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Highly pathogenic avian influenza H5N1 viruses cause severe disease in humans, and dysregulation of cytokine responses is believed to contribute to the pathogenesis of human H5N1 disease. However, mechanisms leading to the increased induction of proinflammatory cytokines by H5N1 viruses are poorly understood. We show that the innate sensing receptor RIG-I is involved in interferon regulatory factor 3 (IRF3), NF-κB nuclear translocation, p38 activation, and the subsequent interferon (IFN) β, IFN-λ1, and tumor necrosis factor α induction during H5N1 infection. Soluble mediators from H5N1-infected human macrophages upregulate RIG-I, MDA5, and TLR3 to much higher levels than those from seasonal H1N1 in uninfected human macrophages and alveolar epithelial cells via paracrine IFNAR1/JAK but not IFN-λ receptor signaling. Compared with H1N1 virus-induced mediators, H5N1 mediators markedly enhance the cytokine response to PolyIC and to both seasonal and H5N1 virus infection in a RIG-I-dependent manner. Thus, sensitizing neighboring cells by upregulation of RIG-I contributes to the amplified cytokine cascades during H5N1 infection. [ABSTRACT FROM AUTHOR]

Accurate characterization of biomechanical characteristics of the vocal fold is critical for understanding the regulation of vocal fundamental frequency ( F0), which depends on the active control of the intrinsic laryngeal muscles as well as the passive biomechanical response of the vocal fold lamina propria. Specifically, the tissue stress-strain response and viscoelastic properties under cyclic tensile deformation are relevant, when the vocal folds are subjected to length and tension changes due to posturing. This paper describes a constitutive modeling approach quantifying the relationship between vocal fold stress and strain (or stretch), and establishes predictions of F0 with the string model of phonation based on the constitutive parameters. Results indicated that transient and time-dependent changes in F0, including global declinations in declarative sentences, as well as local F0 overshoots and undershoots, can be partially attributed to the time-dependent viscoplastic response of the vocal fold cover. [ABSTRACT FROM AUTHOR]

Objective. This study compared the networks of extended family and friendship relationships of children conceived via donor insemination with lesbian versus heterosexual parents. Design. Eighty families participated; 55 of the families were headed by lesbian parents and 25 were headed by heterosexual parents. Parents reported their children's contact with grandparents and other important adults. Results. Most children had regular contact with grandparents, other relatives, and adult nonrelatives outside their immediate households, and there were no differences in this regard as a function of parental sexual orientation. Both children of lesbian and heterosexual parents had more frequent contact with the parents of their biological mother than with the parents of their father or other mother. Conclusions. Contrary to negative stereotypes, children of lesbian mothers were described as having regular contact with grandparents. Regardless of parental sexual orientation, children were described as being in more frequent contact with grandparents to whom they were biologically linked. [ABSTRACT FROM AUTHOR]

A quantitative output-cost ratio (OCR) is proposed for objective use in voice production and is defined as the ratio of the acoustic output intensity to the collision intensity of the vocal folds. Measurement of the OCR is demonstrated in a laboratory experiment using 5 excised larynges and a transducer designed for use on human subjects. Data were gathered at constant fundamental frequency (150 Hz). Subglottal pressure was varied from 1.0 to 1.6 kPa, and glottal width at the vocal processes was varied from a pressed condition to a 2-mm gap. The OCR was plotted as a function of glottal width. With no vocal tract, the excised larynx experiments yielded a broad maxima in the OCR curves, across all subglottal pressure conditions, at about 0.6 mm. Computer simulations indicate that sharper maxima may occur when the influence of the vocal tract is taken into account. The potential clinical utility of the OCR is discussed for treatment of a wide range of voice disorders, including those involving both hyper- and hypoadduction. [ABSTRACT FROM AUTHOR]

Abstract Background Fatal human respiratory disease associated with influenza A subtype H5N1 has been documented in Hong Kong, and more recently in Vietnam, Thailand and Cambodia. We previously demonstrated that patients with H5N1 disease had unusually high serum levels of IP-10 (interferon-gamma-inducible protein-10). Furthermore, when compared with human influenza virus subtype H1N1, the H5N1 viruses in 1997 (A/Hong Kong/483/97) (H5N1/97) were more potent inducers of pro-inflammatory cytokines (e.g. tumor necrosis factor-a) and chemokines (e.g. IP-10) from primary human macrophages in vitro, which suggests that cytokines dysregulation may play a role in pathogenesis of H5N1 disease. Since respiratory epithelial cells are the primary target cell for replication of influenza viruses, it is pertinent to investigate the cytokine induction profile of H5N1 viruses in these cells. Methods We used quantitative RT-PCR and ELISA to compare the profile of cytokine and chemokine gene expression induced by H5N1 viruses A/HK/483/97 (H5N1/97), A/Vietnam/1194/04 and A/Vietnam/3046/04 (both H5N1/04) with that of human H1N1 virus in human primary alveolar and bronchial epithelial cells in vitro. Results We demonstrated that in comparison to human H1N1 viruses, H5N1/97 and H5N1/04 viruses were more potent inducers of IP-10, interferon beta, RANTES (regulated on activation, normal T cell expressed and secreted) and interleukin 6 (IL-6) in primary human alveolar and bronchial epithelial cells in vitro. Recent H5N1 viruses from Vietnam (H5N1/04) appeared to be even more potent at inducing IP-10 than H5N1/97 virus. Conclusion The H5N1/97 and H5N1/04 subtype influenza A viruses are more potent inducers of proinflammatory cytokines and chemokines in primary human respiratory epithelial cells than subtype H1N1 virus. We suggest that this hyper-induction of cytokines may be relevant to the pathogenesis of human H5N1 disease.

