Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.

Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K+) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.

Inhaled treprostinil in pulmonary hypertension associated with COPD: PERFECT study results.

BACKGROUND: Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (ClinicalTrials.gov: NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. METHODS: Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. RESULTS: In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. CONCLUSIONS: The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

Mutual influence between language and perception in multi-agent communication games.

Language interfaces with many other cognitive domains. This paper explores how interactions at these interfaces can be studied with deep learning methods, focusing on the relation between language emergence and visual perception. To model the emergence of language, a sender and a receiver agent are trained on a reference game. The agents are implemented as deep neural networks, with dedicated vision and language modules. Motivated by the mutual influence between language and perception in cognition, we apply systematic manipulations to the agents' (i) visual representations, to analyze the effects on emergent communication, and (ii) communication protocols, to analyze the effects on visual representations. Our analyses show that perceptual biases shape semantic categorization and communicative content. Conversely, if the communication protocol partitions object space along certain attributes, agents learn to represent visual information about these attributes more accurately, and the representations of communication partners align. Finally, an evolutionary analysis suggests that visual representations may be shaped in part to facilitate the communication of environmentally relevant distinctions. Aside from accounting for co-adaptation effects between language and perception, our results point out ways to modulate and improve visual representation learning and emergent communication in artificial agents.

Tagging and Capturing of Lentiviral Vectors Using Short RNAs.

Lentiviral (LV) vectors have emerged as powerful tools for transgene delivery ex vivo but in vivo gene therapy applications involving LV vectors have faced a number of challenges, including the low efficiency of transgene delivery, a lack of tissue specificity, immunogenicity to both the product encoded by the transgene and the vector, and the inactivation of the vector by the human complement cascade. To mitigate these issues, several engineering approaches, involving the covalent modification of vector particles or the incorporation of specific protein domains into the vector's envelope, have been tested. Short synthetic oligonucleotides, including aptamers bound to the surface of LV vectors, may provide a novel means with which to retarget LV vectors to specific cells and to shield these vectors from neutralization by sera. The purpose of this study was to develop strategies to tether nucleic acid sequences, including short RNA sequences, to LV vector particles in a specific and tight fashion. To bind short RNA sequences to LV vector particles, a bacteriophage lambda N protein-derived RNA binding domain (λN), fused to the measles virus hemagglutinin protein, was used. The λN protein bound RNA sequences bearing a boxB RNA hairpin. To test this approach, we used an RNA aptamer specific to the human epidermal growth factor receptor (EGFR), which was bound to LV vector particles via an RNA scaffold containing a boxB RNA motif. The results obtained confirmed that the EGFR-specific RNA aptamer bound to cells expressing EGFR and that the boxB containing the RNA scaffold was bound specifically to the λN RNA binding domain attached to the vector. These results show that LV vectors can be equipped with nucleic acid sequences to develop improved LV vectors for in vivo applications.

Gastroesophageal reflux disease and head and neck cancers: A systematic review and meta-analysis.

PURPOSE: Gastroesophageal reflux disease (GERD) has been associated with head and neck cancer (HNC), including laryngeal and pharyngeal anatomical sites. A systematic review and meta-analysis was performed to examine these associations. METHODS: Articles were retrieved from the Medline, Web of Science, Scopus, and Embase databases using keywords "gastroesophageal reflux disease", "laryngopharyngeal reflux", "head and neck cancer", and associated variants. Inclusion criteria were English language publications, human subjects, and controlled studies with described development of head and neck cancer among individuals with GERD. 13 studies with a total of 39,824 patients were included. RESULTS: Overall, presence of GERD was associated with an increased risk of developing HNC (OR = 1.86, 95% Confidence Interval [CI] = 1.27-2.74). This association remained significant with laryngeal cancers (OR = 1.95, 95% CI = 1.33-2.86), but not pharyngeal cancers (OR = 1.56, 95% CI = 0.86-2.83). Subgroup analyses of hypopharyngeal (OR = 2.26, 95% CI = 0.67-7.68) and oropharyngeal subsites (OR = 1.39, 95% CI = 0.51-3.84) were not statistically significant. Meta-analysis of studies that objectively assessed reflux, such as pH monitor placement, showed statistical significance (OR = 2.81, 95% CI = 1.36-5.81), while studies that used subjective reporting or chart review of GERD were not significant (OR = 1.46, 95% CI = 0.89-2.40). Association between H. pylori infection and head and neck cancers was not statistically significant (OR = 2.66, 95% CI = 0.59-11.97). CONCLUSION: A diagnosis of GERD is associated with a later diagnosis of HNC, but this association is not significant for pharyngeal cancers. Associations of GERD with HNC may be specific to laryngeal cancers. LEVEL OF EVIDENCE: Systematic review and meta-analysis of case control studies (3a).

