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Motile ciliary disorder (MCD) has been implicated in chronic inflammatory airway diseases such as asthma and COPD.

IMPORTANCE: Three-dimensionally printed nasopharyngeal swabs (3DP swabs) have been used to mitigate swab shortages during the coronavirus disease 2019 (COVID-19) pandemic. Clinical validation for diagnostic accuracy and consistency, as well as patient acceptability, is crucial to evaluate the swab’s performance. OBJECTIVE: To determine the accuracy and acceptability of the 3DP swab for identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN, SETTING, AND PARTICIPANTS: A diagnostic study was conducted from May to July 2020 at 2 tertiary care centers in Singapore with different reference swabs (FLOQSwab [COPAN Diagnostics] or Dacron swab [Deltalab]) and swab processing techniques (wet or dry) to evaluate the performance of the 3DP swab compared with traditional, standard-of-care nasopharyngeal swabs used in health care institutions. The participants were patients with COVID-19 in the first 2 weeks of illness and controls with acute respiratory illness with negative test results for SARS-CoV-2. Paired nasopharyngeal swabs were obtained from the same nostril and tested for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction. The sequence of swabs was randomized based on odd and even participant numbers. MAIN OUTCOMES AND MEASURES: Primary outcome measures were overall agreement (OA), positive percentage agreement (PPA), and negative percentage agreement of the 3DP swab compared with reference swabs. Secondary outcome measures were the correlation of cycle threshold (Ct) values of both swabs. RESULTS: The mean (SD) age of participants was 45.4 (13.1) years, and most participants were men (87 of 89 [97.8%]), in keeping with the epidemiology of the COVID-19 pandemic in Singapore. A total of 79 patients with COVID-19 and 10 controls were recruited. Among the patients with COVID-19, the overall agreement and PPA of the 3DP swab was 91.1% and 93.5%, respectively, compared with reference swabs. The PPA was 100% for patients with COVID-19 who were tested within the first week of illness. All controls tested negative. The reverse-transcriptase polymerase chain reaction Ct values for the ORF1ab and E-gene targets showed a strong correlation (intraclass correlations coefficient, 0.869-0.920) between the 3DP and reference swab on independent testing at each institution despite differences in sample processing. Discordant results for both gene targets were observed only at high Ct values. CONCLUSIONS AND RELEVANCE: In this diagnostic study of 79 patients with COVID-19 and 10 controls, the 3DP swab performed accurately and consistently across health care institutions and could help mitigate strained resources in the escalating COVID-19 pandemic.

Introduction: The gold standard for COVID-19 diagnosis is currently a real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2. This is most commonly performed on respiratory secretions obtained via a nasopharyngeal swab. Due to supply chain limitations and high demand worldwide because of the COVID-19 pandemic, access to commercial nasopharyngeal swabs has not been assured. 3D printing methods have been used to meet the shortfall. For longer-term considerations, 3D printing may not compare well with injection molding as a production method due to the challenging scalability and greater production costs of 3D printing. Methods: To secure sufficient nasopharyngeal swab availability for our national healthcare system, we designed a novel injection molded nasopharyngeal swab (the IM2 swab). We performed a clinical diagnostic study comparing the IM2 swab to the Copan FLOQSwab. Forty patients with a known diagnosis of COVID-19 and 10 healthy controls were recruited. Paired nasopharyngeal swabs were obtained from the same nostril of each participant and tested for SARS-CoV-2 by RT-PCR. Results: When compared to the Copan FLOQswab, results from the IM2 swab displayed excellent overall agreement and positive percent agreement of 96.0% and 94.9%, respectively. There was no significant difference in mean RT-PCR cycle threshold values for the ORF1ab (28.05 vs. 28.03, p= 0.97) and E-gene (29.72 vs. 29.37, p= 0.64) targets, respectively. We did not observe any significant adverse events and there was no significant difference in patient-reported pain. Conclusion: In summary, the IM2 nasopharyngeal swab is a clinically safe, highly accurate option to commercial nasopharyngeal swabs.

