Generalized confidence interval for an agreement between raters.

Estimation and inference are two key components toward the solution of any statistical problem; however, the inferential issues of statistical assessment of agreement among two or more raters have not been well developed as compared to the development of estimation procedures in this area. The fundamental reason for this gap is the complex expression of the concordance correlation coefficient (CCC) that is frequently used in assessing agreement among raters. Large sample-based statistical tests for CCC often fail to produce desired results for small samples. Hence, inferential procedures for small samples are urgently needed to evaluate agreement between raters. We argue that hypothesis testing of CCC has little value in practice due to the absence of a gold standard of agreement. In this article, we construct the generalized confidence interval (GCI) for CCC utilizing a bivariate normal distribution of measurements, and also develop a large sample-based confidence interval (LSCI). We establish satisfactory performance of GCI by providing the desired coverage probability (CP) via simulation. Results of GCI and LSCI are illustrated and compared with a data set of a recent study performed at U.S. Department of Veterans Affairs, Hines.

Comparative transcriptome analysis of auditory OC-1 cells and zebrafish inner ear tissues in the absence of human OSBPL2 orthologues.

In our previous study, Oxysterol-binding protein-related protein 2 (OSBPL2) was first identified as a new deafness-causative gene contribute to non-syndromic hearing loss. However, the underlying mechanism of OSBPL2-induced hearing loss remains unknown. Here, we used hearing-specific cells and tissues OC-1 cells and zebrafish inner ear tissues as models to identify common transcriptome changes in genes and pathways in the absence of human OSBPL2 orthologues by RNA-seq analysis. In total, 2112 differentially expressed genes (DEGs) were identified between wild-type (WT) and Osbpl2-/- OC-1 cells, and 877 DEGs were identified between WT and osbpl2b-/- zebrafish inner ear tissues. Functional annotation implicated Osbpl2/osbpl2b in lipid metabolism, cell adhesion and the extracellular matrix in both OC-1 cells and zebrafish inner ear tissues. Protein-protein interaction (PPI) analysis indicated that Osbpl2/osbpl2b were also involved in ubiquitination. Further experiments showed that Osbpl2-/- OC-1 cells exhibited an abnormal focal adhesion morphology characterized by inhibited FAK activity and impaired cell adhesion. In conclusion, we identified novel pathways modulated by OSBPL2 orthologues, providing new insight into the mechanism of hearing loss induced by OSBPL2 deficiency.

PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B.

Protein phosphatase-2A (PP2A), an important phosphatase in dephosphorylating tau and preserving synapse, is significantly suppressed in Alzheimer's disease (AD), but the mechanism is not well understood. Here, we studied whether phosphotyrosyl phosphatase activator (PTPA) could activate PP2A by reducing its inhibitory phosphorylation at tyrosine 307 (P-PP2AC). We found that overexpression of PTPA activated PP2A by decreasing the level of P-PP2AC with reduced phosphorylation of tau, while knockdown of PTPA inhibited PP2A by increasing the level of P-PP2AC with enhanced tau phosphorylation. We also observed that expression of PTPA could upregulate the protein and mRNA levels of protein tyrosine phosphatase 1B (PTP1B) and simultaneous downregulation of PTP1B eliminated PTPA-induced PP2A activation. Importantly, we also found that the protein level of PTPA is downregulated in the brains of AD patients, and the AD transgenic mouse models with expression of mutant human amyloid precursor protein (hAPP) or the longest human tau (htau), respectively. Our data indicate that PTPA may activate PP2A through activating PTP1B and thus reducing the level of P-PP2AC, therefore upregulation of PTPA may represent a potential strategy in rescuing PP2A and arresting tau pathology in AD.

Silencing PP2A inhibitor by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice.

