Male proboscis monkey cranionasal size and shape is associated with visual and acoustic signalling.

The large nose adorned by adult male proboscis monkeys is hypothesised to serve as an audiovisual signal of sexual selection. It serves as a visual signal of male quality and social status, and as an acoustic signal, through the expression of loud, low-formant nasalised calls in dense rainforests, where visibility is poor. However, it is unclear how the male proboscis monkey nasal complex, including the internal structure of the nose, plays a role in visual or acoustic signalling. Here, we use cranionasal data to assess whether large noses found in male proboscis monkeys serve visual and/or acoustic signalling functions. Our findings support a visual signalling function for male nasal enlargement through a relatively high degree of nasal aperture sexual size dimorphism, the craniofacial region to which nasal soft tissue attaches. We additionally find nasal aperture size increases beyond dental maturity among male proboscis monkeys, consistent with the visual signalling hypothesis. We show that the cranionasal region has an acoustic signalling role through pronounced nasal cavity sexual shape dimorphism, wherein male nasal cavity shape allows the expression of loud, low-formant nasalised calls. Our findings provide robust support for the male proboscis monkey nasal complex serving both visual and acoustic functions.

Numerical simulation of the influence of nasal cycle on nasal airflow.

To study the characteristics of nasal airflow in the presence of nasal cycle by computational fluid dynamics. CT scan data of a healthy Chinese individual was used to construct a three-dimensional model of the nasal cavity to be used as simulation domain. A sinusoidal airflow velocity is set at the nasal cavity entrance to reproduce the breathing pattern of a healthy human. There was a significant difference in the cross-sectional area between the two sides of the nasal cavity. Particularly, the decongested side is characterized by a larger cross-section area, and consequently, by a larger volume with respect to the congested side. The airflow velocity, pressure, and nasal resistance were higher on the congested narrow side. The temperature regulation ability on the congested narrow side was stronger than that on the decongested wider side. During the nasal cycle, there are differences in the nasal cavity function between the congested and decongested sides. Therefore, when evaluating the impact of various factors on nasal cavity function, the nasal cycle should be considered.

Assessing nasal airway resistance and symmetry: An approach to global perspective through computational fluid dynamics.

This study aimed to explore the variability in nasal airflow patterns among different sexes and populations using computational fluid dynamics (CFD). We focused on evaluating the universality and applicability of dimensionless parameters R (bilateral nasal resistance) and ϕ (nasal flow asymmetry), initially established in a Caucasian Spanish cohort, across a broader spectrum of human populations to assess normal breathing function in healthy airways. In this retrospective study, CT scans from Cambodia (20 males, 20 females), Russia (20 males, 18 females), and Spain (19 males, 19 females) were analyzed. A standardized CFD workflow was implemented to calculate R-ϕ parameters from these scans. Statistical analyses were conducted to assess and compare these parameters across different sexes and populations, emphasizing their distribution and variances. Our results indicated no significant sex-based differences in the R parameter across the populations. However, moderate sexual dimorphism in the ϕ parameter was observed in the Cambodian group. Notably, no geographical differences were found in either R or ϕ parameters, suggesting consistent nasal airflow characteristics across the diverse human groups studied. The study also emphasized the importance of using dimensionless variables to effectively analyze the relationships between form and function in nasal airflow. The observed consistency of R-ϕ parameters across various populations highlights their potential as reliable indicators in both medical practice and further CFD research, particularly in diverse human populations. Our findings suggest the potential applicability of dimensionless CFD parameters in analyzing nasal airflow, highlighting their utility across diverse demographic and geographic contexts. This research advances our understanding of nasal airflow dynamics and underscores the need for additional studies to validate these parameters in broader population cohorts. The approach of employing dimensionless parameters paves the way for future research that eliminates confounding size effects, enabling more accurate comparisons across different populations and sexes. The implications of this study are significant for the advancement of personalized medicine and the development of diagnostic tools that accommodate individual variations in nasal airflow.

Effects of decongestion on nasal cavity air conditioning efficiency: a CFD cohort study.

