Designing a Deep Learning-Driven Resource-Efficient Diagnostic System for Metastatic Breast Cancer: Reducing Long Delays of Clinical Diagnosis and Improving Patient Survival in Developing Countries.

Breast cancer is one of the leading causes of cancer mortality. Breast cancer patients in developing countries, especially sub-Saharan Africa, South Asia, and South America, suffer from the highest mortality rate in the world. One crucial factor contributing to the global disparity in mortality rate is long delay of diagnosis due to a severe shortage of trained pathologists, which consequently has led to a large proportion of late-stage presentation at diagnosis. To tackle this critical healthcare disparity, we have developed a deep learning-based diagnosis system for metastatic breast cancer that can achieve high diagnostic accuracy as well as computational efficiency and mobile readiness suitable for an under-resourced environment. We evaluated 4 Convolutional Neural Network (CNN) architectures: MobileNetV2, VGG16, ResNet50 and ResNet101. The MobileNetV2-based diagnostic model outperformed the more complex VGG16, ResNet50 and ResNet101 models in diagnostic accuracy, model generalization, and model training efficiency. The ROC AUC of MobilenetV2 (0.933, 95% CI: 0.930, 0.936) was higher than VGG16 (0.911, 95% CI: 0.908, 0.915), ResNet50 (0.869, 95% CI: 0.866, 0.873), and ResNet101 (0.873, 95% CI: 0.869, 0.876). The time per inference step for the MobileNetV2 model (15 ms/step) was substantially lower than that of VGG16 (48 ms/step), ResNet50 (37 ms/step), and ResNet110 (56 ms/step). The visual comparisons between the model prediction and ground truth have demonstrated that the MobileNetV2 diagnostic models can identify very small cancerous nodes embedded in a large area of normal cells which is challenging for manual image analysis. Equally Important, the light weight MobleNetV2 models were computationally efficient and ready for mobile devices or devices of low computational power. These advances empower the development of a resource-efficient and high performing AI-based metastatic breast cancer diagnostic system that can adapt to under-resourced healthcare facilities in developing countries.

Zebras Among Us: Advocating for the 30 Million Americans Living with Rare Disease.

Nearly 30 million (about 1 in 10) Americans have a rare disease. On average, rare disease patients wait 6 years for an accurate and definitive diagnosis and see as many as 12 specialists along their diagnostic journey. In this brief article, we highlight some of what is being done across patient care, medical education, policy, and innovation in order to improve the diagnostic and treatment journeys of rare disease patients. We hope that members of the medical education community will appreciate this call to action and engage in the rare disease space.

Prospective >12 Months Outcomes After Vocal Fold Injection Medialization With Silk Microparticle-Hyaluronic Acid Material.

OBJECTIVE: Vocal fold injection medialization (VFIM) is widely used as an initial treatment for unilateral vocal fold paralysis (UVFP). Current practices employ materials that share the limitation of temporary clinical effect from variable resorption rates. A novel silk protein microparticle-hyaluronic acid-based material (silk-HA) has demonstrated cellular infiltration and tissue deposition that may portend a durable medialization effect. We report on ≥12 months outcomes after VFIM with silk-HA. METHODS: Prospective open-label study of patients with UVFP that elected treatment with VFIM with silk-HA. Blinded experts rated laryngeal stroboscopic exams. RESULTS: Seventeen patients with UVFP underwent VFIM with silk-HA. Twelve of the 17 patients have ≥12 months follow-up. Seven patients demonstrated durable treatment benefit ≥12 months after injection with median improvement of 19 (p = 0.0156) in VHI-10. There was no significant change in VHI-10 between 1 and 12 months for these patients. Blinded ratings indicated that 5/7 patients with sustained improvements in VHI-10 exhibited complete or touch glottal closure at 12 months. Two of the seven patients exhibited a small (<1 mm) glottal gap at 12 months. Seven patients experienced initial benefit with later regression 3-4 months after injection. CONCLUSION: VFIM with silk-HA can offer durable improvement in voice-related outcomes for UVFP past 12 months. A subset of patients treated with silk-HA experienced early loss of effect around 3-4 months postinjection. Clinical factors predictive of sustained treatment response to silk-HA injection require further exploration. LEVEL OF EVIDENCE: 3 Laryngoscope, 2023.