Background Visual Analog Scale (VAS) as determined by the patient is recommended by the European Position Paper on Rhinosinusitis and Nasal Polyps 2012 in evaluation of the total severity of the chronic rhinosinusitis (CRS) patients’ symptoms.Objective To evaluate the correlation between evaluations performed by otorhinolaryngologists and CRS patients with commonly used systems.Methods Scores of VAS and Sino-Nasal Outcome Test-20 (SNOT-20) Chinese version were obtained from 110 CRS patients with nasal polyps (CRSwNPs, n = 61) and without nasal polyps (CRSsNPs, n = 49) before surgery, which were compared with scores of Lund–Kennedy endoscopic staging system, the Lund–Mackay computed tomography (CT) staging system, and VAS from 3 attending otorhinolaryngologists.Results The median VAS scores given by CRS patients (6.0; 4.25–7.5) do not correlate significantly with the VAS scores by the 3 otorhinolaryngologists (5.5; 4.83–6.5) with a correlation coefficient of .218 (−0.146 to 0.466). For CRS patients, there was only a moderate correlation between scores of VAS and the SNOT-20 (r= .37), and no significant difference of VAS scores between CRSwNP and CRSsNP, and between unilateral and bilateral nasal polys. For otorhinolaryngologists, a higher median VAS score was found in CRSwNP (6.0; 5.17–7.0), especially in bilateral (6.0; 5.0–7.08) and revision surgery (6.08; 5.33–7.63). The VAS scores of otorhinolaryngologists correlated significantly with the Lund–Mackay CT score (r= .7536) and Lund–Kennedy endoscopic staging (r= .5947).Conclusions VAS scores between patients and physicians are not correlated significantly in this study, but they fall within the same therapeutic range and do not change the clinical management of the patients.

The use of mometasone furoate (MF) intranasal spray in treating adenoid hypertrophy (AH) has a variable outcome due the different methods of adenoid size evaluation. The aim of our study was to evaluate the effect of MF intranasal spray in children and adolescents with AH using a reliable and consistent endoscopic evaluation.

Background Gene expression patterns (particularly, cilia-associated genes) of nasal mucosa, the first-line defense system, in allergic rhinitis (AR) are not well understood.Objective We sought to screen for AR-associated genes in inferior turbinate (IT) from patients with AR, and to validate the expression of common cilia-related genes and ciliary shedding.Methods Prime View™ Human Gene Expression Array, which consisted of more than 530 000 probes covering more than 36 000 transcripts and variants, was employed to compare individual gene expression of ITs from control subjects (n = 11) and patients with AR (n = 19). Gene ontology (GO) analysis was performed with Cytoscape software. Eight of the common cilia-related genes were validated with quantitative polymerase chain reaction. We applied a semiquantitative scoring system for immunofluorescence assay to demonstrate ciliary shedding in 5 areas per paraffin section, with individual sections being scored between 0 (normal ciliary distribution) and 1 (ciliary shedding).Results Compared with control subjects, 160 (38 upregulated and 122 downregulated) genes were differentially expressed for at least 2 folds (all P< .05) in AR. Seven GO categories were significantly enriched, 4 of which were related to cilium assembly and motility. Quantitative polymerase chain reaction validated the predicted direction of change for common cilia-related gene expression. The ciliary distribution score was significantly higher (more prominent ciliary shedding) in AR than in controls (P< .05).Conclusion The significant aberrant cilia-related gene expression, revealed by microarray assays, might be the critical driver of AR where ciliary shedding is prominent.

The traditional health care model is focused on diseases (medicine and natural science) and does not acknowledge patients’ resources and abilities to be experts in their own life based on their lived experiences. Improving health care safety, quality, and coordination, as well as quality of life, is an important aim in the care of patients with chronic conditions. Person-centered care needs to ensure that people’s values and preferences guide clinical decisions. This paper reviews current knowledge to develop (1) digital care pathways for rhinitis and asthma multimorbidity and (2) digitally enabled, person-centered care.1It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally enabled, patient-centered care. The paper includes (1) Allergic Rhinitis and its Impact on Asthma (ARIA), a 2-decade journey, (2) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (3) mHealth impact on airway diseases, (4) from guidelines to digital care pathways, (5) embedding Planetary Health, (6) novel classification of rhinitis and asthma, (7) embedding real-life data with population-based studies, (8) the ARIA-EAACI (European Academy of Allergy and Clinical Immunology) strategy for the management of airway diseases using digital biomarkers, (9) artificial intelligence, (10) the development of digitally enabled, ARIA person-centered care, and (11) the political agenda. The ultimate goal is to propose ARIA 2024 guidelines centered around the patient to make them more applicable and sustainable.