Decongestion reduces blood flow in the nasal turbinates, enlarging the airway lumen. Although the enlarged airspace reduces the trans-nasal inspiratory pressure drop, symptoms of nasal obstruction may relate to nasal cavity air-conditioning. Thus, it is necessary to quantify the efficiency of nasal cavity conditioning of the inhaled air. This study quantifies both overall and regional nasal air-conditioning in a cohort of 10 healthy subjects using computational fluid dynamics simulations before and after nasal decongestion. The 3D virtual geometry model was segmented from magnetic resonance images (MRI). Each subject was under two MRI acquisitions before and after the decongestion condition. The effects of decongestion on nasal cavity air conditioning efficiency were modelled at two inspiratory flowrates: 15 and 30 L min-1 to represent restful and light exercise conditions. Results show inhaled air was both heated and humidified up to 90% of alveolar conditions at the posterior septum. The air-conditioning efficiency of the nasal cavity remained nearly constant between nostril and posterior septum but dropped significantly after posterior septum. In summary, nasal cavity decongestion not only reduces inhaled air added heat by 23% and added moisture content by 19%, but also reduces the air-conditioning efficiency by 35% on average.

Beyond skeletal studies: A computational analysis of nasal airway function in climate adaptation.

OBJECTIVES: Ecogeographic variation in human nasal anatomy has historically been analyzed on skeletal morphology and interpreted in the context of climatic adaptations to respiratory air-conditioning. Only a few studies have analyzed nasal soft tissue morphology, actively involved in air-conditioning physiology. MATERIALS AND METHODS: We used in vivo computer tomographic scans of (N = 146) adult individuals from Cambodia, Chile, Russia, and Spain. We conducted (N = 438) airflow simulations during inspiration using computational fluid dynamics to analyze the air-conditioning capacities of the nasal soft tissue in the inflow, functional, and outflow tract, under three different environmental conditions: cold-dry; hot-dry; and hot-humid. We performed statistical comparisons between populations and sexes. RESULTS: Subjects from hot-humid regions showed significantly lower air-conditioning capacities than subjects from colder regions in all the three conditions, specifically within the isthmus region in the inflow tract, and the anterior part of the internal functional tract. Posterior to the functional tract, no differences were detected. No differences between sexes were found in any of the tracts and under any of the conditions. DISCUSSION: Our statistical analyses support models of climatic adaptations of anterior nasal soft tissue morphology that fit with, and complement, previous research on dry skulls. However, our results challenge a morpho-functional model that attributes air-conditioning capacities exclusively to the functional tract located within the nasal cavity. Instead, our findings support studies that have suggested that both, the external nose and the intra-facial soft tissue airways contribute to efficiently warming and humidifying air during inspiration. This supports functional interpretations in modern midfacial variation and evolution.

Overview of Nasal Airway and Nasal Breathing Evaluation.

Several methods are available for evaluating nasal breathing and nasal airflow, as this evaluation may be made from several different perspectives.Physiologic methods for nasal airway evaluation directly measure nasal airflow or nasal airway resistance, while anatomical methods measure nasal airway dimensions. Subjective methods evaluate nasal breathing through several validated patient-reported scales assessing nasal breathing. Computational fluid dynamics evaluates nasal airflow through the analysis of several physics' variables of the nasal airway.Being familiar to these methods is of utmost importance for the nasal surgeon to be able to understand data provided by the different methods and to be able to choose the combination of evaluation methods that will provide the information most relevant to each clinical situation.

Peak Nasal Inspiratory Flow (PNIF) for Nasal Breathing Evaluation.

Measuring nasal airflow and nasal breathing has been a major goal of rhinology. Many objective methods for measuring nasal airflow or nasal airway resistance or dimensions provide valuable data but are time-consuming and require expensive equipment and trained technicians, thus making these methods less practical for clinical practice. Peak nasal inspiratory flow (PNIF) measurement is fast, unexpensive, noninvasive, and able to provide an objective evaluation of nasal airflow in real-time. Unilateral PNIF measurements allow separated evaluation of each side of the nasal airway and may prove particularly useful when clinical assessment detects significant asymmetry between both nasal cavities.PNIF measurements are most useful for assessing changes in nasal airflow achieved by any form of therapy, including surgical treatment of the nasal airway. These measurements generally correlate with other objective methods for nasal airway evaluation, but not unequivocally with patient-reported evaluation of nasal breathing. Nevertheless, as low PNIF values prevent the sensation of a suitable nasal breathing, PNIF measurement may also prove useful to optimize the decision of how to best address patients with complaints of nasal airway obstruction.