Thirteen dubious ways to detect conserved structural RNAs.

Covariation induced by compensatory base substitutions in RNA alignments is a great way to deduce conserved RNA structure, in principle. In practice, success depends on many factors, importantly the quality and depth of the alignment and the choice of covariation statistic. Measuring covariation between pairs of aligned positions is easy. However, using covariation to infer evolutionarily conserved RNA structure is complicated by other extraneous sources of covariation such as that resulting from homologous sequences having evolved from a common ancestor. In order to provide evidence of evolutionarily conserved RNA structure, a method to distinguish covariation due to sources other than RNA structure is necessary. Moreover, there are several sorts of artifactually generated covariation signals that can further confound the analysis. Additionally, some covariation signal is difficult to detect due to incomplete comparative data. Here, we investigate and critically discuss the practice of inferring conserved RNA structure by comparative sequence analysis. We provide new methods on how to approach and decide which of the numerous long non-coding RNAs (lncRNAs) have biologically relevant structures.

Needle in the Haystack: Wire Bristle Foreign Body Presenting Deep Within the Tongue Base.

OBJECTIVES: To report a case of ingested wire bristle embedded within the extrinsic musculature of the tongue requiring a transcervical approach for removal and to provide a revised algorithm for the management of ingested wire bristles. METHODS: The clinical record of 1 patient who ingested a grill brush wire bristle was reviewed. A literature review was also conducted to refine a treatment algorithm for managing ingested wire bristles. RESULTS: We present a case of a 53-year-old male who accidentally ingested a grill brush wire bristle. After multiple unsuccessful endoscopic attempts at removal, the wire bristle migrated deep into the extrinsic musculature of the tongue, necessitating a transcervical approach for adequate visualization and retrieval. CONCLUSIONS: This is the first case reported of a wire bristle migrating deep into the tongue musculature that was successfully removed via a transcervical approach. Our proposed algorithm provides a comprehensive approach to the management of ingested wire bristles, specifically in cases where endoscopic retrieval is not feasible.

Platelet-Rich Plasma for Vocal Fold Scar: A Preliminary Report of Concept.

INTRODUCTION: Vocal fold atrophy and scar can lead to loss of normal superficial lamina propria, negatively affecting the vibratory function of the vocal fold. These changes can lead to dysphonia, vocal fatigue, decreased volume, and altered pitch. Treatment options for these conditions are limited. Platelet-rich plasma (PRP) consists of platelets, growth factors, and cytokines derived from the patient's own blood and is believed to activate tissue regeneration. The purpose of this study was to review the technical aspects of collecting PRP and injecting it into the vocal fold injection - based on our initial experience with this procedure. CASE: A patient with vocal fold scar was identified and enrolled in an ongoing prospective clinical trial study of a series of 4 monthly subepithelial vocal fold PRP injections, which was temporarily halted due to the COVID-19 pandemic. Patient underwent a single injection of autologous PRP into the left vocal fold. There were no adverse events during the study period. Subjective improvement in voice was noted at 1 month after injection with subsequent return to baseline over the next 4 months. Videostroboscopy performed on postinjection day 1 and day 7 and demonstrated no concerning exam changes. Compared to the preinjection baseline, the patient-reported voice-handicap index-10 (VHI-10) and voice catastrophization index were similar at 4 months following injection (20 to 20 and 4 to 3, respectively). Independent perceptual analysis of voice showed improvement at 4 months postinjection, compared to baseline consensus auditory-perceptual evaluation of voice 60 to 44. CONCLUSIONS: This preliminary report was part of a prospective trial investigating the use of PRP to treat vocal fold atrophy and scar. This work highlights the technical considerations for injecting PRP into the vocal fold. Planned prospective enrollment in this study will help to validate the safety and efficacy of PRP injections.

Flexible Versus Rigid Laryngoscopy: A Prospective, Blinded Comparison of Image Quality.

