Investigating the Vibrational Hypothesis of Olfaction

Introduction: The sense of smell arises from the direct stimulation of olfactory receptors by chemical odourants in the nose. The exact process by which odourants trigger their specific olfactory receptors is still debated. As G protein linked receptors (GCPRs) they may be expected to have similar activation processes to those which have been identified for other similar class A receptors: induced conformational fit, but there are several reasons to suspect that the activation step of these receptors may rely on a unique, quantum level process which probes the vibrational qualities of the bonds within the olfactant molecules. Hypothesis: The olfactory receptor uses a molecular vibration-detecting method to detect the identity of its ligands. Altering the vibrational characteristics of a molecule while preserving its three-dimensional structure alters the perceived odour characteristics to humans through a receptor-level phenomenon. Aims: The aim of this thesis is to demonstrate role of molecular vibration detection in human olfaction by demonstrating a change of odour quality perceived by humans in molecules which have undergone isotopic substitution of hydrogen with deuterium, a process which affects the vibrational, but not shape, characteristics of a molecule. Once this alteration of equality was demonstrated I attempted to identify a possible responsible receptor to facilitate further investigation of whether this is indeed a receptor-level phenomenon. Objectives: The objectives were to: A. Demonstrate the altered odour of isotopically substituted common odourants to humans B. Identify a putative causative olfactory receptor responsible for detection of the molecule identified in A Methods: The demonstration of an objective and reproducible alteration of molecular smell character to humans requires a psychophysical, in-vivo approach, but the locating that alteration at the level of the olfactory receptor requires examining the genes. I thus pursued two strands of inquiry: psychophysical and genomic. My methods can be summarised as: A. Produce "probe molecule " pairs with altered vibration but not shape by selecting and deuterating the appropriate odorant (toluene, acetophenone and Exaltone) B. Demonstrate an objective alteration of the odour after deuteration in multiple volunteers, controlling for contamination of samples, possible confounding odours, and olfactory ability; in a fully blinded experiment C. Identify an inherited specific anosmia for a characterised molecule in a proband family D. Phenotype the inherited specific anosmia E. Examine the genotype via Sanger sequencing of a known candidate gene for abnormalities which segregate with the phenotype F. Examine the genotype via exome sequencing for abnormalities which segregate with the phenotype Results: Broadly, my results demonstrate: A. For one odorant, a musk: Exaltone, isotopic substitution alters the odour character such that human subjects are able to reliably identify the deuterated from undeuterated compound in a blinded two-element forced choice test. (Objective A) B. This finding was not true for another odourant, acetophenone. C. A specific anosmia for a different musk, Galaxolide, existed in three families with musk-anosmic members. (Objective B) D. The only identified human musk receptor (OR5AN1) was not responsible for their specific anosmia to the musk Galaxolide. (Objective B) E. I identified a new previously unsuspected possible causative variant gene OR6B3 which may be responsible for their specific anosmia and a target for further research. (Objective B) Discussion: This thesis presents three major findings. Firstly, that for certain odourants, the isotopic substitution of deuterium for hydrogen, which changes the vibrational characteristics with minimal impact on the conformation, alters the odour character such that human subjects are able to reliably identify the deuterated from undeuterated compound in a blinded two-element forced choice test. This is not true for some other odourants. Secondly that the perception of a musk Galaxolide is impaired in three families without affecting the rest of their olfactory sense and that this specific anosmia is not caused by abnormalities in the only identified human musk receptor OR5AN1. Finally, I also identified a new previously unsuspected possible causative variant gene OR6B3. This project is the first objective demonstration of an isotopic variation in odour quality in humans, and although I was unable to demonstrate that this was a receptor-level property, it remains a finding that is difficult to explain by the standard mechanism of olfaction and which begs further research. Especially as it is potentially a novel method of GCPR activation which may apply to other G-Protein linked Receptors

An appropriate verbal probability lexicon for communicating surgical risks is unlikely to exist

