Mindset in Food Immunotherapy

Mindset in Food Immunotherapy | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Allergy and Immunology This is a preprint and has not been peer reviewed. Data may be preliminary. 19 May 2025 V1 Latest version Share on Mindset in Food Immunotherapy Authors : Dora Zhou F 0009-0001-7896-9765 [email protected] , Pete Smith , and Adam Fox Authors Info & Affiliations https://doi.org/10.22541/au.174764733.34407929/v1 240 views 206 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Abstract Mindset – the attitudes, beliefs, and expectations an individual holds – plays a critical yet often underappreciated role in managing food allergies, especially during oral immunotherapy (OIT). Emotional states such as stress and anxiety can amplify allergic responses and shape how patients experience OIT, influencing adherence and perceived risk. Experimental evidence from behavioural conditioning, neuroimmunology, and placebo research demonstrates that psychological factors can modulate immune function, even in the absence of allergens, through learned associations and expectation-driven physiological responses. Symptom framing also matters. Describing mild OIT symptoms as “positive signals” of progress, rather than “side effects,” may improve emotional responses and support treatment retention. Patient education requires recognition of the patient and parent mindset as emphasised in the Preparing Patients for Oral Immunotherapy (PPOINT) expert consensus guidelines. This acknowledges the mental challenges that OIT can bring and helps to empower patients and their families. Additionally, stress-induced changes to gut barrier integrity and immune activation underline the biological plausibility of mindset-driven effects. Notably, emerging research also shows that immune sensing of allergens can directly shape behaviour, with allergic sensitisation prompting avoidance even in the absence of anaphylaxis. Collectively, these findings support the integration of mindset, emotional regulation, and communication strategies into OIT protocols to reduce adverse events and enhance long-term outcomes. This perspective advocates for a broader application of behavioural science in allergy management, emphasising its feasibility, safety, and clinical relevance. Mindset in Food Immunotherapy Dora F Zhou 1 MBBS, Peter K Smith 2 BMedSci, MBBS, FRACP, PhD and Adam Fox 3 MBBS, FRCP (Paed), MD 1. Barts and the London School of Medicine and Dentistry, London, United Kingdom. 2. Clinical Medicine, Griffith University, Southport Queensland Australia. Orcid ID: 0000-0002-2629-8963 3. Paediatric Allergy, Evelina London Children’s Hospital, London, United Kingdom. Orcid ID: 0000-0002-3533-9798 Abstract Mindset – the attitudes, beliefs, and expectations an individual holds – plays a critical yet often underappreciated role in managing food allergies, especially during oral immunotherapy (OIT). Emotional states such as stress and anxiety can amplify allergic responses and shape how patients experience OIT, influencing adherence and perceived risk. Experimental evidence from behavioural conditioning, neuroimmunology, and placebo research demonstrates that psychological factors can modulate immune function, even in the absence of allergens, through learned associations and expectation-driven physiological responses. Symptom framing also matters. Describing mild OIT symptoms as “positive signals” of progress, rather than “side effects,” may improve emotional responses and support treatment retention. Patient education requires recognition of the patient and parent mindset as emphasised in the Preparing Patients for Oral Immunotherapy (PPOINT) expert consensus guidelines. This acknowledges the mental challenges that OIT can bring and helps to empower patients and their families. Additionally, stress-induced changes to gut barrier integrity and immune activation underline the biological plausibility of mindset-driven effects. Notably, emerging research