Background: Highly pathogenic avian influenza (HPAI) H5N1 virus is entrenched in poultry in Asia and Africa and continues to infect humans zoonotically causing acute respiratory disease syndrome and death. There is evidence that the virus may sometimes spread beyond respiratory tract to cause disseminated infection. The primary target cell for HPAI H5N1 virus in human lung is the alveolar epithelial cell. Alveolar epithelium and its adjacent lung microvascular endothelium form host barriers to the initiation of infection and dissemination of influenza H5N1 infection in humans. These are polarized cells and the polarity of influenza virus entry and egress as well as the secretion of cytokines and chemokines from the virus infected cells are likely to be central to the pathogenesis of human H5N1 disease.Aim: To study influenza A (H5N1) virus replication and host innate immune responses in polarized primary human alveolar epithelial cells and lung microvascular endothelial cells and its relevance to the pathogenesis of human H5N1 disease.Methods: We use an in vitro model of polarized primary human alveolar epithelial cells and lung microvascular endothelial cells grown in transwell culture inserts to compare infection with influenza A subtype H1N1 and H5N1 viruses via the apical or basolateral surfaces.Results: We demonstrate that both influenza H1N1 and H5N1 viruses efficiently infect alveolar epithelial cells from both apical and basolateral surface of the epithelium but release of newly formed virus is mainly from the apical side of the epithelium. In contrast, influenza H5N1 virus, but not H1N1 virus, efficiently infected polarized microvascular endothelial cells from both apical and basolateral aspects. This provides a mechanistic explanation for how H5N1 virus may infect the lung from systemic circulation. Epidemiological evidence has implicated ingestion of virus-contaminated foods as the source of infection in some instances and our data suggests that viremia, secondary to, for example, gastro-intestinal infection, can potentially lead to infection of the lung. HPAI H5N1 virus was a more potent inducer of cytokines (e.g. IP-10, RANTES, IL-6) in comparison to H1N1 virus in alveolar epithelial cells, and these virus-induced chemokines were secreted onto both the apical and basolateral aspects of the polarized alveolar epithelium.Conclusion: The predilection of viruses for different routes of entry and egress from the infected cell is important in understanding the pathogenesis of influenza H5N1 infection and may help unravel the pathogenesis of human H5N1 disease. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the effects of individualized dietary modifications based on the volume-viscosity swallow test (V-VST) on functional oral intake, incidence of pneumonia, and swallowing-related quality of life in individuals with intracerebral hemorrhage., Methods: One hundred and seven participants with signs of dysphagia in the acute and early subacute phases of stroke following intracerebral hemorrhage were randomly assigned into an experimental group for individualized dietary modifications based on V-VST plus routine standard care (n = 53), and a control group for routine care alone (n = 54). Incidence of pneumonia, functional oral intake scale (FOIS) ratings and Eating Assessment Tool (EAT-10) scores before and after intervention were evaluated., Results: A significantly lower incidence of pneumonia was found in the experimental group than in the control group (p < 0.05). Significant group differences were found in functional oral intake and in quality of life, with significantly higher FOIS ratings and significantly lower EAT-10 scores in the experimental group post-intervention (p < 0.001)., Conclusion: These findings suggested that despite being a noninstrumental screening tool, V-VST could facilitate individualized dietary modifications and could be an effective clinical option for reducing the risk of pneumonia, improving functional oral intake and enhancing quality of life in individuals with dysphagia following intracerebral hemorrhage. Future studies should explore how dietary modifications could be more precisely implemented based on the International Dysphagia Diet Standardization Initiative framework., Competing Interests: Declarations. Research involving human participants: This study was approved by the Research Ethics Committee of Second Affiliated Hospital, Xiamen Medical College (approval number 2022090). Informed consent: Written informed consents were obtained from all participants. Competing interests: The authors declare no competing financial or non-financial interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Previous work suggested that phonation threshold pressure (PTP), phonation threshold flow (PTF), and phonation threshold power (PTW) could be effective aerodynamic measures for quantifying glottal incompetence. This study examined how these measures could reflect varying extent of incomplete glottal closure in individuals with voice disorders., Method: Thirty individuals formally diagnosed with glottal incompetence, including 10 with hypofunctional disorders (hypo group) and 20 with hyperfunctional disorders (hyper group), and 30 individuals with normal voice (control group) participated in the study. PTP was measured indirectly by intra-oral pressure during production of bilabial stop consonant-vowel syllables, PTF was measured during the sustained vowel /a/, and PTW was obtained as the product of PTP and PTF. The extent of incomplete glottal closure was quantified by normalized glottal gap (NGG) and normalized glottal gap area (NGGA) based on image analysis of videostroboscopic recordings of sustained /i/., Results: Significant differences in all threshold measures ( p < .05) were found among three participant groups with medium-to-large effect sizes (η p 2 = .128-.220), with significantly higher values for the hypo group than the control group and no significant differences between the hyper and control groups. Receiver operating characteristic (ROC) analysis showed the highest diagnostic or classification accuracy contrasting between the hypo and control groups (area under the ROC curve = .717-.757), with the highest classification accuracy for PTW. There were significant, moderate-to-strong positive correlations with NGG and NGGA for the disorders group (Pearson's r = .4244-.6226) and the hypo group ( r = .5689-.8949)., Conclusions: These measures could be effective for identifying glottal incompetence, especially for hypofunctional disorders. PTW could be more sensitive than PTP and PTF in reflecting the extent of incomplete glottal closure, consistent with theoretical predictions. Their relative sensitivities for quantifying distinct incomplete glottal closures specific to different voice disorders should be evaluated in future studies.

NOise Reduction with DIstribution Corrected (NORDIC) principal component analysis (PCA) has been shown to selectively suppress thermal noise and improve the temporal signal-to-noise ratio (tSNR) in human functional magnetic resonance imaging (fMRI). However, the feasibility to improve data quality for rodent fMRI using NORDIC PCA remains uncertain. NORDIC PCA may also be particularly beneficial for improving topological brain mapping, as conventional mapping requires precise spatiotemporal signals from large datasets (ideally ~1 hour acquisition) for individual representations. In this study, we evaluated the effects of NORDIC PCA compared with "Standard" processing in various rodent fMRI contexts that range from task-evoked optogenetic fMRI to resting-state fMRI. We also evaluated the effects of NORDIC PCA on human resting-state and retinotopic mapping fMRI via population receptive field (pRF) modeling. In rodent optogenetic fMRI, apart from doubling the tSNR, NORDIC PCA resulted in a larger number of activated voxels and a significant decrease in the variance of evoked brain responses without altering brain morphology. In rodent resting-state fMRI, we found that NORDIC PCA induced a nearly threefold increase in tSNR and preserved task-free relative cerebrovascular reactivity (rCVR) across cortical depth. NORDIC PCA further improved the detection of TGN020-induced aquaporin-4 inhibition on rCVR compared with Standard processing without NORDIC PCA. NORDIC PCA also increased the tSNR for both human resting-state and pRF fMRI, and for the latter also increased activation cluster sizes while retaining retinotopic organization. This suggests that NORDIC PCA preserves the spatiotemporal precision of fMRI signals needed for pRF analysis, and effectively captures small activity changes with high sensitivity. Taken together, these results broadly demonstrate the value of NORDIC PCA for the enhanced detection of neural dynamics across various rodent and human fMRI contexts. This can in turn play an important role in improving fMRI image quality and sensitivity for translational and preclinical neuroimaging research., Competing Interests: All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

In 2020, the COVID-19 pandemic caused mandatory lockdowns worldwide, exacerbating mental health issues created by social isolation. Aimed to improve mental health and maintain engagement, the Singapore Art Museum (SAM) rapidly deployed an online programme called Unwind with SAM to engage the public with the museum's contemporary art collection coupled with meditation. The programme focused on the positive effect of arts on mental health, combined with the cognitive benefits of meditation by 'slow-looking' at artworks. This practice-based report reflects on the processes and explores the potential between art, contemplation and cognitive sciences. The first section outlines the current landscape of art and wellness approaches in museums. The second section explains the philosophical framework that guides the programme, alongside a breakdown of components and design rationale. The final part provides a critical reflection and concludes with recommendations for practitioners, managers and scientists to utilise the framework for designing future programmes.