Effective risk communication about medical procedures is critical to ethical shared decision-making. Here, we explore the potential for development of an evidence-based lexicon for verbal communication of surgical risk. We found that Ear, Nose and Throat (ENT) surgeons expressed a preference for communicating such risks using verbal probability expressions (VPEs; e.g., “high risk”). However, there was considerable heterogeneity in the expressions they reported using (Study 1). Study 2 compared ENT surgeons’ and laypeople’s (i.e., potential patients) interpretations of the ten most frequent VPEs listed in Study 1. While both groups displayed considerable variability in interpretations, lay participants demonstrated more, as well as providing systematically higher interpretations than those of surgeons. Study 3 found that lay participants were typically unable to provide unique VPEs to differentiate between the ranges of (low) probabilities required. Taken together, these results add to arguments that reliance on VPEs for surgical risk communication is ill-advised. Not only are there systematic interpretational differences between surgeons and potential patients, but the coarse granularity of VPEs raises severe challenges for developing an appropriate evidence-based lexicon for surgical risk communication. We caution against the use of VPEs in any risk context characterized by low, but very different, probabilities. (PsycInfo Database Record (c) 2022 APA, all rights reserved

Insights into the molecular triggers of parosmia based on gas chromatography olfactometry

Background Parosmia is a debilitating condition in which familiar smells become distorted and disgusting, with consequences for diet and mental health. It is a feature of post-infectious olfactory loss, particularly resulting from COVID-19. There is currently little understanding of its pathophysiology, and the prevailing hypothesis for the underlying mechanism is aberrant growth of regenerating olfactory sensory neurons after damage. Methods We use gas-chromatograph olfactometry to individually present components of a complex olfactory mixture as a rapid screening tool for assessment of both quantitative and qualitative olfactory dysfunction in those with and without parosmia. This allows them to report the associated sensory effects and to identify those molecules which are altered or parosmic in nature. Results Here we show 15 different molecular triggers of this symptom. These trigger molecules are common to many in the parosmic volunteer group and share certain characteristics such as extremely low olfactory threshold and common molecular structure Conclusions We posit that specific highly odour-active molecules are the cause of the parosmic symptom in most cases and initiate the sense of disgust, suggesting that parosmia is, at least in part, a receptor-level phenomenon

Cocaine-induced granulomatosis with polyangiitis—an under-recognized condition

Objectives: Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition./ Methods: We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021./ Results: Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23–66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered./ Conclusion: Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease

Emerging pattern of post-COVID-19 parosmia and its effect on food perception

Olfactory dysfunction is amongst the many symptoms of Long COVID. Whilst most recover their sense of smell and taste within a few weeks, about 10% of cases experience long-term problems, and their smell recovery journey often begins a few months later when everyday items start to smell distorted. This is known as parosmia. The aim of this study was to identify the key food triggers of parosmic distortions and investigate the relationship between distortion and disgust in order to establish the impact of parosmia on the diet and quality of life. In this cross-sectional study (n = 727), respondents experiencing smell distortions completed a questionnaire covering aspects of smell loss, parosmia and the associated change in the valence of everyday items. There was a significant correlation between strength and disgust (p < 0.0001), and when the selected items were reported as distorted, they were described as either unpleasant or gag-inducing 84% of the time. This change in valence associated with loss of expected pleasure and the presence of strange tastes and burning sensations must certainly lead to changes in eating behaviours and serious long-er-term consequences for mental health and quality of life

Patients’ perspectives on qualitative olfactory dysfunction: thematic analysis of social media posts