OBJECTIVE: To compare flexible distal-chip laryngoscopy (FDL) and rigid telescopic laryngoscopy (RTL) in image quality and diagnostic ability. STUDY DESIGN: Prospective cohort study; blinded comparison. METHODS: Eighteen normal adult subjects were recruited to undergo both FDL and RTL and normalized videos were recorded. Three blinded laryngologists compared the videos for color fidelity, illumination, resolution, and vascularity, and indicated superiority with FDL, RTL, or no difference. Raters also reported if an abnormality was seen and in which video it was better visualized. Videos for two subjects were repeated to assess intra-rater reliability, making 20 video comparisons across 3 raters for a total of 60 ratings. Differences in responses were analyzed via Mann-Whitney U and Pearson Χ2. Inter-rater reliability was assessed via Fleiss' kappa, and intra-rater reliability was assessed via percent agreement. RESULTS: RTL was rated superior in all categories of image quality (47 vs 5 vs 8, P < 0.01; 47 vs 7 vs 6, P < 0.01; 51 vs 5 vs 4, P<0.01; 44 vs 9 vs 7, P < 0.01, respectively). An abnormality was seen 33 times with both modalities and 6 times with RTL only. When seen with both modalities, visualization was superior in RTL compared with FDL (29 vs 4, P <0.01). CONCLUSIONS: There was significant superiority of RTL in all categories of image quality, with slight inter-rater agreement for color fidelity, resolution, and vascularity. RTL was also significantly better for visualization of abnormalities. These findings suggest superior image quality in RTL compared with FDL, but further research is required to determine if this difference is clinically significant.

Recalls of Moderate- and High-Risk Otolaryngologic Devices Approved by the US Food and Drug Administration, 2003-2019.

OBJECTIVE: The US Food and Drug Administration (FDA) regulates the marketing of medical devices based on the premarket approval (PMA) or 510(k) pathway. We investigated the relationship among the regulatory pathway of otolaryngologic devices, the number of recalls, and the recall characteristics. STUDY DESIGN: Retrospective cross-sectional analysis. SETTING: Publicly available FDA databases. METHODS: The FDA Ear, Nose, and Throat Devices Panel database was queried for 510(k) clearances and PMA approvals from 1976 to 2019. Device recalls from 2003 to 2019 were reviewed. Devices were then categorized by subspecialty, type, supporting evidence, and PMA supplement type. Logistic regression characterized the odds of recall for each device type and subspeciality. RESULTS: A total of 1061 (57.8%) 510(k) and 778 (42.3%) PMA device applications and modifications were approved. There were 120 (11.3%) recall events associated with 42 unique otolaryngologic devices cleared via the 510(k) pathway, as compared with 25 (3.2%) recall events for 5 unique PMA devices. 510(k) device approvals were more likely to be recalled than PMA device approvals (odds ratio, 3.67; 95% CI, 2.38-5.88; P < .0001). 510(k) surgical devices (odds ratio, 2.1; 95% CI, 1.1-4.4; P = .03) were more likely to be recalled than diagnostic devices. Devices designated for laryngology (70.0%) and general otolaryngology (25.0%) composed the majority of recalls. CONCLUSION: Otolaryngologic devices approved by the FDA via the 510(k) pathway exhibit a higher number of recalls than the PMA pathway. Given the balance between regulation and facilitating innovation, postmarket surveillance and ongoing regulatory improvements are critical to ensure optimal safety of medical devices.

The crystal structure of vaccinia virus protein E2 and perspectives on the prediction of novel viral protein folds.

