How Do Patients and Otolaryngologists Define Dizziness?

OBJECTIVE: To assess for differences in how patients and otolaryngologists define the term dizziness. METHODS: Between June 2020 and December 2022, otolaryngology clinicians and consecutive patients at 5 academic otolaryngology institutions across the United States were asked to define the term "dizziness" by completing a semantics-based questionnaire containing 20 common descriptors of the term within 5 symptom domains (imbalance-related, lightheadedness-related, motion-related, vision-related, and pain-related). The primary outcome was differences between patient and clinician perceptions of dizzy-related symptoms. Secondary outcomes included differences among patient populations by geographic location. RESULTS: Responses were obtained from 271 patients and 31 otolaryngologists. Patients and otolaryngologists selected 7.7 ± 3.5 and 7.1 ± 4.3 symptoms, respectively. Most patients (266, 98.2%) selected from more than 1 domain and 17 (6.3%) patients identified symptoms from all 5 domains. Patients and clinicians were equally likely to define dizziness using terms from the imbalance (difference, -2.3%; 95% CI, -13.2%, 8.6%), lightheadedness (-14.1%; -29.2%, 1.0%), and motion-related (9.4; -0.3, 19.1) domains. Patients were more likely to include terms from the vision-related (23.6%; 10.5, 36.8) and pain-related (18.2%; 10.3%, 26.1%) domains. There were minor variations in how patients defined dizziness based on geographic location. CONCLUSIONS: Patients and otolaryngologists commonly described dizziness using symptoms related to imbalance, lightheadedness, and motion. Patients were more likely to use vision or pain-related terms. Understanding of these semantic differences may enable more effective patient-clinician communication.

Multimodal prehabilitation program in patients with resectable perihilar cholangiocarcinoma: keypoints for an implementation protocol and literature review.

BACKGROUND: Postoperative complications after perihilar cholangiocarcinoma surgical procedure are still very high. The implementation of a multimodal prehabilitation program could improve these outcomes. Based on our experience and that of the literature in hepatobiliary and pancreatic surgery, we propose a protocol to promote its implementation. METHODS: First, we performed a retrospective analysis of the implementation feasibility of a multimodal prehabilitation program in patients' candidates for elective perihilar cholangiocarcinoma surgery in our center. Second, we conducted a literature search of publications in PubMed until December 2022. Relevant data about hepato-pancreato-biliary surgery and prehabilitation programs in features and postoperative outcomes was analyzed. RESULTS: Since October 2020, 11 patients were evaluated for prehabilitation in our hospital. Two of them could not be resected intraoperatively due to disease extension. The median hospital stay was 10 days (iqr, 7-11). There were no major complications and 1 patient died. Of a total of 17 articles related to prehabilitation in hepato-biliary-pancreatic surgery, no reports focusing exclusively on perihilar cholangiocarcinoma were found. Six of the studies had nutritional therapies in addition to physical interventions, and 12 studies used home-based exercise therapy. CONCLUSIONS: Based on our experience and the data obtained from other studies, a prehabilitation program could be useful to improve perioperative physical and mental fitness in patients' candidates for elective perihilar cholangiocarcinoma surgery. However, more well-designed studies are needed to allow us to obtain more evidence.

Are you congested? A comparison of definitions between otolaryngologists and their patients.