Background: Stereotactic radiosurgery (SRS) for the treatment of brain metastases delivers a high dose of radiation with excellent local control but comes with the risk of radiation necrosis (RN), which can be difficult to distinguish from tumor progression (TP). Magnetization transfer (MT) and chemical exchange saturation transfer (CEST) are promising techniques for distinguishing RN from TP in brain metastases. Previous studies used a 2D continuous-wave (ie, block radiofrequency [RF] saturation) MT/CEST approach. The purpose of this study is to investigate a 3D pulsed saturation MT/CEST approach with perfusion MRI for distinguishing RN from TP in brain metastases., Methods: The study included 73 patients scanned with MT/CEST MRI previously treated with SRS or fractionated SRS who developed enhancing lesions with uncertain diagnoses of RN or TP. Perfusion MRI was acquired in 49 of 73 patients. Clinical outcomes were determined by at least 6 months of follow-up or via pathologic confirmation (in 20% of the lesions)., Results: Univariable logistic regression resulted in significant variables of the quantitative MT parameter 1/(R A ·T 2A ), with 5.9 ± 2.7 for RN and 6.5 ± 2.9 for TP. The highest AUC of 75% was obtained using a multivariable logistic regression model for MT/CEST parameters, which included the CEST parameters of AREX Amide,0.625µT ( P  = .013), AREX NOE,0.625µT ( P  = .008), 1/(R A ·T 2A ) ( P  = .004), and T 1 ( P  = .004). The perfusion rCBV parameter did not reach significance., Conclusions: Pulsed saturation transfer was sufficient for achieving a multivariable AUC of 75% for differentiating between RN and TP in brain metastases, but had lower AUCs compared to previous studies that used a block RF approach., Competing Interests: A.S.: Elekta/Elekta AB: Research grant, Consultant, Honorarium for past educational seminars, Travel Expenses. Varian: Honorarium for past educational seminars. BrainLab: Research grant, Consultant, Honorarium for educational seminars, Travel Expenses. AstraZeneca: Honorarium for educational seminars. ISRS: President of the International Stereotactic Radiosurgery Society (ISRS). Seagen Inc: Honorarium for education seminars and research grants. Cerapedics: Honorarium for educational seminars, Travel Expenses. CarboFIX: Honorarium for educational seminars. Servier: Honorarium for educational seminars. C.-L.T.: Travel accommodations/expenses & honoraria for past educational seminars by Elekta; belongs to the Elekta MR-Linac Research Consortium; advisor/consultant with Sanofi and AbbVie. S.M.: Research support from Novartis AG, honoraria from Novartis AG and Ipsen. None related to this work., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: This study examined whether the "Three Bears Passage" (TB), a standard Mandarin reading passage, could elicit significant vocal range variations in individuals with voice disorders. Relative sensitivity of TB versus another existing standard reading passage, "Passage in Mandarin" (PM), for differentiating between individuals with and without voice disorders was also evaluated., Method: Forty-two individuals with normal voice and 30 individuals with voice disorders participated in the study. Maximum fundamental frequency ( f 0 ), minimum f 0 , mean f 0 , f 0 range, maximum vocal intensity, minimum intensity, mean intensity, and intensity range of all participants reading aloud the two passages were measured with Praat to construct speech range profiles (SRPs)., Results: Significantly larger vocal range was found for TB than for PM in individuals with voice disorders, including significantly higher maximum f 0 , mean f 0 , maximum intensity, mean intensity, and significantly larger f 0 range and intensity range. Significantly more limited vocal range was observed in individuals with voice disorders than those without, with more obviously restricted SRPs while reading aloud TB compared to PM. Receiver operating characteristic analysis suggested that TB was more sensitive than PM in distinguishing between individuals with and without voice disorders., Conclusions: Our findings supported the potential of TB as a standard clinical assessment tool for evaluating pathological changes in vocal range. Future studies should explore if therapeutic approaches based on the passage or variations of it could be developed for overcoming functional limitations and restrictions in vocal range for specific voice disorders.

Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Systems neuroscience explores the intricate organization and dynamic function of neural circuits and networks within the brain. By elucidating how these complex networks integrate to execute mental operations, this field aims to deepen our understanding of the biological basis of cognition, behavior, and consciousness. In this chapter, we outline the promising future of systems neuroscience, highlighting the emerging opportunities afforded by powerful technological innovations and their applications. Cutting-edge tools such as awake functional MRI, ultrahigh field strength neuroimaging, functional ultrasound imaging, and optoacoustic techniques have revolutionized the field, enabling unprecedented observation and analysis of brain activity. The insights gleaned from these advanced methodologies have empowered the development of a suite of exciting applications across diverse domains. These include brain-machine interfaces (BMIs) for neural prosthetics, cognitive enhancement therapies, personalized mental health interventions, and precision medicine approaches. As our comprehension of neural systems continues to grow, it is envisioned that these and related applications will become increasingly refined and impactful in improving human health and well-being., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background and Purpose: Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV)., Materials and Methods: Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm 2 /ms within GTV)., Results: In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV)., Conclusion: MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: This study evaluated the efficacy of a 4-week straw phonation in water (SPW) exercise program on aging-related vocal fold atrophy (VFA), with a secondary objective to examine the immediate effects of SPW exercises., Method: Thirty-eight older adults aged 60 years and above formally diagnosed with aging-related VFA were randomly assigned into an experimental group undergoing SPW exercises with an 8-cm depth of straw submersion into water for 4 weeks plus vocal hygiene practice ( n = 20), and a control group with only vocal hygiene practice ( n = 18). Outcome measures included laryngeal endoscopic measures of glottal gap, auditory-perceptual ratings of voice quality, acoustic measures, aerodynamic measures, and standardized self-assessment questionnaire scores. An additional round of acoustic and aerodynamic assessment following 20 min of SPW exercises was conducted to examine the immediate effects., Results: Significant improvements in normalized glottal gap area, perceptual rating of breathiness, smoothed cepstral peak prominence, harmonics-to-noise ratio (HNR), mean oral airflow, subglottal pressure and laryngeal airway resistance at comfortable loudness, Voice-related Quality of Life scores, and Chinese Vocal Fatigue Index Factor 3 scores were observed in the experimental group relative to the control group. There were also significant immediate effects for HNR, mean oral airflow, subglottal pressure, and laryngeal airway resistance., Conclusions: These findings suggested significant immediate improvements in vocal function following SPW exercises, with additional significant improvements in vocal function as well as significant improvements in quality of life following the 4-week SPW exercise program. Further studies with more long-term follow-up are recommended to better understand the efficacy of SPW exercises with deep levels of straw submersion into water as an effective clinical option for the management of hypofunctional dysphonia associated with aging-related VFA.

Objectives: This study developed the Mandarin Chinese version of the Aging Voice Index (AVI), with preliminary validation of the scale for potential clinical applications., Study Design: Scale development., Methods: The experimental procedure involved: (1) cross-cultural adaptation of the original AVI into the Mandarin Chinese version (CAVI); (2) evaluation by expert panel; (3) back translation; (4) pilot testing; (5) development of the final CAVI; (6) scale validation with 68 older adults of 60-89 years old (29 females and 39 males), 34 with voice disorders and 34 age-matched with normal voice. Internal consistency reliability, test-retest reliability, content validity, criterion-related validity, and discriminatory ability (diagnostic accuracy) of the CAVI were evaluated., Results: There were high internal consistency (Cronbach's alpha = 0.9733), high test-retest reliability (intraclass correlation coefficient = 0.9578, p  < 0.01), high content validity (content validity index = 0.9710), high criterion-related validity (Pearson's r  = 0.9439, p  < 0.01 between CAVI and Voice Handicap Index-10; r  = 0.8070, p  < 0.01 between CAVI and voice-related quality of life [V-RQOL]), and significant difference in CAVI scores between the two groups with huge effect size ( t (34.69) = -11.59, Cohen's d  = 2.81, p  < 0.001). Receiver operating characteristic analysis revealed a high diagnostic accuracy of the CAVI, with an area under the curve of 0.9974 ( p  < 0.001) and a cut-off score of 12.0 with 100% sensitivity and 97.1% specificity., Conclusion: Our findings suggested that the CAVI could be a reliable and valid standardized self-assessment questionnaire tool for clinical evaluation of the impact of voice problems specifically for Mandarin-speaking older adults. Further studies should explore a full-scale validation of the CAVI for being a standard clinical tool, including for older adults in Mainland China., Level of Evidence: 3b (case-control study)., (© 2023 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Electrical impedance tomography (EIT) has been employed in the field of medical imaging due to its cost effectiveness, safety profile and portability, but the images generated are relatively low resolution. To address these limitations, we create a novel method using EIT images to generate high resolution structurally aligned images of lungs like those from CT scans. A way to achieve this transformation is via Cycle generative adversarial networks (CycleGAN), which have demonstrated image-to-image translation capabilities across different modalities. However, a generic implementation yields images which may not be aligned with their input image. To solve this issue, we construct and incorporate a Mutual Information (MI) constraint in CycleGAN to translate functional lung EIT images to structural high resolution CT images. The CycleGAN is first trained on unpaired EIT and CT lung images. Afterwards, we generate CT image pairs from EIT images via CycleGANs constrained with MI loss and without this loss. Finally, through generating these 1560 CT image pairs and then comparing the visual results and quantitative metrics, we show that MI constrained CycleGAN produces more structurally aligned CT images, where Normalised Mutual Information (NMI) is increased to 0.2621+/- 0.0052 versus 0.2600 +/- 0.0066, p<0.0001 for non-MI constrained images. By this process, we simultaneously provide functional and structural information, and potentially enable more detailed assessment of lungs.Clinical Relevance- By establishing a structurally aligning generative process via MI Loss in CycleGAN, this study enables EIT-CT conversion, thereby providing functional and structural images for enhanced lung assessment, from just EIT images.

