TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.

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.

An evaluation of gingival phenotype and thickness as determined by indirect and direct methods.

OBJECTIVES: To evaluate gingival phenotype (GP) and thickness (GT) using visual, probing, and ultrasound (US) methods and to assess the accuracy and consistency of clinicians to visually identify GP. MATERIALS AND METHODS: The GP and GT of maxillary and mandibular anterior teeth in 29 orthodontic patients (mean age 25 ± 7.5 years) were assessed using probing and US by a single examiner. General dentist and dental specialist assessors (n = 104) were shown intraoral photographs of the patients, including six repeated images, and asked to identify the GP via a questionnaire. RESULTS: An increasing trend in GT values of thin, medium, and thick biotype probe categories was found, though this was not statistically significant (P = .188). Comparison of probing method to determinations of GT made by US yielded slight agreement (κ = 0.12). Using the visual method, assessors' identification of the second GP determination ranged from poor to moderate agreement (κ = 0.29 to κ = 0.53). CONCLUSIONS: The probe method is sufficient in differentiating between different categories of GP. However, further research is required to assess the sensitivity of the probe method in recognizing phenotypes in the most marginal of cases. Assessors using the visual method lack the ability to identify GP accurately and consistently among themselves.

Effect of craniofacial morphology on gingival parameters of mandibular incisors.

OBJECTIVES: To investigate the association between the width of keratinized gingiva (WKG), gingival phenotype (GP), and gingival thickness (GT) with craniofacial morphology in sagittal and vertical dimensions. MATERIALS AND METHODS: WKG, GP, and GT of mandibular anterior teeth in 177 preorthodontic patients (mean age 18.38 ± 5.16 years) were assessed clinically using a periodontal probe, a Colorvue Biotype Probe, and ultrasound by a single examiner. Patients were grouped into skeletal Class I, II, and III and hyperdivergent, normodivergent, and hypodivergent based on ANB and SN-MP angles. Mandibular incisor inclination (L1-NB) was also measured. Clinical and cephalometric measurements were repeated to assess inter- and intraexaminer reproducibility. RESULTS: A significant association was found between thin GP and skeletal Classes I and III for the left mandibular central incisor (MCI; P = .0183). In skeletal Class III patients, L1-NB angle demonstrated a decreasing trend as phenotype thickness decreased. A significant association was found between thin phenotype and normodivergent and hypodivergent groups for MCIs (left: P = .0009, right: P = .00253). No significant association between WKG or GT and craniofacial morphology was found. CONCLUSIONS: Thin GP is associated with skeletal Class I and III for the left MCI. Thin GP is associated with hypodivergent and normodivergent skeletal patterns for the MCIs. There was no association between WKG and GT and craniofacial morphology in both skeletal and vertical dimensions. Dental compensations that exist due to different craniofacial morphology may influence the GP.

An exploration of instructors' and students' perspectives on remote delivery of courses during the COVID-19 pandemic.

The world-wide pivot to remote learning due to the exogenous shocks of COVID-19 across educational institutions has presented unique challenges and opportunities. This study documents the lived experiences of instructors and students and recommends emerging pathways for teaching and learning strategies post-pandemic. Seventy-one instructors and 122 students completed online surveys containing closed and open-ended questions. Quantitative and qualitative analyses were conducted, including frequencies, chi-square tests, Welch Two-Samples t-tests, and thematic analyses. The results demonstrated that with effective online tools, remote learning could replicate key components of content delivery, activities, assessments, and virtual proctored exams. However, instructors and students did not want in-person learning to disappear and recommended flexibility by combining learning opportunities in in-person, online, and asynchronous course deliveries according to personal preferences. The paper concludes with future directions and how the findings influenced our planning for Fall 2021 delivery. The video abstract for this article is available at https://www.youtube.com/watch?v=F48KBg_d8AE.

Nanowire Architectures Improve Ion Uptake Kinetics in Conjugated Polymer Electrochemical Transistors.