OBJECTIVE: To assess for differences of intended meaning in the description of congestion-related symptoms among otolaryngology patients and clinicians. MATERIALS AND METHODS: Between June 2020 and October 2022, a questionnaire consisting of 16 common descriptors of congestion-related symptoms within four domains (obstructive-related, pressure-related, mucus-related, and other symptoms) was completed by patients and otolaryngologists at five tertiary otolaryngology practices. The primary outcome was to assess differences in patient and clinician perceptions of congestion-related symptoms. Differences based on geographic location was a secondary outcome. RESULTS: A total of 349 patients and 40 otolaryngologists participated. Patients selected a median of 6.8 (standard deviation [SD] 3.0) terms compared with 4.0 (SD 1.6) terms for otolaryngologists (p < 0.001). Otolaryngologists were more likely to select obstruction-related symptoms (difference 6.3%; 95% confidence interval [CI] 3.8%, 8.9%). Patients were more likely to describe congestion using pressure-related (-43.7%; -58.9%, -28.5%), mucus-related (-43.5%; -59.3%, -27.8%), and other symptoms (-44.2; -51.3%, -37.1%) compared with otolaryngologists. There were no significant differences identified based on geographic location with regard to symptom domains on multivariate analysis. CONCLUSIONS: There are differences between otolaryngologists and their patients in the interpretation of the symptoms of congestion. Clinicians tended to have a narrower interpretation of congestion that was limited to the obstruction-related symptom domain, while patients defined congestion more broadly. This has important counseling and communication implications for the clinician.

miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton's tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. The molecular actions of miR-28 and ibrutinib synergistically impair DNA replication by simultaneous inhibition of origin activation and fork progression. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.

Layperson Perception of Reflux-Related Symptoms.

Objective: To assess for differences of intended meaning in the description of reflux-related symptoms among otolaryngology patients and clinicians. Study Design: Cross-sectional survey-based study. Setting: Five tertiary, academic otolaryngology practices. Methods: Between June 2020 and July 2022, a questionnaire consisting of 20 common descriptors of reflux-related symptoms within four domains (throat-, chest-, stomach-, and sensory-related symptoms) was completed by patients. Attending otolaryngologists at five academic medical centers then completed the same survey. The primary outcome was to assess differences in patient and clinician perceptions of reflux-related symptoms. Differences based on geographic location was a secondary outcome. Results: A total of 324 patients and 27 otolaryngologists participated. Patients selected a median of six terms compared with 10.5 for otolaryngologists (p < .001). Otolaryngologists were more likely to select sensory symptoms (difference: 35.8%; 95% confidence interval [CI]: 19.2%, 52.4%), throat-related symptoms (32.4%; 21.2, 43.6%), and chest-related symptoms (12.4%; 8.8, 15.9). Otolaryngologists and patients were equally likely to consider stomach symptoms as related to reflux (4.0%, -3.7%, 11.7%). No significant differences were identified based on geographic location. Conclusion: There are differences between otolaryngologists and their patients in the interpretation of the symptoms of reflux. Patients tended to have a narrower interpretation of reflux with symptoms primarily limited to classic stomach-related symptoms, while clinicians tended to have a broader definition of reflux that included extra-esophageal manifestations of disease. This has important counseling implications for the clinician, as patients presenting with reflux symptoms may not comprehend the relationship of those symptoms to reflux disease.

Layperson Perception of Symptoms Caused by the Sinuses.

OBJECTIVE: To assess the perceived symptoms caused by the sinuses as defined by otolaryngology patients and clinicians. STUDY DESIGN: Multi-institutional cross-sectional study. SETTING: Six academic outpatient otolaryngology practices. METHODS: We performed a multi-institutional, cross-sectional study using a semantics-based questionnaire. Consecutive patients were enrolled at 6 academic otolaryngology centers from June 2020 to May 2021. The primary outcome examined patient and provider definitions for the symptoms caused by the sinuses from a list of 28 proposed terms covering 6 general categories. These data were also collected from otolaryngology faculty at the same institutions. RESULTS: Responses were obtained from 451 patients (54% female, mean age 48.3 years) and 29 otolaryngologists (38% female, mean age 37.4 years). Patients selected a median of 12 terms, compared to 8.5 for otolaryngologists. Among patients, the most frequently selected symptom domains were mucus (419, 92.9%), airflow (412, 91.4%), and pain (389, 86.3%). Compared to clinicians, patients more frequently selected symptoms related to the ear (difference, 48.3%; 95% confidence interval [CI], 34.8%-59.3%), throat (difference, 35.7%, 95% CI, 22.0%-47.5%), systemic (difference, 34.4%, 95% CI, 21.2%-46.0%), mucus (difference, 20.5%, 95% CI, 10.2%-30.6%), and airflow domains (difference, 19.0%, 95% CI, 8.4%-29.3%). Multiple domains were selected by 98% of patients and 79% of providers. CONCLUSION: Semantic differences exist between patients and clinicians regarding the symptoms caused by the sinus with patients having a broader range of perceived symptoms. These differences may provide clues to improve communication between otolaryngologists and their patients.