Structure-function relationships in the nasal cavity of Arctic and subtropical seals.

The heating and moistening of inhaled air, and the cooling and moisture removal from exhaled air, are crucial for the survival of animals under severe environmental conditions. Arctic mammals have evolved specific adaptive mechanisms to retain warmth and water and restrict heat loss during breathing. Here, the role of the porous turbinates of the nasal cavities of Arctic and subtropical seals is studied with this in mind. Mass and energy balance equations are used to compute the time-dependent temperature and water vapor profiles along the nasal passage. A quasi-1D model based on computed tomography images of seal nasal cavities is used in numerical simulations. Measured cross-sectional areas of the air channel and the perimeters of the computed tomography slices along the nasal cavities of the two seal species are used. The model includes coupled heat and vapor transfer at the air-mucus interface and heat transfer at the interfaces between the tissues and blood vessels. The model, which assumes constant blood flow to the nose, can be used to predict the temperature of the exhaled air as a function of ambient temperature. The energy dissipation (entropy production) in the nasal passages was used to measure the relative importance of structural parameters for heat and water recovery. We found that an increase in perimeter led to significant decreases in the total energy dissipation. This is explained by improved conditions for heat and water transfer with a larger complexity of turbinates. Owing to differences in their nasal cavity morphology, the Arctic seal is expected to be advantaged in these respects relative to the subtropical seal.

Soft tissues influence nasal airflow in diapsids: Implications for dinosaurs.

The nasal passage performs multiple functions in amniotes, including olfaction and thermoregulation. These functions would have been present in extinct animals as well. However, fossils preserve only low-resolution versions of the nasal passage due to loss of soft-tissue structures after death. To test the effects of these lower resolution models on interpretations of nasal physiology, we performed a broadly comparative analysis of the nasal passages in extant diapsid representatives, e.g., alligator, turkey, ostrich, iguana, and a monitor lizard. Using computational fluid dynamics, we simulated airflow through 3D reconstructed models of the different nasal passages and compared these soft-tissue-bounded results to similar analyses of the same airways under the lower-resolution limits imposed by fossilization. Airflow patterns in these bony-bounded airways were more homogeneous and slower flowing than those of their soft-tissue counterparts. These data indicate that bony-bounded airway reconstructions of extinct animal nasal passages are far too conservative and place overly restrictive physiological limitations on extinct species. In spite of the diverse array of nasal passage shapes, distinct similarities in airflow were observed, including consistent areas of nasal passage constriction such as the junction of the olfactory region and main airway. These nasal constrictions can reasonably be inferred to have been present in extinct taxa such as dinosaurs.

Intranasal trigeminal sensitivity to mechanical stimuli is associated with the perception of nasal patency.

PURPOSE: The aim of this prospective study was to examine the characteristics of a clinical test for the assessment of nasal trigeminal sensitivity to mechanical stimuli and its association with the perception of nasal patency. METHODS: Thirty-two normosmic healthy subjects participated (17 women and 15 men; age = 26 ± 3 years). Precisely defined air puffs were used with a flow rate of 2L/min for mechanical stimulation. They were presented to the nasal vestibule, nasal septum, and inferior turbinate with various stimulus durations. Thresholds were measured by single-staircase stimuli with changes in stimulus duration in steps of 10 ms. Trigeminal suprathreshold intensity was rated by subjects for stimulus durations of 200, 300, 400, and 500 ms. Test-retest reliability was examined by intraclass correlations (ICCs) and Bland-Altman plot with limits of agreement. Pearson's correlations were calculated between self-rated nasal patency and nasal trigeminal sensitivity. RESULTS: As indicated by trigeminal threshold and suprathreshold intensities, the nasal vestibule is the most sensitive area among the three locations, followed by the nasal septum and the inferior turbinate (p < 0.001). Coefficients of correlations between test and retest were 0.76 for thresholds, and 0.56 suprathreshold intensities (p < 0.001). The Bland-Altman analysis showed a good agreement between test-retest values. In addition, significant positive associations between trigeminal suprathreshold intensities and self-rated nasal obstruction were found at the inferior turbinate (r = 0.4, p < 0.05). CONCLUSION: Reliable assessment of nasal trigeminal sensitivity for air puffs appears to be possible. Nasal trigeminal suprathreshold sensitivity to mechanical stimuli is associated with the perception of nasal patency at the inferior turbinate. This opens a window into the assessment of the perception of nasal airflow in various clinical purposes, especially for patients with sinonasal diseases.