Nonpharmacological Relaxation Technology for Office-Based Rhinologic Procedures.

BACKGROUND: Office-based rhinologic procedures are increasingly performed to control costs and enhance patient convenience. Adequate management of pain and anxiety is essential for the technical performance of these procedures, in addition to ensuring patient comfort. Pharmacologic agents are often used to manage anxiety and pain. Nonpharmacological adjuncts may be useful for achieving these effects without oral opioids and benzodiazepines. METHODS: Charts of patients who underwent office-based rhinologic procedures with the NuCalm system (Solace Lifesciences, Inc., Wilmonton, DE, USA) in combination with local anesthesia were reviewed. NuCalm is a proprietary system that combines cranial electrotherapy stimulation, neuroacoustic software, light-blocking lenses, and topical γ--aminobutyric acid. Patients rated their pain and anxiety before, during, and after the procedure. RESULTS: Twenty-five patients underwent office procedures using the NuCalm system. Preoperative anxiety (2.00) was significantly higher than postoperative anxiety (1.25) according to patient reporting on a 5-point scale (p = 0.005). Preoperative pain (1.83) was not significantly different from intraoperative (2.54) and postoperative pain (2.04, p = 0.054). CONCLUSIONS: A variety of office-based rhinologic procedures are technically feasible and can be performed with adequate patient comfort without the use of oral drugs. Adjuncts to pharmacologic agents may enhance pain control and anxiety management and improve patient tolerance of these procedures.

An Intravascular Tantalum Oxide-based CT Contrast Agent: Preclinical Evaluation Emulating Overweight and Obese Patient Size.

Purpose To compare the CT imaging performance of a carboxybetaine zwitterionic-coated tantalum oxide (TaCZ) nanoparticle CT contrast agent with that of a conventional iodinated contrast agent in a swine model meant to simulate overweight and obese patients. Materials and Methods Four swine were evaluated inside three different-sized adipose-equivalent encasements emulating abdominal girths of 102, 119, and 137 cm. Imaging was performed with a 64-detector row CT scanner at six scan delays after intravenous injection of 240 mg element (Ta or I) per kilogram of body weight of TaCZ or iopromide. For each time point, contrast enhancement of the aorta and liver were measured by using regions of interest. Two readers independently recorded the clarity of vasculature using a five-point Likert scale. Findings were compared by using paired t tests and Wilcoxon signed-rank tests. Results Mean peak enhancement was higher for TaCZ than for iopromide in the aorta (270 HU [σ = 24.5] vs 199 HU [σ = 10.2], P < .001) and liver (61.3 HU [σ = 11.7] vs 45.2 HU [σ = 8], P < .001). Vascular clarity was higher for TaCZ than for iopromide in 63% (132 of 208), 82% (170 of 208), and 86% (178 of 208) of the individual vessels at the 102-, 119-, and 137-cm girths, respectively (P < .01). Arterial clarity scores were higher for TaCZ than for iopromide in 62% (208 of 336) of vessels. Venous clarity scores were higher for TaCZ than for iopromide in 89% (128 of 144) of the veins in the venous phase and in 100% (144 of 144) of veins in the delayed phase (P < .01). No vessel showed higher clarity score with iopromide than with TaCZ. Conclusion An experimental tantalum nanoparticle-based contrast agent showed greater contrast enhancement compared with iopromide in swine models meant to simulate overweight and obese patients. © RSNA, 2018.

Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.

Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

African green monkeys recapitulate the clinical experience with replication of live attenuated pandemic influenza virus vaccine candidates.

Live attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently, while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of ca vaccine candidates. Importance: Ferrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV.

Anesthetic Implications of Ebola Patient Management: A Review of the Literature and Policies.

