Integrating Emotion Perception in Rehabilitation Programs for Cochlear Implant Users: A Call for a More Comprehensive Approach.

PURPOSE: Postoperative rehabilitation programs for cochlear implant (CI) recipients primarily emphasize enhancing speech perception. However, effective communication in everyday social interactions necessitates consideration of diverse verbal social cues to facilitate language comprehension. Failure to discern emotional expressions may lead to maladjusted social behavior, underscoring the importance of integrating social cues perception into rehabilitation initiatives to enhance CI users' well-being. After conventional rehabilitation, CI users demonstrate varying levels of emotion perception abilities. This disparity notably impacts young CI users, whose emotion perception deficit can extend to social functioning, encompassing coping strategies and social competence, even when relying on nonauditory cues such as facial expressions. Knowing that emotion perception abilities generally decrease with age, acknowledging emotion perception impairments in aging CI users is crucial, especially since a direct correlation between quality-of-life scores and vocal emotion recognition abilities has been observed in adult CI users. After briefly reviewing the scope of CI rehabilitation programs and summarizing the mounting evidence on CI users' emotion perception deficits and their impact, we will present our recommendations for embedding emotional training as part of enriched and standardized evaluation/rehabilitation programs that can improve CI users' social integration and quality of life. CONCLUSIONS: Evaluating all aspects, including emotion perception, in CI rehabilitation programs is crucial because it ensures a comprehensive approach that enhances speech comprehension and the emotional dimension of communication, potentially improving CI users' social interaction and overall well-being. The development of emotion perception training holds promises for CI users and individuals grappling with various forms of hearing loss and sensory deficits. Ultimately, adopting such a comprehensive approach has the potential to significantly elevate the overall quality of life for a broad spectrum of patients.

Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors. SIGNIFICANCE: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188.

Questioning the Impact of Vestibular Rehabilitation in Mal de Debarquement Syndrome.

INTRODUCTION: Mal de debarquement syndrome (MdDS) is a rare and poorly understood clinical entity defined as a persistent sensation of rocking and swaying that can severely affect the quality of life. To date, the treatment options are very limited. Even though vestibular rehabilitation (VR) efficacy following peripheral vestibular lesion is well-documented, little is known about its influence on MdDS. The objective of the study was to explore the influence of traditional VR program on postural control in a patient diagnosed with MdDS. METHODS: We assessed 3 different participants: 1 healthy control; 1 participant with identified peripheral vestibular impairment (VI); 1 participant diagnosed with MdDS. Postural control was assessed using a force plate (AMTI, Accusway). Participants were assessed following the modified Clinical Test Sensory Integration Balance protocol (mCTSIB, eyes open on firm surface/eyes closed on firm surface/eyes open on foam/eyes closed on foam). The raw data were exported and analyzed in a custom-made Matlab script (Matlab R2020a). We retrieved the center of pressure velocity in both anterior-posterior and mediolateral directions and performed an analysis of the frequency content using Daubechies wavelet of order 4 with 6 levels of decomposition. Protocol VI and MdDS patients performed a 4-week VR program. Postural control, using a force plate, and Dizziness Handicap Inventory (DHI) were assessed before and after the VR program. Healthy control was assessed twice separated by 1 week without any specific intervention. RESULTS: VI participant showed clear improvement on DHI and sway velocity on condition eyes closed with foam. Accordingly, a reduction of energy content within frequency bands (0.39-0.78 Hz and 0.78-1.56 Hz) was observed post-rehabilitation for VI participant in both conditions with foam. Interestingly, MdDS participant demonstrated a reduction in sway velocity in most of the conditions but the frequency content was not modified by VR and was comparable to healthy control. Accordingly, the DHI of the MdDS participant failed to demonstrate any difference following VR. CONCLUSION: The results of the present study question the use of VR as an efficient treatment option for MdDS. Future studies must recruit a larger sample size and focus on the relationship between illusion of movement and postural characteristics such as sway velocity.

Incidence and Risk Factors of Systemic Adverse Effects and Complications of Ultrasound- and Fluoroscopy-Guided Glucocorticoid Injections: A Retrospective Cohort Study.

