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1.
Cereb Cortex ; 34(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38940832

RESUMO

Nonpainful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging studies have highlighted the value of whole-brain, systems-level investigation for examining sensory processing. However, whole-brain functional magnetic resonance imaging studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high-resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo functional magnetic resonance imaging acquisition at 3T with multi-echo independent component analysis denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to nonpainful brushing of the right hand, left hand, and right foot (n = 10 per location), and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we differentiated the adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.


Assuntos
Mapeamento Encefálico , Tronco Encefálico , Imageamento por Ressonância Magnética , Humanos , Tronco Encefálico/fisiologia , Tronco Encefálico/diagnóstico por imagem , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Adulto , Mapeamento Encefálico/métodos , Adulto Jovem , Córtex Cerebral/fisiologia , Córtex Cerebral/diagnóstico por imagem , Percepção do Tato/fisiologia , Estimulação Física , Mãos/fisiologia
2.
Clin Infect Dis ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690892

RESUMO

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

3.
bioRxiv ; 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38659741

RESUMO

Non-painful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging (fMRI) studies have highlighted the value of whole-brain, systems-level investigation for examining pain processing. However, whole-brain fMRI studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, the differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo fMRI acquisition at 3T with multi-echo independent component analysis (ME-ICA) denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to non-painful brushing of the right hand, left hand, and right foot, and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we were able to differentiate the small, adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.

4.
Appl Nurs Res ; 76: 151784, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38641381

RESUMO

OBJECTIVES: Analyze and verify the association between working conditions and the occurrence of errors in nursing work. BACKGROUND: Many of the known errors in nursing are based on the structural failure of the complex health service system. Our study addresses the question "Is there an association between errors made by nursing workers and working conditions?" METHODS: The study was carried out through a cross-sectional exploratory analysis of 19 ethical-disciplinary processes focused on errors made by nursing workers. The articles were processed, judged, and archived at the Regional Nursing Councils of the Northeast Region of Brazil from 2000 to 2018. The chi-square test or Fisher's exact test was used to verify the relationship between the variables through multivariate analysis. RESULTS: The analyzes show that working conditions can interfere at occurrence in error. This increases the chance of an "inconsequential" error occurring for the patient in poor/very poor working conditions. The most serious errors, "with consequences irreversible" for the patient, only occur from more severe working conditions. Adversely, it was found that there is no statistically significant difference in the frequency of errors in hospitals (33.33 %) compared to "other places" (28.58 %) when these occurred in poor working conditions. When conducting the incident in poor working conditions, there was a minimum of 52 % protection OR = 0.48 % [0.16; 11.80]; (1-0.48)) against these errors in general in the nursing area. CONCLUSION: The strong association was exposed in working conditions classified as bad/very bad/very bad, resulting in the most serious errors and with irreversible consequences for patients. However, a level of protection for different types of workers was noticed in the field, which shows that there is hope that if the work environment changes with more organization, management, and standards of care, we can prevent future errors.


Assuntos
Recursos Humanos de Enfermagem Hospitalar , Condições de Trabalho , Humanos , Brasil , Estudos Transversais
5.
Int J Drug Policy ; 125: 104322, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38245914

