Exploring Olfactory Dysfunction as a Marker of Frailty and Postoperative Outcomes in Head and Neck Cancer.

Importance: Olfactory dysfunction (OD) is increasingly recognized as a robust marker of frailty and mortality. Despite broad recognition of frailty as a critical component of head and neck cancer (HNC) care, there is no standardized frailty assessment. Objective: To assess the prevalence of OD and its association with frailty and postoperative outcomes in HNC. Design, Setting, and Participants: In this prospective cohort study with enrollment between February 17, 2021, to September 29, 2021, at a tertiary academic medical center, 85 eligible adult patients with primary, treatment-naive HNC of mucosal or cutaneous origin were included. Patients with a history of COVID-19, neurocognitive, or primary smell/taste disorders were excluded. Exposures: Prospective olfactory assessments (self-reported, visual analog scale [VAS] and psychophysical, University of Pennsylvania Smell Identification Test [UPSIT]) with concurrent frailty assessment (Risk Analysis Index [RAI]) were used. Olfactory-specific quality of life (QOL) was examined with brief Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS). Main Outcome(s) and Measure(s): The primary outcome was the prevalence of OD as assessed by VAS (0-10, no to normal smell) and UPSIT (0-40, higher scores reflect better olfaction) and its association with frailty (RAI, 0-81, higher scores indicate greater frailty). For surgical patients, secondary outcomes were associations between OD and postoperative length of stay (LOS), 30-day postoperative outcomes, and QOD-NS (0-21, higher scores indicate worse QOL). Results: Among 51 patients with HNC (mean [SD] age, 63 [10] years; 39 [77%] male participants; 41 [80%] White participants), 24 (47%) were frail, and 4 (8%) were very frail. Despite median (IQR) self-reported olfaction by VAS of 9 (8-10), 30 (59%) patients demonstrated measured OD with psychophysical testing. No meaningful association was found between self-reported and psychophysical testing (Hodges-Lehmann, <0.001; 95% CI, -2 to 1); a total of 46 (90%) patients did not report decreased olfaction-specific QOL. Median UPSIT scores were lower in frail patients (Hodges-Lehmann, 6; 95% CI, 2-12). Multivariate modeling demonstrated severe microsmia/anosmia was associated with 1.75 (95% CI, 1.09-2.80) times odds of being frail/very frail and approximately 3 days increased LOS (ß, 2.96; 95% CI, 0.29-5.62). Conclusions and Relevance: Although patients with HNC are unaware of olfactory changes, OD is common and may serve as a bellwether of frailty. In this prospective cohort study, a dose-dependent association was demonstrated between increasing degrees of OD and frailty, and the potential utility of olfaction was highlighted as a touchstone in the assessment of HNC frailty.

E-Cigarettes and Cardiopulmonary Health.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.

Formaldehyde Induces Rho-Associated Kinase Activity to Evoke Airway Hyperresponsiveness.

Formaldehyde, a common indoor air pollutant, exacerbates asthma and synergizes with allergen to induce airway hyperresponsiveness (AHR) in animal models. The mechanisms mediating formaldehyde-induced AHR remain poorly understood. We posit that formaldehyde modulates agonist-induced contractile response of human airway smooth muscle (HASM) cells to elicit AHR. HASM cells were exposed to formaldehyde or vehicle and agonist-induced intracellular Ca2+ ([Ca2+]i) and myosin light-chain phosphatase (MYPT1) phosphorylation were determined. Air-liquid interface-differentiated human bronchial epithelial (HBE) cells were exposed to formaldehyde or vehicle and cocultured with HASM cells. Agonist-induced [Ca2+]i and MYPT1 phosphorylation were determined in the cocultured HASM cells. Precision-cut human lung slices were exposed to PBS or varying concentrations of formaldehyde, and then carbachol-induced airway narrowing was determined 24 hours after exposure. HASM cells were transfected with nontargeting or nuclear factor erythroid-derived 2, like 2 (Nrf-2)-targeting small interfering RNA and exposed to formaldehyde or vehicle, followed by determination of antioxidant response (quinone oxido-reductase 1 and thioredoxin 1) and basal and agonist-induced MYPT1 phosphorylation. Formaldehyde enhanced the basal Rho-kinase activity and MYPT1 phosphorylation with little effect on agonist-induced [Ca2+]i in HASM cells. Formaldehyde induced Nrf-2-dependent antioxidant response in HASM cells, although the MYPT1 phosphorylation was independent of Nrf-2 induction. Although HBE cells exposed to formaldehyde had little effect on agonist-induced [Ca2+]i or MYPT1 phosphorylation in cocultured HASM cells, formaldehyde enhanced carbachol-induced airway responsiveness in precision-cut human lung slices. In conclusion, formaldehyde induces phosphorylation of the regulatory subunit of MYPT1, independent of formaldehyde-induced Nrf-2 activation in HASM cells. The findings suggest that the Rho kinase-dependent Ca2+ sensitization pathway plays a role in formaldehyde-induced AHR.

