The bitter taste of medicines hinders patient compliance, but not everyone experiences these difficulties because people worldwide differ in their bitterness perception. To better understand how people from diverse ancestries perceive medicines and taste modifiers, 338 adults, European and recent US and Canada immigrants from Asia, South Asia, and Africa, rated the bitterness intensity of taste solutions on a 100-point generalized visual analog scale and provided a saliva sample for genotyping. The taste solutions were five medicines, tenofovir alafenamide (TAF), moxifloxacin, praziquantel, amodiaquine, and propylthiouracil (PROP), and four other solutions, TAF mixed with sucralose (sweet, reduces bitterness) or 6-methylflavone (tasteless, reduces bitterness), sucralose alone, and sodium chloride alone. Bitterness ratings differed by ancestry for two of the five drugs (amodiaquine and PROP) and for TAF mixed with sucralose. Genetic analysis showed that people with variants in one bitter receptor variant gene (TAS2R38) reported PROP was more bitter than did those with a different variant (p= 7.6e-19) and that people with either an RIMS2 or a THSD4 genotype found sucralose more bitter than did others (p=2.6e-8, p=7.9e-11, resp.). Our findings may help guide the formulation of bad-tasting medicines to meet the needs of those most sensitive to them.

Over the past decade, tremendous progress has been made in using organoids-three-dimensional, miniature organ-like structures-to model tissues and organs in vitro, including both regenerative tissues (which contain tissue-residing stem/progenitor cells) and largely nonregenerative tissues, such as the brain. Organoids resemble the tissues from which they are derived in many aspects of structure, function, and organization. As a result, organoid models have been used in a variety of fields for cell studies. Many well-written reviews have provided in-depth descriptions of organoid models for various systems. In this article, we review the establishment and application of tissue stem/progenitor cell-derived organoid models relevant to chemosensory cell studies (taste and smell) and discuss the limitations and future directions of using these models to study chemosensation.

BACKGROUND:Olfactory dysfunction (OD) affects many survivors of COVID-19. Prior studies have investigated the use of platelet-rich plasma (PRP) injections for OD. We describe the first randomized controlled trial investigating topical PRP for OD treatment and contribute to existing literature illustrating PRP as an emerging therapeutic. METHODS:This is a single-blinded, randomized controlled trial conducted from July 2022 to December 2023. Adult patients with OD ≥6 months secondary to COVID-19 with Brief Smell Identification Test (BSIT) scores of ≤8/12 or SCENTinel odor intensity of ≤40/100 were included. Patients were randomized to three, monthly PRP or placebo-impregnated Surgifoam treatments into bilateral olfactory clefts. The BSIT, SCENTinel, and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) were completed monthly through month 12. RESULTS:Of 104 patients screened, 83 participated. No significant differences in age, OD duration, BSIT, SCENTinel, or QOD-NS scores were found between PRP (n = 42) and placebo (n = 41) patients at baseline. PRP patients experienced a statistically significant increase in BSIT scores from baseline at months 5‒9, 11, and 12, while placebo patients did not (p < 0.05). However, total BSIT scores were similar between the two groups throughout the study. Neither the SCENTinel odor intensity scores nor the change from baseline were significantly different between the treatment groups. At month 12, PRP patients experienced minor improvement in OD-related quality-of-life compared with placebo. CONCLUSIONS:This study is the first to describe topical PRP as a safe, experimental treatment for OD in humans. PRP may impact odor identification in post-COVID-19 OD patients, although the lack of difference in total BSIT scores highlights the need for further study.

