized controlled trial evidence for the three treatments. Three master clinicians then each presented a 2-minute video demonstration of how those research findings might be applied in a clinical situation. Following that, the convenors moderated a discussion between the distinguished scholar, master clinicians, and delegates regarding the research and how it applies to clinical practice.

Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes.

Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases.

Use of artificial intelligence for the diagnosis of cholesteatoma.

Objectives: Accurate diagnosis of cholesteatomas is crucial. However, cholesteatomas can easily be missed in routine otoscopic exams. Convolutional neural networks (CNNs) have performed well in medical image classification, so we evaluated their use for detecting cholesteatomas in otoscopic images. Study Design: Design and evaluation of artificial intelligence driven workflow for cholesteatoma diagnosis. Methods: Otoscopic images collected from the faculty practice of the senior author were deidentified and labeled by the senior author as cholesteatoma, abnormal non-cholesteatoma, or normal. An image classification workflow was developed to automatically differentiate cholesteatomas from other possible tympanic membrane appearances. Eight pretrained CNNs were trained on our otoscopic images, then tested on a withheld subset of images to evaluate their final performance. CNN intermediate activations were also extracted to visualize important image features. Results: A total of 834 otoscopic images were collected, further categorized into 197 cholesteatoma, 457 abnormal non-cholesteatoma, and 180 normal. Final trained CNNs demonstrated strong performance, achieving accuracies of 83.8%-98.5% for differentiating cholesteatoma from normal, 75.6%-90.1% for differentiating cholesteatoma from abnormal non-cholesteatoma, and 87.0%-90.4% for differentiating cholesteatoma from non-cholesteatoma (abnormal non-cholesteatoma + normal). DenseNet201 (100% sensitivity, 97.1% specificity), NASNetLarge (100% sensitivity, 88.2% specificity), and MobileNetV2 (94.1% sensitivity, 100% specificity) were among the best performing CNNs in distinguishing cholesteatoma versus normal. Visualization of intermediate activations showed robust detection of relevant image features by the CNNs. Conclusion: While further refinement and more training images are needed to improve performance, artificial intelligence-driven analysis of otoscopic images shows great promise as a diagnostic tool for detecting cholesteatomas. Level of Evidence: 3.

Evaluation of inter- and intra-observer variations in prostate gland delineation using CT-alone versus CT/TPUS.

Background: This study aims to explore the role of four-dimensional (4D) transperineal ultrasound (TPUS) in the contouring of prostate gland with planning computed tomography (CT) images, in the absence of magnetic resonance imaging (MRI). Materials and methods: Five radiation oncologists (ROs) performed two rounds of prostate gland contouring (single-blinded) on CT-alone and CT/TPUS datasets obtained from 10 patients who underwent TPUS-guided external beam radiotherapy. Parameters include prostate volume, DICE similarity coefficient (DSC) and centroid position. Wilcoxon signed-rank test assessed the significance of inter-modality differences, and the intraclass correlation coefficient (ICC ) reflected inter- and intra-observer reliability of parameters. Results: Inter-modality analysis revealed high agreement (based on DSC and centroid position) of prostate gland contours between CT-alone and CT/TPUS. Statistical significant difference was observed in the superior-inferior direction of the prostate centroid position (p = 0.011). All modalities yielded excellent inter-observer reliability of delineated prostate volume with ICC > 0.9, mean DSC > 0.8 and centroid position: CT-alone (ICC = 1.000) and CT/TPUS (ICC = 0.999) left-right (L/R); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 0.998) anterior-posterior (A/P); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 1.000) superior-inferior (S/I). Similarly, all modalities yielded excellent intra-observer reliability of delineated prostate volume, ICC > 0.9 and mean DSC > 0.8. Lastly, intra-observer reliability was excellent on both imaging modalities for the prostate centroid position, ICC > 0.9. Conclusion: TPUS does not add significantly to the amount of anatomical information provided by CT images. However, TPUS can supplement planning CT to achieve a higher positional accuracy in the S/I direction if access to CT/MRI fusion is limited.

Contemporary issues with stuttering: The Fourth Croatia Stuttering Symposium.

PURPOSE: During the 2019 Fourth Croatia Clinical Symposium, speech-language pathologists (SLPs), scholars, and researchers from 29 countries discussed speech-language pathology and psychological practices for the management of early and persistent stuttering. This paper documents what those at the Symposium considered to be the key contemporary clinical issues for early and persistent stuttering. METHODS: The authors prepared a written record of the discussion of Symposium topics, taking care to ensure that the content of the Symposium was faithfully reproduced in written form. RESULTS: Seven contemporary issues for our field emerged from the Symposium. CONCLUSION: Effective early intervention is fundamental to proper health care for the disorder. However, as yet, there is no consensus about the timing of early intervention and how it should be managed. Currently, clinical translation is a barrier to evidence-based practice with early stuttering, and proactive strategies were suggested for junior SLPs. Apprehension emerged among some discussants that treatment of early stuttering may cause anxiety. For persistent stuttering, assessment procedures were recommended, as were strategies for dealing with childhood bullying. There was agreement that SLPs are the ideal professionals to provide basic cognitive-behavior therapy for clients with persistent stuttering. Questions were raised about our discipline standards for basic professional preparation programs for stuttering management.