Computational fluid dynamics as surgical planning tool: a pilot study on middle turbinate resection.

Controversies exist regarding the resection or preservation of the middle turbinate (MT) during functional endoscopic sinus surgery. Any MT resection will perturb nasal airflow and may affect the mucociliary dynamics of the osteomeatal complex. Neither rhinometry nor computed tomography (CT) can adequately quantify nasal airflow pattern changes following surgery. This study explores the feasibility of assessing changes in nasal airflow dynamics following partial MT resection using computational fluid dynamics (CFD) techniques. We retrospectively converted the pre- and postoperative CT scans of a patient who underwent isolated partial MT concha bullosa resection into anatomically accurate three-dimensional numerical nasal models. Pre- and postsurgery nasal airflow simulations showed that the partial MT resection resulted in a shift of regional airflow towards the area of MT removal with a resultant decreased airflow velocity, decreased wall shear stress and increased local air pressure. However, the resection did not strongly affect the overall nasal airflow patterns, flow distributions in other areas of the nose, nor the odorant uptake rate to the olfactory cleft mucosa. Moreover, CFD predicted the patient's failure to perceive an improvement in his unilateral nasal obstruction following surgery. Accordingly, CFD techniques can be used to predict changes in nasal airflow dynamics following partial MT resection. However, the functional implications of this analysis await further clinical studies. Nevertheless, such techniques may potentially provide a quantitative evaluation of surgical effectiveness and may prove useful in preoperatively modeling the effects of surgical interventions.

Conductive olfactory losses in chronic rhinosinusitis? A computational fluid dynamics study of 29 patients.

BACKGROUND: Besides sensorineural factors, conductive impediments likely contribute to olfactory losses in chronic rhinosinusitis (CRS) patients, yet no conclusive evidence exists. We aimed to examine possible conductive factors using computational fluid dynamics (CFD) models. METHODS: A total of 29 CRS patients were assessed via odorant detection thresholds (ODTs), rhinomanometry (nasal resistance [NR]), acoustic rhinometry (minimum-cross-sectional area [MCA]) and computed tomography (CT) staging. CFD simulations of nasal airflow and odorant absorption to olfactory region were carried out based on individual CTs. Biopsies of olfactory epithelium (OE) were collected, cryosectioned, stained, and scored for erosion. RESULTS: Significant correlations to ODTs were found for 3 variables: odor absorption in the olfactory region (r = -0.60, p < 0.01), MCA (r = -0.40, p < 0.05), and CT staging (r = 0.42, p < 0.05). However, significant findings were limited to ODTs of the highly soluble l-carvone. Multiple regression analysis revealed that these variables combined, with the addition of NR, can account for 65% of the total variance in ODTs. CT staging correlated significantly with OE erosion (r = 0.77, p < 0.01) and can replace the latter in the regression with comparable outcomes. Partial correlations suggest the contributions of both conductive and sensorineural variables are more prominent if adjusted for the effects of the other. Olfactory loss and inflammatory factors have strong bilateral involvement, whereas conductive factors are independent between sides. As validation, CFD-simulated NRs significantly correlated with rhinomanometrically assessed NRs (r = 0.60, p < 0.01). CONCLUSION: Both conductive and sensorineural mechanisms can contribute to olfactory losses in CRS. CFD modeling provides critical guidance in understanding the role of conductive impediments in olfactory dysfunction in CRS.

Sweet taste and menthol increase cough reflex thresholds.

Cough is a vital protective reflex that is triggered by both mechanical and chemical stimuli. The current experiments explored how chemosensory stimuli modulate this important reflex. Cough thresholds were measured using a single-inhalation capsaicin challenge. Experiment 1 examined the impact of sweet taste: Cough thresholds were measured after rinsing the mouth with a sucrose solution (sweet) or with water (control). Experiment 2 examined the impact of menthol: Cough thresholds were measured after inhaling headspace above a menthol solution (menthol vapor) or headspace above the mineral oil solvent (control). Experiment 3 examined the impact of rinsing the mouth with a (bitter) sucrose octaacetate solution. Rinsing with sucrose and inhaling menthol vapor significantly increased measured cough thresholds. Rinsing with sucrose octaacete caused a non-significant decrease in cough thresholds, an important demonstration of specificity. Decreases in cough reflex sensitivity from sucrose or menthol could help explain why cough syrups without pharmacologically active ingredients are often almost as effective as formulations with an added drug. Further, the results support the idea that adding menthol to cigarettes might make tobacco smoke more tolerable for beginning smokers, at least in part, by reducing the sensitivity of an important airway defense mechanism.

