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TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans. Patients with ATTRwt (n = 18) and V122I ATTRm (n = 11) were longitudinally assessed every 6 months for up to 2 years by functional class assessments, biochemical markers, and echocardiography. At baseline, no differences in clinical characteristics, biomarkers, or echocardiographic parameters were noted between patients with ATTRwt and patients with ATTRm. After 15.5 ± 8 months, there were 11 deaths and 1 cardiac transplant, with higher mortality (73% vs 22%, P = .03) and cardiovascular hospitalization (64% vs 28%, P = .02) among patients with ATTRm. The median survival from diagnosis was 25.6 months for ATTRm vs 43.0 months for ATTRwt (P = .04). Univariate predictors of mortality included disease duration, heart rate ≥70 beats/min, baseline stroke volume, left ventricular ejection fraction <50%, and ATTRm status. For each 6-month increment, the mean 6-minute walk distance declined by 25.8 m, N-terminal pro b-type natriuretic peptide increased by 1,816 pg/mL, and left ventricular ejection fraction fell by 3.2%, for the entire cohort. In this prospective study, disease progression, morbidity, and mortality were observed in ATTR cardiomyopathy, particularly due to V122I, over a short duration. Given the prevalence of this mutation, further study of V122I in at-risk African American patients is warranted.

The traditional approach to time series modeling is based on the Autoregressive Integrated Moving-Average (ARIMA) model (Box and Jenkins, 1970), which is effective in analyzing time series data that exhibit “short-range dependence” (SRD). SRD is characterized by an autocorrelation function (ACF) that goes to zero at an exponential rate, which implies that the observations separated by distant lags are nearly uncorrelated. However, in recent years it has been shown that the ACF tends to zero very slowly in certain types of time-series data, and hence the observations separated by distant lags exhibit strong correlation. This phenomenon is known as long-range dependence (LRD), which has received considerable attention in a wide range of fields including hydrology, biology, computer networks, environmental studies, economics, and finance. Recently, Mandelbrot (1977), Granger and Joyeux (1980), and Hosking (1981) independently introduced the fractional ARIMA (FARIMA) family of models for LRD data. These models have structure similar to the ARIMA(p, d, q ) models, where p and q are the orders of the autoregressive and moving average components respectively, and d is the difference parameter. The key difference between ARIMA and FARIMA models is that in ARIMA models, the parameter d assumes only integer values (i.e., d = 0, 1, 2,…) whereas in FARIMA models, d can be any real number. For a fractional value of d, the difference operator contains an infinite number of terms which introduce long-range dependence into the model. Hence, the identification and estimation of d are critical issues in the FARIMA class of models. In the last few years, many procedures have been proposed for the estimation of d with various degrees of success. Most of these techniques are based on the explosive behavior of the spectral density in the neighborhood of zero, and hence use only frequencies in a carefully chosen neighborhood around zero. This dissertation presents a new semi-parametric method of estimation via a partial linear model. The model is developed based on the semi-parametric structure of the spectral density which separates out the behavior of the spectral density at harmonic frequencies near zero and away from zero. One of the advantage of this technique is that it allows the model to be fitted in the whole range of frequencies, thereby avoiding the issues related to the “choice” of the neighborhood around zero frequencies. Extensive experiments have been conducted to give comprehensive comparisons with other benchmark estimators. These comparisons show that the estimators perform extremely well in the FARIMA(0,d,0) model. However, the proposed estimator, along with the other estimators, has substantial bias in estimating d in general FARIMA(p, d, q) models. This bias is due to the presence of additional short-range dependence structure in the model. To overcome this difficulty, the new estimator is applied to a recursive procedure that accurately estimates all parameters in the FARIMA(p, d, q) model. In particular, this procedure provides a superior estimate of d with enhanced accuracy.