Factors affecting nasal drug delivery and design strategies for intranasal drug delivery. / é¼»è ”è¯ç‰©é€’é€çš„å½±å“å› ç´ å’Œæé«˜é€’é€æ•ˆçŽ‡çš„è®¾è®¡ç­–ç•¥.

Intranasal drug delivery system is a non-invasive drug delivery route with the advantages of no first-pass effect, rapid effect and brain targeting. It is a feasible alternative to drug delivery via injection, and a potential drug delivery route for the central nervous system. However, the nasal physiological environment is complex, and the nasal delivery system requires "integration of medicine and device". Its delivery efficiency is affected by many factors such as the features and formulations of drug, delivery devices and nasal cavity physiology. Some strategies have been designed to improve the solubility, stability, membrane permeability and nasal retention time of drugs. These include the use of prodrugs, adding enzyme inhibitors and absorption enhancers to preparations, and new drug carriers, which can eventually improve the efficiency of intranasal drug delivery. This article reviews recent publications and describes the above mentioned aspects and design strategies for nasal intranasal drug delivery systems to provide insights for the development of intranasal drug delivery systems.

P300 Following Four Voluntarily Regulated Yoga Breathing Practices and Breath Awareness.

Attention was influenced by yoga breathing in previously published research. Each yoga breathing practice uniquely modifies specific breath characteristics. Differences in the study designs, assessment methods and interventions resulted in difficulty in comparing effects between yoga breathing practices. This study aimed (i) to compare four yoga breathing practices on attention using an auditory oddball task and (ii) to determine cardiac autonomic activity associated with attention using heart rate variability. P300 event related potential was recorded simultaneously with heart rate variability before and after 18-minute periods each of (i) high frequency yoga breathing (with increased breath frequency), (ii) bellows yoga breathing (with increased depth of respiration), (iii) alternate nostril yoga breathing (with alternate nostril patency), (iv) bumblebee yoga breathing (with prolonged exhale), (v) breath awareness (with attention to the breath) and (vi) quiet seated rest as control in 38 yoga experienced males (average age ± SD; 24.08 ± 4.01 years). The six sessions were on separate, randomly allocated days. The P300 peak amplitude recorded at Pz was significantly increased after four yoga breathing practices (Bonferroni adjusted post-hoc tests, repeated measures ANOVA). No significant changes were noted in heart rate variability following yoga breathing or control sessions. These findings suggest that the four yoga breathing practices increase the attentional neural resources engaged for this auditory oddball task, irrespective of the characteristic of breath uniquely regulated in the four yoga breathing practices.

Numerical study on the distribution of nitric oxide concentration in the nasal cavity of healthy people during breathing.

BACKGROUND: In the nasal cavity, nitric oxide (NO) is involved in many physiological functions, including antibacterial and antiviral activity, promotion of nasal mucociliary clearance, and regulation of blood vessel expansion in the nasal mucosa. We investigated the distribution of NO concentration in the nasal cavity of healthy individuals during breathing. METHODS: A three-dimensional numerical model of the nasal airway, including the bilateral maxillary sinuses, was created to simulate NO distribution in the nasal cavity during normal breathing. The effect of different nasal airflow velocities and NO concentrations in the maxillary sinus on NO distribution in the nasal cavity was evaluated. The NO concentration in the nasal exhalation of 50 healthy people in Dalian was measured using an NO analyzer, and the growth rate of the NO concentration in the nasal cavity was measured under breath-holding conditions. RESULTS: The distribution of NO concentration in the nasal cavity of healthy people during breathing was obtained from numerical simulation results. Lower the airflow rate, higher was the NO concentration and greater was the diffusion range in the nasal cavity. The NO concentration in the nasal cavity increased with an increase in its concentration in the maxillary sinus, indicating a linear relationship. The NO concentration in the nasal exhalation of healthy people in Dalian and the growth rate of the NO concentration in the nasal cavity under breath-holding conditions were obtained through experiments. The numerical results correspond with the experimental results. CONCLUSIONS: The NO entered the nasal cavity mainly by diffusion and followed the convection flow of the respiratory air in the nasal cavity. NO concentration in the nasal cavity was related to the respiratory airflow velocity and NO concentration in the maxillary sinus. During inspiration, NO was present only in the nasal airway posterior to the maxillary sinus ostium, whereas during exhalation, the exhaled NO diffusely distributed throughout the nasal cavity.