Sublingual immunotherapy (SLIT) has been proven to be safe and effective from an abundance of Western literature, but data from Asia is less complete. This review aims to examine the basic science, safety and efficacy of SLIT in Asian patients, and to determine future research needs in Asia. We performed a literature search on PUBMED, Scopus, and Cochrane Library database for articles on SLIT originating from Asian countries through Nov 2017. There were 18 randomized, double-blind, placebo-controlled trials, of which 9 involved solely paediatric subjects. Overall, sublingual immunotherapy is safe and is efficacious in Asian populations in allergic rhinitis (AR) and asthma. House dust-mite SLIT is effective in both mono- and polysensitized AR patients. Efficacy of SLIT is comparable to subcutaneous immunotherapy. Data on long term efficacy is lacking. A disproportionate majority of research originates from China and Japan, reflecting an asymmetry of access to SLIT within Asia. Significant disparities exist in the development of the allergy speciality, prescription patterns of SLIT, and pharmacological potencies of different SLIT products within and between Asian nations. We conclude that current available evidence suggests SLIT is efficacious in Asians but data quality of evidence is hampered by non-placebo controlled studies with methodological limitations. More data is needed in South and Southeast Asian populations. Future efforts may be directed towards improving access to SLIT in developing countries, standardization of SLIT dosage, and evaluating long term clinical outcomes.

Background Epiphora secondary to nasolacrimal duct obstruction is common in the pediatric age group. The mainstay treatment among these young patients has been conservative. Once epiphora becomes recalcitrant, however, an external or an endonasal approach is considered.Objective Endoscopic dacryocystorhinostomy (EDCR) entails creating an opening from the lacrimal sac directly into the nasal cavity to counteract nasolacrimal duct obstruction. We reviewed the literature to determine the effectiveness and the safety of primary EDCR to treat pediatric nasolacrimal duct obstruction.Method A literature search was conducted by using a number of medical literature data bases for the period from 1995 to 2016. The following search words were used either individually or in combination: epiphora, nasolacrimal duct obstruction, endoscopic dacryocystorhinostomy, powered endoscopic dacryocystorhinostomy, laser-assisted endoscopic dacryocystorhinostomy, children, congenital, acquired, presaccal obstruction, and postsaccal obstruction. In addition, a few articles were identified based on the experience and information provided by the senior authors (B.A., S.H., D.Y.W.). The search was conducted over a 1-month period (January 2017). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions were followed when possible.Results Only 10 original clinical research articles were selected based on our objectives and selection criteria. All the studies were at level of evidence III: nonrandomized and noncomparative prospective or retrospective case series. Altogether, 313 patients with ages that ranged from 4 months to 18 years were enrolled. A total of 352 EDCRs were performed that were either single sided (n = 313) or bilateral (n = 39). The most common causes of the obstruction were classified as congenital, followed by idiopathic, and then acquired. A meta-analysis was not performed because of the heterogeneity of the patient groups and variability of the methods used to measure outcomes.Conclusion Analysis of the results indicated that EDCR was an effective, safe therapeutic approach to treating nasolacrimal duct obstruction in pediatric patients. It should be considered as an alternative procedure to external dacryocystorhinostomy after a failed conservative treatment.

Asia-Pacific Burden of Respiratory Diseases is a cross-sectional, observational study examining the burden of disease in adults with respiratory diseases across six countries. The aim of this study was to describe health care resource use (HCRU), work impairment, cost burden, and health-related quality of life (HRQOL) associated with respiratory disease in the Asia-Pacific.

This article deals with an integrated scheduling problem for a multi-item capacity-constrained production and delivery system. The compatible jobs are firstly processed on a batching machine, and then delivered to a customer by one capacitated transporter. Each job has to be delivered to the customer before its due date. It is assumed that the job which arrives to the customer before its due date will occur an earliness penalty. The problem is to find an integrated schedule such that the total logistics cost is minimised while guaranteeing a certain customer service level. We formulate the problem as a nonlinear model, and show that this problem is intractable. Then we develop a hybrid-coding simulated annealing algorithm for solving the problem. At last, we derive a lower bound to verify performance of this proposed algorithm. Experiments show the efficiency in terms of both solution quality and running time of the proposed algorithm.