Deficits of protein phosphatase-2A (PP2A) play a crucial role in tau hyperphosphorylation, amyloid overproduction, and synaptic suppression of Alzheimer's disease (AD), in which PP2A is inactivated by the endogenously increased inhibitory protein, namely inhibitor-2 of PP2A (I2(PP2A)). Therefore, in vivo silencing I2(PP2A) may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I2(PP2A) (LV-siI2(PP2A)) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI2(PP2A) decreased remarkably the elevated I2(PP2A) in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I2(PP2A) to PP2A catalytic subunit (PP2AC), repression of the inhibitory Leu309-demethylation and elevation of PP2AC. Silencing I2(PP2A) induced a long-lasting attenuation of amyloidogenesis in tg2576 mice with inhibition of amyloid precursor protein hyperphosphorylation and ß-secretase activity, whereas simultaneous inhibition of PP2A abolished the antiamyloidogenic effects of I2(PP2A) silencing. Finally, silencing I2(PP2A) could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I2(PP2A) can efficiently rescue Aß toxicities and improve the memory deficits in tg2576 mice, suggesting that I2(PP2A) could be a promising target for potential AD therapies.

Centralized Quality Assurance of Stereotactic Body Radiation Therapy for the Veterans Affairs Cooperative Studies Program Study Number 2005: A Phase 3 Randomized Trial of Lung Cancer Surgery or Stereotactic Radiotherapy for Operable Early-Stage Non-Small Cell Lung Cancer (VALOR).

PURPOSE: The phase 3 Veterans Affairs Lung Cancer Surgery Or Stereotactic Radiotherapy study implemented centralized quality assurance (QA) to mitigate risks of protocol deviations. This report summarizes the quality and compliance of the first 100 participants treated with stereotactic body radiation therapy (SBRT) in this study. METHODS AND MATERIALS: A centralized QA program was developed to credential and monitor study sites to ensure standard-of-care lung SBRT treatments are delivered to participants. Requirements were adapted from protocols established by the National Cancer Institute's Image and Radiation Oncology Core, which provides oversight for clinical trials sponsored by the National Cancer Institute's National Clinical Trials Network. RESULTS: The first 100 lung SBRT treatment plans were reviewed from April 2017 to October 2022. Tumor contours were appropriate in all submissions. Planning target volume (PTV) expansions were less than the minimum 5 mm requirement in 2% of cases. Critical organ-at-risk structures were contoured accurately for the proximal bronchial tree, trachea, esophagus, spinal cord, and brachial plexus in 75%, 92%, 100%, 100%, and 95% of cases, respectively. Prescriptions were appropriate in 98% of cases; 2 central tumors were treated using a peripheral tumor dose prescription while meeting organ-at-risk constraints. PTV V100% (the percentage of target volume that receives 100% or more of the prescription) values were above the protocol-defined minimum of 94% in all but 1 submission. The median dose maximum (Dmax) within the PTV was 125.4% (105.8%-149.0%; SD ± 8.7%), where values reference the percentage of the prescription dose. High-dose conformality (ratio of the volume of the prescription isodose to the volume of the PTV) and intermediate-dose compactness [R50% (ratio of the volume of the half prescription isodose to the volume of the PTV) and D2cm (the maximum dose beyond a 2 cm expansion of the PTV expressed as a percentage of the prescription dose)] were acceptable or deviation acceptable in 100% and 94% of cases, respectively. CONCLUSIONS: The first 100 participants randomized to SBRT in this study were appropriately treated without safety concerns. A response to the incorrect prescriptions led to preventative measures without further recurrences. The program was developed in a health care system without prior experience with a centralized radiation therapy QA program and may serve as a reference for other institutions.

The generation mechanism underlying the career decision-making difficulties faced by undergraduates in China during the COVID-19 pandemic: a qualitative study based on SCCT theory.