Background: The impact of qualitative olfactory disorders is underestimated. Parosmia, the distorted perception of familiar odors, and phantosmia, the experience of odors in the absence of a stimulus, can arise following postinfectious anosmia, and the incidences of both have increased substantially since the outbreak of COVID-19. Objective: The aims of this study are to explore the symptoms and sequalae of postinfectious olfactory dysfunction syndrome using unstructured and unsolicited threads from social media, and to articulate the perspectives and concerns of patients affected by these debilitating olfactory disorders. Methods: A thematic analysis and content analysis of posts in the AbScent Parosmia and Phantosmia Support group on Facebook was conducted between June and December 2020. Results: In this paper, we identify a novel symptom, olfactory perseveration, which is a triggered, identifiable, and usually unpleasant olfactory percept that persists in the absence of an ongoing stimulus. We also observe fluctuations in the intensity and duration of symptoms of parosmia, phantosmia, and olfactory perseveration. In addition, we identify a group of the most common items (coffee, meat, onion, and toothpaste) that trigger distortions; however, people have difficulty describing these distortions, using words associated with disgust and revulsion. The emotional aspect of living with qualitative olfactory dysfunction was evident and highlighted the detrimental impact on mental health. Conclusions: Qualitative and unsolicited data acquired from social media has provided useful insights into the patient experience of parosmia and phantosmia, which can inform rehabilitation strategies and ongoing research into understanding the molecular triggers associated with parosmic distortions and research into patient benefit

Anosmia as a presenting symptom of SARS-CoV-2 infection in healthcare workers – A systematic review of the literature, case series, and recommendations for clinical assessment and management

Background: Healthcare workers are at the forefront of the ongoing COVID-19 pandemic and are at high risk for both the contraction and subsequent spread of virus. Understanding the role of anosmia as an early symptom of infection may improve monitoring and management of SARS-CoV2 infection. Methodology: We conducted a systematic review of the literature of SARS-CoV2 infection/COVID-19 and anosmia to help inform management of anosmia in healthcare works. We report a case series of healthcare workers, who presented with a loss of sense of smell secondary to COVID-19 infection to demonstrate management principles. RT-PCR was used to confirm COVID-19 positivity and psychophysical testing of olfaction was performed using the British version of the University of Pennsylvania Smell Identification Test, UPSIT. Results: The systematic literature search returned 31 articles eligible for inclusion in the study and informed our recommendations for clinical assessment and management. All three healthcare professionals who presented with loss of sense of smell subsequently tested positive for SARS-CoV-2. Psychophysical testing of olfaction using the UPSIT confirmed mild and moderate microsmia in two, respectively, and normosmia at day 17 in one. Conclusions: Olfactory (± gustatory) dysfunction is indicative of COVID-19 infection and thus has important implications in the context of healthcare workers, or key workers in general, who work in close contact with others if not recognised as suffering from COVID. This leads to a potentially higher likelihood of spreading the virus. In conjunction with our literature review these findings have helped with creating recommendations on the assessment and management of olfactory dysfunction during the ongoing COVID-19 pandemic, both for healthcare workers and patients

Olfactory Nomenclature: An Orchestrated Effort to Clarify Terms and Definitions of Dysosmia, Anosmia, Hyposmia, Normosmia, Hyperosmia, Olfactory Intolerance, Parosmia, and Phantosmia/Olfactory Hallucination

BACKGROUND: Definitions are essential for effective communication and discourse, particularly in science. They allow the shared understanding of a thought or idea, generalization of knowledge, and comparison across scientific investigation. The current terms describing olfactory dysfunction are vague and overlapping. SUMMARY: As a group of clinical olfactory researchers, we propose the standardization of the terms "dysosmia," "anosmia," "hyposmia," "normosmia," "hyperosmia," "olfactory intolerance," "parosmia," and "phantosmia" (or "olfactory hallucination") in olfaction-related communication, with specific definitions in this text. KEY MESSAGES: The words included in this paper were determined as those which are most frequently used in the context of olfactory function and dysfunction, in both clinical and research settings. Despite widespread use in publications, however, there still exists some disagreement in the literature regarding the definitions of terms related to olfaction. Multiple overlapping and imprecise terms that are currently in use are confusing and hinder clarity and universal understanding of these concepts. There is a pressing need to have a unified agreement on the definitions of these olfactory terms by researchers working in the field of chemosensory sciences. With the increased interest in olfaction, precise use of these terms will improve the ability to integrate and advance knowledge in this field