Immersive virtual reality (IVR)-assisted experiential learning has the potential to foster empathy among undergraduate health care students toward older adults with cognitive impairment by facilitating a sense of embodiment. However, the extent of its effectiveness, including enhancing students' learning experiences and achieving intended learning outcomes, remains underexplored. This study aims to evaluate the impacts of IVR-assisted experiential learning on the empathy of undergraduate health care students toward older people with cognitive impairment as the primary outcome (objective 1) and on their learning experience (objective 2) and their attainment of learning outcomes as the secondary outcomes (objective 3). A multiple-methods design was used, which included surveys, focus groups, and a review of the students' group assignments. Survey data were summarized using descriptive statistics, whereas paired 2-tailed t tests were used to evaluate differences in empathy scores before and after the 2-hour IVR tutorial (objective 1). Focus groups were conducted to evaluate the impacts of IVR-assisted experiential learning on the empathy of undergraduate health care students toward older people with cognitive impairment (objective 1). Descriptive statistics obtained from surveys and thematic analyses of focus groups were used to explore the students' learning experiences (objective 2). Thematic analysis of group assignments was conducted to identify learning outcomes (objective 3). A total of 367 undergraduate nursing and occupational therapy students were recruited via convenience sampling. There was a significant increase in the students' empathy scores, measured using the Kiersma-Chen Empathy Scale, from 78.06 (SD 7.72) before to 81.17 (SD 8.93) after (P<.001). Students expressed high satisfaction with the IVR learning innovation, with a high satisfaction mean score of 20.68 (SD 2.55) and a high self-confidence mean score of 32.04 (SD 3.52) on the Student Satisfaction and Self-Confidence scale. Students exhibited a good sense of presence in the IVR learning environment, as reflected in the scores for adaptation (41.30, SD 6.03), interface quality (11.36, SD 3.70), involvement (62.00, SD 9.47), and sensory fidelity (31.47, SD 5.23) on the Presence Questionnaire version 2.0. In total, 3 major themes were identified from the focus groups, which involved 23 nursing students: enhanced sympathy toward older adults with cognitive impairment, improved engagement in IVR learning, and confidence in understanding the key concepts through the learning process. These themes supplement and align with the survey results. The analysis of the written assignments revealed that students attained the learning outcomes of understanding the challenges faced by older adults with cognitive impairment, the importance of providing person-centered care, and the need for an age-friendly society. IVR-assisted experiential learning enhances students' knowledge and empathy in caring for older adults with cognitive impairment. These findings suggest that IVR can be a valuable tool in professional health care education.

Ching-Lung Cheung and colleagues report a genome-wide association study for thyrotoxic periodic paralysis (TPP), a life-threatening complication of thyrotoxicosis, in a Chinese population. They identify associated variants at 17q24.3 near KCNJ2 . Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of thyrotoxicosis. We conducted a genome-wide association study (GWAS) and a replication study with a total of 123 southern Chinese with TPP (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (rs312691: odds ratio (OR) = 3.3; P meta-analysis = 1.8 × 10 −14 ). All subjects with TPP also had Graves' disease, and subsequent TPP versus Graves' disease comparison confirmed that the association at 17q24.3 was specific to TPP. The area under the curve (AUC) of rs312691 genotype for risk prediction of TPP in subjects with Graves' disease was 0.73. Expression quantitative trait locus (eQTL) analysis identified SNPs in the region flanking rs312691 (±10 kb) that could potentially affect KCNJ2 expression ( P = 0.0001). Our study has identified a susceptibility locus associated with TPP and provides insight into the causes of TPP.

Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and KIT and BRAF mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm 2 . Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored KIT mutations, three of which were hotspots. BRAF V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm 2 , lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.

Gene doping is known as the manipulation of congenital traits by gene therapeutic approaches with the intent of illicit athletic performance enhancement. A panel prototype suitable for multiplex gene doping detection by combining multiplex Polymerase Chain Reaction (PCR)-amplification with Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis was developed and examined for its specificity and sensitivity, and its applicability in human sports drug testing programs was assessed. The panel comprises 20 assays for exon-exon-junction detection of seven human transgenes ( EPO, FST, GH1, IGF1, MSTN (propeptide), VEGFA, VEGFD ), which have been considered as material to routine doping controls, in one reaction. Alongside, a suitable reference material (RM) was designed and tested for its utility. An estimated LOD 95 of 1,500 cp / mL or 30 copies (cp) per reaction of the panel and 500 cp / mL or 10 cp per reaction of the RM was determined in plasmid-spiked human whole blood samples. The specificity and applicability of the panel and the RM was further determined by testing equine plasma samples obtained from an animal that received rAAV-delivered human transgenic EPO as well as 111 native human doping control samples.