Purpose:The bad bitter taste of some medicines is a barrier to overcoming non-compliance with medication use, especially life-saving drugs given to children and the elderly. Here we evaluated a new class of bitter blockers (thiazolidinediones; TZDs). Methods:In this study, two TZDs were tested, rosiglitazone (ROSI) and a simpler form of TZD, using a high-potency sweetener as a positive control (neohesperidin dihydrochalcone, NHDC). We tested bitter-blocking effects using the bitter drugs tenofovir alafenamide fumarate (TAF), a treatment for HIV and hepatitis B infection, and praziquantel (PRAZ), a treatment for schistosomiasis, by conducting taste testing with two separate taste panels: a general panel (N=97, 20-23 yrs, 82.5% female, all Eastern European) and a genetically informative panel (N=158, including 68 twin pairs, 18-82 yrs, 76% female, 87% European ancestry). Participants rated the bitterness intensity of the solutions on a 100-point generalized visual analog scale. Findings:Participants in both taste panels rated the bitter drugs TAF and PRAZ as less bitter on average when mixed with NHDC than when sampled alone. ROSI partially suppressed the bitterness of TAF and PRAZ, but effectiveness differed between the two panels: bitterness was significantly reduced for PRAZ but not TAF in the general panel and for TAF but not PRAZ in the genetically informative panel. ROSI was a more effective blocker than the other TZD. Implications:These results suggest that TZDs are partially effective bitter blockers, suggesting other TZDs should be designed and tested with more drugs and on diverse populations to define which ones work best with which drugs and for whom. The discovery of bitter receptor blockers can improve compliance with medication use.

World-wide some 658 million people were infected with coronavirus disease 2019 (COVID-19) and millions suffer from chemosensory impairment associated with long COVID. Current treatments for taste and smell disorders are limited. Involving patients has the potential to catalyze the dynamic exchange and development of new ideas and approaches to facilitate biomedical research and therapeutics. We assessed patients' perceptions of the efficacy of treatments for chemosensory impairment using an online questionnaire completed by 5,815 people in the US Logistic regression determined variables predictive of reported treatment efficacy for patients aged 18 to 24, 25 to 39, 40 to 60, and 60+ yrs. who were treated with nasal steroids, oral steroids, zinc, nasal rinse, smell training, theophylline, platelet-rich plasma, and Omega 3. The most consistent predictor was age, with the majority of those 40 to 60 and 60+ reporting that nasal steroids, oral steroids, zinc, nasal rinse, and smell training were only slightly effective or not effective at all. Many of these treatment strategies target regeneration and immune response, processes compromised by age. Only those under 40 reported more than slight efficacy of steroids or smell training. Findings emphasize the need to include patients of all ages in clinical trials. Older adults with olfactory impairment are at increased risk for Alzheimer's disease (AD). We speculate that olfactory impairment associated with long COVID introduces the potential for a significant rise in AD. Long COVID-associated chemosensory impairment increases the urgency for translational and clinical research on novel treatment strategies. Suggestions for high-priority areas for epidemiological, basic, and clinical research on chemosensory impairment follow.

Human studies have linked stress exposure to unhealthy eating behavior. However, the mechanisms that drive stress-associated changes in eating behavior remain incompletely understood. The sense of taste plays important roles in food preference and intake. In this study, we use a chronic social defeat stress (CSDS) model in mice to address whether chronic stress impacts taste sensation and gene expression in taste buds and the gut. Our results showed that CSDS significantly elevated circulating levels of corticosterone and acylated ghrelin while lowering levels of leptin, suggesting a change in metabolic hormones that promotes food consumption. Stressed mice substantially increased their intake of food and water 3-5 days after the stress onset and gradually gained more body weight than that of controls. Moreover, CSDS significantly decreased the expression of multiple taste receptors and signaling molecules in taste buds and reduced mRNA levels of several taste progenitor/stem cell markers and regulators. Stressed mice showed significantly reduced sensitivity and response to umami and sweet taste compounds in behavioral tests. In the small intestine, the mRNA levels of Gnat3 and Tas1r2 were elevated in CSDS mice. The increased Gnat3 was mostly localized in a type of Gnat3+ and CD45+ immune cells, suggesting changes of immune cell distribution in the gut of stressed mice. Together, our study revealed broad effects of CSDS on the peripheral taste system and the gut, which may contribute to stress-associated changes in eating behavior.