also shows that immune sensing of allergens can directly shape behaviour, with allergic sensitisation prompting avoidance even in the absence of anaphylaxis. Collectively, these findings support the integration of mindset, emotional regulation, and communication strategies into OIT protocols to reduce adverse events and enhance long-term outcomes. This perspective advocates for a broader application of behavioural science in allergy management, emphasising its feasibility, safety, and clinical relevance. Key Message The mindset of both patients and their parents can significantly influence the outcome of food allergen immunotherapy. Prior experiences of allergic reactions may trigger physiological responses even without allergen exposure, due to learned associations and neuroimmune mechanisms. Reframing symptoms as positive signs of progress, rather than side effects, may support adherence and emotional resilience. Communicating these concepts clearly to families can help facilitate the initiation, progression, and successful completion of immunotherapy. Mindset, defined as an individual’s established set of beliefs and attitudes that shape how they view the world around them, is a critical but often overlooked component in allergy management. Emotional states such as stress and anxiety have been shown to amplify the severity and frequency of allergic responses. This interaction also has the potential to impact reactions to oral immunotherapy (OIT), a promising treatment modality for food allergy. While OIT offers significant benefits, such as a reduced risk of accidental reactions, a lower severity of reactions, and ultimately desensitisation, it also has potential risks. These risks, although not entirely avoidable, can be mitigated through measures such as dose reduction during periods of ill health as well as appropriate modulation of patients’ and families’ emotional responses during treatment. An aversive mindset toward OIT usually develops following previous treatment-related reactions. Even mild, non-life-threatening symptoms (e.g. itchy mouth, nasal congestion) or triggers such as the odour may be perceived as a real danger due to learned or perceived association with allergic reactions 1 . Importantly, recent evidence by Florsheim et al. supports the notion that allergic sensitisation itself can drive behavioural avoidance via neuroimmune pathways, even in the absence of severe reactions. In their murine model, immune sensing of food allergens activated brain regions associated with threat detection and induced avoidance behaviour 2 , highlighting that immune responses are deeply intertwined with emotional and behavioural regulation. These findings add biological weight to the concept that mindset and emotional states influence how patients interpret and respond to OIT experiences. Simply altering the language used to describe symptoms to patients can regulate these emotions. Describing these symptoms as “side effects” may inadvertently reinforce anxiety and reduce treatment adherence. Conversely, framing them as “positive signals” that indicate OIT is progressing appropriately can foster a more encouraging outlook and improve treatment retention 1 . This strategic use of positive terminology aligns with the PPOINT and Global Allergy and Asthma European Network (GA 2 LEN) 2022 guidelines, which emphasise the importance of comprehensive patient education in food allergy management 3,4 . GA 2 LEN recommends that patients and caregivers are fully informed about OIT’s efficacy, potential side effects, logistical demands, and long-term commitment 3 . Such education fosters empowerment and agency, reduces anxiety, and builds confidence in self-management. Approaches incorporating psychological, motivational, or behavioural components are also accessible to a broad range of clinicians, including those without specialised OIT training. However, while education is foundational, recent research highlights the added importance of integrating