OBJECTIVES: The aims of the study are to assess the incidence of systemic adverse effects and complications of ultrasound-guided and fluoroscopy-guided glucocorticoid injections and to identify associated risk factors. DESIGN: This retrospective cohort study compared participants who received a glucocorticoid injection at the outpatient clinic and participants who had an appointment but did not receive a glucocorticoid injection. Participants were called to verify whether they had experienced any of the predetermined systemic adverse effects and complications. Multiple binary logistic regression was used to identify systemic adverse effect and complication risk factors. RESULTS: There were 1010 participants in the glucocorticoid injection group and 328 in the nonglucocorticoid injection group. There was no statistically significant difference in the occurrence of systemic infection and decompensated heart failure between the two groups. More participants in the glucocorticoid injection group developed abnormal uterine bleeding and erectile dysfunction, but the differences did not reach statistical significance. Female participants were 1.9 times more likely to develop systemic adverse effects ( P < 0.001). Younger age ( P < 0.001), diabetes ( P = 0.012), and higher glucocorticoid injection doses ( P = 0.024) were also associated with an increased risk of developing systemic adverse effects. CONCLUSIONS: Identified risk factors for developing glucocorticoid injection systemic adverse effects were younger age, female sex, diabetes, tobacco use, and high glucocorticoid injection doses.

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer.

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

Catalyzing Cross-Sector Collaboration: Lessons from a Virtual Pediatric Complex Care Coalition.

BACKGROUND: Children with complex health needs (CCHN) have intersecting medical, behavioral health, and social needs. Unfortunately, fragmentation across health and social services sectors often results in uncoordinated care for CCHN and their families. OBJECTIVE: The purpose of this article is to describe the creation of a statewide cross-sector partnership, the Children's Complex Care Coalition of North Carolina, to identify and act on opportunities for system-level improvements in the care of CCHN. METHODS: We applied a virtual community engagement approach to form an advisory committee of cross-sector collaborators; systematically identify priorities most important and urgent to collaborators for improving systems of care; and host a series of virtual convenings involving more than 90 attendees from across the state to operationalize collaborator-identified priorities into actionable next steps. LESSONS LEARNED: Key facilitators of success for the Children's Complex Care Coalition of North Carolina partnership were investing time in building trusting relationships, particularly with families of CCHN, and aligning goals and priorities with existing local and regional efforts. Challenges included incorporating traditionally under-represented perspectives, right-sizing virtual convening attendance and number of topics covered, and navigating technological difficulties in a virtual environment. CONCLUSIONS: Health systems can catalyze the formation of cross-sector coalitions and community partnerships to advance complex care. Virtual convenings with interactive activities and participatory structures can be an efficient medium to connect coalition members and elicit actionable recommendations for system-level improvements that address the needs of community members.

Epigenetic markers and therapeutic targets for metastasis.

The last few years have seen an increasing number of discoveries which collectively demonstrate that histone and DNA modifying enzyme modulate different stages of metastasis. Moreover, epigenomic alterations can now be measured at multiple scales of analysis and are detectable in human tumors or liquid biopsies. Malignant cell clones with a proclivity for relapse in certain organs may arise in the primary tumor as a consequence of epigenomic alterations which cause a loss in lineage integrity. These alterations may occur due to genetic aberrations acquired during tumor progression or concomitant to therapeutic response. Moreover, evolution of the stroma can also alter the epigenome of cancer cells. In this review, we highlight current knowledge with a particular emphasis on leveraging chromatin and DNA modifying mechanisms as biomarkers of disseminated disease and as therapeutic targets to treat metastatic cancers.

Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer.

The brain is a major sanctuary site for metastatic cancer cells that evade systemic therapies. Through pre-clinical pharmacological, biological, and molecular studies, we characterize the functional link between drug resistance and central nervous system (CNS) relapse in Epidermal Growth Factor Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations, which are poised to proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are regulated through a Ras homolog family member A (RhoA) and Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug-resistant cancer cells, which are enhanced by RhoA/SRF signaling and the brain TME during the evolution of osimertinib-resistant disease.

Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation.

Metastatic breast cancer remains a major cause of cancer-related deaths in women, and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, a combination of WDR5 targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities.

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.

The Model Minority Myth, Data Aggregation, and the Role of Medical Schools in Combating Anti-Asian Sentiment.

