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In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab—a monoclonal antibody to N-terminal tau—in patients with early Alzheimer’s disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized ( n  = 654); received ( n  = 650) low-dose (125 mg once every 4 weeks (q4w), n  = 58; 375 mg q12w, n  = 58), intermediate-dose (600 mg q4w, n  = 106) or high-dose (2,000 mg q4w, n  = 214) gosuranemab or placebo (q4w, n  = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid ( n  = 327) and/or tau positron emission tomography ( n  = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant ( P  < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

This article attempts to build a bridge between the existing factor and impact research on senior citizens' use of social media. A random sample of 392 senior citizens was surveyed, and 109 of them were social media users. This article aimed to understand the reasons for and the potential effects of using social media on one's perceived affectionate support, social compensation and social pressure. The result demonstrated that social media could help senior citizens gain more social compensation and social pressure, while affectionate support could be acquired only via face to face communication.

Persistent upregulation of signaling by cytokine tumor necrosis factor–like weak inducer of apoptosis (TWEAK) through its receptor fibroblast growth factor–inducible molecule-14 (Fn14) promotes chronic inflammation and tissue destruction. The aim of this study was to explore the safety and tolerability of the TWEAK-blocking monoclonal antibody BIIB023 and determine its pharmacokinetics and effects on TWEAK pathway pharmacodynamic markers in rheumatoid arthritis (RA). Phase I, first-in-human, 2-part, multicenter, double-blind, dose-escalation study. Patients were randomized to a single dose of BIIB023 (0.03–20 mg/kg) (n = 38) or placebo (n = 15) as an add-on to methotrexate. Three open-label cohorts of RA patients taking background disease-modifying antirheumatic drugs and stable tumor necrosis factor (TNF) inhibitor therapy (n = 12) received a single-dose of BIIB023 of 2, 10, or 20 mg/kg and were assessed over 70 days. The incidence of treatment-emergent adverse events for the BIIB023 monotherapy cohorts and open-label cohorts of BIIB023 as add-on therapy to TNF inhibitors compared with placebo were 47% and 50% versus 33%, respectively. Serum exposure to BIIB023 increased in a dose-dependent manner from 0.03 to 20 mg/kg, but not in direct proportion to dose level. After administration, the time course of BIIB023 serum concentration was multiphasic and showed expedited elimination when levels decreased to < 10 µg/mL. Serum-soluble TWEAK levels were suppressed at all dose levels by 6 hours post-dose and recovered to baseline between days 7 and 28. A trend toward downward modulation of serum biomarkers of inflammatory response was suggested in monocyte chemoattractant protein 1, inducible protein 10, macrophage inflammatory protein 1β, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo. Single-dose BIIB023 showed a favorable safety and tolerability profile in RA. Suppression of serum-soluble TWEAK for ≤ 28 days was observed and downward trends in serum biomarkers suggested.

Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years. Patients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL. The integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were ≥5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of ≥2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a ≥5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age ≤40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores. These HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT00420212; NCT00451451.

Purpose Language history is an important factor in masked speech recognition. Listeners who acquire the target language later in life perform more poorly than native speakers. However, there are inconsistencies in the literature regarding performance of bilingual speakers who begin learning the target language early in life. The purpose of this experiment was to evaluate speech-in-noise and speech-in-speech recognition for highly proficient early bilingual listeners compared to monolingual and late bilingual listeners. Method Three groups of young adults participated: native monolingual English speakers, bilingual Mandarin-English speakers who learned English from birth (early bilinguals), and native Mandarin speakers who learned English later in life (late bilinguals). All participants had normal hearing and were full-time college students. Recognition was assessed for English sentences in speech-shaped noise and two-talker English speech. Participants provided linguistic and demographic information, and late bilinguals completed the Versant test of spoken English abilities. Results All listeners performed better in speech-shaped noise than two-talker speech. Performance was similar for monolingual and early bilinguals. Late bilinguals performed more poorly overall. There was evidence for a stronger association between masked speech recognition and English dominance for late bilinguals compared to early bilinguals. Conclusion These results support the conclusion that bilingualism itself does not necessarily result in a disadvantage when recognizing masked speech in noise and speech in speech. For populations similar to those studied here (highly proficient early bilinguals), it would be appropriate to evaluate masked speech recognition using the same simple stimuli and normative data used for monolingual speakers of English.

Machine learning and natural language processing techniques are being integrated into chemistry and materials science, finding utility at field and domain levels of research. While these tools have existed, the relative recent emergence of these tools within high-level programming languages like Python means that they have only recently begun to be utilized at scale. In this dissertation, I explore the ways in which these tools can be applied in field-specific settings and a general, domain-level one. In one, I develop a new analysis methodology utilizing image registration, dimensionality reduction, and multivariate analysis to derive information from multimodal atomic force microscopy images. In a second, I utilize and develop reusable code for a Python package within the scanning probe community to obtain insights about and examine impacts of different physical contributions to a measured signal in a specialized atomic force microscopy technique. In another, I introduce a practitioner-centric framework for evaluating topic models that moves away from the dichotomic approach utilized in model development with a critical downstream benefit of advancing data-driven materials research via natural language processing. These works illustrate the ways in which existing machine learning and natural language processing are powerful tools and makes a case for the need of domain expertise in their development, much like the symbiotic work of computationalists, experimentalists, and theorists.

Multiple sclerosis (MS) has a significant impact on health-related quality of life (HRQoL) with symptoms adversely affecting many aspects of everyday living. BG-12 (dimethyl fumarate) demonstrated significant efficacy in the phase III studies DEFINE and CONFIRM in patients with relapsing–remitting MS. In CONFIRM, HRQoL was worse in patients with greater disability at baseline, and who relapsed during the study, and improved with BG-12 treatment. Mean Short Form-36 Physical Component Summary scores for BG-12 increased over 2 years and scores for placebo decreased. Coupled with clinical and neuroradiological benefits, these HRQoL results further support BG-12 as an effective oral treatment for relapsing MS.

Music of any culture owns specific cultural and musical particularities, including melody, rhythm, tonality, lyrical narration, and style. Music is distinguished among cultural forms because of its emotionality. It is rich in connecting with and producing memories and, therefore, powerful in generating emotional resonance. Besides lyrical content, musical elements of the song also reveal an encouraging story. The lyrical narration of \"Boundless Oceans, Vast Skies\" is in line with the musical flow. Based on the combination of musical features, lyrical meanings, and cultural references of \"Boundless Oceans, Vast Skies,\" people in Hong Kong might relate the piece of music to a variety of experiences and events and consume the music in a nostalgic way. Music is a rich cultural medium, containing and communicating meanings and feelings and situating identities. Because of these cultural qualities of music, it is without doubt that music can be political, in the sense that it can be a powerful medium communicating political messages and emotions.