RESUMO

OBJECTIVE: Examine differences in neighborhood characteristics and services between overdose hotspot and non-hotspot neighborhoods and identify neighborhood-level population factors associated with increased overdose incidence. METHODS: We conducted a population-based retrospective analysis of Rhode Island, USA residents who had a fatal or non-fatal overdose from 2016 to 2020 using an environmental scan and data from Rhode Island emergency medical services, State Unintentional Drug Overdose Reporting System, and the American Community Survey. We conducted a spatial scan via SaTScan to identify non-fatal and fatal overdose hotspots and compared the characteristics of hotspot and non-hotspot neighborhoods. We identified associations between census block group-level characteristics using a Besag-York-Mollié model specification with a conditional autoregressive spatial random effect. RESULTS: We identified 7 non-fatal and 3 fatal overdose hotspots in Rhode Island during the study period. Hotspot neighborhoods had higher proportions of Black and Latino/a residents, renter-occupied housing, vacant housing, unemployment, and cost-burdened households. A higher proportion of hotspot neighborhoods had a religious organization, a health center, or a police station. Non-fatal overdose risk increased in a dose responsive manner with increasing proportions of residents living in poverty. There was increased relative risk of non-fatal and fatal overdoses in neighborhoods with crowded housing above the mean (RR 1.19 [95 % CI 1.05, 1.34]; RR 1.21 [95 % CI 1.18, 1.38], respectively). CONCLUSION: Neighborhoods with increased prevalence of housing instability and poverty are at highest risk of overdose. The high availability of social services in overdose hotspots presents an opportunity to work with established organizations to prevent overdose deaths.


Assuntos
Overdose de Drogas , Overdose de Opiáceos , Humanos , Overdose de Opiáceos/epidemiologia , Overdose de Opiáceos/prevenção & controle , Overdose de Opiáceos/tratamento farmacológico , Estudos Retrospectivos , Rhode Island/epidemiologia , Overdose de Drogas/epidemiologia , Overdose de Drogas/prevenção & controle , Overdose de Drogas/tratamento farmacológico , Análise Espacial , Analgésicos Opioides
6.
Laryngoscope ; 134(1): 264-271, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37522475

RESUMO

OBJECTIVES: Despite gross anatomic and histologic differences between human and canine vocal folds, similar wave patterns have been described yet not fully characterized. We reconstructed vocal fold (VF) vibration in a canine hemilarynx and performed histologic examination of the same vocal fold. We demonstrate comparable wave patterns while exploring the importance of certain anatomic architectures. METHODS: An in vivo canine hemilarynx was phonated against a glass prism at low and high muscle activation conditions. Vibration was captured using high-speed video, and trajectories of VF medial surface tattooed landmarks were 3D-reconstructed. The method of empirical eigenfunctions was used to capture the essential dynamics of vibratory movement. Histologic examination of the hemilarynx was performed. RESULTS: Oscillation patterns were highly similar between the in vivo canine and previous reports of ex vivo human models. The two most dominant eigenfunctions comprised over 90% of total variance of movement, representing opening/closing and convergent/divergent movement patterns, respectively. We demonstrate a vertical phase difference during the glottal cycle. The time delay between the inferior and superior VF was greater during opening than closing for both activation conditions. Histological examination of canine VF showed not only a thicker lamina propria layer superiorly but also a distinct pattern of thyroarytenoid muscle fibers and fascicles as described in human studies. CONCLUSIONS: Histologic and vibratory examination of the canine vocal fold demonstrated human vocal fold vibratory patterns despite certain microstructural differences. This study suggests that the multilayered lamina propria may not be fundamental to vibratory patterns necessary for human-like voice production. LEVEL OF EVIDENCE: NA (Basic science study) Laryngoscope, 134:264-271, 2024.


Assuntos
Vibração , Prega Vocal , Animais , Cães , Humanos , Prega Vocal/fisiologia , Fonação/fisiologia , Glote/fisiologia , Mucosa Laríngea
7.
Laryngoscope ; 134(2): 764-772, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37597170

RESUMO

OBJECTIVE: Numerous pharmacological and cell-based treatments have shown promise in preventing vocal fold (VF) scarring when applied at the time of injury. A common clinical scenario, however, is the finding of mature scar impeding voicing. Many treatments are less effective in remodeling existing scar tissue. This objective of this study is to determine if a cell-based outer vocal fold replacement (COVR) effectively restores VF function when applied to existing scar. METHODS: Eighteen rabbits were allocated to three groups: unilateral COVR implant at the time of cordectomy (acute COVR); unilateral cordectomy followed by COVR implant 2 months later (chronic COVR); and unilateral cordectomy followed by sham implant surgery 2 months later (chronic scar). Larynges were harvested 2 months after implant or sham surgery. RESULTS: All larynges in the COVR groups demonstrated human leukocyte antigen labeling on immunohistochemistry (IHC). COVR groups had increased hyaluronic acid content compared with normal. VF stiffness as measured by elastic moduli in acute COVR and chronic COVR were similar to their contralateral unoperated VF. CONCLUSION: COVR implantation in both acutely injured and chronically scarred VF demonstrate persistence of implanted cells, restored tissue biomechanics, and increased hyaluronic acid content. LEVEL OF EVIDENCE: NA Laryngoscope, 134:764-772, 2024.