As of mid-October 2014, the ongoing Ebola epidemic in Western Africa has affected approximately 10,000 patients, approached a 50% mortality rate, and crossed political and geographic borders without precedent. The disease has spread throughout Liberia, Guinea, and Sierra Leone. Isolated cases have arrived in urban centers in Europe and North America. The exponential growth, currently unabated, highlights the urgent need for effective and immediate management protocols for the various health care subspecialties that may care for Ebola virus disease patients. We conducted a comprehensive review of the literature to identify key areas of anesthetic care affected by this disease. The serious potential for "high-risk exposure" and "direct contact" (as defined by the Centers for Disease Control and Prevention) of anesthesiologists caring for Ebola patients prompted this urgent investigation. A search was conducted using MEDLINE/PubMed, MeSH, Cochrane Review, and Google Scholar. Key words included "anesthesia" and/or "ebola" combined with "surgery," "intubation," "laryngoscopy," "bronchoscopy," "stethoscope," "ventilation," "ventilator," "phlebotomy," "venous cannulation," "operating room," "personal protection," "equipment," "aerosol," "respiratory failure," or "needle stick." No language or date limits were applied. We also included secondary-source data from government organizations and scientific societies such as the Centers for Disease Control and Prevention, World Health Organization, American Society of Anesthesiologists, and American College of Surgeons. Articles were reviewed for primary-source data related to inpatient management of Ebola cases as well as evidence-based management guidelines and protocols for the care of Ebola patients in the operative room, infection control, and health care worker personal protection. Two hundred thirty-six articles were identified using the aforementioned terminology in the scientific database search engines. Twenty articles met search criteria for information related to inpatient Ebola virus disease management or animal virology studies as primary or secondary sources. In addition, 9 articles met search criteria as tertiary sources, representing published guidelines. The recommendations developed in this article are based on these 29 source documents. Anesthesia-specific literature regarding the care of Ebola patients is very limited. Secondary-source guidelines and policies represent the majority of available information. Data from controlled animal experiments and tuberculosis patient research provide some evidence for the existing recommendations and identify future guideline considerations.

Acquired substrate preference for GAB1 protein bestows transforming activity to ERBB2 kinase lung cancer mutants.

Activating mutations in the αC-ß4 loop of the ERBB2 kinase domain, such as ERBB2(YVMA) and ERBB2(G776VC), have been identified in human lung cancers and found to drive tumor formation. Here we observe that the docking protein GAB1 is hyper-phosphorylated in carcinomas from transgenic mice and in cell lines expressing these ERBB2 cancer mutants. Using dominant negative GAB1 mutants lacking canonical tyrosine residues for SHP2 and PI3K interactions or lentiviral shRNA that targets GAB1, we demonstrate that GAB1 phosphorylation is required for ERBB2 mutant-induced cell signaling, cell transformation, and tumorigenesis. An enzyme kinetic analysis comparing ERBB2(YVMA) to wild type using physiologically relevant peptide substrates reveals that ERBB2(YVMA) kinase adopts a striking preference for GAB1 phosphorylation sites as evidenced by ∼150-fold increases in the specificity constants (kcat/Km) for several GAB1 peptides, and this change in substrate selectivity was predominantly attributed to the peptide binding affinities as reflected by the apparent Km values. Furthermore, we demonstrate that ERBB2(YVMA) phosphorylates GAB1 protein ∼70-fold faster than wild type ERBB2 in vitro. Notably, the mutation does not significantly alter the Km for ATP or sensitivity to lapatinib, suggesting that, unlike EGFR lung cancer mutants, the ATP binding cleft of the kinase is not significantly changed. Taken together, our results indicate that the acquired substrate preference for GAB1 is critical for the ERBB2 mutant-induced oncogenesis.

Validated Symptom Outcomes Following Septal Perforation Repair: Application of the NOSE-Perf Scale.