The Glashow resonance describes the resonant formation of a W − boson during the interaction of a high-energy electron antineutrino with an electron 1 , peaking at an antineutrino energy of 6.3 petaelectronvolts (PeV) in the rest frame of the electron. Whereas this energy scale is out of reach for currently operating and future planned particle accelerators, natural astrophysical phenomena are expected to produce antineutrinos with energies beyond the PeV scale. Here we report the detection by the IceCube neutrino observatory of a cascade of high-energy particles (a particle shower) consistent with being created at the Glashow resonance. A shower with an energy of 6.05 ± 0.72 PeV (determined from Cherenkov radiation in the Antarctic Ice Sheet) was measured. Features consistent with the production of secondary muons in the particle shower indicate the hadronic decay of a resonant W − boson, confirm that the source is astrophysical and provide improved directional localization. The evidence of the Glashow resonance suggests the presence of electron antineutrinos in the astrophysical flux, while also providing further validation of the standard model of particle physics. Its unique signature indicates a method of distinguishing neutrinos from antineutrinos, thus providing a way to identify astronomical accelerators that produce neutrinos via hadronuclear or photohadronic interactions, with or without strong magnetic fields. As such, knowledge of both the flavour (that is, electron, muon or tau neutrinos) and charge (neutrino or antineutrino) will facilitate the advancement of neutrino astronomy. A particle shower detected by the IceCube Neutrino Observatory at the very high energy of the Glashow resonance demonstrates its potential for the study of high-energy particle physics and astrophysics.

IntroductionSarcopenia is a geriatric syndrome characterised by progressive loss of skeletal muscle mass and function with risks of adverse outcomes and becomes more prevalent due to ageing population. Elastic-band exercise, vibration treatment and hydroxymethylbutyrate (HMB) supplementation were previously proven to have positive effects on the control of sarcopenia. The purpose of this study is to evaluate the effectiveness of elastic-band exercise or vibration treatment with HMB supplementation in managing sarcopenia. Our findings will provide a safe and efficient strategy to mitigate the progression of sarcopenia in older people and contribute to higher quality of life as well as improved long-term health outcomes of elderly people.Methods and analysisIn this single-blinded, randomised controlled trial (RCT), subjects will be screened for sarcopenia based on the Asian Working Group for Sarcopenia (AWGS) definition and 144 sarcopenic subjects aged 65 or above will be recruited. This RCT will have three groups evaluated at two time points to measure changes over 3 months—the control and the groups with combined HMB supplement and elastic-band resistance exercise or vibration treatment. Changes in muscle strength in lower extremity will be the primary outcome. Muscle strength in the upper extremity, gait speed, muscle mass (based on AWGS definition), functional performance in terms of balancing ability and time-up-and-go test and quality of life will be taken as secondary outcomes. In addition, each participant’s daily activity will be monitored by a wrist-worn activity tracker. Repeated-measures analysis of variance will be performed to compare within-subject changes between control and treatment groups at two time points of pretreatments and post-treatments.Ethics and disseminationThe procedures have been approved by the Joint CUHK-NTEC Clinical Research Management Office (Ref. CREC 2018.602) and conformed to the Declaration of Helsinki. Results will be disseminated through peer-reviewed publications, conferences and workshops.Trial registration numberNCT04028206.

Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally. Many transcription factors bind to regulatory DNA elements distant from gene promoters. Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor α (ER-α) in the human genome. We found that most high-confidence remote ER-α-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-α functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes. Gene regulation: the ER-α interactome Many transcription factors bind to regulatory DNA elements that are distant from gene promoters, and such distal binding sites are thought to regulate transcription through long-range chromatin interactions. In order to study how this remote control is organized in a complex genome, Fullwood et al . use a technique termed ChIA-PET (chromatin interaction analysis by paired-end tag sequencing) to detect and map the chromatin interaction network mediated by oestrogen receptor α (ER-α) in human cancer cells. In the resulting global chromatin interactome map, most high-confidence remote ER-α-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-α functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. Many transcription factors bind to regulatory DNA elements that are distant from gene promoters. These distal binding sites are thought to regulate transcription through long-range chromatin interactions, but, until now, the impact of chromatin interactions on transcription regulation has not been investigated in a genome-wide manner. A new strategy — chromatin interaction analysis by paired-end tag sequencing — is now described for the de novo detection of global chromatin interactions.