Jacobs Institute of Women's Health
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Part 1: Assessing Treatment Effectiveness and Recovery in Patients With Unilateral Vocal Fold Paresis/Paralysis Using Measures of Acoustic Glottal Stop Production
No full textOBJECTIVES/HYPOTHESIS: A group of patients with unilateral vocal fold paresis/paralysis (UVFP) were studied following surgery after a year\u27s observation to assess treatment effectiveness. A second group was studied following no intervention for up to 12 months to assess spontaneous recovery. Novel acoustic measures of glottal stop production (GSP) were used to assess changes in laryngeal function. It was hypothesized that these measures would reflect change following treatment as effectively as more traditional measures. Following observation or injection, a return of the acoustic GSP measures to within normal limits (WNL) would be related to patient-reported voice normalization (ie, return to premorbid quality), a standard measure of recovery. STUDY DESIGN: The design was retrospective, analytical, observational, case-control study. METHODS: Forty-four patients diagnosed by a certified otolaryngologist with UVFP participated (13 observed, 7 injected, and 24 following surgeries), with iatrogenic (22), idiopathic (18), and viral (4) etiologies. Acoustic measures based on GSP (ie, onset and offset intensity differences and slopes) and number of voicing cessations were studied, as well as traditional outcome measures, including maximum phonation time (MPT), airflow, s/z ratio, jitter, and shimmer. Agreement using Cohen\u27s kappa coefficients between patient-reported voice normalization and the return to WNL for both measure types following observation or injection was also studied. RESULTS: Improvements were demonstrated for both measure types following treatment. Traditional outcome measures demonstrated larger effect sizes. Significant increases in the number of voicing cessations within individuals were found postobservation. Fair/moderate Cohen\u27s kappa coefficients for those observed and injected were reported between patient-reported normalized voice and return to WNL of airflow (0.45) and onset slope values (0.3) and at least one voicing cessation present (0.35). CONCLUSIONS: Acoustic GSP measures were able to reflect treatment effectiveness, and with further study, may be useful for monitoring peripheral nerve recovery over time
Prenatal Cell-Free DNA Sequencing and Intrahepatic Cholangiocarcinoma
No full textPrenatal cell-free DNA (cfDNA) sequencing is a screening method that utilizes circulating cfDNA in maternal blood to identify fetal chromosomal abnormalities. Beyond its primary application in prenatal care, cfDNA sequencing can detect occult maternal malignancies before they manifest clinically, presenting a critical window for early therapeutic intervention. Here we report a single case in detail from the Incidental DEtection of maternal Neoplasia Through non-Invasive cell-Free DNA analysis (IDENTIFY) study, in which an abnormal cfDNA sequencing result from an asymptomatic pregnant woman identified locally advanced cholangiocarcinoma. Her disease was successfully treated with a multi-modal approach, and she achieved an ongoing complete response
Towards trustworthiness of precision medicine research for people with disabilities
No full textPeople with disabilities are underrepresented in general (i.e., non-disability specific) precision medicine research (PMR), limiting access to its benefits. This commentary examines key reasons for this limited participation, focusing on the role of (dis)trust. We identify areas for further inquiry to guide researchers and enhance the trustworthiness of PMR for people with disabilities
Zmym2 Alters Expression of Key Craniofacial Genes
No full textTo identify novel Six1-interacting proteins, we previously screened the fly interactome for Sine oculis-binding partners whose orthologues are also expressed in Xenopus embryos. We identified a zinc-finger MYM-containing protein-Zmym2-based on its sequence similarity in a few domains also found in the Drosophila and vertebrate Sine oculis-binding proteins (Sobp). Because recent studies established Zmym2 as a transcriptional repressor that interacts with Six4 during renal development, herein we assessed whether it interacts with Six1, can modify Six1\u27s transcriptional activity, and is involved in cranial neural crest or placode gene expression. Although during early development Zmym2 is expressed in many of the same tissues as Six1 and contains several domains also found in Sobp, we did not detect any interaction by co-immunoprecipitation and did not detect any effect on Six1 + Eya1 transcriptional activity in cultured cells. Nonetheless, increasing the level of Zmym2 in embryos resulted in broader expression domains of neural border, neural tube and neural crest genes, and smaller placode gene domains. These results suggest that although Zmym2 is unlikely to be a bone fide Six1 interacting protein, it appears to indirectly antagonize Six1 function during cranial placode development, promoting neural plate and neural crest gene expression
Targeting the Glucose-Insulin Link in Head and Neck Squamous Cell Carcinoma Induces Cytotoxic Oxidative Stress and Inhibits Cancer Growth