Organic electrochemical transistors are believed to face an inherent material design tension between optimizing for ion mobility and for electronic mobility. These devices transduce ion uptake into electrical current, thereby requiring high ion mobility for efficient electrochemical doping and rapid turn-on kinetics and high electronic mobility for the maximum transconductance. Here, we explore a facile route to improve operational kinetics and volumetric capacitance in a high-mobility conjugated polymer (poly[2,5-(2-octyldodecyl)-3,6-diketopyrrolopyrrole-alt-5,5-(2,5-di(thien-2-yl)thieno [3,2-b]thiophene)], DPP-DTT) by employing a nanowire morphology. For equivalent thicknesses, the DPP-DTT nanowire films exhibit consistently faster kinetics (∼6-10× faster) compared to a neat DPP-DTT film. The nanowire architectures show ∼4× higher volumetric capacitance, increasing from 7.1 to 27.7 F/cm3, consistent with the porous structure better enabling ion uptake throughout the film. The nanowires also exhibit a small but energetically favorable shift in a threshold voltage of ∼17 mV, making the nanostructured system both faster and energetically easier to electrochemically dope compared to neat films. We explain the variation using two atomic force microscopy methods: in situ electrochemical strain microscopy and nanoinfrared imaging via photoinduced force microscopy. These data show that the nanowire film's structure allows greater swelling and ion uptake throughout the active layer, indicating that the nanowire architecture exhibits volumetric operation, whereas the neat film is largely operating via the field effect. We propose that for higher-mobility materials, casting the active layer in a nanowire form may offer faster kinetics, enhanced volumetric capacitance, and possibly lower threshold voltage while maintaining desirable device performance.

Relationship between residual kidney function and symptom burden in haemodialysis patients.

BACKGROUND: Residual kidney function (RKF) has been associated with improved solute clearance and survival in haemodialysis (HD) patients. However, whether RKF impacts symptom burden in HD patients is unknown. AIMS: To determine the prevalence of RKF in HD patients and to explore associations between higher levels of RKF with symptom burden, as well as clinical and biochemical parameters. METHODS: This is a single-centre, retrospective, observational study. RKF was assessed as urea clearance (KRU) by interdialytic urine collection. Symptom burden was measured using the palliative care outcome scale renal questionnaire. RESULTS: A total of 90 maintenance HD patients was recruited; 31.9% had KRU ≥1 mL/min/1.73 m2 . Patients with KRU ≥1 mL/min/1.73 m2 reported fewer symptoms (5.3 ± 3.5 vs 7.7 ± 3.8) (P = 0.011), including less shortness of breath (15% vs 55%) (P = 0.0013) and vomiting (0% vs 30%) (P = 0.0016). Higher RKF was associated with lower ß2 -microglobilin (P < 0.0001), and lower serum potassium (P = 0.02), but no difference in phosphate, haemoglobin, C-reactive protein or serum albumin. CONCLUSION: Higher RKF was significantly associated with fewer symptoms, and lower serum ß2 -microglobulin and potassium, suggesting that strategies to preserve RKF may be beneficial.

Effects of Language History on Sentence Recognition in Noise or Two-Talker Speech: Monolingual, Early Bilingual, and Late Bilingual Speakers of English.

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.

The effect of target/masker fundamental frequency contour similarity on masked-speech recognition.

Greater informational masking is observed when the target and masker speech are more perceptually similar. Fundamental frequency (f0) contour, or the dynamic movement of f0, is thought to provide cues for segregating target speech presented in a speech masker. Most of the data demonstrating this effect have been collected using digitally modified stimuli. Less work has been done exploring the role of f0 contour for speech-in-speech recognition when all of the stimuli have been produced naturally. The goal of this project was to explore the importance of target and masker f0 contour similarity by manipulating the speaking style of talkers producing the target and masker speech streams. Sentence recognition thresholds were evaluated for target and masker speech that was produced with either flat, normal, or exaggerated speaking styles; performance was also measured in speech spectrum shaped noise and for conditions in which the stimuli were processed through an ideal-binary mask. Results confirmed that similarities in f0 contour depth elevated speech-in-speech recognition thresholds; however, when the target and masker had similar contour depths, targets with normal f0 contours were more resistant to masking than targets with flat or exaggerated contours. Differences in energetic masking across stimuli cannot account for these results.