The morphogenesis of vaccinia virus (VACV, family Poxviridae), the smallpox vaccine, is a complex process involving multiple distinct cellular membranes and resulting in multiple different forms of infectious virion. Efficient release of enveloped virions, which promote systemic spread of infection within hosts, requires the VACV protein E2 but the molecular basis of E2 function remains unclear and E2 lacks sequence homology to any well-characterised family of proteins. We solved the crystal structure of VACV E2 to 2.3 Å resolution, revealing that it comprises two domains with novel folds: an N-terminal annular (ring) domain and a C-terminal globular (head) domain. The C-terminal head domain displays weak structural homology with cellular (pseudo)kinases but lacks conserved surface residues or kinase features, suggesting that it is not enzymatically active, and possesses a large surface basic patch that might interact with phosphoinositide lipid headgroups. Recent deep learning methods have revolutionised our ability to predict the three-dimensional structures of proteins from primary sequence alone. VACV E2 is an exemplar 'difficult' viral protein target for structure prediction, being comprised of multiple novel domains and lacking sequence homologues outside Poxviridae. AlphaFold2 nonetheless succeeds in predicting the structures of the head and ring domains with high and moderate accuracy, respectively, allowing accurate inference of multiple structural properties. The advent of highly accurate virus structure prediction marks a step-change in structural virology and beckons a new era of structurally-informed molecular virology.

A Novel Approach to Vocal Fold Mucous Retention Cysts: Awake KTP Laser-Assisted Marsupialization.

Vocal fold mucous retention cysts are an important etiology of dysphonia and have classically been treated via microsurgical excision under general anesthesia. We present four cases that were treated with a novel technique of awake potassium-titanyl-phosphate laser-assisted marsupialization under local anesthesia. Reasons for in-office treatment included older age, medical comorbidities, and desire to avoid surgery/general anesthesia. No recurrences were observed and all patients had improved vocal quality, with a mean reduction in Voice Handicap Index-10 of 12.5. Hence, awake potassium-titanyl-phosphate laser treatment exhibits potential as a modality for addressing vocal fold mucous retention cysts in select patients with favorable outcomes.

Pulmonary Function Tests May Better Predict Dyspnea-Severity in Patients with Subglottic Stenosis Compared to Clinician-Reported Stenosis.

OBJECTIVE: Patients with subglottic stenosis (SGS) present with varied degree of breathing complaints. The dyspnea index (DI) is a 10-question patient-reported outcome measure designed to measure the severity of upper airway obstruction. We set out to determine whether pulmonary function tests or clinician-reported degree of stenosis best predicted DI scores. METHODS: Thirty patients with SGS were retrospectively reviewed over a 6-year period. One visit from each patient was included. Data including peak expiratory flow rate (PEFR), body-mass index (BMI), clinician-reported degree of stenosis, and DI scores were reviewed. Multiple linear regression was performed to determine how degree of stenosis and PEFR % predicted the variation in DI score. RESULTS: PEFR % better predicted DI scores compared to degree of stenosis (partial correlation -0.32 vs 0.17). After stepwise elimination, PEFR % remained in the regression and was significantly associated with DI scores (F[1, 29] = 9.38, P = .005). BMI did not demonstrate a linear relationship with DI scores and was not included in the regression (r = -.02). The PEFR % unstandardized coefficient was -0.25 (95% CI: -0.42 to -0.08, P = .005). The model predicts that a 4% increase in the PEFR % results in a 1-point decrease in the DI score (95% CI: -1.68 to -0.32). CONCLUSION: This study suggests that pulmonary function tests may be a better in-office measure to substantiate the severity of symptoms in patients with SGS.

Association of Severe Tongue Edema With Prone Positioning in Patients Intubated for COVID-19.

OBJECTIVES/HYPOTHESIS: Prone positioning is frequently used in patients intubated for COVID-19-related lung injury to improve oxygenation. At our institution, we observed severe tongue edema develop in some of these patients. Hence, we sought to determine the incidence of tongue edema in this cohort and whether prone positioning was a risk factor associated with this complication. STUDY DESIGN: Retrospective cohort study. METHODS: A single-system retrospective cohort study of patients intubated for respiratory failure secondary to COVID-19 who subsequently developed clinically notable tongue edema from March 13 to July 5, 2020. RESULTS: 260 patients were intubated for COVID-19-related respiratory failure during the study period. 158 patients (60.8%) underwent at least one episode of proning. Twelve patients in total (4.6%) developed clinically significant tongue edema. Eleven of the twelve patients (91.7%) who developed tongue edema underwent proning prior to the development of edema. Prone positioning was associated with an increased incidence of tongue edema (odds ratio [OR] 7.56, 95% confidence interval [CI] 0.96-59.46, P = .027). In all proned patients who developed edema, this complication was noted during proning or shortly after supination (range, 0-4 days). Tongue edema was primarily managed with conservative measures; one patient required tracheostomy for definitive management. CONCLUSIONS: Tongue edema appears to develop in a subset of patients with COVID-19 who are intubated. It appears to be associated with prone positioning but is likely multifactorial in nature. Further investigation into its incidence and pathophysiology is warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:287-289, 2022.