Symptom Localization May Differentiate Subtypes of Eustachian Tube Dysfunction.

OBJECTIVE: To evaluate the predictive ability of symptom self-localization to distinguish obstructive eustachian tube dysfunction from non-obstructive salpingitis. METHODS: Adult (age ≥18 years) patients with a primary complaint of aural discomfort who underwent diagnostic nasal endoscopy and tympanometry at a tertiary academic center were enrolled. Symptoms were self-localized by using a single finger on the affected side. All patients completed the 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) and underwent scoring of eustachian tube inflammation using the Endoscopic Evaluation of the Eustachian Tube (3ET) system. RESULTS: Seventy-three patients were included in the study. Symptoms were localized to the external auditory canal (EAC) in 28 (38.4%), to the infratemporal fossa (ITF) below the lobule in 37 (50.7%), and to the preauricular region in 8 (11.0%). Demographics and medical history were similar between groups. The EAC group had significantly more negative tympanometric peak pressure (TPP) (median, -92.0 daPa; IQR, 95.5) and higher 3ET scores. In contrast, the ITF group had normal TPP (median, -2.0 daPa; IQR, 7.0) and higher 3ET scores. The preauricular group was more likely to have temporomandibular joint or pterygoid muscle pain. ETDQ-7 scores did not differ significantly between groups. CONCLUSION: Symptom localization is associated with specific objective findings in the evaluation of aural discomfort. Patients with pain localizing to the ITF are more likely to have findings of eustachian tube salpingitis without obstruction whereas patients with symptoms deep in the EAC are more likely to have findings consistent with obstructive eustachian tube dysfunction. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1818-1823, 2023.

Spontaneous Thalamic Activity Modulates the Cortical Innervation of the Primary Visual Nucleus of the Thalamus.

Sensory processing relies on the correct development of thalamocortical loops. Visual corticothalamic axons (CTAs) invade the dorsolateral geniculate nucleus (dLGN) of the thalamus in early postnatal mice according to a regulated program that includes activity-dependent mechanisms. Spontaneous retinal activity influences the thalamic incursion of CTAs, yet the perinatal thalamus also generates intrinsic patterns of spontaneous activity whose role in modulating afferent connectivity remains unknown. Here, we found that patterned spontaneous activity in the dLGN contributes to proper spatial and temporal innervation of CTAs. Disrupting patterned spontaneous activity in the dLGN delays corticogeniculate innervation under normal conditions and upon eye enucleation. The delayed innervation was evident throughout the first two postnatal weeks but resumes after eye-opening, suggesting that visual experience is necessary for the homeostatic recovery of corticogeniculate innervation.

What do we mean when we have a "sinus infection?"

INTRODUCTION: Sinus infections are a common reason patients seek medical care. However, the intended meaning of the term sinus infection among patients and otolaryngologists is incompletely understood. METHODS: In this multi-institutional cross-sectional study, a semantics-based questionnaire was provided to consecutive patients presenting to otolaryngology clinics at six academic centers from June 2020 until May 2021. The primary outcome was respondent definitions for sinus infection from a list of 28 proposed terms covering six general categories. Secondary outcome measures included differences between geographic regions. RESULTS: Responses were obtained from 560 patients (54% female, mean age 48.9 years) and 29 otolaryngologists (42% female, mean age 37.4 years). Patients and otolaryngologists selected a median of 10 and 11 terms, respectively, to define a sinus infection. Among patients the most frequently selected symptom categories were mucus (500, 89.3%), pressure/pain (480, 85.7%), and airflow (468, 83.6%). Compared to patients, clinicians selected with greater frequency the symptom categories of pressure/pain (14.3% difference; 95% CI, 7.6% to 22.5%), mucus (10.7% difference; 95% CI, 4.7% to 18.3%) and airflow (13.0% difference; 95% CI, 4.8% to 21.7%). Multiple categories were selected by 96% of patients and 100% of providers. CONCLUSION: The definition of sinus infection appears variable for both patients and otolaryngologists, though patients appear to apply a broader range of symptoms to the term sinus infection. There were no pronounced geographic differences in the description of a sinus infection in this US sample population. Patients commonly described sinus infection in the context of pain-related symptoms. Appreciation of these semantic differences may enable more effective patient-clinician communication.