The impact of caregiver stigma on real-life social experience of Taiwanese adolescents with autism spectrum disorder.

LAY ABSTRACT: Caregivers of people with autism spectrum disorder commonly experience stigma. As a result, they may avoid contact with others, in turn, influencing their child's social participation. This study aimed to explore the impact of stigma perceived by the caregivers on the everyday social experience of Taiwanese adolescents with autism spectrum disorder. We asked 76 adolescents with autism spectrum disorder who did not have intellectual disability (69 males, aged 10-16 years) to carry a mobile device for 7 days. The device prompted them 7 times each day to record who they were interacting with, what they perceived, and how they felt about their social interactions. In addition, we asked their caregivers to complete the Affiliate Stigma Scale to measure their experience of stigma. We found that participants whose caregivers perceived high levels of stigma were more likely to spend time with family members and less likely to be interested in interacting with people at school. Those participants also were more likely to experience anxiety while interacting with family. Our study suggests that it is important for clinicians to implement support services for adolescents with autism spectrum disorder and help caregivers in managing stigma to promote their child's social participation.

ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation.

Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in amyotrophic lateral sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells from healthy controls, familial ALS, and sporadic ALS patients were differentiated toward spinal MNs, cortical neurons, and cardiomyocytes. Metabolic flux analyses reveal an MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, Sirtuin-3 (SIRT3) functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.

Cerebrovascular reactivity and cerebral autoregulation are improved in the supine posture compared to upright in healthy men and women.

Cerebrovascular reactivity and cerebral autoregulation are two major mechanisms that regulate cerebral blood flow. Both mechanisms are typically assessed in either supine or seated postures, but the effects of body position and sex differences remain unclear. This study examined the effects of body posture (supine vs. seated vs. standing) on cerebrovascular reactivity during hyper and hypocapnia and on cerebral autoregulation during spontaneous and slow-paced breathing in healthy men and women using transcranial Doppler ultrasonography of the middle cerebral artery. Results indicated significantly improved cerebrovascular reactivity in the supine compared with seated and standing postures (supine = 3.45±0.67, seated = 2.72±0.53, standing = 2.91±0.62%/mmHg, P<0.0167). Similarly, cerebral autoregulatory measures showed significant improvement in the supine posture during slow-paced breathing. Transfer function measures of gain significantly decreased and phase significantly increased in the supine posture compared with seated and standing postures (gain: supine = 1.98±0.56, seated = 2.37±0.53, standing = 2.36±0.71%/mmHg; phase: supine = 59.3±21.7, seated = 39.8±12.5, standing = 36.5±9.7°; all P<0.0167). In contrast, body posture had no effect on cerebral autoregulatory measures during spontaneous breathing. Men and women had similar cerebrovascular reactivity and similar cerebral autoregulation during both spontaneous and slow-paced breathing. These data highlight the importance of making comparisons within the same body position to ensure there is not a confounding effect of posture.

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy.

Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pathways uniquely activated in SMA motor neurons, including a hyperactivated ER stress pathway, neuronal hyperexcitability, and defective spliceosomes. To investigate why motor neurons are more affected than other neural types, we developed a spinal organoid model of SMA. We demonstrate overt motor neuron degeneration in SMA spinal organoids, and this degeneration can be prevented using a small molecule inhibitor of CDK4/6, indicating that spinal organoids are an ideal platform for therapeutic discovery.

English-only treatment of bilingual speakers who stutter: Generalization of treatment effects from English to Mandarin.

PURPOSE: Speech language pathologists often do not speak the dominant language of their clients and so the language of treatment is an important consideration. This research investigated whether stuttering treatment delivered in English resulted in reductions in stuttering in English and Mandarin bilingual Singaporean speakers. METHOD: Participants were 19 English-Mandarin bilinguals who stuttered. They received a speech re-structuring intensive program (IP) delivered in English only. Three 10-minute conversations in English and Mandarin, sampled at pre-treatment, immediately post IP, 4 weeks post IP and 12 weeks post IP, were analysed by two English-Mandarin bilingual clinicians for percentage of syllables stuttered (%SS). RESULT: After English-only treatment, stuttering reductions were found to generalize to Mandarin. Stuttering reductions were significantly higher in English compared to Mandarin at 4 weeks post-IP, but there was no significant difference in the stuttering reductions between languages at the end of IP and at 12 weeks post-IP. Mean %SS scores for English and Mandarin were comparable with the outcome data reported for a similar intensive speech-restructuring program for monolingual English-speaking adults. CONCLUSION: The results of this study show that stuttering reductions can be achieved in two languages following treatment in one language only. Future research in this area is proposed.

The reliability of a severity rating scale to measure stuttering in an unfamiliar language.