As COVID-19 continues to spread worldwide, the record number of graduates in China and pressure resulting from the economic downturn have led to low confidence in employment among college students, and the difficulties associated with career decision-making have gradually developed into a psychological barrier to the successful employment of Chinese college students. Using the "purposive sampling" approach to qualitative research, this study selected 20 undergraduates exhibiting delayed employment from a university as our research sample and used the career self-management model of social cognitive career theory (SCCT) as an analytical framework to conduct semistructured interviews with the aim of exploring influencing factors associated with and generation mechanism underlying the career decision-making difficulties experienced by Chinese undergraduates during the COVID-19 pandemic. According to the career self-management model of SCCT theory, the four variables of individual, parents, peers and social environment influence Chinese undergraduates' career decision-making difficulties. On this basis, this study proposes a multivariable and single-subject generation mechanism to explain undergraduates' career decision-making difficulties and tries to explicate the mental changes associated with the career decision-making difficulties encountered by undergraduates exhibiting delayed employment by reference to mind sponge theory.

AAPM Task Group Report 306: Quality control and assurance for tomotherapy: An update to Task Group Report 148.

Since the publication of AAPM Task Group (TG) 148 on quality assurance (QA) for helical tomotherapy, there have been many new developments on the tomotherapy platform involving treatment delivery, on-board imaging options, motion management, and treatment planning systems (TPSs). In response to a need for guidance on quality control (QC) and QA for these technologies, the AAPM Therapy Physics Committee commissioned TG 306 to review these changes and make recommendations related to these technology updates. The specific objectives of this TG were (1) to update, as needed, recommendations on tolerance limits, frequencies and QC/QA testing methodology in TG 148, (2) address the commissioning and necessary QA checks, as a supplement to Medical Physics Practice Guidelines (MPPG) with respect to tomotherapy TPS and (3) to provide risk-based recommendations on the new technology implemented clinically and treatment delivery workflow. Detailed recommendations on QA tests and their tolerance levels are provided for dynamic jaws, binary multileaf collimators, and Synchrony motion management. A subset of TPS commissioning and QA checks in MPPG 5.a. applicable to tomotherapy are recommended. In addition, failure mode and effects analysis has been conducted among TG members to obtain multi-institutional analysis on tomotherapy-related failure modes and their effect ranking.

COVID-19 in China: A Rapid Review of the Impacts on the Mental Health of Undergraduate Students.

Public health crises pose challenges for governments and health systems, and the coronavirus disease 2019 (COVID-19) has presented major challenges to humans worldwide. In the context of COVID-19 in China, we explore the impacts of the pandemic on the mental health of undergraduate students. We examine pandemic prevention and control measures in Chinese universities through a rapid review and use our findings to explain the difficulties that undergraduate students face. Moreover, our analysis examines the impacts on five aspects of mental health: emotional aspects, personality, interpersonal relationships, learning behavior and employment options. Additionally, we provide implications in four areas based on the application of the study: strengthening psychological intervention, promoting government information disclosure, improving family communication and adjusting self-awareness.

Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling.

Defective primary cilia cause a range of diseases called ciliopathies, which include hearing loss (HL). Variants in the human oxysterol-binding protein like 2 (OSBPL2/ORP2) are responsible for autosomal dominant nonsyndromic HL (DFNA67). However, the pathogenesis of OSBPL2 deficiency has not been fully elucidated. In this study, we show that the Osbpl2-KO mice exhibited progressive HL and abnormal cochlear development with defective cilia. Further research revealed that OSBPL2 was located at the base of the kinocilia in hair cells (HCs) and primary cilia in supporting cells (SCs) and functioned in the maintenance of ciliogenesis by regulating the homeostasis of PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) on the cilia membrane. OSBPL2 deficiency led to a significant increase of PI(4,5)P2 on the cilia membrane, which could be partially rescued by the overexpression of INPP5E. In addition, smoothened and GL13, the key molecules in the Sonic Hedgehog (Shh) signaling pathway, were detected to be downregulated in Osbpl2-KO HEI-OC1 cells. Our findings revealed that OSBPL2 deficiency resulted in ciliary defects and abnormal Shh signaling transduction in auditory cells, which helped to elucidate the underlying mechanism of OSBPL2 deficiency in HL.