This study demonstrates the feasibility of predicting NAFLD using multi-spectral electrical impedance tomography (EIT), group source separation, constant reference EIT and anthropometric measures. Vibration-controlled Transient Elastography (VCTE) Controlled Attenuated Parameter (CAP; n = 121) and magnetic resonance imaging-proton density fat fraction (MRI-PDFF; n = 34) achieved a sensitivity of 70.9% and specificity of 73.8% with our CAP predicting model and sensitivity of 77.8% and specificity of 80.0% with our MRI-PDFF predicting model. In summary, a portable EIT can be a cost-effective and self-administrable alternative for widespread home-based and community-based diagnostic screening and treatment monitoring of NAFLD.Clinical Relevance- Portable multi-spectral EIT system has the sensitivity and specificity to potentially unlock biomedical imaging in telemedicine for home-based and community-based screening, staging and monitoring for NAFLD.

Recently, deep learning based methods have shown potential as alternative approaches for lung time difference electrical impedance tomography (tdEIT) reconstruction other than traditional regularized least square methods, that have inherent severe ill-posedness and low spatial resolution posing challenges for further interpretation. However, the validation of deep learning reconstruction quality is mainly focused on simulated data rather than in vivo human chest data, and on image quality rather than clinical indicator accuracy. In this study, a variational autoencoder is trained on high-resolution human chest simulations, and inference results on an EIT dataset collected from 22 healthy subjects performing various breathing paradigms are benchmarked with simultaneous spirometry measurements. The deep learning reconstructed global conductivity is significantly correlated with measured volume-time curves with correlation > 0.9. EIT lung function indicators from the reconstruction are also highly correlated with standard spirometry indicators with correlation > 0.75.Clinical Relevance- Our deep learning reconstruction method of lung tdEIT can predict lung volume and spirometry indicators while generating high-resolution EIT images, revealing potential of being a competitive approach in clinical settings.

Chronic kidney disease (CKD) is an escalating global health concern, and non-invasive means for early CKD detection is eagerly awaited. Here, we explore the potential of using home-based frequency-difference electrical impedance tomography (fdEIT) to evaluate CKD based on bio-conductivity characteristics. We performed bio-conductivity measurement in vivo paired with standard estimated glomerular filtration rate (eGFR) measurements on a N=126 CKD patients by EIT and traditional blood and urine tests, respectively. We developed an EIT processing pipeline that extracts the kidney regions from EIT images. We further developed a regression model and a CKD classification scheme. Our results showed a significant correlation between EIT-features and eGFR, and the classification scheme shows sensitivity and specificity of 76.2% and 74.6% respectively considering stages 1 and 2 CKD versus stages 3, 4 and 5 CKD. These results suggest the feasibility of EIT to be used as a portable, self-administrated and home-based approach for CKD early diagnostic screening and longitudinal monitoring.Clinical Relevance-The results presented here demonstrates a cost-effective, home-based and self-administrative screening process on chronic kidney disease patients, thereby enhancing the quality and area of possible application of telemedicine. By achieving this, the process presented here can relieve the burden of public health system.

Recent development of affordable, portable and self-administrable electrical impedance tomography (EIT) system demonstrated the feasibility of using standalone EIT and subject's anthropometrics to predict the gold standard spirometry indicators for lung-function assessment. Compared to spirometry, the system showed the advantage of providing spatial mapping of the spirometry indicators. Nevertheless, the previous study was limited to healthy subjects. Here, we recruited (N=88): 47 lung disease patients and 41 healthy controls to perform simultaneous EIT and spirometry measurements to validate the capabilities of the system. Lung disease patients include 13 interstitial lung disease (ILD), 10 asthma, 8 chronic obstructive pulmonary disease (COPD), 8 bronchiectasis, and 8 with other diseases including left pneumonectomy, lung cancer, lung tumor, lymphangioleiomyomatosis, motor neuron disease, heart failure and bronchiolitis obliterans syndrome. The results showed significant correlation of the predicted global spirometry indicators (p<0.0001) and significant distinguishability between most disease groups and healthy subjects demonstrating the capability of the EIT system in diagnostic screening. Furthermore, the regional mapping of the spirometry indicators is evaluated and shown to be distinct for each disease group, providing an additional dimension for medical professionals to diagnose and monitor lung disease patients.Clinical Relevance- This establishes the significance of EIT-based global and regional indicators for assessing lung function on lung disease patients.

Although a few large-scale studies have investigated multilevel anterior cervical discectomy and fusion (ACDF) and laminoplasty (LAMP) and their related complications for cervical spondylotic myelopathy (CSM), the optimal surgical intervention remains controversial. Therefore, we compared their 30 days of postoperative complications. Through the 2010-2019 ACS NSQIP Participant Use Data Files, we estimated the risk of serious morbidity, reoperation, readmission, mortality, and other postoperative complications. Initially, propensity score matching (PSM) of the preoperative characteristics of both groups was performed for further analysis. Multivariable logistic regression analysis provided OR and 95% CI for comparative complications. After PSM, 621 pairs of cohorts were generated for both groups. Increased frequency of postoperative complications was observed in the LAMP group, especially for surgical wound infection, no matter whether superficial (ACDF/LAMP = 0%/1.13%, p = 0.0154) or deep wound infection (ACDF/LAMP = 0%/0.97%, p = 0.0309). The mean length of total hospital stays (ACDF/LAMP = 2.25/3.11, p < 0.0001) and days from operation to discharge (ACDF/LAMP = 2.12/3.08, p < 0.0001) were longer, while the hospitalization rate for over 30 days (ACDF/LAMP = 4.67%/7.41%, p = 0.0429) and unplanned reoperation (ACDF/LAMP = 6.12%/9.34%, p = 0.0336) were higher in LAMP. Results also indicated congestive heart failure as a risk factor (adjusted OR = 123.402, p = 0.0002). Conclusively, multilevel ACDF may be a safer surgical approach than LAMP for CSM in terms of perioperative morbidities, including surgical wound infection, prolonged hospitalization, and unplanned reoperation. However, these approaches showed no significant differences in systemic complications and perioperative mortality.