No full textUNLABELLED: Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy with limited targeted therapy options and poor patient outcomes. Thus, identifying unique dependencies, including HNSCC-specific metabolic reprogramming, is imperative for improving treatment strategies for this disease. In this study, we show that HNSCC relies on elevated glucose transporter 1 (GLUT1)-mediated glucose uptake to support redox homeostasis and tumor growth. Analyses of GLUT1 expression data in tumors and cancer cell lines reveal significant upregulation of GLUT1 in HNSCC relative to both normal tissue and other cancer subtypes and that high GLUT1 expression correlates with poorer clinical outcomes. Using a basal epithelial layer-specific GLUT1-knockout mouse model, we demonstrate that GLUT1 ablation in HNSCC cells of origin markedly attenuates tumor initiation and progression, implicating the necessity of GLUT1 in HNSCC tumorigenesis. Building on this observation, combining pharmacologic inhibition of GLUT1 with pro-oxidants such as vitamin C and auranofin induces potent cytotoxicity in vitro and in vivo, partly by precipitating oxidative stress. We further observe that insulin signaling is required to sustain glucose uptake and redox homeostasis, as insulin receptor knockdown decreases proliferation and increases reactive oxygen species levels. Together, these results suggest that although GLUT1 overexpression is a key driver of glucose uptake, insulin signaling also contributes to the metabolic and oncogenic pathways underlying HNSCC progression. Consequently, strategies that co-target GLUT1 and insulin signaling to restrict glucose flux may synergize with pro-oxidant therapies, offering a promising therapeutic avenue for HNSCC. SIGNIFICANCE: Enhanced GLUT1 expression and oncogenic insulin signaling drive elevated glucose uptake in HNSCC, which contribute to the maintenance of redox homeostasis and tumor growth. Disrupting both glucose uptake and redox balance may offer a promising therapeutic approach
Academic Service Partnerships: A 21st Century Business Strategy to Integrate Physician Assistant Learners Into a Value-Based Health Care Delivery Model
No full textAlthough there has been a surge in physician assistant (PA) programs in the United States, PA programs have concurrently experienced challenges with partnering with a sufficient pool of clinical training sites. During the long-lived fee-for-service era, many programs have relied on transactional relationships with individual clinicians, hospitals, community health centers, private practices, and other entities to provide the required clinical experiences for PA learners. These arrangements often involved bargaining a supervised clinical experience in exchange for continuing medical education credit or other incentives included in a clinician\u27s benefits package. However, with the recent transformation of the US health care delivery system into a value-based care model, academic service partnerships have emerged as valuable solutions. Academic service partnerships uniquely integrate health professions learners into health systems by providing more sustainable, results-driven clinical experiences that benefit the program, the clinical training site, and the patients
Modeling of Dysferlinopathy (LGMDR2) Progression: A Longitudinal Fat Fraction Analysis
No full textBACKGROUND AND OBJECTIVES: Limb-girdle muscular dystrophy R2 (LGMDR2) is characterized by progressive muscle weakness usually leading to severe disability. The rate of progression and disease severity is variable among patients, although factors influencing this variability are not completely understood. The Dysferlinopathy Clinical Outcome Study is a natural history study that followed patients with LGMDR2 for 3 consecutive years using functional outcome measures and skeletal muscle MRI.The aim of our study was to develop statistical models able to describe fat fraction (FF) progression of the lower limbs in patients with LGMDR2 using clinical and radiologic variables to better understand which factors influence disease progression and improve the design of future clinical trials. METHODS: We used linear-mixed modeling to analyze changes in FF over time according to patients\u27 age. We calculated the average FF trajectory for each muscle of the lower limbs. We built 2 multivariate models for each segment adding other clinical factors and using likelihood ratio test and residuals\u27 analysis to determine whether they better fitted observed FF values. RESULTS: Muscles that participated in the same joint movement progressed similarly over time. FF was expected to be higher the older patients were and the earlier the age at symptom onset. Women had absolute FF values 8.8% higher than men in the lower leg. No differences in FF trajectory were seen based on ethnic groups (White, Asian, Black, or Hispanic), genetic variants, or residual dysferlin expression. Although multivariate models showed a better global fit to the data, there was no improvement in representing individual patient variability. DISCUSSION: In conclusion, this study provides a better understanding of skeletal muscle fat replacement progression in the lower limb muscles of patients with LGMDR2, highlighting the influence of age at symptom onset, sex, and baseline motor function, which should be considered in the design and analysis of clinical trials. Although complex models improved the overall data fit, they did not improve the accuracy in identifying changes at a patient level, underlying the need for further research and validation and the fact that other variables we have not measured are probably influencing progression