Impact of the Location of Nasal Septal Deviation on the Nasal Airflow and Air Conditioning Characteristics.

The location of nasal septal deviation (NSD) directly impacts nasal physiology. The objective is to examine, using computational fluid dynamics (CFD), the difference in the airflow and air conditioning characteristics according to the location of NSD. Twenty patients with septal deviation were divided into two: 10 caudal septal deviation (CSD) and 10 posterior septal deviation (PSD). Physiological variables were compared and numerical models for nasal cavity were created with CT scans. Cases with CSD had distinctive features including restricted airflow partition, larger nasal resistance, and decreased surface heat flux in the more obstructed side (MOS), and lower humidity and air temperature in the lesser obstructed side (LOS). Physiological differences were observed according to the location of septal deviation, CSD cases exhibit significantly more asymmetric airflow characteristics and air conditioning capacity between LOS and MOS.

Factors affecting nasal drug delivery and design strategies for intranasal drug delivery / 浙江大学学报·医学版

Intranasal drug delivery system is a non-invasive drug delivery route with the advantages of no first-pass effect, rapid effect and brain targeting. It is a feasible alternative to drug delivery via injection, and a potential drug delivery route for the central nervous system. However, the nasal physiological environment is complex, and the nasal delivery system requires "integration of medicine and device". Its delivery efficiency is affected by many factors such as the features and formulations of drug, delivery devices and nasal cavity physiology. Some strategies have been designed to improve the solubility, stability, membrane permeability and nasal retention time of drugs. These include the use of prodrugs, adding enzyme inhibitors and absorption enhancers to preparations, and new drug carriers, which can eventually improve the efficiency of intranasal drug delivery. This article reviews recent publications and describes the above mentioned aspects and design strategies for nasal intranasal drug delivery systems to provide insights for the development of intranasal drug delivery systems.

Detailed comparative analysis of environmental microparticle deposition characteristics between human and monkey nasal cavities using a surface mapping technique.

Inhaled particulate matter is associated with nasal diseases such as allergic rhinitis, rhinosinusitis and neural disorders. Its health risks on humans are usually evaluated by measurements on monkeys as they share close phylogenetic relationship. However, the reliability of cross-species toxicological extrapolation is in doubt due to physiological and anatomical variations, which greatly undermine the reliability of these expensive human surrogate models. This study numerically investigated in-depth microparticle transport and deposition characteristics on human and monkey (Macaca fuscata) nasal cavities that were reconstructed from CT-images. Deposition characteristics of 1-30µm particles were investigated under resting and active breathing conditions. Similar trends were observed for total deposition efficiencies and a single correlation using Stokes Number was fitted for both species and both breathing conditions, which is convenient for monkey-human extrapolation. Regional deposition patterns were carefully compared using the surface mapping technique. Deposition patterns of low, medium and high inertial particles, classified based on their total deposition efficiencies, were further analyzed in the 3D view and the mapped 2D view, which allows locating particle depositions on specific nasal regions. According to the particle intensity contours and regional deposition profiles, the major differences were observed at the vestibule and the floor of the nasal cavity, where higher deposition intensities of medium and high inertial particles were shown in the monkey case than the human case. Comparisons of airflow streamlines indicated that the cross-species variations of microparticle deposition patterns are mainly contributed by two factors. First, the more oblique directions of monkey nostrils result in a sharper airflow turn in the vestibule region. Second, the monkey's relatively narrower nasal valves lead to higher impaction of medium and high inertial particles on the nasal cavity floor. The methods and findings in this study would contribute to an improved cross-species toxicological extrapolation between human and monkey nasal cavities.

Interspecies comparison of heat and mass transfer characteristics in monkey and human nasal cavities.