Assuntos
Cicatriz , Prega Vocal , Animais , Coelhos , Humanos , Cicatriz/prevenção & controle , Cicatriz/cirurgia , Cicatriz/patologia , Prega Vocal/patologia , Ácido Hialurônico/farmacologia
8.
Laryngoscope ; 134(3): 1327-1332, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37676064

RESUMO

INTRODUCTION: Asymmetry of vocal fold (VF) vibration is common in patients with voice complaints and also observed in 10% of normophonic individuals. Although thyroarytenoid (TA) muscle activation plays a crucial role in regulating VF vibration, how TA activation asymmetry relates to voice acoustics and perception is unclear. We evaluated the relationship between TA activation asymmetry and the resulting acoustics and perception. METHODS: An in vivo canine model of phonation was used to create symmetric and increasingly asymmetric VF vibratory conditions via graded stimulation of bilateral TA muscles. Naïve listeners (n = 89) rated the perceptual quality of 100 unique voice samples using a visual sort-and-rate task. For each phonatory condition, cepstral peak prominence (CPP), harmonic amplitude (H1-H2), and root-mean-square (RMS) energy of the voice were measured. The relationships between these metrics, vibratory asymmetry, and perceptual ratings were evaluated. RESULTS: Increasing levels of TA asymmetry resulted in declining listener preference. Furthermore, only severely asymmetric audio samples were perceptually distinguishable from symmetric and mildly asymmetric conditions. CPP was negatively correlated with TA asymmetry: voices produced with larger degrees of asymmetry were associated with lower CPP values. Listeners preferred audio samples with higher values of CPP, high RMS energy, and lower H1-H2 (less breathy). CONCLUSION: Listeners are sensitive to changes in voice acoustics related to vibratory asymmetry. Although increasing vibratory asymmetry is correlated with decreased perceptual ratings, mild asymmetries are perceptually tolerated. This study contributes to our understanding of voice production and quality by identifying perceptually salient and clinically meaningful asymmetry. LEVEL OF EVIDENCE: N/A (Basic Science Study) Laryngoscope, 134:1327-1332, 2024.


Assuntos
Disfonia , Voz , Humanos , Animais , Cães , Vibração , Acústica da Fala , Voz/fisiologia , Fonação/fisiologia , Acústica , Percepção
9.
J Clin Transl Sci ; 7(1): e242, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38033705

RESUMO

The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT's are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.

10.
Laryngoscope Investig Otolaryngol ; 8(4): 886-894, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37621286

RESUMO

Objective: Patients with advanced laryngeal cancer are typically presented with divergent treatment options, namely chemoradiation versus total laryngectomy. This study aims to understand general perspectives of the factors involved in this decision-making process. Methods: Surveys were constructed using specialized conjoint analysis software. Seven attributes integral to the decision-making process for advanced laryngeal cancer treatment were included. Results: Three hundred one healthy adult volunteers completed the decision-making program. The relative impact of each treatment attribute on decision making across all participants was scored with an average importance score (standard deviation) as follows: Lifespan 22.2% (±8.5), Voicing 21.4% (±5.9), Swallowing 19.1% (±7.3), Cancer Cure 14.9% (±6.2), Mode of Breathing 11.0% (±3.7), Self-Image 6.7% (±2.9), and Treatment Type 4.8% (±3.0). Conclusions: General public opinion ranked lifespan, voicing, and swallowing aspects as similarly important, and all were ranked more important than probability of cure. These data demonstrate a variety of priorities among participants and the need for tailored discussions when determining treatment choice for advanced laryngeal cancer. Level of Evidence: Level 4.

