Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial.

BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. METHODS: Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. RESULTS: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Infants distinguish and represent pattern as an object feature from externally generated patterns superimposed on real, 3-dimensional objects' surfaces.

As infants form object representations, the patterns viewed on objects' surfaces may be challenging to decipher because these patterns may be created from the surface reflectance of an object (an object property) or from an external source, such as a cast shadow. We tested 7 ½-month-old infants' use of cues that specify the source of patterns seen on the surfaces of real, 3-dimensional objects to individuate those objects. Results suggest that when forming object representations based on patterns, 7½-month-olds rely heavily on temporal and depth cues to distinguish patterns inherent to the object from other types of patterns.

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Olivocochlear efferent contributions to speech-in-noise recognition across signal-to-noise ratios.

The medial olivocochlear (MOC) efferent system modifies cochlear output to aid signal detection in noise, but the precise role of efferents in speech-in-noise understanding remains unclear. The current study examined the contribution of the MOC reflex for speech recognition in noise in 30 normal-hearing young adults (27 females, mean age = 22.7 yr). The MOC reflex was assessed using contralateral inhibition of transient-evoked otoacoustic emissions. Speech-in-noise perception was evaluated using the coordinate response measure presented in ipsilateral speech-shaped noise at signal-to-noise ratios (SNRs) ranging from -12 to 0 dB. Performance was assessed without and with the presence of contralateral noise to activate the MOC reflex. Performance was significantly better with contralateral noise only at the lowest SNR. There was a trend of better performance with increasing contralateral inhibition at the lowest SNR. Threshold of the psychometric function was significantly correlated with contralateral inhibition. Response time on the speech task was not significantly correlated with contralateral inhibition. Results suggest that the MOC reflex contributes to listening in low SNRs and the relationship between the MOC reflex and perception is highly dependent upon the task characteristics.

Developmental changes in infants' categorization of anger and disgust facial expressions.

For decades, scholars have examined how children first recognize emotional facial expressions. This research has found that infants younger than 10 months can discriminate negative, within-valence facial expressions in looking time tasks, and children older than 24 months struggle to categorize these expressions in labeling and free-sort tasks. Specifically, these older children, and even adults, consistently misidentify disgust expressions as anger. Although some scholars have hypothesized that young infants would also be unable to categorize anger and disgust expressions, this question has not been empirically tested. In addition, very little research has examined developmental changes in infants' perceptual categorization abilities with high arousal, within-valence emotions. For this reason, the current study tested 10- and 18-month-olds in a looking time task and found that both age groups could perceptually categorize anger and disgust facial expressions. Furthermore, 18-month-olds showed a heightened sensitivity to novel anger expressions, suggesting that, over the second year of life, infants' emotion categorization skills undergo developmental change. These findings are the first to demonstrate that young infants can categorize anger and disgust facial expressions and to document how this skill develops and changes over time. (PsycINFO Database Record

Give Me a Hand: Adult Involvement During Object Exploration Affects Object Individuation in Infancy.

The development of object individuation, a fundamental ability that supports identification and discrimination of objects across discrete encounters, has been examined extensively by researchers. There are significant advancements in infants' ability to individuate objects during the first year-and-a-half. Experimental work has established a timeline of object individuation abilities and revealed some mechanisms underlying this ability, however, the influence of adult assistance during object exploration has not yet been explored. The current study investigates the effect of adult involvement during object exploration on infants' object individuation abilities. In Experiment 1a and 1b, we examined 9.5-month-old infants' colour-based object individuation following adult-assisted multisensory object exploration. Two components of adult interaction were of particular interest: facilitation of object manipulation (grasping, rotating, and attention-getting behaviours) and social engagement (smiling, pointing, attention-getting verbalizations, and object-directed gaze). Experiment 2a and 2b assessed these components with 4.5-month-olds to examine their impact across development. The results showed that after adult-guided object exploration, both 9.5- and 4.5-month-old infants successfully individuated previously undifferentiated objects. Results of Experiments 1b and 2b provide implications for the mechanisms underlying the scaffolding influence of adult interaction during infant behaviours.

Depression training for nurses: Evaluation of an innovative program.

This article describes evaluation results related to a CD-based depression training program that incorporates the collaborative care principles of the Improving Mood-Providing Access to Collaborative Treatment (IMPACT) model of care. The four-part training program used workplace exercises and case-based learning to change daily care practices as part of the training. The relevance and application of depression assessment, treatment, care planning, communication, and referral methods were addressed using a mixed-methods evaluation that accompanied the dissemination of 513 training packets statewide. Evaluations were returned by 250 participants. Items related to the extent to which training changed care practices (n = 19) and outcomes of care for older adults (n = 13) consistently received high scores. Responses to open-ended questions resulted in positive comments related to assessment, monitoring, communication, and interventions such as scheduling pleasant activities. Results indicate the training program may positively influence nursing practice and collaboration with interdisciplinary providers.

Morphology and evolutionary implications of the annual cycle of secretion and sperm storage in spermathecae of the salamander Ambystoma opacum (Amphibia: Ambystomatidae).

Females of the marbled salamander, Ambystoma opacum, store sperm in exocrine glands called spermathecae in the roof of the cloaca. Eggs are fertilized by sperm released from the spermathecae during oviposition. Some sperm remain in the spermathecae following oviposition, but these sperm degenerate within a month and none persists more than 6 mo after oviposition. Thus, sperm storage between successive breeding seasons does not occur. Apical secretory vaculoes are abundant during the fall mating season and contain a substance that is alcian blue+ at pH 2.5. Production of secretory vacuoles decreases markedly after oviposition, and the glands are inactive by the summer months. Ambystoma opacum is a terrestrial breeder, and some mating occurs prior to arrival at pond basins where oviposition occurs. Mating prior to arrival at the ovipository site may prolong the breeding season, leading to fitness implications for both males and females. Females have opportunities for more matings, and the possibilities for sperm competition in the spermathecae are enhanced. © 1995 Wiley-Liss, Inc.