The COVID-19 pandemic has resulted in an alarming increase in hate incidents directed toward Asian Americans and Pacific Islanders (AAPIs), including verbal harassment and physical assault, spurring the nationwide #StopAsianHate movement. This rise in anti-Asian sentiment is occurring at a critical time of racial reckoning across the United States, galvanized by the Black Lives Matter movement, and of medical student calls for the implementation of antiracist medical curricula. AAPIs are stereotyped by the model minority myth, which posits that AAPIs are educated, hardworking, and therefore able to achieve high levels of success. This myth acts as a racial wedge between minorities and perpetuates harm that is pervasive throughout the field of medicine. Critically, the frequent aggregation of all AAPI subgroups as one monolithic community obfuscates socioeconomic and cultural differences across the AAPI diaspora while reinforcing the model minority myth. Here, the authors illustrate how the model minority myth and data aggregation have negatively affected the recruitment and advancement of diverse AAPI medical students, physicians, and faculty. Additionally, the authors discuss how data aggregation obscures health disparities across the AAPI diaspora and how the model minority myth influences the illness experiences of AAPI patients. Importantly, the authors outline specific actionable policies and reforms that medical schools can implement to combat anti-Asian sentiment and support the AAPI community.

Main regulatory factors of marbling level in beef cattle.

The content of intramuscular fat (IMF), that determines marbling levels is considered as one of the vital factors influencing beef sensory quality including tenderness, juiciness, flavour and colour. The IMF formation in cattle commences around six months after conception, and continuously grows throughout the life of the animal. The accumulation of marbling is remarkably affected by genetic, sexual, nutritional and management factors. In this review, the adipogenesis and lipogenesis process regulated by various factors and genes during fetal and growing stages is briefly presented. We also discuss the findings of recent studies on the effects of breed, gene, heritability and gender on the marbling accumulation. Various research reported that feeding during pregnancy, concentrate to roughage ratios and the supplementation or restriction of vitamin A, C, and D are crucial nutritional factors affecting the formation and development of IMF. Castration and early weaning combined with high energy feeding are effective management strategies for improving the accumulation of IMF. Furthermore, age and weight at slaughter are also reviewed because they have significant effects on marbling levels. The combination of several factors could positively affect the improvement of the IMF deposition. Therefore, advanced strategies that simultaneously apply genetic, sexual, nutritional and management factors to achieve desired IMF content without detrimental impacts on feed efficiency in high-marbling beef production are essential.

Geographic distribution of Pythium insidiosum infections in the United States.

OBJECTIVE: To describe the geographic distribution of infections caused by Pythium insidiosum in dogs, horses, and other animal species in the US. ANIMALS: For the last 20 years, we have collected data from cases of pythiosis in 1,150 horses, 467 dogs, and other species (59) from various geographic locations in the US. PROCEDURES: Due to lost data (from 2006 to 2016), the selected cases include years 2000 to 2005 and 2016 to 2020. The selection of cases was based on infected host clinical features, serum samples demonstrating strong positive anti-P insidiosum IgG titers in serologic assays, and positive results on ≥ 1 of the following diagnostic modalities: microbial culture on 2% Sabouraud dextrose agar, histologic evaluation, PCR assay, and wet mount cytologic evaluation (with potassium hydroxide). RESULTS: Most confirmed P insidiosum infections were found in horses and dogs in the southeastern US. Interestingly, in Texas, no cases were found west of longitude 100°W. Few pythiosis cases were diagnosed in west-coast states. Equine cases were more often diagnosed during summer and fall months, but canine cases were more often diagnosed between September and February. Cases in other species were discovered in the same geographic areas as those in dogs and horses. CLINICAL RELEVANCE: To our knowledge, this is the first report providing the ecological distribution of P insidiosum infection in affected species in the US. Results of this study illustrated the importance of including P insidiosum in the differential diagnostic scheme of nonhealing skin lesions or intestinal granulomatous masses, particularly in dogs and horses inhabiting or having visited endemic areas.

Measuring Faculty Effort: A Quantitative Approach That Aligns Personal and Institutional Goals in Pathology at Yale.