12.
bioRxiv ; 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37503125

RESUMO

Motor-task functional magnetic resonance imaging (fMRI) is crucial in the study of several clinical conditions, including stroke and Parkinson's disease. However, motor-task fMRI is complicated by task-correlated head motion, which can be magnified in clinical populations and confounds motor activation results. One method that may mitigate this issue is multi-echo independent component analysis (ME-ICA), which has been shown to separate the effects of head motion from the desired BOLD signal but has not been tested in motor-task datasets with high amounts of motion. In this study, we collected an fMRI dataset from a healthy population who performed a hand grasp task with and without task-correlated amplified head motion to simulate a motor-impaired population. We analyzed these data using three models: single-echo (SE), multi-echo optimally combined (ME-OC), and ME-ICA. We compared the models' performance in mitigating the effects of head motion on the subject level and group level. On the subject level, ME-ICA better dissociated the effects of head motion from the BOLD signal and reduced noise. Both ME models led to increased t-statistics in brain motor regions. In scans with high levels of motion, ME-ICA additionally mitigated artifacts and increased stability of beta coefficient estimates, compared to SE. On the group level, all three models produced activation clusters in expected motor areas in scans with both low and high motion, indicating that group-level averaging may also sufficiently resolve motion artifacts that vary by subject. These findings demonstrate that ME-ICA is a useful tool for subject-level analysis of motor-task data with high levels of task-correlated head motion. The improvements afforded by ME-ICA are critical to improve reliability of subject-level activation maps for clinical populations in which group-level analysis may not be feasible or appropriate, for example in a chronic stroke cohort with varying stroke location and degree of tissue damage.

13.
PLoS One ; 18(7): e0278357, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37450553

RESUMO

BACKGROUND AND AIM: The Telangana cancer care program is a proactive, comprehensive initiative encompassing infrastructure development, human resource skilling and ensuring financial protection to those below poverty line. The broad aim of this exercise was to identify modalities to augment the Telangana State Cancer Control Plan to implement a sustainable comprehensive cancer care model for Telangana. METHODS: We conducted in-depth interviews of stakeholders (17 patients and 25 health care providers) to identify barriers and challenges to access existing cancer care system in Telangana; calculated the magnitude of cancer and commensurate workload (in terms of visits to tertiary cancer care system for cancer management and human and equipment requirement) for the next 15 years (from 2022 to 2037). Using the anecdotal evidence and information from stakeholders' interviews, we developed patient-journey funnels for oral, breast, and cervical cancer patients to highlight patient leakages at various levels of cancer care. RESULTS: We estimated a 13%, 28%, and 44.7% increase in the number of new cancer cases and the resultant workload (number of visits to health care centre, chemotherapy sessions, radiotherapy sessions, surgeries, specialized human resources and equipment), for the year 2027, 2032, and 2037, respectively, compared to the year 2022. The stakeholders mentioned 'delayed access' to healthcare system as the main reason for the poor prognosis of patients. The common reasons cited for 'delayed access' were: poor cancer-literacy including prevailing myths and misconception, financial barriers, and rural residence. The patient journey funnel for cancer care revealed a major leakage from 'screened-positive' to 'diagnosis confirmation' step. The estimated patient leakage varied from ~70% to 90% from 'screened-positive' till 'treatment completion'. CONCLUSION: In this study, we anticipated a steady increase in the number of new cancers cases and resultant workload for the state of Telangana from the year 2022 to 2037. This may further be accompanied with limited access or utilization of cancer care system. To manage this public health issue, government should take appropriate measures to improve cancer literacy at the community level as well as increase human resources and necessary equipment.


