Efficacy and safety of etrasimod, a sphingosine 1-phosphate receptor modulator, in adults with moderate-to-severe atopic dermatitis (ADVISE).

BACKGROUND: Etrasimod is an oral, selective, sphingosine 1-phosphate (S1P) receptor1,4,5 modulator in development for immune-mediated inflammatory disorders. Efficacy and safety of orally administered S1P receptor modulation in atopic dermatitis (AD) have not yet been examined. OBJECTIVE: To assess the efficacy and safety of etrasimod monotherapy in adults with moderate-to-severe AD. METHODS: In this phase 2, randomized, double-blind, placebo-controlled trial, participants (≥18 years) with moderate-to-severe AD defined as baseline validated Investigator's Global Assessment (vIGA-AD) score ≥ 3, Eczema Area and Severity Index (EASI) score ≥ 16, and body surface area involvement ≥10% were randomized 1:1:1 to once-daily oral etrasimod 1 mg, 2 mg or placebo for 12 weeks. The primary outcome was percent change in EASI score from baseline at week 12, assessed in the Full Analysis Set (all randomized participants). Key secondary outcomes were achievement of a vIGA-AD score of 0 or 1 with a ≥2-point improvement from baseline and EASI-75 response at Week 12. Safety was assessed during the double-blind period. RESULTS: One hundred and forty participants were randomized to etrasimod 2 mg (n = 47), 1 mg (n = 47) or placebo (n = 46). At Week 12, percent change in EASI score was -57.2% in the etrasimod 2-mg group versus -48.4% in the placebo group (p = 0.18). A significantly greater proportion of participants receiving etrasimod 2 mg achieved vIGA-AD scores of 0 or 1 with a ≥2-point improvement at Week 12 versus placebo (29.8% vs. 13.0%; p = 0.045); however, EASI-75 response was not statistically significant versus placebo. Treatment-emergent adverse events (AEs) occurred in 59.6%, 40.4% and 47.8% of participants receiving etrasimod 2 mg, 1 mg and placebo, respectively. There were no serious AEs or deaths. CONCLUSIONS: The primary outcome was not met, although efficacy was observed for etrasimod 2 mg on several clinician- and patient-assessed measures, and both 1- and 2-mg doses were well tolerated, warranting further clinical investigation in AD.

A mobile-optimized artificial intelligence system for gestational age and fetal malpresentation assessment.

Background: Fetal ultrasound is an important component of antenatal care, but shortage of adequately trained healthcare workers has limited its adoption in low-to-middle-income countries. This study investigated the use of artificial intelligence for fetal ultrasound in under-resourced settings. Methods: Blind sweep ultrasounds, consisting of six freehand ultrasound sweeps, were collected by sonographers in the USA and Zambia, and novice operators in Zambia. We developed artificial intelligence (AI) models that used blind sweeps to predict gestational age (GA) and fetal malpresentation. AI GA estimates and standard fetal biometry estimates were compared to a previously established ground truth, and evaluated for difference in absolute error. Fetal malpresentation (non-cephalic vs cephalic) was compared to sonographer assessment. On-device AI model run-times were benchmarked on Android mobile phones. Results: Here we show that GA estimation accuracy of the AI model is non-inferior to standard fetal biometry estimates (error difference -1.4 ± 4.5 days, 95% CI -1.8, -0.9, n = 406). Non-inferiority is maintained when blind sweeps are acquired by novice operators performing only two of six sweep motion types. Fetal malpresentation AUC-ROC is 0.977 (95% CI, 0.949, 1.00, n = 613), sonographers and novices have similar AUC-ROC. Software run-times on mobile phones for both diagnostic models are less than 3 s after completion of a sweep. Conclusions: The gestational age model is non-inferior to the clinical standard and the fetal malpresentation model has high AUC-ROCs across operators and devices. Our AI models are able to run on-device, without internet connectivity, and provide feedback scores to assist in upleveling the capabilities of lightly trained ultrasound operators in low resource settings.

Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof-of-Concept Trial.

BACKGROUND: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. OBJECTIVES: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). METHODS: Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. RESULTS: Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (-4.78) and solriamfetol (-4.82 to -5.72; P > 0.05). MWT improved dose-dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). CONCLUSIONS: Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spirulina and C-phycocyanin reduce cytotoxicity and inflammation-related genes expression of microglial cells.

OBJECTIVE: Our aim was to investigate the effects of Spirulina on BV-2 microglial cell cytotoxicity and inflammatory genes expression. METHODS: BV-2 microglial cells were treated with lipopolysaccharide (LPS) (1 µg/ml) and various concentrations of Spirulina platensis water extract or its active component (C-phycocyanin (C-PC)) for 24 hours. Cytotoxicity (lactate dehydrogenase (LDH) release) and expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNAs were assayed. RESULTS: LPS increased LDH production and up-regulated expression of iNOS, COX-2, TNF-α, and IL-6 by BV-2 microglial cells. However, Spirulina platensis water extract and C-PC significantly reduced LPS-induced LDH release, and expression of iNOS, COX-2, TNF-α, and IL-6 mRNAs. CONCLUSION: Spirulina can reduce the cytotoxicity and inhibit expression of inflammation-related genes of LPS-stimulated BV-2 microglial cells.

Hedges enhance memory but inhibit retelling.

We examined the effects of hedges and the discourse marker like on how people recalled specific details about precise quantities in spontaneous speech. We found that listeners treated hedged information differently from like-marked information, although both are thought to be indicators of uncertainty or vagueness. In addition, hedges had different effects depending on whether speakers were (1) retelling conversations to another person or (2) answering questions about material they had heard. When retelling to another person, listeners were more likely to report information that was either unmarked or marked with a like than hedged information (Experiment 1). Yet when answering questions by themselves, hedges enhanced memory for details, in comparison with likes (Experiment 2). Hedges appear to provide pragmatic cues about what information is reliable enough to repeat in a conversational context. But although hedged information may be left out, it is not forgotten.

Association of cadherin23 single nucleotide polymorphism with age-related hearing impairment in Han Chinese.

OBJECTIVE: Genetic variation of cadheri23 (cdh23; 753G>A in exon 7) has been implicated with age-related hearing impairment (ARHI) in mice. This study aimed to test the association of the CDH23 tag single nucleotide polymorphism (SNP) in intron 7 with ARHI in Han Chinese. STUDY DESIGN: Individual cohort study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: A total of 1175 Han Chinese subjects were divided into the case group (n = 310, 26% with poorest hearing) and the control group (n = 308, the 26% with best hearing) according to the Z(high) score converted from the original frequency-specific hearing thresholds. The CDH23 SNP locus (rs7087735: C/T) in intron 7 (coordinate: 72996763) shown in the HapMap was genotyped with correlation to the hearing phenotype. RESULTS: The genotype distributions of CDH23 (CC/CT/TT) were not significantly different between the case and control group (P = .489). Compared with genotype CC, the odds ratios of the genotypes CT and TT for ARHI were not significantly different after adjustment for other environmental factors (P = .299 for CT; P = .610 for TT). CONCLUSIONS: Despite that the Ahl allele of Cdh23 had been implicated with ARHI in mice, we found no positive association of the CDH23 tag SNP in intron 7 with ARHI in Han Chinese.