mental health support in OIT protocols. Patients, particularly older children and adults, often experience significant trepidation when asked to consume a food they have long been told to avoid. This shift can evoke intense anxiety, with the protective brain overinterpreting benign bodily sensations as signs of an allergic reaction. Such hypervigilance may hinder treatment adherence or prompt premature withdrawal. Recent findings from Trevisonno et al. demonstrate that age-related food aversion and anxiety are among the most common barriers to OIT progression. In particular, parental anxiety was shown to exacerbate these dynamics, influencing not only the child’s willingness to engage with treatment but also decisions around dose escalation and continuation 5 . Similarly, Jiang et al. reported that patient anxiety during OIT was linked to lower adherence, diminished perceived success, and greater dropout rates 6 . These studies highlight the need for psychological support mechanisms not only for patients but also for caregivers. Supporting this idea, a retrospective chart review by Plessis et al. revealed that anxiety contributed to treatment discontinuation in 34% of cases 7 . Collectively, these findings emphasise the importance of targeted intervention aimed at enhancing emotional coping and addressing familial emotional dynamics, which may ultimately improve outcomes in OIT. Emerging evidence also points to neurophysiological interactions that influence therapeutic outcomes. Observations in rodents reveal that allergen sensitisation can induce anxiety-like behaviours, such as reduced exploratory activity, which demonstrates heightened anxiety 8 . These behavioural changes are accompanied by upregulation of the amygdala and paraventricular hypothalamic nucleus, brain regions that are critical for processing stress and fear responses 9 . Florsheim et al.’s work builds upon this paradigm by showing that allergic sensitisation can directly activate brain circuits linked to behavioural avoidance, through immune cell signalling rather than prior anaphylactic experience. This represents a shift in our understanding from avoidance being merely a learned or conditioned response to it being an active, immune-driven behavioural strategy. Recognising these links can help allergists address the psychological dimensions of food immunotherapy more effectively. Behavioural science and immunology intersect through studies replicating Pavlovian conditioning in animal models 10,11,12 . For example, MacQueen et al. demonstrated that an allergic response could be triggered by a neutral stimulus (e.g., audiovisual cue) in the absence of the allergen (e.g., egg albumin) 10 . This finding was replicated by Palermo-Neto et al. with conditioned lung anaphylaxis. Such conditioned responses were associated with elevated serum corticosteroid levels, suggesting that stress is a contributing factor 11 . Similarly, Zimmerman et al. documented conditioned taste aversion in mice exposed to delayed illness cues 12 . Expanding on these foundations, Okada et al. demonstrated that sensitised guinea pigs developed classical conditioning to cues associated with anaphylaxis, provoking allergic mediator release in the absence of the food allergen, further validating the existence of learned immune reactivity 13 . Russell’s findings revealed that histamine release could be elicited through behavioural conditioning, showing that prior stress enhances susceptibility to immune activation via associative learning 14 . Peeke et al. further showed that societally isolated guinea pigs, a model of chronic stress, exhibited significantly amplified conditioned histamine responses, implicating environmental stress as a modulator of immune memory 15 . Irie’s research similarly found that emotionally conditioned cues alone, in the absence of any allergen exposure, could provoke histamine release 16 . Together, these studies highlight how emotional and environmental experiences shape immune