Inhibition of autophagy causes tau proteolysis by activating calpain in rat brain.

The autophagic lysosomal system contributes to the removal of cytosolic components, and abnormality of lysosomal proteases has been reported in the brain of patients with Alzheimer's disease (AD). However, the role of lysosome in tau degradation is still elusive. Here, we infused chloroquine, 3-methyladenine or rapamycin into rat hippocampus or the lateral ventricle to manipulate the autophagic activity and measured the levels of tau protein by Western blotting. We unexpectedly observed that the level of different tau species decreased upon inhibition of lysosomal proteases or macroautophagy by chloroquine or 3-methyladenine. Furthermore, induction of autophagic activity by rapamycin did not induce degradation of tau proteins. To explore the underlying mechanisms for the increased tau degradation induced by autophagic inhibition, we used MG-132, an inhibitor of proteasome and calpain. We found that simultaneous inhibition of proteasome and calpain by MG-132 prevented the chloroquine-induced tau degradation. Further studies demonstrated that the activity of calpain was elevated whereas the activity of proteasome was suppressed in response to inhibition of autophagy by 3-methyladenine or chloroquine. Our data suggest that the lysosomal autophagic system may not degrade tau in the normal adult rat brain and inhibition of autophagy may induce tau proteolysis through activating calpain.

Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity.

Oxysterol-binding protein like 2 (OSBPL2) was identified as a novel causal gene for autosomal dominant nonsyndromic hearing loss. However, the pathogenesis of OSBPL2 deficits in ADNSHL was still unclear. The function of OSBPL2 as a lipid-sensing regulator in multiple cellular processes suggested that OSBPL2 might play an important role in the regulation of cholesterol-homeostasis, which was essential for inner ear. In this study the potential roles of OSBPL2 in cholesterol biosynthesis and ROS production were investigated in Osbpl2-KO OC1 cells and osbpl2b-KO zebrafish. RNA-seq-based analysis suggested that OSBPL2 was implicated in cholesterol biosynthesis and AMPK signaling pathway. Furthermore, Osbpl2/osbpl2b-KO resulted in a reduction of AMPK activity and up-regulation of Srebp2/srebp2, Hmgcr/hmgcr and Hmgcs1/hmgcs1, key genes in the sterol biosynthetic pathway and associated with AMPK signaling. In addition, OSBPL2 was also found to interact with ATIC, key activator of AMPK. The levels of total cholesterol and ROS in OC1 cells or zebrafish inner ear were both increased in Osbpl2/osbpl2b-KO mutants and the mitochondrial damage was detected in Osbpl2-KO OC1 cells. This study uncovered the regulatory roles of OSBPL2 in cellular cholesterol biosynthesis and ROS production. These founds might contribute to the deep understanding of the pathogenesis of OSBPL2 mutation in ADNSHL.

Estradiol attenuates tau hyperphosphorylation induced by upregulation of protein kinase-A.

Protein kinase A (PKA) plays a crucial role in tau hyperphosphorylation, an early event of Alzheimer disease (AD), and 17beta-estradiol replacement in aging women forestalls the onset of AD. However, the role of estradiol in PKA-induced tau hyperphosphorylation is not known. Here, we investigated the effect of 17beta-estradiol on cAMP/PKA activity and the PKA-induced tau hyperphosphorylation in HEK293 cells stably expressing tau441. We found that 17beta-estradiol effectively attenuated forskolin-induced overactivation of PKA and elevation of cAMP, and thus prevented tau from hyperphosphorylation. These data provide the first evidence that 17beta-estradiol can inhibit PKA overactivation and the PKA-induced tau hyperphosphorylation, implying a preventive role of 17beta-estradiol in AD-like tau pathology.

Preliminary in vivo atherosclerotic carotid plaque characterization using the accumulated axial strain and relative lateral shift strain indices.