Background: High radiation doses of stereotactic radiosurgery (SRS) for brain metastases (BM) can increase the likelihood of radiation necrosis (RN). Advanced MRI sequences can improve the differentiation between RN and tumor progression (TP)., Purpose: To use saturation transfer MRI methods including chemical exchange saturation transfer (CEST) and magnetization transfer (MT) to distinguish RN from TP., Study Type: Prospective cohort study., Subjects: Seventy patients (median age 60; 73% females) with BM (75 lesions) post-SRS., Field Strength/sequence: 3-T, CEST imaging using low/high-power (saturation B 1  = 0.52 and 2.0 μT), quantitative MT imaging using B 1  = 1.5, 3.0, and 5.0 μT, WAter Saturation Shift Referencing (WASSR), WAter Shift And B 1 (WASABI), T 1 , and T 2 mapping. All used gradient echoes except T 2 mapping (gradient and spin echo)., Assessment: Voxel-wise metrics included: magnetization transfer ratio (MTR); apparent exchange-dependent relaxation (AREX); MTR asymmetry; normalized MT exchange rate and pool size product; direct water saturation peak width; and the observed T 1 and T 2 . Regions of interests (ROIs) were manually contoured on the post-Gd T 1 w. The mean (of median ROI values) was compared between groups. Clinical outcomes were determined by clinical and radiologic follow-up or histopathology., Statistical Tests: t-Test, univariable and multivariable logistic regression, receiver operating characteristic, and area under the curve (AUC) with sensitivity/specificity values with the optimal cut point using the Youden index, Akaike information criterion (AIC), Cohen's d. P < 0.05 with Bonferroni correction was considered significant., Results: Seven metrics showed significant differences between RN and TP. The high-power MTR showed the highest AUC of 0.88, followed by low-power MTR (AUC = 0.87). The combination of low-power CEST scans improved the separation compared to individual parameters (with an AIC of 70.3 for low-power MTR/AREX). Cohen's d effect size showed that the MTR provided the largest effect sizes among all metrics., Data Conclusion: Significant differences between RN and TP were observed based on saturation transfer MRI., Evidence Level: 3 Technical Efficacy: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Purpose: Teachers are occupational voice users with significant vocal demand. This study examined if a vocal hygiene program could mitigate the effects of occupational vocal demand in primary school teachers across 1 month., Method: Sixty female teachers participated, with 30 in an experimental group receiving vocal hygiene education plus daily home practice for 1 month and 30 in a control group with no intervention. Their vocal changes across the month were quantified with (a) acoustic measures on fundamental frequency ( f o ), vocal intensity, jitter and shimmer, harmonics-to-noise ratio, and smoothed cepstral peak prominence and (b) Voice Handicap Index (VHI-10) and Vocal Fatigue Index (VFI) scores., Results: Analysis of covariance showed significantly larger changes (significant decreases) in conversational f o and in jitter for the experimental group relative to the control group. Post hoc pairwise comparisons following repeated-measures analysis of variance showed significant decreases in conversational f o and in jitter across the month for the experimental group. No significant differences in VHI-10 and VFI scores were found between the groups., Conclusions: Vocal demand-related changes in acoustic measures could be partially mitigated with the vocal hygiene program. Future studies with a more refined intervention program and more long-term follow-up are recommended to better understand the long-term benefits of vocal hygiene programs on primary school teachers.

Plasticity in the brain is impacted by an individual's age at the onset of the blindness. However, what drives the varying degrees of plasticity remains largely unclear. One possible explanation attributes the mechanisms for the differing levels of plasticity to the cholinergic signals originating in the nucleus basalis of Meynert. This explanation is based on the fact that the nucleus basalis of Meynert can modulate cortical processes such as plasticity and sensory encoding through its widespread cholinergic projections. Nevertheless, there is no direct evidence indicating that the nucleus basalis of Meynert undergoes plastic changes following blindness. Therefore, using multiparametric magnetic resonance imaging, we examined if the structural and functional properties of the nucleus basalis of Meynert differ between early blind, late blind and sighted individuals. We observed that early and late blind individuals had a preserved volumetric size and cerebrovascular reactivity in the nucleus basalis of Meynert. However, we observed a reduction in the directionality of water diffusion in both early and late blind individuals compared to sighted individuals. Notably, the nucleus basalis of Meynert presented diverging patterns of functional connectivity between early and late blind individuals. This functional connectivity was enhanced at both global and local (visual, language and default-mode networks) levels in the early blind individuals, but there were little-to-no changes in the late blind individuals when compared to sighted controls. Furthermore, the age at onset of blindness predicted both global and local functional connectivity. These results suggest that upon reduced directionality of water diffusion in the nucleus basalis of Meynert, cholinergic influence may be stronger for the early blind compared to the late blind individuals. Our findings are important to unravelling why early blind individuals present stronger and more widespread cross-modal plasticity compared to late blind individuals., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Chemical exchange saturation transfer (CEST) is a relatively novel magnetic resonance imaging (MRI) technique with an image contrast designed for in vivo measurement of certain endogenous molecules with protons that are exchangeable with water protons, such as amide proton transfer commonly used for neuro-oncology applications. Recent technological advances have made it feasible to implement CEST on clinical grade scanners within practical acquisition times, creating new opportunities to integrate CEST in clinical workflow. In addition, the majority of CEST applications used in neuro-oncology are performed without the use gadolinium-based contrast agents which are another appealing feature of this technique. This review is written for clinicians involved in neuro-oncologic care (nonphysicists) as the target audience explaining what they need to know as CEST makes its way into practice. The purpose of this article is to (1) review the basic physics and technical principles of CEST MRI, and (2) review the practical applications of CEST in neuro-oncology., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Arjun Sahgal: Consultant with Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, Merck, Abbvie, RocheVice President with International Stereotactic Radiosurgery Society (ISRS) Advisory Board with VieCureCo-Chair with AO Spine Knowledge Forum TumorPast educational seminars (honorarium) with AstraZeneca, Elekta AB, Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon, Accuray, Seagen Inc.Research Grant: Elekta AB, Varian, Seagen Inc.Travel accommodations/expenses: Elekta, Varian, BrainLABBelongs to the Elekta MR Linac Research Consortium, Elekta Spine, Elekta Oligometastases and Elekta Linac Based SRS Consortia.All other authors declare no conflicts.

Accessibility of diagnostic screening and treatment monitoring devices for respiratory diseases is critical in promoting healthcare and reducing sudden complications and mortality. Spirometry is the standard for diagnosing and monitoring several lung diseases. However, it lacks regional assessment capabilities necessary for detecting subtle regional changes in certain diseases. It also requires challenging breathing maneuvers difficult for elderlies, children, and diseased patients. Here, we actualized an affordable, portable, and self-administrable electrical impedance tomography (EIT) system for home-based lung function assessment and telemedicine. Through simultaneous EIT-spirometry trials on healthy subjects, we demonstrated that our device can predict spirometry indicators over a wide range and can provide regional mapping of these indicators. We further developed a close-to-effortless breathing paradigm and tested it by longitudinally monitoring a COVID-19 discharged subject and two healthy controls with results suggesting the paradigm can detect initial deterioration followed by recovery. Overall, the EIT system can be widely applicable for lung function screening and monitoring both at homes and clinics., (© 2022. The Author(s).)

Purpose: This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow., Materials and Methods: Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR., Results: All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled ( R =0.68, p <.001)., Conclusion: We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy., Competing Interests: C-LT has received travel accommodations/expenses & honoraria for past educational seminars by Elekta and belongs to the Elekta MR-Linac Research Consortium. JS is employed at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. SM has received research support from Novartis AG, honoraria from Novartis AG and Ipsen and travel support from Elekta, none related to this work. SD serves as the Provincial Lead for CNS Oncology at Ontario Health, Cancer Care Ontario; he receives laboratory research support from Alkermes; he serves on the advisory board of the Subcortical Surgery Group and Xpan Medical; he is a speaker for the Congress of Neurological Surgeons. MR is a co‐inventor of and owns associated intellectual property specific to the image‐guidance system on the Gamma Knife Icon, none related to this work. AS has been a consultant for Varian, Elekta Gamma Knife Icon, BrainLAB, Merck, Abbvie, Roche; Vice President of the International Stereotactic Radiosurgery Society ISRS; Co-Chair of the AO Spine Knowledge Forum Tumor; received honorarium for past educational seminars for AstraZeneca, Elekta AB, Varian, BrainLAB, Accuray, Seagen Inc.; research grant with Elekta AB, Varian, Seagen Inc., BrainLAB; and travel accommodations/expenses with Elekta, Varian and BrainLAB. AS also belongs to the Elekta MR Linac Research Consortium and is a Clinical Steering Committee Member, and chairs the Elekta Oligometastases Group and the Elekta Gamma Knife Icon Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tseng, Chen, Stewart, Lau, Chan, Lawrence, Myrehaug, Soliman, Detsky, Lim-Fat, Lipsman, Das, Heyn, Maralani, Binda, Perry, Keller, Stanisz, Ruschin and Sahgal.)