The importance of residual kidney function in haemodialysis patients.

In contrast to peritoneal dialysis, residual kidney function (RKF) is commonly disregarded for haemodialysis (HD) patients and not regularly monitored or taken into account in routine clinical care. This is despite evidence that higher levels of RKF in HD patients are associated with better outcomes, including survival, total solute clearance, nutrition, inflammation and fluid balance. This review aims to summarise the clinical effects of RKF specifically in HD patients. Some level of RKF is present in over 80% of patients at the time of dialysis initiation, and while this declines over time, up to 30% of patients on HD for 5 years still have a measurable level of native kidney function. There is little evidence on how best to preserve RKF in HD patients, although it has been observed that intensive HD regimens in incident HD patients appear to accelerate RKF decline. RKF is not commonly factored into HD prescription and measures of adequacy, despite the fact that some guidelines such as Kidney Disease Outcomes Quality Initiative (KDOQI) and European Best Practice Guidelines suggest that it is reasonable to do so. This likely relates, at least in part, to perceived concerns regarding the inconvenience of timed urine collections and to the complexity and lack of consensus regarding the methods for integrating the intermittent clearance of HD with the continuous clearance of native renal function. Further research is required into how best to maintain and maximise the benefits of RKF in HD patients.

Identifying Nanoscale Structure-Function Relationships Using Multimodal Atomic Force Microscopy, Dimensionality Reduction, and Regression Techniques.

Correlating nanoscale chemical specificity with operational physics is a long-standing goal of functional scanning probe microscopy (SPM). We employ a data analytic approach combining multiple microscopy modes using compositional information in infrared vibrational excitation maps acquired via photoinduced force microscopy (PiFM) with electrical information from conductive atomic force microscopy. We study a model polymer blend comprising insulating poly(methyl methacrylate) (PMMA) and semiconducting poly(3-hexylthiophene) (P3HT). We show that PiFM spectra are different from FTIR spectra but can still be used to identify local composition. We use principal component analysis to extract statistically significant principal components and principal component regression to predict local current and identify local polymer composition. In doing so, we observe evidence of semiconducting P3HT within PMMA aggregates. These methods are generalizable to correlated SPM data and provide a meaningful technique for extracting complex compositional information that is impossible to measure from any one technique.

Thermal Decomposition Mechanism for Ethanethiol.

The thermal decomposition of ethanethiol was studied using a 1 mm × 2 cm pulsed silicon carbide microtubular reactor, CH3CH2SH + Δ â†’ Products. Unlike previous studies these experiments were able to identify the initial ethanethiol decomposition products. Ethanethiol was entrained in either an Ar or a He carrier gas, passed through a heated (300-1700 K) SiC microtubular reactor (roughly ≤100 µs residence time) and exited into a vacuum chamber. Within one reactor diameter the gas cools to less than 50 K rotationally, and all reactions cease. The resultant molecular beam was probed by photoionization mass spectroscopy and IR spectroscopy. Ethanethiol was found to undergo unimolecular decomposition by three pathways: CH3CH2SH → (1) CH3CH2 + SH, (2) CH3 + H2C═S, and (3) H2C═CH2 + H2S. The experimental findings are in good agreement with electronic structure calculations.

Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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: NCT0042012; NCT00451451.

Effects of BG-12 (dimethyl fumarate) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM study.

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.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis.

BACKGROUND: 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. OBJECTIVE: 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). METHODS: 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. RESULTS: 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 1ß, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo. CONCLUSIONS: 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.