reactivity in profound, enduring ways. Three of these studies are summarised in Figure 1. Figure 1 illustrates three key studies of Pavlovian food allergy responses to ovalbumin. In the absence of a food allergen, but in the presence of the audiovisual cue alone, mice were trained to associate an audiovisual cue with a significant increase in mast cell protease 10 . In the studies by Palermo-Neto et al., co-conditioned mice experienced lower airway anaphylactic responses with audiovisual stimuli alone 11 . The third study summarised a guinea pig study with a conditioned olfactory stimulus that evoked increased histamine release in the absence of the co-conditioned allergen 13 . These concepts align with research in human placebo science. Zion and colleagues demonstrated that expectations could modulate cortisol and immune function. For example, cortisol increases with negative framing and decreases with positive framing, showing that beliefs alone can trigger or suppress immune responses 17 . Howe et al. expands upon this work by demonstrating that physician characteristics, such as warmth and confidence, can significantly enhance the placebo response. This shows that interpersonal dynamics influence physiological outcomes 18 . Moreover, Leibowitz and colleagues have shown that reframing side effects as positive signals of treatment efficacy improves both adherence and clinical outcomes in patients 19 . This growing body of evidence supports a critical insight: psychological and contextual factors not only modulate treatment experience but also biological outcomes. Within the context of OIT, these findings suggest that managing mindset, language, and expectations may reduce the risk of adverse reactions and enhance immunological tolerance. Negative emotional states alone may provoke immune activation, including allergic reactions and even anaphylaxis, emphasising the need for careful psychological regulation during OIT. When experienced during critical development windows, psychological and physiological stressors significantly impact gastrointestinal barrier integrity and inflammation. Experimental models demonstrate that early-life stress, such as maternal separation in rodents, leads to increased intestinal permeability, altered gut microbiota, and long-term changes in immune regulation and behaviour. Maternal deprivation in neonatal rats not only disrupts the mucosal barrier but also provokes sustained immune activation and inflammation in adulthood. These effects are partly mediated by altered glucocorticoid sensitivity in the gut epithelium, which can predispose to barrier dysfunction 20 . Subacute and chronic stress synergistically impair intestinal barrier function, as shown in adult animal models, suggesting that cumulative stress exposure compromises epithelial integrity via neuroimmune mechanisms 21 . Translating these findings to humans, Vanuytsel et al. showed that psychological stress and corticotropin-releasing hormone can increase gut permeability in a mast cell-dependent manner 22 , highlighting a key role of neuro-immune interactions in stress-induced barrier disruption in humans. Altogether, these studies support a mechanistic link between stress, epithelial barrier dysfunction, and low-grade inflammation, processes that heighten susceptibility to immune-mediated conditions like food allergy. In conclusion, mindset potentially plays a pivotal role in the outcome of food immunotherapy. Despite advances in the refinement and implementation of immunotherapy protocols, psychological and behavioural considerations remain underused in current protocols for food allergen OIT. Addressing these aspects offers an opportunity to further improve patient experiences and treatment success in food allergy management. Emphasising mindset, emotional regulation and education as integral components of OIT may result in increased implementation of therapies for patients, families and clinicians, fewer side effects and better clinical