OBJECTIVE: The Nasal Obstruction Symptom Evaluation (NOSE)-Perf scale was developed and validated to measure symptoms associated with nasal septal perforations. This study reports the application of the NOSE-Perf scale to evaluate symptom change following septal perforation repair. METHODS: Patients with NOSE-Perf evaluations ≥6 months following attempted perforation closure from July 2018 to December 2021 utilizing bilateral nasal mucosal flaps with an interposition graft were eligible for study inclusion. Change in NOSE-Perf scores were noted. Patient demographics, perforation size, and concurrent functional procedures were analyzed for impact on symptom outcomes. RESULTS: One-hundred and seventeen patients met the study criteria. Seventy-nine (67.5%) of the patients were female and the mean (range) age at surgery was 47.3 (14-78) years. Repair failure was noted in 7 (6.0%) patients. Mean (SD) preoperative NOSE-Perf score was 25.3 (95% CI, 23.5-27.1) and postoperative score was 7.9 (95% CI, 6.5-9.3). Minimal clinically important difference (MCID) was estimated and greater than 91% of patients had improvement above this threshold. Patient age, perforation size, or concurrent functional procedures did not impact outcomes. Postoperative scores at short (2-4 months), intermediate (5-8 months), and long-term (≥9 months) time periods showed significant improvement (all p < 0.001) compared to preoperative NOSE-Perf scores. CONCLUSION: Significant reduction in nasal symptoms as measured by the NOSE-Perf scale is noted following bilateral mucosal flap repair. Although the nose does not completely normalize following repair, clinically important improvement was noted in at least 91% of patients. The NOSE-Perf scale is positioned to play a role in the standardization of septal perforation evaluation and outcomes assessment. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3067-3072, 2024.

Combined endoscopic sinus surgery and endonasal septal perforation repair: Symptom outcomes and perforation closure rates.

KEY POINTS: Combined endoscopic sinus surgery and nasal septal perforation repair is technically feasible. NOSE-Perf is a recently developed patient-reported outcome measure for nasal septal perforation. The decision to perform combined ESS and NSP repair should be made on a case-by-case basis.

Autologous Interposition Grafts for Mucosal Flap Septal Perforation Repair.

Background: Nasal septal perforation repair is commonly attempted utilizing bilateral nasal mucosal flaps supported with an interposition graft. Objectives: To compare the failure rates for bilateral flap repairs utilizing four different autologous interposition grafts. Methods: This is a retrospective review of a single surgeon's bilateral flap perforation repairs supported with an autologous interposition graft. Study inclusion over the 18-year review period required at least one examination 1 month after surgery. Repair failure rates were calculated and compared for each graft type, and logistic regression was performed for multivariate analysis. Results: For the 356 study patients, median (range) age was 51 years (14-81) and 63.0% were women. Mean (range) perforation length was 13.9 mm (1-45). Median (range) at last follow-up was 11.2 months (1-192). Graft types used (percentage of patients and failure rate) were temporalis fascia (58.7/4.4), septal cartilage (23.3/7.3), auricular perichondrium (13.8/4.1), and septal bone (4.2/6.7) (p > 0.05). Conclusion: There was no significant difference in bilateral mucosal flap perforation repair failure rate when either a temporalis fascia, septal cartilage, auricular perichondrium, or septal bone interposition graft was used.

Assessment of a Novel Tool for the Clinical Grading of Nasal Septal Perforation.

BACKGROUND: Nasal septal perforations (NSP) can have a heterogeneous appearance on endoscopic examination with varying degrees of crusting, inflammatory change, and associated septal deviation. The clinical applicability of these findings as contributors to patient symptoms may be enhanced by use of a standardized assessment. METHODS: Video nasal endoscopy recordings were obtained from 40 patients with NSP. Five raters with varied levels of training ranging from a senior resident to an experienced septal perforation surgeon independently reviewed the videos for the following exam findings: crusting, scarring, granulation tissue, septal deviation, and edema. Scoring for each item was reported on a 3-point (0-2) scale, and each reviewer repeated scoring at a 14-day interval. Interrater and intrarater agreement were calculated using Fleiss kappa for each item and the total scores. Additionally, endoscopy scores were correlated with patient-reported NOSE-Perf symptom scores. RESULTS: Interrater agreement for the overall instrument was in the "fair-to-moderate" range with the following interrater agreement for each item: crusting (0.458-0.575), scarring (0.286-0.308), granulation (0.403-0.406), deviation (0.487-0.494), and edema (0.253-0.406). Intrarater agreement was generally "substantial" for individual items as well as the overall instrument (0.688). The NSP endoscopy scores were moderately correlated with NOSE-Perf scores (r = 0.44, p = 0.008). CONCLUSIONS: An endoscopic evaluation of NSP comprising five exam findings has acceptable interrater and intrarater reliability and correlates with patient-reported outcomes. NSP endoscopy may be applied to future clinical studies for characterization of NSP and assessment of treatment outcomes. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3049-3053, 2024.