Cell type-specific analysis by single-cell profiling identifies a stable mammalian tRNA-mRNA interface and increased translation efficiency in neurons.

The correlation between codon and anticodon pools influences the efficiency of translation, but whether differences exist in these pools across individual cells is unknown. We determined that codon usage and amino acid demand are highly stable across different cell types using available mouse and human single-cell RNA-sequencing atlases. After showing the robustness of ATAC-sequencing measurements for the analysis of tRNA gene usage, we quantified anticodon usage and amino acid supply in both mouse and human single-cell ATAC-seq atlases. We found that tRNA gene usage is overall coordinated across cell types, except in neurons, which clustered separately from other cell types. Integration of these data sets revealed a strong and statistically significant correlation between amino acid supply and demand across almost all cell types. Neurons have an enhanced translation efficiency over other cell types, driven by an increased supply of tRNAAla (AGC) anticodons. This results in faster decoding of the Ala-GCC codon, as determined by cell type-specific ribosome profiling, suggesting that the reduction of tRNAAla (AGC) anticodon pools may be implicated in neurological pathologies. This study, the first such examination of codon usage, anticodon usage, and translation efficiency resolved at the cell-type level with single-cell information, identifies a conserved landscape of translation elongation across mammalian cellular diversity and evolution.

Laryngologists' Reported Decision-Making in Presbyphonia Treatment.

OBJECTIVE: Decision-making regarding behavioral versus procedural intervention in the treatment of presbyphonia has not been well defined. The study objective was to survey laryngologists' reported practice patterns and decision-making in presbyphonia. METHODS: All laryngology faculty in U.S. academic medical centers with residency programs were recruited to complete an anonymous 29-item survey regarding decision-making in presbyphonia treatment. The survey included 5 sections: demographics, first-line treatment distribution, factors that drive decision-making toward procedural intervention, treatment progression if first-line treatment is insufficient, durable treatment. RESULTS: Of 153 laryngologists surveyed, 89 responded (58%). Voice therapy (VT) was the most often reported first-line treatment, with 57% of respondents indicating the majority of their patients receive VT initially. Most respondents (83%) indicated they occasionally use procedural intervention as first-line treatment. Factors driving first-line procedural intervention were severe glottal insufficiency (87%), high occupational/social voice demands (76%), voice not stimulable for change (73%), difficulty attending VT (70%), severe dysphonia (65%), and dysphagia (61%). The majority of respondents indicated the following do not affect their decision to pursue procedural intervention: patient age (88%); medical comorbidities (63%); patient's desire for a "quick fix" (55%); patient-reported outcome measures (51%). Most respondents (81%) use trial injection augmentation before durable treatment. Of durable treatments, bilateral thyroplasty was preferred (71%), followed by CaHA (15%) and lipoinjection (11%). CONCLUSIONS: This study is the first to our knowledge to examine factors that influence decision-making in presbyphonia treatment. While VT remains the most frequent first-line treatment, study results better inform decision-making regarding first-line procedural intervention.

Discovery of 17 conserved structural RNAs in fungi.

Many non-coding RNAs with known functions are structurally conserved: their intramolecular secondary and tertiary interactions are maintained across evolutionary time. Consequently, the presence of conserved structure in multiple sequence alignments can be used to identify candidate functional non-coding RNAs. Here, we present a bioinformatics method that couples iterative homology search with covariation analysis to assess whether a genomic region has evidence of conserved RNA structure. We used this method to examine all unannotated regions of five well-studied fungal genomes (Saccharomyces cerevisiae, Candida albicans, Neurospora crassa, Aspergillus fumigatus, and Schizosaccharomyces pombe). We identified 17 novel structurally conserved non-coding RNA candidates, which include four H/ACA box small nucleolar RNAs, four intergenic RNAs and nine RNA structures located within the introns and untranslated regions (UTRs) of mRNAs. For the two structures in the 3' UTRs of the metabolic genes GLY1 and MET13, we performed experiments that provide evidence against them being eukaryotic riboswitches.