Single cell clonal analysis identifies an AID-dependent pathway of plasma cell differentiation.

Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody-secreting plasma cells. Here, we have addressed the role of activation-induced deaminase (AID), which initiates somatic hypermutation and class switch recombination, in the terminal differentiation of GC B cells. By combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells, we have identified a novel subset of late-prePB cells (L-prePB), which shares the strongest clonal relationships with plasmablasts (PBs). Mice lacking AID have various alterations in the size and expression profiles of transcriptional clusters. We find that AID deficiency leads to a reduced proportion of L-prePB cells and severely impairs transitions between the L-prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state.

DisPhaseDB: An integrative database of diseases related variations in liquid-liquid phase separation proteins.

Motivation: Proteins involved in liquid-liquid phase separation (LLPS) and membraneless organelles (MLOs) are recognized to be decisive for many biological processes and also responsible for several diseases. The recent explosion of research in the area still lacks tools for the analysis and data integration among different repositories. Currently, there is not a comprehensive and dedicated database that collects all disease-related variations in combination with the protein location, biological role in the MLO, and all the metadata available for each protein and disease. Disease-related protein variants and additional features are dispersed and the user has to navigate many databases, with a different focus, formats, and often not user friendly. Results: We present DisPhaseDB, a database dedicated to disease-related variants of liquid-liquid phase separation proteins. It integrates 10 databases, contains 5,741 proteins, 1,660,059 variants, and 4,051 disease terms. It also offers intuitive navigation and an informative display. It constitutes a pivotal starting point for further analysis, encouraging the development of new computational tools.The database is freely available at http://disphasedb.leloir.org.ar.

Insight into membraneless organelles and their associated proteins: Drivers, Clients and Regulators.

In recent years, attention has been devoted to proteins forming immiscible liquid phases within the liquid intracellular medium, commonly referred to as membraneless organelles (MLO). These organelles enable the spatiotemporal associations of cellular components that exchange dynamically with the cellular milieu. The dysregulation of these liquid-liquid phase separation processes (LLPS) may cause various diseases including neurodegenerative pathologies and cancer, among others. Until very recently, databases containing information on proteins forming MLOs, as well as tools and resources facilitating their analysis, were missing. This has recently changed with the publication of 4 databases that focus on different types of experiments, sets of proteins, inclusion criteria, and levels of annotation or curation. In this study we integrate and analyze the information across these databases, complement their records, and produce a consolidated set of proteins that enables the investigation of the LLPS phenomenon. To gain insight into the features that characterize different types of MLOs and the roles of their associated proteins, they were grouped into categories: High Confidence MLO associated (including Drivers and reviewed proteins), Potential Clients and Regulators, according to their annotated functions. We show that none of the databases taken alone covers the data sufficiently to enable meaningful analysis, validating our integration effort as essential for gaining better understanding of phase separation and laying the foundations for the discovery of new proteins potentially involved in this important cellular process. Lastly, we developed a server, enabling customized selections of different sets of proteins based on MLO location, database, disorder content, among other attributes (https://forti.shinyapps.io/mlos/).

Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming.

Neural cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterized by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and astrocytes. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across these two brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis reveals the existence of common nucleus-specific progenitors for neurons and astrocytes. Consistent with their shared molecular signature, regional specificity is maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.

Patients With Systemic Lupus Erythematosus Show an Increased Arterial Stiffness That is Predicted by IgM Anti-ß2 -Glycoprotein I and Small Dense High-Density Lipoprotein Particles.