Assuntos
Atenção à Saúde , Neoplasias do Colo do Útero , Feminino , Humanos , Pessoal de Saúde , Instalações de Saúde
14.
Sci Rep ; 13(1): 10705, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37400470

RESUMO

In laryngeal research, studying the vertical vocal fold oscillation component is often disregarded. However, vocal fold oscillation by its nature is a three-dimensional process. In the past, we have developed an in-vivo experimental protocol to reconstruct the full, three-dimensional vocal fold vibration. The goal of this study is to validate this 3D reconstruction method. We present an in-vivo canine hemilarynx setup using high-speed video recording and a right-angle prism for 3D reconstruction of vocal fold medial surface vibrations. The 3D surface is reconstructed from the split image provided by the prism. For validation, reconstruction error was calculated for objects located at a distance of up to 15 mm away from the prism. The influence of camera angle, changing calibrated volume, and calibration errors were determined. Overall average 3D reconstruction error is low and does not exceed 0.12 mm at 5 mm distance from the prism. Influence of a moderate (5°) and large (10°) deviation in camera angle led to a slight increase in error to 0.16 mm and 0.17 mm, respectively. This procedure is robust towards changes in calibration volume and small calibration errors. This makes this 3D reconstruction approach a useful tool for the reconstruction of accessible and moving tissue surfaces.


Assuntos
Laringe , Prega Vocal , Animais , Cães , Imageamento Tridimensional/métodos , Gravação em Vídeo/métodos , Vibração
15.
medRxiv ; 2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37333243

RESUMO

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

16.
J Clin Transl Sci ; 7(1): e90, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37125061

RESUMO

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies.

17.
NPJ Precis Oncol ; 7(1): 47, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37231247

RESUMO

The identification of BRAF V600 mutation in multiple cancers beyond melanoma and the development of combined BRAF and MEK targeting agents have altered the landscape of tissue-agnostic precision oncology therapies with an impact on survival outcomes. Despite initial efficacy, resistance emerges, and it is pertinent to identify putative resistance mechanisms. We report a case of recurrent glioblastoma (GBM) harboring BRAF V600E alteration who initially responded to combined BRAF + MEK inhibition and subsequently developed treatment resistance by histological transformation to gliosarcoma and acquisition of oncogenic KRAS G12D and an NF1 L1083R mutation. This documented case represents an initial evidence of a developing phenomenon in cancer research as it provides the first evidence of an emergent KRAS G12D/NF1 L1083R aberration with histological transformation occurring concurrently with primary BRAF V600E-altered glioblastoma as a previously unrecognized acquired mechanism of resistance in the setting of combined BRAF and MEK inhibition. This novel finding not only sheds new light on the RAS/MAPK pathway but also highlights the potential for morphological transformation to gliosarcoma, underscoring the critical need for further investigation in this area.

18.
Cancer ; 129(11): 1634-1642, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36946766

RESUMO

The advent of precision medicine has changed the landscape of oncologic biomarkers, drug discovery, drug development, and, more importantly, outcomes for patients with cancer. Precision oncology entails the genomic profiling of tumors to detect actionable aberrations. The advances in clinical next-generation sequencing from both tumor tissue and liquid biopsy and availability of targeted therapies has rapidly entered mainstream clinical practice. In this review, recent major developments in precision oncology that have affected outcomes for patients with cancer are discussed. Rapid clinical development was seen of targeted agents across various mutational profiles such as KRASG12C (which was considered "undruggable" for almost 4 decades), Exon 20 insertions, and RET mutations. Approaches to precision chemotherapy delivery by the introduction of antibody drug conjugates in the armamentarium against lung cancer has been appreciated.