Primary motor cortex (M1) consists of a stack of interconnected but distinct layers (L1-L6) which affect motor control through large-scale networks. However, the brain-wide functional influence of each layer is poorly understood. We sought to expand our knowledge of these layers' circuitry by combining Cre-driver mouse lines, optogenetics, fMRI, and electrophysiology. Neuronal activities initiated in Drd3 neurons (within L2/3) were mainly confined within M1, while stimulation of Scnn1a, Rbp4, and Ntsr1 neurons (within L4, L5, and L6, respectively) evoked distinct responses in M1 and motor-related subcortical regions, including striatum and motor thalamus. We also found that fMRI responses from targeted stimulations correlated with both local field potentials (LFPs) and spike changes. This study represents a step forward in our understanding of how different layers of primary motor cortex are embedded in brain-wide circuitry., Competing Interests: Competing Interest Statement HJL is an employee and shareholder of LVIS. JHL is a founder, shareholder, and consultant for LVIS., (Copyright © 2022. Published by Elsevier Inc.)

Prolonged or excessive stimulation from inhaled toxins may cause oxidative stress and DNA damage that can lead to stress-induced senescence in epithelial cells, which can contribute to several airway diseases. Mounting evidence has shown carbon monoxide (CO) confers cytoprotective effects. We investigated the effects of CO on oxidative stress-induced senescence in human airway epithelium and elucidated the underlying molecular mechanisms. Here, CO pretreatment reduced H 2 O 2 -mediated increases in total reactive oxygen species (ROS) production and mitochondrial superoxide in a human bronchial epithelial cell line (BEAS-2B). H 2 O 2 treatment triggered a premature senescence-like phenotype with enlarged and flattened cell morphology accompanied by increased SA- β -gal activity, cell cycle arrest in G0/G1, reduced cell viability, and increased transcription of senescence-associated secretory phenotype (SASP) genes. Additionally, exposure to H 2 O 2 increased protein levels of cellular senescence markers (p53 and p21), reduced Sirtuin 3 (SIRT3) and manganese superoxide dismutase (MnSOD) levels, and increased p53 K382 acetylation. These H 2 O 2 -mediated effects were attenuated by pretreatment with a CO-containing solution. SIRT3 silencing induced mitochondrial superoxide production and triggered a senescence-like phenotype, whereas overexpression decreased mitochondrial superoxide production and alleviated the senescence-like phenotype. Air-liquid interface (ALI) culture of primary human bronchial cells, which becomes a fully differentiated pseudostratified mucociliary epithelium, was used as a model. We found that apical and basolateral exposure to H 2 O 2 induced a vacuolated structure that impaired the integrity of ALI cultures, increased goblet cell numbers, decreased SCGB1A1+ club cell numbers, increased p21 protein levels, and increased SASP gene transcription, consistent with our observations in BEAS-2B cells. These effects were attenuated in the apical presence of a CO-containing solution. In summary, we revealed that CO has a pivotal role in epithelial senescence by regulating ROS production via the SIRT3/MnSOD/p53/p21 pathway. This may have important implications in the prevention and treatment of age-associated respiratory pathologies., Competing Interests: The authors declare no competing financial interests., (Copyright © 2022 Meng-yun Cai et al.)

Single-session meditation augmentation of sport-specific skill performance was tested with elite junior tennis athletes. Athletes completed one of two styles of mindfulness meditation (focused-attention or open-monitoring) or a control listening condition prior to performing an implicitly sequenced tennis serve return task involving the goal of hitting a target area placed on the service court. Unbeknownst to athletes, six distinct serves followed a repeating second-order conditional sequence for two task blocks before the sequence was altered in a third transfer block. Task performance was operationalized as serve return outcome and analyzed using beta regression modeling. Models analyzed group by block differences in the proportion of returned serves (i.e., non-aces), returns placed in the service court, and target hits. Contrary to previous laboratory findings, results did not support meditation-related augmentation of performance and/or sequence learning. In fact, compared to control, meditation may have impaired performance improvements and acquisition of serve sequence information. It is possible that the effects of single-session meditation seen in laboratory research may not extend to more complex motor tasks, at least in highly-trained adolescents completing a well-learned skill. Further research is required to elucidate the participant, task, and meditation-related characteristics that might promote single-session meditation performance enhancement., Competing Interests: Author AM was employed by Tennis Australia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 O'Connor, Murphy, Kohler, Chan and Immink.)

Purpose: This study attempted to develop and to preliminarily validate the Mandarin Chinese version of the Vocal Fatigue Index (VFI) as a standardized self-assessment questionnaire tool for potential clinical applications., Method: The experimental procedure involved (a) cross-cultural adaptation of the VFI into the Mandarin Chinese version (CVFI), (b) evaluation by an expert panel, (c) back translation, (d) pilot testing, and (e) validation of the questionnaire by three participant groups: 50 with voice disorders, 50 occupational voice users (at-risk group), and 50 with normal voice (control group). Internal consistency, test-retest reliability, content validity, and convergent validity of the CVFI were examined, and discriminatory ability (diagnostic accuracy) for distinguishing between the groups was evaluated., Results: Results showed high internal consistency (Cronbach's alpha ≥ .8817 for the total CVFI scores for all groups), high test-retest reliability (intraclass correlation coefficients ≥ .9072, p < .001 for the total CVFI scores for all groups), high content validity (total content validity index = 0.9368), and high convergent validity (Pearson r ≥ .8155, p < .001 between the total CVFI scores and Factors 1 and 2 scores). Significant differences between the three groups were found in all scores. Receiver operating characteristic analysis revealed a high diagnostic accuracy for distinguishing between the disorders group and the normal group (area under the curve ≥ 0.927, p < .001 for the total CVFI scores and Factors 1 and 2 scores), with cutoff scores of ≥ 36 (total CVFI score), ≥ 23.5 (Factor 1 score), ≥ 7.5 (Factor 2 score), and ≤ 6.5 (Factor 3 score)., Conclusions: These findings suggested that the CVFI could be a reliable and valid self-assessment tool for the clinical evaluation of vocal fatigue in Mandarin Chinese-speaking populations. A full-scale validation study of the CVFI is recommended to verify these results.

Chronic kidney disease (CKD) is an escalating global health concern, and non-invasive means for early CKD detection is eagerly awaited. Here, we explore the potential of using home-based frequency-difference electrical impedance tomography (fdEIT) to evaluate CKD based on bio-conductivity characteristics. We first verified the feasibility of using portable EIT capturing bio-conductivity in fresh pig kidneys ex vivo. We further performed bio-conductivity measurement in vivo paired with standard eGFR measurements on CKD patients by EIT and traditional blood test, respectively. Our results showed a significant correlation between renal bio-conductivity changes captured by fdEIT and standard eGFR scores. These results hold promise to be developed into a non-invasive and portable device for early CKD detection and longitudinal CKD treatment monitoring in clinical, community and home-based settings. Clinical Relevance - A novel non-invasive bio-conductivity approach was developed for CKD classification. The renal assessment with portable EIT device demonstrated the potential to ameliorate the detection and classification of CKD into a portable, accessible, self-administrable home-based process.

