Faculty Bibliography

OBJECTIVE/UNASSIGNED:To determine the outcomes of patients receiving hyperbaric oxygen therapy for sudden sensorineural hearing loss and the impact of patient comorbidities on outcomes. STUDY DESIGN/UNASSIGNED:Retrospective chart review. SETTING/UNASSIGNED:Tertiary referral center. METHODS/UNASSIGNED:All patients over 18 diagnosed with sudden sensorineural hearing loss between 2018 and 2021 who were treated with hyperbaric oxygen therapy were included. Demographic information, treatment regimens and duration, and audiometric and speech perception outcomes were recorded and analyzed. RESULTS/UNASSIGNED:19 patients were included. The median age was 45 years. 53% were female and 21% had pre- existing rheumatologic disorders. The mean duration between hearing loss onset and physician visits was 9.6 days. All patients received an oral steroid course, while 95% also received a median of 3 intratympanic steroid injections. Patients began hyperbaric oxygen therapy an average of 34.2 days after the hearing loss onset for an average of 13 sessions. No significant relationships were found between patient comorbidities and outcomes. Of those who reported clinical improvement, 57% demonstrated complete recovery per Siegel's criteria. There was significant improvement after hyperbaric oxygen therapy for pure tone averages (50.3dB vs. 36.0dB, p<0.01) and word discrimination scores (73% vs 79%, p<0.05) for all patients regardless of reported clinical improvement. CONCLUSION/UNASSIGNED:Hyperbaric oxygen therapy, as an adjunct to steroids, significantly improves recovery from sudden sensorineural hearing loss. The Charlson comorbidity index was not significantly associated with patient outcome, but patients with rheumatologic disorders were less likely to respond. Differentiating the natural history of the disease from hyperbaric oxygen therapy-associated improvements remains a challenge.

Task-sharing approaches that train non-specialist providers (NSPs), people without specialized clinical training, are increasingly utilized to address the global mental health treatment gap. This review consolidates findings from peer reviewed articles on the impact of task-sharing mental health interventions on NSPs at the individual, family and community level. Studies that highlighted facilitators, barriers and recommendations for improving the experiences of NSPs were also included in the review. Fifteen studies, conducted across eight countries, met the inclusion criteria. Seven studies were conducted in Sub-Saharan Africa, six in South and Southeast Asia and two studies were conducted in high-income countries in Europe. Benefits for NSPs included personal application of mental health skills, elevated community status and increased social networks. Challenges include burnout, lack of career progression and difficult workplace environments. Findings indicate that while there were many positive impacts associated with NSPs' work, challenges need to be addressed. Safety and harassment issues reported by female NSPs are especially urgent. Supervision, certifications, increased salaries and job stability were also recognized as significant opportunities. We recommend future intervention studies to collect data on the impact of intervention delivery on NSPs. Research is also needed on the impact of various supervision and health systems strategies on NSPs.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants³. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS⁴. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Functional magnetic resonance imaging (fMRI) has emerged as an essential tool for exploring human brain function. Submillimeter fMRI, in particular, has emerged as a tool to study mesoscopic computations. The inherently low signal-to-noise ratio (SNR) at submillimeter resolutions warrants the use of denoising approaches tailored at reducing thermal noise-the dominant contributing noise component in high-resolution fMRI. NOise Reduction with DIstribution Corrected Principal Component Analysis (NORDIC PCA) is one of such approaches, and has been benchmarked against other approaches in several applications. Here, we investigate the effects that two versions of NORDIC denoising have on auditory submillimeter data. While investigating auditory functional responses poses unique challenges, we anticipated NORDIC to have a positive impact on the data on the basis of previous applications. Our results show that NORDIC denoising improves the detection sensitivity and the reliability of estimates in submillimeter auditory fMRI data. These effects can be explained by the reduction of the noise-induced signal variability. However, we did observe a reduction in the average response amplitude (percent signal change) within regions of interest, which may suggest that a portion of the signal of interest, which could not be distinguished from general i.i.d. noise, was also removed. We conclude that, while evaluating the effects of the signal reduction induced by NORDIC may be necessary for each application, using NORDIC in high-resolution auditory fMRI studies may be advantageous because of the large reduction in variability of the estimated responses.

INTRODUCTION/UNASSIGNED:This study examined the potential interplay between motor development and intervention in support of action understanding. METHODS/UNASSIGNED:Eighty nine-month-old infants completed a tool-use training session and goal imitation paradigm that assessed action understanding in counterbalanced order. A metric of motor development was obtained using the Early Motor Questionnaire. RESULTS/UNASSIGNED:Results indicated that training improved action understanding, particularly for those infants who started out with lower means-end skills. Results further indicated that infants who did not receive any training experience in the lab beforehand, drew on their existing means-end skills. DISCUSSION/UNASSIGNED:These results emphasize independent contributions of training and motor development on action understanding and shed light on the interaction between training and individual motor readiness in facilitating action understanding in infancy.