outcomes. Conflict of Interest Statements Peter Smith declares honoraria, speaker and advisory board fees from GSK, Sanofi and Viatris. Investigator Initiated funding from Sanofi, GSK and Hyloris. Research Funding From NH&MRC and Stafford Fox Foundations. Dora Zhou has no conflict of interest to declare. Adam Fox declares honoraria, speaker and advisory board fees from ALK-abello, Viatris, BBC and ITV. References: 1. Howe LC, Leibowitz KA, Perry MA, Bitler JM, Block W, Kaptchuk TJ, Nadeau KC, Crum AJ. Changing Patient Mindsets about Non-Life-Threatening Symptoms During Oral Immunotherapy: A Randomized Clinical Trial. J Allergy Clin Immunol Pract. 2019 May-Jun;7(5):1550-1559. doi: 10.1016/j.jaip.2019.01.022. Epub 2019 Jan 23. PMID: 30682576; PMCID: PMC6511320. 2. Florsheim EB, Bachtel ND, Cullen JL, Lima BGC, Godazgar M, Carvalho F, Chatain CP, Zimmer MR, Zhang C, Gautier G, Launay P, Wang A, Dietrich MO, Medzhitov R. Immune sensing of food allergens promotes avoidance behaviour. Nature. 2023 Aug;620(7974):643-650. doi: 10.1038/s41586-023-06362-4. Epub 2023 Jul 12. PMID: 37437602; PMCID: PMC10432274. 3. Muraro A, de Silva D, Halken S, Worm M, Khaleva E, Arasi S, Dunn-Galvin A, Nwaru BI, De Jong NW, Rodríguez Del Río P, Turner PJ, Smith P, Begin P, Angier E, Arshad H, Ballmer-Weber B, Beyer K, Bindslev-Jensen C, Cianferoni A, Demoulin C, Deschildre A, Ebisawa M, Fernandez-Rivas MM, Fiocchi A, Flokstra-de Blok B, Gerdts J, Gradman J, Grimshaw K, Jones C, Lau S, Loh R, Alvaro Lozano M, Makela M, Marchisotto MJ, Meyer R, Mills C, Nilsson C, Nowak-Wegrzyn A, Nurmatov U, Pajno G, Podestà M, Poulsen LK, Sampson HA, Sanchez A, Schnadt S, Szajewska H, Van Ree R, Venter C, Vlieg-Boerstra B, Warner A, Wong G, Wood R, Zuberbier T, Roberts G; GA2LEN Food Allergy Guideline Group; GALEN Food Allergy Guideline Group. Managing food allergy: GA 2 LEN guideline 2022. World Allergy Organ J. 2022 Sep 7;15(9):100687. doi: 10.1016/j.waojou.2022.100687. PMID: 36119657; PMCID: PMC9467869. 4. Mack DP, Dribin TE, Turner PJ, Wasserman RL, Hanna MA, Shaker M, Tang MLK, Rodríguez Del Río P, Sobolewski B, Abrams EM, Anagnostou A, Arasi S, Bajowala S, Bégin P, Cameron SB, Chan ES, Chinthrajah S, Clark AT, Detjen P, du Toit G, Ebisawa M, Elizur A, Factor JM, Greiwe J, O’B Hourihane J, Hughes SW, Jones DH, Muraro A, Nowak-Wegrzyn A, Patel NB, Scurlock AM, Shah AN, Sindher SB, Tilles S, Vickery BP, Wang J, Windom HH, Greenhawt M. Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent. J Allergy Clin Immunol. 2024 Jun;153(6):1621-1633. doi: 10.1016/j.jaci.2024.02.019. Epub 2024 Apr 8. PMID: 38597862; PMCID: PMC11461787. 5. Trevisonno J, Venter C, Pickett-Nairne K, Bégin P, Cameron SB, Chan ES, Cook VE, Factor JM, Groetch M, Hanna MA, Jones DH, Wasserman RL, Mack DP. Age-Related Food Aversion and Anxiety Represent Primary Patient Barriers to Food Oral Immunotherapy. J Allergy Clin Immunol Pract. 2024 Jul;12(7):1809-1818.e3. doi: 10.1016/j.jaip.2024.03.014. Epub 2024 Mar 14. PMID: 38492666. 6. Jiang S, Cao S, Collins W, Fast K, Hampton Q, Landes G, Martinez K, Tang H, Sindher S, Chinthrajah S. Self-reported food allergy-associated anxiety during oral immunotherapy declines with time. Journal of Allergy and Clinical Immunology, Volume 149, Issue 2, page AB140, doi.org/10.1016/j.jaci.2021.12.475 7. Plessis AA, Cameron SB, Invik R, Hanna M, Mack DP, Cook VE. Real-world experience: a retrospective pediatric chart review to determine why patients and caregivers discontinue oral immunotherapy. Allergy Asthma Clin Immunol. 2024 Oct 15;20(1):54. doi: 10.1186/s13223-024-00912-9. PMID: 39407324; PMCID: PMC11481366. 8. Basso AS, Pinto FA, Russo M, Britto LR, de Sá-Rocha LC, Palermo Neto J. Neural correlates of IgE-mediated food allergy. J Neuroimmunol. 2003 Jul;140(1-2):69-77. doi: 10.1016/s0165-5728(03)00166-8. PMID: 12864973. 9. Liu Y, Rao B, Li S, Zheng N, Wang J, Bi L, Xu H. Distinct Hypothalamic Paraventricular Nucleus Inputs to the Cingulate Cortex and Paraventricular Thalamic Nucleus Modulate Anxiety and Arousal. Front Pharmacol. 