In this paper, we explore two parameters or strain indices related to plaque deformation during the cardiac cycle, namely, the maximum accumulated axial strain in plaque and the relative lateral shifts between plaque and vessel wall under in vivo clinical ultrasound imaging conditions for possible identification of vulnerable plaque. These strain indices enable differentiation between calcified and lipidic plaque tissue utilizing a new perspective based on the stiffness and mobility of the plaque. In addition, they also provide the ability to distinguish between softer plaques that undergo large deformations during the cardiac cycle when compared to stiffer plaque tissue. Soft plaques that undergo large deformations over the cardiac cycle are more prone to rupture and to release micro-emboli into the cerebral bloodstream. The ability to identify vulnerable plaque, prone to rupture, would significantly enhance the clinical utility of this method for screening patients. We present preliminary in vivo results obtained from ultrasound radio frequency data collected over 16 atherosclerotic plaque patients before these patients undergo a carotid endarterectomy procedure. Our preliminary in vivo results indicate that the maximum accumulated axial strain over a cardiac cycle and the maximum relative lateral shift or displacement of the plaque are useful strain indices that provide differentiation between soft and calcified plaques.

Independent home use of a brain-computer interface by people with amyotrophic lateral sclerosis.

OBJECTIVE: To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months. METHODS: Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28-79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life. RESULTS: Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use. CONCLUSION: The Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used.

Two-dimensional multi-level strain estimation for discontinuous tissue.

A large number of the strain estimation methods presented in the literature are based on the assumption of tissue continuity that establishes a continuous displacement field. However, in certain locations in the body such as the arteries in vivo scanning may produce displacement fields that are discontinuous between the two walls of the artery. Many of the displacement or strain estimators fail when the displacement fields are discontinuous. In this paper, we present a new 2D multi-level motion or displacement tracking method for accurate estimation of the strain in these situations. The final high-resolution displacement estimate is obtained using two processing steps. The first step involves an estimation of a coarse displacement estimate utilizing B-mode or envelope signals. To reduce computational time, the coarse displacement estimates are obtained starting from down-sampled B-mode pre- and post-compression image pairs using a pyramidal processing approach. The coarse displacement estimate obtained from the B-mode data is used to guide the final 2D cross-correlation computations on radio-frequency (RF) data. Results from finite element simulations and in vivo experimental data demonstrate the feasibility of this approach for imaging tissue with discontinuous displacement fields.

Improvement of elastographic displacement estimation using a two-step cross-correlation method.

The cross-correlation algorithm used to compute the local strain components for elastographic imaging requires a minimum radio-frequency data segment length of around 10 wavelengths to obtain accurate and precise strain estimates with a reasonable signal-to-noise ratio. Shorter radio-frequency data segments generally introduce increased estimation errors as the information content in the data segment reduces. However, shorter data segments and increased overlaps are essential to improve the axial resolution in the strain image. In this paper, we propose a two-step cross-correlation technique that enables the use of window lengths on the order of a single wavelength to provide displacement and strain estimates with similar noise properties as those obtained with a 10 wavelength window. The first processing step utilizes a window length on the order of 10 wavelengths to obtain coarse displacement estimates between the pre- and post-compression radio frequency data frames. This coarse displacement is then interpolated and utilized as the initial guess-estimate for the second cross-correlation processing step using the smaller window. This step utilizes a single wavelength window to improve the axial resolution in strain estimation, without significantly compromising the noise properties of the image. Simulation and experimental results show that the signal-to-noise and contrast-to-noise ratio estimates improve significantly at the smaller window lengths with the two-step processing when compared with the use of a similar sized window in the currently utilized single window method.

Spatial-angular compounding for elastography using beam steering on linear array transducers.