Evaluating the prevalence of olfactory dysfunction in a pediatric population.

Although smell loss has several potential etiologies (e.g., head trauma, allergic rhinitis, and enlarged adenoids) that are common among children, studies evaluating the prevalence of olfactory dysfunction in the pediatric population are rare. Several challenges confront the clinician or researcher hoping to evaluate odor identification ability in young children. Children are likely to be unfamiliar with many of the odor stimuli used in adult tests and have limited ability to read and identify labels to select from alternative choices, which is the typical adult response option. Consequently, specialized forms of olfactory tests must be developed for this population. Based on the format of the San Diego Odor Identification Test(1) and the delivery system of the Brief Smell Identification Test,(2) we are developing a short form odor identification test utilizing standardized odor stimuli in which participants match 6 odorants to pictures of the odor source. The pilot version of this test is being administered to children between the ages of 3-17 as part of the pre-surgical intake evaluation at the A.I. duPont Hospital for Children and as part of basic research studies at the Monell Center. The hospital study population is broad and includes children undergoing ear, nose, and throat surgery as well as controls subjects (children undergoing general surgery), with approximately 50 children per week eligible for evaluation. To improve correct interpretation of the results, stimulus familiarity is evaluated by having the child's parent/guardian also complete the test and answer a short questionnaire about the child's experience with the various odor stimuli. The challenges confronted in studying this clinical population as well as extrapolation to larger populations will be discussed.

Assessment of smoking status based on cotinine levels in nasal lavage fluid.

Cotinine is a principal metabolite of nicotine with a substantially longer half-life, and cotinine levels in saliva, urine or serum are widely used to validate self-reported smoking status. The nasal cavity and olfactory system are directly exposed to tobacco smoke in smokers and in non-smokers who live with or work around smokers. However, despite the potential for a direct impact of tobacco smoke on the nasal epithelium and olfactory neurons, no prior studies have assessed cotinine levels in nasal mucus. We sought to determine whether cotinine levels in nasal lavage fluid (NLF) would provide a reasonable estimate of smoke exposure. We assayed cotinine using a competitive immunoassay in NLF from 23 smokers, 10 non-smokers exposed to tobacco smoke (ETS) and 60 non-smokers who did not report smoke exposure. NLF cotinine levels were significantly higher in smokers than in non-smokers, regardless of their exposure to ambient tobacco smoke. Cotinine levels in this small group of exposed non-smokers were not significantly different than those of non-exposed non-smokers. A cutoff of 1 ng/ml provided a sensitivity of 91% and a specificity of 99% for smoking status in this sample. Data were consistent with self-reported smoking status, and a cutoff of 1.0 ng/ml NLF cotinine may be used to classify smoking status. While saliva is the most easily obtained body fluid, NLF can be used to provide an objective and precise indication of smoking status and more directly reflects smoke exposure in the nasal and olfactory mucosa.

Evaluation of long-term occupational exposure to styrene vapor on olfactory function.

The primary sensory neurons of the olfactory system are chronically exposed to the ambient environment and may therefore be susceptible to damage from occupational exposure to many volatile chemicals. To investigate whether occupational exposure to styrene was associated with olfactory impairment, we examined olfactory function in 2 groups: workers in a German reinforced-plastics boat-manufacturing facility having a minimum of 2 years of styrene exposure (15-25 ppm as calculated from urinary metabolite concentrations, with historical exposures up to 85 ppm) and a group of age-matched workers from the same facility with lower styrene exposures. The results were also compared with normative data previously collected from healthy, unexposed individuals. Multiple measures of olfactory function were evaluated using a standardized battery of clinical assessments from the Monell-Jefferson Chemosensory Clinical Research Center that included tests of threshold sensitivity for phenylethyl alcohol (PEA) and odor identification ability. Thresholds for styrene were also obtained as a measure of occupational olfactory adaptation. Styrene exposure history was calculated through the use of past biological monitoring results for urinary metabolites of styrene (mandelic acid [MA], phenylglyoxylic acid [PGA]); current exposure was determined for each individual using passive air sampling for styrene and biological monitoring for styrene urinary metabolites. Current mean effective styrene exposure during the day of olfactory testing for the group of workers who worked directly with styrene resins was 18 ppm styrene (standard deviation [SD] = 14), 371 g/g creatinine MA + PGA (SD = 289) and that of the group of workers with lower exposures was 4.8 ppm (SD = 5.2), 93 g/g creatinine MA+PGA (SD = 100). Historic annual average exposures for all workers were greater by a factor of up to 6x. No differences unequivocally attributable to exposure status were observed between the Exposed and Comparison groups or between performance of either group and normative population values on thresholds for PEA or odor identification. Although odor identification performance was lower among workers with higher ongoing exposures, performance on this test is not a pure measure of olfactory ability and is influenced by familiarity with the stimuli and their sources. Consistent with exposure-induced sensory adaptation, however, elevated styrene thresholds were significantly associated with higher occupational exposures to styrene. In summary, the present study found no evidence among a cross-section of reinforced-plastics workers that current or historical exposure to styrene was associated with a general impairment of olfactory function. When taken together with prior studies of styrene-exposed workers, these results suggest that styrene is not a significant olfactory toxicant in humans at current exposure levels.