OBJECTIVE: To investigate the metabolic and immunologic factors associated with the presence of central arterial stiffness as measured by the augmentation index (AIx). METHODS: We conducted a cross-sectional study of 69 female patients with systemic lupus erythematosus (SLE) compared with a control group of 34 healthy women. The anthropometrical variables, the vascular studies, and the analytic data were obtained the same day. The AIx was assessed by peripheral arterial tonometry. The analysis of lipoprotein populations was performed using nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Arterial stiffness was increased in patients with SLE compared with control subjects (mean ± SD 20.30 ± 21.54% versus 10.84 ± 11.51%; P = 0.0021). Values for the AIx were correlated with the Framingham risk score (r = 0.481, P < 0.001), carotid intima-media thickness (r = 0.503, P < 0.001), systolic blood pressure (r = 0.270, P < 0.001), and age (r = 0.365, P < 0.001). Patients receiving antimalarial drugs had a lower AIx (mean ± SD 11.74 ± 11.28% versus 24.97 ± 20.63%; P = 0.024). The AIx was correlated with the atherogenic lipoproteins analyzed by NMR. The immunologic variables associated with the AIx were C4 (r = 0.259, P = 0.046) and IgM anti-ß2 -glycoprotein I (IgM anti-ß2 GPI) (r = 0.284, P = 0.284). In the multivariate analysis, age (ß = 0.347, 95% confidence interval [95% CI] 0.020-0.669, P = 0.035), IgM ß2 GPI (ß = 0.321, 95% CI 0.024-0.618, P = 0.035) and small dense high-density lipoprotein (HDL) particles (ß = 1.288, 95% CI 0.246-2.329, P = 0.017) predicted the AIx. CONCLUSION: SLE patients had increased arterial stiffness compared with healthy control subjects. Arterial stiffness was decreased in patients treated with antimalarial drugs. Age, IgM ß2 GPI, and the number of small dense HDL particles predicted the AIx.

Tourniquet-ALPPS is a promising treatment for very large hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

When very large hepatocellular carcinomas (HCCs) and intrahepatic cholangiocarcinoma (IHCCs) with insufficient future liver remnants are treated using associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), the outcome is often poor. We therefore tested the efficacy of a modified version of that technique, tourniquet-ALPPS. A review of the literature examining outcomes of HCC and IHCC patients treated with ALPPS revealed the incidences of morbidity ≥ III and postoperative mortality to be respectively 20.7% and 16.1% among HCC patients and 50% and 45.4% among IHCC patients. In the present case series, in which HCC and IHCC patients were treated with tourniquet-ALPPS, median tumor size was 100 mm (range: 70-200 mm). After surgical stage I, there was no morbidity, no mortality and the median future liver remnant had increased at day 7 by 76%. In surgical stage II, 100% of tumors were resectable (8 right trisectionectomies, 5 with inferior vena cava resection). Two patients experienced serious morbidity ≥ IIIB and 1 patient died (11%). One- and 3-year overall survival was 75% and 60%, respectively. Thus tourniquet-ALPPS appears to be an effective alternative to classical ALPPS for the treatment of patients with HCC or IHCC.

Lung cancer diagnosis by trained dogs.

OBJECTIVES: Early lung cancer (LC) diagnosis is key to improve prognosis. We explored here the diagnostic performance of a trained dog to discriminate exhaled gas samples obtained from patients with and patients without LC and healthy controls. METHODS: After appropriate training, we exposed the dog (a 3-year-old cross-breed between a Labrador Retriever and a Pitbull) to 390 samples of exhaled gas collected from 113 individuals (85 patients with LC and 28 controls, which included 11 patients without LC and 17 healthy individuals) for a total of 785 times. RESULTS: The trained dog recognized LC in exhaled gas with a sensitivity of 0.95, a specificity of 0.98, a positive predictive value of 0.95 and a negative predictive value of 0.98. The area under the curve of the receiver-operating characteristics curve was 0.971. CONCLUSIONS: This study shows that a well-trained dog can detect the presence of LC in exhaled gas samples with an extremely high accuracy.