Spatial-angular compounding is a new technique that enables the reduction of noise artifacts in ultrasound elastography. Under this method, compounded elastograms are obtained from a spatially weighted average of local strain estimated from radio frequency (rf) echo signals acquired at different insonification angles. In previous work, the acquisition of the rf signals was performed through the lateral translation of a phased-array transducer. Clinical applications of angular compounding would, however, require the utilization of beam steering on linear-array transducers to obtain angular data sets, which is more efficient than translating phased-array transducers. In this article, we investigate the performance of angular compounding for elastography by using beam steering on a linear-array transducer. Quantitative experimental results demonstrate that spatial angular compounding provides significant improvement in both the elastographic signal-to-noise ratio and the contrast-to-noise ratio. For the linear array transducer used in this study, the optimum angular increment is around 1.5 degrees-3.75 degrees, and the maximum angle that can be used in angular compounding should not exceed 10 degrees.

Stability of heterogeneous elastography phantoms made from oil dispersions in aqueous gels.

A set of five tissue-mimicking phantoms with cylindrical inclusions were produced for assessing long-term stability of geometry and elastic properties and assessing accuracy of determination of elastic properties. The base aqueous materials were either gelatin or a mixture of agar and gelatin. Stiffness was controlled by selection of the volume percent consisting of microscopic safflower oil droplets. Cylinder diameters remained unchanged within 1% or 2% over many months. Strain ratios from elastograms of the phantoms were stable over many months, implying that elastic contrasts were also stable. Test samples, called production samples, for measurement of Young's moduli were made at the time of manufacture of each phantom and were stored separately from one another. Each production sample was homogeneous and consisted of either inclusion material or background material. For all five phantoms, it was found that the elastic contrast computed using Young's modulus values determined using the production samples accurately represented the true elastic contrasts in the corresponding phantom. This finding was established by the fact that the (true) elastic contrasts determined using samples excised from the phantoms themselves agreed with the elastic contrasts obtained using the homogeneous production samples.

Anthropomorphic breast phantoms for testing elastography systems.

Two equivalent anthropomorphic breast phantoms were constructed, one for use in ultrasound elastography and the other in magnetic resonance (MR) elastography. A complete description of the manufacturing methods is provided. The materials used were oil-in-gelatin dispersions, where the volume percent oil differentiates the materials, primarily according to Young's moduli. Values of Young's moduli are in agreement with in vitro ranges for the corresponding normal and abnormal breast tissues. Ultrasound and nuclear magnetic resonance (NMR) properties are reasonably well represented. Phantoms of the type described promise to aid researchers who are developing hardware and software for elastography. Examples of ultrasound and MR elastograms of the phantoms are included to demonstrate the utility of the phantoms. Also, the level of stability of elastic properties of the component materials is quantified over a 15-month period. Such phantoms can serve as performance-assessing intermediaries between simple phantoms (consisting, for example, of homogeneous cylindrical inclusions in a homogeneous background) and a full-scale clinical trial. Thus, premature clinical trials may be avoided.

Tissue-mimicking agar/gelatin materials for use in heterogeneous elastography phantoms.

Five 9 cm x 9 cm x 9 cm phantoms, each with a 2-cm-diameter cylindrical inclusion, were produced with various dry-weight concentrations of agar and gelatin. Elastic contrasts ranged from 1.5 to 4.6, and values of the storage modulus (real part of the complex Young's modulus) were all in the soft tissue range. Additives assured immunity from bacterial invasion and can produce tissue-mimicking ultrasound and NMR properties. Monitoring of strain ratios over a 7 to 10 month period indicated that the mechanical properties of the phantoms were stable, allowing about 1 month for the phantom to reach chemical equilibrium. The only dependable method for determining the storage moduli of the inclusions is to make measurements on samples excised from the phantoms. If it is desired to produce and accurately characterize a phantom with small inclusions with other shapes, such as an array of small spheres, an auxiliary phantom with the geometry of the cylindrical inclusion phantoms or the equivalent should be made at the same time using the same materials. The elastic contrast can then be determined using samples excised from the auxiliary phantom. A small increase of about 10% in volume of the cylindrical inclusions occurred-a tolerable increase. Interestingly, the smallest increase (about 5%) occurred in the phantom with the largest elastic contrast.