Electrical impedance tomography (EIT) is a bio-medical imaging modality that has several clinical applications namely for human lungs. Yet, its relationship with gold standard lung diagnostic tools including spirometry is not available. In this study, simultaneous EIT and spirometry measurements were collected for 14 healthy subjects who performed forced breathing paradigms of different efforts simulating a wide range of spirometry indicators. It is demonstrated that EIT can predict standard spirometry indicators over a wide dynamic range, with a potential sensitivity and specificity of 98% and 100%, respectively, in detecting obstructive patterns. It is also shown that EIT can provide a regional mapping of the spirometry indicator which are shown to be consistent with their corresponding global indicators. Overall, EIT can predict spirometry indicators and can assess regional lung health through parametric mapping. Clinical Relevance- This study shows that EIT can infer standard spirometry indicators and potentially assess regional lung health. Therefore, EIT can be used for screening, diagnosis, and monitoring of obstructive and resistive lung diseases.

Here, we tested the feasibility of predicting CAP with multi-spectral EIT. Conductivity and CAP were acquired from nonalcoholic fatty liver disease patients using a portable EIT system and vibration-controlled transient elastography (VCTE). We then used frequency-difference conductivity and waist-over-height as prediction features to estimate CAP and found an adj. R 2 of 0.92. We further developed a novel prediction method by incorporating EIT spectral unmixing reconstruction and demonstrated an improvement in CAP estimation. Last, we optimized the EIT acquisition process by minimizing the total variance of the CAP estimator. Clinical Relevance: EIT can estimate clinical-standard liver disease classification. This portable EIT system is potentially cost-effective and self-administrable with short acquisition time (3 mins), while VCTE are costly and usually requires a trained personnel to operate with longer acquisition time (5-10 mins).

NOise Reduction with DIstribution Corrected (NORDIC) principal component analysis (PCA) has been shown to selectively suppress thermal noise and improve temporal signal-to-noise ratio (tSNR) in human functional magnetic resonance imaging (fMRI). However, the feasibility to improve rodent fMRI using NORDIC PCA has not been explored. In this study, we developed a rodent fMRI preprocessing pipeline by incorporating NORDIC and evaluated its performance in a range of rodent fMRI applications from resting-state fMRI to task-evoked fMRI using optogenetics. In resting-state fMRI, we demonstrated a significant increase in tSNR by more than 3 times after NORDIC correction with reduced variance and improved task-free relative cerebrovascular reactivity (rCVR) across cortical depth. In optogenetic fMRI, apart from tSNR increase, more activated voxels and a significant decrease in the variance of activated brain signals were observed after NORDIC correction without apparent change in brain morphology. Taken together, our results signified the values of NORDIC correction for better detection of brain activities in rodent fMRI. Clinical Relevance: NORDIC PCA increases temporal signalto- noise ratio in rodent resting-state and task-evoked functional MRI, which can play an important role in improving the image quality for translational medicine and preclinical research, and for guiding future clinical neuroimaging.

Cell-free extrachromosomal circular DNA (eccDNA) as a distinct topological form from linear DNA has recently gained increasing research interest, with possible clinical applications as a class of biomarkers. In this study, we aimed to explore the relationship between nucleases and eccDNA characteristics in plasma. By using knockout mouse models with deficiencies in deoxyribonuclease 1 (DNASE1) or deoxyribonuclease 1 like 3 (DNASE1L3), we found that cell-free eccDNA in Dnase1l3-/- mice exhibited larger size distributions than that in wild-type mice. Such size alterations were not found in tissue eccDNA of either Dnase1-/- or Dnase1l3-/- mice, suggesting that DNASE1L3 could digest eccDNA extracellularly but did not seem to affect intracellular eccDNA. Using a mouse pregnancy model, we observed that in Dnase1l3-/- mice pregnant with Dnase1l3+/- fetuses, the eccDNA in the maternal plasma was shorter compared with that of Dnase1l3-/- mice carrying Dnase1l3-/- fetuses, highlighting the systemic effects of circulating fetal DNASE1L3 degrading the maternal eccDNA extracellularly. Furthermore, plasma eccDNA in patients with DNASE1L3 mutations also exhibited longer size distributions than that in healthy controls. Taken together, this study provided a hitherto missing link between nuclease activity and the biological manifestations of eccDNA in plasma, paving the way for future biomarker development of this special form of DNA molecules.

Purpose: This study examined the acoustic properties of Taiwanese (Southern Min) lexical tones produced in esophageal speech (ES) and pneumatic artificial laryngeal speech (PAL), including onset fundamental frequency (F0), slope of F0 contour, duration, and amplitude (intensity) of the vowel portion of syllables carrying seven Taiwanese tones., Method: Seven ES speakers, seven PAL speakers, and 18 normal laryngeal (NL) speakers (all male) read aloud target syllables carrying the tones in monosyllables, disyllables, and sentences. Acoustic features were measured with Praat ., Results: Acoustic analysis revealed (a) no significant effects of linguistic level on acoustic parameters except for duration, which generally significantly decreased from monosyllables to disyllables to sentences for Tones 1 and 5; (b) significant differences across the speaker groups in onset F0 (PAL > ES > NL), duration (PAL > NL and PAL > ES for all tones), and mean amplitude (PAL > NL > ES); and (c) no significant difference in mean slope of F0 contour across the speaker groups., Conclusions: These preliminary data on acoustic properties of Taiwanese tones produced by ES and PAL speakers could facilitate the design of therapeutic strategies for improving the intelligibility of alaryngeal lexical tones. Further studies are recommended to examine the relative perceptual importance of the acoustic parameters.

Background: The coronavirus disease 2019 (COVID-19) pandemic has become a major public health threat. This study aims to evaluate the effect of virus mutation activities and policy interventions on COVID-19 transmissibility in Hong Kong., Methods: In this study, we integrated the genetic activities of multiple proteins, and quantified the effect of government interventions and mutation activities against the time-varying effective reproduction number R t ., Findings: We found a significantly positive relationship between R t and mutation activities and a significantly negative relationship between R t and government interventions. The results showed that the mutations that contributed most to the increase of R t were from the spike, nucleocapsid and ORF1b genes. Policy of prohibition on group gathering was estimated to have the largest impact on mitigating virus transmissibility. The model explained 63.2% of the R t variability with the R 2 ., Conclusion: Our study provided a convenient framework to estimate the effect of genetic contribution and government interventions on pathogen transmissibility. We showed that the S, N and ORF1b protein had significant contribution to the increase of transmissibility of SARS-CoV-2 in Hong Kong, while restrictions of public gathering and suspension of face-to-face class are the most effective government interventions strategies., Competing Interests: Conflicts of Interest M.H.W and B.C.Y.Z are shareholders of Beth Bioinformatics Co., Ltd. B.C.Y.Z is a shareholder of Health View Bioanalytics Ltd. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Repeated seizure activity can lead to long-term changes in seizure dynamics and behavior. However, resulting changes in brain-wide dynamics remain poorly understood. This is due partly to technical challenges in precise seizure control and in vivo whole-brain mapping of circuit dynamics. Here, we developed an optogenetic kindling model through repeated stimulation of ventral hippocampal CaMKII neurons in adult rats. We then combined fMRI with electrophysiology to track brain-wide circuit dynamics resulting from non-afterdischarge (AD)-generating stimulations and individual convulsive seizures. Kindling induced widespread increases in non-AD-generating stimulation response and ipsilateral functional connectivity and elevated anxiety. Individual seizures in kindled animals showed more significant increases in brain-wide activity and bilateral functional connectivity. Onset time quantification provided evidence for kindled seizure propagation from the ipsilateral to the contralateral hemisphere. Furthermore, a core of slow-migrating hippocampal activity was identified in both non-kindled and kindled seizures, revealing a novel mechanism of seizure sustainment and propagation., Competing Interests: Declaration of interests J.H.L. is a founder, consultant, and board member of LVIS. J.H.L. and M.C. are inventors on an invention disclosure titled “Predicting successful generation and inhibition of seizure-like afterdischarges and mapping their seizure networks using fMRI.”, (Copyright © 2021 Elsevier Inc. All rights reserved.)