US medical schools increasingly seek ways to reduce costs and improve productivity. One aspect of this effort has been the development of performance-based incentives for individual faculty. A myriad of such plans exist. Typically, they incentivize clinical revenue generation but vary widely in how teaching, investigation, and administrative contributions are recognized. In Pathology at Yale, we have developed a transparent metrically driven approach that recognizes all missions and allows faculty significant control over their career path. Although some metrics derive from traditional measures such as workload relative value units and one's level of grant support, the key concept underpinning our approach is to define one's contributions not in terms of the revenue generated, but rather on the effort devoted to each of our missions, benchmarked against national or local standards. Full-time faculty are paid a competitive rank-based salary and are expected to contribute at least 100% effort in support of the school's missions: clinical, research, education, administration, and professional service. Metrics define the effort assigned to each activity. Faculty achieving greater than 100% effort receive bonus compensation in proportion to their excess effort. By codifying explicitly how such effort is recognized into a single metric (% effort), we achieve a process that better aligns the professional and personal goals of faculty with the aims of the school. To facilitate its implementation, we have developed a web-based software platform called SWAY (Standardized Workload Analysis at Yale) that enables faculty to monitor their progress and record their activities in real time.

Preclinical Models for the Study of Lung Cancer Pathogenesis and Therapy Development.

Experimental preclinical models have been a cornerstone of lung cancer translational research. Work in these model systems has provided insights into the biology of lung cancer subtypes and their origins, contributed to our understanding of the mechanisms that underlie tumor progression, and revealed new therapeutic vulnerabilities. Initially patient-derived lung cancer cell lines were the main preclinical models available. The landscape is very different now with numerous preclinical models for research each with unique characteristics. These include genetically engineered mouse models (GEMMs), patient-derived xenografts (PDXs) and three-dimensional culture systems ("organoid" cultures). Here we review the development and applications of these models and describe their contributions to lung cancer research.

Facilitating Imaging Mass Spectrometry of Microbial Specialized Metabolites with METASPACE.

Metabolite annotation from imaging mass spectrometry (imaging MS) data is a difficult undertaking that is extremely resource intensive. Here, we adapted METASPACE, cloud software for imaging MS metabolite annotation and data interpretation, to quickly annotate microbial specialized metabolites from high-resolution and high-mass accuracy imaging MS data. Compared with manual ion image and MS1 annotation, METASPACE is faster and, with the appropriate database, more accurate. We applied it to data from microbial colonies grown on agar containing 10 diverse bacterial species and showed that METASPACE was able to annotate 53 ions corresponding to 32 different microbial metabolites. This demonstrates METASPACE to be a useful tool to annotate the chemistry and metabolic exchange factors found in microbial interactions, thereby elucidating the functions of these molecules.

18-year-old woman • chest pain • shortness of breath • electrocardiogram abnormality • Dx?

► Chest Pain ► Shortness of breath ► Electrocardiogram abnormality.

Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF.

Discordant responses between brain metastases and extracranial tumors can arise from branched tumor evolution, underscoring the importance of profiling mutations to optimize therapy. However, the morbidity of brain biopsies limits their use. We investigated whether cell-free DNA (cfDNA) in CSF could serve as an effective surrogate marker for genomic profiling of intraparenchymal (IP) brain metastases. METHODS: CSF and blood were collected simultaneously from patients with progressive brain metastases undergoing a craniotomy or lumbar puncture. Mutations in both biofluids were measured using an error-suppressed deep sequencing method previously published by our group. Forty-three regions of 24 cancer-associated genes were assayed. RESULTS: This study enrolled 14 patients with either IP brain metastases (n = 12) or cytology-positive leptomeningeal disease (LMD, n = 2) and two controls with normal pressure hydrocephalus. Primary cancer types were lung, melanoma, renal cell, and colorectal. cfDNA was measurable in all sixteen samples of CSF. Cancer-associated mutations were found in the CSF of ten patients (eight with IP [67%] and two with LMD [100%]) and plasma of five patients (five with IP [42%] and none with LMD). All patients with plasma cfDNA had extracranial tumors. Among the five patients in the cohort who also had mutation data from time-matched brain metastasis tissue, four patients (80%) had matching mutations detected in CSF and brain, whereas only one patient (20%) had matching mutations detected in plasma and brain. CONCLUSION: The detection of mutational DNA in CSF is not restricted to LMD and was found in two thirds of patients with IP brain metastases in our cohort. Analysis of CSF can be a viable alternative to biopsy for detection of somatic mutations in brain metastases.