There are many practical production systems with distribution operations where finished jobs are transferred from supplier to the customer by transporters. In these systems, the coordination of production and logistics operations can help to improve overall system performance and reduce the total operation cost. This paper focuses on two categories of integrated scheduling problems. One is Integrated Scheduling of Production–Distribution Problems (ISPDP) and the other is Integrated Scheduling of Production–Inventory–Distribution Problems (ISPIDP). This paper presents a review of the state–of–the–art articles and suggests the corresponding further research directions for the above two categories of integrated scheduling problems.

Cement kilning system is the most important issue in the cement production process. Its fault recognition is the key issue which influences the quality of cement and the safety of the production process. In traditional ways, the efficiency in fault recognition is low, and the lag time of recognition is long. To improve the efficiency of the fault recognition, we propose a hybrid method based on both kernel principle component analysis (KPCA) and modified particle swarm optimisation (MPSO). First, KPCA extracts the non-linear features from the high-dimensional samples, which can eliminate the redundant information. Second, through the method of taking the features extracted by KPCA as the input of MPSO clustering, the MPSO clustering can obtain the optimal results of the recognition for cement kilning system. The simulation results show the efficiency and precision of the proposed algorithm for the practical cement kilning system.

To summarize the current knowledge of cellular and molecular mechanisms of nasal epithelial repair and remodeling during physical and pathophysiological conditions.

Background Although epithelial stem/progenitor cells have been isolated from many parts of the human airway epithelium such as lung and trachea, there is limited information in regard to stem cells in nasal epithelium. The aim of this study was to determine if (1) human nasal epithelial stem/progenitor cells (hNESPCs) can be isolated and propagatedin vitro and (2) allogeneic adult primary human fibroblasts can serve as a feeder layer for hNESPCs expansion under serum-free conditions.Methods Primary cells taken from inferior turbinate biopsy specimens (n = 3) were enzymically dissociated and plated on either allogeneic human fibroblasts or murine NIH 3T3 fibroblasts, in a chemical-defined medium supplemented with growth factors. Self-renewal, proliferation, and differentiation potential were compared.Results The optimized media were capable of supporting the undifferentiated growth and expansion of hNESPCs on both feeder cells. The doubling time and cloning efficiency of hNESPCs cultured on a human feeder layer were comparable with that cultured on 3T3 feeders. Significantly, the hNESPCs on both feeder layers could be cultured for four passages, and they can differentiate into ciliated columnar cells and goblet cells at the air–liquid interface, resembling thein vivo mucociliary airway epithelium.Conclusion Our results showed the feasibility of expanding hNESPCs for clinical purpose by using human feeder layer, avoiding components of animal source, while preserving their self-renewal and differentiation potential. This study represents an early step toward a better understanding of hNESPCs, and serum -free media plus human feeder potentially would be an ideal method for making clinical grade hNESPCs on a large scale.

This paper studies a production scheduling problem with delivery considerations in which a set of identical jobs are batch processed on a machine and then, finished jobs need to be delivered to a customer by a capacitated vehicle. Particularly, we assume the existence in production stage of an inventory which works as a buffer to balance the abilities of the two logistical stages. The objective is to find a joint schedule such that the sum of setup, production, delivery and inventory cost is minimised. We formulate the problem as a mixed integer programming model and propose four heuristic algorithms, such as genetic algorithm (GA), simulated annealing (SA), hybrid GA-SA (HGASA) and hybrid SA-GA (HSAGA), for solving it. To evaluate the proposed heuristics, we propose a lower bound by Lagrangian relaxation method. Computational experiments show that the proposed HGASA and HSAGA are efficient on randomly generated problem instances, and perform better than the simple heuristics, GA and SA.