Translation, cultural adaptation, and validation of the NOSE-Perf scale to Brazilian Portuguese.

OBJECTIVE: To perform the translation, cultural adaptation, and validation of the NOSE-Perf Scale to Brazilian Portuguese. METHODS: This study was divided into two stages. In the first stage, the questionnaire was submitted for translation and cultural adaptation, following the guidelines recommended by the ISPOR Task Force (International Society for Pharmacoeconomics and Outcomes Research). Then, the Brazilian Portuguese version of the NOSE-Perf scale was applied to a group with septal perforation and a control group. The group with perforation answered the questionnaire again after one month. Internal consistency, test-retest reliability, and discriminant validity were assessed. RESULTS: The Brazilian Portuguese version of the NOSE-Perf scale was applied to 32 participants, 16 from the group with septal perforations and 16 controls. The instrument obtained high internal consistency, with Cronbach's alpha scores of 0.986. High reliability was also obtained, with Spearman's correlation coefficient of 0.996 (p < 0.001) and the intraclass correlation coefficient of 0.965 with a 95% Confidence Interval (95% CI) of 0.886‒0.988. The NSP group obtained a mean total score of 13.8 ±â€¯12.6 and the control group a score of 2.3 ±â€¯1.8, with a statistical difference between the groups (p < 0.001), demonstrating good discriminant validity. CONCLUSION: The Brazilian Portuguese version of the NOSE-Perf scale is a reliable and valid instrument for measuring symptoms in patients with nasal septum perforations. LEVEL OF EVIDENCE: Level 2-Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.

The clinical presentation of PIT1 positive pituitary neuroendocrine tumor immunonegative for growth hormone, prolactin, and thyroid stimulating hormone with analysis of clinical and immunostaining dissociation.

BACKGROUND: PIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs. METHODS: We conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction. RESULTS: As for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8-17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients. CONCLUSIONS: Patients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.

Features of Importance in Nasal Endoscopy: Deriving a Meaningful Framework.

OBJECTIVE: Critical components of the nasal endoscopic examination have not been definitively established for either the normal examination or for clinical disorders. This study aimed to identify concordance among rhinologists regarding the importance of examination findings for various nasal pathologies. STUDY DESIGN: A consortium of 19 expert rhinologists across the United States was asked to rank the importance of findings on nasal endoscopy for 5 different sinonasal symptom presentations. SETTING: An online questionnaire was distributed in July 2023. METHODS: The questionnaire utilized JotForm® software and featured 5 cases with a set of 4 identical questions per case, each covering a common indication for nasal endoscopy. Rankings were synthesized into Normalized Attention Scores (NASs) and Weighted Normalized Attention Scores (W-NASs) to represent the perceived importance of each feature, scaled from 0 to 1. RESULTS: General concordance was found for examination findings on nasal endoscopy within each case. The perceived features of importance differed between cases based on clinical presentation. For instance, in evaluating postnasal drip, the middle meatus was selected as the most important structure to examine (NAS, 0.73), with mucus selected as the most important abnormal finding (W-NAS, 0.66). The primary feature of interest for mucus was whether it was purulent or not (W-NAS, 0.67). Similar analyses were performed for features in each case. CONCLUSION: The implicit framework existing among rhinologists may help standardize examinations and improve diagnostic accuracy, augment the instruction of trainees, and inform the development of artificially intelligent algorithms to enhance clinical decision-making during nasal endoscopy.

Ultrasound-mediated targeted drug delivery: recent success and remaining challenges.

The potential clinical value of developing a novel, nonviral, ultrasound-directed gene and drug delivery system is immense. Investigators soon will initiate clinical trials with the goal of treating a wide variety of maladies using noninvasive, ultrasound-based technology. The ongoing, scientific validation associated with promising preclinical success portents a novel range of therapeutics. The clinical utility and eventual clinical successes await vigorous testing. This review highlights the recent successes and challenges within the field of ultrasound-mediated drug delivery.