Air conditioning in the nasal airways plays an important role in regulating ambient atmospheric temperature and humidity conditions of the inhaled air. Inevitably, it may alter the behaviour and fate of inhaled ambient aerosols within the human respiratory airways due to hygroscopic growth and droplet evaporation, which is a phenomena of variations in particle sizes due to physical and chemical reactions on particle surfaces in different temperature and humidity fields. Although laboratory animals have been widely used to predict health effects of human exposure to ambient substances, the nasal temperature and humidity responses in animal surrogates and human nasal cavities are still less-investigated. This paper provides a comparative study between two monkey and two human nasal subjects under the same ambient temperature and humidity conditions, where nasal models were reconstructed from CT images and the heat and mass transfer process incorporating with the intricate nose anatomy were modelled by the computational fluid dynamics (CFD) approach. Present model comparison revealed that the monkey nasal models can reach equilibrium temperature and moisture state for inhaled ambient air in a much shorter distance compared to the human models. This indicate that heat transfer in the monkey models is more effective compared to the human models due to having a higher complexity coefficient and a smaller hydraulic radius. Hence, in order to achieve comparable or similar inhalation exposure patterns in animal surrogates, corresponding adjustments such as changing the size of released particles, or the inhalation flow rates, to achieve comparable particle Stokes number are needed. The outcomes of this study would provide informative insights for future inhalation toxicology studies related to hygroscopic materials and targeted drug delivery through nasal airways.

3D numerical simulation of hot airflow in the human nasal cavity and trachea.

BACKGROUND AND OBJECTIVE: The primary function of the human respiratory system is gas and moisture exchange, and conditioning inhaled air to prevent damage to the lungs and alveoli. In a fire incident, exposed soft tissues contract and the respiratory system may be severely damaged, possibly leading to respiratory failure and even respiratory arrest. The purpose of this study is to numerically simulate hot airflow in the human upper airway and trachea to investigate heat and moisture transfer and induced thermal injuries. METHODS: For analysis, the airflow is assumed to be laminar and steady, and simulations have been carried out at volume flow rates of 5 and 10 L/min, inlet temperatures of 70-240 °C, and relative humidity up to 40%. The mucous layer and surrounding tissues are incorporated into the conducting zone of the model. The blood perfusion is considered at different rates up to 5(Kg/m3.s) to regulate the temperature, and the vapor concentration is coupled with the energy equation. RESULTS: The temperature and humidity distribution on the airway wall were calculated for all the studied conditions in order to find the mild and severe burn for different inhaled air temperatures. At the inlet temperatures of 70 and 100 °C, there are mild burns in several nasal cavity regions. At the higher temperatures of 160 and 200 °C, these areas suffer from severe burns and mild burns occur at the superior parts and nasopharynx. Rapid evaporation and tissue destruction will be observed if anyone breathes the 240 °C air. CONCLUSIONS: The results show that the hot inlet temperatures drop below 44 °C when passing through the upper airway, and the lower airway was not affected. Increasing the inlet temperature from 70 to 240 °C extends the burns from mild to severe and the affected areas from the beginning of the nasal cavity to the pharynx.

Importance of the numerical schemes in the CFD of the human nose.

Computational fluid dynamics of the air flow in the human nasal cavities, starting from patient-specific Computer Tomography (CT) scans, is an important tool for diagnostics and surgery planning. However, a complete and systematic assessment of the influence of the main modelling assumptions is still lacking. In designing such simulations, choosing the discretization scheme, which is the main subject of the present work, is an often overlooked decision of primary importance. We use a comparison framework to quantify the effects of the major design choices. The reconstructed airways of a healthy, representative adult patient are used to set up a computational study where such effects are systematically measured. It is found that the choice of the numerical scheme is the most important aspect, although all varied parameters impact the solution noticeably. For a physiologically meaningful flow rate, changes of the global pressure drop up to more than 50% are observed; locally, velocity differences can become extremely significant. Our results call for an improved standard in the description of this type of numerical studies, where way too often the order of accuracy of the numerical scheme is not mentioned.

[Correlation between nasal mucosal temperature change and nasal airflow perception].

The mechanism of nasal airflow perception remains little known. It is currently believed that the main mechanism for perceiving nasal patency is to activate transient receptor potential melastatin subtype 8. Computer fluent dynamics show that increased airflow and heat flux are associated with higher subjective scores. Similarly, physical measurements of the nasal cavity using a temperature probe show a correlation between the lower nasal mucosa temperature and better results. Trigeminal function detection also indirectly confirms this. This literature review aimed to explore the role of nasal mucosal temperature change in the subjective perception of nasal patency and the secondary aim was to appraise the relevant evidence about the mechanism.