OBJECTIVES:Diagnosis of smell/taste dysfunction is necessary for appropriate medical care. This study examines factors affecting testing and diagnosis of smell/taste disorders .METHODS:The online USA Smell and Taste Patient Survey was made available to US patients with smell/taste disorders between April 6-20, 2022. 4,728 respondents were included.RESULTS:1,791 (38%) patients reported a documented diagnosis. Patients most often saw family practitioners (34%), otolaryngologists (20%), and Taste/Smell clinics (6%) for smell/taste dysfunction. 64% of patients who went to Taste/Smell clinics received smell testing, followed by 39% of patients who saw otolaryngologists, and 31% of patients who saw family practitioners. Factors associated with increased odds of diagnosis included age (25-39 years (OR 2.97, 95% CI [2.25, 3.95]), 40-60 (OR 3.3, 95% CI [2.56, 4.52]), and >60 (OR 4.25, 95% CI [3.21, 5.67]) vs. 18-24 years), male gender (OR 1.26, 95% CI [1.07, 1.48]), insurance status (private (OR 1.61, 95% CI [1.15, 2.30]) or public (OR 2.03, 95% CI [1.42, 2.95]) vs. uninsured), perception of their family practitioner to be knowledgeable (OR 2.12, 95% CI [1.16, 3.90]), otolaryngologic evaluation (OR 6.17, 95% CI [5.16, 7.38]), and psychophysical smell testing (OR 1.77, 95% CI [1.42, 2.22]).CONCLUSION:Psychophysical testing, otolaryngologic evaluation, patient assessment of family practitioner knowledge level, insurance, age, and gender are significant factors in obtaining smell/taste dysfunction diagnosis. This study identifies barriers to diagnosis including lack of insurance or access to specialist evaluation and highlights the importance of educating family practitioners in diagnosis and management of patients with smell/taste disorders.

The olfactory receptor neurons (ORNs) are a unique cell type involved in the initial perception of odors. These specialized epithelial cells are located in the neuroepithelium of the nasal cavities and directly connect the nasal cavity with the central nervous system (CNS) via axons, which traverse the cribriform plate to synapse within the olfactory bulb. ORNs are derived from precursor cells that lie adjacent to the basal lamina of the olfactory epithelium. These precursor cells divide several times and their progeny differentiate into mature sensory neurons throughout life. In addition to its major and critical role in sensory transduction, the olfactory neuroepithelium may be an important tissue for viral replication and represents a potential site for viral entry into the CNS. In general, to gain access to the CNS, neurotropic viruses such as henipaviruses can use peripheral neural pathways or the circulatory system. However, the olfactory system has been reported to provide a portal of entry to the CNS for henipaviruses. The ability to obtain biopsies from living human subjects and culture these cells in the laboratory provides the opportunity to examine viral replication and effects on a neuronal cell population. As the most exposed and unprotected segment of the nervous system, the olfactory neuroepithelium may have an important role in neuropathology and systemic dissemination of viruses with established CNS effects. This chapter presents methods for primary culture of human ORNs, which have been used successfully by multiple investigators. The protocol provides a consistent, heterogeneous olfactory epithelial cell population, which demonstrates functional responses to odorant mixtures and exhibits several key features of the olfactory receptor neuron phenotype, encompassing olfactory receptors and signaling pathways.

It is estimated that 20%-67% of those with COVID-19 develop olfactory disorders, depending on the SARS-CoV-2 variant. However, there is an absence of quick, population-wide olfactory tests to screen for olfactory disorders. The purpose of this study was to provide a proof-of-concept that SCENTinel 1.1, a rapid, inexpensive, population-wide olfactory test, can discriminate between anosmia (total smell loss), hyposmia (reduced sense of smell), parosmia (distorted odor perception), and phantosmia (odor sensation without a source). Participants were mailed a SCENTinel 1.1 test, which measures odor detection, intensity, identification, and pleasantness, using one of 4 possible odors. Those who completed the test (N = 287) were divided into groups based on their self-reported olfactory function: quantitative olfactory disorder only (anosmia or hyposmia, N = 135), qualitative olfactory disorder only (parosmia and/or phantosmia; N = 86), and normosmia (normal sense of smell; N = 66). SCENTinel 1.1 accurately discriminates quantitative olfactory disorders, qualitative olfactory disorders, and normosmia groups. When olfactory disorders were assessed individually, SCENTinel 1.1 discriminates between hyposmia, parosmia, and anosmia. Participants with parosmia rated common odors less pleasant than those without parosmia. We provide proof-of-concept that SCENTinel 1.1, a rapid smell test, can discriminate quantitative and qualitative olfactory disorders, and is the only direct test to rapidly discriminate parosmia.