Facial Pressure Injuries from Prone Positioning in the COVID-19 Era.

OBJECTIVE/HYPOTHESIS: This study aimed to determine the incidence of facial pressure injuries associated with prone positioning for COVID-19 patients as well as to characterize the location of injuries and treatments provided. METHODS: This was a retrospective chart review of 263 COVID-19 positive patients requiring intubation in the intensive care units at MedStar Georgetown University Hospital and MedStar Washington Hospital Center between March 1st and July 26th, 2020. Information regarding proning status, duration of proning, presence, or absence of facial pressure injuries and interventions were collected. Paired two-tailed t-test was used to evaluate differences between proned patients who developed pressure injuries with those who did not. RESULTS: Overall, 143 COVID-19 positive patients required proning while intubated with the average duration of proning being 5.15 days. Of those proned, 68 (47.6%) developed a facial pressure injury. The most common site involved was the cheek with a total of 57 (84%) followed by ears (50%). The average duration of proning for patients who developed a pressure injury was significantly longer when compared to those who did not develop pressure injuries (6.79 days vs. 3.64 days, P < .001). CONCLUSIONS: Facial pressure injuries occur with high incidence in patients with COVID-19 who undergo prone positioning. Longer duration of proning appears to confer greater risk for developing these pressure injuries. Hence, improved preventative measures and early interventions are needed. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2139-E2142, 2021.

Idiopathic Ulcerative Laryngitis: A National Survey of Academic Laryngologists.

OBJECTIVES: Idiopathic ulcerative laryngitis (IUL) is a rare disorder characterized by ulceration in the mid-membranous portions of the vocal folds. The etiology and optimal management of this condition are poorly understood. We aimed to survey laryngologists on their experiences with managing IUL in order to better understand the diagnosis and treatment of this unusual condition. METHODS: An online survey was sent to 149 laryngologists practicing at academic institutions in the United States. Survey questions assessed respondents' professional backgrounds and clinical experiences with IUL. Individual responses were tallied and calculated as percentages of total responses. RESULTS: A total of 96 out of 149 academic laryngologists completed the survey, leading to an overall response rate of 64.4%. All respondents reported that they had encountered IUL in practice, including 56.3% who reported having seen 1-10 cases, 22.9% reporting 11-20 cases, and 20.8% reporting greater than 20 cases over their careers. Dysphonia (99.0%) and cough (84.4%) were the two co-occurring primary presenting symptoms reported. Most base diagnosis on laryngeal videostroboscopy (93.8%). Fungal/bacterial cultures and operative biopsy had been performed by approximately 30% of respondents with occasional candidiasis reported but otherwise negative or nonspecific results. Common therapies used were empiric: antireflux therapy (91.7%), modified voice rest (91.7%), and oral steroids (80.2%). Among survey respondents with experience managing more than 10 cases of IUL, many found complete voice rest (60.0%), oral steroids (55.9%), behavioral cough suppression (46.7%), and modified voice rest (46.3%) to be at least moderately effective treatment options. Resolution of symptoms was most commonly reported to occur over the course of 1-3 months (59.4%) and recurrences were seen not very often or never (85.4%). However, permanent sequelae were common, including vocal fold stiffness (89.6%) and dysphonia (81.3%). CONCLUSIONS: IUL is a rare disorder of unknown etiology. Diagnosis is typically made with laryngeal videostroboscopy and spontaneous resolution occurs over 1-3 months. Laryngologists commonly treat empirically with antireflux therapy, voice rest, antimicrobials, and oral steroids. While no empiric treatment appears to be highly effective for the management of IUL, complete or modified voice rest, oral steroids, and behavioral cough suppression may be the most effective of the currently available options. Further research is necessary to improve the understanding and optimal management of IUL.