2022 Jan 28;13:814623. doi: 10.3389/fphar.2022.814623. PMID: 35153786; PMCID: PMC8832877. 10. MacQueen G, Marshall J, Perdue M, Siegel S, Bienenstock J. Pavlovian conditioning of rat mucosal mast cells to secrete rat mast cell protease II. Science. 1989 Jan 6;243(4887):83-5. doi: 10.1126/science.2911721. PMID: 2911721. 11. Palermo-Neto J, Guimarães RK. Pavlovian conditioning of lung anaphylactic response in rats. Life Sci. 2000 Dec 29;68(6):611-23. doi: 10.1016/s0024-3205(00)00966-8. PMID: 11205876. 12. Zimmerman CA, Bolkan SS, Pan-Vazquez A, Wu B, Keppler EF, Meares-Garcia JB, Guthman EM, Fetcho RN, McMannon B, Lee J, Hoag AT, Lynch LA, Janarthanan SR, López Luna JF, Bondy AG, Falkner AL, Wang SS, Witten IB. A neural mechanism for learning from delayed postingestive feedback. 2025 Apr 2. doi: 10.1038/s41586-025-08828-z. PMID: 37873112; PMCID: PMC10592633. 13. Okada H, Nagata S, Ishikawa T, Ago Y. [Classical conditioning of anaphylaxis in sensitized guinea pigs]. Arerugi. 1992 Nov;41(11):1614-7. Japanese. PMID: 1283510. 14. Russell M, Dark KA, Cummins RW, Ellman G, Callaway E, Peeke HV. Learned histamine release. Science. 1984 Aug 17;225(4663):733-4. doi: 10.1126/science.6205449. PMID: 6205449. 15. Peeke HV, Dark K, Ellman G, McCurry C, Salfi M. Prior stress and behaviorally conditioned histamine release. Physiol Behav. 1987;39(1):89-93. doi: 10.1016/0031-9384(87)90349-0. PMID: 3562657. 16. Irie M, Nagata S, Endo Y. Effect of isolation on classical conditioned histamine release in guinea pigs. Neurosci Res. 2002 Sep;44(1):31-5. doi: 10.1016/s0168-0102(02)00081-0. PMID: 12204290. 17. Zion SR, Crum AJ. Mindsets Matter: A New Framework for Harnessing the Placebo Effect in Modern Medicine. Int Rev Neurobiol. 2018;138:137-160. doi: 10.1016/bs.irn.2018.02.002. Epub 2018 Mar 20. PMID: 29681322. 18. Howe LC, Goyer JP, Crum AJ. ”Harnessing the placebo effect: Exploring the influence of physician characteristics on placebo response”: Correction. Health Psychol. 2022 Nov;41(11):873. doi: 10.1037/hea0001235. Epub 2022 Aug 4. PMID: 35925707. 19. Leibowitz KA, Howe LC, Crum AJ. Changing mindsets about side effects. BMJ Open. 2021 Feb 1;11(2):e040134. doi: 10.1136/bmjopen-2020-040134. PMID: 33526496; PMCID: PMC7849892. 20. Barreau F, Ferrier L, Fioramonti J, Bueno L. Neonatal maternal deprivation triggers long term alterations in colonic epithelial barrier and mucosal immunity in rats. Gut. 2004 Apr;53(4):501-6. doi: 10.1136/gut.2003.024174. PMID: 15016743; PMCID: PMC1774003. 21. Lauffer A, Vanuytsel T, Vanormelingen C, Vanheel H, Salim Rasoel S, Tóth J, Tack J, Fornari F, Farré R. Subacute stress and chronic stress interact to decrease intestinal barrier function in rats. Stress. 2016;19(2):225-34. doi: 10.3109/10253890.2016.1154527. Epub 2016 Mar 7. PMID: 26947111. 22. Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, Salim Rasoel S, Tόth J, Holvoet L, Farré R, Van Oudenhove L, Boeckxstaens G, Verbeke K, Tack J. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014 Aug;63(8):1293-9. doi: 10.1136/gutjnl-2013-305690. Epub 2013 Oct 23. PMID: 24153250. Information & Authors Information Version history V1 Version 1 19 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Allergy and Immunology Authors Affiliations Dora Zhou F 0009-0001-7896-9765 [email protected] Barts Health NHS Trust View all articles by this author Pete Smith Griffith University Griffith Health View all articles by this author Adam Fox Evelina London Children's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 240 views 206 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Dora Zhou F, Pete Smith, Adam Fox. Mindset in Food Immunotherapy. Authorea . 19 May 2025. DOI: https://doi.org/10.22541/au.174764733.34407929/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.174764733.34407929/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a003cedf8a35df88',t:'MTc3OTUzNjY2MA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();