Background The aim of this study was to evaluate effects of functional endoscopic sinus surgery (FESS) on transient nasal aerodynamic flow patterns using computational fluid dynamics (CFD) simulations.Methods A three-dimensional model of the nasal cavity was constructed from CT scans of a patient with FESS interventions on the right side of the nasal cavity. CFD simulations were then performed for unsteady aerodynamic flow modeling inside the nasal cavity as well as the sinuses.Results Comparisons of the local velocity magnitude and streamline distributions inside the left and right nasal cavity and maxillary sinus regions were presented. Because of the FESS procedures in the right nasal cavity, existences and distributions of local circulations (vortexes) were found to be significantly different for the same nasal airflow rate but at different acceleration, deceleration, or quiet phases in the maxillary sinus region on the FESS side. Because of inertia effects, local internal airflow with circulation existences was continuous throughout the whole respiration cycle. With a larger peak inspiration flow rate, the airflow intensity inside the enlarged maxillary sinus increased significantly. Possible outcomes on functional performances of the nose were also examined and discussed.Conclusion Surgical enlargements of natural ostium of the maxillary sinus will change the aerodynamic patterns inside the main nasal cavity and maxillary sinus regions, which may affect normal nasal physiological functions. Local inertia effects play more important roles for the internal nasal airflow pattern changes and thus such conventional FESS procedures should be carefully planned.

Background The aim of this study was to evaluate effects of nasal bone fractures on nasal aerodynamic flow patterns using computational fluid dynamics (CFD) simulations.Methods A three-dimensional model of nasal cavity with a nasal bone fracture was constructed from computerized tomography (CT) scans of a patient with use of software Mimics 13.0 (The Materilize Group, Leuven, Belgium). CFD simulations were performed using Fluent 6.3 (ANSYS, Inc., Canonsburg, PA) with a turbulent flow model. Numerical results were presented with velocity, streamline, and pressure contour distributions in left and right nasal cavities and were compared with those of a healthy one. Possible outcomes on functional performances or patencies of the nose were also examined and discussed.Results For the nose with a nasal bone fracture, distributions of velocity contours showed there was more airflow in the right nasal cavity than in the left one, especially for inspiration status. In the left cavity, the airflow was redirected irregularly and there were also more circulations with larger sizes, higher pressure jumps, and greater wall shear stresses. Flow partitioning in the right and left cavities was noticeable with a larger nasal resistance compared with the healthy one. When the inspirational flow rate was increased, pressure jump from the nostril to the nasopharynx increased faster.Conclusion The aerodynamic flow was redistributed greatly for the nose with a nasal bone fracture compared with the healthy one, which might affect local normal nasal functions. Such physical assessments of nasal airflow based on a model from the patients’ CT scans may help clinicians determine the best treatment in advance.

Background The aim of this study was to evaluate the effects of inferior turbinate surgery on nasal airway heating capacity using computational fluid dynamics (CFD) simulations.Methods Heat transfer simulations were performed for a normal nasal cavity and others with severely enlarged inferior turbinates, before and after three simulated surgical procedures: (1) resection of the lower third free edge of the inferior turbinate, (2) excision of the head of the inferior turbinate, and (3) radical inferior turbinate resection. The models were run with three different environmental temperatures.Results The changes of airflow pattern with the reduction of inferior turbinate affected heat transfer greatly. However, the distribution of wall heat flux showed that the main location for heat exchange was still the anterior region. Under the cold environment, the nasal cavities with the head of inferior turbinate reduction were capable of heating the inspired air to 98.40% of that of the healthy one; however, for the case with lower third of inferior turbinate excised, the temperature was 11.65% lower and for the case with radical inferior turbinate resection, 18.27% lower temperature compared with the healthy nasal cavity.Conclusion The healthy nasal cavity is able to warm up or cool down the inspiratory airflow under different environmental temperature conditions; for the nasal cavities with turbinate surgeries, partial inferior turbinate reduction can still sustain such heating capacity. However, too much or total turbinate resection may impair the normal function of temperature adjustment by nasal mucosa.