Assuntos
Neoplasias Pulmonares , Medicina de Precisão , Humanos , Terapia de Alvo Molecular , Biomarcadores Tumorais/genética , Oncologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação
19.
Otolaryngol Head Neck Surg ; 169(2): 317-324, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36939459

RESUMO

OBJECTIVE: Partial epiglottidectomy has a role in improving dysphagia due to epiglottic obstruction. This study evaluates objective parameters of swallow function in patients who underwent partial epiglottidectomy. STUDY DESIGN: Retrospective study design. SETTING: Tertiary Care University Academic Medical Center. METHODS: A review was performed of patients who underwent CO2 laser partial epiglottidectomy for the treatment of dysphagia at a single tertiary care academic center over a 4-year period. Objective swallowing parameters were evaluated from pre- and postoperative modified barium swallow studies using SwallowTail Advanced Measurement software using blinded reviewers. The postswallow pharyngeal residue (bolus clearance ratio or BCR), spatiotemporal swallowing variables (oropharyngeal [OPT], hypopharyngeal [HPT], and total pharyngeal transit times [TPT]), and airway protection (Penetration-Aspiration Scale [PAS]) were analyzed. Student paired t test was used to determine significant changes in outcome parameters pre- and postsurgery. RESULTS: Forty-three patients (age range 45-92 years, median 70) met the inclusion criteria. A majority (69.8%) had a history of external beam radiation therapy for head and neck cancer. BCR decreased significantly from a mean of 31.7% presurgery to 24.2% (p = .01) postsurgery. OPT, HPT, and TPT did not differ significantly postsurgery. The mean Eating Assessment Tool-10 score improved from 25.1 to 20.2 after treatment (p = .03). PAS score improved by 15.4% and remained stable at 66.2% after surgery. CONCLUSION: Partial epiglottidectomy improves pharyngeal bolus clearance in properly selected patients with dysphagia due to epiglottic obstruction. Patients demonstrated stable swallow function with the benefit of reduced postswallow residue following surgical intervention.


Assuntos
Transtornos de Deglutição , Neoplasias de Cabeça e Pescoço , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/cirurgia , Deglutição , Estudos Retrospectivos , Epiglote/cirurgia , Fluoroscopia
20.
Laryngoscope ; 133(2): 357-365, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35633189

RESUMO

INTRODUCTION: Although phonatory glottal posture and airflow pulse shape affect voice quality, studies to date have been limited by visualization of vocal fold (VF) vibration from a superior view. We performed a 3D reconstruction of VF vibratory motion during phonation from a medial view and assessed the glottal volume waveform and resulting acoustics as a function of neuromuscular stimulation. STUDY DESIGN: In vivo canine hemilarynx phonation. METHODS: Across 121 unique combinations of the superior laryngeal nerve (SLN) and recurrent laryngeal nerve (RLN) stimulation, the hemilarynx was excited to the oscillation with airflow. VF medial surface reference points were tracked on high-speed video, mapped into 3D space, and surface shape was restored using cubic spline interpolation. Glottal surface shape, reconstruction-based parameters, and glottal volume waveform were calculated. Fundamental frequency (F0), cepstral peak prominence (CPP), and harmonic amplitude (H1-H2) were measured from high-quality audio samples. RESULTS: The glottis was convergent during opening and divergent during closing. Neuromuscular activation changed phonatory glottal shape and reduced glottal volume. Significant reduction in glottal volume and closing quotient were present with SLN stimulation. RLN stimulation significantly increased F0 and CPP and decreased H1-H2 (constricted glottis), while SLN effects were similar and synergistic with concurrent RLN stimulation. CONCLUSION: 3D reconstruction of in vivo medial surface vibration revealed effects of laryngeal nerve stimulation on glottal vibratory pattern and acoustic correlates of voice quality. SLN activation resulted in significantly quicker glottal closure per cycle, decreased glottal volume, and higher-pitched, less breathy, and less noisy voice. RLN had a similar effect on acoustic measures. LEVEL OF EVIDENCE: NA, Basic Science Laryngoscope, 133:357-365, 2023.


Assuntos
Glote , Imageamento Tridimensional , Animais , Cães , Glote/fisiologia , Prega Vocal/fisiologia , Fonação/fisiologia , Qualidade da Voz , Vibração
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