Numerical modeling of nasal obstruction and endoscopic surgical intervention: outcome to airflow and olfaction.

BACKGROUND: Mechanical obstruction of odorant flow to the olfactory neuroepithelium may be a primary cause of olfactory loss in nasal-sinus disease patients. Surgical removal of nasal obstruction may facilitate the recovery of olfactory ability. Unfortunately, quantifying the functional impact of nasal obstruction and subsequent surgical outcomes using acoustic rhinometry, rhinomanometry, or CT scans is inadequate. METHODS: Using computational fluid dynamics (CFD) techniques, we can convert patient CT scans into anatomically accurate 3D numerical nasal models that can be used to predict nasal airflow and odorant delivery rates. These models also can be rapidly modified to reflect anatomic changes, e.g., surgical removal of polyps. RESULTS: CFD modeling of one patient's nose pre- and postsurgery showed significant improvement in postsurgical ortho- and retronasal airflow and odorant delivery rate to olfactory neuroepithelium (> 1000 times), which correlated well with olfactory recovery. CONCLUSION: This study has introduced a novel technique (CFD) to calculate nasal airflow dynamics and its effects on olfaction, nasal obstruction, and sinus disease. In the future, such techniques may provide a quantitative evaluation of surgical outcome and an important preoperative guide to optimize nasal airflow and odorant delivery.

Acetic acid recovery of gynecologic liquid-based samples of apparent low squamous cellularity.

OBJECTIVE: To characterize cervicovaginal cytology samples with < 5,000 squamous cells on the initial ThinPrep slide (Cytyc Corp., Boxborough, Massachusetts, U.S.A) and to attempt sample recovery using acetic acid. STUDY DESIGN: Cervicovaginal cytology samples with <5,000 squamous cells on the original ThinPrep slide and residuum were reprocessed by adding 3 mL of 3:1 CytoLyt (Cytyc)/glacial acetic acid with production of a second slide. Both slides were reviewed for squamous cell quantitation and the presence of background material and abnormal cells. RESULTS: From a total of 1,833 cases, 147 (8.0%) were identified for reprocessing; 71 (48.3%) were grossly bloody and 58 (39.4%) grossly cloudy. Reprocessing resulted in a second slide with > 5,000 squamous cells in 116 (78.9%) cases and was most effective on cloudy samples (89.7% recovery) and bloody samples (71.8% recovery). Abnormal cells were identified in 13 (8.9%) reprocessed samples. In all but 2 cases the abnormal cells were present on the initial slide and demonstrated the same degree of abnormality as the reprocessed slide but were fewer in number. CONCLUSION: Acetic acid recovery increases squamous cell recovery when initially inadequate, reducing the number of unsatisfactory cases and in rare cases identifying a cytologically significant lesion not apparent on the original slide.

Setting occupational exposure limits in humans: contributions from the field of experimental psychology.

Psychophysical methods from the field of experimental psychology are evaluated for their utility in the derivation of occupational exposure limits (OELs) for volatile chemicals based on acute sensory irritation in humans. The lateralization threshold method, which involves the localization of trigeminal vapor to the stimulated nostril, is evaluated for its underlying assumptions, reliability and validity. Whole body exposures, on the other hand, which involve the controlled, ambient exposure of human subjects to the irritant at one or a series of concentrations for an extended period are also discussed. It is concluded that the single-organ psychophysical method is largely resistant to response bias is practical and economical. However, its reliability and validity need further assessment. Whole body exposures, while having enhanced ecological validity, are more prone to demand characteristics, response bias, and subject beliefs than the traditional psychophysical procedures. An approach that involves the exposure of only the most sensitive organs such as the eyes and nose, via a mask or facebox, could facilitate the administration and alternation of odorant/irritant stimuli over a wide range of concentrations while enhancing ecological validity.