Recent studies have shown the evocation of lateral spread response (LSR) due to the compression of the facial nerve in hemifacial spasm (HFS). Intraoperative monitoring (IOM) of LSR could help locate neurovascular conflicts and confirm adequate micro-vascular decompression (MVD) while treatment of hemifacial spasm (HFS). However, studies on early LSR loss before decompression in HFS surgery are sparse, indicating the need to understand various perceptions on it. Therefore, we retrospectively analyzed 50 adult HFS patients who underwent MVD during the period of September 2018-June 2021. We employed IOM combining traditional LSR (tLSR) and dual LSR (dLSR). One patient was excluded owing to the lack of LSR induction throughout the surgery, while 49 were divided into groups A ( n = 14) and B ( n = 35), designated as with or without early LSR loss groups, respectively, and offending vessels were analyzed. The mean age of group A patients was significantly younger (47.8 ± 8.6) than that of group B (53.9 ± 10.6) ( p = 0.0393). The significant predominating offending vessel in group A was the anterior inferior cerebellar artery (AICA, 78.57%). However, group B included those with AICA (28.57%), posterior inferior cerebellar artery (PICA, 22.86%), vertebral artery (VA) involved (25.71%), and combined AICA and PICA (22.86%). Group B exhibited poorer clinical outcomes with more complications. Conclusively, early LSR loss might occur in the younger population, possibly due to the AICA offending vessel. The compression severity of offending vessels may determine the occurrence of early LSR loss.

The annual epidemics of seasonal influenza is partly attributed to the continued virus evolution. It is challenging to evaluate the effect of influenza virus mutations on evading population immunity. In this study, we introduce a novel statistical and computational approach to measure the dynamic molecular determinants underlying epidemics using effective mutations (EMs), and account for the time of waning mutation advantage against herd immunity by measuring the effective mutation periods (EMPs). Extensive analysis is performed on the sequencing and epidemiology data of H3N2 epidemics in ten regions from season to season. We systematically identified 46 EMs in the hemagglutinin (HA) gene, in which the majority were antigenic sites. Eight EMs were located in immunosubdominant stalk domain, an important target for developing broadly reactive antibodies. The EMs might provide timely information on key substitutions for influenza vaccines antigen design. The EMP suggested that major genetic variants of H3N2 circulated in Southeast Asia for an average duration of 4.5 years (SD 2.4) compared to a significantly shorter 2.0 years (SD 1.0) in temperate regions. The proposed method bridges population epidemics and molecular characteristics of infectious diseases, and would find broad applications in various pathogens mutation estimations., Competing Interests: Declaration of Competing Interest MHW is a shareholder of Beth Bioinformatics Co., Ltd, and BCYZ is a shareholder of Health View Bioanalytics Ltd. Others declare no competing interest., (Copyright © 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Elevated production of lactate is a key characteristic of aberrant tumour cell metabolism and can be non-invasively measured as an early marker of tumour response using deuterium ( 2 H) MRS. Following treatment, changes in the 2 H-labelled lactate signal could identify tumour cell death or impaired metabolic function, which precede morphological changes conventionally used to assess tumour response. In this work, the association between apoptotic cell death, extracellular lactate concentration, and early treatment-induced changes in the 2 H-labelled lactate signal was established in an in vitro tumour model. Experiments were conducted at 7 T on acute myeloid leukaemia (AML) cells, which had been treated with 10 μg/mL of the chemotherapeutic agent cisplatin. At 24 and 48 h after cisplatin treatment the cells were supplied with 20 mM of [6,6'- 2 H 2 ]glucose and scanned over 2 h using a two-dimensional 2 H MR spectroscopic imaging sequence. The resulting signals from 2 H-labelled glucose, lactate, and water were quantified using a spectral fitting algorithm implemented on the Oxford Spectroscopy Analysis MATLAB toolbox. After scanning, the cells were processed for histological stains (terminal deoxynucleotidyl transferase UTP nick end labelling and haematoxylin and eosin) to assess apoptotic area fraction and cell morphology respectively, while a colorimetric assay was used to measure extracellular lactate concentrations in the supernatant. Significantly lower levels of 2 H-labelled lactate were observed in the 48 h treated cells compared with the untreated and 24 h treated cells, and these changes were significantly correlated with an increase in apoptotic fraction and a decrease in extracellular lactate. By establishing the biological processes associated with treatment-induced changes in the 2 H-labelled lactate signal, these findings suggest that 2 H MRS of lactate may be valuable in evaluating early tumour response., (© 2021 John Wiley & Sons, Ltd.)

Whole-brain imaging approaches and optogenetic manipulations are powerful tools to map brain-wide neural circuits in vivo. To date, functional magnetic resonance imaging (fMRI) provides the most comprehensive evaluation of such large-scale circuitry. However, functional ultrasound imaging (fUSI) has recently emerged as a complementary imaging modality that can extend such measurements towards the context of diverse behavioral states and tasks. Nevertheless, in order to properly interpret the fUSI signal during these complicated scenarios, it must first be carefully validated against well-established technologies, such as fMRI, in highly controlled experimental settings. Here, to address this need, we compared subsequent fMRI and fUSI recordings in response to direct neuronal activation via optogenetics in the same animals under an identical anesthetic protocol. Specifically, we applied various intensities of light stimulation to the primary motor cortex (M1) of mice and compared the spatiotemporal dynamics of the elicited fMRI and fUSI signals. Overall, our general linear model analysis (t-scores) and time series analysis (z-scores) revealed that fUSI was more sensitive than fMRI for detecting optogenetically-induced neuronal activation. Local field potential recordings in the bilateral M1 and striatum also better co-localized with fUSI activation patterns than those of fMRI. Finally, the fUSI response contained distinct arterial and venous components that provide vascular readouts of neuronal activity with vessel-type specificity., Competing Interests: Declaration of Competing Interest JHL is a founder, shareholder, and consultant for LVIS., (Copyright © 2021. Published by Elsevier Inc.)

Glaucoma is primarily considered an eye disease with widespread involvements of the brain. Yet, it remains unclear how cerebrovasculature is regulated in glaucoma and how different brain regions coordinate functionally across disease severity. To address these questions, we applied a novel whole-brain relative cerebrovascular reactivity (rCVR) mapping technique using resting-state functional magnetic resonance imaging (fMRI) without gas challenges to 38 glaucoma patients and 21 healthy subjects. The relationships between rCVR, visual-evoked fMRI response, and resting-state functional connectivity in glaucoma were then established. In the visual cortex, rCVR has a decreasing trend with glaucoma severity (p<0.05), and is coupled with visual-evoked response and functional connectivity in both hemispheres (p<0.001). Interestingly, rCVR in the basal forebrain (BF) has an increasing trend with glaucoma severity (p<0.05). The functional connectivity between right diagonal band of Broca (a sub-region of BF) and lateral visual cortex decreases with glaucoma (p<0.05), while such connectivity is inversely coupled with rCVR in the BF (p<0.05), but not the visual cortex. Overall, we demonstrate opposite trends of rCVR changes in the visual cortex and BF in glaucoma patients, suggestive of compensatory actions in vascular reserve between the two brain regions. The neurovascular coupling within the visual cortex appears deteriorated in glaucoma, whereas the association between BF-visual cortex functional connectivity and rCVR of BF indicates the functional and vascular involvements in glaucoma beyond the primary visual pathway.