Background Nasal obstruction (NO) is a very common symptom, but its effect on nasal physiology has not been fully understood. We performed this study to determine the effect of severity of NO due to inferior turbinate hypertrophy on airflow pattern using the computational fluid dynamics simulations.Methods A three-dimensional nasal cavity model was constructed from the MRI scans of a healthy human subject. Nasal cavities corresponding to healthy, moderate, and severe NO was simulated by enlarging the inferior turbinate geometrically, which can be documented by approximately one-third reduction of the minimum cross-sectional area (1.453 cm2in the healthy nose) for the moderate (0.873 cm2) and two-thirds (0.527 cm2) for the severe obstruction.Results Total negative pressure through the nasal cavity increased during the inspiratory phase by almost twofold (-19 Pa) and threefold (-33 Pa) for moderate and severe blockage, respectively, compared with the increase of total negative pressure of -10 Pa in a healthy nose. In cases of moderate and severe blockage, a higher velocity and shear stress was observed at the nasopharynx and dorsal region of the nasal cavity. Moreover, nasal valve function will not exist in severe NO because of the changes of airflow pattern at the original nasal valve location.Conclusion Impairment of nasal airflow and physiology is evidenced in NO caused by inferior turbinate hypertrophy. Data of this study may help in predicting the aerodynamic effects of surgical correction of the inferior turbinate hypertrophy.

Histamine exerts its biological effect an humans through interaction with four histamine receptors (H1R, H2R, H3R and H4R). Histamine is a major mediator of allergic rhinitis (AR) that produces classical symptoms (sneezing, itching, rhinorrhea and congestion) both in adults and children. Nasal itch, sneezes, and rhinorrhoea are predominantly neural, while congestion is predominantly vascular. Antagonism of H1 receptors reduces majority of AR symptoms, which act primarily by the reversible and competitive inhibition of histamine action at H1R. To date, antihistamines are among the most commonly used pharmacological treatments in AR. This paper reviews the characteristic of histamine and histamine receptors in humans and the implication of antihistamine on AR.

Nasal obstruction, the cardinal symptom of persistent (perennial) allergic rhinitis, is one of the most common symptoms encountered in primary care and in specialist clinics. It is difficult to quantify by clinical examination, and, hence, objective assessment of the nasal airway is critical to rhinologic research. Nasal obstruction in persistent allergic rhinitis must be treated the year round, and therefore treatment choices, costs, and compliance all become important public health issues.

Allergic rhinitis is charterized as an inflammatory disease of the nasal mucosa. In clinical practice, H1-antihistamines and topical corticosteroids are most commonly used pharmacological agents for the treatment of allergic rhinitis. The beneficial effects of steroids depend upon their long-term anti-inflammatory effect rather than upon direct receptor antagonism. This is different to H1-antihistamines, which block both neural and vascular H1 receptors and have a clinical effect on symptoms such as nasal itching, sneezing, and rhinorrhea. H1-antihistamines are rapidly absorbed and most of them are metabolized by the hepatic cytochrome P system and begin to reduce nasal symptoms (itching and sneezing) within one hour. Understanding of both the efficacy and the pharmacological properties of these commonly used drugs in the treatment of nasal allergic inflammation and its related nasal symptoms is very important. From a clinical viewpoint, it will provide a useful guideline for an appropriate use of these drugs.

This paper reviews our previous studies on an objective evaluation of nasal symptoms, a quantitative determination of biochemical mediators, and inflammatory cells in nasal secretions of atopic patients after nasal allergen challenge (NAC) and during natural allergen exposure. The use of the micro-suction technique has proved to be a useful and reliable nasal sampling method permitting quantitative analysis of important mediators in nasal secretions. This has provided accurate data on the activity of some important inflammatory cells such as mast cells, basophils, and eosinophils in allergic rhinitis. Our studies demonstrate that a significant increase in the concentrations of histamine, tryptase, and LTC4in nasal secretions occurs within seconds or minutes after NAC, and this is accompanied by itching, sneezing, rhinorrhea, and nasal obstruction. The infiltration and activation of eosinophils are found to be the predominant condition during the late-phase reaction (LPR), which is mainly characterized by unilateral and/or bilateral nasal obstruction with little sneezing and rhinorrhea. The latter condition is found to be very much similar to the pathophysiology of patients with ongoing allergic rhinitis. In conclusion, our studies demonstrate that patients with ongoing allergic rhinitis seem to be in a continuous late phase state of eosinophil and increased mediator release, a condition that can explain priming and nonspecific hyperreactivity of the nasal mucous membrane.