Treatments in women experiencing natural menopause: a cohort study from the USA, the UK and Germany
No full textOBJECTIVES: This study aimed to describe treatment patterns among naturally menopausal women from the USA, the UK and Germany. METHODS: Using health claims (the USA) and electronic health records (the UK and Germany), women aged 40-65 years with a first record of natural menopause (index date) from 2009 to 2022 were identified. Women with a history of bilateral oophorectomy, total hysterectomy, endocrine therapy for breast cancer or hormone/non-hormone therapy for menopausal symptoms were excluded. Treatments evaluated following the index date were hormone therapy, benzodiazepines, antidepressants, anticonvulsants and the antihypertensive clonidine. RESULTS: In total, 1,260,742 (the USA), 214,374 (the UK) and 124,542 (Germany) women were included, and treatments were recorded in 38.8%, 33.4% and 28.8%, respectively. Among these, the majority received one treatment class, mostly hormone therapy (44.2% for the USA, 41.1% for the UK, 92.6% for Germany), benzodiazepines (25.3% for the USA, 6.8% for the UK, 2.2% for Germany) and antidepressants (18.6% for the USA, 33.5% for the UK, 4.1% for Germany). Discontinuation rates at 6 months from starting initial treatment were 75.0-88.0% for hormone therapy, 65.0-85.0% for antidepressants and ≥98% for benzodiazepines. Treatment switches occurred in 25.4% (the USA), 21.8% (the UK) and 1.7% (Germany). CONCLUSIONS: Continuation rates with current treatments for women experiencing natural menopausal symptoms are low, indicating an unmet need for effective and acceptable therapies
Strengthening care in collaboration with people with lived experience of psychosis in Uganda (SCAPE-U): A protocol for a cluster randomized controlled feasibility trial
No full textBACKGROUND: Mental health services are most effective and equitable when designed, delivered, and evaluated in collaboration with People With Lived Experience of mental health conditions (PWLE). However, PWLE are rarely involved in health systems strengthening, and when they are, it is limited to specific components (e.g., peer helpers) rather than multi-tiered collaboration in the full continuum of home to community to facility based services. Moreover, programs that do involve PWLE typically involve people with a history of substance use conditions or common mental disorders. The collaboration of People With Lived Experience of Psychosis (PWLP) is especially rare. Therefore, we aim to explore the feasibility of collaborating with PWLP for health systems strengthening in this feasibility trial. METHODS: This pilot cluster randomized controlled feasibility trial will randomize 36 health facilities to a standard implementation arm where primary care workers (PCW) will be trained by mental health specialists (control), or a collaborative care model with added co-facilitation of PCW trainings by PWLP as well as home visits by PWLP to service users (intervention). The intervention condition is referred to as Strengthening CAre in collaboration with People with lived Experience of psychosis in Uganda (SCAPE-U). The 36 health facilities will be distributed across six clusters with three clusters in each arm. PhotoVoice will be used to train PWLP to be co-facilitators of PCW training and provide home-based support to service users in the intervention arm. The primary outcomes of the feasibility trial will be the feasibility, acceptability, and safety of collaborating with PWLP. Data will also be collected on individual-level outcomes for PCWs, and service users to inform the feasibility of data collection and obtain effect size estimates. DISCUSSION: Findings from this feasibility trial will inform a fully powered trial to evaluate the benefits of an implementation strategy characterized by collaboration with PWLP across the continuum of healthcare services. TRIAL REGISTRATION: ClinicalTrials.gov. number: NCT05863572. Date of registration: May 18, 2023. URL of trial registry record: https://clinicaltrials.gov/study/NCT05863572?term=NCT05863572&rank=1
The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors
No full textAngelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive and language impairments, seizures, reduced or fragmented sleep, motor ataxia, and a characteristic happy affect. AS arises due to the neuronal loss of UBE3A, an E3 ligase that regulates protein abundance through the addition of lysine 48 (K48)-linked polyubiquitin chains to proteins targeted for degradation by the ubiquitin proteasome system (UPS). Using a dual SMAD inhibition protocol to derive cortical neurons from human induced pluripotent stem cells, we examined UBE3A deletion effects on the neuronal proteome by liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS identified 645 proteins differentially abundant between UBE3A knockout (KO) and isogenic UBE3A wild-type control cortical neurons. Proteins with increased abundance with UBE3A loss of function include GRIPAP1 and PACSIN1, synaptic proteins implicated in AMPA receptor recycling. We provide evidence UBE3A polyubiquitinates PACSIN1 and GRIPAP1 to regulate protein turnover, with potential implications for impaired activity-dependent synaptic plasticity observed in AS