With increasing multiculturalism, speech-language pathologists (SLPs) are likely to work with stuttering clients from linguistic backgrounds that differ from their own. No research to date has estimated SLPs' reliability when measuring severity of stuttering in an unfamiliar language. Therefore, this study was undertaken to estimate the reliability of SLPs' use of a 9-point severity rating (SR) scale, to measure severity of stuttering in a language that was different from their own. Twenty-six Australian SLPs rated 20 speech samples (10 Australian English [AE] and 10 Mandarin) of adults who stutter using a 9-point SR scale on two separate occasions. Judges showed poor agreement when using the scale to measure stuttering in Mandarin samples. Results also indicated that 50% of individual judges were unable to reliably measure the severity of stuttering in AE. The results highlight the need for (a) SLPs to develop intra- and inter-judge agreement when using the 9-point SR scale to measure severity of stuttering in their native language (in this case AE) and in unfamiliar languages; and (b) research into the development and evaluation of practice and/or training packages to assist SLPs to do so.

Injection laryngoplasty with hyaluronic acid for unilateral vocal cord paralysis. Randomized controlled trial comparing two different particle sizes.

The objective was to determine if particle size affects durability of medialization in patients undergoing injection laryngoplasty (IL) with hyaluronic acid (HA) for unilateral vocal cord paralysis (UVCP). We hypothesized that large particle-size HA (LPHA) persists longer after injection to produce a more durable vocal result. The study design used was a prospective randomized controlled single-blind trial. Patients underwent IL with Restylane (small particle-size HA, SPHA) or Perlane (LPHA) (Q-Med AB, Uppsala, Sweden). Injections were performed transcutaneously in the outpatient clinic. The Voice Handicap Index (VHI) at 6 months postinjection was the primary outcome measure. Secondary outcomes included videostroboscopic findings, and objective acoustic and aerodynamic measures. Seventeen patients (eight SPHA, nine LPHA) were available for follow-up at 6 months. Normalized VHI scores at 6 months after IL were significantly lower in the LPHA group compared to the SPHA group when not adjusted for age and sex (P=0.027). After adjustment, the difference was not significant (P=0.053) but the LPHA group trended toward lower normalized VHI scores. The findings support the hypothesis that the larger particle-size of LPHA makes this material more durable than SPHA for IL. This material may be considered for temporary medialization in patients with UVCP in whom medium-term improvement of at least 6 months is desirable. The transcutaneous route can be used safely in the office setting in non-anticoagulated patients.

Stuttering in English-Mandarin bilingual speakers: the influence of language dominance on stuttering severity.

PURPOSE: English and Mandarin are the 2 most spoken languages in the world, yet it is not known how stuttering manifests in English-Mandarin bilinguals. In this research, the authors investigated whether the severity and type of stuttering is different in English and Mandarin in English-Mandarin bilinguals, and whether this difference was influenced by language dominance. METHOD: Thirty English-Mandarin bilinguals who stutter (BWS), ages 12-44 years, were categorized into 3 groups (15 English-dominant, 4 Mandarin-dominant, and 11 balanced bilinguals) using a self-report classification tool. Three 10-min conversations in English and Mandarin were assessed by 2 English-Mandarin bilingual clinicians for percent syllables stuttered (%SS), perceived stuttering severity (SEV), and types of stuttering behaviors using the Lidcombe Behavioral Data Language (LBDL; Packman & Onslow, 1998; Teesson, Packman, & Onslow, 2003). RESULTS: English-dominant and Mandarin-dominant BWS exhibited higher %SS and SEV scores in their less dominant language, whereas the scores for the balanced bilinguals were similar for both languages. The difference in the percentage of stutters per LBDL category between English and Mandarin was not markedly different for any bilingual group. CONCLUSIONS: Language dominance appeared to influence the severity but not the types of stuttering behaviors in BWS. Clinicians working with BWS need to assess language dominance when diagnosing stuttering severity in bilingual clients.

Scalloped channels enhance tear mixing under hydrogel contact lenses.

PURPOSE: Tear exchange under a soft contact lens is directly related to the amount of lateral and transverse lens motion. Hydrodynamic modeling suggests that channels placed on the back surface of a soft lens will reduce fluid resistance and increase transverse lens movement. This study measured the effect of posterior lens surface scalloped channels on tear exchange. METHODS: Tear exchange in the postlens tear film (PoLTF) was estimated using a fluorometer to measure the exponential depletion of high-MW fluorescein under the lens expressed as the time to deplete 95% of dye (T95). A total of 32 subjects wore two pairs of identical lenses except that the experimental lens had 12 scalloped channels placed radially in the midperiphery of the posterior lens surface, whereas lenses without channels served as controls. RESULTS: The mean +/- standard error T95 values for the channel lenses was 28 +/- 2 minutes compared with 32 +/- 2 minutes for the control lenses (p = 0.107). There was a marginally significant difference in T95 between two lens groups in Asian eyes (p = 0.054). CONCLUSION: Placing scallop-shaped channels on high-H2O content soft lenses improved the postlens tear pumping in Asian eyes.