Effect of anatomy on human nasal air flow and odorant transport patterns: implications for olfaction.

Recent studies that have compared CT or MRI images of an individual's nasal anatomy and measures of their olfactory sensitivity have found a correlation between specific anatomical areas and performance on olfactory assessments. Using computational fluid dynamics (CFD) techniques, we have developed a method to quickly (

Perceived odor and irritation of isopropanol: a comparison between naïve controls and occupationally exposed workers.

OBJECTIVES: To assess sensory irritation levels from isopropanol (IPA) unconfounded by subjective evaluations of odor for comparison against the recommended exposure limits (400 ppm threshold limit value (TLV); American Conference of Governmental Industrial Hygienists). METHOD: The lateralization method was used to assess intra-nasal irritation thresholds for IPA, while odor detection thresholds were also measured. Thresholds for 1-butanol and phenyl ethyl alcohol (PEA) were obtained as positive and negative irritant controls. To compare potency and hedonic characteristics, subjects provided subjective ratings of odor, irritation and annoyance intensity for three concentrations of each chemical. Workers occupationally exposed to IPA ( n=26) were compared with previously unexposed controls ( n=26). RESULTS: The (geometric) mean odor detection threshold for IPA was slightly higher among exposed workers than controls (39 ppm vs. 11 ppm). Lateralization thresholds measuring intra-nasal irritation were elevated when compared with controls (6,083 ppm in exposed workers vs. 3,361 ppm in naïve controls), with a significantly higher proportion of phlebotomists being unable to lateralize the maximum concentration regarded as safe, than controls. Calculations of the 6th percentile for lateralization thresholds revealed that 95% of the sample did not experience sensory irritation below 512 ppm. Thus, while odor detection thresholds were well below the current recommended exposure limits, the irritation thresholds were well above these values. The odor, irritation and annoyance from IPA was perceived, on average, as between weak and almost strong, from lowest to highest concentration. CONCLUSIONS: The results indicate that current exposure guidelines would be adequately protective of the acute adverse effect of nasal sensory irritation, as operationally defined by the intra-nasal lateralization threshold. Exposures to higher concentrations should perhaps be evaluated on the basis of existing knowledge about systemic, rather than local (e.g., irritation), toxic effects. IPA appears to be a weak sensory irritant and occupational exposure to IPA appears to elicit small changes in sensitivity that do not generalize to other odorants (e.g., PEA and 1-butanol) and are likely to be reversible.

Acute sensory irritation from exposure to isopropanol (2-propanol) at TLV in workers and controls: objective versus subjective effects.

OBJECTIVES: Phlebotomists occupationally exposed to isopropanol (IPA) (2-propanol) and naïve controls (n = 12 per group) were exposed to the time-weighted average threshold limit value of 400 p.p.m. IPA for 4 h in an environmental chamber to investigate: (i) acute effects of sensory irritation using subjective health symptom reports and objective, physiological end-points; and (ii) differences in measured effects in relation to exposure history. METHODS: Before, during and after exposure subjects gave self-reports of health complaints. During exposure subjects rated the intensity of the odor, sensory irritation and annoyance. Objective end-points of ocular hyperemia, nasal congestion, nasal secretion and respiration were obtained at various times before, during and after exposure. Results were compared with exposure to phenylethyl alcohol (PEA), a negative control for irritation, and to clean air (CA), a negative control for odor and irritation, using a within-subjects design. RESULTS: Significantly higher intensity ratings of odor, irritation and annoyance were reported during the exposure to IPA, when compared with exposure to CA or PEA. Nevertheless, the overall level of reported sensory irritation to IPA was low and perceived as 'weak' on average. Health symptom ratings were not significantly elevated for IPA as compared with PEA or CA exposure. The only physiological end-point that showed a change exclusively in the IPA condition was respiration frequency: relative to baseline, respiration frequency increased in response to IPA in both groups. No differences were encountered between the occupationally exposed and the control groups. CONCLUSIONS: The increase in respiration frequency in response to IPA may reflect either a reflexive change due to sensory irritation (an autonomic event) or a voluntary change in breathing in response to perception of an unpleasant, solvent-like odor (a physiological event caused by cognitive mediation). Our findings on objective end-points, including nasal and ocular sensory irritation, did not confirm subjective irritation reports. Irritation reports and odor intensity decreased, rather than increased, over time, lending credence to the cognitive argument and suggesting that the elevated subjective responses to IPA may be mediated by responses to its odor.